Samuel H Yalkowsky

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Journals/Publications

• Carvajal, M. T., & Yalkowsky, S. (2019). Effect of pH and Ionic Strength on the Solubility of Quinoline: Back-to-Basics. AAPS PharmSciTech, 20(3), 124.
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  The interest of quinoline as a contaminant agent and as scaffold for the development of new therapeutic agent warrants to revisit the pH-solubility behavior of quinoline (Q) and quinoline derivatives (Q-derivatives) with possible salting-out effect. Q is a weak base with potential hazard upon exposure that may be occupational by inhalation or ingestion of or dermal exposure to particulates in certain industries; or simply by inhalation of cigarette smoke. In contrast, quinoline and its derivatives are useful in diverse therapeutic applications such as anticancer, antiseptic, antipyretic, antiviral, and antimalarial. These claims have raised the possibility of using quinoline motif for the synthesis of new drugs; however, it may act as a pollutant on soil and water as ionizable organic compounds (IOC). The solubility and partitioning behavior of Q may be a critical factor in determining the extent of inhalation and oral absorption or sorption onto soil and water. Studies on the solubility of Q have been reported; however, due to Q-derivatives distinctive usage, it is necessary to revisit and evaluate the solubility profile of Q at different pH levels and ionic strengths. This study reports a simple analytical method for determining the solubility of nitrogen heterocyclic compounds and possible salting-out effect as a function of pH, buffer concentration, and ionic strength. This information can be of value when developing Q-derivatives and to enhance understanding of Q as well as its derivatives behavior in the gastrointestinal tract or when evaluating the presence of Q as an environmental contaminant.
• Alantary, D., & Yalkowsky, S. H. (2018). Comments on prediction of the aqueous solubility using the general solubility equation (GSE) versus a genetic algorithm and a support vector machine model. Pharmaceutical Development and Technology, 23(7), 739-740.
• Alantary, D., & Yalkowsky, S. H. (2018). Estimating the Physicochemical Properties of Polysubstituted Aromatic Compounds Using UPPER. Journal of pharmaceutical sciences, 107(1), 297-306.
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  The UPPER model (Unified Physicochemical Property Estimation Relationships) has been used to predict 9 essential physicochemical properties of pure compounds. It was developed almost 25 years ago and has been validated by the Yalkowsky group for almost 2000 aliphatic, aromatic, and polyhalogenated hydrocarbons. UPPER is based on a group of additive and nonadditive descriptors along with a series of well-accepted thermodynamic relationships. In this model, the 2-dimensional chemical structure is the only input needed. This work extends the applicability of UPPER to hydrogen bonding and non-hydrogen bonding aromatic compounds with several functional groups such as alcohol, aldehyde, ketone, carboxylic acid, carbonate, carbamate, amine, amide, nitrile as well as aceto, and nitro compounds. The total data set includes almost 3000 compounds. Aside from the enthalpies and entropies of melting and boiling, no training set is used for the calculation of the properties. The results show that UPPER enables a reasonable estimation of all the considered properties.
• Alantary, D., & Yalkowsky, S. H. (2018). Estimating the physicochemical properties of polysubstituted aromatic compounds using UPPER. Journal of Pharmaceutical Sciences, 107(1), 297-306.
• Evans, D., Yalkowsky, S., Wu, S., Pereira, D., & Fernandes, P. (2018). Overcoming the Challenges of Low Drug Solubility in the Intravenous Formulation of Solithromycin. Journal of pharmaceutical sciences, 107(1), 412-418.
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  Solithromycin is a fluoro-ketolide (a fourth-generation macrolide) antibiotic that has been undergoing clinical trials for the treatment of community-acquired bacterial pneumonia. In this study, development of the tri-amino acid-buffered solithromycin intravenous (IV) formulation was performed to minimize the occurrence of infusion-associated local adverse events (infusion-site pain or phlebitis) observed in patients who received the tartaric acid-buffered IV formulation with a lower buffered capacity during phase I clinical trials. Development of the tri-amino acids-buffered solithromycin IV formulation was achieved using a dynamic in vitro precipitation model. Computational modeling also supports the superiority of the amino acid-buffered formulation over the tartaric aid-buffered formulation.
• Patel, R. B., & Yalkowsky, S. H. (2018). A rule of unity for human intestinal absorption 3: Application to pharmaceuticals.. Biopharmaceutics & Drug Disposition, 39(2), 67-74.
• Yalkowsky, S. H. (2018). Overcoming the Challenges of Low Drug Solubility in the Intravenous Formulation of Solithromycin. Journal of Pharmaceutical Sciences, 107(1), 412-418.
• Yalkowsky, S. H., & Alantary, D. (2018). Estimation of melting points of organics. Journal of Pharmaceutical Sciences, 107(5), 1211-1227.
• Yalkowsky, S. H., & Patel, R. (2018). A rule of unity for human intestinal absorption 3- application to pharmaceuticals. Biopharm & Drug Disp, 39(2), 67-74.
• Alantary, D., & Yalkowsky, S. (2017). Comments on prediction of the aqueous solubility using the general solubility equation (GSE) versus a genetic algorithm and a support vector machine model. Pharmaceutical development and technology, 1-2.
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  The general solubility equation (GSE) is the state-of-the-art method for estimating the aqueous solubilities of organic compounds. It is an extremely simple equation that expresses aqueous solubility as a function of only two inputs: the octanol-water partition coefficient calculated by readily available softwares like clogP and ACD/logP, and the commonly known melting point of the solute. Recently, Bahadori et al. proposed that their genetic algorithm support vector machine is a "better" predictor. This paper compares the use of the of Bahadori et al. model for the prediction of aqueous solubility to the existing GSE model.
• Patel, R. B., & Yalkowsky, S. H. (2017). A Rule of Unity for Human Intestinal Absorption 3: Application to Pharmaceuticals. Biopharmaceutics & drug disposition.
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  The rule of unity is based on a simple absorption parameter, Π, that can accurately predict whether or not an orally administered drug will be well absorbed or poorly absorbed. The intrinsic aqueous solubility and octanol-water partition coefficient, along with the drug dose are used to calculate Π. We show that a single delineator value for Π exist that can distinguish whether a drug is likely to be well absorbed (FA ≥ 0.5) or poorly absorbed (FA < 0.5) at any specified dose. The model is shown to give 82.5 percent correct predictions for over 938 pharmaceuticals. The maximum well-absorbed dose (i.e., the maximum dose that will be more than 50 percent absorbed) calculated using this model can be utilized as a guideline for drug design and synthesis.
• Yalkowsky, S. H., & Alantary, D. (2015). Soilubility of organic compounds in octanol. Int. J. Pharm.
• Yalkowsky, S. H., & Alantary, D. (2017). Estimation of melting points of organics. Journal of pharmaceutical sciences.
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  UPPER (Unified Physical Property Estimation Relationships) is a system of empirical and theoretical relationships that relate twenty physicochemical properties of organic molecules to each other and to chemical structure. Melting point is a key parameter in the UPPER Scheme because it is a determinant of several other properties including vapor pressure, and Solubility. This review describes the first principals calculation of the melting points of organic compounds from structure. The calculation is based on the fact that the melting point, Tm, is equal to the ratio of the heat of melting, ΔHm, to the entropy of melting, ΔSm. The heat of melting is shown to be an additive-constitutive property. However, the entropy of melting is not entirely group additive. It is primarily dependent on molecular geometry, including parameters which reflect the degree of restriction of molecular motion in the crystal to that of the liquid. Symmetry, eccentricity, chirality, flexibility, and hydrogen bonding, each decrease molecular freedom in different ways and thus make different contributions to the total entropy of fusion. The relationships of these entropy determining parameters to chemical structure are used to develop a reasonably accurate means of predicting the melting points over 2000 compounds.
• Alantary, D., & Yalkowsky, S. (2016). Calculating the Solubilities of Drugs and Drug-Like Compounds in Octanol. Journal of pharmaceutical sciences, 105(9), 2770-3.
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  A modification of the Van't Hoff equation is used to predict the solubility of organic compounds in dry octanol. The new equation describes a linear relationship between the logarithm of the solubility of a solute in octanol to its melting temperature. More than 620 experimentally measured octanol solubilities, collected from the literature, are used to validate the equation without using any regression or fitting. The average absolute error of the prediction is 0.66 log units.
• Evans, D. C., Kudenov, M. W., Sassenrath, K. C., Dereniak, E. L., & Yalkowsky, S. H. (2016). Imaging of in vitro parenteral drug precipitation. International journal of pharmaceutics, 512(1), 219-23.
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  Solid particulate matter introduced into the bloodstream as a result of parenteral drug administration can produce serious pathological conditions. Particulate matter that cannot be eliminated by pre-infusion filtration is often the result of drug precipitation that occurs when certain parenteral formulations are mixed with blood. A new device is designed to model the mixing of drug formulations with flowing blood utilizing a uniquely designed flow cell and a CCD camera to view the formulation as it is mixed with a blood surrogate in real time. The performance of the proposed device is measured using 3 commercially available parenteral formulations previously tested using a validated in vitro model.
• Admire, B., Lian, B., & Yalkowsky, S. H. (2015). Estimating the physicochemical properties of polyhalogenated aromatic and aliphatic compounds using UPPER: part 1. Boiling point and melting point. Chemosphere, 119, 1436-40.
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  The UPPER (Unified Physicochemical Property Estimation Relationships) model uses enthalpic and entropic parameters to estimate 20 biologically relevant properties of organic compounds. The model has been validated by Lian and Yalkowsky on a data set of 700 hydrocarbons. The aim of this work is to expand the UPPER model to estimate the boiling and melting points of polyhalogenated compounds. In this work, 19 new group descriptors are defined and used to predict the transition temperatures of an additional 1288 compounds. The boiling points of 808 and the melting points of 742 polyhalogenated compounds are predicted with average absolute errors of 13.56 K and 25.85 K, respectively.
• Admire, B., Lian, B., & Yalkowsky, S. H. (2015). Estimating the physicochemical properties of polyhalogenated aromatic and aliphatic compounds using UPPER: part 2. Aqueous solubility, octanol solubility and octanol-water partition coefficient. Chemosphere, 119, 1441-6.
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  The UPPER (Unified Physicochemical Property Estimation Relationships) model uses additive and non-additive parameters to estimate 20 biologically relevant properties of organic compounds. The model has been validated by Lian and Yalkowsky (2014) on a data set of 700 hydrocarbons. Recently, Admire et al. (2014) expanded the model to predict the boiling and melting points of 1288 polyhalogenated benzenes, biphenyls, dibenzo-p-dioxins, diphenyl ethers, anisoles and alkanes. In this work, 19 new group descriptors are determined and used to predict the aqueous solubilities, octanol solubilities and the octanol-water coefficients.
• Patel, R. B., Admire, B., & Yalkowsky, S. H. (2015). The rule of unity for human intestinal absorption 2: application to pharmaceutical drugs that are marketed as salts. Current drug delivery, 12(2), 238-43.
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  The efficiency of the human intestinal absorption (HIA) of the 59 drugs which are marketed as salts is predicted using the rule of unity. Intrinsic aqueous solubilities and partition coefficients along with the drug dose are used to calculate modified absorption potential (MAP) values. These values are shown to be related to the fraction of the dose that is absorbed upon oral administration in humans (FA). It is shown that the MAP value can distinguish between drugs that are poorly absorbed (FA
• Yalkowsky, S. H. (2014). Carnelley's rule and the prediction of melting point. J. Pharm.Sci, 103, 2629-2634.
• Yalkowsky, S. H., & Admire, B. (2014). Estimating Physical properties ...1. Boiling point nd melting point. Chemosphere, 119, 1436-1440.
• Yalkowsky, S. H., & Admire, B. (2015). Estimating Physical Properties=...2.Aqueous solubility, octanol solubility and partition coefficient. Chemosphere, 119, 1441-1446.
• Yalkowsky, S. H., Patel, R., & Alantary, D. (2015). Application of the Henderson-Hasselbalch Equation. ADMET and DMPK, 3(4), 359-362.
• Lian, B., & Yalkowsky, S. H. (2014). Unified physicochemical property estimation relationships (UPPER). Journal of pharmaceutical sciences, 103(9), 2710-23.
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  The knowledge of physicochemical properties of organic compounds becomes increasingly important in pharmaceutical sciences, chemical engineering, and other fields. In this study, we developed UPPER (Unified Physicochemical Property Estimation Relationships), a comprehensive model for the estimation of 20 physicochemical properties of organic compounds. UPPER is a system of thermodynamically sound relationships that relate the various phase-transition properties to one another, which includes transition heats, transition entropies, transition temperatures, molar volume, vapor pressure, solubilities and partition coefficients in different solvents, and so on. UPPER integrates group contributions with the molecular geometric factors that affect transition entropies. All of the predictions are directly based on molecular structure. As a result, the proposed model provides a simple and accurate prediction of the properties studied. UPPER is designed to predict industrially, pharmaceutically, and environmentally relevant physicochemical properties. It can be an aid for the efficient design and synthesis of compounds with optimal physicochemical properties.
• Yalkowsky, S. H. (2014). Carnelley's rule and the predictionof melting point. J. Pharm. Sci., 103(9), 2629-2634.
• Yalkowsky, S. H. (2014). The rule of unity in human intestinal absorption. current drug delivery.
• Yalkowsky, S. H. (2014). Unified physicochemical property estimation relationships UPPER. J. Pharm. Sci., 103(9), 2112-2119.
• Admire, B., & Yalkowsky, S. H. (2013). Predicting the octanol solubility of organic compounds. Journal of Pharmaceutical Sciences, 102(7), 2112-2119.
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  PMID: 23609069;Abstract: The molar octanol solubility of an organic nonelectrolytes can be reasonably predicted solely from its melting point provided that its liquid (or a hypothetical super-cooled liquid) form is miscible with octanol. The aim of this work is to develop criteria to determine if the real or hypothetical liquid form of a given compound will be miscible with octanol based on its molar volume and solubility parameter. Fortunately, most organic compounds (including most drugs) conform to the criteria for complete liquid miscibility, and therefore have solubilities that are proportional to their melting points. The results show that more than 95% of the octanol solubilities studied are predicted with an error of less than 1 logarithmic unit. © 2013 Wiley Periodicals, Inc.
• Yalkowsky, S., Admire, B., & Yalkowsky, S. H. (2013). Predicting the octanol solubility of organic compounds. Journal of pharmaceutical sciences, 102(7).
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  The molar octanol solubility of an organic nonelectrolytes can be reasonably predicted solely from its melting point provided that its liquid (or a hypothetical super-cooled liquid) form is miscible with octanol. The aim of this work is to develop criteria to determine if the real or hypothetical liquid form of a given compound will be miscible with octanol based on its molar volume and solubility parameter. Fortunately, most organic compounds (including most drugs) conform to the criteria for complete liquid miscibility, and therefore have solubilities that are proportional to their melting points. The results show that more than 95% of the octanol solubilities studied are predicted with an error of less than 1 logarithmic unit.
• Yalkowsky, S., Narazaki, R., Sanghvi, R., & Yalkowsky, S. H. (0). Estimation of drug precipitation upon dilution of pH-controlled formulations. Molecular pharmaceutics, 4(4).
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  An equation is developed for estimating the precipitation that may occur upon diluting or injecting a (pH-)solubilized drug formulation. Since it is based on equilibrium, it is the worst case scenario for precipitation. This equation can be programmed in any commercially available spread sheet program such as Excel. According to the proposed equation, the type and the strength of the buffer species are the most significant factors that affect the pH and solubility of a drug in its microenvironment during dilution. To demonstrate the utility and robustness of the proposed equation, experimental measurements were performed using phenytoin as the model drug. The result suggests that the proposed equation can be used to indicate the possibility and the degree of precipitation that would occur upon injection. This provides a useful tool for the design of a successful pH-controlled solution formulation.
• Guo, D., Cain, J. P., O'Connell, S., Gardner, E. R., Pisle, S., Figg, W. D., Tabibi, S. E., & Yalkowsky, S. H. (2012). Preformulation study of NSC-726796. AAPS PharmSciTech, 13(2), 661-673.
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  PMID: 22552929;PMCID: PMC3364376;Abstract: A stability-indicating high-performance liquid chromatography method to quantify 2-(2,4-difluorophenyl)-4,5,6,7-tetrafluoroisoindoline-1,3-dione (NSC-726796) and its three main degradation products was developed. This method was used to investigate its degradation kinetics and mechanism. The reaction follows first-order kinetics and appears to be base catalyzed with the maximum stability at pH 1. The products were identified as 2-(2,4- difluorophenylcarbamoyl)-3,4,5,6-tetrafluorobenzoic acid (NSC-749820), 2,4-difluoroaniline, and tetrafluorophthalic acid. The parent drug, NSC-726796, was also found to react with methanol and ethanol. NSC-726796 demonstrates antiangiogenic activity, however, when its degradant NSC749820 does not show antiangiogenic activity. © 2012 American Association of Pharmaceutical Scientists.
• Lian, B., & Yalkowsky, S. H. (2012). Molecular geometry and boiling related thermodynamic properties. Journal of Chemical Thermodynamics, 54, 250-253.
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  Abstract: Boiling related thermodynamic properties are important parameters in research. In this study, a model integrating both additive groups and non-additive molecular geometric factors has been developed for the calculation of boiling enthalpy, entropy and temperature. The calculated values are in good agreement with the measured values of 470 compounds. This model provides a simple and accurate estimation of enthalpy of boiling, entropy of boiling and boiling temperatures with absolute average errors of 0.62 kJ/mol, 1.15 J/K·mol and 7.13 K respectively. © 2012 Elsevier Ltd. All rights reserved.
• Lian, B., & Yalkowsky, S. H. (2012). Molecular geometry and melting point related properties. Industrial and Engineering Chemistry Research, 51(51), 16750-16754.
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  Abstract: Melting point and melting-related properties are important in many fields of research. However, they are relatively hard to predict. In this study, an intuitive and simple model, which integrates both additive group contribution values and nonadditive molecular geometric descriptors, has been developed for the estimation of the total enthalpy and entropy of melting as well as the melting point. This model is evaluated using the available reported values of 557 structurally diverse compounds from various molecular shape families. The predicted values are in good agreement with the experimental values of all 3 properties studied. The average absolute errors for the estimation of enthalpy and entropy of melting are 1.80 kJ/mol, 7.09 J/K mol, respectively. The average absolute error for predicting the melting point is 23.14 K, which is much less than that of the well-known EPI Suite program (60.29 K). © 2012 American Chemical Society.
• Yalkowsky, S. H. (2012). Perspective on improving passive human intestinal absorption. Journal of Pharmaceutical Sciences, 101(9), 3047-3050.
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  PMID: 22374839;Abstract: Methods such as pH adjustment, cosolvency, complexation, and micellization are routinely used to increase the concentration of dissolved drug in the gastrointestinal (GI) lumen over that of a saturated solution. However, these solubilizing agents also reduce the membrane-water distribution coefficient so that the membrane transport rate is not changed. Also, dilution of a formulation upon administration results in: (1) a pH change toward that of the GI fluid, (2) an exponential decrease in cosolvency, and (3) disassociation of complexes and the disintegration of micelles. As a result, these solubilizing agents cannot be expected to produce any increase in membrane transport-limited drug absorption over that of a suspension of unformulated drug. © 2012 Wiley Periodicals, Inc.
• Yalkowsky, S., & Yalkowsky, S. H. (2012). Perspective on improving passive human intestinal absorption. Journal of pharmaceutical sciences, 101(9).
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  Methods such as pH adjustment, cosolvency, complexation, and micellization are routinely used to increase the concentration of dissolved drug in the gastrointestinal (GI) lumen over that of a saturated solution. However, these solubilizing agents also reduce the membrane-water distribution coefficient so that the membrane transport rate is not changed. Also, dilution of a formulation upon administration results in: (1) a pH change toward that of the GI fluid, (2) an exponential decrease in cosolvency, and (3) disassociation of complexes and the disintegration of micelles. As a result, these solubilizing agents cannot be expected to produce any increase in membrane transport-limited drug absorption over that of a suspension of unformulated drug.
• Yalkowsky, S., Guo, D., Cain, J. P., O'Connell, S., Gardner, E. R., Pisle, S., Figg, W. D., Tabibi, S. E., & Yalkowsky, S. H. (2012). Preformulation study of NSC-726796. AAPS PharmSciTech, 13(2).
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  A stability-indicating high-performance liquid chromatography method to quantify 2-(2,4-difluorophenyl)-4,5,6,7-tetrafluoroisoindoline-1,3-dione (NSC-726796) and its three main degradation products was developed. This method was used to investigate its degradation kinetics and mechanism. The reaction follows first-order kinetics and appears to be base catalyzed with the maximum stability at pH 1. The products were identified as 2-(2,4-difluorophenylcarbamoyl)-3,4,5,6-tetrafluorobenzoic acid (NSC-749820), 2,4-difluoroaniline, and tetrafluorophthalic acid. The parent drug, NSC-726796, was also found to react with methanol and ethanol. NSC-726796 demonstrates antiangiogenic activity, however, when its degradant NSC749820 does not show antiangiogenic activity.
• Evans, D. C., & Yalkowsky, S. H. (2011). A simplified prediction of entropy of melting for energetic compounds. Fluid Phase Equilibria, 303(1), 10-14.
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  Abstract: A new widely applicable model for the prediction of the entropy of melting of organic compounds is presented. The use of three simple geometry based parameters: rotational symmetry, flexibility, and eccentricity enables the simple and accurate prediction of this important property. This paper demonstrates the use of the model for energetic compounds. © 2010 Elsevier B.V.
• Lian, B., & Yalkowsky, S. H. (2011). A simplified approach to predict the heat of melting for organic compounds. Chemometrics and Intelligent Laboratory Systems, 108(2), 150-153.
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  Abstract: In this study, a simple and widely applicable approach for predicting the heat of melting (ΔHm) of organic compounds is described. The model uses only three simple molecular descriptors: rotational symmetry, flexibility, and eccentricity numbers plus measured melting points to predict the heat of melting with a root mean square error (RMSE) of 3.77KJ/Mol. © 2011 Elsevier B.V.
• Jain, P., & Yalkowsky, S. H. (2010). Prediction of aqueous solubility from SCRATCH. International Journal of Pharmaceutics, 385(1-2), 1-5.
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  PMID: 19819319;Abstract: This study proposes the SCRATCH model for the aqueous solubility estimation of a compound directly from its structure. The algorithm utilizes predicted melting points and predicted aqueous activity coefficients. It uses two additive, constitutive molecular descriptors (enthalpy of melting and aqueous activity coefficient) and two non-additive molecular descriptors (symmetry and flexibility). The latter are used to determine the entropy of melting. The melting point prediction is trained on over 2200 compounds whereas the aqueous activity coefficient is trained on about 1640 compounds, making the model very rigorous and robust. The model is validated using a 10-fold cross-validation on a dataset of 883 compounds for the aqueous solubility prediction. A comparison with the general solubility equation (GSE) suggests that the SCRATCH predicted aqueous solubilities have a slightly greater average absolute error. This could result from the fact that SCRATCH uses two predicted parameters whereas the GSE utilizes one measured property, the melting point. Although the GSE is simpler to use, the drawback of requiring an experimental melting point is overcome in SCRATCH which can predict the aqueous solubility of a compound based solely on its structure and no experimental values. © 2009 Elsevier B.V. All rights reserved.
• Yalkowsky, S. H., & Min, W. u. (2010). Estimation of the ideal solubility (crystal-liquid fugacity ratio) of organic compounds. Journal of Pharmaceutical Sciences, 99(3), 1100-1106.
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  PMID: 19739108;Abstract: Melting point, entropy of melting and heat capacity of melting are required for the calculation of the ideal solubility of a solid solute via the Clausius-Clapyron equation. This article reviews the published approximations of estimating entropy and heat capacity of melting. By comparing the available experimental results to calculated values the authors attempt to identify the best estimation of the ideal solubility and crystal-liquid fugacity ratio for organic compounds. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association.
• Yalkowsky, S., Guo, D., Myrdal, P. B., Karlage, K. L., O'Connell, S. P., Wissinger, T. J., Tabibi, S. E., & Yalkowsky, S. H. (2010). Stability of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in combination. AAPS PharmSciTech, 11(1).
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  In vivo, the DNA methyltransferase inhibitor, 5-fluoro-2'-deoxycytidine (FdCyd, NSC-48006), is rapidly converted to its unwanted metabolites. Tetrahydrouridine (THU, NSC-112907), a cytidine deaminase inhibitor can block the first metabolic step in FdCyd catabolism. Clinical studies have shown that co-administration with THU can inhibit the metabolism of FdCyd. The National Cancer Institute is particularly interested in a 1:5 FdCyd/THU formulation. The purpose of this study was to investigate the in vitro pH stability of FdCyd and THU individually and in combination. A stability-indicating high-performance liquid chromatography method for the quantification of both compounds and their degradants was developed using a ZIC(R)-HILIC column. The effect of THU and FdCyd on the in vitro degradation of each other was studied as a function of pH from 1.0 to 7.4 in aqueous solutions at 37 degrees C. The degradation of FdCyd appears to be first-order and acid-catalyzed. THU equilibrates with at least one of its degradants. The combination of FdCyd and THU in solution does not affect the stability of either compound. The stability and compatibility of FdCyd and THU in the solid state at increased relative humidity and at various temperatures are also evaluated.
• Chu, K. A., & Yalkowsky, S. H. (2009). An interesting relationship between drug absorption and melting point. International Journal of Pharmaceutics, 373(1-2), 24-40.
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  PMID: 19429285;Abstract: The ability to predict the extent of passive intestinal drug absorption is very important for efficient lead candidate selection and development. Physicochemical-based absorption predictive models previously developed use solubility, partition coefficient and pKa as drug input parameters for intestinal absorption. Alternatively, this study looks at the relationship between melting point and passive transport for poorly soluble drugs. It is based entirely on the expression derived from the General Solubility Equation (GSE) that relates melting point to the product of intrinsic solubility and partition coefficient. Given that the melting point of a compound is one of the first and more reliable physical properties measured, it can be advantageously used as a guide in early drug discovery and development. This paper elucidates the interesting relationship between the melting point and dose to the fraction absorbed of poorly soluble drugs, i.e., class II and IV compounds in the Biopharmaceutics Classification System. The newly defined melting point based absorption potential (MPbAP) parameter is successful at distinguishing 90% of the 91 drugs considered being well absorbed (FA > 0.5) or poorly absorbed. In general, lower melting compounds are more likely to be well absorbed than higher melting compounds for any given dose. The fraction absorbed for drugs with high melting temperatures is limited by the dose to a greater degree than it is for low melting compounds. © 2009 Elsevier B.V. All rights reserved.
• Chu, K. A., & Yalkowsky, S. H. (2009). Predicting aqueous solubility: The role of crystallinity. Current Drug Metabolism, 10(10), 1184-1191.
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  PMID: 20166998;Abstract: This paper revisits the role of crystallinity in predicting the aqueous solubility of a wide variety of organic compounds. Box and Comer (Current Drug Metabolism, 2008, 9, 869-878) fitted solubility data for 86 drugs to an equation based solely on log P. The General Solubility Equation of Jain and Yalkowsky, which accounts for the crystal lattice energy, was applied to the same data set and gives more accurate solubility predictions. In this simple comparison between two solubility prediction methods, we show that log P alone is only half of the solution, and that there is a need to include the melting point when dealing with crystalline solutes. © 2009 Bentham Science Publishers Ltd.
• Guo, D., Nichol, G. S., Cain, J. P., & Yalkowsky, S. H. (2009). 2-[N-(2,4-Difluoro-phen-yl)carbamo-yl]-3,4,5,6-tetra-fluoro-benzoic acid. Acta Crystallographica Section E: Structure Reports Online, 65(11), o2644.
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  PMID: 21578258;PMCID: PMC2971039;Abstract: The title compound, C14H5F6NO3, was synthesized by condensation of tetra-fluoro-phthalic anhydride and 2,4-difluoro-aniline. It was then recrystallized from hexane to give a nonmerohedral twin with two crystallographically unique mol-ecules in the asymmetric unit. The refined twin fraction is 0.460 (3). Torsional differences between the aryl rings and the central amide group account for the presence of two unique mol-ecules. The compound packs as double tapes formed by O- H⋯O and N- H⋯O hydrogen-bonding inter-actions between each unique mol-ecule and its symmetry equivalents.
• Min, W. u., & Yalkowsky, S. (2009). Erratum: Estimation of the molar heat capacity change on melting of organic compounds. (Industrial and Engineering Chemistry Research (2009) 48 (1063-1066)). Industrial and Engineering Chemistry Research, 48(6), 3260-.
• Min, W. u., & Yalkowsky, S. (2009). Estimation of the molar heat capacity change on melting of organic compounds. Industrial and Engineering Chemistry Research, 48(2), 1063-1066.
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  Abstract: A simple equation to predict the differential molar heat capacity (ΔCp m) of the solid and liquid forms for the organic compounds at their melting point (T m) is developed. Only three parameters are used: the molecular flexibility number (τ), the molecular symmetry number (σ), and the hydrogen bond number (HBN). The results for more than 100 compounds show that the average absolute error of ΔCp m is 13.4 J/(mol K). This is less than the average absolute errors obtained by any of the three schemes proposed in a previous report [Pappa, G. D.; Voutsas, E. C.; Magoulas, K.; Tassios, D. P. Ind. Eng. Chem. Res. 2005, 44, 3799]. © 2009 American Chemical Society.
• Yalkowsky, S., Chu, K. A., & Yalkowsky, S. H. (2009). An interesting relationship between drug absorption and melting point. International journal of pharmaceutics, 373(1-2).
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  The ability to predict the extent of passive intestinal drug absorption is very important for efficient lead candidate selection and development. Physicochemical-based absorption predictive models previously developed use solubility, partition coefficient and pK(a) as drug input parameters for intestinal absorption. Alternatively, this study looks at the relationship between melting point and passive transport for poorly soluble drugs. It is based entirely on the expression derived from the General Solubility Equation (GSE) that relates melting point to the product of intrinsic solubility and partition coefficient. Given that the melting point of a compound is one of the first and more reliable physical properties measured, it can be advantageously used as a guide in early drug discovery and development. This paper elucidates the interesting relationship between the melting point and dose to the fraction absorbed of poorly soluble drugs, i.e., class II and IV compounds in the Biopharmaceutics Classification System. The newly defined melting point based absorption potential (MPbAP) parameter is successful at distinguishing 90% of the 91 drugs considered being well absorbed (FA>0.5) or poorly absorbed. In general, lower melting compounds are more likely to be well absorbed than higher melting compounds for any given dose. The fraction absorbed for drugs with high melting temperatures is limited by the dose to a greater degree than it is for low melting compounds.
• Yalkowsky, S., Chu, K. A., & Yalkowsky, S. H. (2009). Predicting aqueous solubility: the role of crystallinity. Current drug metabolism, 10(10).
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  This paper revisits the role of crystallinity in predicting the aqueous solubility of a wide variety of organic compounds. Box and Comer (Current Drug Metabolism, 2008, 9, 869-878) fitted solubility data for 86 drugs to an equation based solely on log P. The General Solubility Equation of Jain and Yalkowsky, which accounts for the crystal lattice energy, was applied to the same data set and gives more accurate solubility predictions. In this simple comparison between two solubility prediction methods, we show that log P alone is only half of the solution, and that there is a need to include the melting point when dealing with crystalline solutes.
• Yalkowsky, S., Sanghvi, R., Mogalian, E., Machatha, S. G., Narazaki, R., Karlage, K. L., Jain, P., Tabibi, S. E., Glaze, E., Myrdal, P. B., & Yalkowsky, S. H. (2009). Preformulation and pharmacokinetic studies on antalarmin: a novel stress inhibitor. Journal of pharmaceutical sciences, 98(1).
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  The preformulation, solubilization and pharmacokinetic evaluation of antalarmin, a stress inhibitor, have been conducted. Antalarmin has a poor water solubility of less than 1 microg/mL and is weakly basic with an experimentally determined pK(a) of 5.0. Multiple solubilization approaches including pH-control either alone or in combination with cosolvents, surfactants and complexing agents have been investigated. The applicability of lipid-based systems has also been explored. Four formulations, each with a targeted drug loading capacity of 100 mg/mL, show potential for oral administration. Three of these formulations are aqueous solutions (10% ethanol + 40% propylene glycol; 20% cremophor EL; 20% sulfobutylether-beta-cyclodextrin) each buffered at pH 1. The fourth formulation is a lipid-based formulation comprising of 20% oleic acid, 40% cremophor EL and 40% Labrasol. No precipitation was observed following dilution of the four formulations with water and enzyme free simulated gastric fluid. However, only the lipid-based formulation successfully resisted drug precipitation following dilution with enzyme free simulated intestinal fluid. Pharmacokinetic analysis conducted in rats revealed that the 20% cremophor EL solution formulation has a fivefold higher oral bioavailability compared to a suspension formulation. The lipid-based formulation resulted in over 12-fold higher bioavailability as compared to the suspension formulation, the highest amongst the formulations examined.
• Jain, P., Sepassi, K., & Yalkowsky, S. H. (2008). Comparison of aqueous solubility estimation from AQUAFAC and the GSE. International Journal of Pharmaceutics, 360(1-2), 122-147.
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  PMID: 18514447;Abstract: The GSE (General Solubility Equation) and AQUAFAC (Aqueous Functional Group Activity Coefficients) are two empirical models for aqueous solubility prediction. This study compares the aqueous solubility estimation of a set of 1642 pharmaceutically and environmentally related compounds, using the two methods. The average absolute errors in the solubility prediction are 0.543 log units for AQUAFAC and 0.576 log units for the GSE. About 88.0% of the AQUAFAC solubilities and 83.0% of the GSE molar aqueous solubilities are predicted within one log unit of the observed values. The marginally greater accuracy of AQUAFAC is due to the fact that it utilizes fitted-parameters for many structural fragments and is based on experimental solubility data. The GSE on the other hand is a simpler, non-regression based equation which uses two parameters for solubility prediction.
• Kuehl, P. J., Brenner, T., Jain, P. K., Karlage, K., Sepassi, K., Yang, G., Mayersohn, M., Yalkowsky, S. H., & Myrdal, P. B. (2008). Formulation and in vivo evaluation of chlorpropham (CIPC) oral formulations. Journal of pharmaceutical sciences, 97(12), 5222-8.
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  The objective of these studies was to examine the in vivo performance of oral formulations of chlorpropham (CIPC). In order to develop a new oral formulation several different solubilization techniques were evaluated, namely: cosolvents, surfactants, and complexing agents. The solubilization data indicated that a conventional solution formulation was not plausible. Two self-emulsifying drug delivery systems (SEDDS) were developed and evaluated for stability. Both SEDDS formulations were found to be chemically stable. In vivo analysis of a SEDDS formulation, a suspension formulation and an intravenous bolus dose was conducted in F344 rats. Pharmacokinetic analysis of the formulation data indicated that the SEDDS formulation provided only marginally better oral bioavailability compared to a suspension formulation. While SEDDS formulations often result in greater bioavailability this was not observed for CIPC. In vivo analysis indicate that CIPC results in a situation where the dissolution rate of CIPC from the suspension is not rate limiting, rather the absorption rate in the GI tract is rate-limiting. This paradigm is the result of CIPCs low melting point and the relatively small particle size of the suspension which facilitate the dissolution in the GI tract.
• Sanghvi, R., Narazaki, R., Machatha, S. G., & Yalkowsky, S. H. (2008). Solubility improvement of drugs using N-methyl pyrrolidone. AAPS PharmSciTech, 9(2), 366-376.
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  PMID: 18431671;PMCID: PMC2976935;Abstract: The solubilization efficiency of N-methyl pyrrolidone (NMP) has been determined and compared to that of ethanol and propylene glycol for 13 poorly soluble drugs. NMP is found to be a more efficient solubilizer for all the drugs studied. The solubility enhancement as high as about 800-fold is obtained in 20% v/v NMP solution as compared to water. The mechanism of drug solubilization by NMP has also been investigated. It is proposed that NMP enhances drug solubility by simultaneously acting as a cosolvent and a complexing agent. A mathematical model is used to estimate the drug solubility in NMP-water mixture, according to which the total solubility enhancement is a sum of the two effects. This model describes the experimental data well and is more accurate than other models. A large and uniform reduction in the surface tension of water as a function of NMP concentration demonstrates its cosolvent effect. The complexation is supported by the fact that i's strength is affected by the temperature and the polarity of the medium. A strong correlation exists between log Kow of the drugs and the cosolvency coefficients. The correlation between log Kow and the complexation coefficients is weak suggesting that factors such as molecular shape and aromaticity of the drug molecule are significant in determining the complexation strength. This has been confirmed by the absence of a significant complexation between NMP and linear drug-like solutes. © American Association of Pharmaceutical Scientists 2008.
• Yalkowsky, S., Jain, P., Sepassi, K., & Yalkowsky, S. H. (2008). Comparison of aqueous solubility estimation from AQUAFAC and the GSE. International journal of pharmaceutics, 360(1-2).
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  The GSE (General Solubility Equation) and AQUAFAC (Aqueous Functional Group Activity Coefficients) are two empirical models for aqueous solubility prediction. This study compares the aqueous solubility estimation of a set of 1642 pharmaceutically and environmentally related compounds, using the two methods. The average absolute errors in the solubility prediction are 0.543 log units for AQUAFAC and 0.576 log units for the GSE. About 88.0% of the AQUAFAC solubilities and 83.0% of the GSE molar aqueous solubilities are predicted within one log unit of the observed values. The marginally greater accuracy of AQUAFAC is due to the fact that it utilizes fitted-parameters for many structural fragments and is based on experimental solubility data. The GSE on the other hand is a simpler, non-regression based equation which uses two parameters for solubility prediction.
• Yalkowsky, S., Sanghvi, R., Narazaki, R., Machatha, S. G., & Yalkowsky, S. H. (2008). Solubility improvement of drugs using N-methyl pyrrolidone. AAPS PharmSciTech, 9(2).
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  The solubilization efficiency of N-methyl pyrrolidone (NMP) has been determined and compared to that of ethanol and propylene glycol for 13 poorly soluble drugs. NMP is found to be a more efficient solubilizer for all the drugs studied. The solubility enhancement as high as about 800-fold is obtained in 20% v/v NMP solution as compared to water. The mechanism of drug solubilization by NMP has also been investigated. It is proposed that NMP enhances drug solubility by simultaneously acting as a cosolvent and a complexing agent. A mathematical model is used to estimate the drug solubility in NMP-water mixture, according to which the total solubility enhancement is a sum of the two effects. This model describes the experimental data well and is more accurate than other models. A large and uniform reduction in the surface tension of water as a function of NMP concentration demonstrates its cosolvent effect. The complexation is supported by the fact that it's strength is affected by the temperature and the polarity of the medium. A strong correlation exists between log K (ow) of the drugs and the cosolvency coefficients. The correlation between log K (ow) and the complexation coefficients is weak suggesting that factors such as molecular shape and aromaticity of the drug molecule are significant in determining the complexation strength. This has been confirmed by the absence of a significant complexation between NMP and linear drug-like solutes.
• Jain, A., & Yalkowsky, S. H. (2007). Comparison of two methods for estimation of melting points of organic compounds. Industrial and Engineering Chemistry Research, 46(8), 2589-2592.
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  Abstract: This study compares the melting point predictions of UPPER to MPBPWIN for over 2200 organic compounds. The average absolute error (AAE) and root-mean-square error (RMSE) in melting point prediction using UPPER are 30.1 deg and 39.7 deg, while MPBPWIN gives an AAE of 44.5 deg and RMSE of 58.4 deg. UPPER provides more accurate melting point predictions because it accounts for both the additive enthalpic and nonadditive entropie contributions to melting. © 2007 American Chemical Society.
• Jain, N., Machatha, S. G., Tabibi, S. E., & Yalkowsky, S. H. (2007). Degradation kinetics and mechanism of RH1, a new anti-tumor agent: A technical note. AAPS PharmSciTech, 8(1).
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  PMID: 17408216;PMCID: PMC2750669;Abstract: The degradation of RH1 in aqueous solution is found to be both acid and base catalyzed. The maximum stability is obtained in neutral pH but still degrades by 10% (t90) after just 1 week. The stability profile at pH 5 was done, and 4 major degradation products were observed in acid solutions. LC-MS was performed and the molecular weights determined, from which a degradation mechanism was proposed. Degradation products I, II, and III form 2 isomers each depending on which aziridine group is hydrolyzed. No significant effect of light or the presence of antioxidants was observed, indicating that photodegradation and oxidation are not likely degradation reactions. Copyright © 2006. All Rights Reserved.
• Jain, P., & Yalkowsky, S. H. (2007). Solubilization of poorly soluble compounds using 2-pyrrolidone. International Journal of Pharmaceutics, 342(1-2), 1-5.
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  PMID: 17570624;Abstract: The solubilization of nine poorly soluble compounds in aqueous solution by 2-pyrrolidone has been studied. Solubility enhancement as high as 500-fold is achieved using 20% 2-pyrrolidone. A comparison shows that 2-pyrrolidone is a better solubilizer than glycerin, propylene glycol, polyethylene glycol 400 or ethanol. The observed solubilization curves are deconvoluted into components representing complexation and cosolvency. A clear linear relationship exists between the cosolvency solubilization power (σ) of 2-pyrrolidone and the partition coefficient (log Kow) of the drug (R2 = 0.96) extending over three orders of magnitude. The stability constants for the formation of 1:1 complex (K1:1) involving 2-pyrrolidone and the drugs have been calculated. A weaker correlation (R2 = 0.74) is observed between the complexation constants and the partition coefficients of respective drugs. This study indicates that 2-pyrrolidone, like NMP, can act as a complexant at low concentrations and as a cosolvent at high concentrations and that both these properties are affected by the partition coefficient of the solute.
• Narazaki, R., Sanghvi, R., & Yalkowsky, S. H. (2007). Estimation of drug precipitation upon dilution of pH-controlled formulations. Molecular Pharmaceutics, 4(4), 550-555.
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  PMID: 17530775;Abstract: An equation is developed for estimating the precipitation that may occur upon diluting or injecting a (pH-)solubilized drug formulation. Since it is based on equilibrium, it is the worst case scenario for precipitation. This equation can be programmed in any commercially available spread sheet program such as Excel. According to the proposed equation, the type and the strength of the buffer species are the most significant factors that affect the pH and solubility of a drug in its microenvironment during dilution. To demonstrate the utility and robustness of the proposed equation, experimental measurements were performed using phenytoin as the model drug. The result suggests that the proposed equation can be used to indicate the possibility and the degree of precipitation that would occur upon injection. This provides a useful tool for the design of a successful pH-controlled solution formulation. © 2007 American Chemical Society.
• Narazaki, R., Sanghvi, R., & Yalkowsky, S. H. (2007). Estimation of drug precipitation upon dilution of pH-cosolvent solubilized formulations. Chemical and Pharmaceutical Bulletin, 55(8), 1203-1206.
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  PMID: 17666845;Abstract: This manuscript is a study of precipitation of insoluble drug upon dilution from the pH-cosolvent solubilized formulation with simulated blood fluid. An equation is developed to estimate drug precipitation upon dilution of combined pH-cosolvent solubilized formulations. This is an extension of a previous equation used for the estimation of drug precipitation from simple pH controlled formulations. The proposed equation considers the effect of the cosolvent and its concentration on the pKa of the drug as well as all buffering species. According to the proposed equation and our experimental data, the addition of cosolvent on the pH solubilized formulation could increase total drug solubility in the formulation. However, the solubility after dilution became lower than the 0% ethanol formulation because of the change in both drug and buffer pKa values. Since this equation is based on the equilibrium condition, it is the worst case scenario for precipitation. This equation provides useful information regarding the feasibility of the successful use of pH-cosolvent combinations in drug formulation. © 2007 Pharmaceutical Society of Japan.
• Sanghvi, R., Evans, D., & Yalkowsky, S. H. (2007). Stacking complexation by nicotinamide: A useful way of enhancing drug solubility. International Journal of Pharmaceutics, 336(1), 35-41.
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  PMID: 17145146;Abstract: The solubility enhancement of 11 poorly soluble drugs by complexation using nicotinamide has been studied. The solubilization efficiency of nicotinamide has been compared to that of hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin. Solubility enhancements as high as 4000-fold are observed in 20% (w/v) nicotinamide solution. Furthermore, nicotinamide is more effective than cyclodextrins for solubilizing some of the drugs. The mechanism of drug solubilization by nicotinamide is investigated by studying the effects of nicotinamide concentration on the surface tension and the conductivity of water. A slight break in both, the surface tension and conductivity is noticed at around 10% (w/v), suggesting self-association at higher concentrations. Corresponding breaks in the solubility profiles of estrone and griseofulvin at similar concentrations support self-association. Based on this observation it appears that at low concentrations, one molecule of nicotinamide undergoes complexation with one drug molecule to form a 1:1 complex. At higher concentrations, two molecules of nicotinamide undergo complexation with one drug molecule forming a 1:2 complex. The complexation constants have been calculated for all the drugs and the data are well described by this model. Expectedly, increasing the temperature reduces the complexation constants. © 2006 Elsevier B.V. All rights reserved.
• Sepassi, K., & Yalkowsky, S. H. (2007). Simplified estimation of the octanol-air partition coefficient. Industrial and Engineering Chemistry Research, 46(7), 2220-2223.
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  Abstract: The octanol-air partition coefficient is commonly used to understand the extent of chemical partitioning between the atmosphere and organic matter in the environment. In this study, octanol-air partition coefficients were estimated by generating an expression from combining empirical equations for the molar octanol solubility and saturated vapor pressures of organic compounds. The resultant equation simply estimates octanol-air partition coefficients from boiling points, entropies of boiling, and heat capacity changes on boiling. © 2007 American Chemical Society.
• Yalkowsky, S., Jain, P., & Yalkowsky, S. H. (2007). Solubilization of poorly soluble compounds using 2-pyrrolidone. International journal of pharmaceutics, 342(1-2).
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  The solubilization of nine poorly soluble compounds in aqueous solution by 2-pyrrolidone has been studied. Solubility enhancement as high as 500-fold is achieved using 20% 2-pyrrolidone. A comparison shows that 2-pyrrolidone is a better solubilizer than glycerin, propylene glycol, polyethylene glycol 400 or ethanol. The observed solubilization curves are deconvoluted into components representing complexation and cosolvency. A clear linear relationship exists between the cosolvency solubilization power (sigma) of 2-pyrrolidone and the partition coefficient (log K(ow)) of the drug (R(2)=0.96) extending over three orders of magnitude. The stability constants for the formation of 1:1 complex (K(1:1)) involving 2-pyrrolidone and the drugs have been calculated. A weaker correlation (R(2)=0.74) is observed between the complexation constants and the partition coefficients of respective drugs. This study indicates that 2-pyrrolidone, like NMP, can act as a complexant at low concentrations and as a cosolvent at high concentrations and that both these properties are affected by the partition coefficient of the solute.
• Yalkowsky, S., Narazaki, R., Sanghvi, R., & Yalkowsky, S. H. (2007). Estimation of drug precipitation upon dilution of pH-cosolvent solubilized formulations. Chemical & pharmaceutical bulletin, 55(8).
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  This manuscript is a study of precipitation of insoluble drug upon dilution from the pH-cosolvent solubilized formulation with simulated blood fluid. An equation is developed to estimate drug precipitation upon dilution of combined pH-cosolvent solubilized formulations. This is an extension of a previous equation used for the estimation of drug precipitation from simple pH controlled formulations. The proposed equation considers the effect of the cosolvent and its concentration on the pK(a) of the drug as well as all buffering species. According to the proposed equation and our experimental data, the addition of cosolvent on the pH solubilized formulation could increase total drug solubility in the formulation. However, the solubility after dilution became lower than the 0% ethanol formulation because of the change in both drug and buffer pK(a) values. Since this equation is based on the equilibrium condition, it is the worst case scenario for precipitation. This equation provides useful information regarding the feasibility of the successful use of pH-cosolvent combinations in drug formulation.
• Yalkowsky, S., Sanghvi, R., Evans, D., & Yalkowsky, S. H. (2007). Stacking complexation by nicotinamide: a useful way of enhancing drug solubility. International journal of pharmaceutics, 336(1).
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  The solubility enhancement of 11 poorly soluble drugs by complexation using nicotinamide has been studied. The solubilization efficiency of nicotinamide has been compared to that of hydroxypropyl-beta-cyclodextrin and sulfobutylether-beta-cyclodextrin. Solubility enhancements as high as 4000-fold are observed in 20% (w/v) nicotinamide solution. Furthermore, nicotinamide is more effective than cyclodextrins for solubilizing some of the drugs. The mechanism of drug solubilization by nicotinamide is investigated by studying the effects of nicotinamide concentration on the surface tension and the conductivity of water. A slight break in both, the surface tension and conductivity is noticed at around 10% (w/v), suggesting self-association at higher concentrations. Corresponding breaks in the solubility profiles of estrone and griseofulvin at similar concentrations support self-association. Based on this observation it appears that at low concentrations, one molecule of nicotinamide undergoes complexation with one drug molecule to form a 1:1 complex. At higher concentrations, two molecules of nicotinamide undergo complexation with one drug molecule forming a 1:2 complex. The complexation constants have been calculated for all the drugs and the data are well described by this model. Expectedly, increasing the temperature reduces the complexation constants.
• Jain, A., & Yalkowsky, S. H. (2006). Estimation of melting points of organic compounds-II. Journal of Pharmaceutical Sciences, 95(12), 2562-2618.
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  PMID: 17034051;Abstract: A model for calculation of melting points of organic compounds from structure is described. The model utilizes additive, constitutive and nonadditive, constitutive molecular properties to calculate the enthalpy of melting and the entropy of melting, respectively. Application of the model to over 2200 compounds, including a number of drugs with complex structures, gives an average absolute error of 30.1°. © 2006 Wiley-Liss, Inc.
• Jain, N., Yang, G., Machatha, S. G., & Yalkowsky, S. H. (2006). Estimation of the aqueous solubility of weak electrolytes. International Journal of Pharmaceutics, 319(1-2), 169-171.
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  PMID: 16839718;Abstract: Jain and Yalkowsky [Jain, N., Yalkowsky, S.H., 2001. Estimation of the aqueous solubility. I. Application to organic non-electrolytes. J. Pharm. Sci. 90, 234-252.] demonstrated that the general solubility equation (GSE) can be used to estimate the aqueous solubility of organic non-electrolytes. In this study the applicability of the GSE was extended to weak electrolytes. It is demonstrated that the GSE estimates the aqueous solubility of 949 compounds, including 367 weak electrolytes with an AAE of 0.58. It is also shown that the intrinsic solubilities of weak acids for which the pKa + log Sw ≤ 0 and for weak bases for which pKa - log Sw ≤ 14 are within a factor of 2 of the total solubilities. © 2006 Elsevier B.V. All rights reserved.
• Johnson, J. L., & Yalkowsky, S. H. (2006). Reformulation of a new vancomycin analog: An example of the importance of buffer species and strength. AAPS PharmSciTech, 7(1).
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  Abstract: The purpose of this research was to use our previously validated dynamic injection apparatus as a rapid method for screening pH-adjusted formulations of a new vancomycin analog, Van-An, for their potential to precipitate upon dilution. In 1 vial, Van-An was reconstituted according to the manufacturer's instructions. In a separate vial, the Van-An formulation's existing phosphate buffer species was supplemented with acetate buffer, which has a pKa in the desired range: between the pH values of the formulation (pH 3.9) and blood (pH 7.4). The formulations were injected using the dynamic injection apparatus into a flowing stream of isotonic Sorensen's phosphate buffer at rates of 0.25, 0.5. 1, and 2 mL/min. The peaks obtained with the spectrophotometer were reproducible for each injection rate/formulation combination. For the phosphate-buffered formulation, the least amount of precipitation was obtained at the 0.25 mL/min injection rate. Acetate buffer was able to substantially reduce such precipitation. even at the highest injection rate. The opacity peaks for the formulation with the acetate addition were significantly smaller (P < .05) than those obtained for the unaltered formulation at all 4 injection rates. The results suggest that acetate is a better buffer species than phosphate for the pH range defined. Furthermore, we present evidence to support a generally applicable approach to screening new formulations of drug products that may be clinically useful for reducing the incidence of phlebitis in humans. Copyright ©2003. All Rights Reserved.
• Johnson, J. L., Yan, H. e., Jain, A., & Yalkowsky, S. H. (2006). Improving cyclodextrin complexation of a new antihepatitis drug with glacial acetic acid. AAPS PharmSciTech, 7(1), E1-E6.
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  Abstract: The purpose of this study was to develop and evaluate a solid nonaqueous oral dosage form for a new hepatitis C drug, PG301029, which is insoluble and unstable in water. Hydroxypropyl-β-cyclodextrin (HPβCD) and PG301029 were dissolved in glacial acetic acid. The acetic acid was removed by rotoevaporation such that the drug exists primarily in the complexed form. The stability of formulated PG301029 was determined upon dry storage and after reconstitution in simulated intestinal fluid (SIF), simulated gastric fluid (SGF), and water. Formulated PG301029 was found to be stable upon storage and can be reconstituted with water to a concentration 200 times that of the intrinsic solubility. Once reconstituted, the powder dissolves rapidly and PG301029 remains stable for 21 hours in SGF, SIF, and water. The unique use of acetic acid and HPβCD results in a solid dosage form of PG301029 that is both soluble and stable in water. Copyright ©2003. All Rights Reserved.
• L, J., & Yalkowsky, S. H. (2006). Reformulation of a new vancomycin analog: an example of the importance of buffer species and strength.. AAPS PharmSciTech [electronic resource]., 7(1), E5.
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  PMID: 16584164;Abstract: The purpose of this research was to use our previously validated dynamic injection apparatus as a rapid method for screening pH-adjusted formulations of a new vancomycin analog, Van-An, for their potential to precipitate upon dilution. In 1 vial, Van-An was reconstituted according to the manufacturer's instructions. In a separate vial, the Van-An formulation's existing phosphate buffer species was supplemented with acetate buffer, which has a pKa in the desired range: between the pH values of the formulation (pH 3.9) and blood (pH 7.4). The formulations were injected using the dynamic injection apparatus into a flowing stream of isotonic Sorensen's phosphate buffer at rates of 0.25, 0.5, 1, and 2 mL/min. The peaks obtained with the spectrophotometer were reproducible for each injection rate/formulation combination. For the phosphate-buffered formulation, the least amount of precipitation was obtained at the 0.25 mL/min injection rate. Acetate buffer was able to substantially reduce such precipitation, even at the highest injection rate. The opacity peaks for the formulation with the acetate addition were significantly smaller (P < .05) than those obtained for the unaltered formulation at all 4 injection rates. The results suggest that acetate is a better buffer species than phosphate for the pH range defined. Furthermore, we present evidence to support a generally applicable approach to screening new formulations of drug products that may be clinically useful for reducing the incidence of phlebitis in humans.
• L, J., Yan, H. e., Jain, A., & Yalkowsky, S. H. (2006). Improving cyclodextrin complexation of a new antihepatitis drug with glacial acetic acid.. AAPS PharmSciTech [electronic resource]., 7(1), E18.
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  PMID: 16584148;PMCID: PMC2750500;Abstract: The purpose of this study was to develop and evaluate a solid nonaqueous oral dosage form for a new hepatitis C drug, PG301029, which is insoluble and unstable in water. Hydroxypropyl-beta-cyclodextrin (HPbetaCD) and PG301029 were dissolved in glacial acetic acid. The acetic acid was removed by rotoevaporation such that the drug exists primarily in the complexed form. The stability of formulated PG301029 was determined upon dry storage and after reconstitution in simulated intestinal fluid (SIF), simulated gastric fluid (SGF), and water. Formulated PG301029 was found to be stable upon storage and can be reconstituted with water to a concentration 200 times that of the intrinsic solubility. Once reconstituted, the powder dissolves rapidly and PG301029 remains stable for 21 hours in SGF, SIF, and water. The unique use of acetic acid and HPbetaCD results in a solid dosage form of PG301029 that is both soluble and stable in water.
• Sanghvi, R., & Yalkowsky, S. H. (2006). Estimation of heat capacity of boiling of organic compounds. Industrial and Engineering Chemistry Research, 45(1), 451-453.
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  Abstract: The aim of this study is to develop a widely applicable model for predicting the heat-capacity change associated with boiling at atmospheric pressure (AC pb) of organic compounds. A semiempirical model is generated utilizing a flexibility index (τ) and a hydrogen-bonding parameter. This model is based upon experimental apparent ΔC pb values of 619 organic compounds. The average absolute error for the estimation is [7.1 J/K mol. The proposed model quantitatively establishes the impact of flexibility and hydrogen bonding on the apparent ~ΔC pb It is shown to be more accurate when compared to some of the previously described methods. © 2006 American Chemical Society.
• Sanghvi, R., & Yalkowsky, S. H. (2006). Estimation of the normal boiling point of organic compounds. Industrial and Engineering Chemistry Research, 45(8), 2856-2861.
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  Abstract: A semiempirical model has been developed for the estimation of the normal boiling points of organic compounds. The normal boiling point is calculated as the ratio of the enthalpy of boiling to the entropy of boiling. Both these values are estimated independently using a combination of additive group contribution and nonadditive molecular descriptors. A group contribution model is proposed for the estimation of the enthalpy of boiling, based on the experimental data for 1322 structurally diverse organic compounds. The average absolute error associated with this estimation is 0.83 kJ/mol. A semiempirical model has been developed for the estimation of the entropy of boiling using experimental entropy data for the entire set. This model is a modification of Trouton's rule and takes into account the effect of hydrogen bonding and molecular flexibility. The average absolute error associated with this estimation is 4.7 J/(K mol). The average absolute error associated with the estimation of the normal boiling point, calculated as a ratio of the enthalpy of boiling to the entropy of boiling, for the entire data set is 9.3 K (2.3%). A good correlation is observed between the estimated and the experimental boiling points with an r 2 of 0.98. This model is easy to use, accurate, and applicable to a wide variety of organic compounds. © 2006 American Chemical Society.
• Sepassi, K., & Yalkowsky, S. H. (2006). Solubility prediction in Octanol: A technical note. AAPS PharmSciTech, 7(1), E1-E8.
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  Abstract: The purpose of this work was to derive an equation for the rapid estimation of octanol solubilities of organic compounds. Solubilities ranging over 4 orders of magnitude were predicted with an average absolute error of 0.39 logarithmic units using melting point alone. The greatest error in prediction occurred for strongly bonded compounds. Copyright ©2003. All Rights Reserved.
• Sepassi, K., & Yalkowsky, S. H. (2006). Solubility prediction in octanol: a technical note.. AAPS PharmSciTech [electronic resource]., 7(1), E26.
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  PMID: 16584157;PMCID: PMC2750733;Abstract: The purpose of this work was to derive an equation for the rapid estimation of octanol solubilities of organic compounds. Solubilities ranging over 4 orders of magnitude were predicted with an average absolute error of 0.39 logarithmic units using melting point alone. The greatest error in prediction occurred for strongly bonded compounds.
• Sepassi, K., Nichol, C. S., & Yalkowsky, S. H. (2006). The napsylate salt of carbendazim: 2-(methoxy-carbonylamino)benzimidazolium naphthalene1-sulfonate. Acta Crystallographica Section E: Structure Reports Online, 62(11), o5172-o5173.
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  Abstract: In the title compound, C9H10N3O 2+⋯C10H7O3S -, the asymmetric unit comprises a carbendazim cation and a napsylate anion. Three intermolecular N-H⋯O hydrogen bonds stabilize the structure. © 2006 International Union of Crystallography All rights reserved.
• Sepassi, K., Sanghvi, T., & Yalkowsky, S. H. (2006). The besylate salt of carbendazim: 2-(methoxy-carbonylamino)benzimidazolium benzenesulfonate. Acta Crystallographica Section E: Structure Reports Online, 62(10), o4403-o4404.
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  Abstract: In the title compound, C9H10N3O 2+.C6H5O3S-, the asymmetric unit comprises a carbendazim cation and a besylate anion. Three intermolecular N-H⋯O hydrogen bonds stabilize the structure. © 2006 International Union of Crystallography. All rights reserved.
• Yalkowsky, S. H., Johnson, J. L., Sanghvi, T., & Machatha, S. G. (2006). A 'rule of unity' for human intestinal absorption. Pharmaceutical Research, 23(10), 2475-2481.
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  PMID: 16933099;Abstract: The ability to predict the passive intestinal absorption of organic compounds can be a valuable tool in drug design. Although Lipinski's 'rule of 5' is commonly used for this purpose, it does not routinely give reliable results. An alternative 'rule of unity' is proposed to predict the absorption efficiency of orally administered drugs that are passively transported. The rule of unity based upon the theoretical principals that govern passive transport. The 'rule of 5' and the 'rule of unity' are compared using experimentally determined passive human intestinal absorption data for 155 drugs. Absorption values which are >50% of the dose are classified as well absorbed and absorption values which are 50% of the dose are classified as classified as poorly absorbed. Comparison of the two models using a receiver operating characteristic (ROC) plot and McNemar's test reveal striking differences in absorption predictability. The 'rule of 5' gives twice as many false predictions than the 'rule of unity.' © 2006 Springer Science+Business Media, LLC.
• Yalkowsky, S., He, Y., & Yalkowsky, S. H. (2006). Solubilization of monovalent weak electrolytes by micellization or complexation. International journal of pharmaceutics, 314(1).
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  In order to prepare a liquid formulation for a weak electrolyte, micellization or complexation is often applied with the solution pH controlled to have some of the drug molecules ionized. The efficiency of the micellization is evaluated by either the micellar solubilization capacities, kappau, and kappai or the micellar partition coefficients, Ku(m) and Ki(m), for the unionized and ionized drug species. Similarly, the efficiency of complexation is evaluated by either the complex solubilization capacities, tauu and taui or the drug-ligand binding constants,Ku(1:1) and Ki(1:1). In this study, the experimental values of these descriptors were generated for seven ionizable drugs. The relationships of the logarithms of each descriptor to the logarithm of the octanol-water partition coefficient of the unionized drug (log Pu) and ionized drug species (log Pi) were evaluated. Although kappa and tau cannot be predicted, this study shows that Km and K1:1 are dependent on log P for both the unionized and ionized drug species. Thus, the total drug solubility for a weak electrolyte solubilized by micellization or complexation can be predicted at any pH.
• Yalkowsky, S., He, Y., Tabibi, S. E., & Yalkowsky, S. H. (2006). Solubilization of two structurally related anticancer drugs: XK-469 and PPA. Journal of pharmaceutical sciences, 95(1).
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  The efficiency of a solubilization technique is determined by the physical-chemical properties of the drug. This study investigates the solubilization on two structurally related anticancer drugs, XK-469 and PPA. XK-469 is much less polar than PPA with an intrinsic solubility of 0.000274 mg/mL, which is about 10,000 fold less than that of PPA. Fortunately, its physical-chemical properties make it much more formulatable. An ionizable drug can be solubilized by pH adjustment with cosolvency, micellization, or complexation. Both XK-469 and PPA are weak acids with pKa values of 2.7 and 2.9, respectively. Thus, they can be solubilized by pH adjustment. At pH 4.55, neither cosolvency, micellization nor complexation has much effect on the solubility of PPA. However, these techniques can significantly increase the solubility of XK-469. In fact, the solubility of XK-469 in 20% HPbetaCD at pH 4.55 is 5.85 mg/mL, which is more than 20,000 times greater than its intrinsic solubility. With the solubilization descriptors obtained from the experimental data for both unionized and ionized drug species at pH 1.0 and pH 4.55, the solubility of each drug at any pH and excipient concentration can be estimated. Then, a solubilization technique can be chosen for preparing a desired final drug concentration.
• Yalkowsky, S., Jain, A., & Yalkowsky, S. H. (2006). Estimation of melting points of organic compounds-II. Journal of pharmaceutical sciences, 95(12).
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  A model for calculation of melting points of organic compounds from structure is described. The model utilizes additive, constitutive and nonadditive, constitutive molecular properties to calculate the enthalpy of melting and the entropy of melting, respectively. Application of the model to over 2200 compounds, including a number of drugs with complex structures, gives an average absolute error of 30.1 degrees.
• Yalkowsky, S., Johnson, J. L., & Yalkowsky, S. H. (2006). Reformulation of a new vancomycin analog: an example of the importance of buffer species and strength. AAPS PharmSciTech, 7(1).
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  The purpose of this research was to use our previously validated dynamic injection apparatus as a rapid method for screening pH-adjusted formulations of a new vancomycin analog, Van-An, for their potential to precipitate upon dilution. In 1 vial, Van-An was reconstituted according to the manufacturer's instructions. In a separate vial, the Van-An formulation's existing phosphate buffer species was supplemented with acetate buffer, which has a pKa in the desired range: between the pH values of the formulation (pH 3.9) and blood (pH 7.4). The formulations were injected using the dynamic injection apparatus into a flowing stream of isotonic Sorensen's phosphate buffer at rates of 0.25, 0.5, 1, and 2 mL/min. The peaks obtained with the spectrophotometer were reproducible for each injection rate/formulation combination. For the phosphate-buffered formulation, the least amount of precipitation was obtained at the 0.25 mL/min injection rate. Acetate buffer was able to substantially reduce such precipitation, even at the highest injection rate. The opacity peaks for the formulation with the acetate addition were significantly smaller (P < .05) than those obtained for the unaltered formulation at all 4 injection rates. The results suggest that acetate is a better buffer species than phosphate for the pH range defined. Furthermore, we present evidence to support a generally applicable approach to screening new formulations of drug products that may be clinically useful for reducing the incidence of phlebitis in humans.
• Yalkowsky, S., Johnson, J. L., He, Y., Jain, A., & Yalkowsky, S. H. (2006). Improving cyclodextrin complexation of a new antihepatitis drug with glacial acetic acid. AAPS PharmSciTech, 7(1).
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  The purpose of this study was to develop and evaluate a solid nonaqueous oral dosage form for a new hepatitis C drug, PG301029, which is insoluble and unstable in water. Hydroxypropyl-beta-cyclodextrin (HPbetaCD) and PG301029 were dissolved in glacial acetic acid. The acetic acid was removed by rotoevaporation such that the drug exists primarily in the complexed form. The stability of formulated PG301029 was determined upon dry storage and after reconstitution in simulated intestinal fluid (SIF), simulated gastric fluid (SGF), and water. Formulated PG301029 was found to be stable upon storage and can be reconstituted with water to a concentration 200 times that of the intrinsic solubility. Once reconstituted, the powder dissolves rapidly and PG301029 remains stable for 21 hours in SGF, SIF, and water. The unique use of acetic acid and HPbetaCD results in a solid dosage form of PG301029 that is both soluble and stable in water.
• Yalkowsky, S., Sepassi, K., & Yalkowsky, S. H. (2006). Solubility prediction in octanol: a technical note. AAPS PharmSciTech, 7(1).
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  The purpose of this work was to derive an equation for the rapid estimation of octanol solubilities of organic compounds. Solubilities ranging over 4 orders of magnitude were predicted with an average absolute error of 0.39 logarithmic units using melting point alone. The greatest error in prediction occurred for strongly bonded compounds.
• Yan, H. e., & Yalkowsky, S. H. (2006). Solubilization of monovalent weak electrolytes by micellization or complexation. International Journal of Pharmaceutics, 314(1), 15-20.
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  PMID: 16580158;Abstract: In order to prepare a liquid formulation for a weak electrolyte, micellization or complexation is often applied with the solution pH controlled to have some of the drug molecules ionized. The efficiency of the micellization is evaluated by either the micellar solubilization capacities, κu, and κi or the micellar partition coefficients, Kum and Kim, for the unionized and ionized drug species. Similarly, the efficiency of complexation is evaluated by either the complex solubilization capacities, τu and τi or the drug-ligand binding constants, Ku1 : 1 and Ki1 : 1. In this study, the experimental values of these descriptors were generated for seven ionizable drugs. The relationships of the logarithms of each descriptor to the logarithm of the octanol-water partition coefficient of the unionized drug (log Pu) and ionized drug species (log Pi) were evaluated. Although κ and τ cannot be predicted, this study shows that Km and K1:1 are dependent on log P for both the unionized and ionized drug species. Thus, the total drug solubility for a weak electrolyte solubilized by micellization or complexation can be predicted at any pH. © 2006 Elsevier B.V. All rights reserved.
• Yan, H. e., Tabibi, S. E., & Yalkowsky, S. H. (2006). Solubilization of two structurally related anticancer drugs: XK-469 and PPA. Journal of Pharmaceutical Sciences, 95(1), 97-107.
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  PMID: 16315229;Abstract: The efficiency of a solubilization technique is determined by the physical-chemical properties of the drug. This study investigates the solubilization on two structurally related anticancer drugs, XK-469 and PPA. XK-469 is much less polar than PPA with an intrinsic solubility of 0.000274 mg/mL, which is about 10000 fold less than that of PPA. Fortunately, its physical-chemical properties make it much more formulatable. An ionizable drug can be solubilized by pH adjustment with cosolvency, micellization, or complexation. Both XK-469 and PPA are weak acids with pKa values of 2.7 and 2.9, respectively. Thus, they can be solubilized by pH adjustment. At pH 4.55, neither cosolvency, micellization nor complexation has much effect on the solubility of PPA. However, these techniques can significantly increase the solubility of XK-469. In fact, the solubility of XK-469 in 20% HPβCD at pH 4.55 is 5.85 mg/mL, which is more than 20000 times greater than its intrinsic solubility. With the solubilization descriptors obtained from the experimental data for both unionized and ionized drug species at pH 1.0 and pH 4.55, the solubility of each drug at any pH and excipient concentration can be estimated. Then, a solubilization technique can be chosen for preparing a desired final drug concentration. © 2005 Wiley-Liss, Inc.
• L., J., & Yalkowsky, S. H. (2005). Two new parameters for predicting the entropy of melting: Eccentricity (ε) and spirality (μ). Industrial and Engineering Chemistry Research, 44(19), 7559-7566.
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  Abstract: The prediction of the entropy of fusion of organic compounds is studied. Rotational symmetry (σ) and flexibility (φ) have already been shown to contribute to the orientational and conformational entropy of fusion, respectively. Eccentricity (ε) and spirality (μ) are two new parameters that influence translational and configurational entropy, ε is defined as the ratio of the volume of a box around a rigid molecule to the cubed radius of a sphere containing the same molecular van der Waals volume. μ is defined as the number of benzolc[c]phenanthrene regions present in the molecule. This moiety results in repulsion and out of plane twisting to maximize the distance between hydrogens. Enthalpy of melting, melting point, and geometrical data for 117 compounds were gathered from the literature. The database consists of alkanes, polycyclic aromatic hydrocarbons, alkyl benzenes, and other alkyl aromatics. The addition of ε and μ to σ and φ as predictors for the entropy of melting revealed a best fit melting point prediction line with a slope close to unity and a coefficient of determination (R 2) of 0.90. In addition, the average absolute error of melting point estimation was improved from 90 K to 43 K. Hence, the newly defined ε and μ parameters offer significant improvement when combined with σ and φ in the prediction of the entropies of melting and, consequently, melting points of organic molecules. © 2005 American Chemical Society.
• Machatha, S. G., & Yalkowsky, S. H. (2005). Bilinear model for the prediction of drug solubility in ethanol/water mixtures. Journal of Pharmaceutical Sciences, 94(12), 2731-2734.
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  PMID: 16258999;Abstract: A new bilinear function that accounts for the disparity between the log-linear and parabolic models for cosolvent solubilization is presented, where ethanol was used as the model cosolvent. This accounts for both the initial and terminal slopes in the ethanol/water solubility profiles of semi-polar solutes. The proposed model has only two fitted parameters σA and σB, which represent the initial and terminal asymptotes in the solubility profiles. The bilinear function can also model the ethanol/water solubility profile more accurately than the log-linear model and a general parabolic model. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association.
• Machatha, S. G., & Yalkowsky, S. H. (2005). Comparison of the octanol/water partition coefficients calculated by ClogP®, ACDlogP and KowWin® to experimentally determined values. International Journal of Pharmaceutics, 294(1-2), 185-192.
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  PMID: 15814243;Abstract: The experimental octanol/water partition coefficient data, of 108 compounds from the data set [Rytting, E., Lentz, K.A., Chen, X., Qian, F., Venkatesh, S., 2004. A quantitative structure-property relationship for predicting drug solubility in PEG 400/water cosolvent systems. Pharm. Res. 21, 237-244] was compared to calculated values using the computer programs ClogP®, ACD/logPdb® and KowWin®. It was found that all the three programs have a user friendly interface but ClogP® appears to be the more accurate predictor of log Kow. © 2005 Elsevier B.V. All rights reserved.
• Machatha, S. G., Sanghvi, T., & Yalkowsky, S. H. (2005). Structure determination and characterization of carbendazim hydrochloride dihydrate. AAPS PharmSciTech, 6(1), E115-E119.
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  PMID: 16353955;PMCID: PMC2750419;Abstract: The objective of this study was to synthesize and characterize the hydrochloride salt of carbendazim with the aim of improving the intrinsic solubility of the parent compound. Carbendazim hydrochloride dihydrate was synthesized for the purpose of increasing the aqueous solubility of the parent drug, carbendazim. This was done with the commonly used saturation and cooling method. The structure was determined by single crystal radiograph crystallography, and the hydrochloride salt was found to be a dihydrate. The salt crystallized in a P 21 21 21 (#19) space group, which is typical for nonplanar, achiral, and noncentrosymmetric molecules. The asymmetric unit is comprised of 1 molecule each of carbendazim and chloride and 2 water molecules. The carbendazim molecules arrange themselves in a helical structure, with the waters and the chloride molecules in the channel linking the helix. The crystal lattice is held together by numerous hydrogen bonds, as well as van der Waals interactions. The melting point of the salt is 125.6°C. The solubility of the salt is 6.08 mg/mL, which is a thousand-fold increase from the intrinsic solubility (6.11 μg/mL) of the free base. Copyright ©2003. All Rights Reserved.
• Ran, Y., Jain, A., & Yalkowsky, S. H. (2005). Solubilization and preformulation studies on PG-300995 (an anti-HIV drug). Journal of Pharmaceutical Sciences, 94(2), 297-303.
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  PMID: 15570598;Abstract: This study investigates the solubilization of a potential anti-human immunodeficiency virus agent [PG-300995 or 2-(2-thiophenyl)-4-azabenzoimidazole] for oral administration. The intrinsic solubility of PG-300995 is 51 μg/mL. Multiple approaches including combinations of pH control and cosolvency, micellization, or complexation were used to improve the solubility of PG-300995. The combined techniques increased the solubility of both the unionized and ionized species. The solubility of the drug increased from 20 to 200 times depending on the pH and concentration of solubilization agents. The following formulations which contain the desired doses of 5 and 10 mg/mL were developed for oral administration. Formulation A: 10 mg/mL PG-300995 in 20% sulfobutyl ether-β-cyclodextrin at pH 2; formulations B: 5 mg/mL PG-300995 in 10% sulfobutyl ether-β-cyclodextrin at pH 2; formulation C: 5 mg/mL PG-300995 in 10% ethanol+40% propylene glycol at pH 2. No precipitation was observed after series dilution of these three formulations with water or pH 2 buffers. These formulations are stable for at least 6 months after storing at room temperature and 37°C. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association.
• Yalkowsky, S., He, Y., Johnson, J. L., & Yalkowsky, S. H. (2005). Oral formulation of a novel antiviral agent, PG301029, in a mixture of gelucire 44/14 and DMA (2:1, wt/wt). AAPS PharmSciTech, 6(1).
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  To develop an oral formulation for PG301029, a novel potent agent for the treatment of Hepatitis C virus infection, that not only has very low aqueous solubility but also degrades rapidly in water. The solubility of PG301029 was determined in water, various aqueous media, and several neat organic solvents. The stability of PG301029 was monitored at room temperature in buffers for 4 days, and in several neat organic solvents for up to 8 mo. Drug concentrations were measured by high-performance liquid chromatography (HPLC). Based on solubility and stability data, Gelucire 44/14 and DMA (N,N-dimethylacetamide) at a weight ratio of 2 to 1 were chosen as the formulation vehicle. After the vehicle was prepared, it was maintained in liquid form at approximately 40 degrees C until the PG301029 was dissolved. The final formulation product was a semisolid at room temperature. The bioavailability of the formulation was tested on 4 female BALB/c mice. PG301029 is insoluble in all tested aqueous media, while its solubility is promising in DMA. This compound is unstable in aqueous media and some organic solvents; however, it is stable in DMA. This proposed formulation is able to hold up to 10 mg/mL of drug and is stable at 4 degrees C. The shelf life for this formulation stored at 4degreesC is extrapolated to be greater than 4 years. This formulation dramatically increases the bioavailability of PG301029. This nonaqueous formulation solves the stability, solubility, and bioavailability problems for PG301029. This semisolid formulation can easily be incorporated into soft elastic capsules.
• Yalkowsky, S., Machatha, S. G., & Yalkowsky, S. H. (2005). Bilinear model for the prediction of drug solubility in ethanol/water mixtures. Journal of pharmaceutical sciences, 94(12).
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  A new bilinear function that accounts for the disparity between the log-linear and parabolic models for cosolvent solubilization is presented, where ethanol was used as the model cosolvent. This accounts for both the initial and terminal slopes in the ethanol/water solubility profiles of semi-polar solutes. The proposed model has only two fitted parameters sigmaA and sigmaB, which represent the initial and terminal asymptotes in the solubility profiles. The bilinear function can also model the ethanol/water solubility profile more accurately than the log-linear model and a general parabolic model.
• Yalkowsky, S., Machatha, S. G., & Yalkowsky, S. H. (2005). Comparison of the octanol/water partition coefficients calculated by ClogP, ACDlogP and KowWin to experimentally determined values. International journal of pharmaceutics, 294(1-2).
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  The experimental octanol/water partition coefficient data, of 108 compounds from the data set [Rytting, E., Lentz, K.A., Chen, X., Qian, F., Venkatesh, S., 2004. A quantitative structure-property relationship for predicting drug solubility in PEG 400/water cosolvent systems. Pharm. Res. 21, 237-244] was compared to calculated values using the computer programs ClogP, ACD/logPdb and KowWin. It was found that all the three programs have a user friendly interface but ClogP appears to be the more accurate predictor of log K(ow).
• Yalkowsky, S., Machatha, S. G., Sanghvi, T., & Yalkowsky, S. H. (2005). Structure determination and characterization of carbendazim hydrochloride dihydrate. AAPS PharmSciTech, 6(1).
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  The objective of this study was to synthesize and characterize the hydrochloride salt of carbendazim with the aim of improving the intrinsic solubility of the parent compound. Carbendazim hydrochloride dihydrate was synthesized for the purpose of increasing the aqueous solubility of the parent drug, carbendazim. This was done with the commonly used saturation and cooling method. The structure was determined by single crystal radiograph crystallography, and the hydrochloride salt was found to be a dihydrate. The salt crystallized in a P 2(1) 2(1) 2(1) (#19) space group, which is typical for nonplanar, achiral, and noncentrosymmetric molecules. The asymmetric unit is comprised of 1 molecule each of carbendazim and chloride and 2 water molecules. The carbendazim molecules arrange themselves in a helical structure, with the waters and the chloride molecules in the channel linking the helix. The crystal lattice is held together by numerous hydrogen bonds, as well as van der Waals interactions. The melting point of the salt is 125.6 degrees C. The solubility of the salt is 6.08 mg/mL, which is a thousand-fold increase from the intrinsic solubility (6.11 microg/mL) of the free base.
• Yan, H. e., Johnson, J. L., & Yalkowsky, S. H. (2005). Oral formulation of a novel antiviral agent, PG301029, in a mixture of gelucire 44/14 and DMA (2:1, wt/wt). AAPS PharmSciTech, 6(1), E1-E5.
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  PMID: 16353952;PMCID: PMC2750404;Abstract: To develop an oral formulation for PG301029, a novel potent agent for the treatment of Hepatitis C virus infection, that not only has very low aqueous solubility but also degrades rapidly in water. The solubility of PG301029 was determined in water, various aqueous media, and several neat organic solvents. The stability of PG301029 was monitored at room temperature in buffers for 4 days, and in several neat organic solvents for up to 8 mo. Drug concentrations were measured by high-performance liquid chromatography (HPLC). Based on solubility and stability data, Gelucire 44/14 and DMA (N,N-dimethylacetamide) at a weight ratio of 2 to 1 were chosen as the formulation vehicle. After the vehicle was prepared, it was maintained in liquid form at ∼40°C until the PG301029 was dissolved. The final formulation product was a semisolid at room temperature. The bioavailability of the formulation was tested on 4 female BALB/c mice. PG301029 is insoluble in all tested aqueous media, while its solubility is promising in DMA. This compound is unstable in aqueous media and some organic solvents; however, it is stable in DMA. This proposed formulation is able to hold up to 10 mg/mL of drug and is stable at 4°C. The shelf life for this formulation stored at 4°C is extrapolated to be greater than 4 years. This formulation dramatically increases the bioavailability of PG301029. This nonaqueous formulation solves the stability, solubility, and bioavailability problems for PG301029. This semisolid formulation can easily be incorporated into soft elastic capsules.
• Clark, R. W., Yalkowsky, S. H., & Johnson, J. L. (2004). Three-dimensional model for water (multiple letters). Journal of Chemical Education, 81(1), 34-.
• Jain, A., Ran, Y., & Yalkowsky, S. H. (2004). Effect of pH-sodium lauryl sulfate combination on solubilization of PG-300995 (an anti-HIV agent): A technical note. AAPS PharmSciTech, 5(3).
• Jain, A., Ran, Y., & Yalkowsky, S. H. (2004). Effect of pH-sodium lauryl sulfate combination on solubilization of PG-300995 (an anti-HIV agent): a technical note.. AAPS PharmSciTech [electronic resource]., 5(3), e45.
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  PMID: 15760078;PMCID: PMC2750268;
• Jain, A., Yang, G., & Yalkowsky, S. H. (2004). Estimation of melting points of organic compounds. Industrial and Engineering Chemistry Research, 43(23), 7618-7621.
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  Abstract: A combination of additive group contributions and nonadditive molecular parameters is employed to estimate the normal melting points of 1215 organic compounds. The melting points are calculated from the ratio of the total phase change enthalpy and entropy of melting. The total phase change enthalpy of melting is calculated from the enthalpic group contributions, whereas the total phase change entropy of melting is estimated using a semiempirical equation based on only two nonadditive molecular parameters. The average absolute error in estimating the melting points of these organic compounds is 33.2 K. This is a relatively low value considering the wide range of pharmaceutically and environmentally relevant organic compounds included in this data set.
• Jain, A., Yang, G., & Yalkowsky, S. H. (2004). Estimation of total entropy of melting of organic compounds. Industrial and Engineering Chemistry Research, 43(15), 4376-4379.
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  Abstract: The aim of this study is to provide a simple means of estimating the total entropy of melting (ΔSmtot) for a wide range of pharmaceutically and environmentally relevant organic compounds. A semiempirical equation based on only 2 molecular descriptors, the rotational symmetry number(σ) and the molecular flexibility number (Φ), has been used to calculate ΔSmtot for 1799 organic compounds. The average absolute error in estimating ΔSmtot is 12.3 J/K·mol. This method gives entropy predictions that are comparable to those of a recently published group additivity method that utilizes 144 group contribution values.
• MacHatha, S. G., & Yalkowsky, S. H. (2004). Estimation of the ethanol/water solubility profile from the octanol/water partition coefficient. International Journal of Pharmaceutics, 286(1-2), 111-115.
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  PMID: 15501007;Abstract: While the ethanol/water solubility profiles of very polar and very non-polar drugs are monotonic, many semi-polar drugs show a maximum solubility at an ethanol volume fraction (f max) between 0 and 1. A sigmoidal relationship was observed between the value of f max and the log of the octanol/water partition coefficient (log K ow) of the solute. This relationship reasonably predicts the value of the volume fraction of ethanol that gives maximum solubility (f max). Combining this sigmoidal relationship with the previously reported linear relationship between the log K ow and the initial slope of the plot of log solubility versus ethanol composition [Li, A., Yalkowsky, S.H., 1994. Solubility of organic solutes in ethanol/water mixtures. J. Pharm. Sci. 83, 1735-1740] enables the estimation of the total ethanol/water solubility profile. © 2004 Elsevier B.V. All rights reserved.
• Machatha, S. G., Bustamante, P., & Yalkowsky, S. H. (2004). Deviation from linearity of drug solubility in ethanol/water mixtures. International Journal of Pharmaceutics, 283(1-2), 83-88.
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  PMID: 15363504;Abstract: A new empirical function that describes the deviation from linearity of solubility of a drug in an ethanol/water matrix is applied to the experimental data for 51 compounds. The proposed model is a more accurate predictor of the co-solvent solubility profile than a general third order polynomial with the same number of parameters. Both the root mean square error and average absolute error for the proposed model are significantly lower than those of existing models. The model also accurately predicts the fraction of co-solvent that gives maximum solubility (f max). © 2004 Elsevier B.V. All rights reserved.
• Yalkowsky, S., He, Y., & Yalkowsky, S. H. (2004). Solubilization of the neutral and charged forms of 2,4,6-trichlorophenol by hydroxypropyl-beta-cyclodextrin, or methyl-beta-cyclodextrin in water. Journal of hazardous materials, 108(1-2).
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  The solubility of 2,4,6-trichlorophenol (TCP) in hydroxypropyl-beta-cyclodextrin (HPbetaCD), or methyl-beta-cyclodextrin (MebetaCD) at pH 3.0 and 8.8 reported by Hanna et al. [J. Hazard. Mater. B100 (2003) 109] is reevaluated in this paper. The complexations of the individual dissolved forms were examined. As expected, the neutral TCP complexes more strongly with the cyclodextrins than the charged species. However, in spite of its lower complexation constant, the charged form of TCP forms more complex with each CD, and thus is solubilized to a greater extent.
• Yalkowsky, S., Jain, A., Ran, Y., & Yalkowsky, S. H. (2004). Effect of pH-sodium lauryl sulfate combination on solubilization of PG-300995 (an anti-HIV agent): a technical note. AAPS PharmSciTech, 5(3).
• Yalkowsky, S., Machatha, S. G., & Yalkowsky, S. H. (2004). Estimation of the ethanol/water solubility profile from the octanol/water partition coefficient. International journal of pharmaceutics, 286(1-2).
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  While the ethanol/water solubility profiles of very polar and very non-polar drugs are monotonic, many semi-polar drugs show a maximum solubility at an ethanol volume fraction (f(max)) between 0 and 1. A sigmoidal relationship was observed between the value of f(max) and the log of the octanol/water partition coefficient (logK(ow)) of the solute. This relationship reasonably predicts the value of the volume fraction of ethanol that gives maximum solubility (f(max)). Combining this sigmoidal relationship with the previously reported linear relationship between the logK(ow) and the initial slope of the plot of log solubility versus ethanol composition [Li, A., Yalkowsky, S.H., 1994. Solubility of organic solutes in ethanol/water mixtures. J. Pharm. Sci. 83, 1735-1740] enables the estimation of the total ethanol/water solubility profile.
• Yalkowsky, S., Machatha, S. G., Bustamante, P., & Yalkowsky, S. H. (2004). Deviation from linearity of drug solubility in ethanol/water mixtures. International journal of pharmaceutics, 283(1-2).
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  A new empirical function that describes the deviation from linearity of solubility of a drug in an ethanol/water matrix is applied to the experimental data for 51 compounds. The proposed model is a more accurate predictor of the co-solvent solubility profile than a general third order polynomial with the same number of parameters. Both the root mean square error and average absolute error for the proposed model are significantly lower than those of existing models. The model also accurately predicts the fraction of co-solvent that gives maximum solubility (fmax).
• Yalkowsky, S., Yang, G., Jain, N., & Yalkowsky, S. H. (2004). Combined effect of SLS and (SBE)(7M)-beta-CD on the solubilization of NSC-639829. International journal of pharmaceutics, 269(1).
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  Complexation and micellization are two effective ways of solubilizing drugs. In this study, the combined effect of surfactant and complexant on the solubilization of a poorly water soluble compound (NSC-639829) is investigated. With increasing concentration of sodium lauryl sulphate (SLS) in solutions of fixed concentration of (SBE)(7M)-beta-CD, the total solubility of the drug decreases linearly, reaches a minimum and then increases linearly. At each minimum, the molar ratio of SLS to (SBE)(7M)-beta-CD is close to unity. The above observation is attributed to the fact that the surfactant molecule competes with the drug to "fit" in the non-polar cyclodextrin cavity. The surfactant depletes cyclodextrin to form a 1:1 complex. Once the concentration of free SLS reaches the CMC, it starts forming micelles and hence, solubilizes the drug. A slight decrease of the solubilizing power is noticed in the presence of SLS/(SBE)(7M)-beta-CD complex. The combined use of two solubilizing agents, a surfactant and a complexant, results in a much lower solubility than when either one is used alone at the same concentration. The surfactant molecule acts as a competitive inhibitor in the solubilization of the drug by the complexant. Similarly the complexant "pulls" the surfactant out of solution, making it unavailable for solubilizing the drug.
• Yan, H. e., & Yalkowsky, S. H. (2004). Solubilization of the neutral and charged forms of 2,4,6-trichlorophenol by hydroxypropyl-β-cyclodextrin, or methyl-β-cyclodextrin in water. Journal of Hazardous Materials, 108(1-2), 129-131.
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  PMID: 15081172;Abstract: The solubility of 2,4,6-trichlorophenol (TCP) in hydroxypropyl-β- cyclodextrin (HPβCD), or methyl-β-cyclodextrin (MeβCD) at pH 3.0 and 8.8 reported by Hanna et al. [J. Hazard. Mater. B100 (2003) 109] is reevaluated in this paper. The complexations of the individual dissolved forms were examined. As expected, the neutral TCP complexes more strongly with the cyclodextrins than the charged species. However, in spite of its lower complexation constant, the charged form of TCP forms more complex with each CD, and thus is solubilized to a greater extent. © 2004 Elsevier B.V. All rights reserved.
• Yang, G., Jain, N., & Yalkowsky, S. H. (2004). Combined effect of SLS and (SBE)_7M-β-CD on the solubilization of NSC-639829. International Journal of Pharmaceutics, 269(1), 141-148.
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  PMID: 14698585;Abstract: Complexation and micellization are two effective ways of solubilizing drugs. In this study, the combined effect of surfactant and complexant on the solubilization of a poorly water soluble compound (NSC-639829) is investigated. With increasing concentration of sodium lauryl sulphate (SLS) in solutions of fixed concentration of (SBE)7M-β-CD, the total solubility of the drug decreases linearly, reaches a minimum and then increases linearly. At each minimum, the molar ratio of SLS to (SBE)7M-β-CD is close to unity. The above observation is attributed to the fact that the surfactant molecule competes with the drug to "fit" in the non-polar cyclodextrin cavity. The surfactant depletes cyclodextrin to form a 1:1 complex. Once the concentration of free SLS reaches the CMC, it starts forming micelles and hence, solubilizes the drug. A slight decrease of the solubilizing power is noticed in the presence of SLS/(SBE)7M-β-CD complex. The combined use of two solubilizing agents, a surfactant and a complexant, results in a much lower solubility than when either one is used alone at the same concentration. The surfactant molecule acts as a competitive inhibitor in the solubilization of the drug by the complexant. Similarly the complexant "pulls" the surfactant out of solution, making it unavailable for solubilizing the drug. © 2003 Published by Elsevier B.V.
• Jain, A., Sanghvi, T., & Yalkowsky, S. H. (2003). Liposome formulation of NSC-639829 using halothane as a solvent: A technical note. AAPS PharmSciTech, 4(4), 413-417.
• Jain, A., Sanghvi, T., & Yalkowsky, S. H. (2003). Liposome formulation of NSC-639829 using halothane as a solvent: a technical note.. AAPS PharmSciTech [electronic resource], 4(4), E52.
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  PMID: 15198547;PMCID: PMC2750645;
• Johnson, J. L., Yan, H. e., & Yalkowsky, S. H. (2003). Prediction of precipitation-induced phlebitis: A statistical validation of an in vitro model. Journal of Pharmaceutical Sciences, 92(8), 1574-1581.
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  PMID: 12884244;Abstract: To avoid phlebitis, new intravenous (IV) parenterals are often screened by injection into animals. This method is not only expensive and time consuming, it is also detrimental to the animals. An alternate method, focusing on precipitation as the cause, uses an in vitro dynamic injection model that requires less money and time and reduces the need for live models. Validation of the dynamic injection apparatus, for predicting mechanical phlebitis, is established. Twenty-one currently marketed IV products were injected into isotonic Sorenson's phosphate buffer flowing at 5 mL/min. The resulting opacities, produced by precipitation, are measured in an ultraviolet flow cell. These opacity data, coupled with literature reports on phlebitis occurrence, were used to generate a logistic regression that indicates the probability of phlebitis given an opacity value measured by the apparatus. Regression results are supported by a receiver operator characteristic curve that establishes the most ideal cut-off opacity value. This opacity value provides the highest combined sensitivity (statistical power) and specificity while minimizing false-positive and false-negative results. Both analyses show that an opacity value of 0.003 best delineates phlebitic and nonphlebitic products. Measures of sensitivity (0.83), specificity (0.93), positive predictive value (0.93), and negative predictive value (0.78) indicate the model's predictive accuracy and reliability. These results support the use of the dynamic model in place of animals for preliminary phlebitis testing of new IV injectables. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association.
• Nina, N. i., & Yalkowsky, S. H. (2003). Prediction of Setschenow constants. International Journal of Pharmaceutics, 254(2), 167-172.
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  PMID: 12623192;Abstract: The Setschenow (salting out) constant by sodium chloride is related to molar volume, aqueous solubility, and octanol-water partition coefficient, Kow, of the drug solute. This study validates a previously proposed relationship between the salting out constant of a solute and its partition coefficient. It also shows that the partition coefficient is a better descriptor of salting out than either molar volume or solubility. © 2003 Elsevier Science B.V. All rights reserved.
• Ran, Y., & Yalkowsky, S. H. (2003). Halothane, a novel solvent for the preparation of liposomes containing 2-4′-amino-3′-methylphenyl benzothiazole (AMPB), an anticancer drug: A technical note. AAPS PharmSciTech, 4(2).
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  PMID: 12916902;PMCID: PMC2750598;
• Sanghvi, T., Jain, N., Yang, G., & Yalkowsky, S. H. (2003). Estimation of aqueous solubility by the General Solubility Equation (GSE) the easy way. QSAR and Combinatorial Science, 22(2), 258-262.
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  Abstract: The General Solubility Equation (GSE) provides a simple method of estimating the molar aqueous solubility of an organic non-electrolyte in water (Sw) as a function of its celsius melting point (MP) and octanol-water partition coefficient (Kow): log Sw = -0.01(MP-25) - log Kow + 0.5 The melting term of the GSE is based upon the Clausius-Clapyron equation and Walden's rule. The aqueous activity coefficient is assumed to be the reciprocal of the octanol-water partition coefficient. The constant is based upon the molarity of pure octanol. There are no fitted parameters in the GSE. Extension of the GSE to weak electrolytes in buffered aqueous solutions is straightforward. The concentration of the ionized species, Si, is accounted for by incorporating one additional term, which contains the pKa of the solute and pH of the solution. For a weak acid, Stotal = Sw + Si = Sw [1 + 10(PH-pKa)] The solubility of a weak electrolyte in unbuffered water requires further consideration because the solute will determine the pH of the solution. It is shown that in unbuffered media Stotal = Sw + Si = Sw + (SwKa)1/2 Thus, it is not necessary to explicitly know the pH of the saturated solution to estimate the solubility of a weak electrolyte in water. The GSE is validated on data set of over a thousand compounds, covering a wide range of structural categories. The GSE is compared to a number of other solubility estimation techniques using the criteria of accuracy of fit, applicability, parsimony, convenience, and elegance.
• Yalkowsky, S., He, Y., Li, P., & Yalkowsky, S. H. (2003). Solubilization of Fluasterone in cosolvent/cyclodextrin combinations. International journal of pharmaceutics, 264(1-2).
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  The combined effect of cosolvent (methanol (MeOH), ethanol (EtOH), or n-propanol (n-PrOH)) and complexant hydroxypropyl-beta-cyclodextrin (HP beta CD) on the solubility of Fluasterone is evaluated and explained with a simple equation. The calculated constants in the equation not only quantitatively describe the dependence of drug solubility on cosolvent and ligand concentrations, but also explain the minima that are observed in the Fluasterone solubility versus cosolvent concentration curves at fixed HP beta CD concentrations.
• Yalkowsky, S., Jain, A., Sanghvi, T., & Yalkowsky, S. H. (2003). Liposome formulation of NSC-639829 using halothane as a solvent: a technical note. AAPS PharmSciTech, 4(4).
• Yalkowsky, S., Johnson, J. L., He, Y., & Yalkowsky, S. H. (2003). Prediction of precipitation-induced phlebitis: a statistical validation of an in vitro model. Journal of pharmaceutical sciences, 92(8).
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  To avoid phlebitis, new intravenous (IV) parenterals are often screened by injection into animals. This method is not only expensive and time consuming, it is also detrimental to the animals. An alternate method, focusing on precipitation as the cause, uses an in vitro dynamic injection model that requires less money and time and reduces the need for live models. Validation of the dynamic injection apparatus, for predicting mechanical phlebitis, is established. Twenty-one currently marketed IV products were injected into isotonic Sorenson's phosphate buffer flowing at 5 mL/min. The resulting opacities, produced by precipitation, are measured in an ultraviolet flow cell. These opacity data, coupled with literature reports on phlebitis occurrence, were used to generate a logistic regression that indicates the probability of phlebitis given an opacity value measured by the apparatus. Regression results are supported by a receiver operator characteristic curve that establishes the most ideal cut-off opacity value. This opacity value provides the highest combined sensitivity (statistical power) and specificity while minimizing false-positive and false-negative results. Both analyses show that an opacity value of 0.003 best delineates phlebitic and nonphlebitic products. Measures of sensitivity (0.83), specificity (0.93), positive predictive value (0.93), and negative predictive value (0.78) indicate the model's predictive accuracy and reliability. These results support the use of the dynamic model in place of animals for preliminary phlebitis testing of new IV injectables.
• Yalkowsky, S., Ni, N., & Yalkowsky, S. H. (2003). Prediction of Setschenow constants. International journal of pharmaceutics, 254(2).
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  The Setschenow (salting out) constant by sodium chloride is related to molar volume, aqueous solubility, and octanol-water partition coefficient, K(ow), of the drug solute. This study validates a previously proposed relationship between the salting out constant of a solute and its partition coefficient. It also shows that the partition coefficient is a better descriptor of salting out than either molar volume or solubility.
• Yalkowsky, S., Ran, Y., & Yalkowsky, S. H. (2003). Halothane, a novel solvent for the preparation of liposomes containing 2-4'-amino-3'-methylphenyl benzothiazole (AMPB), an anticancer drug: a technical note. AAPS PharmSciTech, 4(2).
• Yan, H. e., Ping, L. i., & Yalkowsky, S. H. (2003). Solubilization of Fluasterone in cosolvent/cyclodextrin combinations. International Journal of Pharmaceutics, 264(1-2), 25-34.
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  PMID: 12972333;Abstract: The combined effect of cosolvent (methanol (MeOH), ethanol (EtOH), or n-propanol (n-PrOH)) and complexant hydroxypropyl-β-cyclodextrin (HPβCD) on the solubility of Fluasterone is evaluated and explained with a simple equation. The calculated constants in the equation not only quantitatively describe the dependence of drug solubility on cosolvent and ligand concentrations, but also explain the minima that are observed in the Fluasterone solubility versus cosolvent concentration curves at fixed HPβCD concentrations. © 2003 Elsevier B.V. All rights reserved.
• Lee, Y., Simamora, P., Pinsuwan, S., & Yalkowsky, S. H. (2002). Review on the systemic delivery of insulin via the ocular route. International Journal of Pharmaceutics, 233(1-2), 1-18.
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  PMID: 11897405;Abstract: Systemic drug absorption from the ocular route is well known. Although there is some absorption from the conjunctival sac, the nasal meatus is the site where the majority of systemic absorption of instilled drug takes place. This article reviews the principles of systemic absorption of insulin applied topically to the eye. The physiological and pharmaceutical considerations for formulation development and the strategy of improving the systemic absorption and bioavailability of insulin are also discussed. © 2002 Elsevier Science B.V. All rights reserved.
• Millard, J. W., Alvarez-Núñez, F., & Yalkowsky, S. H. (2002). Solubilization by cosolvents: Establishing useful constants for the log-linear model. International Journal of Pharmaceutics, 245(1-2), 153-166.
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  PMID: 12270252;Abstract: The purpose of this study was to develop constants for the log-linear cosolvent model, thereby allowing accurate prediction of solubilization in the most common pharmaceutical cosolvents: propylene glycol, ethanol, polyethylene glycol 400, and glycerin. The solubilization power (σ) of each cosolvent was determined for a large number of organic compounds from the slope of their log-solubility vs. cosolvent volume fraction plots. The solubilization data at room temperature were either experimentally determined or obtained from the literature. The slopes of the nearly linear relationship between solubilization power and solute hydrophobicity (logKow) were obtained by linear regression analysis for each considered cosolvent. Thus, knowing or calculating a compound's partition coefficient is all that is needed to predict solubilization. © 2002 Elsevier Science B.V. All rights reserved.
• Nina, N. i., Sanghvi, T., & Yalkowsky, S. H. (2002). Independence of the product of solubility and distribution coefficient of pH. Pharmaceutical Research, 19(12), 1862-1866.
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  PMID: 12523666;Abstract: Purpose. The relationship between the pH, solubility, and partition coefficient was investigated to show that the product of intrinsic values of solubility and partition coefficient is equal to the product of total values of solubility and distribution coefficient at different pH. Methods. The pH distribution profiles were obtained from the literature and the pH solubility profiles were obtained from the literature or calculated from their intrinsic solubility and pKa. Results. The pH solubility and pH distribution coefficient profiles of 25 compounds were investigated to show that the product of intrinsic solubility (SW) and intrinsic octanol-water partition coefficient (KOW) is equal to the product of total solubility of a partially ionized solute (ST) and its octanol-buffer distribution coefficient (KD) at any pH where ion pair formation and salt precipitation are not present. Conclusions. The fact that SW·KOW can be used instead of ST·KD to model the absorption of partially ionized drugs in the gastrointestinal tract has important biopharmaceutical implications.
• Nina, N. i., Sanghvi, T., & Yalkowsky, S. H. (2002). Solubilization and preformulation of carbendazim. International Journal of Pharmaceutics, 244(1-2), 99-104.
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  PMID: 12204569;Abstract: The solubilization of carbendazim by pH in combination with cosolvents, surfactants or complexants was investigated. At pH 7 the total drug solubility is 6.11±0.45 μg/ml which increases by 1-7 fold with cosolvent, surfactant or complexant. However, at pH 2 the solubility increases by 250 times. Cosolvents have a negligible effect (50% increase) on the total drug solubility at pH 2 because of the high polarity of the cationic drug. Also pH combined with nonionic surfactants does not improve solubility, as relatively less polar micelles are not able to accommodate the cationic drug. Interestingly, the total drug solubility increases by combining pH 2 with complexants, as they can form a complex with the isolated aromatic ring of both the unionized and the ionized drug. The proposed oral formulation of 1 mg/ml carbendazim at pH 2 does not precipitate in the presence of Seven Up or water. But it does precipitate with pH 7 buffer when diluted 1:10 but not 1:100 or 1:250. © 2002 Elsevier Science B.V. All rights reserved.
• Nina, N. i., Sanghvi, T., & Yalkowsky, S. H. (2002). Stabilization and preformulation of anticancer drug - SarCNU. International Journal of Pharmaceutics, 249(1-2), 257-264.
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  PMID: 12433453;Abstract: The stability of SarCNU (NSC364432), 1-(2-chloroethyl)-3-sarcosinamide-1-nitrosourea in several pharmaceutically acceptable solvents was investigated by high pressure liquid chromatography (HPLC). The influences of light, ionic strength, pH, buffer concentration, and the following excipients: benzyl alcohol, ascorbic acid, sodium bisulfite, and disodium EDTA were studied at room temperature. The stability of the drug was also determined in water, EtOH, PG, Capmul PG, DMSO, and in different combinations of these cosolvents at four different temperatures. The degradation of the drug, which is catalyzed not only by general but also by specific acid and base, follows first order kinetics. Antioxidants, EDTA, and light have no effect on the degradation rate, suggesting oxidation is not a major degradation pathway. The t90 in pure cosolvent is 25-50 times higher than that in water or semi-aqueous vehicles. Neat EtOH can be used to store the drug in a nonaqueous concentrate that is diluted with aqueous solvent prior to injection. © 2002 Elsevier Science B.V. All rights reserved.
• Ran, Y., Yan, H. e., Yang, G., Johnson, J. L., & Yalkowsky, S. H. (2002). Estimation of aqueous solubility of organic compounds by using the general solubility equation. Chemosphere, 48(5), 487-509.
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  PMID: 12146628;Abstract: The general solubility equation (GSE) proposed by Jain and Yalkowsky was used to estimate aqueous solubility of 1026 non-electrolytes. The only parameters used in the GSE are melting points (MP) and octanol-water partition coefficients (Kow). No fitted parameters and no training set are employed in the GSE. The experimental solubility values were taken from the AQUASOL dATAbASE. The average absolute error and the root-mean-square error in the solubility estimates are 0.38 and 0.53 log units, respectively. Thus, with an observed MP and calculated Kow; the users can obtain a reasonable estimation of the aqueous solubility of any organic non-electrolyte. © 2002 Elsevier Science Ltd. All rights reserved.
• Yalkowsky, S., Lee, Y., Simamora, P., Pinsuwan, S., & Yalkowsky, S. H. (2002). Review on the systemic delivery of insulin via the ocular route. International journal of pharmaceutics, 233(1-2).
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  Systemic drug absorption from the ocular route is well known. Although there is some absorption from the conjunctival sac, the nasal meatus is the site where the majority of systemic absorption of instilled drug takes place. This article reviews the principles of systemic absorption of insulin applied topically to the eye. The physiological and pharmaceutical considerations for formulation development and the strategy of improving the systemic absorption and bioavailability of insulin are also discussed.
• Yalkowsky, S., Ni, N., Sanghvi, T., & Yalkowsky, S. H. (2002). Independence of the product of solubility and distribution coefficient of pH. Pharmaceutical research, 19(12).
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  The relationship between the pH, solubility, and partition coefficient was investigated to show that the product of intrinsic values of solubility and partition coefficient is equal to the product of total values of solubility and distribution coefficient at different pH.
• Yalkowsky, S., Ni, N., Sanghvi, T., & Yalkowsky, S. H. (2002). Solubilization and preformulation of carbendazim. International journal of pharmaceutics, 244(1-2).
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  The solubilization of carbendazim by pH in combination with cosolvents, surfactants or complexants was investigated. At pH 7 the total drug solubility is 6.11 +/- 0.45 microg/ml which increases by 1-7 fold with cosolvent, surfactant or complexant. However, at pH 2 the solubility increases by 250 times. Cosolvents have a negligible effect (50% increase) on the total drug solubility at pH 2 because of the high polarity of the cationic drug. Also pH combined with nonionic surfactants does not improve solubility, as relatively less polar micelles are not able to accommodate the cationic drug. Interestingly, the total drug solubility increases by combining pH 2 with complexants, as they can form a complex with the isolated aromatic ring of both the unionized and the ionized drug. The proposed oral formulation of 1 mg/ml carbendazim at pH 2 does not precipitate in the presence of Seven Up or water. But it does precipitate with pH 7 buffer when diluted 1:10 but not 1:100 or 1:250.
• Yalkowsky, S., Ni, N., Sanghvi, T., & Yalkowsky, S. H. (2002). Stabilization and preformulation of anticancer drug--SarCNU. International journal of pharmaceutics, 249(1-2).
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  The stability of SarCNU (NSC364432), 1-(2-chloroethyl)-3-sarcosinamide-1-nitrosourea in several pharmaceutically acceptable solvents was investigated by high pressure liquid chromatography (HPLC). The influences of light, ionic strength, pH, buffer concentration, and the following excipients: benzyl alcohol, ascorbic acid, sodium bisulfite, and disodium EDTA were studied at room temperature. The stability of the drug was also determined in water, EtOH, PG, Capmul PG, DMSO, and in different combinations of these cosolvents at four different temperatures. The degradation of the drug, which is catalyzed not only by general but also by specific acid and base, follows first order kinetics. Antioxidants, EDTA, and light have no effect on the degradation rate, suggesting oxidation is not a major degradation pathway. The t(90) in pure cosolvent is 25-50 times higher than that in water or semi-aqueous vehicles. Neat EtOH can be used to store the drug in a nonaqueous concentrate that is diluted with aqueous solvent prior to injection.
• Yalkowsky, S., Ran, Y., He, Y., Yang, G., Johnson, J. L., & Yalkowsky, S. H. (2002). Estimation of aqueous solubility of organic compounds by using the general solubility equation. Chemosphere, 48(5).
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  The general solubility equation (GSE) proposed by Jain and Yalkowsky was used to estimate aqueous solubility of 1026 non-electrolytes. The only parameters used in the GSE are melting points (MP) and octanol-water partition coefficients (Kow). No fitted parameters and no training set are employed in the GSE. The experimental solubility values were taken from the AQUASOL dATAbASE. The average absolute error and the root-mean-square error in the solubility estimates are 0.38 and 0.53 log units, respectively. Thus, with an observed MP and calculated Kow; the users can obtain a reasonable estimation of the aqueous solubility of any organic non-electrolyte.
• Yalkowsky, S., Yang, G., Ran, Y., & Yalkowsky, S. H. (2002). Prediction of the aqueous solubility: comparison of the general solubility equation and the method using an amended solvation energy relationship. Journal of pharmaceutical sciences, 91(2).
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  An Amended Solvation Energy Relationship (ASER) was recently reported to successfully predict the aqueous solubilities of a set of 664 organic compounds. The average absolute error and root mean square error are 0.43 and 0.62 log units, respectively. When the General Solubility Equation (GSE) is applied to the same set of compounds, it gives an average absolute error of 0.45 log units and a root mean square error of 0.62 log units. These results are similar to those of the ASER method. The advantages and disadvantages of each method are discussed. It is shown that when the two methods agree with each other, they also agree with the experimentally determined values.
• Yang, G., Ran, Y., & Yalkowsky, S. H. (2002). Prediction of the aqueous solubility: Comparison of the General Solubility Equation and the method using an Amended Solvation Energy Relationship. Journal of Pharmaceutical Sciences, 91(2), 517-533.
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  PMID: 11835210;Abstract: An Amended Solvation Energy Relationship (ASER) was recently reported to successfully predict the aqueous solubilities of a set of 664 organic compounds. The average absolute error and root mean square error are 0.43 and 0.62 log units, respectively. When the General Solubility Equation (GSE) is applied to the same set of compounds, it gives an average absolute error of 0.45 log units and a root mean square error of 0.62 log units. These results are similar to those of the ASER method. The advantages and disadvantages of each method are discussed. It is shown that when the two methods agree with each other, they also agree with the experimentally determined values. © 2002 Wiley-Liss, Inc.
• Jain, N., & Yalkowsky, S. H. (2001). Estimation of the aqueous solubility I: Application to organic nonelectrolytes. Journal of Pharmaceutical Sciences, 90(2), 234-252.
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  PMID: 11169540;Abstract: The estimation of aqueous solubilities of organic nonelectrolytes by the General Solubility Equation (GSE) as proposed by Valvani and Yalkowsky (1980) is used in this study. The data and assumptions on which the GSE are based are reevaluated, and the equation is revised. The revised GSE is validated on a set of 580 pharmaceutically, environmentally, and industrially relevant nonelectrolytes. The revised equation has a stronger theoretical background and provides a more accurate estimation of aqueous solubility. © 2001 Wiley-Liss, Inc.
• Jain, N., Yang, G., Tabibi, S., & Yalkowsky, S. H. (2001). Solubilization of NSC-639829. International Journal of Pharmaceutics, 225(1-2), 41-47.
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  PMID: 11489553;Abstract: Solubilization using pH combined with cosolvents, surfactants, and complexants are investigated for NSC-639829, an investigational anti-tumor agent. The intrinsic solubility of the drug is approximately 30 ng/ml and it has an ionizable dimethyl aniline group with an approximate base pKa of 5. Samples buffered at pH 1.0, 2.0, and 7.0 with various concentrations of the solubilizing agents were used to study the solubilization of NSC-629829 when present as charged and uncharged species. The solubilization of NSC-639829 was found to be much more effective when the drug was present primarily in ionized form. At pH values 1.0 and 2.0 where the surfactant (SLS) and complexant (SBEβCD) carried a negative charge enhanced solubilities of more than a million-fold were observed for the drug. © 2001 Elsevier Science B.V. All rights reserved.
• Nina, N. i., Tesconi, M., Tabibi, S., Gupta, S., & Yalkowsky, S. H. (2001). Use of pure t-butanol as a solvent for freeze-drying: A case study. International Journal of Pharmaceutics, 226(1-2), 39-46.
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  PMID: 11532568;Abstract: 1-(2-Chloroethyl)-3-sarcosinamide-1-nitrosourea, (SarCNU) (NSC-364432) is a new antitumor drug that is of interest to the National Cancer Institute. It is intended for use as an intravenous injection. Although SarCNU is sufficiently soluble in water to obtain the desired dosage, it is highly unstable. Its T90 in aqueous solution at room temperature is less than 6 h. Neat tertiary butyl alcohol (TBA), a low toxicity, high vapor pressure and low melting solvent, was determined to be an excellent freeze-drying medium. Lyophilization of SarCNU from pure TBA produces a uniform cake composed of needle-shaped crystals. Thermal analysis and gas chromatography indicate that the cake contains less than 0.001% residual solvent. The SarCNU cake can be readily reconstituted with either water or an aqueous solution of 40% propylene glycol and 10% ethanol. The reconstituted solutions are stable for 4 and 13 h, respectively. © 2001 Elsevier Science B.V. All rights reserved.
• Peterson, D. L., & Yalkowsky, S. H. (2001). Comparison of Two Methods for Predicting Aqueous Solubility. Journal of Chemical Information and Computer Sciences, 41(6), 1531-1534.
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  PMID: 11749579;Abstract: This study compares the solubility predictions of the two parameter general solubility equation (GSE) of Jain and Yalkowsky with the 171 parameter Klopman group contribution approach. Melting points and partition coefficients were obtained for each of the compounds from Klopman's test set. Using these two variables, the solubility of each compound was calculated by the GSE and compared to the values predicted by Klopman. Both methods give reasonable solubility predictions. The data of Klopman produced an average absolute error (AAE) of 0.71 and a root-mean-square error (RMSE) of 0.86, while the GSE had an AAE of 0.64 and a RMSE of 0.92.
• Ran, Y., & Yalkowsky, S. H. (2001). Prediction of drug solubility by the general solubility equation (GSE). Journal of Chemical Information and Computer Sciences, 41(2), 354-357.
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  PMID: 11277722;Abstract: The revised general solubility equation (GSE) proposed by Jain and Yalkowsky is used to estimate the aqueous solubility of a set of organic nonelectrolytes studied by Jorgensen and Duffy. The only inputs used in the GSE are the Celsius melting point (MP) and the octanol water partition coefficient (Kow). These are generally known, easily measured, or easily calculated. The GSE does not utilize any fitted parameters. The average absolute error for the 150 compounds is 0.43 compared to 0.56 with Jorgensen and Duffy's computational method, which utilitizes five fitted parameters. Thus, the revised GSE is simpler and provides a more accurate estimation of aqueous solubility of the same set of organic compounds. It is also more accurate than the original version of the GSE.
• Ran, Y., Jain, N., & Yalkowsky, S. H. (2001). Prediction of Aqueous Solubility of Organic Compounds by the General Solubility Equation (GSE). Journal of Chemical Information and Computer Sciences, 41(3-6), 1208-1217.
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  PMID: 11604020;Abstract: The revised general solubility equation (GSE) is used along with four different methods including Huuskonen's artificial neural network (ANN) and three multiple linear regression (MLR) methods to estimate the aqueous solubility of a test set of the 21 pharmaceutically and environmentally interesting compounds. For the selected test sets, it is clear that the GSE and ANN predictions are more accurate than MLR methods. The GSE has the advantages of being simple and thermodynamically sound. The only two inputs used in the GSE are the Celsius melting point (MP) and the octanol water partition coefficient (Kow). No fitted parameters and no training data are used in the GSE, whereas other methods utilize a large number of parameters and require a training set. The GSE is also applied to a test set of 413 organic nonelectrolytes that were studied by Huuskonen. Although the GSE uses only two parameters and no training set, its average absolute errors is only 0.1 log units larger than that of the ANN, which requires many parameters and a large training set. The average absolute error AAE is 0.54 log units using the GSE and 0.43 log units using Huuskonen's ANN modeling. This study provides evidence for the GSE being a convenient and reliable method to predict aqueous solubilities of organic compounds.
• Ran, Y., Zhao, L., Qing, X. u., & Yalkowsky, S. H. (2001). Solubilization of cyclosporin A. AAPS PharmSciTech, 2(1).
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  Abstract: This study investigated the solubilization of cyclosporin A (CsA), a neutral undecapeptide, by cosolvency, micellization, and complexation. Cosolvents (ethanol, propylene glycol, polyethylene glycol, tetrahydrofurfuryl alcohol polyethyleneglycol ether, and glycerin), surfactants (polyoxyethylene sorbitan monooleate [(Tween 80)], polyoxyethylene sorbitan monolaurate [(Tween 20)], and Cremophor EL), and cyclodextrins (α-cyclodextrin [(αCD)] and hydroxypropyl-β-cyclodextrin[(HPβCD)] were used as solubilizing agents in this study. Surfactants had a noticeable effect in increasing CsA solubility. Twenty percent solutions of Tween 20, Tween 80, and Cremophor EL increased the solubility by 60 to 160 fold. Cyclodextrins can increase the CsA solubility, but αCD was more effective than HPβCD. Cosolvents on the other hand did not increase the solubility of CsA as much as expected from the LOGP (logrithm of water-octanol partition coefficent) value of CsA.
• Ran, Y., Zhao, L., Xu, Q., & Yalkowsky, S. H. (2001). Solubilization of cyclosporin A.. AAPS PharmSciTech [electronic resource], 2(1), E2.
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  PMID: 14727890;Abstract: This study investigated the solubilization of cyclosporin A (CsA), a neutral undecapeptide, by cosolvency, micellization, and complexation. Cosolvents (ethanol, propylene glycol, polyethylene glycol, tetrahydrofurfuryl alcohol polyethyleneglycol ether, and glycerin), surfactants (polyoxyethylene sorbitan monooleate [(Tween 80)], polyoxyethylene sorbitan monolaurate [(Tween 20)], and Cremophor EL), and cyclodextrins (alpha-cyclodextrin [(alphaCD)] and hydroxypropyl-beta-cyclodextrin[(HPbetaCD)] were used as solubilizing agents in this study. Surfactants had a noticeable effect in increasing CsA solubility. Twenty percent solutions of Tween 20, Tween 80, and Cremophor EL increased the solubility by 60 to 160 fold. Cyclodextrins can increase the CsA solubility, but alphaCD was more effective than HPbetaCD. Cosolvents on the other hand did not increase the solubility of CsA as much as expected from the LOGP (logarithm of water-octanol partition coefficient) value of CsA.
• Sanghvi, T., Ni, N., & Yalkowsky, S. H. (2001). A simple modified absorption potential. Pharmaceutical Research, 18(12), 1794-1796.
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  PMID: 11785703;
• Simamora, P., Alvarez, J. M., & Yalkowsky, S. H. (2001). Solubilization of rapamycin. International Journal of Pharmaceutics, 213(1-2), 25-29.
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  PMID: 11165091;Abstract: The solubilization of rapamycin, a poorly water soluble investigational immunosuppressive drug, by facilitated hydrotropy is presented. Partially water-miscible aromatic solutes (such as benzyl alcohol, benzoate, or benzoic acid) can be solubilized by water-miscible cosolvents, such as ethanol and propylene glycol. Once solubilized, the partially miscible aromatic solute becomes a solubilizing agent. This technique yielded a dramatic (> 1000-fold) increase in the aqueous solubility of rapamycin. © 2001 Elsevier Science B.V.
• Zhao, L., & Yalkowsky, S. H. (2001). Stabilization of eptifibatide by cosolvents. International Journal of Pharmaceutics, 218(1-2), 43-56.
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  PMID: 11337148;Abstract: Eptifibatide is a potent and highly specific inhibitor of platelet receptor glycoprotein IIb/IIIa and is indicated in the treatment of acute coronary syndrome. The commercial product Integrilin® (eptifibatide) Injection requires a cold/refrigerator storage condition. In an effort to improve the drug stability for room temperature storage and transportation, this study proposed a semi-aqueous formulation that contains 2 mg/ml eptifibatide, 10% ethanol, 40% propylene glycol and 50% 0.025 M citrate buffer. The stability study was conducted in the pH range 4.25-6.25 under accelerated temperatures: 48, 60, 72.5°C. The results indicate that the proposed semi-aqueous vehicles substantially increased the drug stability in comparison with aqueous vehicles. The predicted drug shelf-life T90 at 25°C shows that an almost twofold increase can be achieved by formulating eptifibatide in the semi-aqueous vehicle, which is 60 months at its maximum stability of pH 5.75, as opposed to the 33 months in the aqueous vehicle at its maximum stability of pH 5.25. © 2001 Elsevier Science B.V.
• Alvarez-Núñez, F., & Yalkowsky, S. H. (2000). Relationship between Polysorbate 80 solubilization descriptors and octanol-water partition coefficients of drugs. International Journal of Pharmaceutics, 200(2), 217-222.
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  PMID: 10867251;Abstract: The molar solubilization capacities (κ) and the molar micelle-water partition coefficients (K(M)(N)) in Polysorbate 80 of several drugs (including barbiturates, steroids, and benzoic acid derivatives) are related to their log octanol-water partition coefficients (logP). Both κ and K(M)(N) values were calculated from solubility versus Polysorbate 80 concentration profiles, which were either experimentally determined or obtained from the literature. There is a linear relationship between logP of the tested compounds and the logarithm of the molar micelle-water partition coefficient (logK(M)(N)). On the other hand molar solubilization capacities are nearly independent of logP. It is shown that the ability of Polysorbate 80 to solubilize a drug can be predicted from its logP value. Copyright (C) 2000 Elsevier Science B.V.
• Na, N. i., El-Sayed, M. M., Sanghvi, T., & Yalkowsky, S. H. (2000). Estimation of the effect of NaCl on the solubility of organic compounds in aqueous solutions. Journal of Pharmaceutical Sciences, 89(12), 1620-1625.
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  PMID: 11042610;Abstract: The Setschenow constant, K(salt), of a nonelectrolyte in a NaCl solution is shown to be related to the logarithm of its octanol-water partition coefficient, log K(ow), determined by K(salt) = A log K(ow) + B, where K(ow) is the octanol-water partition coefficient of the solute and the coefficients A and B are constants. The values of A and B were empirically determined from literature data for 62 organic compounds and validated for a test set of 15 compounds including several drugs. (C) 2000 Wiley-Liss, Inc.
• Negvesky, G. J., Butrus, S. I., Abifarah, H. A., Lee, Y. C., & Yalkowsky, S. H. (2000). Ocular gelfoam disc-applicator for pupillary dilation in humans. Journal of Ocular Pharmacology and Therapeutics, 16(4), 311-315.
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  PMID: 10977126;Abstract: This study investigates a gelfoam disc device as an alternative topical ophthalmic drug delivery system for pupillary dilation in humans. Gelfoam (®Pharmacia and Upjohn) discs were impregnated with 0.60 mg of tropicamide racemate and 1.7 mg of 1-phenylephrine hydrochloride by an ethanol solvent evaporation method. Twenty randomly selected human subjects received baseline examinations, including blood pressure, pulse rate and biomicroscopy of the ocular surface. One impregnated gelfoam disc was placed in the inferior fornix of a randomly selected eye. Simultaneously, the fellow eye was treated with two topically administered drops, one from a phenylephrine hydrochloride 2.5% solution and one from a tropicamide 1% solution. A single, masked observer measured the pupillary diameter in both eyes at various time intervals under constant ambient conditions. Administration of the topical drops was repeated in the fellow eye. At maximum pupillary dilation, the disc was removed, and a post-dilation biomicroscopic exam was performed. Blood pressure and pulse rate were rechecked. The gelfoam-treated eyes' median change in dilation diameter was approximately 25% greater (a two-fold increase in pupillary area) (p< 0.001) at 15.2 min (median time to maximum dilation) than the topically treated fellow eyes. The median change in systolic blood pressure (+1.0 mmHg) and diastolic blood pressure (-1.0 mmHg) was not statistically significant (p>0.1). The average pulse rate was decreased 7 beats per minute (p=0.004). A gelfoam disc may serve as an ophthalmic drug delivery system for pupillary dilation or as a model for other multiple-dose topical drugs.
• Alvarez-Núñez, F., & Yalkowsky, S. H. (1999). Buffer capacity and precipitation control of pH solubilized phenytoin formulations. International Journal of Pharmaceutics, 185(1), 45-49.
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  PMID: 10425364;Abstract: The main objective of this investigation is to develop a phenytoin (DPH) intravenous formulation that does not precipitate upon dilution. The effect of the buffer capacity at pH 12 of several DPH formulations on the extent and lag-time of DPH precipitation upon dilution with Sorensen's phosphate buffer (SPB) is evaluated. DPH precipitation was evaluated by means of static and dynamic in vitro dilution methods. It is shown that an increase in the formulation buffer capacity decreases substantially the extent of DPH precipitation and increases the lag-time for precipitation. In addition, a comparison between static and dynamic in vitro methods to measure precipitation is presented. Copyright (C) 1999 Elsevier Science B.V.
• Alvarez-Núñez, F., Rosin, D. A., & Yalkowsky, S. H. (1999). A spin filter method for continuous evaluation of hemolysis. Journal of Pharmaceutical Sciences, 88(10), 1041-1043.
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  PMID: 10514353;Abstract: A novel method for quantifying hemolysis is described. This method uses a spin filter to separate the free hemoglobin from the red blood cells suspended in the test solution. This procedure enables the use of a closed loop system that continuously measures hemolysis spectrophotometrically. It is shown that hemolysis does not always stop after the solution has been quenched with normal saline. In fact, the process of hemolysis induced by chemicals such as potassium oleate is relatively slow.
• Dannenfelser, R., & Yalkowsky, S. H. (1999). Predicting the total entropy of melting: Application to pharmaceuticals and environmentally relevant compounds. Journal of Pharmaceutical Sciences, 88(7), 722-724.
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  PMID: 10393571;Abstract: Experimental entropy of melting values for physical property estimation schemes, such as solubility and vapor pressure, are not readily available. In this study a semiempirical equation, which contains two molecular parameters, is used to estimate the total entropy of melting for a variety of pharmaceutically and environmentally relevant compounds. A database of experimental entropy values consisting of over 370 different compounds was compiled from literature. A molecular rotational symmetry number and a molecular flexibility number for each compound were defined. The simple equation does very well in predicting the total entropy of melting for the complex set of molecules with an average error of 21%.
• Jain, N., & Yalkowsky, S. H. (1999). UPPER III: Unified physical property estimation relationships. Application to non-hydrogen bonding aromatic compounds. Journal of Pharmaceutical Sciences, 88(9), 852-860.
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  PMID: 10479346;Abstract: The UPPER scheme uses four additive and two nonadditive parameters and several well-known equations to calculate 21 physical properties of organic compounds strictly from molecular structure. The scheme allows reasonable estimations of melting and boiling points, aqueous and octanol solubilities, air-octanol, air-water, and octanol-water partition coefficients, vapor pressure, and other properties. In this report non-hydrogen bonding aromatic compounds are used to evaluate a portion of the UPPER scheme.
• Lee, Y., & Yalkowsky, S. H. (1999). Effect of formulation on the systemic absorption of insulin from enhancer-free ocular devices. International Journal of Pharmaceutics, 185(2), 199-204.
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  PMID: 10460915;Abstract: Several Gelfoam(®) (absorbable gelatin sponge, USP) based surfactant free devices containing either sodium or zinc insulin were prepared with diluted acetic or hydrochloric acid. They were evaluated by the lowering of the blood glucose concentration in rabbits. The systemic absorption of insulin from the device can be enhanced by using a 5% or higher concentration of acetic acid solution as well as 1% HCl solution. The results indicate that the proposed device prepared with up to 30% of acetic acid solution produced no eye irritation. A single device containing 0.2 mg of insulin is sufficient to control the blood glucose levels in a uniform manner (60% of initial) for over 8 h. Copyright (C) 1999 Elsevier Science B.V.
• Lee, Y., & Yalkowsky, S. H. (1999). Ocular devices for the controlled systemic delivery of insulin: In vitro and in vivo dissolution. International Journal of Pharmaceutics, 181(1), 71-77.
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  PMID: 10370204;Abstract: Both in vitro flow-through and in vivo device removal methods were utilized to determine the dissolution rate of insulin from a Gelfoam® based eye device. The dissolution profiles generated by these two methods are comparable. The in vivo data suggests that there is a direct relationship between blood glucose lowering and the rate of release of insulin from the device. The in vitro dissolution results indicate that the release of insulin from the device is flow-rate dependent. The prolonged activity of the insulin is due to the gradual release of insulin from the device which results from the lachrymal system's slow and constant tear production. Copyright (C) 1999 Elsevier Science B.V.
• Lee, Y., & Yalkowsky, S. H. (1999). Systemic absorption of insulin from a Gelfoam® ocular device. International Journal of Pharmaceutics, 190(1), 35-40.
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  PMID: 10528094;Abstract: In previous reports (Lee et al., 1997b; Lee and Yalkowsky, 1999), it has been shown that insulin, delivered by an acidified Gelfoam (absorbable gelatin sponge, USP) based ocular device, can be efficiently absorbed into the systemic circulation without the aid of an absorption enhancer. The role of acid in the enhancer-free absorption of insulin is investigated in this report. Gelfoam ocular devices containing 0.2 mg of sodium insulin prepared with either water or 10% acetic acid were evaluated in rabbits. The results suggest that a change in the Gelfoam upon treatment with acid is responsible for the efficient systemic absorption of insulin from these enhancer-free devices. Copyright (C) 1999 Elsevier Science B.V.
• Ping, L. i., Patel, H., Tabibi, S. E., Vishnuvajjala, R., & Yalkowsky, S. H. (1999). Evaluation of intravenous flavopiridol formulations. PDA Journal of Pharmaceutical Science and Technology, 53(3), 137-140.
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  PMID: 10754703;Abstract: Flavopiridol is currently under consideration as a parenteral treatment of breast tumors. The solubility of this poorly water-soluble compound can be increased by a number of methods. However, because of its low water solubility, precipitation of the solubilized drug upon injection can be a problem. The potential of several flavopiridol formulations to precipitate is evaluated using a static serial dilution technique. It is shown that formulations containing up to 10 mg/mL of flavopiridol which produce negligible precipitation on dilution can be developed.
• Ping, L. i., Tabibi, S. E., & Yalkowsky, S. H. (1999). Solubilization of flavopiridol by pH control combined with cosolvents, surfactants, or complexants. Journal of Pharmaceutical Sciences, 88(9), 945-947.
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  PMID: 10479359;Abstract: This study investigates the roles of both ionized and unionized species of flavopiridol in solubilization by complexation, micellization, and cosolvency. Control of pH was used in combination with surfactants (polysorbate 20 and polysorbate 80), cosolvents (ethanol and propylene glycol), as well as uncharged and anionic complexing agents [hydroxypropyl β-cyclodextrin (HPβCD) and sulfobutyl ether β-cyclodextrin (SBEβCD)] to solubilize flavopiridol. These combined techniques increase not only the solubility of the un-ionized flavopiridol but also the solubility of the ionized drug. This study confirms that previously developed equations effectively characterize the roles of pH, pk(a), and either complexation constant, micelle partition coefficient, or cosolvent solubilizing power in determining drug total aqueous solubility.
• Ping, L. i., Tabibi, S. E., & Yalkowsky, S. H. (1999). Solubilization of ionized and un-ionized flavopiridol by ethanol and polysorbate 20. Journal of Pharmaceutical Sciences, 88(5), 507-509.
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  PMID: 10229640;Abstract: Because the ionized species is more polar than its unionized counterpart, it is often assumed that the ionized species of the drug does not make a meaningful contribution to solubilization by either cosolvents or surfactants. This report extends previous studies on solubilization of the ionic species by a combination of pH control and complexation to pH control and micellization and to pH control and cosolvency. The total aqueous solubility is expressed as the addition of the concentration of all contributing species: free un-ionized drug [D(u)], free ionized drug [D(i)], un-ionized drug micelle [D(u)M], and ionized drug micelle [D(i)M] for surfactant, and free un-ionized drug [D(u)/(c)] and free ionized drug [D(i)/(c)] for cosolvent. The equations indicate that under certain conditions the ionized species can be more important in determining the drug total solubility than the un-ionized species. Flavopiridol, a weak base, is used to test these newly generated equations. As expected, the micellar partition coefficient and solubilization power for ionized flavopiridol are both less than those of the un-ionized species. However, at acidic pH, the solubilities of the ionized drug in surfactant micelles [D(i)M] and in cosolvent-water [D(i)/(c)] are both much greater than that of the un-ionized drug. This difference is because the solubilization of the ionized drug is proportional to its aqueous solubility, and its solubility [D(i)] can be as much as 24-fold greater than that of the free un-ionized species [D(u)].
• Ping, L. i., Zhao, L., & Yalkowsky, S. H. (1999). Combined effect of cosolvent and cyclodextrin on solubilization of nonpolar drugs. Journal of Pharmaceutical Sciences, 88(11), 1107-1111.
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  PMID: 10564056;Abstract: Solubility enhancement has broad implications in parenteral formulation design. A simple mathematical model has been developed to describe the combined effect of cosolvency and complexation on nonpolar drug solubilization. The total drug solubility is determined by the summation of three drug species present in the solution: free drug [D], drug-ligand binary complex [DL], and drug-ligand-cosolvent ternary complex [DLC]. The proposed model established the dependencies of these three species upon the intrinsic drug solubility, [D(u)], the cosolvent solubilizing power, σ, the binary and ternary intrinsic complexation constants, K(b)(int) and K(t)(int), and the cosolvent destabilizing powers for the binary and the ternary complexes, ρ(b) and ρ(t). A nonpolar solute, Fluasterone, is used to evaluate the newly generated equation. The model explains the decline in drug solubility produced by low cosolvent concentrations as well as the increase in the solubility produced by high cosolvent concentrations that are observed at all cyclodextrin concentrations.
• Pinsuwan, S., Alvarez-Núñez, F. A., Tabibi, E. S., & Yalkowsky, S. H. (1999). Degradation kinetics of 4-dedimethylamino sancycline, a new anti-tumor agent, in aqueous solutions. International Journal of Pharmaceutics, 181(1), 31-40.
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  PMID: 10370200;Abstract: The kinetics of degradation of the new anti-tumor drug, 4-dedimethylamino sancycline (col-3) in aqueous solution at 25(o)C were investigated by high-pressure liquid chromatography (HPLC) over the pH-range of 2-10. The influences of pH, buffer concentration, light, temperature, and some additives on the degradation rate were studied. The degradation of col-3 was found to follow first order kinetics. A rate expression covering the degradation of the various ionic forms of the drug was derived and shown to account for the shape of the experimental pH-rate profile. Under basic conditions, the degradation of col-3 involves oxidation, which is catalyzed by metal ions and inhibited by EDTA and Sodium bisulfite. Copyright (C) 1999 Elsevier Science B.V.
• Pinsuwan, S., Alvarez-Núñez, F. A., Tabibi, S. E., & Yalkowsky, S. H. (1999). Spectrophotometric determination of acidity constants of 4- dedimethylamino sancycline (Col-3), a new antitumor drug. Journal of Pharmaceutical Sciences, 88(5), 535-537.
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  PMID: 10229645;Abstract: A spectrophotometric technique was used to determine the acidity constants of 4-dedimethylamino sancycline (Col-3), a new antitumor drug. The apparent pK(a) values of Col-3 in 0.5% methanol aqueous media at approximately 25 °C with a constant ionic strength of 0.2 were calculated manually and graphically to be 5.64 ± 0.17 (pK(a1)) and 8.35 ± 0.07 (pK(a2)). In addition, the computer program SQUAD was used to confirm Col-3 pK(a) values. The pK(a) values obtained by SQUAD were pK(a1) 5.63 ± 0.14 and pK(a2) 8.39 ± 0.04. These results are in agreement with the tetracycline- like structure of Col-3.
• Tesconi, M. S., Bramer, S. L., & Yalkowsky, S. H. (1999). The preparation of soft gelatin capsules for a radioactive tracer study. Pharmaceutical Development and Technology, 4(4), 507-513.
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  PMID: 10578504;Abstract: Clinical doses are developed for the oral coadministration of radiolabeled and nonlabeled forms of a poorly soluble investigational compound: OPC-41061. The release rates of the labeled and nonlabeled forms are equated and matched to the release rate of the polymer spray-dried form of the drug in the proposed market product. The study involves the physicochemical characterization of the powders using thermal analysis and dissolution testing, development and extemporaneous manufacture of liquid- filled soft gelatin capsules, and dissolution and stability testing of the final dosage form. Thermal analysis indicated that the labeled powder was amorphous and that the nonlabeled powder, which had been jet-milled, was crystalline. Dissolution testing of the jet-milled and spray-dried powders indicated that the former was released at a significantly slower rate. A liquid formulation containing 25% dimethyl acetamide and 75% polyethylene glycol 400 (PEG 400) solubilized the desired dose of 60 mg and exhibited a drug profile that was similar to the spray-dried formulation. The final formulation was a soft gelatin capsule containing 60 mg of drug, including 100 μCi radioactivity, dissolved in 0.8 ml of a 25% dimethyl acetamide/75% PEG 400 solution. The formulation was chemically and physically stable for a period greater than the duration of the study.
• Tesconi, M. S., Morris, R. H., & Yalkowsky, S. H. (1999). A practical method for the estimation of ambient vaporization rates of compounds. Chemosphere, 38(13), 3193-3209.
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  Abstract: A practical method for the estimation of ambient vaporization rates of a diverse set of organic compounds is presented. The method utilizes thermogravimetric analysis (TGA) to measure the vaporization rates of solids and liquids at elevated temperatures and reduced pressures. The rates are correlated with functions of temperature and pressure using multiple linear regression. The empirical equation generated for each compound is used to estimate its vaporization rate at ambient temperature and pressure. Good agreement was found between predicted and measured values. Samples (with vapor pressures that range between 10-5 Pa and 101 Pa) are exposed to both stagnant air and to a 60 cm/sec (1.3 mph) air flow in order to determine the usefulness of the method when vaporization is influenced by convective air flow. The 60 cm/sec air flow produced a similar increase in the vaporization rates of all of the compounds, indicating that a simple proportionality constant can be employed to adjust estimated evaporation rates for air flow velocity.
• Tesconi, M. S., Sepassi, K., & Yalkowsky, S. H. (1999). Freeze-drying above room temperature. Journal of Pharmaceutical Sciences, 88(5), 501-506.
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  PMID: 10229639;Abstract: This study investigates the use of solid, organic compounds to lyophilize drugs without conventional freeze-drying equipment. The aim of the investigation is to find a pharmaceutically acceptable solvent or solvent combination that is appropriate for freeze-drying on the basis of its ability to (1) solubilize hydrophobic drugs, (2) provide a stable environment for water-sensitive compounds, (3) be rapidly and completely removed from the product under vacuum, and (4) produce cakes that are readily reconstituted. A eutectic formed from 1,1,1-trichloro-2-methyl-2-propanol (chlorobutanol) hemihydrate and dimethyl sulfone (DMSO2) is determined to be a suitable medium.
• Zhao, L., & Yalkowsky, S. H. (1999). A combined group contribution and molecular geometry approach for predicting melting points of aliphatic compounds. Industrial and Engineering Chemistry Research, 38(9), 3581-3584.
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  Abstract: A combined approach that utilizes both group contribution and simple molecular geometric parameters is employed to predict normal melting points for a variety of aliphatic compounds. The melting points are estimated from the ratio of the enthalpy and the entropy of melting. The former is calculated from the sum of enthalpic group contributions and correction factors, whereas the latter is calculated using a modification of Walden's rule. Approximately 1040 melting point data were compiled and analyzed by multiple regression. The root-mean-square error of the estimation is 34.4 K. This is relatively low given the complexity of melting and the diversity of the database used. A comparison of the proposed method with the method of Joback and Reid8 was performed on 50 aliphatic compounds that were not used in the training set. The average absolute error for this method is approximately 20%, whereas that for the Joback and Reid data is 34%. The higher prediction accuracy of the proposed method suggests that the melting point prediction can better be approached by using both group contribution (enthalpic) and simple molecular geometric parameters (entropic).
• Zhao, L., Na, N. i., & Yalkowsky, S. H. (1999). A modification of Trouton's rule by simple molecular parameters for hydrocarbon compounds. Industrial and Engineering Chemistry Research, 38(1), 324-327.
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  Abstract: The entropy of vaporization at the normal boiling point (ΔS(b)) is an important property in the chemical engineering and environmental sciences. This paper presents a simple modification of Trouton's rule to estimate this property for a variety of hydrocarbon compounds including alkanes, alkenes, alkynes, dienes, cycloalkanes, and alkyl aromatics. The equation contains three easy-to-determine parameters that describe important molecular features: flexibility, symmetry, and planarity. The entropy data were calculated from experimental enthalpy data of 477 different organic compounds at the normal boiling point. The average percentage error for the prediction is 1.30 by the proposed method, 2.79 by Trouton's rule, 1.62 by Kistiakowsky's method, 1.51 by Vetere's method, and 2.23 by the group contribution method of Ma and Zhao.
• Zhao, L., Ping, L. i., & Yalkowsky, S. H. (1999). Predicting the Entropy of Boiling for Organic Compounds. Journal of Chemical Information and Computer Sciences, 39(6), 1112-1116.
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  Abstract: This study aims to predict the entropy of boiling (ΔSb) for organic compounds by considering parameters that are indicative of both molecular geometry and molecular association. The proposed method is a modification of Trouton's rule. It utilizes three geometric parameters, σ, τ, and ω, that address molecular symmetry, flexibility, and planarity, respectively, as well as a set of group contributors that focus on hydrogen-bonding and strong dipolar interactions. The molecular geometry parameters are unique in that they reflect the ordering of molecules in the liquid that cannot be described by group contribution. The database of 903 organic compounds covers a broad array of structural categories. The root mean square error for the prediction is 2.12 J/mol·K, which is very low given the diversity of the database. An independent entropy dataset of 31 compounds was used to show that the proposed method is more accurate than four published methods. The success of this approach illustrates the need for nonadditive structural parameters along with group additive parameters to characterize phase change entropy.
• Zhao, L., Ping, L. i., & Yalkowsky, S. H. (1999). Solubilization of fluasterone. Journal of Pharmaceutical Sciences, 88(10), 967-969.
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  PMID: 10514340;Abstract: Solubilization of nonpolar drugs constitutes one of the most important tasks in parenteral formulations design. This study investigates and assesses the solubility enhancement of Fluasterone by various techniques including cosolvency, micellization, and complexation. Of the solubilizing agents used, the modified β-cyclodextrins were found to be the most effective. The solubility of Fluasterone is 1.55 x 10-4 mM, 3.13 mM, and 4.04 mM in water, 20% sulfobutyl ether-β-cyclodextrin (SBEβCD), and 20% hydroxypropyl-β- cyclodextrin (HPβCD), respectively.
• Heimbecher, S., Lee, Y., Tabibi, S. E., & Yalkowsky, S. H. (1998). Mechanism of dansylation of the polyamine pentaazapentacosane ·5 HCl. International Journal of Pharmaceutics, 160(1), 21-29.
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  Abstract: Dansylation of the pentaamine pentaazapentacosane ·5 HCl (PAPC) produces only the perdansyl product. This occurs even under conditions of pH and dansyl chloride concentration most likely to produce partially dansylated products. This result is explained by a mechanism whereby only completely unionized amine molecules will dansylate. The proposed mechanism is supported by the dansylation versus pH profile of PAPC versus that of a reference monoamine (piperidine ·HCl). After 4 h at room temperature and pH 9.5, 100% of piperidine is dansylated while under the same conditions only 10% of PAPC is derivatized. A pH greater than 10.5 is required to completely dansylate PAPC. This difference is significantly greater than would be predicted from the pK(a) values but it is consistent with the proposed mechanism.
• Krzyzaniak, J. F., & Yalkowsky, S. H. (1998). Lysis of human red blood cells 3: Effect of contact time on surfactant- induced hemolysis. PDA Journal of Pharmaceutical Science and Technology, 52(2), 66-69.
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  PMID: 9610170;Abstract: The percent hemolysis induced by various surfactants was determined as a function of the formulation composition and formulation:blood contact time using the dynamic in vitro method of Krzyzaniak et al. (1). The amount of hemolysis induced by nonionic surfactant formulations is shown to be relatively low and to increase only slightly with contact time. However, when ionic surfactant formulations are used, hemolysis is shown to increase dramatically with surfactant concentration and to be sigmoidally related to the logarithm of contact time. Since surfactant-induced hemolysis is dependent on both the surfactant concentration and the contact time, intravascular hemolysis must be evaluated using an in vitro method that simulates the intravenous injection site. With this information, hemolytically safe surfactant formulations can be developed for intravenous administration.
• McCandless, R., & Yalkowsky, S. H. (1998). Effect of hydroxypropyl-β-cyclodextrin and pH on the solubility of levemopamil HCl. Journal of Pharmaceutical Sciences, 87(12), 1639-1642.
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  PMID: 10189280;Abstract: Levemopamil was solubilized by varying the concentration of hydroxypropyl-β-cyclodextrin (HPβCD) and by the alteration of pH. The drug molecule has two sites for possible complexation with HPβCD, creating the possibility of either 1:1 or 1:2 complexation. The solubility as a function of HPβCD concentration of the charged and uncharged forms of the drug follows the A(L) and A(P) complexation models, respectively. This suggests that the charged drug forms a 1:1 complex, whereas the neutral drug forms both 1:1 and 1:2 complexes.
• Núñez, F. A., & Yalkowsky, S. H. (1998). Solubilization of diazepam. PDA Journal of Pharmaceutical Science and Technology, 52(1), 33-36.
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  PMID: 9580239;Abstract: Several attempts to increase diazepam solubility are in the literature. This study discusses these different solubilization approaches. Specific reference is given to the rationale in the application of pH control, cosolvency, surfactants, and cyclodextrins. It was found than cosolvency is a more attractive means of solubilizing diazepam than either pH control, surfactants, or cyclodextrins. Advantages, assumptions, and limitations of these diazepam solubilization techniques are also described.
• Ping, L. i., Vishnuvajjala, R., Tabibi, S. E., & Yalkowsky, S. H. (1998). Evaluation of in vitro precipitation methods. Journal of Pharmaceutical Sciences, 87(2), 196-199.
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  PMID: 9519153;Abstract: Four in vitro precipitation methods were tested and evaluated using flavopiridol and diazepam formulations. The methods include static serial dilution, dynamic injection, and dropwise addition with and without stirring. The results generated from these methods are comparable and complementary. The static serial dilution method is most effective in quantifying the amount of precipitation and more descriptive of the formation and redissolution of the precipitate than the others. The dynamic injection method, however, has its merit in more realistically simulating the physiological environment of drug-blood interaction near the injection sites.
• Simamora, P., Dannenfelser, R., Tabibi, S. E., & Yalkowsky, S. H. (1998). Emulsion formulations for intravenous administration of paclitaxel. PDA Journal of Pharmaceutical Science and Technology, 52(4), 170-172.
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  PMID: 9752712;
• Simamora, P., Nadkarni, S. R., Lee, Y. -., & Yalkowsky, S. H. (1998). Controlled delivery of pilocarpine. 2. In-vivo evaluation of Gelfoam® device. International Journal of Pharmaceutics, 170(2), 209-214.
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  Abstract: In this report, an ocular device for the controlled delivery of pilocarpine was evaluated in albino rabbits using miosis as a bioassay for efficacy. The device was fabricated using Gelfoam® (absorbable gelatin sponge, USP) in the form of a matrix system. The efficacy of the device was compared in a cross-over study to the two conventional ophthalmic pilocarpine dosage forms, the eyedrop and the gel. The in-vivo results show that the gelfoam device is more effective than the two conventional pilocarpine dosage forms in prolonging the duration of the pilocarpine activity. Copyright (C) 1998 Elsevier Science B.V.
• Yalkowsky, S. H., Krzyzaniak, J. F., & Ward, G. H. (1998). Formulation-related problems associated with intravenous drug delivery. Journal of Pharmaceutical Sciences, 87(7), 787-796.
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  PMID: 9649344;
• Heimbecher, S., Lee, Y., Tabibi, S. E., & Yalkowsky, S. H. (1997). Derivatization and high-performance liquid chromatographic analysis of pentaazapentacosane pentahydrochloride. Journal of Chromatography B: Biomedical Applications, 691(1), 173-178.
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  PMID: 9140771;Abstract: A rapid high-performance liquid chromatographic method for determination of the dansyl derivative of pentaazapentacosane (PAPC) pentahydrochloride has been developed. The chromatographic system uses a reversed-phase C8 column, a mobile phase of acetic acid buffer and acetonitrile and UV detection. The dansylation conditions were optimized with a pH of 11.0 and a 20-fold dansyl chloride excess. The yield of dansyl PAPC increased 10-fold as the reaction pH was changed from 9.5 to 10.5. Under derivatization conditions of pH 8.5-11.0 and 1-30-fold excess dansyl chloride only perdansyl PAPC was found.
• Krzyzaniak, J. F., A., F., Raymond, D. M., & Yalkowsky, S. H. (1997). Lysis of human red blood cells. 4. Comparison of in vitro and in vivo hemolysis data. Journal of Pharmaceutical Sciences, 86(11), 1215-1217.
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  PMID: 9383728;Abstract: The dynamic in vitro method developed by the authors and other available in vitro methods were used to determine the degree of hemolysis induced by several cosolvent vehicles that have previously been evaluated in vivo. The in vitro data generated for each of these vehicles was compared with the in vivo hemolysis data to assess the ability of the method to estimate in vivo hemolysis. The results show that the in vitro data generated by the dynamic method are in agreement with the in vivo data for each vehicle. Therefore, the potential for formulations to induce intravascular hemolysis after injection can be determined by this dynamic in vitro method with this information hemolytically safe formulations can more easily be prepared.
• Krzyzaniak, J. F., Raymond, D. M., & Yalkowsky, S. H. (1997). Lysis of human red blood cells 2: Effect of contact time on cosolvent induced hemolysis. International Journal of Pharmaceutics, 152(2), 193-200.
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  Abstract: The degree of hemolysis induced by several cosolvent formulations is evaluated at various contact times using the dynamic in vitro method developed by Krzyzaniak (Krzyzanik, J.F., Raymond, D.M. and Yalkowsky, S.H., Lysis of Human Red Blood Cells 1: Effect of Contact Time on Water Induced Hemolysis, PDA J. Pharm. Sci. and Tech., 50 (1996) 223-226). Hemolysis is shown to increase with cosolvent concentration and to be sigmoidally related to the logarithm of the formulation:blood contact time. With this information, a physiologically realistic in vitro method with a formulation:blood ratio of 0.1 and a contact time of 1 s has been developed and used to estimate the amount of hemolysis occurring after an intravenous injection of some commonly used cosolvent formulations.
• Lee, Y., Pinsuwan, S., & Yalkowsky, S. H. (1997). A comparison of AQUAFAC group q-values to their corresponding CLOGP f-values. Chemosphere, 35(4), 775-782.
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  Abstract: Previous studies have shown that AQUAFAC is more accurate than the general solubility equation for the estimation of aqueous solubility. The relationship between AQUAFAC group q-values and their corresponding CLOGP f-values is investigated in this study. The q- and f-values are comparable in magnitude for hydrocarbon and halocarbon groups but not for hydrogen bonding groups.
• Lee, Y., Simamora, P., & Yalkowsky, S. H. (1997). Effect of Brij-78 on systemic delivery of insulin from an ocular device. Journal of Pharmaceutical Sciences, 86(4), 430-433.
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  PMID: 9109043;Abstract: An ocular insert is developed for the controlled systemic delivery of insulin. Commercially available Gelfoam absorbable gelatin sponge, USP, is used in the fabrication of the ocular insert in the form of a matrix system. Two eyedrop formulations and 13 eye device formulations were evaluated. The efficacy of insulin ocular delivery was quantitated by monitoring the changes in its pharmacological response (i.e., blood glucose lowering). The in vivo results from devices containing 0.5 or 1.0 mg of insulin with 20 μg of p.- 2. ether (Brij-78) give a substantial improvement in insulin activity and a significant prolongation in its duration compared with the eyedrops. In addition, the mean blood glucose concentration returns to nearly normal levels within 60 rain after the removal of the device. Overall, the application of the Gelfoam device makes it feasible to obtain a prolonged systemic delivery of insulin within the desired therapeutic levels without the risk of hypoglycemia.
• Lee, Y., Simamora, P., & Yalkowsky, S. H. (1997). Systemic delivery of insulin via an enhancer-free ocular device. Journal of Pharmaceutical Sciences, 86(12), 1361-1364.
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  PMID: 9423146;Abstract: Sodium insulin and zinc insulin ocular devices are developed for the systemic delivery of insulin. The devices consist of Gelfoam (absorbable gelatin sponge, USP) as an insulin carrier and do not contain any surfactant or absorption enhancer. Sodium insulin was dissolved in either distilled water, 30% ethanol, or 10% acetic acid for either eyedrop or device preparations. Because of its low solubility in water and aqueous ethanol solution, zinc insulin was dissolved in 10% acetic acid-water solution for eye devices preparation. Commercially availabile Humulin R was selected as another source of zinc insulin and was used as an eyedrop as well as one device preparation. Only 10% acetic acid solution-treated insulin devices produce significant blood glucose reduction. The dose of insulin used in this study is
• Nunez, F. A., & Yalkowsky, S. H. (1997). Correlation between log P and ClogP for some steroids. Journal of Pharmaceutical Sciences, 86(10), 1187-1189.
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  PMID: 9344178;
• Núñez, F. A., & Yalkowsky, S. H. (1997). Foaming activity and pK(a) of some surface active compounds. International Journal of Pharmaceutics, 151(2), 193-199.
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  Abstract: A novel method to determine the pK(a) of surface active compounds is presented. Since the ionized and unionized forms of amphiphiles have distinct surface and foaming properties, foamability as a function of pH can be used to obtain an approximate pK(a). Since foam is easily produced and measured, this method requires no specialized equipment. The foamability-pH profile is sigmoidal for both weak acids and bases, and a change of the foam activity is consistently observed in the region of their pK(a). The above relationship is confirmed using the following surface active compounds: amitriptyline, cyclohexylamine, dexverapamil, 3,5-diiodothyropropionic acid (DITPA), diphenhydramine, heptanoic acid, n-heptylamine, ibuprofen, laurylcarnitine, naphthoic acid, oleic acid and phenytoin.
• Tesconi, M., Pikal, M. J., & Yalkowsky, S. H. (1997). A method for the rapid estimation of sublimation rates of organic compounds at standard temperature and pressure. Journal of Pharmaceutical Sciences, 86(11), 1299-1302.
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  PMID: 9383744;Abstract: A method for the rapid estimation of the sublimation rates of organic compounds at standard temperature and pressure (STP; 298 K and 101.3 kPa, respectively) is presented. Thermogravimetric analysis was used to obtain accelerated sublimation rates for anthracene at a series of elevated temperatures and reduced pressures. An empirical equation relating these parameters was used to extrapolate to the STP sublimation rate. This value is in good agreement with the measured value.
• An, L. i., Andren, A. W., & Yalkowsky, S. H. (1996). Choosing a cosolvent: Solubilization of naphthalene and cosolvent property. Environmental Toxicology and Chemistry, 15(12), 2233-2239.
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  Abstract: The addition of an organic cosolvent to water can increase the aqueous solubility of many hydrophobic organic compounds (HOCs). This work examines the correlations between the change of naphthalene solubility and various physicochemical properties of the cosolvent added to the system. Results show that the dielectric constant and surface tension do not correlate with the solubilization power of cosolvent toward naphthalene. The solubility parameter correlates well with increases in naphthalene solubility and therefore provides a convenient tool when screening cosolvents for their ability to enhance HOC solubility in various environmental engineering applications. Other properties investigated include the octanol/water partition coefficient, interfacial tension, E(T)(30), viscosity, and hydrogen bonding capacities.
• Dannenfelser, R., & Yalkowsky, S. H. (1996). Estimation of Entropy of Melting from Molecular Structure: A Non-Group Contribution Method. Industrial and Engineering Chemistry Research, 35(4), 1483-1486.
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  Abstract: The total entropy of melting for a variety of compounds is estimated by a modification of Walden's rule. This modification accounts for the effects of both molecular rotational symmetry and molecular flexibility upon entropy. The simple semiempirical equation gives an average error of 12.5 J/K·mol when applied to more than 930 different compounds.
• Dannenfelser, R., Surakitbanharn, Y., Tabibi, S. E., & Yalkowsky, S. H. (1996). Parenteral formulation of flavopiridol (NSC-649890). PDA Journal of Pharmaceutical Science and Technology, 50(6), 356-359.
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  PMID: 9038080;Abstract: Flavopiridol [5,7-dihydroxy-8-(4-N-methyl-2-hydroxypyridyl)-6'- chloroflavone hydrochloride] is a flavonoid with weak electrolyte properties and an intrinsic aqueous solubility of 0.024 mg/mL. Neither consolvency, complexation, nor pH control alone can produce an acceptable 10 mg/mL formulation that will not precipitate when diluted with blood. However, a combination of buffer and cyclodextrin or buffer and cosolvent can produce an acceptable 10 mg/mL formulation. In this paper, Flavopiridol is shown to be stable for at least one year in 30% hydroxypropyl β-cyclodextrin/0.1 M citrate buffer (4.52). This formulation does not precipitate for at least one hour upon dilution with Sorensen's phosphate buffer pH 7.4.
• Krzyzaniak, J. F., Raymond, D. M., & Yalkowsky, S. H. (1996). Lysis of human red blood cells 1: Effect of contact time on water induced hemolysis. PDA Journal of Pharmaceutical Science and Technology, 50(4), 223-226.
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  PMID: 8810837;Abstract: A dynamic in vitro method for the determination of the degree of hemolysis induced by parenteral formulations is presented. This method utilizes a dual syringe pump apparatus that enables the mixing of a formulation with blood in various ratios and for various contact times. Formulations with varying tonicity were used to test the method. Hemolysis is shown to be directly related to both the hypotonicity of the test solution and the contact time. The proposed method makes it possible to evaluate the hemolytic effects of parenteral formulations at physiologically realistic contact times and formulation:blood ratios.
• Simamora, P., Lee, Y. -., & Yalkowsky, S. H. (1996). Ocular device for the controlled systemic delivery of insulin. Journal of Pharmaceutical Sciences, 85(10), 1128-1130.
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  PMID: 8897284;
• Simamora, P., Pinsuwan, S., Surakitbanharn, Y., & Yalkowsky, S. H. (1996). Studies in phlebitis VIII: Evaluations of pH solubilized intravenous dexverapamil formulations. PDA Journal of Pharmaceutical Science and Technology, 50(2), 123-128.
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  PMID: 8935779;Abstract: Injectable and infusion formulations of dexverapamil are evaluated for their potential to produce phlebitis. The evaluation technique utilizes two independent in vitro methods and two in vivo methods to screen a pH solubilized drug for its potential to induce phlebitis due to precipitation at the injection site. One method is based upon a theoretical calculation that simulates the change of solubility upon dilution. Its predictions are confirmed by the second method which consists of an in vitro precipitation experiment. Thermal and visual evaluations are then obtained from an in vivo rabbit ear injection. Dexverapamil formulations that have low buffering capacity are shown to contribute to the incidence of phlebitis to a greater extent than the properly buffered formulations. The calculation and the in vitro precipitation experiment are found to be useful in formulating pH solubilized parenterals. They enable the formulator to optimize pH, drug concentration, and buffer concentration without the need for animal studies. The results of this study show the importance of selecting a buffer that provides adequate buffer capacity in the formulations.
• Walters, W. P., & Yalkowsky, S. H. (1996). ESCHER - A computer program for the determination of external rotational symmetry numbers from molecular topology. Journal of Chemical Information and Computer Sciences, 36(5), 1015-1017.
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  Abstract: An algorithm for determining the external rotational symmetry number of a molecule from a SMILES1 string has been developed. ESCHER operates by first locating the center or centers of graphical symmetry for the molecule and the equivalence classes of atoms connected to the center or centers. The center(s) of graphical symmetry is the atom(s) which is(are) most symmetrical with respect to the connections to other atoms. These are then used to calculate the symmetry number, σ.
• An, L. i., Pinsuwan, S., & Yalkowsky, S. H. (1995). Estimation of solubility of organic compounds in 1-octanol. Industrial and Engineering Chemistry Research, 34(3), 915-920.
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  Abstract: Five methods were evaluated for their ability to estimate the solubility of organic compounds in 1-octanol. OCTASOL is a modified group contribution method developed in this study. Another proposed method uses the product of octanol-water partition coefficient (Kow) and water solubility (Sw) as the approximate of octanol solubility. The average absolute error of the estimate obtained from using OCTASOL is 0.25 log units for the training set (N = 180), and 0.29 log units for a test set (N = 10). When the KowSw method is used, the error is 0.29 log units (N = 124). Three other approaches (ideal solubility, regular solution theory, and UNIFAC) are also evaluated. Their average absolute errors are 0.85 (N = 209), 0.58 (N = 174), and 0.31 (N = 131) log units, respectively.
• Pinsuwan, S., An, L. i., & Yalkowsky, S. H. (1995). Correlation of octanol/water solubility ratios and partition coefficients. Journal of Chemical and Engineering Data, 40(3), 623-626.
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  Abstract: The octanol/water solubility ratio (So/Sw) was found to be highly correlated with the octanol/water partition coefficient (Kow) of 82 pharmaceutically and environmentally relevant compounds. The solubility ratio gives comparable estimates to that of the group contribution (log P(calcd)) method for estimating the partition coefficient of the compounds used in this study. © 1995 American Chemical Society.
• Surakitbanharn, Y., McCandless, R., Krzyzaniak, J. F., -, R. D., & Yalkowsky, S. H. (1995). Self-association of dexverapamil in aqueous solution. Journal of Pharmaceutical Sciences, 84(6), 720-723.
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  PMID: 7562411;Abstract: The pK(a) and intrinsic solubility of monomeric dexverapamil were determined from its pH-solubility profile to be 8.90 and 6.6 x 10-5 M, respectively. The solubility of dexverapamil below pH 7.0 was higher than expected on the basis of the aforementioned values. This unusually high solubility is believed to be due to the self-association of cationic dexverapamil. The apparent pK(a) of the self-associated drug is estimated to be ~7.99. The self-association of dexverapamil hydrochloride is supported by the fact that it is surface active and that it increases the solubility of both naphthalene and anthracene in aqueous solutions. The dependence of the drug solubility on pH and the solubilization of naphthalene and anthracene as a function of ionized drug concentration suggest that the self-associated dexverapamil is a cationic dimer.
• Li, A., & Yalkowsky, S. H. (1994). Solubility of organic solutes in ethanol/water mixtures. Journal of Pharmaceutical Sciences, 83(12), 1735-1740.
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  PMID: 7891303;Abstract: The log-linear solubilization model was applied to the experimental solubility data of 109 organic compounds in ethanol/water mixtures. It is found that the extent of solubilization strongly depends on the solute hydrophobicity and the ethanol concentration in the solvent mixture. Patterns of deviation from the log-linear model are related to the structure and hydrophobicity of the solutes. Predictive equations were obtained by regression of the experimental data with solute octanol/water partition coefficient (log K(ow)). The logarithms of the solubilization and the solute log K(ow) range over 11 orders of magnitude. The solubilities of chrysene, perylene, benzo[a]pyrene, pentachlorobenzene, and hexachlorobenzene in ethanol/water mixtures were experimentally determined, and the results fit well into the model.
• Simamora, P., & Yalkowsky, S. H. (1994). Group contribution methods for predicting the melting points and boiling points of aromatic compounds. Industrial & Engineering Chemistry Research, 33(5), 1405-1409.
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  Abstract: Simple methods are proposed to estimate the boiling points and the melting points of aromatic compounds from chemical structure. The transition temperatures are determined by the estimation of both the enthalpy and the entropy of transition. The enthalpies of boiling and melting are both estimated as additive constitutive properties. The entropy of boiling is assumed to be constant as described by Trouton's rule, while the entropy of melting is estimated using a modification of Walden's rule. The latter utilizes the nonadditive nonconstitutive molecular property, rotational symmetry. © 1994 American Chemical Society.
• Surakitbanharn, Y., Simamora, P., Ward, G. H., & Yalkowsky, S. H. (1994). Precipitation of pH solubilized phenytoin. International Journal of Pharmaceutics, 109(1), 27-33.
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  Abstract: Precipitation of phenytoin often occurs as it is diluted by blood after intravenous injection. The presence and the amount of precipitate depend upon the initial pH and buffer capacity of the formulation vehicle. The prediction of phenytoin precipitation can be carried out in vitro using isotonic Sorensen's phosphate buffer (SPB) to simulate blood. An equation is developed to calculate the change in solubility resulting from the change in pH due to dilution. This equation is very difficult to solve analytically because it involves a high order polynomial. However, it can be solved numerically using a spreadsheet program. The relationship between pH or solubility and dilution can then be presented graphically. Therefore, the precipitation of any pH solubilized drug due to dilution under various conditions can be easily predicted. This is illustrated for several aqueous phenytoin solutions. © 1994.
• Nadkarni, S. R., & Yalkowsky, S. H. (1993). Controlled delivery of pilocarpine. 1. In vitro characterization of Gelfoam® matrices. Pharmaceutical Research, 10(1), 109-112.
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  PMID: 8430046;Abstract: The potential of Gelfoam absorbable gelatin sponge as a carrier for ophthalmic delivery of pilocarpine was examined. Prolonged in vitro release of pilocarpine was achieved through pharmaceutical modification of the device by embedding a retardant in the pores. The device embedded with cetyl ester wax released pilocarpine in a zero-order pattern (release exponent = 0.93 ± 0.04) for up to 5 hr. This result corresponded well with a linear penetrant uptake by this device. The device impregnated with polyethylene glycol 400 monostearate exhibited anomalous drug transport with a release exponent of 0.63 ± 0.02. The absorption of water by this retardant and the formation of a gel layer on the surface slowed the penetration of the release medium into the deeper sections of the matrix, as well as the rapid outward diffusion of drug, resulting in a prolonged release of pilocarpine.
• Simamora, P., Miller, A. H., & Yalkowsky, S. H. (1993). Melting point and normal boiling point correlations: Applications to rigid aromatic compounds. Journal of Chemical Information and Computer Sciences, 33(3), 437-440.
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  Abstract: Simple group contribution approaches have been developed to estimate the boiling point and melting point of rigid organic molecules based on their chemical structures. The boiling point estimation requires only additive constitutive properties, whereas melting point prediction employs additive constitutive properties and symmetry. The effects of intramolecular hydrogen bonding and the presence of ortho substituents in biphenyls on the boiling and melting temperatures are discussed. © 1993 American Chemical Society.
• Ward, G. H., & Yalkowsky, S. H. (1993). Studies in phlebitis IV: Injection rate and amiodarone-induced phlebitis. Journal of Parenteral Science and Technology, 47(1), 40-43.
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  PMID: 8445500;Abstract: Using a rabbit ear model and techniques developed previously (1) the relationship between injection rate and injection phlebitis is investigated for amiodarone HCl and its vehicle. A number of injection rates ranging from 0.02 to 3.0 ml/min are studied using this model. Thermal measurements and visual evaluations are used for phlebitis quantitation. The severity of phlebitis is found to be dependent upon the injection rate for amiodarone HCl while the vehicle did not produce phlebitis at any rate. Strong correlations between the thermal measurements and visual evaluations are found for both amiodarone HCl and its vehicle.
• Ward, G. H., & Yalkowsky, S. H. (1993). Studies in phlebitis V: Hemolysis as a model for phlebitis. Journal of Parenteral Science and Technology, 47(1), 44-46.
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  PMID: 8445501;
• Ward, G. H., & Yalkowsky, S. H. (1993). Studies in phlebitis VI: Dilution-induced precipitation of amiodarone HCL. Journal of Parenteral Science and Technology, 47(4), 161-165.
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  PMID: 8410561;
• Yalkowsky, S. H. (1993). A two-dimensional model for water. Journal of Chemical Education, 70(8), 614-615.
• Yalkowsky, S. H. (1993). Estimation of the aqueous solubility of complex organic compounds. Chemosphere, 26(7), 1239-1261.
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  Abstract: The aqueous solubility of organic compounds depends on two contributing parameters: the ideal solubility and the activity coefficient. The methods available for the prediction of aqueous solubility have the ideal solubility term in common. They differ in the way they account for the activity coefficient. Various empirical and theoretical methods for predicting activity coefficients are compared in this report. The methods were first used with a Training Set of solutes. The same methods were then applied to a Test Set of solutes, which consisted of a series of compounds of pharmaceutical and environmental relevance. The Test Set encompassed a wide variety of chemical structures and high degree of structural complexity. Only those methods with a sound theoretical rationale are useful for both the Training and Test sets. A comparative evaluation of the methods tested was made through the quantification of the accuracy of their predictions and their range of applicability. © 1993.
• Yalkowsky, S. H., Davis, E., & Clark, T. (1993). Stabilization of aspartame by polyethylene glycol 400. Journal of Pharmaceutical Sciences, 82(9), 978-.
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  PMID: 8229702;
• Mishra, D. S., & Yalkowsky, S. H. (1992). Ideal solubility of a solid solute: Effect of heat capacity assumptions. Pharmaceutical Research, 9(7), 958-959.
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  PMID: 1438014;
• Ward, G. H., & Yalkowsky, S. H. (1992). The role of the effective concentration in interpreting hemolysis data. Journal of Parenteral Science and Technology, 46(5), 161-162.
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  PMID: 1432454;Abstract: Problems inherent in traditional methods of determining the hemolytic activity of parenteral compounds are discussed. Data taken from a study which closely models the conditions present for an intravenous injection are re- examined. An equation is given which combines several variables into a single parameter, the effective concentration. A strong relationship is found between the effective concentration of the compound of interest and the hemolysis produced.
• Yalkowsky, S. H., & Patel, S. D. (1992). Acceleration of heat transfer in vial freeze-drying of pharmaceuticals. II. A fluid cushion device. Pharmaceutical Research, 9(6), 753-758.
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  PMID: 1409357;Abstract: A simple device for the improvement of freeze-drying efficiency is described. The device is an aluminum foil bag which contains a small amount of glycerin. The device can be either reusable or disposable. When placed on a freeze-drying tray the liquid is about 1 mm thick. When vials are placed on the device it conforms to the shape of the vial bottoms. Since both the aluminum foil and the glycerin are better heat conductors than a vacuum, the device improves heat transfer from the shelf to the vial. Drying times obtained with and without the device are compared for different sizes as well as different types of vials. In most cases the use of the device reduces the drying time by nearly a factor of two. The use of the device also increases vial-to-vial uniformity and mimimizes the effect of spillage.
• Caldwell, H. C., & Yalkowsky, S. H. (1991). Letters to the editor. Pharmaceutical Research, 8(3), 419-.
• Dannenfelser, R. M., Paric, M., White, M., & Yalkowsky, S. H. (1991). A compliation of some physico-chemical properties for chlorobenzenes. Chemosphere, 23(2), 141-165.
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  Abstract: A compilation of some physico-chemical properties for chlorobenzenes are given. The literature values for the solution properties have been evaluated and whenever possible average values are given. © 1991.
• Egermann, H., Bolton, S., & Yalkowsky, S. (1991). Comments on 'particle size and content uniformity,' by Yalkowsky and Bolton. Pharmaceutical Research, 8(8), 1076-.
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  PMID: 1924165;
• Hardaway, L. A., & Yalkowsky, S. H. (1991). Cosolvent effects on diuron solubility. Journal of Pharmaceutical Sciences, 80(2), 197-198.
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  PMID: 2051330;
• Mishra, D. S., & Yalkowsky, S. H. (1991). Estimation of vapor pressure of some organic compounds. Industrial and Engineering Chemistry Research, 30(7), 1609-1612.
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  Abstract: An accurate and thermodynamically sound equation for the estimation of vapor pressure of organic solids and liquids is developed. This equation utilizes improved estimation schemes for the entropies of vaporization and melting over Trouton's rule and Walden's rule. It also utilizes improved estimations of the heat capacity changes associated with vaporization and melting. The equation, which has no adjustable parameters, is shown to successfully estimate the vapor pressures of a large number of organic compounds.
• Ward, G. H., Nolan Jr., P. E., Chawla, M., & Yalkowsky, S. H. (1991). Studies in phlebitis: Detection and quantitation using a thermographic camera. Pharmaceutical Research, 8(1), 76-79.
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  PMID: 2014211;Abstract: A new method for the detection of acute phlebitis in superficial veins is investigated. A thermographic camera is utilized for the quantitation of temperature changes in a rabbit ear model. A control group receiving no injection is compared against each of five treatment groups receiving these commercially available parenterals: amiodarone hydrochloride, phenytoin sodium, mechlorethamine hydrochloride, cephalothin sodium, and diazepam. The vehicles of the above-mentioned drugs as well as several commonly used organic cosolvents are also investigated. Local tissue responses to the parenteral challenges are measured and a good correlation between the visual and the thermographic data was seen.
• Ward, G. H., Nolan Jr., P. E., White, M., & Yalkowsky, S. H. (1991). Studies in phlebitis. II. Early detection of amiodarone-induced phlebitis in a rabbit model. Pharmaceutical Research, 8(6), 801-803.
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  PMID: 2062813;
• White, M., & Yalkowsky, S. H. (1991). Studies in phlebitis. III. Evaluation of diazepam and phenytoin. Pharmaceutical Research, 8(10), 1341-1342.
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  PMID: 1796055;
• Yalkowsky, S. H., & Mishra, D. S. (1991). Vapor pressure estimation for organic compounds. Science of the Total Environment, The, 109-110(C), 243-250.
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  Abstract: An accurate and thermodynamically sound equation for the estimation of the vapor pressure of organic solids and liquids is developed. This equation utilizes improved estimation schemes for the entropies of vaporization and melting over Trouton's rule and Walden's rule. It also utilizes improved estimations of the heat capacity changes associated with vaporization and melting. The equation, which has no adjustable parameters, is shown to estimate successfully the vapor pressures of a wide variety of organic compounds. © 1991.
• Abramowitz, R., & Yalkowsky, S. H. (1990). Estimation of aqueous solubility and melting point of PCB congeners. Chemosphere, 21(10-11), 1221-1229.
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  Abstract: A simple method has been developed to estimate the solubility of 208 PCB congeners based on estimating the melting point of the compound and the total surface area. © 1991.
• Abramowitz, R., & Yalkowsky, S. H. (1990). Melting point, boiling point, and symmetry. Pharmaceutical Research, 7(9), 942-947.
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  PMID: 2235894;
• Mishra, D. S., & Yalkowsky, S. H. (1990). A flat circular hole device for zero-order release of drugs: Characterization of the moving dissolution boundary. Pharmaceutical Research, 7(11), 1195-1197.
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  PMID: 2293221;
• Mishra, D. S., & Yalkowsky, S. H. (1990). Estimation of entropy of vaporization: Effect of chain length. Chemosphere, 21(1-2), 111-117.
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  Abstract: The entropy of vaporization of organic non-hydrogen bonding compounds can be estimated by using the following modifications of Trouton's rule: (1) for rigid molecules, ΔSv = 20 cal/deg·mole; (2) for long chain derivatives of such molecules, ΔSv = 20 + 0.16(n-5) cal/deg·mole, where n is the number of flexible links in the chain, and n > 5. These simple rules provide a good estimation for the entropy of vaporization which is sufficiently accurate to obtain reasonable estimations of vapor pressure. © 1990.
• Mishra, D. S., & Yalkowsky, S. H. (1990). Solubility of organic compounds in nonaqueous systems. Polycyclic aromatic hydrocarbons in benzene. Industrial and Engineering Chemistry Research, 29(11), 2278-2283.
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  Abstract: The present paper deals with the evaluation of some widely used models used to calculate activity coefficients and the assumption for the ideal solubility for some polycyclic aromatic hydrocarbons in benzene. The results show that, for ideal solubility, ΔCp ≈ 0 is a better approximation than ΔCp ≈ ΔSf. The values obtained for the entropic activity coefficients are similiar from both UNIFAC and Flory-Huggins theories. The residual activity coefficients calculated from Scatchard-Hilderbrand theories gives better predictions for the solubility of polycyclic aromatic hydrocarbons in benzene than does UNIFAC theory.
• Yalkowsky, S. H., & Bolton, S. (1990). Particle size and content uniformity. Pharmaceutical Research, 7(9), 962-966.
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  PMID: 2235898;
• Yalkowsky, S. H., & Mishra, D. S. (1990). Comment on "prediction of aqueous solubility of organic chemicals based on molecular structure. 2. Application to pnas, pcbs, pcdds, etc." [4]. Environmental Science and Technology, 24(6), 927-929.
• Yalkowsky, S. H., Mishra, D. S., & Morris, K. R. (1990). Dependence of vapor pressure of solids and liquids on various thermodynamic parameters. Chemosphere, 21(1-2), 107-110.
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  Abstract: An accurate and thermodynamically sound equation for the estimation of the vapor pressure of organic compounds and liquids is developed. The equation requires physicochemical parameters: entropies of melting and vaporization, heat capacity change on melting and vaporization, and melting and bonding temperatures. © 1990.
• Dannenfelser, R., & Yalkowsky, S. H. (1989). Database for aqueous solubility of nonelectrolytes. Computer Applications in the Biosciences, 5(3), 235-236.
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  PMID: 2766010;Abstract: The ARIZONA dATAbASE of Aqueous Solubility (Yalkowsky et al., 1987) was developed. At the present time, it is the largest and most comprehensive compilation of aqueous solubility available for unionised organic compounds.
• Neau, S. H., Flynn, G. L., & Yalkowsky, S. H. (1989). The influence of heat capacity assumptions on the estimation of solubility parameters from solubility data. International Journal of Pharmaceutics, 49(3), 223-229.
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  Abstract: Regular solution theory indicates that solubility parameters of crystalline organic compounds can be estimated from solubilities in London solvents. The equation for this purpose is: IN X2 - ΔHf RTf (Tf-T) T + ΔCp R (Tf - T) T - ln Tf T - V2θ21 RT (δ1 - δ2)2 where X2 is the mole fraction solubility of a compound in a solvent with a solubility parameter of δ1. With the exception of ΔCp, all parameters in the equation necessary to estimate the solute parameter, δ2, can either be suitably approximated or readily determined experimentally. In order to use the equation, simplifying assumptions have been made concerning ΔCp, namely: ΔCp = 0 or ΔCp = ΔSf, the entropy of fusion. In the present work, we have considered the extent to which these assumptions influence the magnitude of solubility parameters estimated from solubilities in n-hexane, n-heptane, n-dodecane, cyclohexane, carbon tetrachloride, toluene and benzene. Using n-alkyl p-aminobenzoates as test compounds, it is shown that solubility-based solubility parameters are relatively insensitive to the form of the equation used to calculate δ2. Specifically, solubility parameter estimations based on the two simplifying assumptions differ by no more than 0.2 (cal/ml) 1 2, an increment of the order of the presumed inherent error of estimation. © 1989.
• Patel, S. D., Gupta, B., & Yalkowsky, S. H. (1989). Acceleration of heat transfer in vial freeze-drying of pharmaceuticals. I: Corrugated aluminium quilt. Journal of Parenteral Science and Technology, 43(1), 8-14.
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  PMID: 2926606;Abstract: The medium offering the greatest resistance to heat transfer from the freeze-dryer shelf to the moving and subliming interface within the product is the space between the flat shelf top and the concave vial bottom. The resistance to heat transfer can be greatly reduced by improving the thermal conductivity of this intervening space. Several heat transfer augmentation devices, which fill this gap, are described. The devices are inexpensive and easy to use. Experimental data show that the resistance of the intervening space is reduced appreciably and the drying time is greatly reduced.
• Tarr, B. D., & Yalkowsky, S. H. (1989). Enhanced intestinal absorption of cyclosporin in rats through the reduction of emulsion droplet size. Pharmaceutical Research, 6(1), 40-43.
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  PMID: 2717516;
• Banerjee, S., & Yalkowsky, S. H. (1988). Cosolvent-induced solubilization of hydrophobic compounds into water. Analytical Chemistry, 60(19), 2153-2155.
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  Abstract: The solubilization of toluene into water by propylene glycol and methanol was measured by a novel liquid Chromatographic procedure. The relationship between solubilization and cosolvent content is linear up to 10-20 vol % of cosolvent, beyond which conventional logarithmic behavior is observed. The point of departure from linearity is believed to signal the onset of interaction between the extended hydration shells of the cosolvent. For propylene glycol, the volume of this shell is about 500 mL/mol, and the solubility of toluene within the shell is about 1.3 times its solubility in pure water. © 1988 American Chemical Society.
• Mishra, D. S., Patel, S. D., Marsh, D., & Yalkowsky, S. H. (1988). Low temperature solubility of antibiotics: oxacillin sodium.. Journal of Parenteral Science and Technology, 42(6), 177-180.
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  PMID: 3221277;
• Morris, K. R., Abramowitz, R., Pinal, R., Davis, P., & Yalkowsky, S. H. (1988). Solubility of aromatic pollutants in mixed solvents. Chemosphere, 17(2), 285-298.
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  Abstract: The solubility behavior of several aromatic and polynuclear aromatic pollutants was determined in a variety of water/cosolvent mixtures. The data was used to test a log-linear solubility model and develop a relationship for determining the slope of the log-linear solubility curve. © 1988.
• Pinal, R., & Yalkowsky, S. H. (1988). Solubility and partitioning IX: Solubility of hydantoins in water. Journal of Pharmaceutical Sciences, 77(6), 518-522.
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  PMID: 3171932;Abstract: An expression for estimating the aqueous solubility of weak electrolytes under different conditions of temperature and pH has been proposed in a previous publication. The expression, based on the additivity of free energy, separates solubility into three independent contributions. In the present work, the equation is tested with a different set of 18 solutes within the range of temperature of 20 to 50°C and of pH of 1 to 10. The results show that the theoretical relationship between aqueous solubility and the three independent contributions used in the equation is in excellent agreement with the experimental data.
• Yalkowsky, S. H., Pinal, R., & Banerjee, S. (1988). Water solubility: a critique of the solvatochromic approach.. Journal of Pharmaceutical Sciences, 77(1), 74-77.
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  PMID: 3346826;Abstract: The reasoning and some of the assumptions behind the solvatochromic approach to water solubility are evaluated, particularly in relation to its claims. It is shown that the contribution of the pi term is uncertain, and that it can be dropped from the correlation without substantially affecting the degree of fit. The solvatochromic method is compared with the long-standing relationship between solubility and the octanol-water partition coefficient, and it is demonstrated that the latter offers a far superior route to solubility estimation.
• Patel, S. D., & Yalkowsky, S. H. (1987). Development of an intravenous formulation for the antiviral drug 9-(β-D-arabinofuranosyl)-adenine. Journal of Parenteral Science and Technology, 41(1), 15-20.
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  PMID: 3559829;Abstract: An analytical procedure for the analysis of 9-(β-D-arabinofuranosyl)-adenine (ara-A) was developed and used to determine its solubility as well as stability. A reversed-phase high performance liquid chromatographic method was used to quantitate intact drug and to determine its degradation products in aqueous solutions. The solubility of ara-A was determined in different cosolvent-water mixtures as well as in different pH-buffers. The aqueous solubility of ara-A increased exponentially with a linear increase in the volume fraction of the cosolvent. Stability studies indicate that ara-A is relatively stable in dimethylsulfoxide, dimethylacetamide, and dimethylformamide. In vitro precipitation was studied to evaluate the relative potential for precipitation of the drug on injection. Based on these findings, ara-A may be dissolved in the 70% dimethylsulfoxide-water mixture at 15 mg/ml and injected at a rate of 2 ml/min.
• Pinal, R., & Yalkowsky, S. H. (1987). Solubility and partitioning VII: Solubility of barbiturates in water. Journal of Pharmaceutical Sciences, 76(1), 75-85.
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  PMID: 3585730;
• Reed, K. W., & Yalkowsky, S. H. (1987). Lysis of human red blood cells in the presence of various cosolvents. III. The relationship between hemolytic potential and structure. Journal of Parenteral Science and Technology, 41(1), 37-39.
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  PMID: 3559834;Abstract: A novel in vitro hemolytic method was used by the authors to determine hemolytic potentials of various water miscible solvents. The novel method differs from the standard in vitro hemolytic method [Husa, W.J., and Adams, J.R., 'Isotonic Solutions. II. The Permeability of Red Corpuscles to Various Substances,' J. Am. Pharm. Assoc. Sci. Ed., 33, 329 (1944)] in that the red blood cell and solvent mixture is washed with normal saline to remove the solvent and any other substances which may interfere with the visible absorption spectrum of hemoglobin. LD50s for the lysis of red blood cells were used as measures of the solvents' hemolytic potentials and were obtained by mixing variable amounts of whole blood with a constant amount of solvent. The experimentally determined LD50s were regressed against the physico-chemical properties of the solvents using uni- and multivariate analysis. General relationships between the structures of the solvents and their hemolytic potential (LD50s) were obtained. A quantitative structure activity relationship was not obtained for the thirteen solvents studied. However, the hemolytic potential of methanol, ethanol, iso-propanol, n-propanol, and n-butanol was directly related to the alcohols' log (partition coefficient).
• Rubino, J. T., & Yalkowsky, S. H. (1987). Cosolvency and cosolvent polarity. Pharmaceutical Research, 4(3), 220-230.
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  PMID: 3509285;
• Rubino, J. T., & Yalkowsky, S. H. (1987). Cosolvency and deviations from log-linear solubilization. Pharmaceutical Research, 4(3), 231-236.
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  PMID: 3509286;
• Rubino, J. T., Blanchard, J., & Yalkowsky, S. H. (1987). Solubilization by cosolvents IV: Benzocaine, diazepam and phenytoin in aprotic cosolvent-water mixtures. Journal of Parenteral Science and Technology, 41(5), 172-176.
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  PMID: 3694340;Abstract: The log-linear solubility equation, log (S(m)/S(w)) = fσ, where S(m) and S(w) are the solubilities of drug in the solvent mixture and water respectively, f is the volume fraction of cosolvent, and σ is the slope of the log (S(m)/S(w)) vs. f plot, has been applied to the solubilities of benzocaine, diazepam, and phenytoin in mixtures of polar, aprotic cosolvents, and water. These solvent systems were considered as two groups based on the functional group of the cosolvents; ethers (dioxane, dimethyl isosorbide, triglyme) and double-bonded oxygen compounds (DMSO, DMA, DMF). Solubilities are generally higher in both groups of cosolvent-water mixtures compared to amphiprotic cosolvent-water mixtures. This may be due to the lack of self-association of these cosolvents through hydrogen bonds and their relatively high-base strength. Positive and negative deviation from the predicted linear behavior occurs in these solvents systems as in the case of the amphiprotic cosolvent-water systems. Positive deviation is seen for all three solutes in the case of the ether cosolvent-water mixtures and for benzocaine and phenytoin in the double-bonded oxygen cosolvent-water mixtures. Negative deviations are seen for diazepam in the latter solvent system. The potential reasons for these deviations are discussed.
• Tarr, B. D., & Yalkowsky, S. H. (1987). A new parenteral vehicle for the adminstration of some poorly water soluble anti-cancer drugs. Journal of Parenteral Science and Technology, 41(1), 31-33.
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  PMID: 3559832;Abstract: A new parenteral vehicle was developed for three poorly water soluble anti-cancer drugs using pluronic L64. A ternary cosolvent system containing pluronic L64 (60%), ethanol (30%), and polysorbate 80 (10%) was formulated. All three drugs tested were stable in this vehicle. Methods of administration usually involve a simple dilution of one part formulation with 2 parts water. The water-diluted formulation of the three drugs studies is physically stable for three days prior to crystallization.
• Tarr, B. D., Sambandan, T. G., & Yalkowsky, S. H. (1987). A new parental emulsion for the administration of taxol. Pharmaceutical Research, 4(2), 162-165.
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  PMID: 2908138;
• Pywell, E. J., Yalkowsky, S. H., & Collett, J. H. (1986). The effect of a rate controlling membrane on release from polyhema hydrogels. Drug Development and Industrial Pharmacy, 12(11-13), 1767-1775.
• Reed, K. W., & Yalkowsky, S. H. (1986). Lysis of human red blood cells in the presence of various cosolvents. II. The effect of differing NaCl concentrations. Journal of Parenteral Science and Technology, 40(3), 88-94.
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  PMID: 3746578;
• Kuu, W. -., & Yalkowsky, S. H. (1985). Multiple-hole approach to zero-order release. Journal of Pharmaceutical Sciences, 74(9), 926-933.
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  PMID: 4067846;Abstract: We describe an approach to zero-order drug delivery systems that utilizes a device consisting of multiple holes uniformly distributed in an impermeable membrane. The interior of the device is filled with a suspension of a drug in a polymeric matrix. Near zero-order release is attained by using the proper density and configuration of holes on the surface of the device.
• Reed, K. W., & Yalkowsky, S. H. (1985). Lysis of human red blood cells in the presence of various cosolvents. Journal of Parenteral Science and Technology, 39(2), 65-68.
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  Abstract: Two in vitro methods are presented which enable the evaluation of virtually any solution for the production of lysis in intramuscular and intravenous administration. These methods differ from the standard hemolytic method in that the RBCs and ghosts, which remain after mixing test solution with RBCs, are washed with normal saline. The intact RBCs are then lysed with water. Since the final measurement is always made in pure water, the effects of vehicle components on the absorbance or solubility of hemoglobin are virtually eliminated. These methods were used to evaluate propylene glycol (PG), dimethyl sulfoxide (DMSO), ethanol (EtOH), polyethylene glycol 400 (PEG 400), dimethyl acetamide (DMA), and dimethyl isosorbide (DMI) for hemolytic potential in comparison to a reference of 10% EtOH, 40% PG, and 50% water. Measured LD 50 values for lysis of RBCs are expressed as total volume percent of cosolvent in whole blood. These values are: 39.5% DMI, 37.0% DMA, 30.0% PEG 400, 21.2% EtOH, 10.3% reference, 5.7% PG, and 5.1% DMSO.
• Reed, K. W., & Yalkowsky, S. H. (1985). Lysis of human red blood cells in the presence of various cosolvents.. Journal of Parenteral Science and Technology, 39(2), 64-69.
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  PMID: 3989614;
• Rubino, J. T., & Yalkowsky, S. H. (1985). Solubilization by cosolvents III: diazepam and benzocaine in binary solvents. Journal of Parenteral Science and Technology, 39(3), 106-111.
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  PMID: 3998967;Abstract: The solubilities of diazepam and benzocaine in various cosolvent-water mixtures have been measured and the ability of the log-linear solubility equation, log (S(m)/Sw) = σf, to predict the experimental solubilities examined. In general, the logarithmic increase in solubility (expressed as the ratio of the solubility in the solvent mixture, S(m), and water, Sw) with increasing volume fraction of cosolvent, f, was observed. Positive or negative deviation from the predicted linear behavior was observed for both solutes in all of the solvent systems studied. The magnitude of the slopes, σ of the log (S(m)/Sw) vs. f plots agreed with the order of the polarities of the cosolvents. These results are compared with those of a similar study involving the drug phenytoin. The slopes of the log (S(m)/Sw) vs. f plots were approximately in the same rank order for each cosolvent-water mixture. It was also observed that the patterns of curvature in the log (S(m)/Sw) vs. f plots for a given cosolvent-water system are similar for all three drugs. This suggests that the source of deviation of the observed solubility from the predicted solubility may primarily be due to interactions between the cosolvent and water.
• Yalkowsky, S. H., & Rubino, J. T. (1985). Solubilization by cosolvents I: Organic solutes in propylene glycol-water mixtures. Journal of Pharmaceutical Sciences, 74(4), 416-421.
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  PMID: 3999002;Abstract: An equation describing solubilization in aqueous systems by cosolvents was developed by treating a mixed solvent as a linear combination of its components. This equation can successfully explain both the exponential increases and the exponential decreases in aqueous solubility that are frequently observed with the addition of cosolvent. It also provides a means of estimating to what extent a particular drug can be solubilized and how much cosolvent would be required to accomplish a particular degree of solubilization.
• Patton, J. S., Stone, B., Papa, C., Abramowitz, R., & Yalkowsky, S. H. (1984). Solubility of fatty acids and other hydrophobic molecules in liquid trioleoylglycerol.. Journal of Lipid Research, 25(2), 189-197.
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  PMID: 6707527;Abstract: The fat solubilities of some long chain fatty acids, alcohols, alkanes, and triacyglycerols, and of some aromatic, chlorinated aromatic, and chlorinated aliphatic hydrocarbons were measured in trioleoylglycerol. Above their melting temperature, all test compounds are theoretically miscible with liquid fat. Below their melting temperature the solubility of all test compounds can be estimated by the equation: log (mole fraction solubility) = (Formula: see text) where delta Sf, the entropy of fusion, can be estimated from chemical structure according to Yalkowsky and Valvani (J. Pharm. Sci. 1980. 69:912-922), and the melting point (Tm) is either known or experimentally determined. For long chain compounds, solubility in trioleoylglycerol dropped precipitously with an increase in melting point. For the aromatic and chlorinated compounds, the drop was more gradual. Since the entropy of fusion of rigid aromatic compounds is approximately 13.5 e.u. at room temperature, their solubility in triacylglycerol is a linear function of melting point.
• Rubino, J. T., Blanchard, J., & Yalkowsky, S. H. (1984). Solubilization by cosolvents II: Phenytoin in binary and ternary solvents. Journal of Parenteral Science and Technology, 38(6), 215-221.
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  PMID: 6527203;Abstract: The solubility of the poorly water-soluble drug phenytoin in binary and ternary mixtures of cosolvents and water has been found to be adequately described by the log-linear solubility equation, log (S(m)/S(w)) = Σ(in) = 1 (σ(i) f(i)), where S(m) is the solubility of the drug in the solvent mixture, S(w) is the solubility of drug in water, f(i) is the volume fraction of cosolvent and σ(i) is the slope. The rank order of the slopes of the solubilization curves appears to parallel the polarity of the cosolvent. For most of the cosolvents tested, some degree of deviation from ideal solubilizing behavior exists. The amount of deviation depends upon both the type and amount of cosolvent used. The largest deviation is seen when higher volume fractions (0.7-0.9) of cosolvent are used and was greater for ethanol-water systems than the glycol-water systems. The same reasons for nonideal solubility seen in the binary solvent mixtures may be responsible for the nonideality seen in the ternary solvent systems. In spite of the curvature seen in these plots, the log-linear solubility equation can be very useful in estimating the solubility of a drug in water-cosolvent mixtures. If the solubility of the drug in water and pure cosolvent is known, the solubility in water-cosolvent mixtures can be estimated by plotting these two points on semi-log paper and connecting them with a straight line.
• Yalkowsky, S. H. (1983). PHYSICAL CHEMICAL PARAMETERS RELATING TO SORPTION AND PARTITIONING.. National Meeting - American Chemical Society, Division of Environmental Chemistry, 23(2), 186-187.
• Yalkowsky, S. H., Valvani, S. C., & Johnson, B. W. (1983). In vitro method for detecting precipitation of parenteral formulations after injection. Journal of Pharmaceutical Sciences, 72(9), 1014-1017.
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  PMID: 6631683;Abstract: Many injectable formulations currently on the market, including diazepam and alprazolam, utilize one or more cosolvents to solubilize the active constituents. On injection into an aqueous medium, some of these components tend to precipitate. A simple procedure is described for measuring the degree of precipitation that occurs when a solubilized drug is injected. This in vitro technique was used to show that alprazolam injection shows less precipitation than diazepam injection under all tested conditions, and that the precipitation observed with diazepam can be controlled by ensuring that the formulation is injected very slowly. This simple technique also can be used during preformulation development to evaluate the relative potential for precipitation of various formulations.
• Yalkowsky, S. H., Valvani, S. C., & MacKay, D. (1983). Estimation of the aqueous solubility of some aromatic compounds. Residue Reviews, Vol. 85, 43-55.
• Yalkowsky, S. H., Valvani, S. C., & Roseman, T. J. (1983). Solubility and partitioning. VI: Octanol solubility and octanol-water partition coefficients. Journal of Pharmaceutical Sciences, 72(8), 866-870.
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  PMID: 6620139;Abstract: A simple equation for the estimation of the aqueous solubility of crystalline solutes was previously derived based on the assumption that the presence of water does not significantly alter the crystal properties of the solute. The data presented verify the solubility equation for a set of 36 nonelectrolytes and weak electrolytes. Using the same set of solutes, the two major assumptions used to derive the equation were also verified: that the octanol solubility of nonelectrolytes is exponentially proportional to the melting point of the solute and that the octanol-water solubility ratio is a good approximation of the octanol-water partition coefficient.
• Valvani, S. C., Yalkowsky, S. H., & Roseman, T. J. (1981). Solubility and partitioning IV: Aqueous solubility and octanol-water partition coefficients of liquid nonelectrolytes. Journal of Pharmaceutical Sciences, 70(5), 502-507.
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  PMID: 7241352;
• Yalkowsky, S. H. (1981). Solubility and partitioning V: Dependence of solubility on melting point. Journal of Pharmaceutical Sciences, 70(8), 971-973.
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  PMID: 7310682;
• Yalkowsky, S. H., & Valvani, S. C. (1981). Correlation of water solubility with octanol-water partition coefficient: A response. Journal of Pharmaceutical Sciences, 70(10), 1177-1178.
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  PMID: 7299660;
• Banerjee, S., Yalkowsky, S. H., & Valvani, S. C. (1980). Water solubility and octanol/water partition coefficients of organics. Limitations of the solubility-partition coefficient correlation. Environmental Science and Technology, 14(10), 1227-1229.
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  Abstract: The water solubilities (S) and octanol/water partition coefficients (K) of a wide variety of organic compounds have been measured. It is shown that a previously described correlation between these two parameters may be invalid for high-melting solids. Alternative methods for constructing K-S correlations are discussed. © 1980 American Chemical Society.
• Mackay, D., Bobra, A., Shiu, W. Y., & Yalkowsky, S. H. (1980). Relationships between aqueous solubility and octanol-water partition coefficients. Chemosphere, 9(11), 701-711.
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  Abstract: The physical chemical equations relating solubility to octanol water partition coefficient are presented and used to develop a new correlation between these quantities which includes a melting point (fugacity ratio) correction. The correlation is satisfactory for 45 organic compounds but it is not applicable to organic acids. When applied to very high molecular weight (> 290) compounds the correlation is less satisfactory; either it is believed because the data are inaccurate or because the tendency for these compounds to partition into organic phases is less than expected. This may have profound environmental implications. © 1980.
• Mackay, D., Mascarenhas, R., Shiu, W. Y., Valvani, S. C., & Yalkowsky, S. H. (1980). Aqueous solubility of polychlorinated biphenyls. Chemosphere, 9(5-6), 257-264.
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  Abstract: Aqueous solubility data for chlorinated biphenyls are compiled and a correlation developed from which the isomer solubility can be estimated from melting point and total surface area. © 1980.
• Yalkowsky, S. H., & Valvani, S. C. (1980). Solubility and partitioning I: Solubility of nonelectrolytes in water. Journal of Pharmaceutical Sciences, 69(8), 912-922.
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  PMID: 7400936;
• Martin, E., Yalkowsky, S. H., & Wells, J. E. (1979). Fusion of disubstituted benzenes. Journal of Pharmaceutical Sciences, 68(5), 565-568.
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  PMID: 430490;Abstract: The entropy of fusion of 84 disubstituted benzenes was essentially constant and independent of the participation of the compounds in intramolecular or intermolecular hydrogen bonding. It was also independent of the shapes, sizes, and dipole moments of the rigid molecules studied. While the entropy of fusion was independent of these parameters, the melting point and the heat of fusion showed a direct dependence on molecular properties.
• Yalkowsky, S. H. (1979). ESTIMATION OF ENTROPIES OF FUSION OF ORGANIC COMPOUNDS.. Ind Eng Chem Fundam, 18(2), 108-111.
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  Abstract: The entropy of fusion for many drugs and molecules of intermediate size can be estimated in the following manner: (1) for rigid molecules, DELTA S//f approximately equals 13. 5 eu; (2) for long chain derivatives of such molecules, DELTA S//f approximately equals 13. 5 plus or minus 2. 5(n minus 5) eu, where n is the number of flexible links in the chain. In most cases, these simple rules will provide an estimate of DELTA S//f which is sufficiently accurate to obtain reasonable estimates of ideal solubility.
• Yalkowsky, S. H., & Roseman, T. J. (1979). Stability of E-type prostaglandins in triacetin. Journal of Pharmaceutical Sciences, 68(1), 114-115.
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  PMID: 758446;
• Yalkowsky, S. H., & Valvani, S. C. (1979). SOLUBILITIES AND PARTITIONING - 2. RELATIONSHIPS BETWEEN AQUEOUS SOLUBILITIES, PARTITION COEFFICIENTS, AND MOLECULAR SURFACE AREAS OF RIGID AROMATIC HYDROCARBONS.. J Chem Eng Data, 24(2), 127-129.
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  Abstract: The aqueous solubilities of 31 polycyclic aromatic hydrocarbons and indan can be accurately estimated from melting point and either molecular surface area or f values. (The latter being an approximation of the octanol-water partition coefficient based upon group contribution values. ) In both cases, the coefficient of the melting point term is close to 0. 01 and the correlation coefficient exceeds 0. 987.
• Yalkowsky, S. H., J., O. R., & Valvani, S. C. (1979). SOLUBILITY AND PARTITIONING - 3. THE SOLUBILITY OF HALOBENZENES IN WATER.. Industrial & Engineering Chemistry, Fundamentals, 18(4), 351-353.
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  Abstract: The aqueous molar solubilities S//w of 26 mono- and multi-halogenated benzenes at 25 plus or minus 1 degree C were determined. These values, along with values obtained from the literature for nine additional compounds, can be estimated by log S//w equals minus 0. 0095(MP)- 0. 9874 log (PC) plus 0. 7178, where (MP) is the melting point in degree C and (PC) is the estimated octanol-water partition coefficient for each halobenzene. The data were also found to be in agreement with log S//w equals minus 0. 0103(MP)- 0. 04225(TSA) plus 3. 2970, where (TSA) is the total molecular surface area of the halobenzene.
• Flanagan, D. R., & Yalkowsky, S. H. (1977). Convective diffusional analysis for drug transport through a tubular polymeric membrane. Journal of Pharmaceutical Sciences, 66(3), 337-340.
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  PMID: 300434;Abstract: The transport of three p-aminobenzoate esters (ethyl, butyl, and hexyl) through a tubular dimethyl polysiloxane membrane into a flowing liquid was investigated. The tubular configuration permits the exact determination of the convective diffusional contribution to membrane transport with models that account for fluid hydrodynamics. The observed transport behavior ranged from complete convective diffusion control for the hexyl ester to complete membrane control for the ethyl ester; the butyl ester exhibited a change in control with flow rate. The implications of convective diffusional considerations to intestinal absorption and dissolution studies are discussed.
• Mille, M., Yalkowsky, S. H., & Zografi, G. (1977). Limitations in the use of acylcarnitine titration data. Journal of Colloid And Interface Science, 62(2), 364-365.
• Yalkowsky, S. H., & Valvani, S. C. (1977). Precipitation of solubilized drugs due to injection or dilution. Drug Intelligence and Clinical Pharmacy, 11(7), 417-419.
• Valvani, S. C., Yalkowsky, S. H., & Amidon, G. L. (1976). Solubility of nonelectrolytes in polar solvents. VI. Refinements in molecular surface area computations. Journal of Physical Chemistry, 80(8), 829-835.
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  Abstract: A simplified calculation method for computation of molecular and group surface area of organic molecules is proposed. For surface area calculations the molecule is treated as a collection of intersecting spheres comprised of individual atoms or molecular groups. The importance and use of a solvent radius for molecular surface area calculations is critically examined, and it is shown that the solvent radius is not an essential determinant in describing the aqueous solubility-surface area relationship. The application of the proposed method for correlating the surface areas with aqueous solubilities of several linear, branched, and cyclic aliphatic alcohols and hydrocarbons is presented. A quantitative comparison of the new calculation method with a previously published method is presented and several advantages of the proposed method are discussed.
• Yalkowsky, S. H., & Valvani, S. C. (1976). Partition coefficients and surface areas of some alkylbenzenes. Journal of Medicinal Chemistry, 19(5), 727-728.
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  PMID: 1271417;Abstract: The experimentally measured log P values (logarithms of partition coefficients) of a number of alkylbenzenes are shown to be quantitatively related to the hydrocarbon surface area HSA of the molecule by π = 0.0275 × HSA - 0.863 (correlation coefficient = 0.996, standard deviation = 0.071). The use of surface area as a correlating parameter eliminates the need for correction factors to account for branching, cyclization, ring fusion, and "backfolding". Furthermore, surface area calculations provide a conceptual basis for understanding how conformation can effect partitioning.
• Yalkowsky, S. H., Valvani, S. C., & Amidon, G. L. (1976). Solubility of nonelectrolytes in polar solvents. IV. Nonpolar drugs in mixed solvents. Journal of Pharmaceutical Sciences, 65(10), 1488-1494.
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  PMID: 978408;Abstract: The molecular and group surface area approach to solubility is shown to be applicable to mixed aqueous solvent systems. An equation is derived which is consistent with the exponential increase in the aqueous solubility of nonpolar drugs that frequently accompanies the addition of a cosolvent. This equation predicts that: (a) the ability of a drug to be solubilized by a cosolvent is proportional to its hydrophobic surface area per molecule, and (b) the ability of a cosolvent to solubilize any drug is inversely proportional to its interfacial tension against a reference liquid hydrocarbon. These predictions are experimentally verified with solubility studies of several alkyl p aminobenzoates in propylene glycol water mixtures and of hexyl p aminobenzoate in mixtures of water with ethanol, methanol, ethylene glycol, propylene glycol, glycerin, and formamide.
• Amidon, G. L., Yalkowsky, S. H., Anik, S. T., & Valvani, S. C. (1975). Solubility of nonelectrolytes in polar solvents. V. Estimation of the solubility of aliphatic monofunctional compounds in water using a molecular surface area approach. Journal of Physical Chemistry, 79(21), 2239-2246.
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  Abstract: The molecular surface areas for 158 aliphatic hydrocarbons, olefins, alcohols, ethers, ketones, aldehydes, esters, and fatty acids have been computed and correlated with their aqueous solubilities. The hydrocarbon and functional group contributions to the free energy of solution are compared and discussed with particular regard to the chosen standard state. The results indicate that the functional group contributions to the free energy of solution in water are nearly equivalent from the pure liquid standard state while being significantly different when the gas phase (1 mmHg) standard state is chosen. The interpretation of the differing hydrocarbon surface area slopes is shown to be complicated by mutual miscibility considerations (water solubility in the pure liquid) and by the presence of curvature for the longer chain length (greater than C10) compounds. The curvature in the alcohol and fatty acid data is shown to become very evident when correction is made to the pure (supercooled) liquid standard state for the solid compounds. Finally the surface area method is shown to hold considerable promise in its extension to the solubility estimation of complex organic molecules with limited aqueous solubilities.
• Sinkula, A. A., & Yalkowsky, S. H. (1975). Rationale for design of biologically reversible drug derivatives: prodrugs. Journal of Pharmaceutical Sciences, 64(2), 181-210.
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  PMID: 1127579;
• Yalkowsky, S. H., Amidon, G. L., Zografi, G., & Flynn, G. L. (1975). Solubility of nonelectrolytes in polar solvents. III: Alkyl p aminobenzoates in polar and mixed solvents. Journal of Pharmaceutical Sciences, 64(1), 48-52.
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  PMID: 1133705;
• Amidon, G. L., Yalkowsky, S. H., & Leung, S. (1974). Solubility of nonelectrolytes in polar solvents II: Solubility of aliphatic alcohols in water. Journal of Pharmaceutical Sciences, 63(12), 1858-1866.
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  PMID: 4449016;
• Flynn, G. L., Yalkowsky, S. H., & Roseman, T. J. (1974). Mass transport phenomena and models: theoretical concepts.. Journal of Pharmaceutical Sciences, 63(4), 479-510.
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  PMID: 4828694;
• Flynn, G. L., Yalkowsky, S. H., & Weiner, N. D. (1974). General influence of physicochemical properties on drug receptor combination. Journal of Pharmaceutical Sciences, 63(2), 300-304.
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  PMID: 4813262;
• Roseman, T. J., & Yalkowsky, S. H. (1974). Influence of solute properties on release of p aminobenzoic acid esters from silicone rubber: theoretical considerations. Journal of Pharmaceutical Sciences, 63(10), 1639-1643.
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  PMID: 4436810;
• Yalkowsky, S. H., & Flynn, G. L. (1974). Correlation and prediction of mass transport across membranes II: Influence of vehicle polarity on flux from solutions and suspensions. Journal of Pharmaceutical Sciences, 63(8), 1276-1280.
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  PMID: 4851195;
• Yalkowsky, S. H., Slunick, T. G., & Flynn, G. L. (1974). Effects of alkyl chain length on biological activity: alkyl p aminobenzoate induced narcosis in goldfish. J.PHARM.SCI., 63(5), 691-695.
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  PMID: 4829988;Abstract: On the basis of a diffusional model and certain well known physical chemical relationships, equations were derived which describe the relative biological activities of alkyl homologs. These equations were applied to the goldfish turnover time produced by both saturated solutions and equimolar solutions of eight n alkyl esters of p aminobenzoic acid. The results show that the apparant parabolic structure activity curve can be described quite well by a simple solubility limited diffusional model.
• Zografi, G., & Yalkowsky, S. H. (1974). Interfacial properties of polar liquids against nonpolar phases.. Journal of Pharmaceutical Sciences, 63(10), 1533-1536.
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  PMID: 4436783;
• Roseman, T. J., & Yalkowsky, S. H. (1973). Physicochemical properties of prostaglandin F2α (tromethamine salt): solubility behavior, surface properties, and ionization constants. Journal of Pharmaceutical Sciences, 62(10), 1680-1685.
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  PMID: 4752113;
• Yalkowsky, S. H., & Flynn, G. L. (1973). Transport of alkyl homologs across synthetic and biological membranes: a new model for chain length-activity relationships.. Journal of Pharmaceutical Sciences, 62(2), 210-217.
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  PMID: 4686391;
• Yalkowsky, S. H., Carpenter, O. S., Flynn, G. L., & Slunick, T. G. (1973). Drug absorption kinetics in goldfish. Journal of Pharmaceutical Sciences, 62(12), 1949-1954.
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  PMID: 4762163;
• Flynn, G. L., & Yalkowsky, S. H. (1972). Correlation and prediction of mass transport across membranes. I. Influence of alkyl chain length on flux-determining properties of barrier and diffusant.. Journal of Pharmaceutical Sciences, 61(6), 838-852.
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  PMID: 5046096;
• Flynn, G. L., Carpenter, O. S., & Yalkowsky, S. H. (1972). Total mathematical resolution of diffusion layer control of barrier flux.. Journal of Pharmaceutical Sciences, 61(2), 312-314.
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  PMID: 5059815;
• Yalkowsky, S. H., & Zografi, G. (1972). Calculation of partial molal volume in micellar systems.. Journal of Pharmaceutical Sciences, 61(5), 793-795.
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  PMID: 5035793;
• Yalkowsky, S. H., Flynn, G. L., & Amidon, G. L. (1972). Solubility of nonelectrolytes in polar solvents.. Journal of Pharmaceutical Sciences, 61(6), 983-984.
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  PMID: 5046131;
• Yalkowsky, S. H., Flynn, G. L., & Slunick, T. G. (1972). Importance of chain length on physicochemical and crystalline properties of organic homologs.. Journal of Pharmaceutical Sciences, 61(6), 852-857.
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  PMID: 5046097;
• Zografi, G., & Yalkowsky, S. H. (1972). Comments on the apparent shape of micelles.. Journal of Pharmaceutical Sciences, 61(4), 651-652.
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  PMID: 5014331;
• Yalkowsky, S. H., & Zografi, G. (1970). Potentiometric titration of monomeric and micellar acylcarnitines.. Journal of Pharmaceutical Sciences, 59(6), 798-802.
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  PMID: 5423081;
• Yalkowsky, S. H., & Zografi, G. (1970). Some micellar properties of long-chain acylcarnitines. Journal of Colloid And Interface Science, 34(4), 525-533.
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  PMID: 5500979;Abstract: The acid dissociation constants of long-chain esters of carnitine (β-hydroxy-γ-trimethylammonium-butyrate) above the critical micelle concentration were determined potentiometrically at several concentrations of added KCl. As the degree of protonation β increases the apparent pK values decrease owing to the increased positive charge on the micelle. The difference in pK between the neutral (zwitterionic) micelle and the value at any given β was used to determine the surface potential of the micelle Ψ at that degree of protonation. At each degree of protonation the measured surface potential was related to the surface charge density σ with the aid of the calculations of Loeb, Wiersema, and Overbeek for a spherical impenetrable particle. The surface potentials and surface charge densities of lauryl-, myristyl-, and palmitylcarnitine are nearly identical at a given degree of protonation and ionic strength, and, as expected, increasing the ionic strength produces a decrease in the surface potential. From the partial molal volume of each surfactant in the micelle and the calculated surface charge density it was possible to calculate the aggregation number n of the micelle. Good agreement was found between the calculated values of n and values obtained from light-scattering experiments at several ionic strengths and degrees of protonation. © 1970.