Solubility behaviour of haloperidol in individual solvents determination of partial solubility parameters.

The solubility behaviour of haloperidol in individual solvents ranging from non-polar to highly polar solvents was studied. Extended Hansen's method was used to analyze the solubility data and obtain partial solubility parameters of haloperidol. Flory-Huggin's size connection term 'B' was found to further improve the prediction of solubility. A four parameter extended Hansen's approach involving proton-donor and proton-acceptor parameters was also used in fitting the solubility data to a theoretical model. The term Wh, used as an empirical measure of solute-solvent interaction due to hydrogen bonding was used in calculating B. Different approaches were thus used in fitting the experimental solubility data to obtain regression equations which aim to provide a reasonable prediction of solubility of haloperidol in untested solvents. Solubility parameter was calculated from the partial solubility parameter values obtained from the different methods of data analysis, and compared with the theoretically obtained values. Solubility parameter of haloperidol is fixed at 10.58 H.     

Predicting the solubility of sulfamethoxypyridazine in individual solvents. II: Relationship between solute-solvent interaction terms and partial solubility parameters

In the first paper in the series, an expanded system of parameters was devised to account for orientation and induction effects, and the term Wh was introduced to replace delta 1h delta 2h of the extended Hansen solubility approach. In the present report, a new term, Kh = Wh/delta 1h delta 2h is observed to take on values larger or smaller than unity depending on whether the hydrogen bonded solute-solvent interaction is larger or smaller than predicted by the term delta 1h delta 2h. The acidic delta a and basic delta b solubility parameters are used to represent two parameters, sigma and tau, suggested by Small in his study of proton donor-acceptor properties. The Small equation, including a heat of mixing term for hydrogen bonded species, is shown to be capable of semiquantitative evaluation. A partial molar heat delta H2h of hydrogen bonding is calculated using delta h and Wh terms; delta H2h is found to be correlated with the logarithm of the residual activity coefficient, In alpha R, a term representing strong solute-solvent interaction. The terms Wh, delta H2h, and In alpha 2R may be used to test the deviation from the geometric mean assumed in regular solution theory, and to replace the hydrogen bonding terms of the extended Hansen three-parameter model. The solubility of sulfamethoxypyridazine in 30 solvents is used to test the semiempirical solubility equations. The results are interpreted in terms of partial solubility parameters and the proton donor-acceptor properties of the solvents.     

The modified extended Hansen method to determine partial solubility parameters of drugs containing a single hydrogen bonding group and their sodium derivatives: benzoic acid/Na and ibuprofen/Na

Sodium salts are often used in drug formulation but their partial solubility parameters are not available. Sodium alters the physical properties of the drug and the knowledge of these parameters would help to predict adhesion properties that cannot be estimated using the solubility parameters of the parent acid. This work tests the applicability of the modified extended Hansen method to determine partial solubility parameters of sodium salts of acidic drugs containing a single hydrogen bonding group (ibuprofen, sodium ibuprofen, benzoic acid and sodium benzoate). The method uses a regression analysis of the logarithm of the experimental mole fraction solubility of the drug against the partial solubility parameters of the solvents, using models with three and four parameters. The solubility of the drugs was determined in a set of solvents representative of several chemical classes, ranging from low to high solubility parameter values. The best results were obtained with the four parameter model for the acidic drugs and with the three parameter model for the sodium derivatives. The four parameter model includes both a Lewis-acid and a Lewis-base term. Since the Lewis acid properties of the sodium derivatives are blocked by sodium, the three parameter model is recommended for these kind of compounds. Comparison of the parameters obtained shows that sodium greatly changes the polar parameters whereas the dispersion parameter is not much affected. Consequently the total solubility parameters of the salts are larger than for the parent acids in good agreement with the larger hydrophilicity expected from the introduction of sodium. The results indicate that the modified extended Hansen method can be applied to determine the partial solubility parameters of acidic drugs and their sodium salts.     

A new method to determine the partial solubility parameters of polymers from intrinsic viscosity.

A modification of the extended Hansen method, formerly used to determine the partial solubility parameters of drugs and non-polymeric excipients is tested with a polymer for the first time. The proposed method relates the logarithm of the intrinsic viscosities of the polymer in a series of solvents and solvent mixtures with the Hansen (three parameter model) and Karger (four parameter model) partial solubility parameters. The viscosity of diluted solutions of hydroxypropyl methylcellulose (HPMC) was determined in pure solvents and binary mixtures of varying polarity. The intrinsic viscosity was obtained from the common intercept of the Huggins and Kraemer relationships. The intrinsic viscosity tends to increase with increasing the solubility parameter of the medium. The results show that hydrogen bonding and polarity of the polymer largely determine polymer-solvent interactions. The models proposed provided reasonable partial and total solubility parameters for the polymer and enable one to quantitatively characterize, for the first time, the Lewis acid-base ability of a polymer thus, providing a more realistic picture of hydrogen bonding for solvent selection/compatibility and to predict drug-polymer interactions. Combination of the dispersion and polar parameters into a single non-specific solubility parameter was also tested. The results extend earlier findings and suggest that the models are quite versatile and may be applied to drugs, non-polymeric and polymeric excipients.     

Relationship between swelling of hydroxypropylmethylcellulose and the Hansen and Karger partial solubility parameters

A model that relates the equilibrium swelling of hydroxypropylmethylcellulose to the partial solubility parameters of both the polymer and the solvents is proposed to interpret and correlate the experimental data. The non-specific interactions are expressed as the dispersion delta(d) and polar delta(p) solubility parameters of Hansen, or as a combination of both. Hydrogen bonding is represented by the acidic delta(a) and the basic delta(b) Karger solubility parameters. The results are compared with models including the same parameters for non-specific interactions (delta(d) and delta(p)) and the Hansen hydrogen bonding parameter delta(h). Equilibrium swelling of this hydrophilic polymer that is widely used in drug formulation is measured in pure solvents covering a wide polarity range. In a qualitative way, swelling increases in solvents with higher Hildebrand solubility parameters and stronger hydrogen bonding capability, and it decreases in non-polar solvents. Single polarity indexes, such as the Hildebrand solubility parameter or the partition coefficient (PC), do not fit well the overall experimental data. The best correlations were obtained with the proposed model, providing at the same time an interpretation consistent with the physical meaning of the terms included in the equation. Swelling increases as the non-specific interactions of the polymer and the solvents become alike, and as the Lewis acid-base interactions of the polymer (1) and the solvent (2) represented by the products delta(1a)delta(2b) and delta(1b)delta(2a) become greater. Conversely, hydrogen bonding self association of the solvents (the product delta(1a)delta(1b)) lowers swelling. The results show that the Karger hydrogen bonding parameters provide a better approach than the Hansen hydrogen bonding parameter to correlate the swelling behavior of a hydrophilic polymer.     

Proposition of group molar constants for sodium to calculate the partial solubility parameters of sodium salts using the van Krevelen group contribution method.

The aim of this study is to propose, for the first time, a set of group molar constants for sodium to calculate the partial solubility parameters of sodium salts. The values were estimated using the few experimental partial solubility parameters of acid/sodium salt series available either from the literature (benzoic acid/Na, ibuprofen acid/Na, diclofenac Na) or determined in this work (salicylic acid/Na, p-aminobenzoic acid/Na, diclofenac), the group contribution method of van Krevelen to calculate the partial parameters of the acids, and three reasonable hypothesis. The experimental method used is a modification of the extended Hansen approach based on a regression analysis of the solubility mole fraction of the drug lnX(2) against models including three- or four-partial solubility parameters of a series of pure solvents ranging from non-polar (heptane) to highly polar (water). The modified method combined with the four-parameter model provided the best results for both acids and sodium derivatives. The replacement of the acidic proton by sodium increased the dipolar and basic partial solubility parameters, whereas the dispersion parameter remained unaltered, thus increasing the overall total solubility parameter of the salt. The proposed group molar constants of sodium are consistent with the experimental results as sodium has a relatively low London dispersion molar constant (identical to that of -OH), a very high Keesom dipolar molar constant (identical to that of -NO(2), two times larger than that of -OH), and a very high hydrogen bonding molar constant (identical to that of -OH). The proposed values are: F((Na)d)=270 (J cm(3))(1/2) mol(-1); F((Na)p)=1030 (J cm(3))(1/2) mol(-1); U((Na)h)=17000 J mol(-1). Like the constants for the other groups, the group molar constants proposed for sodium are certainly not the exact values. However, they are believed to be a fair approximation of the impact of sodium on the partial solubility parameters and, therefore, can be used as such in the group contribution method of van Krevelen.     

Estimation of the solubility parameter of trimethoprim by current methods

Group contribution, the extended Hildebrand solubility (EHS) and the extended Hansen solubility approaches are utilised to estimate the solubility parameter value of trimethoprim. The solubility data in the binary solvent series showed peak solubility at the solubility parameter of solvent, 11.7 H. The regression expression on the lines of the EHS approach yielded 12.06 H. The data on the solubility of trimethoprim in individual solvents was processed as per the extended Hansen approach. The partial solubility parameters were obtained and are used to estimate the solubility parameter, 12.93 H. Extending the Flory-Huggins size correction to this approach gave a value of 10.95 H and improved the correlation coefficient by 3 percent. Partitioning of hydrogen bonding (four parameter approach) didn't improve the value.     

In silico prediction of drug solubility in water-dioxane mixtures using the Jouyban-Acree model

A numerical method based on the Jouyban-Acree model was presented for prediction of drug solubility in water-dioxane mixtures at various temperatures. The method requires drug solubility in monosolvent systems, i.e. two data points for each temperature of interest. The mean percentage deviation (MPD) of predicted solubilities was calculated to show the accuracy of the predicted data and 27% was found as the average MPD for 36 data sets studied. The proposed numerical method reduced the number of required experimental data from five to two points and could also be extended to predict solubility at various temperatures.     

Determination of partial solubility parameters of five benzodiazepines in individual solvents

Three and four component partial solubility parameters for diazepam, lorazepam, oxazepam, prazepam and temazepam were determined using the extended and expanded Hansen regression models. A comparison was made also with solubility parameters calculated by the group contribution method proposed by Van Krevelen. Although a limited number of solvents was used, the results from the present study indicate that the partial solubility parameters obtained from the experimental regression models clearly reflect the structural differences in these five structurally related molecules. High R(2)-values were observed in the regression models (0.932 < or =R(2)< or =0.984), except for lorazepam (0.606 < or =R(2)< or =0.825). This was attributed to difficulties in obtaining reliable values of the temperature and heat of fusion due to thermal decomposition of this compound. Introduction of the Flory-Huggins size correction parameter did not improve the R(2)- and F-values in any of the regression models used.     

Application of Hansen solubility parameters for understanding and prediction of drug distribution in microspheres

In an emulsion solvent extraction/evaporation process for the preparation of microspheres the employed solvents have a tremendous influence on the characteristics of the resulting particles. Nevertheless the solvent selection is often based on empirical data rather than on calculated values. The purpose of this investigation was to use the concept of solubility parameters for interpretation and improved understanding of solvent effects in the process of microparticle preparation. Partial solubility parameters of 3-{2-[4-(6-Fluor-1,2-benzisoxazol-3-yl)piperidino]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-on, which was used as a model drug, were determined experimentally using an extended Hansen regression model. Poly(lactide-co-glycolide) microparticles were prepared with an emulsion solvent removal process employing methylene chloride and its mixtures with benzyl alcohol and n-butanol. It could be shown, that the encapsulation efficiency was influenced by the change of the solvent composition during the extraction process. Furthermore the solvent selection had an essential influence on the morphological state of the drug and it could be shown and explained, that by a decrease of the dissolving power a completely amorphous product was obtained.     

Prediction of drug solubility in amphiphilic di-block copolymer micelles: the role of polymer-drug compatibility

The goal of the current study was to assess the value of predictive computational approaches for estimating drug solubility in hydrated micelles formed from di-block copolymers of polyethylene glycol (PEG) and random copolyesters of epsilon-caprolactone (CL) and trimethylene carbonate (TMC) using drug-polymer compatibility as assessed through the Flory-Huggins interaction parameter (chi). In order to accomplish this, the compatibility of several well-known model drugs (associated with the four biopharmaceutics classification system (BCS) classes) was assessed with both segments of the amphiphilic di-block copolymer PEG-b-P(CL-co-TMC). Compatibilities were estimated based on the Hansen modification of the Hildebrand approach using Molecular Modeling Pro software. Experimental solubilities for model drugs were determined using a shake-flask technique at various polymer concentrations. The solubilities of 8 compounds in 10% w/v micelle solutions were in relatively good agreement with the predicted drug-polymer compatibility. In addition, the approach allows for the selection of a suitable di-block copolymer for optimal solubilization of a specific drug. Furosemide was assessed as a model with results suggesting that it can be best entrapped in a di-block copolyester containing a relatively high CL content. The data suggests that prediction of drug solubilization of block copolymer-based micelles may be facilitated by assessing the compatibility of the drug for the component polymeric domains.     

Solubility in binary solvent systems. IV. Prediction of naphthalene solubilities using the UNIFAC group contribution model

This work extends the UNIFAC group contribution method of solid-liquid equilibria to binary solvent mixtures, and compares its predictions to experimental solubilities for naphthalene in 16 different solvent mixtures. Deviations between experimental and calculated values are of the order of 10–20% for most solvent systems, and are comparable in magnitude to deviations noted in the pure solvents. The ability of the UNIFAC model to provide reasonable estimates of naphthalene solubilities based only on heat of fusion data and group contribution parameters suggests that the model may be useful in the area of drug design.     

A new expanded solubility parameter approach

The partial or Hansen solubility parameters (HSP) are important properties of the various substances and very useful tools for the selection of their solvents or the prediction of their behaviour in numerous applications. Their design and evaluation relies on the basic rule of "similarity matching" for solubility. The present work attempts to enhance the capacity of HSPs by incorporating into their evaluation the other basic rule of solubility, namely, the rule of "complementarity matching". This is done in a simple and straightforward manner by splitting the hydrogen bonding HSP into its acidic or proton donor component and its basic or proton acceptor one. The splitting is based on the third σ-moments of the screening charge distributions or sigma profiles of the quantum-mechanics based COSMO-RS theory. The whole development and application does not involve any sophisticated calculations or any strong specific background. The new method has been applied to a variety of solubility data for systems of pharmaceutical interest in order to verify the significant improvement over the classical HSP approach. The application of the new method requires, of course, the knowledge of the HSPs. For this reason, in Appendix A is presented an updated version of a robust and reliable group-contribution method for the calculation of the HSPs. The key features of this combined tool are critically discussed.     

Excess free energy approach to the estimation of solubility in mixed solvent systems I: Theory

An approach is developed by which the solubility of an organic compound in mixed solvents may be estimated. In this approach, an expression for the excess Gibbs free energy of mixing for multicomponent solvent systems was used to obtain parameters characteristic of the interaction between the solvents. A fairly simple equation which predicts the solubility of a solute in a binary solvent system over the entire solvent composition range was then derived. The equation may be partitioned into terms that contain (a) pure solvent solubilities, (b) solvent-solvent interaction contributions, and (c) contributions from the solute-mixed solvent interactions. The required data are the molar volume of the solute, the pure solvent solubilities, and, theoretically, one experimentally determined solubility in a solvent mixture. The equation can be easily extended for systems with three or more solvents.     

Prediction of solubility in nonideal multicomponent systems using the UNIFAC group contribution model

There is a need to identify suitable blends of solvents to dissolve drugs. Empirical approaches, such as trial-and-error and response surface, require several solubility measurements. In this study the UNIFAC method was used to predict solubility in highly nonideal multicomponent systems in which only the solute enthalpy of fusion and melting point must by measured. UNIFAC combines a group contribution approach with the UNIQUAC model for activity coefficients. Parameters characterizing interactions among constituent groups of a molecule have been previously determined from binary vapor pressure data. These tabulated group parameters are used to predict activity coefficients for newly synthesized compounds. These coefficients, together with the ideal solubility, permit a prediction of solubility. The solubility of 4-hexylresorcinol in ethyl acetate, ethyl myristate, and hexane mixtures was both measured and calculated using UNIFAC. The predicted solubilities were within 10% of the experimental solubilities for all but 3 of 21 mixtures. Since the method accounted for positive and negative deviations from ideality in a hydrogen-bonding system of molecules having different sizes, it shows great potential for use in pharmacy.     

Mathematical representation of solute solubility in binary mixture of supercritical fluids by the Jouyban-Acree model

Applicability of a solution model for calculating the solute solubility in binary mixtures of supercritical fluids at different SCF compositions and pressures was shown using phenanthrene solubility data in supercritical carbon dioxide and supercritical ethane at 313 K and a pressure range of 100-350 bar. The correlation ability of the proposed model was evaluated by fitting all data points and computing error term employing back-calculated solubilities. The prediction capability of the model was assessed by dividing each data set to two subsets, namely training and test subsets. The predicted solubilities using trained models were used to calculate the prediction error term. The results show that both correlative and predictive error terms were less than the experimentally obtained RSD values.     

Partial-solubility Parameters of Naproxen and Sodium Diclofenac

The expanded Hansen method was tested for determination of the solubility parameters of two non-steroidal anti-inflammatory drugs, naproxen and sodium diclofenac. This work describes for the first time the application of the method to the sodium salt of a drug. The original dependent variable of the expanded Hansen method, involving the activity coefficient of the drug, was compared with the direct use of the logarithm of the mole fraction solubility lnX₂ in the solubility models. The solubility of both drugs was measured in pure solvents of several chemical classes and the activity coefficient was obtained from the molar heat and the temperature of fusion. Differential scanning calorimetry was performed on the original powder and on the solid phase after equilibration with the pure solvents, enabling detection of possible changes of the thermal properties of the solid phase that might change the value of the activity coefficient. The molar heat and temperature of fusion of sodium diclofenac could not be determined because this drug decomposed near the fusion temperature. The best results for both drugs were obtained with the dependent variable lnX₂ in association with the four-parameter model which includes the acidic and basic partial-solubility parameters δ_a and δ_b instead of the Hansen hydrogen bonding parameter δ_h. Because the dispersion parameter does not vary greatly from one drug to another, the variation of solubility among solvents is largely a result of the dipolar and hydrogen-bonding parameters, a fact that is being consistently found for other drugs of small molecular weight. These results support earlier findings with citric acid and paracetamol that the expanded Hansen approach is suitable for determining partial-solubility parameters. The modification introduced in the expanded Hansen method, i.e. the use of lnX₂ as the dependent variable, provides better results than the activity coefficient used in the original method. This is advantageous for drugs such as sodium diclofenac for which the ideal solubility cannot be estimated. This paper shows for the first time that the method is suitable for determination of the partial-solubility parameters of a sodium salt of a drug, sodium diclofenac.     

Determination of solubility profiles of eflucimibe polymorphs: experimental and modeling

This work presents the determination of the phase diagram of two polymorphs of Eflucimibe in pure solvents and solvent mixtures at different temperatures. Solid phase changes were analysed by Differential Scanning Calorimetry. Solubility measurements show that the solubility of the two forms are very similar. Experimental data obtained in ethanol, reported in a Van t'Hoff plot, exhibit a transition temperature around 265 K. A single maximum is observed when solubility is plotted against the solubility parameters of solvents or solvent mixture and it is not related to a solid phase change. This phenomenon, known as a positive synergetic effect, has been explained in term of evolution of solute-solvents polar interactions. Several thermodynamics models (UNIFAC, UNIQUAC, Wilson, Scatchard Hildebrand ... ) were tested in order to predict the Liquid-Solid Equilibrium for this system. The semi empirical model UNIQUAC gives the best fit. The results obtained are in good agreement with the experimental data (mean deviation lower than 5%) and the solubility maximum found experimentally for each polymorph is also well described.     

Prediction of drug solubility from structure

The aqueous solubility of a drug is an important factor affecting its bioavailability. Numerous computational methods have been developed for the prediction of aqueous solubility from a compound's structure. A review is provided of the methodology and quality of results for the most useful procedures including the model implemented in the QikProp program. Viable methods now exist for predictions with less than 1 log unit uncertainty, which is adequate for prescreening synthetic candidates or design of combinatorial libraries. Further progress with predictive methods would require an experimental database of highly accurate solubilities for a large, diverse collection of drug-like molecules.