Solubility of drugs in aqueous solutions. Part 2: binary nonideal mixed solvent

As in a previous paper [Int. J. Pharm. 258 (2003) 193–201], the Kirkwood–Buff theory of solutions was employed to calculate the solubility of a solid in mixed solvents. Whereas in the former paper the binary solvent was assumed ideal, in the present one it was considered nonideal. A rigorous expression for the activity coefficient of a solute at infinite dilution in a mixed solvent [Int. J. Pharm. 258 (2003) 193–201] was used to obtain an equation for the solubility of a poorly soluble solid in a nonideal mixed solvent in terms of the solubilities of the solute in the individual solvents, the molar volumes of those solvents, and the activity coefficients of the components of the mixed solvent.

The Flory–Huggins and Wilson equations for the activity coefficients of the components of the mixed solvent were employed to correlate 32 experimental data sets regarding the solubility of drugs in aqueous mixed solvents. The results were compared with the models available in literature. It was found that the suggested equation can be used for an accurate and reliable correlation of the solubilities of drugs in aqueous mixed binary solvents. It provided slightly better results than the best literature models but has also the advantage of a theoretical basis.     

Solubility of drugs in aqueous solutions. Part 4. Drug solubility by the dilute approximation

As in our previous publications in this journal [Int. J. Pharm. 258 (2003a) 193; Int. J. Pharm. 260 (2003b) 283; Int. J. Pharm. 267 (2003c) 121], this paper is concerned with the solubility of poorly soluble drugs in aqueous mixed solvents. In the previous publications, the solubilities of drugs were assumed to be low enough for the so-called infinite dilution approximation to be applicable. In contrast, in the present paper, the solubilities are considered to be finite and the dilute solution approximation is employed. As before, the fluctuation theory of solutions is used to express the derivatives of the activity coefficient of a solute in a ternary solution (dilute solute concentrations in a binary solvent) with respect to the concentrations of the solvent and cosolvent. The expressions obtained are combined with a theoretical equation for the activity coefficient of the solute. As a result, the activity coefficient of the solute was expressed through the activity coefficients of the solute at infinite dilution, solute mole fraction, some properties of the binary solvent (composition, molar volume and activity coefficients of the components) and parameters reflecting the nonidealities of binary species. The expression thus obtained was used to derive an equation for the solubility of poorly soluble drugs in aqueous binary solvents which was applied in two different ways. First, the nonideality parameters were considered as adjustable parameters, determined from experimental solubility data. Second, the obtained equation was used to correct the solubilities of drugs calculated via the infinite dilution approximation. It was shown that both procedures provide accurate correlations for the drug solubility.     

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.     

Solubility of pioglitazone hydrochloride in ethanol,N-methyl pyrrolidone,polyethylene glycols and water mixtures at 298.20 °K

Background and the purpose of the study

Solubility of pharmaceuticals is still a challenging subject and solubilization using cosolvents is the most common technique used in the pharmaceutical industry. The purpose of this study was reporting and modeling the experimental molar solubility of pioglitazone hydrochloride (PGZ-HCl) in binary and ternary mixtures of ethanol (EtOH), N-methyl pyrrolidone (NMP), polyethylene glycols (PEGs) 200, 400, 600 and water along with the density of saturated solutions at 298.2 °K.

Methods

To provide a computational method, the Jouyban-Acree model was fitted to the solubilities of the binary solvents, and solubilities of the ternary solvents were back-calculated by employing the solubility data in mono-solvents. In the next step, the ternary interaction terms were added to the model and the prediction overall mean percentage deviation (MPD) of the ternary data was reduced. Also a previously proposed version of the model was used to predict the solubility of PGZ-HCl in binary and ternary mixtures employing the experimental solubility data in mono-solvents.

Results

The overall MPD of the model for fitting the binary data and predicted data of ternary solvents were 2.0 % and 50.5 %, respectively. The overall MPD of the predicted solubilities in ternary solvents using the ternary interaction terms in the model was 34.2 %, and by using the proposed version of the Jouyban-Acree model for binary and ternary data the overall correlation and prediction errors were 18.0 and 15.0 %, respectively.

Conclusion

The solubility of PGZ-HCl was increased by addition of EtOH, NMP, PEGs 200, 400 and 600 to aqueous solutions. The reported data extended the available solubility data of pharmaceuticals which are crucial in formulation of liquid dosage forms. The constants of the Jouyban-Acree model using the generated data are also reported which provides the possibility of solubility prediction in other solvent mixtures and temperatures.     

Solubility of drugs in aqueous solutions. Part 5. Thermodynamic consistency test for the solubility data

This paper is devoted to the verification of the quality of experimental data regarding the solubility of sparingly soluble solids, such as drugs, environmentally important substances, etc. in mixed solvents. A thermodynamic consistency test based on the Gibbs-Duhem equation for ternary mixtures is suggested. This test has the form of an equation, which connects the solubilities of the solid, and the activity coefficients of the constituents of the solute-free mixed solvent in two mixed solvents of close compositions. The experimental data regarding the solubility of sparingly soluble substances can be verified with the suggested test if accurate data for the activity coefficients of the constituents of the solute-free mixed solvent are available. The test was applied to a number of systems representing the solubilities of sparingly soluble substances in mixed solvents. First, the test was scrutinized for four nonaqueous systems for which accurate solubility data were available. Second, the suggested test was applied to a number of systems representing experimental data regarding the solubility of sparingly soluble substances in aqueous mixed solvents.     

Comparison of methods for predicting dissolution and the theoretical implications of particle-size-dependent solubility

Experimental dissolution data of cilostazol suspensions and hydrocortisone powders were simulated using either the Wang-Flanagan equation (1999. J Pharm Sci 88:731-738; 2002. J Pharm Sci 91:534-542) or the method of Johnson and coworkers (1989. Int J Pharm 51:9-17; 1993. Pharm Res 10:1308-1314; 1996. Pharm Res 13:1795-1798; 2003. Drug Dev Ind Pharm 29:833-842). Both methods were able to simulate experimental data with similar accuracy. For the method of Johnson and coworkers (1989. Int J Pharm 51:9-17; 1993. Pharm Res 10:1308-1314; 1996. Pharm Res 13:1795-1798; 2003. Drug Dev Ind Pharm 29:833-842), a single set of hydrodynamic assumptions was able to simulate both cilostazol and hydrocortisone with similar accuracy. For the Wang-Flanagan equation (1999. J Pharm Sci 88:731-738; 2002. J Pharm Sci 91:534-542), significantly different diffusion layer thicknesses gave the best simulations for cilostazol and hydrocortisone, but a single value of 38 μm provided good overall simulation of dissolution. The general computational method was enhanced to make solubility dependent on particle size, according to the Ostwald-Freundlich equation; it was also able to simulate Ostwald ripening. The enhanced computational method provided no way to explain the large increase in bioavailability of cilostazol in dogs when the drug was dosed as a nanoparticle versus micronized preparation. The method provides a computational tool for exploring theoretical implications and explaining the behavior of nanoparticles.     

The effect of temperature on the solubilities of testosterone propionate in low polarity solvents

The solubilities of testosterone propionate have been determined between 25 and 100° in 15 solvents and compared with theoretical values obtained from regular solution theory. Entropy considerations show that solvent-solute interactions occur in some solvents, increasing the solubility and resulting in deviations from regular solution behaviour. “Regular solutions” are obtained only in saturated hydrocarbon solvents, and the solubility is more accurately predicted as the temperature approaches the melting point, and as the molar volumes of solvent approach that of the solute.     

Influence of solvent composition on the solid phase at equilibrium with saturated solutions of quinolones in different solvent mixtures

The dissolution profiles and solubilities of three quinolonic drugs (oxolinic, pipemidic, and nalidixic acids) in different solvent mixtures were studied. The behavior of the solid phase, during solubility experiments was in-depth investigated with the aim of detecting possible crystalline modifications, such as polymorphic transitions or solvate formations, that might modify drug stability and/or solubility properties. In order to test the influence of both the nature and polarity of the co-solvents, aqueous and non-aqueous binary mixtures have been prepared by using Lewis base (dioxane and ethyl acetate) and amphiprotic co-solvents (ethanol and water). Differential scanning calorimetry (DSC), hot stage microscopy, IR spectroscopy and X-ray powder diffraction were used in combination with solubility and dissolution studies to characterize and investigate the solid state properties of the original powders and the corresponding ones at equilibrium with the different pure solvents and solvent mixtures examined. The solid phases of nalidixic and oxolinic acids did not show any change after equilibration with the various pure solvents or binary solvent mixtures, regardless the chemical nature of the examined solvents. On the contrary, in the case of pipemidic acid, the different analytical techniques used to characterize the drug solid state enabled identification of a solvated form at equilibrium with pure dioxane and a trihydrated form in aqueous mixtures of water with both ethanol (amphiprotic) or dioxane (Lewis base) in a concentration range from 10 to 100% water.     

Modeling the Solubility of Pharmaceuticals in Pure Solvents and Solvent Mixtures for Drug Process Design

The knowledge of the solubility of pharmaceuticals in pure solvents and solvent mixtures is crucial for designing the crystallization process of drug substances. The first step in finding optimal crystallization conditions is usually a solvent screening. Since experiments are very time consuming, a model which allows for solubility predictions in pure solvents and solvent mixtures based only on a small amount of experimental data is required. In this work, we investigated the applicability of the thermodynamic model perturbed-chain statistical associating fluid theory (PC-SAFT) to correlate and to predict the solubility of exemplary five typical drug substances and intermediates (paracetamol, ibuprofen, sulfadiazine, p-hydroxyphenylacetic acid, and p-aminophenylacetic acid) in pure solvents and solvent mixtures. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4205–4215, 2009     

Solubility of drugs in aqueous solutions. Part 1. Ideal mixed solvent approximation

The present paper deals with the application of the fluctuation theory of solutions to the solubility of poorly soluble drugs in aqueous mixed solvents. The fluctuation theory of ternary solutions is first used to derive an expression for the activity coefficient of a solute at infinite dilution in an ideal mixed solvent and, further, to obtain an equation for the solubility of a poorly soluble solid in an ideal mixed solvent. Finally, this equation is adapted to the solubility of poorly soluble drugs in aqueous mixed solvents by treating the molar volume of the mixed solvent as nonideal and including one adjustable parameter in its expression. The obtained expression was applied to 32 experimental data sets and the results were compared with the three parameter equations available in the literature.     

The effect of dry mixing on the apparent solubility of hydrophobic, sparingly soluble drugs.

The effect of dry mixing on the apparent solubility of two hydrophobic sparingly soluble drugs was studied. The materials were mixed with NaCl or glass beads in a Turbula mixer and the changes in solubility were monitored. It was shown that dry mixing caused an increase in the apparent solubility of test materials. It is suggested that the surfaces of the particles become activated and disordered during the dry mixing process. This peripheral surface disorder appears to be responsible for the increase in solubility. It was also shown that apparent solubility of the drugs after dry mixing was strongly dependent on the amount of drug added to the solvent, increasing with increasing concentrations. A plateau was established gradually at higher proportions of drug to solvent. Finally the applicability of the solubility model described by Mosharraf et al. (1999) [Mosharraf, M., Sebhatu, T., Nystr?m, C., 1999. The effects of disordered structure on solubility and dissolution rates of hydrophilic, sparingly soluble drugs. Int. J. Pharm. 177, 29-51] to the solubility behaviour of the hydrophobic sparingly soluble drugs tested in this study was confirmed. The results suggested that the equilibrium solubility plateau levels of a disordered material are determined by the degree and the location of disorder on the individual particles.     

Ternary systems of naproxen with hydroxypropyl-beta-cyclodextrin and aminoacids

The purpose of the present study was to investigate the combined effect of hydroxypropyl-beta-cyclodextrin and different aminoacids (L-lysine, LYS; L-valine, VAL; L-iso-leucine, LEU; and L-arginine, ARG) on the solubility of naproxen, a poorly water-soluble anti-inflammatory drug. Aqueous solubilities of naproxen in binary and ternary systems with hydroxypropyl-beta-cyclodextrin and each aminoacid were determined. The pH was measured in all solubility studies and its role on drug solubility variation was evaluated. Arginine was the most effective aminoacid in improving drug solubility and the only one which showed a synergistic effect when used in combination with hydroxypropyl-beta-cyclodextrin. In contrast, some reduction with respect to the theoretical drug solubility (i.e. the sum of the solubilities in the presence of cyclodextrin and aminoacid separately) was observed in ternary combinations with the other aminoacids. This occurred also in the case of lysine, despite the higher solubility of its ternary system in comparison with the binary cyclodextrin complex at pH 7. Phase-solubility experiments showed that the ternary system with arginine (pH approximately 7) exhibited a stability constant 3.6 times higher and was about 5.5 times more effective in improving drug solubility than the binary complex in buffered (pH approximately 7) aqueous solutions. These results demonstrated that the high increase in the drug solubility shown by ternary systems with arginine was not simply due to a favorable pH change but to multicomponent complex formation. Solid products of naproxen with hydroxypropyl-beta-cyclodextrin, and/or arginine, prepared by different methods, were characterized by Differential Scanning Calorimetry (DSC), Hot Stage Microscopy (HSM) and Scanning Electron Microscopy (SEM).     

The effects of pH and mixed solvent systems on the solubility of oxytetracycline

The solubility of oxytetracycline (OTC) in aqueous and mixed solvent systems was studied. The effects of pH and cosolvent composition on the solubility and apparent dissociation constants (pKa') of OTC were determined by a solubility method. The pKa' values of OTC in each mixed solvent system were estimated and used to generate expressions for predicting drug solubility in each cosolvent as a function of pH. Cosolvent systems of PEG 400, propylene glycol, glycerin, and 2-pyrrolidone were studied in the pH range of 2.5-9. Solubility results showed increased solubility with increased cosolvent concentration, especially in 2-pyrrolidone solvent systems. These results also showed that cosolvents enhanced drug solubility through either their effects on polarity of the solvent medium or complex formation with OTC. Aqueous and mixed solvent systems at lower pH values resulted in higher OTC solubilization because the drug existed primarily in its cationic form. A mass balance equation including all ionic species of OTC allowed for estimation of the intrinsic solubilities and pKa' values in each solvent system. pKa' values and intrinsic solubility of the OTC zwitterion increased with increasing cosolvent content. These parameters allowed prediction of drug solubility within the pH range and cosolvent concentrations used in this study.     

Estimation of the aqueous solubility of weak electrolytes

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 pK(a)+log S(w)相似文献   

A Modification of the Extended Hildebrand Approach to Predict the Solubility of Structurally Related Drugs in Solvent Mixtures

Abstract— A modification of the extended Hildebrand equation is proposed to estimate the solubility of an organic drug in solvent mixtures. The equation accurately reproduces the solubility of four sulphonamides in dioxane-water mixtures without requiring the heat of fusion of the solute. A single equation is obtained for predicting the solubility of related drugs using the solubilities of the drugs in the pure solvents, dioxane and water, and solute-solvent interaction terms consisting of the solubility parameter, δ₂, of the solute and the solubility parameter, δ₁, and basic partial solubility parameter, δ_1b, of the solvent mixture. By this procedure a single equation was obtained to estimate the solubilities of three xanthines in dioxane-water and another equation to obtain the solubilities of four sulphonamides. The equation obtained for sulphonamides is able to predict the experimental solubilities of two parent compounds, sulphasomidine and sulphathiazole, and the solubilities of a drug of different structure, p-hydroxybenzoic acid. This suggests that the intermolecular solute-solvent interaction of sulphonamides and p-hydroxybenzoic acid are similar. The results indicate that the solubility behaviour of drugs having different structures may be modelled using a common equation provided that they show similar solute-solvent interactions.     

Predicting the Octanol Solubility of Organic Compounds

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. and the American Pharmacists Association J Pharm Sci 102:2112–2119, 2013     

Structure formation and characterization of injectable drug loaded biodegradable devices: In situ implants versus in situ microparticles

The objective of the study was to investigate key formulation variables affecting the release of bupivacaine hydrochloride, a local anesthetic, from different in situ forming biodegradable drug delivery devices. The formulations included ISM systems [in situ microparticles, a poly(lactide)-solvent phase dispersed into an external oil phase] and poly(lactide) solutions (in situ implant systems). The solubility of the biodegradable polymer poly(d,l-lactide) (PLA) in various organic solvents was determined using the Hansen multicomponent solubility parameter concept. The solvent release from ISM and polymer solutions into phosphate buffer which influences the polymer precipitation rate was investigated as a function of the type of solvent, polymer concentration and polymer:oil phase ratio by using a HPLC assay. Scanning electron microscopy (SEM) was performed in order to relate the drug release to the surface properties of the precipitated implants or microparticles. Suitable solvents for the preparation of the in situ forming drug delivery systems, such as N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO) and 2-pyrrolidone were found using the Hansen multicomponent solubility parameter concept. The injection of the polymer solutions (in situ implants) into the aqueous medium led to a rapid solvent/non-solvent exchange. The resulting in situ implants were porous, thus explaining the rapid initial drug release. Upon contact with the release medium, the internal polymer phase of the ISM system solidified and formed microparticles as shown by SEM measurements. Due to the presence of an external oil phase the solvent release into the buffer medium from ISM was significantly slower compared to the polymer solutions. The solvent release of the ISM systems into the phosphate buffer decreased with increasing polymer concentration and decreasing polymer:oil phase ratio. The type of solvent used also affected the solvent release. A slower solvent release into the aqueous medium resulted in less porous microparticles, thus explaining the reduced initial drug release from ISM systems compared to the polymer solutions.     

Comparison of various cosolvency models for calculating solute solubility in water-cosolvent mixtures

Previously published cosolvency models are critically evaluated in terms of their ability to mathematically correlate solute solubility in binary solvent mixtures as a function of solvent composition. Computational results show that the accuracy of the models is improved by increasing the number of curve-fit parameters. However, the curve-fit parameters of several models are limited. The combined nearly ideal binary solvent/Redlich-Kister, CNIBS/R-K, was found to be the best solution model in terms of its ability to describe the experimental solubility in mixed solvents. Also resented is an extension of the mixture response surface model. The extension was found to improve the correlational ability of the original model.