Enthalpy and Entropy Contributions to the Solubility of Sulphamethoxypyridazine in Solvent Mixtures Showing Two Solubility Maxima

The solubility of sulphamethoxypyridazine was measured at several temperatures in mixtures of water: ethanol and ethanol: ethyl acetate. Sulphamethoxypyridazine was chosen as a model drug to compare the solvation effects of proton donor-proton acceptor (water and ethanol) and proton acceptor (ethyl acetate) solvents and mixtures of these solvents because this drug contains functional groups capable of Lewis acid-base interaction. A plot of the mole fraction solubility against the solubility parameter (δ₁) of these solvent mixtures showed two solubility maxima, one at δ₁ = 30·87 MPa^1/2 (20:80 v/v water: ethanol) and another at δ₁ = 20·88 MPa^1/2 (30:70 v/v ethanol: ethyl acetate) at all the temperatures under study. The enthalpies and entropies of mixing as well as the enthalpies and entropies of transfer of sulphamethoxypyridazine from ethanol to water:ethanol and ethanol:ethyl acetate mixtures were calculated to compare solvation characteristics of the solvent mixtures toward the drug. As ethanol is added to water, the entropy increases and the structure of the solvent mixture became less ordered, favouring the interaction of the drug with the solvent mixture. On the other hand, in the case of the ethanol: ethyl acetate mixture, solubility is favoured by the more negative enthalpy values. This way, the same result, i.e. a solubility maximum, is obtained by different routes. In the ethanol: water mixtures, the dissolution process is entropy-controlled while enthalpy is the driving force in the case of ethanol: ethyl acetate mixtures. The two solvent systems show enthalpy-entropy compensation. Water deviates from the linear relationship due possibly to its hydrophobic effect.     

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.     

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     

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     

Solubility Prediction of Satranidazole in Propylene Glycol-Water Mixtures Using Extended Hildebrand Solubility Approach

Extended Hildebrand solubility approach is used to estimate the solubility of satranidazole in binary solvent systems. The solubility of satranidazole in various propylene glycol-water mixtures was analyzed in terms of solute-solvent interactions using a modified version of Hildebrand-Scatchard treatment for regular solutions. The solubility equation employs term interaction energy (W) to replace the geometric mean (δ₁δ₂), where δ₁ and δ₂ are the cohesive energy densities for the solvent and solute, respectively. The new equation provides an accurate prediction of solubility once the interaction energy, W, is obtained. In this case, the energy term is regressed against a polynomial in δ₁ of the binary mixture. A quartic expression of W in terms of solvent solubility parameter was found for predicting the solubility of satranidazole in propylene glycol-water mixtures. The expression yields an error in mole fraction solubility of ~3.74%, a value approximating that of the experimentally determined solubility. The method has potential usefulness in preformulation and formulation studies during which solubility prediction is important for drug design.     

The Estimation of Solubility in Binary Solvents: Application of the Reduced 3-Suffix Solubility Equation to Ethanol–Water Mixtures

The reduced 3-suffix solubility equation (R3SSE) is applied to the characterization of solubility in the ethanol–water system. The data needed are the solubility of the compound in each of the pure solvents and at one ethanol–water composition. This composition has been estimated from solubility data to be 0.56 volume fraction of ethanol. The solubility obtained at this volume fraction is used to estimate the ternary solute–solvent interaction constant, C ₂. The R3SSE, with the C ₂ thus obtained, predicts the mixed solvent solubilities of the compounds tested, as accurately as that obtained from several volume fractions. The superiority of the R3SSE over two related equations—a simple second-degree polynomial equation and a simplified form of the R3SSE which neglects contributions to solubility from the solvent mixture—is also demonstrated for a number of solutes.     

Solubility Prediction of Satranidazole in Aqueous N,N-dimethylformamide Mixtures Using Extended Hildebrand Solubility Approach

The solubility of satranidazole in several water–N,N-dimethylformamide mixtures was analysed in terms of solute–solvent interactions and data were treated on the basis of extended Hildebrand solubility approach. The solubility profile of satranidazole in water–N,N-dimethylformamide mixtures shows a curve with a solubility maxima well above the ideal solubility of drug. This is attributed to solvation of the drug with the water–N,N-dimethylformamide mixture, and indicates that the solute–solvent interaction energy (W) is larger than the geometric mean (δ₁δ₂) of regular solution theory. The new approach provides an accurate prediction of solubility once the interaction energy (W) is obtained. In this case, the energy term is regressed against a polynomial in δ₁ of the binary solvent mixture. A quartic expression of W in terms of solvent solubility parameter was found for predicting the mole fraction solubility of satranidazole in the studied mixtures. The method has potential usefulness in preformulation and formulation studies during which solubility prediction is important for drug design.     

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 (pK′_a) of OTC were determined by a solubility method. The pK′_a 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 pK′_a values in each solvent system. pK′_a 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.     

Predicting Blood-Brain Transport of Drugs: A Computational Approach

Purpose. This study was conducted to determine the efficacy of using nonempirical parameters in the estimation of blood-brain transport, inferred from central nervous system (CNS) activity, for a set of twenty-eight compounds. Methods. A discriminant function analysis was used to construct three distinct models based on topological indices, a hydrogen-bonding parameter, and logP. Results. These models correctly predict the CNS activity of twenty-seven of the twenty-eight compounds. Conclusions. Nonempirical parameters may be used effectively in the estimation the cerebrovascular penetration for known and newly designed drugs.     

Predicting the Tensile Strength of Compacted Multi-Component Mixtures of Pharmaceutical Powders

Purpose Pharmaceutical tablets are generally produced by compacting a mixture of several ingredients, including active drugs and excipients. It is of practical importance if the properties of such tablets can be predicted on the basis of the ones for constituent components. The purpose of this work is to develop a theoretical model which can predict the tensile strength of compacted multi-component pharmaceutical mixtures.Methods The model was derived on the basis of the Ryshkewitch‐Duckworth equation that was originally proposed for porous materials. The required input parameters for the model are the relative density or solid fraction (ratio of the volume of solid materials to the total volume of the tablets) of the multi-component tablets and parameters associated with the constituent single-component powders, which are readily accessible. The tensile strength of tablets made of various powder blends at different relative density was also measured using diametrical compression.Results It has been shown that the tensile strength of the multi-component powder compacts is primarily a function of the solid fraction. Excellent agreement between prediction and experimental data for tablets of binary, ternary and four-component blends of some widely used pharmaceutical excipients was obtained.Conclusion It has been demonstrated that the proposed model can well predict the tensile strength of multi-component pharmaceutical tablets. Thus, the model will be a useful design tool for formulation engineers in the pharmaceutical industry.     

Solvent Effects on the Solubility and Physical Stability of Human Insulin-Like Growth Factor I

Purpose. The solubility and physical stability of human Insulin-like Growth Factor I (hIGF-I) were studied in aqueous solutions with different excipients. Methods. The solubility of hIGF-I was determined by UV-absorption and quantification of light blocking particles. The physical stability of hIGF-I was studied with differential scanning calorimetry (DSC) and circular dichroism (CD) spectroscopy. Results. Human IGF-I precipitated at low temperature in the presence of 140 mM benzyl alcohol and 145 mM sodium chloride. CD data showed that the tertiary structure of hIGF-I during these conditions was perturbed compared to that in 5 mM phosphate buffer. In the presence of benzyl alcohol 290 mM mannitol stabilized hIGF-I. Sodium chloride or mannitol by themselves had no effect on either the solubility or the tertiary structure. Benzyl alcohol was attracted to hIGF-I, whereas sodium chloride was preferentially excluded. The attraction of benzyl alcohol was reinforced by sodium chloride leading to salting-out of hIGF-I. The CD-data indicated interactions of benzyl alcohol with phenylalanine in hIGF-I. Thermal denaturation of hIGF-I occurred in all solutions with sodium chloride, whereas mannitol or benzyl alcohol had no effect on the thermal stability. The thermal stability of hlGF-I was thus decreased in 145 mM sodium chloride although it was excluded from hIGF-I. Conclusions. The self-association and thermal aggregation of hIGF-I is driven by hydrophobic interactions. Benzyl alcohol is attracted to hIGF-I and induces changes in the tertiary structure causing hydrophobic attraction of the protein at low temperatures.     

Enhancement of the Solubility and Efficacy of Poorly Water-Soluble Drugs by Hydrophobically-Modified Polysaccharide Derivatives

Purpose This work was intended to develop and evaluate a new polymeric system based on amphiphilic carboxymethylpullulans (CMP₄₉C₈ and CMP₁₂C₈) that can spontaneously self-assemble in aqueous solutions and efficiently solubilize hydrophobic drugs. Methods The self-assembling properties of CMP₄₉C₈ and CMP₁₂C₈ were characterized by fluorescence spectroscopy and surface tension measurements. The solubilization of benzophenone and docetaxel was assessed from surface tension measurements, UV spectrometry and HPLC assays. The in vitro cytoxicity of CMP₄₉C₈ solutions and the docetaxel commercial vehicle (Tween 80?/Ethanol–water) were evaluated in the absence and in the presence of docetaxel. Results Compared to CMP₁₂C₈, CMP₄₉C₈ in aqueous solutions appeared to self-organize into monomolecular aggregates containing hydrophobic nanodomains, and to significantly increase the apparent solubility of benzophenone. Docetaxel solubility could also be improved in the presence of CMP₄₉C₈ but to a lower extent due to the surface properties of the drug. Nevertheless, in vitro, the cytotoxicity studies revealed that against cancer cells, the CMP₄₉C₈-docetaxel formulation was equipotent to the commercial docetaxel one. Furthermore, in the absence of the drug, CMP₄₉C₈ appeared less cytotoxic against macrophages than the Tween? 80/Ethanol–water. Conclusions CMP₄₉C₈ is a good candidate for solubilizing hydrophobic drugs and could be applied to docetaxel formulations.     

Predicting the Solubility of the Anti-Cancer Agent Docetaxel in Small Molecule Excipients using Computational Methods

Purpose To develop an in silico model that provides an accurate prediction of the relative solubility of the lipophilic anticancer agent docetaxel in various excipients. Materials and Methods The in silico solubility of docetaxel in the excipients was estimated by means of the solubility (δ) and Flory-Huggins interaction (χ _FH) parameters. The δ values of docetaxel and excipients were calculated using semi-empirical methods and molecular dynamics (MD) simulations. Cerius² software and COMPASS force-field were employed for the MD simulations. The χ _FH values for the binary mixtures of docetaxel and excipient were also estimated by MD simulations. Results The values obtained from the MD simulations for the solubility of docetaxel in the various excipients were in good agreement with the experimentally determined values. The simulated values for solubility of docetaxel in tributyrin, tricaproin and vitamin E were within 2 to 6% of the experimental values. MD simulations predicted docetaxel to be insoluble in β-caryophyllene and this result correlated well with experimental studies. Conclusions The MD model proved to be a reliable tool for selecting suitable excipients for the solubilization of docetaxel. Electronic supplementary material The online version of this article (doi: ) contains supplementary material, which is available to authorized users.     

Solvent effects on chemical processes. I: Solubility of aromatic and heterocyclic compounds in binary aqueous-organic solvents.

The standard free energy change (delta G0) for equilibrium dissolution in binary solvent mixtures is written as a sum of effects arising from solvent-solvent interactions (the general medium effect), solvent-solute interactions (the solvation effect), and solute-solute interactions (the intersolute effect). The general medium effect is given by gA gamma, where g is a curvature correction factor to the surface tension (gamma) and A is the molecular cavity surface area. A new feature is the definition of gamma to be that value appropriate to the equilibrium mean solvation shell composition. The solvation effect is modeled by stoichiometric stepwise competitive equilibria between the two solvent components for the solute. The intersolute effect includes the crystal energy and solution phase interactions. In this work, water was solvent component 1, and various miscible organic cosolvents served as solvent component 2. Relating all data to the fully aqueous solution gives an explicit expression for delta M delta G0, the solvent effect on the free energy change, as a function of the mole fractions x1 and x2. This function is a binding isotherm. Nonlinear regression leads (for a two-step solvation scheme) to estimates of the solvation exchange constants K1 and K2 and the parameter gA. This relationship was applied to 44 systems comprising combinations of 31 solutes and eight organic cosolvents. Curve fits were good to excellent, and most of the parameter estimates had physically reasonable magnitudes.     

Estimation of the Increase in Solubility of Drugs as a Function of Bile Salt Concentration

Purpose. The objective of this study was to develop a model to predict the extent to which bile salts can enhance the solubility of a drug, based on the physicochemical properties of the compound. The ability to predict bile salt solubilization of poorly soluble drugs would be a key component in determining which drugs will exhibit fed vs. fasted differences in drug absorption. Methods. A correlation between the logarithm of the octanol/water partition coefficient [log P] of six steroidal compounds and their solubilities in the presence of various concentrations of sodium taurocholate at 37°C, log [SR] = 2.234 + 0.606 log [P] (r² = 0.987) where SR is the ratio of the solubilization capacity of the bile salt to the solubilization capacity of water for the drug, was used to predict the solubility of five further compounds with diverse structures. The solubilities of the compounds in presence of sodium taurocholate were then measured. Results. The predicted solubilities were within 10% of the experimentally observed solubilities for griseofulvin, cyclosporin A and pentazocine. The model overpredicted the solubility of phenytoin and diazepam in 15 mM sodium taurocholate solution by a factor of 1.33 and 1.62 respectively. Conclusions. The expected increase in solubility as a function of bile salt concentration can be estimated on the basis of the partition coefficient and aqueous solubility of the compound.     

Inhibiting the Gastric Burst Release of Drugs from Enteric Microparticles: The Influence of Drug Molecular Mass and Solubility

Undesired drug release in acid medium from enteric microparticles has been widely reported. In this paper, we investigate the relative contribution of microparticle and drug properties, specifically microsphere size and drug’s molecular weight and acid solubility, on the extent of such undesired release. A series of nine drugs with different physicochemical properties were successfully encapsulated into Eudragit S and Eudragit L microparticles using a novel emulsion solvent evaporation process. The process yielded spherical microparticles with a narrow size distribution (27–60 and 36–56 mm for Eudragit L and Eudragit S microparticles, respectively). Upon incubation in acid medium (pH 1.2) for 2 h, the release of dipyridamole, cinnarizine, amprenavir, bendroflumethiazide, budesonide and prednisolone from both Eudragit microparticles was less than 10% of drug load and conformed with the USP specifications for enteric dosage forms. In contrast, more than 10% of the entrapped paracetamol, salicylic acid and ketoprofen were released. Multiple regression revealed that the drug’s molecular weight was the most important factor that determined its extent of release in the acid medium, while its acid solubility and microsphere’s size had minor influences.     

New Formulation Technique for Solubility and Dissolution Rate Enhancement of Poorly Soluble Drugs

Pharmaceutical Chemistry Journal - Ebastine (EBS) is a second-generation non-sedating antihistamine used for the prevention and treatment of allergic rhinitis and chronic idiopathic urticaria. It...     

Solubility and partitioning. IX: Solubility of hydantoins in water

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 degrees 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.