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.     

Extended hildebrand solubility approach: satranidazole in mixtures of dioxane and water

The extended Hildebrand solubility parameter approach is used to estimate the solubility of satranidazole in binary solvent systems. The solubility of satranidazole in various dioxane-water mixtures was analyzed in terms of solute-solvent interactions using a modified version of Hildebrand-Scatchard treatment for regular solutions. The solubility of satranidazole in the binary solvent, dioxane-water shows a bell-shaped profile with a solubility maximum well above the ideal solubility of the drug. This is attributed to solvation of the drug with the dioxane-water mixture, and indicates that the solute-solvent interaction energy is larger than the geometric mean (δ(1)δ(2)) of regular solution theory. The new approach provides an accurate prediction of solubility once the interaction energy is obtained. In this case, the energy term is regressed against a polynomial in δ(1) of the binary mixture. A quartic expression of W in terms of solvent solubility parameter was found for predicting the solubility of satranidazole in dioxane-water mixtures. The method has potential usefulness in preformulation and formulation studies during which solubility prediction is important for drug design.     

A Solubility and Related Physicochemical Property Comparison of Buprenorphine and Its 3-Alkyl Esters

Pharmaceutical Research -     

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.     

Solubility and Related Physicochemical Properties of Narcotic Analgesics

The physicochemical properties of select opioid and anilinopiperidine narcotic analgesics were investigated. The solubilities of the narcotics in hexane and water and, for morphine, in other organic solvents were determined. Regular solution theory seems to be applicable to the solubility behavior of morphine in solvents that lack strong dipoles and hydrogen bonds. A best-fit solubility parameter of 13.2 (cal/cm³) for morphine was determined from its solubilities in London solvents and its ideal solubility. Calculation of morphine's solubility parameter from its hexane solubility alone and its melting properties gave a corresponding ₂ value. These measured solubility parameters were appreciably larger than the solubility parameter estimated from molar attraction constants. Solubility parameters of hydromorphone, codeine, fentanyl, and sufentanil were also calculated from respective hexane solubilities, melting points, and heats effusion and were 11.7, 10.9, 9.8, and 9.7 (cal/cm³) . For these compounds, experimental solubility parameters agreed with solubility parameters estimated from molar attraction constants. Because meperidine, fentanyl, and sufentanil exhibit low levels of intracrystalline cohesion, as reflected in low melting points and relatively modest heats of fusion, theoretically projected ideal solubilities and actual solubilities in organic solvents measured for them were considerably higher than determined for morphine and its analogues. Consistent with the solubilities, the octanol–water partition coefficients of the two 4-anilinopiperidine analogues and of meperidine were several orders of magnitude larger than those of the opioids, evidencing the fact that meperidine, fentanyl, and sufentanil are substantially more lipophilic than the opioids.     

气相色谱法测定环孢素口服溶液中乙醇和丙二醇含量

目的：建立气相毛细管色谱法测定环孢素口服溶液中的乙醇和丙二醇含量;方法：色谱柱为TG-624(30 m × 0.25 mm × 1.4 μm),采用程序升温;进样口温度：200 ℃;检测器温度：220 ℃;柱流量：0.2 ml.min^-1;进样量：1 μl;进样方式：分流;分流比：20:1;载气：氮气;内标物为正丙醇,溶剂为二甲基亚砜。结果：乙醇在1.491 mg.ml^-1～3.479 mg.ml^-1的范围内,其峰面积与浓度呈良好线性关系,y=0.5376x-0.0422, r=0.9999;高、中、低三个浓度的加样回收率分别为99.6%、100.8%、99.5%;定量限为19.9 mg.ml^-1,检测限为6.0 mg.ml^-1;重复性和中间精密度的RSD分别为0.04%﹑0.33%。丙二醇在1.4639 mg.ml^-1～3.4157 mg.ml^-1的范围内线性关系良好,y=0.3924x-0.0152, r =0.9997;高、中、低三个浓度的加样回收率分别为101.3%、100.5%、100.6%;定量限为19.5 mg.ml^-1,检测限为5.8 mg.ml^-1;重复性和中间精密度的RSD分别为0.60%﹑0.74%。结论：经验证,该方法简便易行,线性、专属性、耐用性、精密度、稳定性良好,可用于测定环孢素口服溶液中乙醇和丙二醇含量。     

气相色谱法测定环孢素口服溶液中乙醇和丙二醇含量

目的：建立气相毛细管色谱法测定环孢素口服溶液中的乙醇和丙二醇含量;方法：色谱柱为TG-624(30 m × 0.25 mm × 1.4 μm),采用程序升温;进样口温度：200 ℃;检测器温度：220 ℃;柱流量：0.2 ml.min^-1;进样量：1 μl;进样方式：分流;分流比：20:1;载气：氮气;内标物为正丙醇,溶剂为二甲基亚砜。结果：乙醇在1.491 mg.ml^-1～3.479 mg.ml^-1的范围内,其峰面积与浓度呈良好线性关系,y=0.5376x-0.0422, r=0.9999;高、中、低三个浓度的加样回收率分别为99.6%、100.8%、99.5%;定量限为19.9 mg.ml^-1,检测限为6.0 mg.ml^-1;重复性和中间精密度的RSD分别为0.04%﹑0.33%。丙二醇在1.4639 mg.ml^-1～3.4157 mg.ml^-1的范围内线性关系良好,y=0.3924x-0.0152, r =0.9997;高、中、低三个浓度的加样回收率分别为101.3%、100.5%、100.6%;定量限为19.5 mg.ml^-1,检测限为5.8 mg.ml^-1;重复性和中间精密度的RSD分别为0.60%﹑0.74%。结论：经验证,该方法简便易行,线性、专属性、耐用性、精密度、稳定性良好,可用于测定环孢素口服溶液中乙醇和丙二醇含量。     

丙二醇与丙三醇红外光谱鬼峰的研究

目的：发现丙二醇与丙三醇红外光谱中鬼峰出现的缘由,建立方法去除鬼峰的干扰。方法：比较不同含水量样品的红外图谱膜法得到的红外光谱,分析鬼峰出现的原因;通过加热膜法控制鬼峰。结果：膜法制图1645cm^-1处有中等强度吸收峰,且含水量越高该峰强愈大;加热膜法制图该吸收峰消失或峰强显著降低。结论：鬼峰为水的吸收峰,采用加热膜法可避免鬼峰出现或有效控制鬼峰强度。     

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.     

Thermodynamics in the Prediction of the Solubilities of Binary Mixtures of the Diastereoisomers and Enantiomers of Ephedrine

Equations derived from the Clausius–Clapeyron and Prigogine–Defay equations were used to determine the free energy of mixing for diastereoisomers and enantiomers from heats of fusion and transition temperature data. These equations are applied to the thermodynamics of mixing of the six binary equimolar combinations of (lR,2S)-ephedrine, (1S,2R)-ephedrine; and (1R,2R)- and (1S,2S)-pseudo-ephedrine isomers. The relative equilibrium solubility of the binary mixtures in water is consistent with thermodynamic calculations.     

Effect of pH and solubility on in vitro skin penetration of methotrexate from a 50% v/v propylene glycol-water vehicle

In vitro percutaneous absorption of methotrexate from a saturated solution in a 50% v/v propylene glycol-water vehicle was examined across suitably characterized human cadaver skin. A detailed study of solubility and pH parameters in the range of 2–6 pH units was conducted. A clear trend towards increasing steady-state penetration rate with increasing pH was evident. Relatively high lag times were observed even at optimal pH values emphasizing the importance of prolonged application of drug to achieve therapeutic concentrations. From a vehicle at pH 2, the steady-state rate of penetration was very low and the data suggested drug binding with stratum corneum. Although the drug solubility in the vehicle was considerably lower at pH 4 than at pH 2–3, the steady-state rate and extent of penetration were higher. Both drug solubility and steady-state penetration rate were significantly higher at pH 5.29 than at pH 4. Increasing the vehicle pH to 6.34 increased the drug solubility as well as steady-state rate of penetration but the percent amount penetrated declined. The lag times were also large at this pH. Relatively high drug solubility and gradually increasing contribution of shunt pathways probably account for this result. In view of the observed pH-solubility profile, for a 50% v/v propylene glycol-water vehicle, a pH between 4 and 5 would appear to provide the most favorable environment for passive diffusion since the concentration of unionized methotrexate would be optimal.     

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.     

Forecasting the Oral Absorption Behavior of Poorly Soluble Weak Bases Using Solubility and Dissolution Studies in Biorelevant Media

Pharmaceutical Research -     

Prediction and improvement of protected peptide solubility in organic solvents*

A predictive method of solubility for protected peptide fragments of globular proteins was described. The solubility prediction was performed on the basis of both the randomness of peptide structures in a solid state and the existence of tertiary peptide bonds such as X-Pro and X-(Z)Y bonds, in which X and Y are arbitrary amino acid residues and Z is a suitable protecting group for the X-Y peptide bond. In order to predict the randomness, the coil conformational parameter, P_e, was utilized. Solubility prediction by this method was success fully applied to the two classes of protected peptides composed solely of hydrophobic and of various amino acid residues. The solubility test results also indicate that the protection of peptide bonds at suitable intervals is effective in achieving a remarkable improvement in the solubility of extraordinarily insoluble peptides. Lastly, the strategy for the selection of the coupling routes in the protein syntheses was proposed.     

The Application of Modeling and Prediction to the Formation and Stability of Amorphous Solid Dispersions

Amorphous solid dispersion (ASD) formulation development is frequently difficult owing to the inherent physical instability of the amorphous form, and limited understanding of the physical and chemical interactions that translate to initial dispersion formation and long-term physical stability. Formulation development for ASDs has been historically accomplished through trial and error or experience with extant systems; however, rational selection of appropriate excipients is preferred to reduce time to market and decrease costs associated with development. Current efforts to develop thermodynamic and computational models attempt to rationally direct formulation and show promise. This review compiles and evaluates important methods used to predict ASD formation and physical stability. Recent literature in which these methods are applied is also reviewed, and limitations of each method are discussed.