B. Escalera

Solubility behavior of polymorphs I and II of mefenamic acid in solvent mixtures.

The dissolution profile and solubility of two polymorphic forms of mefenamic acid were studied in solvent mixtures of ethanol-water and ethyl acetate-ethanol. The solubility parameter (delta) was used to study the effect of polarity on the solubility behavior of the two polymorphs. Differential scanning calorimetry and infrared spectroscopy were performed on the original powders and on the solid phases after contact with the solvent systems for the characterization and identification of the polymorphs. The dissolution rates of both polymorphs is greater in the less polar mixtures (ethyl acetate-ethanol) of lower solubility parameter values. Form II showed larger dissolution rates and saturation concentrations than Form I in all the solvent systems studied. The solid phase of Form II converts totally to Form I after equilibration with the solvents. The rate of conversion was faster in the least polar mixtures. The solubility of both polymorphs reaches a single maximum at 80% ethyl acetate in ethanol, delta = 20.09 MPa1/2. The modified extended Hildebrand method was used to predict the solubility profile of each polymorph. A single equation was obtained for both polymorphs which includes the solubility parameter of the mixtures and the logarithm of the solubility mole fraction of each polymorph in water. The Hildebrand solubility parameter of mefenamic acid is independent of the crystalline form and was determined from two methods giving quite similar values, delta 2 = 20-21 MPa1/2.

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, δ1b, 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.

Influence of temperature on the solubilization of thiabendazole by combined action of solid dispersions and co-solvents

Co-solvents and solid dispersions with polyvinyl pyrrolidone were tested to increase solubility of thiabendazole. Solid dispersions were prepared by the solvent method and analyzed by differential scanning calorimetry. The solubility was measured at 15-35 degrees C in aqueous (ethanol-water) and non-aqueous (ethanol-ethyl acetate) mixtures. Combination of solid dispersions with cosolvents increased the water solubility of thiabendazole in a larger extent that each method separately. The effect of the solid dispersions is greatest in water and it decreases nonlinearly as the volume fraction of ethanol-in water increases. The solubility enhancement is smaller in ethanol-ethyl acetate and is uncorrelated with co-solvent concentration. Solubility parameters delta were used to predict drug/carrier compatibility and related to solubility profiles. Thiabendazole shows an intermediate behaviour between solubility curves with two peaks (more polar drugs with larger delta values) and a single peak (less polar drugs with lower delta values). The solid dispersions increase the solubility parameter of thiabendazole from delta=24 to delta=25.7 MPa(1/2). The model of Bustamante et al. allowed solubility prediction including jointly both mixtures whereas the equation of Jouyban et al. was able to predict the solubility at several temperatures in each binary mixture separately, using a few experiments.

Solubility Parameter-Based Methods for Predicting the Solubility of Sulfapyridine in Solvent Mixtures

AbstractSulfapyridine is used to test the extended Hildebrand approach for predicting solubility in dioxane-water mixtures. The method provided good agreement with the experimental data. A modification of this method, that directly relates the logarithm of the mole fraction solubility with the solubility parameter of the solvent mixture (δ1) gave results comparable to that of the extended Hildebrand approach. This suggests that the volume fraction of the solvent can be disregarded in the solubility equation. The modified method does not require the knowledge of the ideal solubility of the drug. A single equation based on the solubilities of several sulfonamides is able to accurately calculate the solubility profile of sulfapyridine from 0 to 70% water in dioxane. Beyond 70% water, the extended Hildebrand method or its simplified form provide less errors, but these methods require 12-14 experimental solubilities, whereas the single equation only needs two experimental solubilities.

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.

Thermodynamics of Cosolvent Action: Phenacetin, Salicylic Acid and Probenecid

The solubility of phenacetin, salicylic acid, and probenecid in ethanol-water and ethanol-ethyl acetate mixtures at several temperatures (15-40 degrees C) was measured. The solubility profiles are related to medium polarity changes. The apparent thermodynamic magnitudes and enthalpy-entropy relationships are related to the cosolvent action. Salicylic acid and probenecid show a single peak against the solubility parameter delta(1) of both solvent mixtures, at 40% (delta(1) = 21.70 MPa(1/2)) and 30% (delta(1) = 20.91 MPa(1/2)) ethanol in ethyl acetate, respectively. Phenacetin displays two peaks at 60% ethanol in ethyl acetate (23.30 MPa(1/2)) and 90% ethanol in water (delta(1) = 28.64 MPa(1/2)). The apparent enthalpies of solution display a maximum at 30% (phenacetin and salicylic acid) and 40% (probenecid) ethanol in water, respectively. Two different mechanisms, entropy at low ethanol ratios, and enthalpy at high ethanol ratios control the solubility enhancement in the aqueous mixture. In the nonaqueous mixture (ethanol-ethyl acetate) enthalpy is the driving force throughout the whole solvent composition for salicylic acid and phenacetin. For probenecid, the dominant mechanism shifts from entropy to enthalpy as the ethanol in ethyl acetate concentration increases. The enthalpy-entropy compensation plots corroborate the different mechanisms involved in the solubility enhancement by cosolvents.

Hildebrand solubility parameter to predict drug release from hydroxypropyl methylcellulose gels.

An equation including the Hildebrand solubility parameter δ of the drugs is used for the first time to model drug release from hydroxypropyl methylcellulose (HPMC) gels: l nM = -21.578 + 2.102 δ-0.037 δ(2)+0.48 ln t + 1.028 ln C(i) (r(2) = 0.94 for a total of 286 cases). The experimentally determined release data of six drugs having different polarity (caffeine, theophylline, paracetamol, salicylic acid, naproxen and diclofenac) at several initial concentrations C(i) were included in the equation. In general, the amount of drug delivered is linear at the first 5-6h of the release profiles and the zero order constants K(o) increase as the solubility parameter of the drugs become larger. The Peppas exponential law M/M(∞) = Kt(n) is applicable to larger fractional release, until 67-87% (48-51 h) for the less polar drugs (diclofenac and naproxen, lower δ values) and more than 80% (26-28 h) for the more polar drugs (higher δ values, theophylline, salicylic acid, caffeine and paracetamol). The Peppas release rate (lnK) shows a parabolic relationship with the drug solubility parameter. The diffusional exponent n varies between 0.40 and 0.58 indicating that drug release is mainly controlled by diffusion. An extended form of the Peppas equation is also tested for each drug including all the initial concentrations: lnM = a + b ln t + c ln C(i) (r(2) = 0.88-0.94). The logarithm of the octanol-water partition coefficients can also be used in combination with the drug concentrations.

The E and C model for predicting the solubility of drugs in pure solvents

The E and C model for hydrogen bonding is used together with nonspecific solubility parameters to predict the solubility of a Lewis base solute in a series of solvents of several chemical classes. A linear relationship between enthalpies of hydrogen bonding calculated from the Drago model and entropies obtained from a few experimental solubilities allows the prediction of the entropy contribution for the other solvents. Correct orders of magnitude are predicted in solvents of all polarities (from benzene to glycerin) which were not used to obtain the empirical relationships. The results suggest that the E and C model may be useful to reduce the experimental work usually needed for predicting solubility of drugs in pure solvents of different acid-base characteristics.

Innovación Pedagógica y Elaboración de una Guía de Aprendizaje en Tecnología Farmacéutica Industrial

Resumen El objetivo del presente trabajo, es disenar un plan didactico siguiendo estrategias de ensenanza-aprendizaje marcadas por las orientaciones europeas y plantear un sistema de evaluacion que responde a las exigencias del modelo de formacion implantado. Se incluye en el estudio aspectos relacionados con la formacion por competencias. La aplicacion de esta guia consigue incluir mejoras adaptadas a las necesidades detectadas a partir de sucesivos cursos academicos y que pueden seguir usandose hasta que se pongan en marcha los nuevos planes de estudio. Ademas, en el ambito del alumnado se obtuvo un gran interes por la asignatura con un alto grado de motivacion y compromiso. Muchas de estas cuestiones sirven como punto de partida y de reflexion previa, e incluso ayudan a mejorar el plan docente de la asignatura. Palabras clave: guia de aprendizaje, competencias, evaluacion, plan didactico, innovacion Pedagogical Innovation and Elaboration of a Learning Guide In Industrial Pharmaceutical Technology