Development of clinical dosage forms for a poorly water-soluble drug II: formulation and characterization of a novel solid microemulsion preconcentrate system for oral delivery of a poorly water-soluble drug.

The solution of a poorly water-soluble drug in a liquid lipid-surfactant mixture, which served as a microemulsion preconcentrate, was converted into a solid form by incorporating it in a solid polyethylene glycol (PEG) matrix. The solid microemulsion preconcentrates thus formed consisted of Capmul PG8 (propylene glycol monocaprylate) as oil, Cremophor EL (polyoxyl 35 castor oil) as surfactant, and hydrophilic polymer PEG 3350 as solid matrix. The drug (aqueous solubility: 0.17 microg/mL at pH 1-8 and 25 degrees C) was dissolved in a melt of the mixture at 65-70 degrees C and then the hot solution was filled into hard gelatin capsules; the liquid gradually solidified upon cooling below 55 degrees C. The solid system was characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), confocal Raman microscopy (CRM), and the dispersion testing in water. It was confirmed that a solid microemulsion preconcentrate is a two-phase system, where clusters of crystalline PEG 3350 formed the solid structure (m.p. 55-60 degrees C) and the liquid microemulsion preconcentrate dispersed in between PEG 3350 crystals as a separate phase. The drug remained dissolved in the liquid phase. In vitro release testing showed that the preconcentrate dispersed readily in water forming a microemulsion with the drug dissolved in the oil particles (<150 nm) and the presence of PEG 3350 did not interfere with the process of self-microemulsification.

Measurement of surface pH of pharmaceutical solids: a critical evaluation of indicator dye-sorption method and its comparison with slurry pH method.

Two methods for the measurement of surface pH of pharmaceutical solids, namely, the dye-sorption method and the slurry pH method, were compared. High purity drug substances, instead of excipients, were used as model solids, because acidic or basic impurities present in excipients could influence slurry pH. Solid test samples were prepared by sorption of methanol-water solutions of several indicator dyes, and their diffuse reflectance UV-visible spectra were measured. The solid surface pH values were estimated by comparing base-to-acid peak ratios of the diffuse reflectance UV-visible spectra of solid samples to the calibration plots of dye solutions in aqueous standard buffers of known pH. In the slurry pH method, pH values of concentrated slurries of the compounds in water were considered to represent solid surface pH. The agreement between the two methods was mixed and depended on the compound or the indicator used. It was concluded that in many cases calibration plots of indicator dye spectra in aqueous buffers were not applicable to the solid state, and, as a result, the reliability of the method was low. The slurry method provided a simple and reliable measurement of surface pH indicating that concentrated slurry may closely represent solid surface pH.

Effect of chloride ion on dissolution of different salt forms of haloperidol, a model basic drug.

The effect of chloride ion (Cl-) on dissolution rates of hydrochloride, mesylate (methanesulfonate) and phosphate salt forms of a model drug, haloperidol, was investigated. The dissolution rates of the salts in 0.01 M HCl from rotating disks followed the order of mesylate>>phosphate>hydrochloride. With additional chloride ion, a decrease in dissolution rate of the hydrochloride salt was observed due to the common ion effect. Dissolution rates of mesylate and phosphate salts also decreased due to their conversion to the HCl salt form on the surfaces of dissolving disks, however, the dissolution rates of mesylate and phosphate salts under identical chloride ion concentrations were still higher than that of the HCl salt. In powder dissolution studies, it was observed that kinetics of nonhydrochloride-to-hydrochloride salt conversion play a major role in dissolution; the mesylate dissolved completely (<5 min) before its dissolution rate could be impeded by its conversion to the hydrochloride salt form. Therefore, despite the potential for conversion to a hydrochloride salt form, certain nonhydrochloride salt forms may still be preferred for dosage form development due to kinetic advantages during dissolution, such as higher apparent dissolution rate of a nonhydrochloride salt before it could completely convert to the hydrochloride form.