Crystallization of probucol from solution and the glassy state.

Crystallization of probucol (PBL) from both solution and glassy solid state was investigated. In the crystallization study from solution, six solvents and three methods, i.e., evaporation, addition of a poor solvent, and cooling on ice, were used to obtain various crystal forms. In addition to common two crystal forms (forms I and II), two further forms (forms III and cyclohexane-solvate) were found in this study, and their thermodynamic relationships were determined. Forms I and II are likely to be enantiotropically related with thermodynamic transition temperature below 5°C. Isothermal crystallization studies revealed that PBL glass initially crystallized into form III between 25 and 50°C, and then transformed to form I. The isothermal crystallization appears to be a powerful option to find uncommon crystal forms. The crystallization of PBL was identified to be pressure controlled, thus the physical stability of PBL glass is higher than that of typical compounds.

Enhanced Boosting of Oral Absorption of Lopinavir Through Electrospray Coencapsulation with Ritonavir.

In vivo activities of absorption enhancers coencapsulated with poorly absorptive drugs in the same enteric-coated particles were evaluated. Lopinavir [a substrate of cytochrome P450 3A (CYP3A)] and ritonavir (an inhibitor of CYP3A-mediatd metabolism) were used as a model drug and a model absorption enhancer, respectively. Lopinavir and ritonavir were encapsulated into enteric-coated particles as amorphous forms using coaxial electrospray deposition. The electrospray treatment resulted in dramatic improvement of dissolution profiles of both compounds, probably because of complete amorphization and superior dispersion efficiency of the particles. Poor absorption of lopinavir in rats was observed after oral administration of enteric-coated particles containing lopinavir alone. When the particles were coadministered with enteric-coated particles containing ritonavir alone, lopinavir absorption was boosted. The boosting effect was further enhanced when ritonavir was coencapsulated with lopinavir into the same enteric-coated particles. A significant increase in area under the plasma concentration-time curve reflected an extension of mean residence time rather than an elevation of Cmax . Lopinavir absorption was improved presumably because lopinavir was always accompanied by a practical amount of ritonavir required for the boosting during the gastrointestinal transit of the particles. Not only did the electrospray coencapsulation technique improve drug absorption, but also increased trough concentration that might result in the reduction of the number of doses.