Physicochemical properties of the amorphous drug, cast films, and spray dried powders to predict formulation probability of success for solid dispersions: etravirine.

Solid dispersion technology represents an enabling approach to formulate poorly water-soluble drugs. While providing for a potentially increased oral bioavailability secondary to an increased drug dissolution rate, amorphous dispersions can be limited by their physical stability. The ability to assess formulation risk in this regard early in development programs can not only help in guiding development strategies but can also point to critical design elements in the configuration of the dosage form. Based on experience with a recently approved solid dispersion-based product, Intelence® (etravirine), a three part strategy is suggested to predict early formulate-ability of these systems. The components include an assessment of the amorphous form, a study of binary drug/carrier cast films and the evaluation of a powder of the drug and polymer processed in a manner relevant to the intended final dosage form. A variety of thermoanalytical, spectroscopic, and spectrophotometric approaches were applied to study the prepared materials. The data suggest a correlation between the glass forming ability and stability of the amorphous drug and the nature of the final formulation. Cast films can provide early information on miscibility and stabilization and assessment of processed powders can help define requirements and identify issues with potential final formulations.

An investigation into the crystallisation behaviour of an amorphous cryomilled pharmaceutical material above and below the glass transition temperature.

The aim of this study was to evaluate the glass transition and recrystallisation of a cryomilled drug, TMC125 (Etravirine), with particular emphasis on assessing the physical stability of the drug above and below the glass transition temperature. DSC (conventional, fast and modulated temperature) and variable temperature ATR-FTIR spectroscopy were employed to monitor the glass transition and crystallisation behaviour of the material. The isothermal crystallisation behaviour was investigated at temperatures below T(g). The humidity-induced crystallisation behaviour of the material was evaluated using dynamic vapour sorption (DVS). The glass transition (99 degrees C) was measured in isolation from the crystallisation process using fast DSC, while ATR-FTIR allowed identification of the polymorph formed on recrystallisation. At a heating rate of 0.2 degrees C/min, the onset temperature of the crystallisation exotherm (67 degrees C) was 32 degrees C below T(g). Evidence is presented for incomplete crystallisation under isothermal conditions. In conclusion, the study has ascertained the crystallisation profile of cryomilled Etravirine under both isothermal and scanning conditions, with the material showing marked physical instability below the measured T(g).