Challenges in the development of hydrate phases as active pharmaceutical ingredients--an example.

The challenges during pilot plant scale-up of the SAR474832 API (active pharmaceutical ingredient) production in view of crystallization, isolation, drying and micronization are reported. A variety of different solid-state analytical and spectroscopic techniques (also coupled methods) were applied in order to understand the complex phase transition behaviour of the crystallographic phase (form 1) chosen for development: a partially non-stoichiometric channel-hydrate (x (1+1.25) H(2)O) crystallizing from pure water in the crystal habit of fine needles, which tend to agglomerate upon isolation and drying. Processes have been developed for drying, sieving and micronization by jetmilling to avoid non-desired phase transitions (overdrying effects) into other hydrate forms. Special methods have been established to minimize, monitor and control the formation of amorphous content during the particle size reduction steps. By optimizing all production parameters it was possible to produce API batches in 10 kg scale with physical quality suitable for oral formulations (e.g. particle size d 90 value<20 μm, water content and crystallographic phase corresponding to desired form 1 of SAR474832).