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).

Changes in the carotenoid content of apricot (Prunus armeniaca, var Bergeron) during enzymatic browning: ß-carotene inhibition of chlorogenic acid degradation.

Considering the numerous beneficial effects in human health ascribed to carotenoids, studies were performed to investigate the modification of carotenoid amount and composition during apricot enzymatic browning. First works on bruised apricot purees have shown a trans-ß-carotene isomerisation (20%) induced by enzymatic browning. To clarify this isomerisation, oxidation of chlorogenic acid in presence of trans-ß-carotene, catalysed by purified apricot polyphenoloxidase (PPO), was followed by HPLC and polarography. Isomerisation rate of trans-ß-carotene in its cis isomer was found to increase with chlorogenic acid concentration. Moreover, trans-ß-carotene was shown to be a potent inhibitor of phenol degradation. This inhibition was partially ascribed to PPO inhibition (non-competitive inhibitor towards phenol with an apparent Ki close to 0.5 mM, a mixed type inhibitor towards oxygen with an apparent Ki close to 0.15 mM). The additional inhibition was explained by non-enzymatic reactions involving trans-ß-carotene and chlorogenic acid o-quinones and leading to phenol regeneration and carotene isomerisation. © 2000 Society of Chemical Industry.