An example of how to handle amorphous fractions in API during early pharmaceutical development: SAR114137--a successful approach.

The so-called pharmaceutical solid chain, which encompasses drug substance micronisation to the final tablet production, at pilot plant scale is presented as a case study for a novel, highly potent, pharmaceutical compound: SAR114137. Various solid-state analytical methods, such as solid-state Nuclear Magnetic Resonance (ssNMR), Differential Scanning Calorimetry (DSC), Dynamic Water Vapour Sorption Gravimetry (DWVSG), hot-stage Raman spectroscopy and X-ray Powder Diffraction (XRPD) were applied and evaluated to characterise and quantify amorphous content during the course of the physical treatment of crystalline active pharmaceutical ingredient (API). DSC was successfully used to monitor the changes in amorphous content during micronisation of the API, as well as during stability studies.

From laboratory to pilot plant: the solid-state process development of a highly potent cathepsin S/K inhibitor.

The solid-state development for the low dose drug molecule SAR114137, a selective and reversible inhibitor of cysteine cathepsin S/K, is reported. Six polymorphic forms as well as various solvate phases were discovered by an extensive polymorphism screening. The solid phase characterizations revealed that phase 1, from which a single crystal structure could be obtained, is the thermodynamically most stable form and therefore it was chosen for pharmaceutical development.

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.