(170c) Transformation of an Amorphous API to Crystalline Hydrate and Co-Crystals

This research relates to a novel crystalline hydrate form of a Gilead development compound, GS-A, and novel crystalline co-crystals of GS-A with different co-formers.

Prior to the discovery of the crystalline hydrate form, GS-A existed for many years as an amorphous solid.  The first crystalline form was discovered through solvent mediated transformation of the amorphous material in water over an extended period of time, which produced GS-A hydrate.  The interaction between water molecules and GS-A molecules, especially hydrogen bonding between the two, appears to support the crystalline structure of the hydrate form.  The crystalline monohydrate is more stable and much less hygroscopic than the amorphous form, which make it a more suitable form for development.  

Development of a crystallization process to isolate GS-A crystalline hydrate on large scale will be discussed.  The parameters investigated include: solvent system, order of addition and seed loading.  Solvent systems which produced GS-A as the crystalline hydrate include: methanol/H₂O, ethanol/H₂O, 2-propanol/H₂O, di-isopropyl ether/toluene/H₂O and isopropyl acetate/heptane/H₂O.  One set of conditions were optimized to produce GS-A crystalline hydrate on multi-kilogram scale.

Additionally, GS-A+L-tartaric acid, GS‑A+D-tartaric acid, GS-A+malonic acid, GS-A+L-malic acid, GS-A+D-malic, and GS-A+benzoic acid co-crystals were discovered. In two cases, co-crystals were formed through slow crystallization from a resin at ambient temperature: L-Tartaric acid and benzoic acid.  Crystallization from solution was effective in producing co-crystals of GS-A with L-tartaric acid, malonic acid, L-malic acid, and D-malic acid.  This discovery is based on the expected significant degree of hydrogen bonding between GS-A and the co-former molecules.  These co-crystals of GS-A show improved physical properties (such as their anhydrous nature and higher melting points) compared to the crystalline monohydrate.