|If I am overdried, re-hydrate me!|
Credit: Rassias et al., OPRD
Polymorphism undoubtedly will continue to be an issue for developing drug substances and for continued manufacture of drug products... Solid-state transformations should not be overlooked. Hydrates may be overdried; rehydration of a dried phosphate salt was carried out by passing moist nitrogen through the dryer.For the above overdrying event, Dr. Anderson cites this Organic Process Research and Development paper  from workers at GSK:
Upon drying, however, 1 dehydrates, and significant efforts were made to meet the challenge of consistent preparation of the monophosphate monohydrate salt. In collaboration with our Particle Science and Physical Properties departments no other hydrated forms were identified by standard solid form screening methods.
Subsequently, the dehydration of the monohydrate was shown to be fully reversible by DSC, GVS, XRPD, and Raman spectroscopy. At scale, a reconditioning process was implemented using a Boltz dryer to achieve dehydration followed by the application of a moist nitrogen stream through the dryer to rehydrate to the monohydrate. This method proved robust and consistent for the manufacture of iNOS inhibitor 1 which was also analysed by a variety orthogonal techniques including chiral HPLC (99.9% PAR), metal analysis (Pd not detected), phosphate and water analysis (consistent with the monophoshate mononohydrate stoichiometry), and XRPD (consistent with desired polymorph and crystallinity).I suspect that overdrying events (especially when polymorphs are involved) are not usually so simple to fix, so it's still incumbent on process chemists to define the temperature parameters of drying steps and for operators to keep a careful watch over their drying temperatures. That said, it is very interesting to learn that, in this case, the solution was to "overdry" the material and then re-hydrate the molecule.
1. Rassias, G.*, Hermitage, S.A.*; Sanganee, M.J.; Kincey, P.M.; Smith, N.M.; Andrews, I.P.; Borrett, G.T.; Slater, G.R. "Development of a Supply Route for the Synthesis of an iNOS Inhibitor: Complications of the Key SN2 Reaction." Org. Process Res. Dev., 2009, 13 (4), pp 774–780.