Wednesday, August 13, 2014

Process Wednesday: overdried a hydrate? You can rehydrate it!

If I am overdried, re-hydrate me!
Credit: Rassias et al., OPRD
Flipping through Practical Process Research and Development, I happened upon an interesting entry in the index: "overdrying." Here's what Neal Anderson has to say about it: 
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 [1] 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.


  1. for process/formulation people: If I remember correctly, isn't this the actual reason why hydrates are shunned if possible, when you are developing crystal salt form of active substance? Maybe screening more salt forms would have avoided this complication...

  2. Milkshake I would suggest "shunned" may be a little strong but as hydrate forms may have a (undeserved?) reputation to misbehave in terms of desired reproducibility and control and sometimes stability profile if they are encountered should prompt the antenna to tingle plus promote more experimental work upfront to help avoid an unpleasant surprise later. While screening alternate salts and conditions is always a good idea typically for these aspects of a project there is always great pressure and no/limited time frame to come up with anything to move forward and therefore will start with simplistic and known compositions or conditions and unless do see immediate problems rarely get a chance to engage in much true development. Its too bad as both crystallization and formulation efforts are often amenable to matrix/DOE type approach that can generate extensive data with less work that may only ever get done until two to four years late when actually do run into a plant issues (and of course then demands include extremely quick response under critical management microscope). In the end like most of development its about learning as much as possible and paying attention to determine if having a hydrate may or may not increase problems.