Meeting Customer Needs: Tailoring the Physical Properties of An Active Pharmaceutical Ingredient Through Crystal Engineering

A pharmaceutical compound recently in development exists as two enantiotropic anhydrate polymorphs and as a dihydrate, with the dihydrate being unstable in the formulated product.  Patient expectations of a small tablet required a high concentration of drug substance in the product.  A high shear wet granulation process cannot be used as part of tablet manufacture to avoid conversion to the dihydrate.  As a result, a dry granulation process was required.  The high drug load required the drug substance to have good flow properties as a dry powder.  API produced by a typical temperature and anti-solvent driven crystallization process generated API with poor powder flow characteristics; tablets produced using this API had to be manually sorted to meet tablet weight requirements.  The poor flow characteristics, resulting from a needle-like particle morphology and small particle size, led to the loss of tablet weight control. 

Particle morphology was improved through the careful control of supersaturation, the incorporation of in situ milling during crystallization, and thermal cycling.  The result of the crystal engineering process is particles having a rod-like morphology approaching cubes.  The particles are three times wider on average than those produced from a conventional crystallization.  The flow characteristics are greatly improved and have enabled tablets to be manufactured using a dry process at high (greater than 35%) drug loads with low tablet weight relative standard deviation.  The control of polymorph selectivity will also be discussed.