(23b) Slurry Crystallization of Water-Insoluble Drug Substance – Overcoming Challenges in Solubility and Miscibility Requirements for Solvents and Anti-Solvents

In the crystallization development of water-insoluble drug substances, a common issue encountered is the availability of proper solvents and anti-solvents.  Ideally, a proper solvent would possess a sufficient solubility at the beginning to dissolve the drug substance, and then its solubility can be sufficiently reduced by adding a solvent-miscible anti-solvent, to crystallize out the drug substance.  The dual requirements of solubility and miscibility for both solvents and anti-solvents can be challenging from time to time.

In our case, we present a unique slurry crystallization approach as one solution to bypass such constraints.  In the 1^st part of the slurry crystallization process, the drug substance is slurried in the solvent which has only limited drug substance solubility.  The slurry is seeded with the drug substance of the right crystal form, which subsequently converts all un-dissolved drug substance to the correct crystal form.  By this approach, the solubility constraint to dissolve the entire drug substance is successfully bypassed.

In the 2^nd part of the slurry crystallization process, the slurry is charged to an anti-solvent, which has a very low solubility, in order to minimize the loss in the mother liquor.  As mentioned, the anti-solvent may not be miscible with the solvent used in the 1^st part of the process.  To overcome this, the solvent is distilled off during the transfer so that its level is kept at a level below the miscibility boundary of solvent and anti-solvent.  As a result, the miscibility requirement of solvent and anti-solvent can be successfully bypassed.

In this presentation, we demonstrated a case of slurry crystallization to illustrate the this features, using ethyl-acetate as solvent and water as anti-solvent.