(410a) Separation of Impurities From Active Pharmaceutical Ingredients (APIs) by Selective Co-Crystal Formation

Most pharmaceutical manufacturing processes consist of a series of syntheses resulting in the final formation and then purification of the API. The compounds formed during the synthetic process (intermediates) require purification prior to the next chemical step. Existing methods, such as crystallization, liquid-liquid extraction, and chromatography, can be effective but either require several steps (such as filtration and re-suspension) or are expensive. In the final separation of the API, crystallization is normally used but in some cases certain impurities are very difficult to remove and hence we would need multiple crystallizations. Therefore, we are looking into a new separation of APIs/intermediates from impurities by selectively forming impurity co-crystals.

We have developed a systematic approach to separate the API/intermediate from its impurity by selective impurity co-crystal formation. The ibuprofen/ketoprofen system was chosen as a model system used to demonstrate the ability to selectivity form a co-crystal with a target compound in which the solubility of the co-crystal formed with the impurity target is decreased. This result then allows the impurity to be removed by crystallization.  We are also investigating the formation of co-crystals with impurities which substitute into the crystal lattice.  In this case we are evaluating whether by forming the impurity-ligand complex in solution we can prevent the lattice substitution of the impurity.

The correct choice of solvent and measurement of phase solubility diagrams are an important part of developing our proposed separation process.  Experimental results for ibuprofen/ketoprofen system and several other systems will be presented.