Tailoring crystal shape and polymorphism using combinations of solvents and a structurally related additive

Abstract

Controlling polymorphism is one of the most difficult challenges for the pharmaceutical industry. Polymorphs of the same compound can have very different properties that might affect the quality of the final drug. Many studies have focused on trying to determine robust methods to produce specific polymorphs that exhibit the desired characteristics of the drug (solubility and rate of dissolution in particular). The choice of solvent, pH, kinetic conditions and the presence of impurities can all have very strong effects on the polymorphic outcome of cooling crystallization. In this work, the crystallization of ortho-aminobenzoic acid (OABA) in the presence of a structurally related additive (benzoic acid) will be studied using both in situ PAT tools and offline techniques. The effect on morphology, polymorphic outcome, polymorphic transformation kinetics and tendency towards agglomeration in different solvents will be studied using a large variety of instrumentation. The incorporation of benzoic acid in solid solution in the three different polymorphs of OABA will also be quantified and discussed. The results of the crystallization experiments and offline analysis will be compared and interpreted using the information on the crystal structures of the three OABA polymorphs from the Cambridge Crystallographic database.