Applications of co-crystals in API synthesis

Dr Manuel Henry (Boehringer Ingelheim) - presentation at the Crystallization Workshop in Milan, Italy.

Co-crystallization is documented since many decades in chemistry in general, and in pigments especially. In the pharmaceutical industry, co-crystals became more recently a hot topic with the willingness to tailor API (Active Pharmaceutical Ingredient) characteristics such as solubility or stability.

Did you know that the Crystal16 helps you to determine solubility curves within 4 hours using only 100 mg of material? With more and more complex molecules, which sometimes hardly crystallize or don’t present acid-base center, co-crystals are seen as an alternative to difficult processes (amorphization, spray-drying…) or expensive non-conventional formulations. Moreover the possibility to gain intellectual property with these new solid forms, made them attractive to brand and generic companies too.

If the actual literature in the field of co-crystallization in pharmaceutical industry is overwhelmed by this focus on improving API characteristics, co-crystals can be more largely used during the chemical synthesis. Based on industrial case studies, co-crystallization offers a variety of possibilities such as: 

• Development of an alternative form of a highly solvatomorphic API
• Purification (chemical impurities, heavy metal contamination) of a crude API
• Design of an optical resolution of an API or of an intermediate

This can be labor intensive and time consuming. Crystal16 and Crystalline instruments offer invaluable tools to automate the execution of such experiments in quick, controllable and reproducible manner.

Different aspects of the development of co-crystallization and optical resolution performed at Boehringer Ingelheim were conducted with the use of the Crystal16 and Crystalline instruments.

• Screening methodologies
• Design of experiments
• Phase diagram to improve yield
• Phase diagram to improve optical resolution
• Stability
• Cleavage
• Polymorphism