Crystal engineering

Co-crystal solid forms are gaining increased significance in the pharmaceutical and chemical industry as an efficient way to modify the physicochemical properties of organic molecules like Active Pharmaceutical Ingredients (APIs), intermediates and other synthetic products.
 

A co-crystal can be described as a crystalline structure formed by two different or more molecular entities where, in contrast to salts, the intermolecular interactions are not ionic, but weak forces like hydrogen bonding and π-π stacking.
 

The big advantage of co-crystals compared to salts is that co-crystallisation is also applicable to non-ionisable molecules where salt formation is not possible.
 
Co-crystals offer great potential in various fields:
 

• Chiral resolution: whether a molecule is ionisable or not, selective diastereomeric co-crystallisation can be attainable using an enantiomerically pure coformer.
• Separation and purification: co crystals can be a good option, especially with non-ionisable products, to purify some intermediates, consequently avoiding expensive chromatographic techniques.
• Crystallisation of non-solid products: liquids, pastes and oily products can become a solid form by means of co-crystallisation, leading to more robust and efficient manufacturing processes.
• Improvement of solid state properties (of APIs and other organic substances): several important characteristics of pharmaceutical substances like solubility, bioavailability, stability, hygroscopicity, morphology, filtration and flowability can be modified by means of co-crystal formation. In the case of APIs, it is remarkable that the number of pharmaceutically acceptable co-crystal formers is larger than the number of counter ions for salt formation.
   

Compared to amorphous solid forms, co-crystals tend to be more stable and have a more predictable behaviour. Furthermore, due to the higher complexity of their crystal structure (when compared to single component systems), co-crystals are less prone to suffer polymorphic transformations, thus avoiding undesirable downstream processing surprises.
 

Over the last years, the number of pharmaceutical co-crystals has been increasing dramatically. Their novelty, utility and not obvious preparation make co-crystals an interesting approach from the point of view of intellectual property. In the case of commercial APIs, a patent of a co-crystal with better drug properties than previously known forms could be of high commercial value. Co-crystals do not involve structural modification of the parent molecules, therefore, in the case of designing co-crystals of marketed drugs, their development programs (including clinical trials) shall be significantly shorter and less risky than those of New Chemical Entities (NCEs).
 

Enantia has considerable experience in the field of co-crystals and an enthusiastic team with its own approach to co-crystal screening, offering a combination of rational design and a powerful set of synthetic and analytical techniques.