Novel Challenges in Crystal Engineering: Polymorphs and New Crystal Forms of Active Pharmaceutical Ingredients

Abstract

Crystal engineering and co-crystallization have evolved in recent years and gained a special interest not only in academia but also in the pharmaceutical field as it has been shown that the physical and pharmacokinetic properties of new crystal forms (solvates, salts, molecular salts, co-crystals, polymorphs) are different when compared to pure APIs1-16. Actually, producing co-crystals of pharmaceuticals has been reported to change their melting points3, solubility and dissolution rates2, 4, moisture uptake17, physical and chemical stability18 and in vivo exposure9, 19-21. The leading idea is that the potentiality of new different forms may open to innovation and new drug discoveries as well as to intellectual property protection via patenting of new forms of “old drugs”5, 7, 22. The diversity of forms that crystalline solids may attain is mainly due to non-covalent interactions resulting in different molecular assemblies that imply an energetic interplay between enthalpy and entropy. Although organic salts are traditionally the preferred crystal form of APIs because of their higher solubility and/or increased degree of crystallinity, the potential number of suitable organic salts is limited to the counterions specified by the Food and Drug Administration (FDA) as generally regarded as safe (GRAS). This limitation stimulates the development of other suitable forms and recently co-crystals have been gaining relevance in studies and some of them have already shown to improve therapeutic utility as well as reducing the side effects even when compared with marketed drugs. Consequently, APIs represent a particular great challenge to crystal engineers, because they are inherently predisposed for self-assembly since their utility is usually the result of the presence of one or more exofunctional supramolecular moieties. However, the crystal packing of APIs is even less predictable than that of other organics due to their multiple avenues for self-assembly. Additionally, APIs are commonly valuable chemical entities and therefore the diversity of the crystal forms of those molecules is of great importance for the variability of properties and potential intellectual property. Co-crystals are most commonly thought of as structural homogeneous crystalline materials that contain two or more neutral building blocks that are present in definite stoichiometric amounts and are obtained through the establishment of strong hydrogen bonds and other non-covalent interactions such as halogen bonds, π-π and coulombic interactions. However,