Recent Advances in Polymorph Discovery Methods of Organic Crystals

Abstract

Polymorphism, the ability of the same substance to crystallize in more than one crystal structure, is a common phenomenon in organic crystals, influencing the physicochemical properties of solid materials in many important fields (foods, dyes and pigments, high energic materials, pharmaceuticals, etc.). The utilization of various polymorph discovery methods could increase the possibility of finding polymorphs with desired properties, achieving an optimal performance of the final product. Recently, there has been a steady development of polymorph discovery in both experimental and computational methods. To better guide the polymorph discovery, this paper reviews the recent advances in the polymorph screening methods of organic crystals, mainly including solution crystallization, melt crystallization, and crystal structure prediction. This paper also summarizes the nucleation theory in polymorphic systems to understand the formation of polymorphs and highlights the mechanisms of polymorph discovery by the kinds of methods. Finally, challenges of polymorph discovery are briefly discussed, aimed to shorten the screening time and make the polymorph discovery more effective.

Polymorphism in Pyridine-2,6-dicarboxamides: The Role of Molecular Conformation in Hydrate Formation

“…Considering the classical nucleation theory, crystallization occurs in stages, meaning the process evolves from the molecule into highly stable nuclei, which can evolve into larger nuclei until they reach a point of no return that will make the proto crystals stable enough to form the crystal. This process can be compared to a Darwinian selection, where the most stable nuclei survive and, among them, the most cooperative. , Additionally, the crystalline design and functional properties of supramolecular systems do not depend on the properties of individual molecules.…”

“…This is because many compounds form polymorphs with large energy differences. − However, when considering polymorph competition, we could imagine the formation of only the most stable because the process in equilibrium must move in this direction. This energy can be important in the case of metastable polymorphs that, in an internal structural rearrangement process, can decay into more stable crystalline phases . In this sense, insights into the difference in energy between the first formed nuclei and the search for parameters to understand the stages can be an important path to help shed more light on polymorph crystallization.…”

“…Although the chemical nature of the polymorphs remains the same, the physical properties (e.g., solubility and melting point) and spectroscopic properties (e.g., Raman, IR, and SSNMR) can vary. 2,3 Considering the classical nucleation theory, 5 crystallization occurs in stages, meaning the process evolves from the molecule into highly stable nuclei, which can evolve into larger nuclei until they reach a point of no return that will make the proto crystals stable enough to form the crystal. This process can be compared to a Darwinian selection, where the most stable nuclei survive and, among them, the most cooperative.…”

“…This energy can be important in the case of metastable polymorphs that, in an internal structural rearrangement process, can decay into more stable crystalline phases. 5 In this sense, insights into the difference in energy between the first formed nuclei and the search for parameters to understand the stages can be an important path to help shed more light on polymorph crystallization. Another critical challenge is studying polymorph formation that includes solvent molecules, especially water molecules, in their crystalline structure.…”

Polymorphs, cocrystal and hydrate of nilutamide

“…Polymorphism plays an important role in various branches of contemporary material science, affecting the functional properties of pharmaceutical formulations, semiconductors, high-energy materials, dyes and pigments, etc. [1][2][3] In the realm of pharmaceutics, the alteration in packing arrangements and conformation of drug molecules in a crystal can cause significant changes in the most essential physicochemical properties of an active pharmaceutical ingredient (API), i.e., solubility, 4 dissolution rate, 5 elastic modulus and hardness, 6,7 melting points, physical and chemical stability, 8,9 as well as its biological activity. 10 Despite the fact that screening for polymorphs is currently embedded in the development pipeline of drug compounds, 11,12 the appearance of polymorphs remains largely unpredictable, as no reliable algorithm allowing for the discovery of potential polymorphic forms presently exists.…”