Ritonavir Revisited: Melt Crystallization Can Easily Find the Late-Appearing Polymorph II and Unexpectedly Discover a New Polymorph III

Abstract

Identification of a thermodynamically stable polymorph is an important step in the early stage of drug development. Ritonavir (RIT) is a well-known case where the most stable polymorph II emerged after being marketed, leading to a loss of $250 million. Herein, we report the findings that routine melt crystallization can reveal the late-appearing polymorph II of RIT at small supercooling, but the probability of nucleation is very low. The addition of 30–50% polyethylene glycol (PEG) promotes the crystallization of Form II as the only phase at low supercooling, making it easier to detect in polymorphism screening. During the course of our research, a new polymorph, denoted Form III, was unexpectedly discovered, crystallizing as the major phase from neat RIT melts. Single crystals of Form III were grown from melt microdroplets. Benefiting from the ability of synchrotron radiation to detect weak diffraction signals that cannot be accessible by a laboratory diffractometer, a reasonable structure of Form III was solved with slight disorder relative to thiazole groups (P1 space group and Z′ = 4). The thermodynamic stability ranking of the three true polymorphs is Form II > Form I > Form III, as opposed to the order of solubility. The capacity to efficiently reveal rich polymorphs, especially the kinetically hindered polymorph, and rapidly grow single crystals of a new phase for structure determination together highlights the necessity of incorporating melt crystallization into routine methods for pharmaceutical polymorphism screening.

Comprehensive Insights into Sulfaguanidine in the Solid State: An Experimental and Computational Study

“…The only question is, whether it is possible to adjust the external conditions in such a way that polymorphism can be realized or not", the probability of discovering polymorphs of a compound is influenced by time and resources allocated to research on that particular compound. This assertion is exemplified by recent findings of new polymorphs of substances like dapsone, 25 thymine, 26 indomethacine, 27 ritonavir, 28 etc.…”

An Overview on Polymorph Preparation Methods of Active Pharmaceutical Ingredients

“…15 Melt crystallization technology has advantages such as low energy consumption, moderate operating temperature, and no additives required, which has been used to prepare polymorphs of API, such as form II and form III of ritonavir and forms VII, VIII, and IX of paracetamol. 16 Sublimation crystallization can be used not only to manufacture iodine, naphthalene, and ferric chloride with high purity but also to produce polymorphs of glycine, pyrimethamine, and so on. 17 3.1.…”

“…According to the generation approach of supersaturated solutions, the solution crystallization method can be further subdivided into cooling crystallization, evaporative crystallization, vacuum cooling crystallization, reactive crystallization, antisolvent crystallization, and so on . Melt crystallization technology has advantages such as low energy consumption, moderate operating temperature, and no additives required, which has been used to prepare polymorphs of API, such as form II and form III of ritonavir and forms VII, VIII, and IX of paracetamol . Sublimation crystallization can be used not only to manufacture iodine, naphthalene, and ferric chloride with high purity but also to produce polymorphs of glycine, pyrimethamine, and so on …”

Substantial Confinement of Crystal Growth of Organic Crystalline Materials in Metal–Organic Membrane Microshells

“…Bioactive organic compounds, including water-insoluble vitamins, 1 carotenoids, 2 and phenolic acids, 3 have demonstrated beneficial effects such as anticancer, 4 neuroprotective, 5 anti-inflammatory, 6 antioxidant, 7 and UV blocking activities 8 in the fields of functional foods, 9,10 pharmaceutical, 11,12 and cosmetics. 13,14 They are often categorized as organic crystalline materials (OCMs) that typically possess a periodically ordered lattice, 15 resulting in their poor solubility in formulations.…”

“…Bioactive organic compounds, including water-insoluble vitamins, carotenoids, and phenolic acids, have demonstrated beneficial effects such as anticancer, neuroprotective, anti-inflammatory, antioxidant, and UV blocking activities in the fields of functional foods, , pharmaceutical, , and cosmetics. , They are often categorized as organic crystalline materials (OCMs) that typically possess a periodically ordered lattice, resulting in their poor solubility in formulations. Furthermore, the OCMs possess unique molecular structures including long alkyl chains, hydroxyl groups, and unsaturated double bonds, resulting in a variety of strong intermolecular interactions such as hydrogen bonds, van der Waals interaction, and π–π stacking. − These features cause the OCMs to not only aggregate and sediment in liquid media but also compromise their chemical stability. , Encapsulation has emerged as a crucial strategy for addressing these inherent drawbacks.…”