Ritonavir Form III: A Coincidental Concurrent Discovery

Parent, Stephan D.; Smith, Pamela A.; Purcell, Dale K.; Smith, Daniel T.; Bogdanowich-Knipp, Susan J.; Bhavsar, Ami; Chan, Larry; Croom, Jordan M.; Bauser, Haley; McCalip, Andrew; Byrn, Stephen R.; Radocea, Adrian

doi:10.1021/acs.cgd.2c01017

Cited by 9 publications

(9 citation statements)

References 30 publications

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“…High-throughput polymorph screening by Morissette et al 8 revealed (see Table 1) the existence of two new solvates (forms IIIa and V) as well as a further (metastable) phase (form IV), but up to now their full crystal structures have not been reported, albeit recent work 9 through melt crystallisation has now resulted in a further solid form with its crystal structure (form IIIb, 10 see Table 1). In this respect, due to the form III nomenclature being claimed for both the form identified from screening 8 and that recently crystallised from the melt, 9 for clarity we have referred to these two structures herein after as forms IIIa and IIIb, respectively.…”

Section: Introductionmentioning

confidence: 99%

A quaternary solid-form of ritonavir: an oxalate salt oxalic acid co-crystal acetone solvate

et al. 2023

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Section: Introductionmentioning

confidence: 99%

A quaternary solid-form of ritonavir: an oxalate salt oxalic acid co-crystal acetone solvate

et al. 2023

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“…This project was launched in early 2020, but regrettably, obtaining insufficient data due to COVID-19 until now. During our research, two labs − reported the discovery of RIT Form III, and gave the crystallographic parameters by SCXRD or PXRD indexing, both of which are similar to our results solved from the data collected using a laboratory diffractometer ( C 2 space group and Z ′ = 1 with a significantly serious disorder, Figure S1). One of the most significant differences between the synchrotron structure and the in-house device structure is Z ′, the number of conformations in the asymmetric unit.…”

Section: Discussionmentioning

confidence: 90%

“…In fact, as mentioned by Parent et al, the PXRD pattern of Form III has been reported in 2014 but was erroneously identified as Form IV . The melt microdroplet strategy for single crystal cultivation and synchrotron radiation for data collection together enabled the correct structure elucidation and complete identification of this new phase.…”

Section: Discussionmentioning

confidence: 98%

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

Liu

Chen

et al. 2023

Mol. Pharmaceutics

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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.

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“…However, the possibility that form I is favored kinetically but not thermodynamically is supported by experimental observations, such as the frequent omission of molecules of H 2 O and the associated rapid growth of crystals along the a - and b -axes. If so, form I of pitolisant hydrochloride is vulnerable to being supplanted by the appearance of a more stable form, as in the notorious case of ritonavir. − The CSP results (Figure ) suggest the structures of several potential lower-energy polymorphs.…”

Section: Resultsmentioning

confidence: 99%

Exploring Polymorphism: Hydrochloride Salts of Pitolisant and Analogues

Patel,

Leduc,

Nunez Avila

et al. 2024

Crystal Growth & Design

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Pitolisant hydrochloride is used to treat excessive daytime sleepiness in adults with narcolepsy. The drug is formulated as a crystalline solid, and a monoclinic P2 1 form has been claimed in patents, but little additional information about the structure and polymorphism of the compound has been published. No new forms were obtained when we grew crystals from solution under various conditions. Re-examination of the crystals revealed a disordered and partially hydrated structure that resembles the one reported earlier but is not identical. Further insight was obtained by synthesizing analogues of pitolisant with its Cl substituent replaced by Me, F, and Br, followed by structural analysis of the hydrochloride salts by X-ray diffraction. Pitolisant hydrochloride and its three analogues showed very similar solid-state behavior, and each compound yielded new metastable forms when crystallized from melts. The lifetime of metastable form III of pitolisant hydrochloride could be extended significantly by adding small amounts of the fluoro analogue, but none of the metastable forms could be obtained as single crystals suitable for structural analysis. Computational predictions of the polymorphic landscapes of pitolisant hydrochloride and its analogues identified possible structures of the metastable forms. Dual experimental and computational approaches are already widely used in polymorphic screening, but our work shows the value of broadening these searches to include sets of structural analogues.

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Ritonavir Form III: A Coincidental Concurrent Discovery

Cited by 9 publications

References 30 publications

A quaternary solid-form of ritonavir: an oxalate salt oxalic acid co-crystal acetone solvate

A quaternary solid-form of ritonavir: an oxalate salt oxalic acid co-crystal acetone solvate

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

Exploring Polymorphism: Hydrochloride Salts of Pitolisant and Analogues

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