Polymorphism of Piroxicam: New Polymorphs by Melt Crystallization and Crystal Structure Prediction

Yao, Changlin; Guzei, Ilia A.; Jin, Yingdi; Ruan, Shigang; Sun, Geng; Gui, Yue; Wang, Lei; Yu, Lian

doi:10.1021/acs.cgd.0c01165

Cited by 36 publications

(37 citation statements)

References 36 publications

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“…Further formation of polymorphs can be investigated using melt crystallization. This methodology was employed in the research that discovered two new forms of piroxicam (46). There are ongoing experiments investigating other possible polymorphs from melt crystallization, and the results will be included in future publications of the current study.…”

Section: Solid-state Chemistry and Polymorph Screenmentioning

confidence: 99%

Salts and Polymorph Screens for Bedaquiline

et al. 2021

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Bedaquiline is used to treat multi-resistant tuberculosis in adults. The fumarate salt is commercially available and used in the product Sirturo. To provide open access to bedaquiline molecule once the patent on the chemical substance expires, new salts were screened. This work offers additional information on the bedaquiline system, as new salts may present better pharmacokinetic properties. The current studies focus on the attempted isolation of the acetate, benzoate, benzenesulfonate, hydrobromide, succinate, hydrochloride, tartrate, lactate, maleate, malate, and mesylate salts of bedaquiline. Potential salts were screened using a unique combination of conventional screening, and small-scale experiments supplemented by crystallographic analysis and infrared microspectroscopy. Salts were prepared on a larger scale by dissolving 1:1 ratios of the individual salt formers and bedaquiline base (30 mg, 0.055 mmol) in different solvents and allowing the solutions to evaporate or crystallize. X-ray diffraction (XRD) techniques and spectroscopic and thermal analyses were employed to characterize the salts. The benzoate and maleate salts were selected as lead candidates after reviewing preliminary characterization data. To determine the most stable forms for the leads, a polymorph screen was conducted using solvents of various polarities. These salt screens successfully generated five new salts of bedaquiline, namely, benzoate, maleate, hydrochloride, besylate, and mesylate. The existence of these salts was confirmed by powder XRD, proton NMR, and IR spectroscopies. TGA and DSC thermal analysis along with hot-stage optical microscopy were further used to characterize the salts. The polymorph screen conducted on the salts suggested the absence of additional polymorphs at 1 g scale.

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Section: Solid-state Chemistry and Polymorph Screenmentioning

confidence: 99%

Salts and Polymorph Screens for Bedaquiline

et al. 2021

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“…For example, ten fully characterized polymorphs have been reported for anti-cancer drug candidate galnunisertib, 2 nine for flufenamic acid 3 , aripiprazole, 4 and tolfenamic acid, 5 six for the energetic material triacetone-triperoxide (TATP), 6 and at least five polymorphs for many other species. [7][8][9][10][11][12][13][14] Large numbers of crystalline phases are also found for small molecules such as water, 15 nitrogen, 16 and carbon dioxide. 17,18 The molecule 5-methyl-2-[(2-nitrophenyl) amino]-3-Fig.…”

Section: Introductionmentioning

confidence: 99%

How many more polymorphs of ROY remain undiscovered

et al. 2022

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“…Although solution crystallization is the traditional method for polymorph screening, melt crystallization is now revealing a growing list of pharmaceutical polymorphs that cannot be obtained from solution. [3][4][5][6][7][8][9][10][11] Employing X-ray diffraction techniques is the standard approach for identifying polymorphism and since melt crystallization usually yields polycrystalline spherulites it is challenging to elucidate the structures of melt-crystallized polymorphs. Recently, we developed a general method for rapidly growing single crystals from melt microdroplets.…”

Section: Introductionmentioning

confidence: 99%

Indomethacin Polymorph δ Revealed To Be Two Plastically Bendable Crystal Forms by 3D Electron Diffraction: Correcting a 47‐Year‐Old Misunderstanding**

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Xiao

et al. 2022

Angewandte Chemie

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Indomethacin is a clinically classical non-steroidal anti-inflammatory drug that has been marketed since 1965. The third polymorph, Form δ, was discovered by both melt and solution crystallization in 1974. δ-indomethacin cannot be cultivated as large single crystals suitable for X-ray crystallography and, therefore, its crystal structure has not yet been determined. Here, we report the structure elucidation of δ-indomethacin by 3D electron diffraction and reveal the truth that melt-crystallized and solution-crystallized δ-indomethacin are in fact two polymorphs with different crystal structures. We propose to keep the solution-crystallized polymorph as Form δ and name the melt-crystallized polymorph as Form θ. Intriguingly, both structures display plastic flexibility based on a slippage mechanism, making indomethacin the first drug to have two plastic polymorphs. This discovery and correction of a 47-year-old misunderstanding signify that 3D electron diffraction has become a powerful tool for polymorphic structural studies.

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Polymorphism of Piroxicam: New Polymorphs by Melt Crystallization and Crystal Structure Prediction

Cited by 36 publications

References 36 publications

Salts and Polymorph Screens for Bedaquiline

Salts and Polymorph Screens for Bedaquiline

How many more polymorphs of ROY remain undiscovered

Indomethacin Polymorph δ Revealed To Be Two Plastically Bendable Crystal Forms by 3D Electron Diffraction: Correcting a 47‐Year‐Old Misunderstanding**

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