New Polymorph of Indomethacin: Screening by Solid-State Guest Exchange and Characterization Using Fast Scanning Calorimetry

Gataullina, Karina V.; Buzyurov, Aleksey V.; Gerasimov, Alexander V.; Gatiatulin, Askar K.; Ziganshin, Marat A.; Schick, Christoph; Gorbatchuk, Valery V.

doi:10.1021/acs.cgd.3c00443

Cited by 3 publications

(2 citation statements)

References 56 publications

(149 reference statements)

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“…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, thymine, indomethacine, ritonavir, etc.…”

Section: Introductionmentioning

confidence: 81%

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

Widauer,

Petrick,

Braun

2024

Crystal Growth & Design

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A thorough re-examination of sulfaguanidine’s (SGD) solid-state behavior was conducted, 65 years after the initial report on SGD polymorphism. This investigation focuses on the polymorphic nature of the compound, the formation of hydrates and solvates, and the pivotal role of experimental and computational methods in screening, assessing stability, and understanding transformation processes. The findings confirm the presence of five anhydrates (AH-I–V), two monohydrate polymorphs (Hy1-I and Hy1-II), and nine solvates (with tetrahydrofuran, methanol, ethanol, t-butanol, acetone, cyclohexanone, dimethyl sulfoxide, dimethyl formamide, and dimethyl acetamide). Notably, nine novel structures–two anhydrates and seven solvates–are reported, solved from powder X-ray diffraction data. Calorimetric measurements have revealed that AH-II is the thermodynamically stable polymorph at room and low temperatures. In contrast, AH-I emerges as the stable polymorph at higher temperatures, yet it exhibits remarkable kinetic stability at RT and demonstrates greater stability in terms of hydration. The anhydrate forms exhibit distinctive packing arrangements, while the two hydrates share a close structural resemblance. Among the seven structurally characterized solvates, only the tetrahydrofuran and dimethyl sulfoxide solvates are isostructural. Controlled desolvation experiments enabled the formation of AH-I, AH-II, and, notably, AH-V for the first time. The anhydrate and monohydrate crystal structure prediction studies reveal that the computed lowest-energy structures correspond to experimentally observed forms and propose models for the elusive AH-IV structure. Overall, the exploration of SGD’s solid-state landscape confirms a rich array of highly stable H-bonding motifs and packing arrangements, positioning this study as an ideal model for complex solid-state systems and shedding light on its intricate solid-state nature.

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Section: Introductionmentioning

confidence: 81%

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

Widauer,

Petrick,

Braun

2024

Crystal Growth & Design

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“…Exploring new solid forms for active pharmaceutical ingredients (APIs), including polymorphic forms, solvates, and cocrystals, is essential to overcome challenges throughout the processes of its synthesis, purification, pharmaceutical formulation, and subsequent storage. The solid form can significantly influence its solubility, powder property, stability, mechanical property, bioavailability, etc. − Solvates were often formed in the recrystallizing process in solution, in which solvent is inserted in the crystal lattice at fixed stoichiometry. When the solvent escapes from crystal lattice, solvates transform into other solvent-free polymorphic forms, which is a very important method for screening new forms. ,− In summary, polymorphism is recognized as an intrinsic characteristic of the crystalline state.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Structural Landscape for a Thrombopoietin Receptor Agonist Avatrombopag Maleate: An Innovative Trihydrate Forms with Improved Solubility Found

Liu,

Dai,

Shi

et al. 2024

Crystal Growth & Design

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Avatrombopag maleate (AVAT), a second-generation oral thrombopoietin (TPO) receptor agonist, is currently in development for the therapeutic management of thrombocytopenia. The present study introduces a novel comparative analysis that elucidates the intricate relationship between the crystallographic structures and the diverse physicochemical properties inherent to the complex polymorphic forms of the Avatrombopag (AVA) maleic salt. Seven solid-state forms, including two polymorphic forms (AVAT-B, AVAT-C), a new trihydrate (AVAT-3H), and four solvates (AVAT-A, AVAT-dimethyl sulfoxide (AVAT-DMSO), AVAT-dimethylformamide (AVAT-DMF), and AVAT-tetrahydrofuran (AVAT-THF)), were synthesized and analyzed in detail. Although the powder diffraction patterns for polymorphs AVAT-A, AVAT-B, and AVAT-C have been previously reported, our study marks the inaugural report of their crystallographic structures. Trihydrate and three new solvates were initially identified and subjected to a comprehensive characterization through thermal analysis, X-ray diffraction, etc. Thermal stability and transformation in aqueous solutions for different forms were conducted. Surprisingly, it was found that all five other solid forms except AVAT-B would be transformed to AVAT-3H when suspended in aqueous solution. All solvates retained their original framework structure after the removal of part of the solvent and could not lose all solvents until decomposition. AVAT trihydrate did not lose water upon storage under ambient conditions. Furthermore, the solubility profiles of AVAT-B, AVAT-C, and AVAT-3H were meticulously determined. By integrating the distinct molecular conformations with the respective intermolecular and intramolecular interactions as well as the packing arrangements, we were able to elucidate the underlying factors influencing their phase behavior. The insights gained from this analysis were instrumental in simulating crystal growth, thereby facilitating a comprehensive understanding of the specific interactions that govern the phase behavior of these compounds.

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The Continuous and Reversible Transformation of the Polymorphs of an MGAT2 Inhibitor (S-309309) from the Anhydrate to the Hydrate in Response to Relative Humidity

Miyano,

Sugita,

Ueda

2024

Pharmaceutics

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Polymorphic control is vital for the quality control of pharmaceutical crystals. Here, we investigated the relationship between the hydrate and anhydrate polymorphs of a monoacylglycerol acyltransferase 2 inhibitor (S-309309). Solvent evaporation and slurry conversion revealed two polymorphs, the hydrate and the solvate. The solvate was transformed into the hydrate by heating. X-ray powder diffraction demonstrated that the hydrate was transformed into an anhydrate via an intermediate state when heated. These crystal forms were confirmed under controlled humidity conditions; the presence of the anhydrate, the intermediate hydrate, or the hydrate depended on the relative humidity at 25 °C. The stoichiometry of S-309309 in water in the hydrate form was 4:1. The hydrates and anhydrates exhibited similar crystal structures and stability. The water of hydration in the intermediate hydrate was 0.1–0.15 mol according to the dynamic vapor sorption profile. The stability and dissolution profile of the anhydrate and hydrate showed no significant change due to similar crystal lattices and quick rehydration of the anhydrate. A mechanism for the reversible crystal transformation between the anhydrate and pseudo-polymorphs of the hydrate was discovered. We concluded that S-309309 causes a pseudo-polymorphic transformation; however, this is not a critical issue for pharmaceutical use.

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New Polymorph of Indomethacin: Screening by Solid-State Guest Exchange and Characterization Using Fast Scanning Calorimetry

Cited by 3 publications

References 56 publications

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

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

Exploring the Structural Landscape for a Thrombopoietin Receptor Agonist Avatrombopag Maleate: An Innovative Trihydrate Forms with Improved Solubility Found

The Continuous and Reversible Transformation of the Polymorphs of an MGAT2 Inhibitor (S-309309) from the Anhydrate to the Hydrate in Response to Relative Humidity

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