Polymorphs, Regulations, Crystallization, and Solid‐State Chemistry

Byrn, Stephen R.; Pfeiffer, Ralph R.; Stowell, Joseph G.

doi:10.1002/chin.200544299

Cited by 181 publications

(240 citation statements)

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“…1,2 Different polymorphs display unique physiochemical properties, such as stability, solubility and bioavailability. 3–5 Hence polymorph characterization from early stage drug discovery through drug product formulation is essential, and the importance of identifying polymorphs is recognized by several regulatory requirements.…”

Section: Introductionmentioning

confidence: 99%

Polymorph Discrimination Using Low Wavenumber Raman Spectroscopy

Roy

Chamberlin

Matzger

2013

Org. Process Res. Dev.

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Characterization of crystalline polymorphs and their quantitation has become an integral part of the pre-clinical drug development process. Raman spectroscopy is a powerful technique for the rapid identification of phases of pharmaceuticals. In the present work we demonstrate the use of low wavenumber Raman vibrational spectroscopy (including phonon measurement) for discrimination among polymorphs. A total of 10 polymorphic pharmaceuticals were employed to conduct a critical assessment. Raman scattering in the low frequency region (10–400 cm−1), which includes crystal lattice vibrations, has been analyzed and the results indicate lattice phonon Raman scattering can be used for rapid discrimination of polymorphic phases with additional discriminating power compared to conventional collection strategies. Moreover structural insight and conformational changes can be detected with this approach.

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Section: Introductionmentioning

confidence: 99%

Polymorph Discrimination Using Low Wavenumber Raman Spectroscopy

Roy

Chamberlin

Matzger

2013

Org. Process Res. Dev.

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“…The existence of different solid-state forms of a compound is important as these usually show different physical properties, 1,2 for example, solubility, density, hardness, melting point, etc. Polymorphism and solvate formation is important for both fundamental research and industrial practice.…”

Section: Introductionmentioning

confidence: 99%

Solid-State Forms of β-Resorcylic Acid: How Exhaustive Should a Polymorph Screen Be?

Braun

Karamertzanis

Arlin

et al. 2010

Crystal Growth & Design

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A combined experimental and computational study was undertaken to establish the solid-state forms of β-resorcylic acid (2,4-dihydroxybenzoic acid). The experimental search resulted in nine crystalline forms: two concomitantly crystallizing polymorphs, five novel solvates (with acetic acid, dimethyl sulfoxide, 1,4-dioxane, and two with N,N-dimethyl formamide), in addition to the known hemihydrate and a new monohydrate. Form II°, the thermodynamically stable polymorph at room temperature, was found to be the dominant crystallization product. A new, enantiotropically related polymorph (form I) was obtained by desolvation of certain solvates, sublimation experiments, and via a thermally induced solid−solid transformation of form II° above 150 °C. To establish their structural features, interconversions, and relative stability, all solid-state forms were characterized with thermal, spectroscopic, X-ray crystallographic methods, and moisture-sorption analysis. The hemihydrate is very stable, while the five solvates and the monohydrate are rather unstable phases that occur as crystallization intermediates. Complementary computational work confirmed that the two experimentally observed β-resorcylic acid forms I and II° are the most probable polymorphs and supported the experimental evidence for form I being disordered in the p-OH proton position. These consistent outcomes suggest that the most practically important features of β-resorcylic acid crystallization under ambient conditions have been established; however, it appears impractical to guarantee that no additional metastable solid-state form could be found.

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“…1–3 Meticulous analysis of the polymorphic landscape provides valuable insights into structure-property relations which extend beyond pharmaceuticals into other areas such as explosives, pigments etc. On the other hand, polymorphism poses a major challenge to emerging crystal structure prediction methods and indeed represents a frontier for computational chemistry.…”

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confidence: 99%