Solid State Forms of Theophylline: Presenting a New Anhydrous Polymorph

Seton, Linda; Khamar, Dikshitkumar; Bradshaw, Ian J.; Hutcheon, Gillian A.

doi:10.1021/cg100165t

Cited by 70 publications

(81 citation statements)

References 22 publications

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“…[37][38][39][40][41][42] Recently, a new anhydrous form IV has been reported. 43,44 However, reproduction of this form following the published procedure of slurry conversion in methanol failed in our hands. Another crystal form has been reported to be obtained by antisolvent precipitation using supercritical CO 2 and CHF 3 as antisolvent.…”

Section: Introductionmentioning

confidence: 95%

New Insights into an Old Molecule: Interaction Energies of Theophylline Crystal Forms

Fucke

McIntyre

Wilkinson

et al. 2012

Crystal Growth & Design

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'New insights into an old molecule : interaction energies of theophylline crystal forms.', Crystal growth design., 12 (3). pp. 1395-1401. Further information on publisher's website:http://dx.doi.org/10.1021/cg201499sPublisher's copyright statement:This document is the Accepted Manuscript version of a Published Work that appeared in nal form in Crystal growth design, copyright c American Chemical Society after peer review and technical editing by the publisher. To access the nal edited and published work see http://dx.doi.org/10.1021/cg201499sAdditional information:Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-pro t purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO• the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. The asthma therapeutic theophylline exists in at least three anhydrous polymorphs and a monohydrate. The single-crystal X-ray structure of the high-temperature polymorph form I is presented for the first time and the energetic relationship between forms I and II is investigated using the partial charges and chemical hardness analysis (PACHA) algorithm. It is shown that the interactions in the form I crystal network are stronger, especially the hydrogen bond. The singlecrystal neutron structure of the monohydrate demonstrates static disorder of the water molecule as well as dynamic disorder of the methyl groups. PACHA investigations based on the neutron coordinates reveal that the homomeric interactions in this form are stronger than the interaction of the water with the host molecules. The dehydration of the hydrate should thus leave the theophylline network intact, explaining the isomorphic powder X-ray diffractograms of the monohydrate and its dehydrated form III.

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Section: Introductionmentioning

confidence: 95%

New Insights into an Old Molecule: Interaction Energies of Theophylline Crystal Forms

Fucke

McIntyre

Wilkinson

et al. 2012

Crystal Growth & Design

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“…48 A new nonsolvated polymorphic form of theophylline has been crystallized and shown by a number of measurements to be the most thermodynamically stable anhydrous crystal form. 49 This form-IV exhibited the lowest solubility in methanol, with forms I and II being found to undergo solvent-mediated phase transformations into form-IV if the slurry was allowed to stand for a sufficient amount of time. The nonsolvated forms I, II, and IV were all stable in the solid state, but all three forms would convert to the monohydrate in aqueous suspensions.…”

Section: Structural Characterization and Properties Of Polymorphs Andmentioning

confidence: 97%

Polymorphism and Solvatomorphism 2010

Brittain¹

2012

Journal of Pharmaceutical Sciences

128

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“…40,[41][42][43][44][45][46] Form II (orthorhombic, space group Pna2 1 ), is the most commonly encountered polymorph, and was long believed to be the thermodynamic form of theophylline under ambient conditions, though it has recently been shown that Form IV is in fact more stable. 47 The crystal structure of Form II was determined by…”

Section: Introductionmentioning

confidence: 99%

Highly Unusual Triangular Crystals of Theophylline: The Influence of Solvent on the Growth Rates of Polar Crystal Faces

Eddleston

Hejczyk

Cassidy

et al. 2015

Crystal Growth & Design

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A noteworthy feature of the compound theophylline is that it forms crystals with a triangular habit, an extremely rare phenomenon for an organic molecule. Here, we investigate the formation of these crystals, comprised of the polymorph Form II (Pna2 1 ), and demonstrate that the triangles are obtained from solvents which are highly hydrophobic, or which have a hydrogen bond acceptor group and no hydrogen bond donor group. The formation of the triangular crystal habit is rationalized on the basis of the way such solvents interact with the inequivalent (001) and (00-1) polar crystal faces of Form II. Interactions are significantly stronger at one face than the other, inhibiting growth in one direction and limiting crystal growth to a single, triangle shaped, growth sector. This rationalization also enabled interesting surface features observed by atomic force microscopy to be interpreted. Furthermore, we report a second, previously unreported, type of triangular crystal of theophylline for which the angle at the tip of the triangle is obtuse rather than acute. These crystals are proposed, with the aid of transmission electron microscopy and crystal structure prediction, to be a new polymorphic form of theophylline. Kingdom A noteworthy feature of the compound theophylline is that it forms crystals with a triangular habit, an extremely rare phenomenon for an organic molecule. Here, we investigate the formation of these crystals, comprised of the polymorph Form II (Pna2 1 ), and demonstrate that the triangles are obtained from solvents which are highly hydrophobic, or which have a hydrogen bond acceptor group and no hydrogen bond donor group. The formation of the triangular crystal habit is rationalized on the basis of the way such solvents interact with the inequivalent (001) and 4 (00-1) polar crystal faces of Form II. Interactions are significantly stronger at one face than the other, inhibiting growth in one direction and limiting crystal growth to a single, triangle shaped, growth sector. This rationalization also enabled interesting surface features observed by atomic force microscopy to be interpreted. Furthermore, we report a second, previously unreported, type of triangular crystal of theophylline for which the angle at the tip of the triangle is obtuse rather than acute. These crystals are proposed, with the aid of transmission electron microscopy and crystal structure prediction, to be a new polymorphic form of theophylline.

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Solid State Forms of Theophylline: Presenting a New Anhydrous Polymorph

Cited by 70 publications

References 22 publications

New Insights into an Old Molecule: Interaction Energies of Theophylline Crystal Forms

New Insights into an Old Molecule: Interaction Energies of Theophylline Crystal Forms

Polymorphism and Solvatomorphism 2010

Highly Unusual Triangular Crystals of Theophylline: The Influence of Solvent on the Growth Rates of Polar Crystal Faces

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