Transmission Electron Microscopy of Pharmaceutical Materials

Eddleston, Mark D.; Bithell, Erica G.; Jones, William

doi:10.1002/jps.22220

Cited by 53 publications

(57 citation statements)

References 47 publications

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“…However, electron microscopy and electron diffraction reveals the existence of the new polymorph as micro-impurity. 47 In the present work we report the single-crystal neutron structure of theophylline monohydrate and lattice-energy calculations of the hydrate as well as the anhydrous forms I and II using the PACHA algorithm. 48 The aim is to rationalise the thermodynamic stability and mutual interconversion of the THEO crystal forms using non-empirical energy calculations based on the experimental crystalstructure coordinates.…”

Section: Introductionmentioning

confidence: 99%

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: 99%

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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“…1-14.9 at the end of the chapter. (Amigo 2010;Breitkreitz and Poppi 2012;Chen et al 2011;Gendrin et al 2008;Jørgensen et al 2009;Kazarian and Ewing 2013;McIntosh et al 2012;Pavia et al 2001;PratsMontalbán et al 2012;Reich 2005;Van Eerdenbrugh and Taylor 2011;Zeitler et al 2007) Change in frequency of incident electromagnetic radiation due to the absorption or inelastic scattering of a portion resonant to the frequency of molecular, lattice or phonon vibration (stretching, bending, bending, rocking, wagging, scissoring, etc (Carlton 2011;Dieing et al 2011;Eddleston et al 2010;Vitez et al 1998) Interaction of molecular solids with optical/electronic source resulting information on morphology, solid state Polarized light microscopy Identification of solid form based on birefringence and morphology Scanning electron microscopy (SEM) Focused electron beam scanned over the specimen surface under a high vacuum Penetrate the sample interior and the emitted electrons produces the specimen topography Transmission electron microscopy (TEM) Spatial variation of the inelastic interaction of electron beam while transmitting through a sample produces highly resolved image Thermo-gravimetry (TGA; Giron et al 2004) Weight change of the sample as a function of temperature and/or time measured using a sensitive microbalance (Barnes et al 2011;Brown and Vickerman 1984;Chehimi et al 2011;Clark 1977;Harding et al 2007;Ho and Heng 2013;Pollock and Hammiche 2001;Sitterberg et al 2010;Thielmann and Levoguer 2002;Voelkel et al 2009) Atomic force microscopy (AFM) A sharp probe on a flexible cantilever tip (10-20 nm) scanned...…”

Section: Post-approvalmentioning

confidence: 97%

Structural Characterization of Amorphous Solid Dispersions

Paudel

Meeus

Mooter

2014

Advances in Delivery Science and Technology

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“…Form II is the most commonly observed theophylline polymorph, whereas Form V is a seldom observed crystal form that has been previously isolated during supercritical antisolvent crystallisations of theophylline, 35 and in trace amounts during crystallisations from methanol. 36 Here, thermal dissociation of the acetamide cocrystal has provided an alternative route to observing this unusual crystal form of theophylline, albeit as a minor phase in a mixture with Form II.…”

Section: Cocrystal Stabilitymentioning

confidence: 99%

Investigation of an Amide-Pseudo Amide Hydrogen Bonding Motif within a Series of Theophylline:Amide Cocrystals

Eddleston

Arhangelskis

Fábián

et al. 2015

Crystal Growth & Design

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The pharmaceutically active compound theophylline (T) was cocrystallized with the amides formamide (1), acetamide (2), N-methylformamide (3), N,N-dimethylformamide (4), benzamide (5), and pyrazinamide (6), with systems T:1, T:5, and T:6 displaying polymorphic behavior. The cocrystals with formamide (T:1), acetamide (T:2), and benzamide (T:5), and one polymorph of the cocrystal with pyrazinamide (T:6-I), contain an R 2 2 (9) hydrogen bonding motif between the amide cocrystal formers and the HN−C−CO moiety of the theophylline molecule (an amide-pseudo amide synthon). This motif was, however, absent from the other polymorph of the pyrazinamide cocrystal (T:6-II) and also from the N-methylformamide cocrystal (T:3) (and is not possible in the N,N-dimethylformamide cocrystal (T:4)). These observations are rationalized using hydrogen bond propensity calculations, although limitations of using such calculations for predicting cocrystallization are noted. The amide-pseudo amide synthon is favored when theophylline cocrystallizes with both primary amides and with secondary amides which are locked in a cis configuration. On heating, all cocrystals were found to dissociate before melting due to loss of the amide, making stability to dissociation a more meaningful measure of cocrystal stability than melting point for these systems. On dissociation of the cocrystals, theophylline typically crystallizes as the commonly observed polymorph Form II. In the case of the acetamide cocrystal (T:2), however, the rarely observed metastable polymorph, Form V, crystallizes concomitantly with Form II suggesting that cocrystal dissociation on heating could be a strategy for identifying novel polymorphic forms of compounds.

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Transmission Electron Microscopy of Pharmaceutical Materials

Cited by 53 publications

References 47 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

Structural Characterization of Amorphous Solid Dispersions

Investigation of an Amide-Pseudo Amide Hydrogen Bonding Motif within a Series of Theophylline:Amide Cocrystals

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