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

Abstract

'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.

Powder crystallography of pharmaceutical materials by combined crystal structure prediction and solid-state 1H NMR spectroscopy

“…In contrast, all predicted structures in which one of the oxygen atoms acts as the hydrogen bond acceptor lead to very high deviations in chemical shifts; these structures are labelled in Figure 14. The ability to distinguish between possible hydrogen bonding patterns is important for theophylline, whose polymorphs differ in which hydrogen bond acceptors are used 67,68 .…”

Preparation of theophylline inhalable microcomposite particles by wet milling and spray drying: The influence of mannitol as a co-milling agent

“…It is prone to process-induced solid-state transformations as it exists in four polymorphic forms (forms I-IV) along with a monohydrate form (Fucke et al, 2012). Form II is the stable polymorph at room temperature while the monohydrate is the stable form in water and at high relative humidity environment.…”

Theoretical Model and Experimental Investigations on Solution-Mediated Polymorphic Transformation of Theophylline: From Polymorph I to Polymorph II

“…Theophylline has four crystal polymorphs [15], in which crystal polymorphs I and II are common pharmaceuticals. Literature [15,16] showed that polymorph I would gradually transform to polymorph II, which is thermodynamically more stable during downstream processing or storage. However, the affecting factors and kinetics of theophylline transformation from polymorph I to polymorph II have not been reported.…”