Role of Coformer and Excipient Properties on the Solid-State Stability of Theophylline Cocrystals

Sampada Koranne, Joseph F. Krzyzaniak, Suman Luthra, Kapildev K. Arora, Raj Suryanarayanan

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28 Scopus citations


The stability of theophylline cocrystals composed of acidic (glutaric acid), basic (isonicotinamide), or neutral (benzamide) coformers was evaluated in the presence of several excipients. Tablets of theophylline-glutaric acid (TG) and theophylline-isonicotinamide (TINT) cocrystals were stable "as is" (no excipient) after storage at 40 °C/75% RH for 1 week. However, TG and TINT cocrystals dissociated rapidly in the presence of basic and acidic excipients, respectively. The dissociation reaction was water-mediated, and theophylline, the reaction product, was identified by powder X-ray diffractometry. In the case of theophylline-benzamide cocrystal, storage of tablets with and without excipients at 40 °C/75% RH for 1 week resulted in a cocrystal polymorphic transformation. Thus, the potential for excipient-induced cocrystal dissociation exists for cocrystals composed of acidic and basic coformers. Moreover, if the coformer renders the cocrystal highly water-soluble, even in the presence of neutral excipients, there is a propensity for dissociation.

Original languageEnglish (US)
Pages (from-to)868-875
Number of pages8
JournalCrystal Growth and Design
Issue number2
StatePublished - Feb 6 2019

Bibliographical note

Funding Information:
The authors thank Pfizer Global R&D for financial support. Dr. Sheri Shamblin is acknowledged for her thoughtful comments. The laboratory XRD studies were carried out in the Characterization Facility, University of Minnesota, which receives partial support from the NSF through the MRSEC program. Zhaohui Lei (Pfizer), Kushal Sehgal, Davin Routiola, Anasuya Sahoo, and Rahul Lalge are acknowledged for their help.

Publisher Copyright:
Copyright © 2019 American Chemical Society.

Copyright 2019 Elsevier B.V., All rights reserved.


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