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.
Bibliographical noteFunding 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.
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