Tablets containing a theophylline-glutaric acid (TG) cocrystal dissociated rapidly forming crystalline theophylline (20-30%), following storage at 40 °C/75% RH for 2 weeks. Control tablets of TG cocrystal containing no excipients were stable under the same conditions. The dissociation reaction was water-mediated, and the theophylline concentration (the dissociation product), monitored by synchrotron X-ray diffractometry, was strongly influenced by the formulation composition. Investigation of the binary compacts of the TG cocrystal with each excipient revealed the influence of excipient properties (hydrophilicity, ionizability) on cocrystal stability, providing mechanistic insights into a dissociation reaction. Ionizable excipients with a strong tendency to sorb water, for example, sodium starch glycolate and croscarmellose sodium, caused pronounced dissociation. Microcrystalline cellulose (MCC), while a neutral but hydrophilic excipient, also enabled solution-mediated cocrystal dissociation in intact tablets. Magnesium stearate, an ionizable but hydrophobic excipient, interacted with the cocrystal to form a hygroscopic product. The interaction is believed to be initiated in the disordered cocrystal-excipient particle interface. In contrast, the cocrystal was stable in the presence of lactose, a neutral excipient with no tendency to sorb water. The risk of unintended cocrystal dissociation can be mitigated by avoiding contact with water both during processing and storage.
Bibliographical noteFunding Information:
The authors thank Pfizer Global R&D for financial support. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOC) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. The laboratory XRD studies in this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC program. Subarna Samanta, Kushal Sehgal, Ceren Karahan, Naga Duggirala, and Sheri Shamblin are acknowledged for their help.
Copyright © 2018 American Chemical Society.
- cocrystal dissociation, cocrystal stability
- drug product
- magnesium stearate
- microenvironmental acidity
- synchrotron X-ray diffractometry
- tablet formulation