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Cocrystal Formation during Cogrinding and Storage is Mediated by Amorphous Phase

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Abstract

Purpose

The purpose of this work was to investigate the mechanisms of cocrystal formation during cogrinding and storage of solid reactants, and to establish the effects of water by cogrinding with hydrated form of reactants and varying RH conditions during storage.

Methods

The hydrogen bonded 1:1 carbamazepine–saccharin cocrystal (CBZ–SAC) was used as a model compound. Cogrinding of solid reactants was studied under ambient and cryogenic conditions. The anhydrous, CBZ (III), and dihydrate forms of CBZ were studied. Coground samples were stored at room temperature at 0% and 75% RH. Samples were analyzed by XRPD, FTIR and DSC.

Results

Cocrystals prepared by cogrinding and during storage were similar to those prepared by solvent methods. The rate of cocrystallization was increased by cogrinding the hydrated form of CBZ and by increasing RH during storage. Cryogenic cogrinding led to higher levels of amorphization than room temperature cogrinding. The amorphous phase exhibited a T g around 41°C and transformed to cocrystal during storage.

Conclusions

Amorphous phases generated by pharmaceutical processes lead to cocrystal formation under conditions where there is increased molecular mobility and complementarity. Water, a potent plasticizer, enhances the rate of cocrystallization. This has powerful implications to control process induced transformations.

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Acknowledgments

We acknowledge Bei Huang for technical assistance with XRPD and FTIR analysis. We gratefully acknowledge funding from Pfizer, Inc., Ann Arbor, MI, and from the Purdue/Michigan Consortium on the Physical and Chemical Stability of Pharmaceutical Solids.

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Author notes

  1. Anongnat Somwangthanaroj

    Present address: Department of Chemical Engineering, Chulalongkorn University, Bangkok, Thailand

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan, USA

    Adivaraha Jayasankar, Anongnat Somwangthanaroj & Naír Rodríguez-Hornedo

  2. Pfizer Global Research and Development, Ann Arbor, Michigan, USA

    Zezhi J. Shao

  3. 428 Church Street, Ann Arbor, Michigan, 48109-1065, USA

    Naír Rodríguez-Hornedo

Authors
  1. Adivaraha Jayasankar
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  2. Anongnat Somwangthanaroj
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Correspondence to Naír Rodríguez-Hornedo.

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Jayasankar, A., Somwangthanaroj, A., Shao, Z.J. et al. Cocrystal Formation during Cogrinding and Storage is Mediated by Amorphous Phase. Pharm Res 23, 2381–2392 (2006). https://doi.org/10.1007/s11095-006-9110-6

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  • DOI: https://doi.org/10.1007/s11095-006-9110-6

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