Role of lattice disorder in water-mediated dissociation of pharmaceutical cocrystal systems

Navpreet Kaur, Naga Kiran Duggirala, Seema Thakral, Raj Suryanarayanan

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Our objective is to mechanistically understand the implications of processing-induced lattice disorder on the stability of pharmaceutical cocrystals. Caffeine-oxalic acid (CAFOXA) and dicalcium phosphate anhydrate (DCPA) were the model cocrystal (drug) and excipient, respectively. Cocrystal-excipient mixtures were milled for short times (≤2 min) and stored at room temperature (RT)/75% RH. Milling-induced lattice disorder was quantified using powder X-ray diffractometry and gravimetric water sorption. Milling for even 10 s resulted in measurable disorder and an attendant tendency of the solid to sorb water. This was followed by cocrystal-excipient interaction leading to dissociation. The proposed mechanism of cocrystal dissociation entails the following sequence: sorption of water by disordered regions, dissolution of CAFOXA and DCPA in the sorbed water, followed by proton transfer from the coformer (oxalic acid) to DCPA, and the formation of hydrates of caffeine and calcium oxalate. As such, CAFOXA is a robust cocrystal, stable even under elevated humidity conditions (RT/98% RH). However, in a drug product environment, routine pharmaceutical processing steps such as milling and compaction have the potential to induce sufficient disorder to render it unstable.

Original languageEnglish (US)
Pages (from-to)3167-3177
Number of pages11
JournalMolecular pharmaceutics
Issue number7
StatePublished - Jul 2019

Bibliographical note

Funding Information:
This work was partially funded by the William and Mildred Peters Endowment Fund. Parts of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from the NSF through the MRSEC program. Portions of this work were conducted at the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nanotechnology Coordinated Infrastructure (NNCI) Network under award number ECCS-1542202.

Publisher Copyright:
© 2019 American Chemical Society.


  • Cocrystal
  • Dissociation
  • Lattice disorder
  • Milling
  • Processing
  • Solid state stability
  • Water


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