Instability in theophylline and carbamazepine hydrate tablets: Cocrystal formation due to release of lattice water

Kapildev K. Arora, Seema Thakral, Raj Suryanarayanan

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Purpose: To demonstrate two sequential solid-state reactions in intact tablets: dehydration of active pharmaceutical ingredient (API), and cocrystal formation between the anhydrous API and a second formulation component mediated by the released water. To evaluate the implication of this in situ phase transformation on the tablet dissolution behavior. Methods: Tablets containing theophylline monohydrate (TPM) and anhydrous citric acid (CA) were stored at 40 C in sealed polyester pouches and the relative humidity in the headspace above the tablet was continuously measured. Dehydration to anhydrous theophylline (TPA) and the product appearance (TPA-CA cocrystal) were simultaneously monitored by powder X-ray diffractometry. Carbamazepine dihydrate and nicotinamide formed the second model system. Results: The water of crystallization released by TPM dehydration was followed first by deliquescence of citric acid, evident from the headspace relative humidity (~ 68%; 40 C), and then the formation of TPA-CA cocrystal in intact tablets. The noncovalent synthesis resulted in a pronounced decrease in the dissolution rate of theophylline from the tablets. Similarly, the water released by dehydration of carbamazepine dihydrate caused the cocrystallization reaction between anhydrous carbamazepine and nicotinamide. Conclusions: The water released by API dehydration mediated cocrystal formation in intact tablets and affected dissolution behavior.

Original languageEnglish (US)
Pages (from-to)1779-1789
Number of pages11
JournalPharmaceutical research
Issue number7
StatePublished - Jul 2013

Bibliographical note

Funding Information:
KKA was partially supported by the William and Mildred Peters Endowment fund. ST gratefully acknowledges the BOYSCAST fellowship awarded by Department of Science and Technology, Govt. of India. We thank Vishard Ragoonanan, Ph.D. and Pinal Mistry for their help. We also thank Dr. John Nelson for his help in recording SEM images. Parts of this work were carried out in the Characterization Facility, University of Minnesota, a member of the NSF-funded Materials Research Facilities Network (


  • carbamazepine dihydrate
  • cocrystal
  • dehydration
  • dissolution
  • phase transformation
  • theophylline monohydrate


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