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 journalArticle

13 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 1 2013


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

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