title: Instability in theophylline and carbamazepine hydrate tablets: cocrystal formation due to release of lattice water.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Kapildev K
authors.initials: KK
authors.lastname: Arora
authors.forename: Seema
authors.initials: S
authors.lastname: Thakral
authors.forename: Raj
authors.initials: R
authors.lastname: Suryanarayanan
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000737:chemistry*; D001993:Bronchodilator Agents / Q000737:chemistry*; D002220:Carbamazepine / Q000737:chemistry*; D019343:Citric Acid / Q000737:chemistry; D003460:Crystallization; D006813:Humidity; D009536:Niacinamide / Q000737:chemistry; D044367:Phase Transition; D033362:Powder Diffraction; D012995:Solubility; D013607:Tablets; D013806:Theophylline / Q000737:chemistry*; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D018712:Analgesics, Non-Narcotic; D001993:Bronchodilator Agents; D013607:Tablets; D014867:Water; D009536:Niacinamide; D019343:Citric Acid; D002220:Carbamazepine; D013806:Theophylline