Journal
PHARMACEUTICAL RESEARCH
Volume 30, Issue 7, Pages 1779-1789Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-013-1022-7
Keywords
carbamazepine dihydrate; cocrystal; dehydration; dissolution; phase transformation; theophylline monohydrate
Funding
- William and Mildred Peters Endowment fund
- Department of Science and Technology, Govt. of India
- NSF
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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. Tablets containing theophylline monohydrate (TPM) and anhydrous citric acid (CA) were stored at 40A degrees 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. The water of crystallization released by TPM dehydration was followed first by deliquescence of citric acid, evident from the headspace relative humidity (similar to 68%; 40A degrees 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. The water released by API dehydration mediated cocrystal formation in intact tablets and affected dissolution behavior.
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