Drug Phase Transformation and Water Redistribution during Continuous Tablet Manufacturing: A Case Study of Carbamazepine Dihydrate

In recent years, continuous tablet manufacturing technologyhasbeen used to obtain regulatory approval of several new drug products.While a significant fraction of active pharmaceutical ingredientsexists as hydrates (wherein water is incorporated stoichiometricallyin the crystal lattice), the impact of processing conditions and formulationcomposition on the dehydration behavior of hydrates during continuousmanufacturing has not been investigated. Using powder X-ray diffractometry,we monitored the dehydration kinetics of carbamazepine dihydrate informulations containing dibasic calcium phosphate, anhydrous (DCPA),mannitol, or microcrystalline cellulose. The combined effect of nitrogenflow and vigorous mixing during the continuous mixing stage of tabletmanufacture facilitated API dehydration. Dehydration was rapid andmost pronounced in the presence of DCPA. The dehydration product,amorphous anhydrous carbamazepine, sorbed a significant fraction ofthe water released by dehydration. Thus, the dehydration process resultedin a redistribution of water in the powder blend. The unintended formationof an amorphous dehydrated phase, which tends to be much more reactivethan its crystalline counterparts, is of concern and warrants furtherinvestigation.

Automated summary

Continuous tablet manufacturing technology has been used to obtain regulatory approval for new drug products. The impact of processing conditions and formulation composition on the dehydration behavior of hydrates during continuous manufacturing has not been studied. Dehydration kinetics of carbamazepine dihydrate were monitored in different formulations using powder X-ray diffractometry. The dehydration was most significant in the presence of DCPA. The unintended formation of an amorphous dehydrated phase warrants further investigation.