Applications of pressure differential scanning calorimetry in the study of pharmaceutical hydrates: I. Carbamazepine dihydrate

The dehydration of carbamazepine dihydrate (C₁₅H₁₂N₂O · 2H₂O) was studied by both conventional differential scanning calorimetry (DSC) and by pressure differential scanning calorimetry. Variable temperature powder X- ray diffractometry (VTXRD) and thermogravimetric analysis were used as complementary techniques. By performing DSC at elevated pressures, the dehydration and vaporization endotherms were separated and it was possible to determine the enthalpy of dehydration. Over the range of 100-600 psi, the enthalpy of dehydration was unaffected by pressure. However, the solid-state of the anhydrous phase formed was influenced by the DSC conditions. At ambient pressure, dehydration resulted in the formation of the γ-form of anhydrous carbamazepine while at elevated pressures, the anhydrous β-form appeared which converted to the γ-form at higher temperatures. At high pressures, the water liberated on dehydration is not immediately removed and its presence appears to be responsible for the formation of β-carbamazepine. VTXRD permitted in situ study of dehydration and this confirmed the DSC results. A specially fabricated sample holder permitted VTXRD studies at elevated pressures.