Influence of Environmental Conditions on the Kinetics and Mechanism of Dehydration of Carbamazepine Dihydrate

Abstract

The object of this project was to study the influence of temperature and water vapor pressure on the kinetics and mechanism of dehydration of carbamazepine dihydrate and to establish the relationship between the dehydration mechanism and the solid-state of the anhydrous phase formed. Three experimental techniques were utilized to study the kinetics of dehydration of carbamazepine dihydrate (C15H12N2O.2H2O)-thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and variable temperature powder X-ray diffractometry (VTXRD). These techniques respectively provide information about the changes in weight, heat flow and solid-state (phase) during the dehydration process. The instrumental setup was modified so that simultaneous control of both the temperature and the water vapor pressure was possible. The experiments were carried out at different temperatures, ranging from 26 to 64 degrees C. In the absence of water vapor, the dehydration followed the 2-dimensional phase boundary controlled model at all the temperatures studied. In the next stage, the water vapor pressure was altered while the studies were carried out at a single temperature of 44 degrees C. The dehydration was 2-dimensional phase boundary controlled at water vapor pressures < or = 5.1 torr while the Avrami-Erofeev kinetics (3-dimensional nucleation) was followed at water vapor pressures > or = 12.0 torr. In the former case, the anhydrous phase formed was X-ray amorphous while it was the crystalline anhydrous gamma-carbamazepine in the latter. Thus a relationship between the mechanism of dehydration and the solid-state of the product phase was evident. The dehydration conditions influence not only the mechanism but also the solid-state of the anhydrous phase formed. While the techniques of TGA and DSC have found extensive use in studying dehydration reactions, VTXRD proved to be an excellent complement in characterizing the solid-states of the reactant and product phases.

Solid-vapor interactions: Influence of environmental conditions on the dehydration of carbamazepine dihydrate

“…In an earlier investigation, the activation energy for dehydration, determined from the study of dehydration kinetics by thermogravimetric analysis, was calculated to be 68.8 kJ/mol. 2 This discrepancy is possibly due to differences in experimental conditions, including sample size, geometry, and gas flow rate.…”

“…We had previously observed that when the kinetics of dehydration was phase boundary controlled, the product was amorphous anhydrate, while nucleation-controlled kinetics resulted in crystalline anhydrate. 2 Thus, the 2 steps observed here possibly signify the formation of, first amorphous, followed by crystalline carbamazepine phases. The higher the vapor pressure (p/p o ≤ 0.07), the faster was the recrystallization and the shorter was the first step.…”

“…The dehydration kinetics (at 44ºC) of carbamazepine dihydrate at water vapor pressures ≤5.1 torr was best described by the 2-dimensional phase boundary controlled model, whereas at vapor pressures ≥12.0 torr, the 3-dimensional nucleation and growth model was best. 2 At an intermediate vapor pressure of 7.6 torr, it was not possible to model the data. From humiditycontrolled XRD results, it was shown that at low vapor pressures, dehydration resulted in an amorphous anhydrate, while at high vapor pressures, the crystalline anhydrate was formed.…”

“…It was earlier observed that, when the dehydration was phase boundary controlled, the product phase was amorphous anhydrate. 2 It is recognized that the reaction mechanism alone cannot form the basis for deducing the solid state of the final product. Even if the dehydration resulted in an amorphous anhydrate, crystallization could then follow.…”

“…In the first case, carbamazepine dihydrate was exposed to 52% RH in the vapor sorption balance for an extended time period followed by exposure to 0% RH (dry nitrogen flow). This procedure was based on previous studies 2,4 that have shown that carbamazepine dihydrate was stable at 52% RH at room temperature and contained a negligible amount of sorbed water. The dehydration profile following this treatment was compared with the one obtained by direct exposure to 0% RH ( Figure 1B).…”