Sublimation characterization and vapor pressure estimation of an HIV nonnucleoside reverse transcriptase inhibitor using thermogravimetric analysis

Abstract

KEYWORDS: sublimation, vapor pressure, thermogravimetric analysis-infrared (TGA-IR) The purpose of this research is to investigate the sublimation process of DPC 963, a second-generation nonnucleoside reverse transcriptase inhibitor for HIV-1 retrovirus, and to better understand the effect of sublimation during active pharmaceutical ingredient (API) manufacture and formulation development, especially the drying processes. Sublimation of DPC 963 at 150°C and above was determined by thermogravimetric analysis-Fourier transform infrared (TGA-FTIR). The rates of sublimation at different temperatures were measured using isothermal TGA. Condensed material was collected and analyzed by differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD), and infrared (IR) spectrometry. Benzoic acid was used as a reference standard to derive a linear logarithmic relationship between sublimation/evaporation rate and vapor pressure specific to the TGA system used in this study. Sublimation and evaporation of DPC 963 were found to follow apparent zero-order kinetics. Using the Eyring equation, the enthalpy and entropy of the sublimation and evaporation processes were obtained. The enthalpies of sublimation and evaporation were found to be 29 and 22 kcal/mol, respectively. The condensed material from the vapor phase was found to exist in 2 physical forms, amorphous and crystalline. Using benzoic acid as a reference standard, vapor pressure of DPC 963 at different temperatures was calculated using the linear logarithmic relationship obtained. DPC 963 undergoes sublimation at appreciable rates at 150°C and above but this is not likely to pose a serious issue during the manufacturing process. Vapor pressure estimation using thermogravimetric analysis provided sufficient accuracy to be used as a fast, simple, and safe alternative to the traditional methods of vapor pressure determination.

Thermodynamic investigations of nitroxoline sublimation by simultaneous DSC-FTIR method and isothermal TG analysis

“…In the temperature region (170–180°C) close to the melting point of 182°C; however, the weight‐loss thermograms at final stage were clearly derived from linear. This might be possibly due to premelting or softening of the crystals and evaporation from a changing ratio of mixture of solid and liquid 21. Here, this rate of weight loss should be a combination of sublimation and evaporation processes.…”

Rapid Estimation of Thermodynamic Parameters and Vapor Pressures of Volatile Materials at Nanoscale

“…This behavior was expected due to the approximation considered in this equation, [18] and has been reported previously for other materials. [4,20,21] However, two extreme values, 62 and 107 kJ mol À1 , have been reported by Oxley et al, who used rising-temperature TGA technique, [22] and Xie et al [23] by using a TGA-FTIR apparatus. This value is in agreement with the values of the activation energy of sublimation of benzoic acid that have been reported in the literature (84.0-95.5 kJ mol À1 ).…”

A fit of the vapours

“…A further refinement incorporated a form of evolved gas analysis whereby the exhaust from the thermobalance was passed through a trap and subsequently examined to determine the fractional evaporation and degradation of the volatilising species [20]. Dobbs [21,22] and Elder [23] reported the use of the Gückel's method to measure the vapour pressures of pesticides and pharmaceutical compounds, an approach that is still occasionally cited in the literature [24,25].…”