Thermal decomposition of matrix metalloproteinase inhibitors: evidence of solid state dimerization.

The thermal properties of three matrix metalloproteinase (MMP) inhibitors were investigated using a variety of instrumental methods. Differential scanning calorimetry revealed highly exothermic processes for all compounds above 200°C, and thermogravimetric analysis resulted in significant step-wise weight losses at the temperatures corresponding to the exothermic transitions. Hot stage microscopy observations for several compounds showed evolution of gas bubbles from crystals at temperatures that correlated with the exotherms. Thermal decomposition involving the hydroxamic acid functional group was suspected and further evaluated using various analytical techniques including reversed-phase HPLC, LC-MS-MS, TGA-FTIR and NMR. The mechanism proposed in the thermal decomposition involves a Lossen Rearrangement to form a dimeric species containing a urea linkage.

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

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 degrees 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 degrees 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.

Polymorphism of roxifiban.

Roxifiban was found to exist in two polymorphic forms. The polymorphs were detected by X-ray powder diffraction and solid-state carbon nuclear magnetic resonance. A slight difference between the two polymorphs was also detected by isothermal microcalorimetry. However, no differences were observed by differential scanning calorimetry, infrared, or Raman spectroscopy. Solubility studies as a function of temperature in a discriminating solvent system permitted characterization of the thermodynamics of the polymorphs. The enthalpy of solution at 25 degrees C was 8.1 kcal/mol and 8.9 kcal/mol for Form I and Form II, respectively, and the thermodynamic transition point was 132 degrees C. The data confirm that the polymorphs are enantiotropic. Form II is the thermodynamically stable crystal form over the practical range of drug substance storage and handling and dosage form processing and storage. However, Form I has been kinetically stable after storage for more than 36 months at 25 degrees C/60% relative humidity with no conversion to Form II occurring.

Solid-state carbon NMR characterization of the polymorphs of roxifiban.

Roxifiban, an experimental antithrombotic prodrug, exists as crystalline forms I and II. A quantitative solid-state nuclear magnetic resonance (NMR) method was developed to characterize the two polymorphs of roxifiban. The differences in the NMR spectra of the polymorphs were utilized in analyses of physical blends of the pure crystalline forms to establish a calibration curve. A detection limit of 9% form II in form I was determined from analysis of a 10% form II blend. Solid-state NMR was a valuable technique to quantify the polymorphic purity of roxifiban where other techniques such as differential scanning calorimetry (DSC) could not be used for this purpose.

Kinetics and mechanism of hydrolysis of efavirenz.

PURPOSE: To determine the kinetics and mechanism of hydrolysis of efavirenz [(S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one] in aqueous solutions. METHODS: The solution stability was examined at 60 degrees C and an ionic strength of 0.3 M over the pH range of 0.6 to 12.8. The loss of efavirenz and the appearance of degradants were followed with a reverse-phase high-performance liquid chromatography assay. Characterization of the degradants was accomplished with liquid chromatography-mass spectrometry. RESULTS: The degradation of efavirenz followed apparent first-order kinetics over the pH range of 0.6 to 12.8 at 60 degrees C. The catalytic effect of phosphate and borate buffers was negligible while acetate and citrate demonstrated buffer catalysis. The overall rate constant indicated a pH minimum (the pH of maximum stability) of approximately 4. Mass spectra data identified a degradant with a molecular weight consistent with hydrolysis of the cyclic carbamate to the corresponding amino alcohol. The degradation route was confirmed with spiking experiments with an authentic sample of the amino alcohol indicating that the carbamate hydrolysis pathway was the predominant reaction throughout the pH range studied. Subsequent degradation of the amino alcohol proceeded at the extremes of the pH range studied via rearrangement to the quinoline. CONCLUSIONS: The pH-rate profile was consistent with a combination of a V-shaped profile in the pH range of 0-9 and a sigmoid-shaped profile in the pH range of 4-13. The plateau that began at pH 10-11 is a result of the ionization of the amine of the carbamate inhibiting the base-catalyzed hydrolysis of efavirenz, given that the ionized form of the carbamate is resonance-stabilized toward hydroxide-catalyzed degradation. Thus, increasing the pH resulted in a parallel decrease in the unionized fraction and increase in hydroxide ion concentration resulting in a constant k(obs) value.