Compatibility by a Nonisothermal Kinetic Study of Azathioprine Associated with Usual Excipients in the Product Quality Review Process

Abstract

Azathioprine is an immunosuppressive drug for several inflammatory disorders. Due to its clinical relevance, to explore the solid-state properties for excipient compatibility in the product quality review process is essential. Fourier transform infrared spectroscopy, powder X-ray diffraction and thermal analysis (thermogravimetry/derivative thermogravimetry (TG/DTG), differential thermal analysis (DTA), and differential scanning calorimetry (DSC)) were applied. The compatibility studies evidenced that starch pregelatinized, colloidal silicon dioxide, and talc are fully compatible with azathioprine. However, stearic acid, magnesium stearate, and mannitol are incompatible after heat supply at temperatures easily reached by industrial processing. The nonlinear Vyazovkin isoconversional treatment performed the kinetic study of the thermal degradation. The activation energies were determined to clarify the influence of each excipient on the thermal drug stability, an essential procedure in the pharmaceutical development, and all over the commercial live span, in Good Manufacturing Practices.

Thermal Stability Kinetics and Shelf Life Estimation of the Redox‐Active Therapeutic and Mimic of Superoxide Dismutase Enzyme, Mn(III) meso‐Tetrakis(N‐ethylpyridinium‐2‐yl)porphyrin Chloride (MnTE‐2‐PyPCl5, BMX‐010)

“…Of note, a solid sample of high-purity MnTE-2-PyPCl 5 stored in a closed vial at room temperature in the dark for 7 years in our laboratories showed no noticeable signs of N -dealkylation when analyzed by thin-layer chromatography (data not shown). As shelf life values may be significantly affected by storage and drug formulations (including the nature of excipients) [ 34 , 52 , 60 ], the calculated t 90% value for MnTE-2-PyPCl 5 is valid if the net solid material is kept in ideal conditions of humidity. As noted, MnTE-2-PyPCl 5 is a hydratable molecule.…”

“…We describe herein the first study on the kinetics of thermal degradation of MnP-based redox-active therapeutics under isothermal and nonisothermal conditions. Additionally, it is worth noting that thermal decomposition kinetic models were evaluated using a state-of-the-art approach, based on the multilayer perceptron (MLP) artificial neural network [48][49][50][51][52]. MnTE-2-PyPCl 5 was chosen as a representative API of the class of Mn(III) 2-N-alkylpyridylporphyrins, currently developed as SOD mimics, biomimetic models, catalytic antioxidants, and redoxactive therapeutics.…”

Solid-state properties of pink clay from Jequitinhonha Valley in Brazil for pre-formulation study

“…Four heating rates dynamic thermogravimetry (TG) curves were obtained in the inert atmosphere, and the activation energy (Ea) along the conversion degree is determined (Vyazovkin, Chrissafis, Di Lorenzo, Koga, Pijolat, Roduit et al, 2014). Several studies have been published using the Vyazovkin method from data on the thermal behavior of pharmaceutical systems (Silva, Fialho, Barbosa, Araujo, Carneiro, Sebastião et al 2021;Freitas-Marques, Araujo, da Silva, Fernandes, Mussel, Sebastião, Yoshida, 2019;Freitas-Marques, Araujo, Fernandes, Mussel, Sebastião, Yoshida, 2020;Freitas-Marques, Araujo, Mussel, Sebastião, Yoshida, 2021). The Vyazovkin method is applied at short intervals, allowing an indirect analysis of multiple steps, as the activation energy varies according to the α degree (conversion process).…”