Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor used worldwide to treat AIDS. The aim of this study was to investigate the structural and dynamic properties of the polymorphic form I of the drug by thermal analysis, Fourier transform infrared spectroscopy, solid-state NMR, and powder X-ray diffraction. A full assignment of 13 C NMR resonances was achieved for the first time. Variable-temperature studies were conducted, and the results were related to changes in the TDF structure and dynamics of specific molecular fragments, especially of the fumarate portion of the molecule. It was found that, under heating, the 13 C NMR signals related to the carbon atoms of the disoproxil fumarate moiety split into two resonances. The region of the phosphonate vicinity also changes. This can reflect the lack of symmetry of the two molecules in the asymmetric unit after heating. This solid−solid transformation was related to DSC and XRD observations.
Kinetic study by thermal decomposition of antiretroviral drugs, Efavirenz (EFV) and Lamivudine (3TC), usually present in the HIV cocktail, can be done by individual adjustment of the solid decomposition models. However, in some cases unacceptable errors are found using this methodology. To circumvent this problem, here is proposed to use a multilayer perceptron neural network (MLP), with an appropriate algorithm, which constitutes a linearization of the network by setting weights between the input layer and the intermediate one and the use of Kinetic models as activation functions of neurons in the hidden layer. The interconnection weights between that intermediate layer and output layer determines the contribution of each model in the overall fit of the experimental data. Thus, the decomposition is assumed to be a phenomenon that can occur following different kinetic processes. In the investigated data, the kinetic thermal decomposition process was best described by R1 and D4 model for all temperatures to EFV and 3TC, respectively. The residual error adjustment over the network is on average 10 3 times lower for EFV and 10 2 times lower for 3TC compared to the best individual kinetic model that describes the process. These improvements in physical adjustment allow detailed study of the process and therefore a more accurate calculation of the kinetic parameters such as the activation energy and frequency factor. It was found E a = 75.230 kJ / mol and s -1 for EFV and E a = 103.25 kJ / mol and s -1 for 3TC.
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.
Some conceptual elements regarding the axiomatic design method were applied to a specific case-study regarding developing modified liberation compressed product (CLM-UN), for use in the agricultural sector as pH regulating agent in soil. The study was orientated towards defining functional requirements, design parameters and process variables for manufacturing the product. Independence and information were evaluated, supporting axiomatic design as an alternative for integral product and process design (as a rational and systemic exercise), facilitating producing products having the quality which future users expect from them.
Benznidazole (BZ) tablets are the currently prescribed treatment for Chagas disease. However, BZ presents limited efficacy and a prolonged treatment regimen with dose-dependent side effects. The design and development of new BZ subcutaneous (SC) implants based on the biodegradable poly-ɛ-caprolactone (PCL) is proposed in this study for a controlled release of BZ and to improve patient compliance. The BZ–PCL implants were characterized by X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy, which indicated that BZ remains in its crystalline state dispersed in the polymer matrix with no polymorphic transitions. BZ–PCL implants, even at the highest doses, induce no alteration of the levels of hepatic enzymes in treated animals. BZ release from implants to blood was monitored in plasma during and after treatment in healthy and infected animals. Implants at equivalent oral doses increase the body’s exposure to BZ in the first days compared with oral therapy, exhibiting a safe profile and allowing sustained BZ concentrations in plasma to induce a cure of all mice in the experimental model of acute infection by the Y strain of T. cruzi. BZ–PCL implants have the same efficacy as 40 daily oral doses of BZ. Biodegradable BZ implants are a promising option to reduce failures related to poor adherence to treatment, with more comfort for patients, and with sustained BZ plasma concentration in the blood. These results are relevant for optimizing human Chagas disease treatment regimens.
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