Christian Fernandes

Dasatinib (DAS) is a biopharmaceutical classification system (BCS) class II drug that is used orally to treat chronic myelogenous leukemia. However, its very low and pH-dependent aqueous solubility severely limits its oral bioavailability. To address this biopharmaceutical limitation, we designed more soluble multicomponent crystalline forms (MCCs) of DAS. Two novel salt solvate forms were successfully obtained via solvent evaporation through reactions with maleic and fumaric acids. A comprehensive solid-state evaluation of these salt solvate forms was conducted by using X-ray diffraction (SCXRD, PXRD), spectroscopy (FT-IR and 1H NMR), and thermal (TG and DSC) analyses. Both MCCs of DAS have displayed substantial enhancements in buffered aqueous solubility (up 1470-fold) and intrinsic dissolution rate (up 312-fold) compared with the parent drug. Furthermore, the DAS MCCs exhibited an increased cytotoxicity and selectivity toward tumor cells. These fulfillments highlight the potential of crystalline salt engineering to enhance the unsatisfactory oral bioavailability and anticancer efficacy of the DAS.

RS -Fluoxetine spontaneously resolves into a conglomerate via tetrafluoroborate salt formation. Sulfate anion produces a kryptoracemate with homochiral chains but lacks enantiomeric discrimination.

Dacarbazine (DTIC) is a widely prescribed oncolytic agent to treat advanced malignant melanomas. Nevertheless, the drug is known for exhibiting low and pH-dependent solubility, in addition to being photosensitive. These features imply the formation of the inactive photodegradation product 2-azahypoxanthine (2-AZA) during pharmaceutical manufacturing and even drug administration. We have focused on developing novel DTIC salt/cocrystal forms with enhanced solubility and dissolution behaviors to overcome or minimize this undesirable biopharmaceutical profile. By cocrystallization techniques, two salts, two cocrystals, and one salt-cocrystal have been successfully prepared through reactions with aliphatic carboxylic acids. A detailed structural study of these new multicomponent crystals was conducted using X-ray diffraction (SCXRD, PXRD), spectroscopic (FT-IR and ¹H NMR), and thermal (TG and DSC) analyses. Most DTIC crystal forms reported display substantial enhancements in solubility (up to 19-fold), with faster intrinsic dissolution rates (from 1.3 to 22-fold), contributing positively to reducing the photodegradation of DTIC in solution. These findings reinforce the potential of these new solid forms to enhance the limited DTIC biopharmaceutical profile.

ObjectiveThe investigation of benznidazole (BZN), excipients, and tablets aims to evaluate their thermal energy and tableting effects. They aim to understand better the molecular and pharmaceutical processing techniques of the formulation.SignificanceThe Product Quality Review, part of Good Manufacturing Practices, is essential to highlight trends and identify product and process improvements.MethodsA set of technique approaches, infrared spectroscopy, X-ray diffraction, and thermal analysis with isoconversional kinetic study, were applied in the protocol.ResultsX-ray experiments suggest talc and alpha-lactose monohydrate dehydration and conversion of beta-lactose to stable alpha-lactose upon tableting. The signal crystallization at 167 degrees C in the DSC curve confirmed this observation. A calorimetric study showed a decrease in the thermal stability of BZN tablets. Therefore, the temperature is a critical process parameter. The specific heat capacity (Cp) of BZN, measured by DSC, was 10.04 J/g at 25 degrees C and 9.06 J/g at 160 degrees C. Thermal decomposition required 78 kJ mol(-1). Compared with the tablet (about 200 kJ mol(-1)), the necessary energy is two-fold lower, as observed in the kinetic study by non-isothermal TG experiment at 5; 7.5; 10; and 15 degrees C min(-1).ConclusionsThese results indicate the necessity of considering the thermal energy and tableting effects of BZN manufacturing, which contributes significantly to the molecular mechanistic understanding of this drug delivery system.