Mechanical, optical, and physicochemical properties of HPMC-based doxazosin mesylate orodispersible films

Abstract In this study, orodispersible films formed from hydroxypropyl methylcellulose (HPMC) E6 (2, 2.5, and 3%) and plasticizers ((glycerin (Gly), propylene glycol (PP), or polyethylene glycol (PEG)), containing doxazosin mesylate, were prepared by the solvent casting method and characterized. Design of experiments (DoE) was used as a statistical tool to facilitate the interpretation of the experimental data and allow the identification of optimal levels of factors for maximum formulation performance. Differential scanning calorimetry (DSC) curves and X-ray powder diffraction (XRPD) diffractograms showed doxazosin mesylate amorphization, probably due to complexation with the polymer (HPMC E6), and the glass transition temperature of the polymer was reduced by adding a plasticizer. Fourier transformed infrared (FTIR) spectroscopy results showed that the chemical structure of doxazosin mesylate was preserved when introduced into the polymer matrix, and the plasticizers, glycerin and PEG, affected the polymer matrix with high intensity. The addition of plasticizers increased the elongation at break and adhesiveness (Gly > PEG > PP), confirming the greater plasticizer effect of Gly observed in DSC and FTIR studies. Greater transparency was observed for the orodispersible films prepared using PP. The addition of citric acid as a pH modifier was fundamental for the release of doxazosin mesylate, and the desirability formulation had a release profile similar to that of the reference product

RP-HPLC simultaneous quantification of rutin, avobenzone, and octyl methoxycinnamate in the presence of hydroxypropyl β-cyclodextrin (HPβCD) and sulfobutyl ether β-cyclodextrin (SBEβCD)

Abstract Development and validation of a simple and fast method of high-performance liquid chromatography with diode array detection (HPLC-DAD) for the simultaneously analysis of rutin, avobenzone, and octyl p-methoxycinnamate is presented. These substances were separated using a Kromasil C18 (250×4.6 mm, 5 μm) column, methanol: water (88:12 v/v) as the mobile phase, and a flow rate of 0.8 mL min−1. The experiment was performed at room temperature and elution was under isocratic conditions. Quantification was performed by external calibration at the wavelength of 325 nm. The validated parameters included linearity, selectivity, precision (repeatability), intermediate precision, accuracy, limit of detection, limit of quantification and robustness. The results of validation were statistically treated using the Action Stat version 3.5.152.34. The selectivity was also evaluated in the presence of two cyclodextrins (2-hydroxypropyl-β-cyclodextrin and β-cyclodextrin sulfobutyl ether sodium). The absence of parallelism between the curves of octyl p-methoxycinnamate in the absence and presence of the β-cyclodextrin sulfobutyl ether sodium in the mobile phase revealed interference from this matrix, thereby indicating the necessity of validating the method in the presence of this, and other matrices. The proposed method was selective, linear, precise, accurate, and robust for the simultaneous determination of rutin, avobenzone, and octyl p-methoxycinnamate.

Inclusion complexes and self-assembled cyclodextrin aggregates for increasing the solubility of benzimidazoles

Albendazole and fenbendazole are imidazole derivatives that exhibit broad spectrum activity against parasites, but the low solubility of these drugs considerably reduces their effectiveness. Complexation of albendazole and fenbendazole with cyclodextrins (ß-cyclodextrin and hydroxypropyl-ß-cyclodextrin) in both water and an aqueous solution of polyvinylpyrrolidone (PVP-k30) was studied to determine if it could increase the solubility and dissolution rate of the drugs. In an aqueous solution, ß-cyclodextrin increased the solubility of albendazole from 0.4188 to ~93.47 µg mL-1 (223×), and of fenbendazole from 0.1054 to 45.56 µg mL-1 (432×); hydroxypropyl-ß-cyclodextrin, on the other hand, increased solubility to ~443.06 µg mL-1 (1058×) for albendazole and ~159.36 µg mL-1 (1512×) for fenbendazole. The combination of hydroxypropyl-ß-cyclodextrin and polyvinylpyrrolidone enabled a solubility increase of 1412× (~591.22 µg mL-1) for albendazole and 1373× (~144.66 µg mL-1) for fenbendazole. The dissolution rate of the drugs was significantly increased in binary and ternary systems, with hydroxypropyl-ß-cyclodextrin proving to be more effective. The presence of the water-soluble PVP-k30 increased the dissolution rate and amorphization of the complexes. Analysis of the changes in displacement and the profile of the cyclodextrin bands in the 1H NMR spectra revealed a molecular interaction and pointed to an effective complexation in the drug/cyclodextrin systems. Monomeric forms and nanoclusters of cyclodextrins were observed in the drug/cyclodextrin systems, suggesting that the increase in solubility of the drugs in the presence of cyclodextrins should not be attributed only to the formation of inclusion complexes, but also to the formation of cyclodextrin aggregates

Multicomponent complex formation between pyrimethamine, cyclodextrins and water-soluble polymers

The combined effect of hydroxypropyl-β-cyclodextrin (HPβCD) and polyvinylpyrrolidone (PVP) or sodium carboxymethylcellulose (CMC) on the solubility of pyrimethamine (PYR) was studied. Equimolar PYR-HPβCD solid systems, in the presence or the absence of 0.25 percent (w/v) PVP or 0.10 percent (w/v) CMC were prepared by coevaporation or freeze-drying, and characterized by differential scanning calorimetry, X-ray diffraction analysis and dissolution profile. Phase-solubility analysis was used to investigate the interactions in aqueous solution between PYR and HPβCD, in the absence or presence of polymers, which showed a linear increase of PYR solubility depending on the concentration of HPβCD. The presence of polymer did not alter the stoichiometry of the complexes. DSC results were indicative of complexation, due to the loss of the characteristic endothermic peak of PYR. X-ray diffraction analysis confirmed the DSC results. Binary and ternary complexes showed higher dissolution rate when compared with the pure drug.

Perfil de dissolução in vitro de comprimidos de primaquina disponíveis para tratamento de malária no Brasil / In vitro dissolution profile of primaquine tablets available for malaria treatment in Brazil

A ineficácia clínica de muitos medicamentos tem servido de alerta para estudos mais profundos sobre os componentes da formulação, processos empregados e características físico-químicas dos fármacos. O objetivo deste trabalho foi avaliar a liberação in vitro de comprimidos de fosfato de primaquina disponíveis no Brasil para tratamento da malária, e o desenvolvimento de novas formulações de liberação convencional. Embora os comprimidos de fosfato de primaquina estudados tenham sido aprovados pelos critérios propostos pela Farmacopéia Americana (2006) para o teste de dissolução, não apresentaram desempenho adequado para o perfil de dissolução, mostrando retenção do fármaco durante a liberação. Os resultados indicam a existência de problemas nos comprimidos de fosfato de primaquina analisados, podendo sugerir como um dos fatores responsáveis pelo aparecimento de resistência dos parasitas.

The clinical inefficacy of many medications has served to highlight the need for deeper studies on the formulation components, processes used and physicochemical characteristics of drugs. The objective of this study was to evaluate the in vitro release of primaquine phosphate from tablets available in Brazil for treating malaria, and the development of new formulations for conventional release. Although the primaquine phosphate tablets studied had been approved according to the criteria proposed by the United States Pharmacopoeia (2006) for the dissolution test, they did not present adequate dissolution performance characteristics, in that there was drug retention during the release process. The results indicate the existence of problems in the primaquine phosphate tablets analyzed, and it may suggest that this is one of the factors responsible for the appearance of parasite resistance.

Dissolução de formas farmacêuticas sólidas contendo antimaláricos e desenvolvimento de comprimidos de primaquina de liberação convencional / Dissolution of solid pharmaceutical forms contend antimalarial and development of tablets of primaquine of conventional liberation

O presente trabalho teve como objetivos, a avaliação das características físico-químicas e parâmetros de dissolução de especialidades farmacêuticas contendo sulfato de quinino, difosfato de cloroquina e fosfato de primaquina disponíveis para o tratamento da malária no Brasil, e o desenvolvimento de formulações de comprimidos de fosfato de primaquina de liberação convencional, considerando-se os requisitos de eficácia, segurança e qualidade assegurada. Comprimidos de sulfato de quinino, difosfato de cloroquina e fosfato de primaquina utilizados no tratamento de malária no Brasil, foram submetidos aos ensaios de peso médio, dureza, friabilidade, teste e perfil de dissolução e ensaios termoanalíticos...