Dissolution profile evaluation of solid pharmaceutical forms containing chloramphenicol marketed in Brazil

The dissolution profile for solid pharmaceutical forms containing chloramphenicol 250 mg available in Brazil was determined using a method from the American Pharmacopoeia (United States Pharmacopoeia, 2004) and then compared. Two different methods of dissolution profile comparison were used: ANOVA, and an independent model. Differences between the formulations were reflected in the dissolution profiles. The presence of metastable polymorphs or amorphous forms of chloramphenicol palmitate might be responsible for variations in the concentration of the drug observed within formulations.O perfil de dissolução de formas farmacêuticas sólidas contendo palmitato de cloranfenicol 250 mg disponíveis no Brasil foi determinada pelo método da Farmacopéia Americana (United States Pharmacopeia, 2004) e comparado. Duas categorias de métodos para comparação dos perfis de dissolução foram utilizadas: ANOVA e modelo independente. Diferenças entre as formulações foram refletidas nos perfis de dissolução. A presença de polimorfos metaestáveis ou formas amorfas de palmitato de cloranfenicol pode ser responsável pelas variações na concentração do fármaco observada nas formulações

Multivariate spectroscopic determination of the lamivudine-zidovudine association

The multivariate spectroscopic determination of lamivudine-zidovudine associations was carried out by partial least square regression (PLS). This model was developed from 20 synthetic mixtures using mean-centered spectral data acquired from 190 to 350 nm and with 3 latent variables. External validation was performed with 6 synthetic mixtures providing prediction errors close to 1%. Moreover, the analysis of commercial drugs showed good results with prediction errors lower than 10%. The multivariate methodology was validated according to International Conference on Harmonization (ICH) criteria, demonstrating precision, accuracy and robustness within legal requirements.A determinação espectroscópica multivariada da associação lamivudina-zidovudina foi realizada por regressão de mínimos quadrados parciais. O modelo foi desenvolvido a partir de 20 misturas sintéticas utilizando-se dados espectrais centrados na média adquiridos entre 190 e 350 nm e 3 variáveis latentes. A validação externa foi realizada a partir de 6 misturas sintéticas, observando-se erros médios de previsão de aproximadamente 1%. Na análise de medicamentos foram obtidos bons resultados, com erros de previsão inferiores a 10%. A metodologia multivariada foi validada de acordo com os critérios do International Conference on Harmonization (ICH), demonstrando precisão, exatidão e robustez compatíveis com a legislação vigente.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal do Paraná Departamento de QuímicaUniversidade Federal de São Paulo (UNIFESP) Departamento de Ciências Exatas e da TerraUNIFESP, Depto. de Ciências Exatas e da TerraSciEL

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 (β-cyclodextrin and hydroxypropyl-β-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, β-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-β-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-β-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-β-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 1 H 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

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

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

Intrinsic dissolution simulation of highly and poorly soluble drugs for BCS solubility classification

Intrinsic dissolution testing allows characterizing drug substances through its dissolution rate when exposed to a specified surface area in a specific dissolution media, This can be used to determine if a drug substance is highly or poorly soluble. In this work. DDDPlus version 4.0 (Simulations Plus, Inc.) was used to simulate intrinsic dissolution experiments for pyrimethamine and metronidazole. These drugs have low and high solubility properties. Predicted intrinsic dissolution rates (IDR) were compared to observed in vitro IDR. Physicochemical parameters from literature and the experimental conditions of the intrinsic dissolution tests for each drug were used as input data into the software. The program was able to predict the IDR of pyrimethamine and metronidazole within a pH range of 1.0 to 7.2. Observed and predicted IDR values for both drugs showed high correlations (R-2 > 0.9424), The IDR values from simulations showed the pH-dependent solubility of pyrimethamine and metronidazole, allowing us to classify the solubility according to the Biopharmaceutics Classification System (BCS). Intrinsic dissolution test simulations using DDDPlus can be used to obtain a BCS solubility classification of a drug substance, helping to reduce the number of laboratory experiments.National Council of Scientific and Technological Development (CNPq/Brazil)Univ Sao Paulo, Fac Pharmaceut Sci, Dept Pharm, Sao Paulo, BrazilUniv Fed Sao Paulo UNIFESP, Inst Environm Chem & Pharmaceut Sci, Dept Exact & Earth Sci, Sao Paulo, BrazilUniv Alberta, Ctr Pharm & Hlth Res, Fac Pharm & Pharmaceut Sci, Edmonton, AB, CanadaUniv Fed Sao Paulo UNIFESP, Inst Environm Chem & Pharmaceut Sci, Dept Exact & Earth Sci, Sao Paulo, BrazilCNPq: 400455/2014-5Web of Scienc

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)

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