Evaluation of the disolution profile of drugs by multivariate electronic spectroscopy

In this work the evaluation of the dissolution profile of captopril-hydrochlorothiazide and zidovudine-lamivudine associations were carried out by multivariate spectroscopic method. The models were developed by partial least square regression from 20 synthetic mixtures using mean-centered spectral data. The external validation was accomplished with 5 synthetic mixtures shown mean prevision error of about 1%. Good agreement was observed in the analyses of commercial drugs (content uniformity and dissolution profile), considering the results obtained by the standard chromatographic method, with prevision error lower than 10%.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

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

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% (w/v) PVP or 0.10% (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.Universidade Federal de São Paulo (UNIFESP) Departamento de Ciências Exatas e da TerraUniversidade Federal do ParanáUniversidade PositivoUniversidade de São Paulo Faculdade de Ciências FarmacêuticasUNIFESP, 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

Dissolução de formas farmacêuticas sólidas contendo antimaláricos e desenvolvimento de comprimidos de primaquina de liberação convencional

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. As amostras de sulfato de quinino, difosfato de cloroquina e fosfato de primaquina avaliados cumpriram as especificações para o teste de dissolução descrito pela Farmacopéia Americana (1999). Os lotes de sulfato de quinino e difosfato de cloroquina apresentaram perfis de dissolução seguindo cinética de dissolução de primeira ordem, enquanto que, comportamento cinético variado foi observado para lotes de fosfato de primaquina. As curvas DSC dos lotes de difosfato de cloroquina analisados mantiveram as características do fármaco; para sulfato de quinino e fosfato de primaquina, as curvas DSC indicaram que a estabilidade do fármaco pode estar comprometida. Nos estudos de compatibilidade fármaco e excipiente, interação foi observada para as misturas tisicas entre fosfato de primaquina e lactose, glicolato de amido sódico, estearato de magnésio e lauril sulfato de sódio, sugerindo incompatibilidade entre eles. Comprimidos de fosfato de primaquina foram preparados baseando-se nos estudos de compatibilidade fármaco e excipiente. Alterações de peso médio, dureza e friabilidade foram observadas durante os estudos de estabilidade. Embora os comprimidos de fosfato de primaquina tenham apresentado uma liberação in vitro adequada do fármaco (dissolução) durante estudo de estabilidade, as características físico-químicas observadas tornam visível a dificuldade para a formulação de produtos contendo fosfato de primaquina com estabilidade adequada.The present work had as objectives the evaluation of the characteristics physical-chemistries and parameters of dissolution of pharmaceutical specialties containing quinine sulphate, chloroquine diphosphate and primaquine phosphate of available for the treatment of the malaria in Brazil and the development of formulations of tablets of phosphate of primaquine of conventional liberation being considered the requirements of effectiveness, safety and insured quality. Quinine sulphate, chloroquine diphosphate and primaquine phosphate tablets used in the malaria treatment in Brazil they were submitted to the rehearsals of medium weight, hardness, friability, test and dissolution profile and rehearsals termoanalytics. The samples of quinine sulphate, chloroquine diphosphate and primaquine phosphate of appraised accomplished the specifications for the dissolution test described by United States Pharmacopeia (1999). The lots of quinine sulphate and chloroquine diphosphate presented dissolution profiles following kinetics of dissolution of first order while varied kinetic behavior was observed for lots of primaquine phosphate. The curves DSC of the lots chloroquine diphosphate analyzed maintained the characteristics of the drug; for quinine sulphate and primaquine phosphate the curves DSC indicated that the stability of the drug is committed. In the studies of compatibility drug and excipient interaction was observed for the physical mixtures between primaquine phosphate and lactose, glycolate of sodic starch, estearate of magnesium and lauryl sulphate of sodium suggesting incompatibility among them. Primaquine phosphate tablets were prepared basing on the studies of compatibility drug and excipient. Alterations of medium weight, hardness and friability were observed during the studies of stability. Although primaquine phosphate tablets have presented liberation in appropriate vitro of the drug (dissolution) during study of stability the characteristics physical chemistries observed tum visible the difficulty for the formulation of products containing primaquine phosphate with appropriate stability

Quality by Design (QbD) como ferramenta para otimização dos processos farmacêuticos

O setor farmacêutico está em constante evolução. A harmonização de normas de produção, com o intuído de garantir eficácia, segurança e qualidade dos medicamentos, consiste em um dos maiores desafios. O conceito “qualidade baseada no projeto” (Quality by design, QbD) propõe uma abordagem sistemática, fundamentada no conhecimento científico e no gerenciamento do risco associado ao processo de fabricação. Nesta abordagem, qualidade é inversamente proporcional a variabilidade. A implementação do conceito de QbD constitui uma ferramenta promissora para a produção farmacêutica pois permite a produção de medicamentos por meio da previsão de riscos, ampliando a possibilidade de gerar produtos com eficácia, segurança e qualidade assegurados, aliado a redução de custos. A implementação deste conceito exige não somente novas tecnologias, mas a mudança no conceito de qualidade

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