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The use of the USP IV apparatus (flow-through cell) has gained acceptance in recent years due to its versatility and ability to discriminate due to its hydrodynamic conditions. Therefore, the objective of the present study was to develop a discriminative dissolution method in the USP IV apparatus using the open-loop configuration, as well as to propose a method to compare non-cumulative dissolution profiles obtained in the open-loop configuration considering kinetic parameters and validate its predictive power through its comparison with independent and dependent methods using five commercial immediate-release tablet drugs (one reference drug and four generic drugs) of metoprolol tartrate as a model drug. The comparison of the non-accumulated dissolution profiles consisted of determining the geometric ratio of Cmax, AUC0∞, AUC0Cmax, and Tmax (kinetic parameters) of the generic/reference drugs, whereby generic drugs "C" and "D" presented the highest probability of similarity since their 90% confidence intervals were included, or they were very close to the acceptance interval (80.00-125.00%). These results were consistent with the f2, bootstrap f2, and dissolution efficiency approaches (independent models). In conclusion, the proposed comparison method can be an important tool to establish similarity in dissolution profiles and to facilitate the development/selection of new formulations and positively ensure bioequivalence in clinical studies.

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RESUMEN La hipertensión arterial es el principal factor de riesgo cardiovascular, y su prevalencia en Paraguay es la mayor de América Latina. El objetivo del presente trabajo fue comparar productos de losartán de 100 mg comprimidos de producción nacional e importada a través de los perfiles de disolución versus su precio. Se tomaron 8 marcas de losartán potásico comercializadas durante el 2017, realizándose los controles de calidad de acuerdo a lo establecido en la Farmacopea Americana (USP 38). Se determinó el porcentaje de principio activo liberado en el medio de disolución establecido por la USP 38, por medio de los perfiles de disolución. Las determinaciones se realizaron por HPLC y espectrofotometría UV/V. Los controles realizados cumplieron con las especificaciones establecidas por la USP 38. No se encontraron diferencias significativas en el análisis estadístico de los perfiles de disolución de las diferentes marcas analizadas. Los resultados demostraron que los precios de las marcas analizadas no afectaban la calidad de los productos, pero sí en el costo del tratamiento de la población de escasos recursos, debido al mayor costo de los productos importados con respecto a los de producción nacional.

ABSTRACT Hypertension is the main cardiovascular risk factor, and its prevalence in Paraguay is the highest in Latin America. The objective of the present work was to compare products of 100 mg losartan tablets made in Paraguay and imported products, through dissolution profiles versus price. Eight brands of potassic losartan commercialized during 2017 were subjected to quality controls in accordance with the provisions of the American Pharmacopoeia (USP 38). The percentage of active principle released in the dissolution medium established by USP 38 was determined by means of dissolution profiles. The determinations were made by HPLC and UV/V spectrophotometry. The controls carried out complied with the specifications established by USP 38. No significant differences were found in the statistical analysis of the dissolution profiles of the different brands analyzed. The results showed that the prices of the brands analyzed did not affect the quality of the products, but they affected the cost of treatment of the low-income population due to the higher cost of imported products compared to those of national production.

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Triclabendazole is the first-line drug of choice to treat and control fasciolasis, a neglected parasitic human disease. It is a class II/IV compound according to the Biopharmaceutics Classification System. Thus, the aim of this study was to improve aqueous solubility and dissolution rate of triclabendazole complexed with 2-hydroxylpropyl-ß-cyclodextrin (HP-ß-CD) and methyl-ß-cyclodextrin (Me-ß-CD) at 1:1 and 1:2 M ratio. The impact of storage on the solubility, dissolution profile, and solid-state properties of such complexes was also investigated. Drug-carrier interactions were characterized by infrared spectroscopy, differential scanning calorimetry, X-ray diffractometry, and scanning electron microscopy. The solubility of triclabendazole improved up to 256- and 341-fold using HP-ß-CD and Me-ß-CD, respectively. In particular, the drug complexed with Me-ß-CD showed a positive deviation from linearity, suggesting that its solubility increases with an increasing concentration of Me-ß-CD concentration in a nonlinear manner. The drug dissolution was found to be improved through complex formation with HP-ß-CD and Me-ß-CD. In particular, the 1:2 M ratio complexes exhibited higher dissolution than the corresponding 1:1 M ratio complexes. The physicochemical characterization of the systems showed strong evidence of amorphous phases and/or of the formation of an inclusion complex. Stored at 25 °C, 60% RH for 24 months, drug complexed with ß-cyclodextrins (CDs) at 1:2 M ratio remained amorphous. Based on these findings, it is postulated that the formation of triclabendazole-CD inclusion complexes produced significant enhancement in both the dissolution and solid-state properties of the drug, which may lead to the development of triclabendazole novel formulations with improved biopharmaceutical characteristics.

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In this work, the dissolution profiles of nine meloxicam tablet brands marketed in Argentina have been evaluated. As meloxicam is a Class 2 Biopharmaceutical Classification System (BSC) drug, interchangeability between commercial products must be demonstrated through in vivo bioequivalence studies. However, in our country, such studies remain to be performed. Dissolution studies have been performed according to USP 38 and evaluated by fitting experimental data to the zero and first-order, the Hixson-Crowell, the Higuchi, and the Weibull model-dependent methods. To test the pertinence of these release models, the Akaike Information Criteria (AIC) were used. All brands satisfied the dissolution profiles (phosphate buffer, pH 7.5) established in the USP. The comparison between the dissolution profiles was carried out by model-dependent and model-independent methods. The Weibull model provided the best kinetic curve adjustment. Brands I, II, IV and VI had the best fitting, with the maximum determination coefficient and the smallest AIC values. Model-independent methods included ratio test and the fit factors. The Dissolution Efficiency (DE) and Mean Dissolution Time (MDT) were analysed with ANOVA and the DGC method. In both cases, brand I did not show similarity with the rest of the brands. Using fit factors, only brands I, II and V were similar to each other. Significant differences were found among the in vitro dissolution profiles of meloxicam tablets belonging to the nine brands. As meloxicam is a class 2 BCS drug, interchangeability between commercial products must be demonstrated through in vivo bioequivalence studies. However, in Argentina, such studies remain to be performed. Our results demonstrate that caution must be exercised as regards interchangeability of generic products.

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O uso de programas de computador para prever a absorção de fármacos em humanos e simular perfis de dissolução tem se tornado uma ferramenta bastante valiosa na área farmacêutica. O objetivo deste trabalho foi utilizar métodos in silico por meio dos programas de computador GastroPlusTM e DDDPlusTM para simular curvas de absorção de fármacos, perfis de dissolução e estabelecer correlações in vitro-in vivo (CIVIVs). O material aqui apresentado é constituído por cinco capítulos incluindo os fármacos cetoprofeno, pirimetamina, metronidazol, fluconazol, carvedilol e doxazosina. No capítulo 1 são apresentadas curvas plasmáticas simuladas para comprimidos matriciais de cetoprofeno, sendo estabelecida a CIVIV. A utilização de simulações de ensaios de dissolução intrínseca para os fármacos pirimetamina e metronidazol como uma ferramenta para classificação biofarmacêutica é detalhada no capítulo 2. No capítulo 3, a simulação de curvas plasmáticas a partir de cápsulas de fluconazol contendo diferentes perfis de dissolução é demonstrada como uma ferramenta para bioisenção. Estudos de CIVIV foram também realizados para comprimidos de liberação imediata de carvedilol a partir dos perfis de dissolução no capítulo 4. Já o capítulo 5 trata da aplicação de simulações de ensaios de dissolução para o desenvolvimento de formulações de liberação prolongada de doxazosina. As simulações das curvas plasmáticas, assim como a CIVIV, obtidas com o auxílio do programa GastroPlusTM, além dos ensaios de dissolução intrínsica e os perfis de dissolução obtidos por meio do uso do programa DDDPlusTM apresentaram-se como ferramentas de grande aplicação na previsão de características biofarmacêuticas sobre os fármacos e formulações, permitindo redução de tempo e custo com trabalho experimental em laboratório

The use of computer programs to predict drug absorption in humans and to simulate dissolution profiles has become a valuable tool in the pharmaceutical area. The objective of this study was to use in silico methods through software GastroPlusTM and DDDPlusTM to simulate drug absorption curves and dissolution profiles, and to establish in vitro-in vivo correlations (IVIVCs). The work presented herein is divided into five chapters and includes the drugs ketoprofen, pyrimethamine, metronidazole, fluconazole, carvedilol and doxazosin. In Chapter 1, simulated plasma curves for ketoprofen matrix tablets are presented and IVIVC was established. The use of simulated intrinsic dissolution tests for pyrimethamine and metronidazole as a tool for biopharmaceutics classification is detailed in Chapter 2. In Chapter 3, simulation of plasma curves for fluconazole capsules with different dissolution profiles is demonstrated as a tool for biowaiver. IVIVC studies were also conducted for carvedilol immediate-release tablets from dissolution profiles in Chapter 4. Chapter 5 covers the application of simulated dissolution tests for development of doxazosin extended-release formulations. Simulation of plasma curves and IVIVC using the software GastroPlusTM as well as intrinsic dissolution tests and dissolution profiles using the software DDDPlusTM proved to be a tool of wide application in predicting biopharmaceutical characteristics of drugs and formulations, allowing the reduction of time and costs of experimental laboratory work

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A simple, precise, economic and minimally operator-dependent method was developed under green analytical chemistry principles, for the simultaneous construction of the dissolution curves of a pharmaceutical association in short time and without employing organic solvents, allowing important savings of labor and resources. The carvedilol (CAR) and hydrochlorothiazide (HCT) combined formulation was employed as a model. The method (OD/UV-MCR) involves on-line sample dilution (OD) and UV detection of the analytes, coupled to multivariate curve resolution with alternating least squares (MCR-ALS). OD/UV-MCR proved to be robust and was successfully validated in accordance to ICH guidelines, fulfilling acceptance criteria for specificity (r(2) of spectral correlation>0.950), linearity [r>0.999 (N=25) in the ranges 1.00-31.1mg l(-1) and 0.51-15.2mg l(-1) for CAR and HCT, respectively] and precision (RSD<2%). Accuracy was assessed by point-to-point comparison between the dissolution profiles furnished by the proposed method with those provided by HPLC analysis, evidencing the usefulness of this monitoring system. In addition, OD/UV-MCR was successfully employed for the comparative analysis of three lots of commercial formulations of the CAR-HCT pharmaceutical association, belonging to a couple of different brands, employing Moore and Flanner's f2 similarity indicator.

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Introducción: el ensayo de disolución es una técnica analítica de empleo común en un laboratorio farmacéutico. Un proceso tecnológico para la elaboración de tabletas fue desarrollado. El ingrediente farmacéutico activo usado fue Tilo ® extracto seco. Objetivo: el objetivo de este trabajo fue desarrollar y validar un ensayo de disolución para evaluar la estabilidad y la calidad de dicho producto. Método: se utilizaron muestras de un lote experimental, un lote placebo y lotes pilotos de tabletas de Tilo ® de 100 mg. Se evaluaron como medios de disolución agua destilada y solución de ácido clorhídrico 0,1 mol/L, realizándose perfiles de disolución a 50, 75 y 100 rpm, empleándose los dos tipos de aparatos establecidos en la literatura para este ensayo (cesta y paleta). El contenido de cumarina fue analizado por HPLC. El ensayo fue validado según la USP. Resultados: los resultados mostraron que el agua destilada fue un medio de disolución adecuado, alcanzándose porcientos de disolución de la droga por encima del 85 por ciento a los 30 minutos, no existiendo diferencias significativas entre los tipos de aparatos recomendados por la USP. Mientras que, los perfiles de disolución a diferentes tiempos y velocidades de agitación mostraron una liberación gradual del principio activo en el tiempo, donde a medida que se incrementa la velocidad de agitación, se incrementa el porcentaje de disolución de la droga en el medio. La validación del ensayo demostró que el mismo era específico y preciso. Conclusiones: se estableció como ensayo de disolución las siguientes condiciones de trabajo: Aparato: paleta, 100 rpm; medio: agua destilada, 500 mL; tiempo: 60 minutos y Temperatura: 37 ± 0,5 ºC(AU)

Introduction: dissolution testing is one of the most common analytical techniques performed in a pharmaceutical analytical laboratory. A technological process for the production of tablets was developed. The active pharmaceutical ingredient used was Tilo ® dry extract. Objective: to develop and to validate the dissolution assay aimed at evaluating the stability study and the quality of this product. Methods: some samples from the experimental batch, the placebo batch and the pilot batches were used in this study. Distilled water and 0,1 mol/L chlorhidric acid were evaluated as dissolution media. The dissolution profiles at 50, 75 and 100 rpm and two types of dissolution devices (basket and paddle) recommended for the USP were evaluated. Coumarin content was analyzed by HPLC method. The dissolution assay was validated according to the United States Pharmacopeia. Results: the results showed that the distilled water was an appropriate dissolution medium, where percentages of released drug higher to 85 percent in 30 minutes were obtained; there were no significant differences among the types of dissolution devices recommended by the USP. The dissolution profiles at different shaking times and speeds showed gradual release of the active principle. As the shaking speed increases, the percentage of the drug dissolution increases in the medium. The assay was considered specific and precise. Conclusions: a type II (paddle) dissolution device, 500 ml of distilled water at 37 ± 0,5 ºC and 100 rpm, were established as parameters of the dissolution assay(AU)

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Introducción: el ensayo de disolución es una técnica analítica de empleo común en un laboratorio farmacéutico. Un proceso tecnológico para la elaboración de tabletas fue desarrollado. El ingrediente farmacéutico activo usado fue Tilo ® extracto seco. Objetivo: el objetivo de este trabajo fue desarrollar y validar un ensayo de disolución para evaluar la estabilidad y la calidad de dicho producto. Método: se utilizaron muestras de un lote experimental, un lote placebo y lotes pilotos de tabletas de Tilo ® de 100 mg. Se evaluaron como medios de disolución agua destilada y solución de ácido clorhídrico 0,1 mol/L, realizándose perfiles de disolución a 50, 75 y 100 rpm, empleándose los dos tipos de aparatos establecidos en la literatura para este ensayo (cesta y paleta). El contenido de cumarina fue analizado por HPLC. El ensayo fue validado según la USP. Resultados: los resultados mostraron que el agua destilada fue un medio de disolución adecuado, alcanzándose porcientos de disolución de la droga por encima del 85 por ciento a los 30 minutos, no existiendo diferencias significativas entre los tipos de aparatos recomendados por la USP. Mientras que, los perfiles de disolución a diferentes tiempos y velocidades de agitación mostraron una liberación gradual del principio activo en el tiempo, donde a medida que se incrementa la velocidad de agitación, se incrementa el porcentaje de disolución de la droga en el medio. La validación del ensayo demostró que el mismo era específico y preciso. Conclusiones: se estableció como ensayo de disolución las siguientes condiciones de trabajo: Aparato: paleta, 100 rpm; medio: agua destilada, 500 mL; tiempo: 60 minutos y Temperatura: 37 ± 0,5 ºC

Introduction: dissolution testing is one of the most common analytical techniques performed in a pharmaceutical analytical laboratory. A technological process for the production of tablets was developed. The active pharmaceutical ingredient used was Tilo ® dry extract. Objective: to develop and to validate the dissolution assay aimed at evaluating the stability study and the quality of this product. Methods: some samples from the experimental batch, the placebo batch and the pilot batches were used in this study. Distilled water and 0,1 mol/L chlorhidric acid were evaluated as dissolution media. The dissolution profiles at 50, 75 and 100 rpm and two types of dissolution devices (basket and paddle) recommended for the USP were evaluated. Coumarin content was analyzed by HPLC method. The dissolution assay was validated according to the United States Pharmacopeia. Results: the results showed that the distilled water was an appropriate dissolution medium, where percentages of released drug higher to 85 percent in 30 minutes were obtained; there were no significant differences among the types of dissolution devices recommended by the USP. The dissolution profiles at different shaking times and speeds showed gradual release of the active principle. As the shaking speed increases, the percentage of the drug dissolution increases in the medium. The assay was considered specific and precise. Conclusions: a type II (paddle) dissolution device, 500 ml of distilled water at 37 ± 0,5 ºC and 100 rpm, were established as parameters of the dissolution assay

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Mycophenolate mofetil (MMF) and mycophenolate sodium (MPS) are an ester and a salt of mycophenolic acid. They have different kinetic in vivo characteristics due to differences in molecular structures, physicochemical properties and formulations administered. In this study, dissolution profiles of reference products were tested in different media to evaluate the effect of pH, kinetic dissolution and the best statistical model that can be used to predict the release of both drugs. The drug release was determined by using a validated ultraviolet spectrophotometry method, λ 250 nm. The method showed to be selective, linear, precise and accurate for MMF in 0.1 M HCl and MPS in sodium phosphate buffer pH 6.8. Dissolution kinetics models of zero order, first order, Higuchi, Hixson-Crowell and Weibull were applied to data in order to select the best fit by linear regression. The regression parameters were estimated and the models were evaluated with the results of residuals and coefficient of determination. The residuals obtained from dissolution kinetics models were random, uncorrelated, and normally distributed with constant variance. The R² values (74.7% for MMF and 95.8% for MPS) demonstrated good ability of the Weibull regression to explain the variability and to predict the drugs' release.

Micofenolato de mofetila (MMF) e micofenolato sódico (MPS) são, respectivamente, éster e sal sódico do ácido micofenólico. Os fármacos possuem características farmacocinéticas distintas em função das diferenças na estrutura molecular, nas propriedades físico-químicas e nas formulações administradas. Neste trabalho, os perfis de dissolução dos medicamentos referências foram testados em diferentes meios de dissolução com o objetivo de avaliar o efeito da variação de pH, a cinética de dissolução e o modelo estatístico mais adequado para prever a dissolução dos fármacos. A liberação dos fármacos foi determinada com método validado por espectroscopia no ultravioleta, λ 250 nm. O método mostrou-se seletivo, linear, preciso e exato para dissolução de MMF em 0,1 M HCl e MPS em tampão fosfato pH 6,8. Os modelos cinéticos de dissolução de ordem zero, primeira ordem, Higuchi, Hixson-Crowell e Weibull foram aplicados com o objetivo de selecionar aquele com o melhor ajuste por regressão linear. Os parâmetros de regressão foram estimados e os ajustes dos modelos foram verificados pelos resíduos e coeficientes de determinação. Os resíduos obtidos foram aleatórios, independentes, apresentaram variância constante e seguiram a distribuição normal. Os valores de R² (74,7% para MMF e 95,8% para MPS) indicaram bom ajuste da regressão de Weibull para explicar a variabilidade e estimar a liberação dos fármacos.

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Se compararon los perfiles de disolución de las tabletas de risperidona 3 mg medicamento genérico producido en Cuba y del Risperdal® (Laboratorios Janssen-Cilag SA), para demostrar su similitud. También se realizó la comparación en varios medios de disolución a diferentes pH para evaluar una posible bioexoneración. Para la cuantificación del principio activo, se utilizó un método por cromatografía líquida de alta resolución, previamente validado. La comparación se realizó sobre la base de los factores de diferenciación y similitud. Los resultados mostraron que no existían diferencias en los perfiles de liberación para las tabletas producidas en Cuba y del producto innovador, así como para los diferentes medios de disolución a los pH utilizados(AU)

The 3 mg Risperidone tablets dissolution profiles, a generic drug produced in Cuba and the Risperidal® (Janssen-Cilag SA Labs) were compared to demonstrate its similarity. Also, we compared some dissolution means at different pH to assess a potential bio-exoneration. To quantify the active principle, a previously validated high-performance liquid chromatography was used. The comparison was conducted on the base of differentiation and similarity factors. Results demonstrated that there weren't differences en release profiles for tablets produced in Cuba and of innovative product, as well as for the different dissolution means at pH used(AU)

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Se compararon los perfiles de disolución de las tabletas de risperidona 3 mg medicamento genérico producido en Cuba y del Risperdal® (Laboratorios Janssen-Cilag SA), para demostrar su similitud. También se realizó la comparación en varios medios de disolución a diferentes pH para evaluar una posible bioexoneración. Para la cuantificación del principio activo, se utilizó un método por cromatografía líquida de alta resolución, previamente validado. La comparación se realizó sobre la base de los factores de diferenciación y similitud. Los resultados mostraron que no existían diferencias en los perfiles de liberación para las tabletas producidas en Cuba y del producto innovador, así como para los diferentes medios de disolución a los pH utilizados.

The 3 mg Risperidone tablets dissolution profiles, a generic drug produced in Cuba and the Risperidal® (Janssen-Cilag SA Labs) were compared to demonstrate its similarity. Also, we compared some dissolution means at different pH to assess a potential bio-exoneration. To quantify the active principle, a previously validated high-performance liquid chromatography was used. The comparison was conducted on the base of differentiation and similarity factors. Results demonstrated that there weren't differences en release profiles for tablets produced in Cuba and of innovative product, as well as for the different dissolution means at pH used.

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