Preparación de comprimidos de desintegración rápida de clorhidrato de ondansetrón mediante el método de compresión directa

To make rapidly disintegrating tablets containing 8 mg ondansetron hydrochloride with suffi cient mechanical integrityas well as a pleasant taste, microcrystalline cellulose (MCC), lactose anhydrous, mannitol and croscarmellose wereformulated. Tablets were prepared by a direct compression method. Tablets properties such as tensile strength, disintegrationtime, wetting time and friability were determined. The two-factor spherical second order composite experimentaldesign was used for the preparation of preliminary batches and the desirability function was employed for theoptimization of preliminary batches. For preparation of the rapidly disintegrating tablets, simplex lattice design withconstraints on the proportion of excipients was utilized. In later design, tensile strength and disintegration time wereselected as dependent variables and concentration of microcrystalline cellulose, concentration of lactose anhydrous andconcentration of mannitol were selected as controlling factors. Mathematical equations and contour plots were usedto relate independent variables with tensile strength and disintegration time. Furthermore, the composite index which considers a positive or negative deviation from an ideal value was calculated for the optimization of the formulation.Contour plots of tensile strength and disintegration time were superimposed to fi nd out the optimized region at whichtablets with an acceptable crushing strength and disintegration time can be produced. The concept of similarity factorsf2 and Sd were used to prove similarity of dissolution in distilled water and simulated saliva (pH 6.8). Rapidly disintegratingtablets with durable structure and desirable taste could be prepared by selecting proper level of MCC, lactoseanhydrous, mannitol, croscarmellose and compression force.Para elaborar comprimidos de desintegración rápida con un contenido de 8 mg de clorhidrato de ondansetrón, consufi ciente integridad mecánica y buen sabor, se preparó una formulación de celulosa microcristalina (CM), lactosaanhidra, manitol y croscarmelosa. Los comprimidos se elaboraron mediante el método de compresión directa. Sedeterminaron propiedades tales como la resistencia a la fractura, el tiempo de desintegración, el tiempo de humidificación y la friabilidad. Para la preparación de los primeros lotes se utilizó el diseño experimental de compuestode segundo orden esférico de dos factores, y para su optimización se empleó la función de deseabilidad. Para lapreparación de los comprimidos de desintegración rápida se utilizó un diseño en retículos simple con restriccionesen la proporción de los excipientes. En un diseño posterior, se seleccionaron como variables independientesla resistencia a la fractura y la concentración de celulosa microcristalina, de lactosa anhidra y de manitol. Pararelacionar las variables independientes con la resistencia a la fractura y el tiempo de desintegración, se utilizaronecuaciones matemáticas y representaciones gráfi cas. Además, para optimizar la formulación, se calculó el índicesintético que considera una desviación positiva o negativa a partir de un valor ideal. Se superpusieron las representacionesgráfi cas de la resistencia a la fractura y el tiempo de desintegración para encontrar la región optimizadaen la que se pueden producir comprimidos con resistencia al aplastamiento y tiempos de desintegración aceptables.Para demostrar la similitud de la disolución en agua destilada y saliva simulada (pH 6,8) se utilizó el concepto delos factores de similitud f2 y Sd. Se podrían preparar comprimidos de desintegración rápida con una estructuraduradera y un sabor agradable si se selecciona el nivel adecuado de CM, lactosa anhidra, manitol, croscarmelosay fuerza de compresión

Método de cromatografía líquida de alta resolución para la determinación simultánea de fosinopril sódico e hidroclorotiazida en formulaciones de comprimidos

A simple, specifi c, accurate and precise reversed phase HPLC method with UV detection for the simultaneous determinationof fosinopril sodium and hydrohclorthiazide in pharmaceutical formulations was developed. The drug solutionwas prepared in mobile phase and was injected into a C18 column with UV detection at 208 nm. The mobile phasewas a mixture of 0.2%w/v phosphoric acid in water and acetonitrile (30:70) delivered at a fl ow rate of 0.5 ml/min at29 0C. The calibration graphs were linear in the range of 10-50 μg/ml (r2 > 0.99) for fosinopril sodium and 6.25-31.35 μg/ml for hydrochlorthiazide (r2 > 0.99). The detection limit was 0.5μg/ml for fosinopril sodium and 1.0 μg/mlfor hydrochlorthiazide with quantitation limit of 10 μg/ml and 6.25 μg/ml for fosinopril sodium and hydrochlorthiazide,respectively. The statistical evaluation of the method was examined by performing intra-day (n=5) and inter-day calibration(n=5) and was found to be satisfactory, with high accuracy, and precision results. Application of the suggestedmethod was successfully applied to the simultaneous determination of fosinopril sodium and hydrochlorthiazide intablets formulation, with high percentage of recovery, good accuracy with precision.Se ha desarrollado un método HPLC de fase inversa con detección de UV sencillo, específi co, exacto y preciso parala determinación de fosinopril sódico e hidroclorotiazida en formulaciones farmacéuticas. La solución de fármacose preparó en fase móvil y se inyectó en una columna C18 con detección de UV a 208 nm. La fase móvil era unamezcla de 0,2% p/v de ácido fosfórico en agua y acetonitrilo (30:70) añadida a una velocidad de fl ujo de 0,5 ml/mina 29 0C. Los gráfi cos de calibración fueron lineales en el rango de 10-50 μg/ml (r2 > 0,99) para el fosinopril sódicoy de 6,25-31,35 μg/ml para la hidroclorotiazida (r2 > 0,99). El límite de detección fue de 0,5 μg/ml para el fosinoprilsódico y de 1,0 μg/ml para la hidroclorotiazida, con un límite de cuantifi cación de 10 μg/ml y 6,25 μg/ml para elfosinopril sódico y la hidroclorotiazida, respectivamente. La evaluación estadística del método se examinó mediantecalibración intradía (n=5) e interdía (n=5) y resultó satisfactoria, con una exactitud y precisión elevadas. El métodosugerido se aplicó con éxito en la determinación simultánea de fosinopril sódico e hidroclorotiazida en formulacionesde comprimidos, con un elevado porcentaje de recuperación, buena exactitud y precisión

Pepsina capturada en gránulos gelificados de κ-carragenato reticulados mediante actividad ionotrópica para una mejora de la estabilidad: Optimización y caracterización fisicoquímica mediante el diseño de Box-Behnken

This work examines the infl uence of process parameters, namely κ-carrageenan concentration, potassium chloride concentration,and hardening time, on pepsin entrapped in ionotropically crosslinked κ-carrageenan beads for improvementof its stability using response surface methodology. A Box-Behnken design was employed to investigate the effect ofprocess variables on the entrapment, time required for 50% enzyme release (T50), time required for 90% enzyme release(T90), and particle size. The beads were prepared by dropping the κ-carrageenan containing pepsin into a magneticallystirred potassium chloride solution. In vitro enzyme release profi le of the beads was fi tted to various release kineticsmodels in order to understand the release mechanism. Topographical characterization was carried out by SEM, andentrapment was confi rmed by FTIR and DSC. Stability testing was carried out according to the ICH guidelines forzones III and IV. A polymeric matrix prepared by 3.0% w/v κ-carrageenan and 0.3 M potassium chloride using theionotropic gelatin method, with a hardening time of 10 min resulted in the production of beads characterized by aspherical disk shaped with a collapsed center, an absence of aggregates, an entrapment of more than 80%, and a T90of less than 40 min. The shelf-life of the pepsin-loaded beads was found to increase to 3.24 years compared with 0.97years for the conventional formulation. It can be inferred that the proposed methodology can be used to prepare pepsinloadedκ-carrageenan beads for stability improvement. In addition, the proper selection of rate-controlling carrageenanconcentration and their interactive potential for crosslinking is important, and will determine the overall size and shapeof beads, the duration and pattern of dissolution profi les, and the enzyme loading capacity.En este trabajo se examina la infl uencia de los parámetros de proceso, particularmente la concentración de κ-carragenato,la concentración de cloruro potásico y el tiempo de endurecimiento, en pepsinas capturadas en gránulos deκ-carragenato reticulados mediante actividad ionotrópica para la mejora de su estabilidad mediante la metodologíade superfi cie de respuesta. Se utilizó un diseño de Box-Behnken para investigar el efecto de las variables de procesoen la captura, el tiempo necesario para la liberación del 50% de las enzimas (T50), el tiempo necesario para laliberación del 90% de las enzimas (T90) y el tamaño de partícula. Los gránulos se prepararon mediante el vertidode gotas de κ-carragenato con pepsina en una solución de cloruro potásico agitada magnéticamente. El perfi l deliberación enzimática in vitro de los gránulos se ajustó a varios modelos cinéticos de liberación para comprender elmecanismo de liberación. La caracterización topográfi ca se realizó mediante microscopía electrónica de barrido (SEM)y la captura se confi rmó a través de espectrometría infrarroja por transformada de Fourier (FTIR) y calorimetríadiferencial de barrido (DSC). La prueba de estabilidad se realizó según las indicaciones de ICH para las zonas IIIy IV. Una matriz polimérica preparada con un 3,0% p/v de κ-carragenato y 0,3 M de cloruro potásico medianteel método de gelifi cación ionotrópica, con un tiempo de endurecimiento de 10 minutos provocó la producción degránulos caracterizados por un disco esférico con un centro aplanado, una ausencia de agregados, una captura demás del 80% y un valor T90 inferior a 40 minutos. Se observó que la vida de almacenamiento de los gránulos cargadoscon pepsina aumentó hasta los 3,24 años en comparación con los 0,97 años de la formulación convencional.Se puede concluir que la metodología propuesta se puede utilizar para preparar gránulos de κ-carragenato cargadosde pepsina para la mejora de la estabilidad. Además, se concluyó que la selección adecuada de la concentración decarragenato con control de la velocidad de liberación y su potencial interactivo para la reticulación es importante,y determinará el tamaño y la forma general de los gránulos, la duración y el patrón de los perfi les de disolución yla capacidad de carga de la enzima

Effect of hydrophilic swellable polymers on dissolution enhancement of carbamazepine solid dispersions studied using response surface methodology

The objective of this work was to study dissolution enhancement efficiency and solid dispersion formation ability of hydrophilic swellable polymers such as sodium carboxymethyl cellulose (Na-CMC), sodium starch glycolate (SSG), pregelatinized starch (PGS), and hydroxypropylmethyl cellulose (HPMC) with carbamazepine using 32 full factorial design for each of the polymers. Solid dispersions of carbamazepine were prepared using solvent evaporation method with around 70% solvent recovery. The independent variables were the amount of polymer and organic solvent. The dependent variables assessed were percentage drug dissolved at various time points and dispersion efficiency (ie, in terms of particle size of solid dispersion). Solid dispersions were evaluated for percentage drug dissolved, wettability, differential scanning calorimetry, scanning electron microscopy, and angle of repose. Multiple linear regression of results obtained led to equations, which generated contour plots to relate the dependent variables. Similarity factor and mean dissolution time were used to compare dissolution patterns obtained in distilled water and simulated gastric fluid United States Pharmacopeia (USP) XXVI of pH 1.2. Maximum drug dissolution was obtained with polymer order Na-CMC>SSG>PGS>HPMC. Particle size of drug was reduced ≈ 10–15, 3–5, 5–7, and 10–25 times in Na-CMC, SSG, PGS, and HPMC solid dispersions, respectively; whereas wettability of solid dispersions was found in the order of Na-CMC>HPMC>PGS>SSG. Angle of repose was found to be in the range of 29° to 35° for all solid dispersions, which shows good flowability characteristics. HPMC showed increase in drug dissolution up to an optimized level; however, furthers increase in its concentration decreased drug dissolution

A Novel Itraconazole Bioadhesive Film for Vaginal Delivery: Design, Optimization, and Physicodynamic Characterization

The purpose of this work was to design and optimize a novel vaginal drug delivery system for more effective treatment against vaginal candidiasis. Itraconazole was formulated in bioadhesive film formulations that could be retained in the vagina for prolonged intervals. The polymeric films were prepared by solvent evaporation and optimized for various physicodynamic and aesthetic properties. In addition, percentage drug retained on vaginal mucosa was evaluated using a simulated dynamic vaginal system as function of time. A polymeric film containing 100 mg itraconazole per unit (2.5 cm × 2.5 cm) have been developed using generally regarded as safe listed excipients. The pH of vaginal film was found to be slightly acidic (4.90 ± 0.04) in simulated vaginal fluid and alkaline (7.04 ± 0.07) in water. The little moisture content (7.66 ± 0.51% w/w) was present in the film, which helps them to remain stable and kept them from being completely dry and brittle. The mechanical properties, tensile strength, and percentage elongation at break (9.64 N/mm2 and 67.56% for ITRF65) reveal that the formulations were found to be soft and tough. The films (ITRF65) contained solid dispersion of itraconazole (2.5)/hydroxypropyl cellulose (1)/polyethylene glycol 400 (0.5), which was found to be the optimal composition for a novel bioadhesive vaginal formulation, as they showed good peelability, relatively good swelling index, and moderate tensile strength and retained vaginal mucosa up to 8 h. Also, the film did not markedly affect normal vaginal flora (lactobacillus) and was noncytotoxic as indicated by the negligible decrease in cell viability