RESUMEN
The objective of this study, was to examine the influence of critical formulation and processing variables as described in the AAPS/FDA Workshop II report on scale-up of oral extended-release dosage forms, using a hydrophilic polymer hydroxypropyl methylcellulose (Methocel K100LV). A face-centered central composite design (26 runs+3 center points) was selected and the variables studied were: filler ratio (lactose:dicalcium phosphate (50:50)), polymer level (15/32.5/50%), magnesium stearate level (1/1.5/2%), lubricant blend time (2/6/10 min) and compression force (400/600/800 kg). Granulations (1.5 kg, 3000 units) were manufactured using a fluid-bed process, lubricated and tablets (100 mg metoprolol tartrate) were compressed on an instrumented Manesty D3B rotary tablet press. Dissolution tests were performed using USP apparatus 2, at 50 rpm in 900 ml phosphate buffer (pH 6.8). Responses studied included percent drug released at Q1 (1 h), Q4, Q6, Q12. Analysis of variance indicated that change in polymer level was the most significant factor affecting drug release. Increase in dicalcium phosphate level and compression force were found to affect the percent released at the later dissolution time points. Some interaction effects between the variables studied were also found to be statistically significant. The drug release mechanism was predominantly found to be Fickian diffusion controlled (n=0.46-0.59). Response surface plots and regression models were developed which adequately described the experimental space. Three formulations having slow-, medium- and fast-releasing dissolution profiles were identified for a future bioavailability/bioequivalency study. The results of this study provided the framework for further work involving both in vivo studies and scale-up.
Asunto(s)
Preparaciones de Acción Retardada/farmacocinética , Metilcelulosa/química , Metoprolol/administración & dosificación , Administración Oral , Química Farmacéutica , Lactosa/análogos & derivados , Metilcelulosa/análogos & derivados , Oxazinas , Análisis de Regresión , Solubilidad , ComprimidosAsunto(s)
Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/normas , Farmacocinética , Acetaminofén/administración & dosificación , Acetaminofén/farmacocinética , Acetaminofén/normas , Administración Oral , Diazepam/administración & dosificación , Diazepam/farmacocinética , Diazepam/normas , Europa (Continente) , Humanos , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Absorción Intestinal , Japón , Equivalencia Terapéutica , Estados Unidos , United States Food and Drug AdministrationRESUMEN
This study was designed to demonstrate that properties of a granulation with a given composition, prepared by the spheronizing technique, could be altered by slight changes in process variables alone to satisfy the requirements of the formulator. A complete factorial experimental design was found satisfactory for demonstrating the range of properties to be expected and for showing statistically significant main effects and any linear interactions between selected variables. Results using two levels of five variables showed that initial water content and spheronizer speed had significant main effects on all primary granulation properties studied. While only one formulation was studied, the data suggest that the factorial design can have utility in predicting the properties of granulations prepared at conditions within the limits imposed by the equipment or formulation.