Identification of critical formulation and processing variables for metoprolol tartrate extended-release (ER) matrix tablets

The objective of this study, was to examine the influence of critical formu lation and processing variables as described in the AAPS/FDA Workshop II re port on scale-up of oral extended-release dosage forms, using a hydrophilic polymer hydroxypropyl methylcellulose (Methocel K100LV). A face-centered c entral composite design (26 runs+3 center points) was selected and the vari ables studied were: filler ratio (lactose:dicalcium phosphate (50:50)), pol ymer level (15/32.5/50%), magnesium stearate level (1/1.5/2%), lubricant bl end 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, lubricate d and tablets (100 mg metoprolol tartrate) were compressed on an instrument ed 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 s tudied included percent drug released at Q(1) (1 h), Q(4), Q(6), Q(12). Ana lysis of variance indicated that change in polymer level was the most signi ficant factor affecting drug release. Increase in dicalcium phosphate level and compression force were found to affect the percent released at the lat er dissolution time points. Some interaction effects between the variables studied were also found to be statistically significant. The drug release m echanism was predominantly found to be Fickian diffusion controlled (n=0.46 -0.59). Response surface plots and regression models were developed which a dequately described the experimental space. Three formulations having slow- , medium- and fast-releasing dissolution profiles were identified for a fut ure bioavailability/bioequivalency study. The results of this study provide d the framework for further work involving both in vivo studies and scale-u p. (C) 1999 Elsevier Science B.V. All rights reserved.