Bioavailability and bioequivalence: an FDA regulatory overview.

Bioavailability and/or bioequivalence studies play a key role in the drug development period for both new drug products and their generic equivalents. For both, these studies are also important in the postapproval period in the presence of certain manufacturing changes. Like many regulatory studies, the assessment of bioavailability and bioequivalence can generally be achieved by considering the following three questions. What is the primary question of the study? What are the tests that can be used to address the question? What degree of confidence is needed for the test outcome? This article reviews the regulatory science of bioavailability and bioequivalence and provides FDA's recommendations for drug sponsors who intend to establish bioavailability and/or demonstrate bioequivalence for their pharmaceutical products during the developmental process or after approval.

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 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.

Investigations of anthelminthic activity and synthesis of new derivatives of perhydroazepine, perhydro-1,4-diazepine, perhydro-1,4-oxazepine and perhydro-1,5-oxazocine.

Anthelminthic activity of new esters of 3,4,5-trimethoxybenzoic acid containing rests of the title heterocyclic amines has been determined. 3-(Perhydroazepinyl)-propyl ester 6 acts on enchytraeids in vitro 56-fold stronger than piperazine adipate, 2-(perhydroazepinyl)-ethyl ester 5 is the most effective in a therapy of mice infested with nematodes.

Use of factorial design to evaluate granulations prepared by spheronization.

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.