Prediction of tablet weight variability in continuous manufacturing.

This paper provides a method for prediction of weight variability of tablets made in rotary tablet presses as a function of material attributes and processing parameters. The goal was to be able to predict whether or not a formulation is suitable for direct compaction continuous manufacturing using the tablet weight variability as a criterion. The work focused on identifying the significant factors affecting the weight variability in tablets, within the design space studied. A wide range of blends with different powder properties were prepared. It was shown that among powder properties, cohesion, bulk density, and particle size were the most significant and sufficient material attributes to explain tablet weight variability. A response surface model was built and validated with three different blends. The model is not formulation dependent and can be expanded to include other blend properties or processing parameters effects.

A comprehensive analysis and optimization of continuous twin-screw granulation processes via sequential experimentation strategy.

Nowadays twin-screw granulation has been emerging as an attractive continuous wet granulation technique. This study was geared towards better process design and understanding with emphasis on bridging the knowledge gap between input and output variables by employing sequential experimentation strategy. A low-dose formulation for granulation experiments contained anhydrous caffeine as the model drug. In the first phase of parameter screening, D-optimal design and stepwise regression were leveraged to develop interaction models following the examination of various quantitative and qualitative factors of potential importance. To maximize the design space dictated by predefined quality target values, several variables were fixed at optimum levels: 700 rpm screw speed, 60° kneading element staggering angle, 5 kneading elements and distributive feed screw in the screw configuration. In the second phase of characterization, response surface design was utilized to investigate the dependence of critical quality attributes of granules and tablets on selected critical process parameters (L/S ratio, throughput and barrel temperature). The results indicated that the influence of throughput and barrel temperature was relatively inferior to L/S ratio. Higher degree of liquid saturation led to granules with narrower size distribution, smaller porosity and enhanced flowability and tablets with declining tensile strength yet slackened drug release.

Statistical comparison of dissolution profiles.

Statistical methods to assess similarity of dissolution profiles are introduced. Sixteen groups of dissolution profiles from a full factorial design were used to demonstrate implementation details. Variables in the design include drug strength, tablet stability time, and dissolution testing condition. The 16 groups were considered similar when compared using the similarity factor f2 (f2 > 50). However, multivariate ANOVA (MANOVA) repeated measures suggested statistical differences. A modified principal component analysis (PCA) was used to describe the dissolution curves in terms of level and shape. The advantage of the modified PCA approach is that the calculated shape principal components will not be confounded by level effect. Effect size test using omega-squared was also used for dissolution comparisons. Effects indicated by omega-squared are independent of sample size and are a necessary supplement to p value reported from the MANOVA table. Methods to compare multiple groups show that product strength and dissolution testing condition had significant effects on both level and shape. For pairwise analysis, a post-hoc analysis using Tukey's method categorized three similar groups, and was consistent with level-shape analysis. All these methods provide valuable information that is missed using f2 method alone to compare average profiles. The improved statistical analysis approach introduced here enables one to better ascertain both statistical significance and clinical relevance, supporting more objective regulatory decisions.

Shear-induced APAP de-agglomeration.

CONTEXT: Active pharmaceutical ingredient agglomerates can generate many solid product regulatory compliance issues. OBJECTIVE: To study the effects of shear rate, strain, type of excipient, and grade of acetaminophen (APAP) on the process of APAP de-agglomeration. MATERIALS AND METHODS: A shear-controlled environment is used to expose six different blends that consist of one of three APAP grades and one of two possible types of excipient to 10 different combinations of shear rate and strain. APAP agglomerates are sifted and weighed. RESULTS: Finer APAP grades lead to blends with more APAP agglomerates and type of excipient only affects the de-agglomeration process for the finest APAP grade. De-agglomeration proceeds mainly as a function of strain with a minor contribution toward further de-agglomeration when larger shear rates are used. DISCUSSION: When mechanical stress (which us proportional to shear rate) overcomes interparticle forces, de-agglomeration occurs. Higher shear rates (and stress) contribute slightly to further APAP de-agglomeration. Extended exposure to stress (strain) reduces the size and the number of agglomerates. Blends with finer APAP present more agglomerates, particularly after low strain exposure. CONCLUSIONS: This article presents a useful method for formulation and process development. Exposing blends to higher shear rates and especially to strain mitigates APAP agglomeration in blends. Finer APAP presents more agglomerates and the type of excipient used affects the degree of APAP agglomeration.