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Abstract
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.
Notes
1Since excipient plays a minor role in the de-agglomeration of semifine and fine APAP, the values in the curves for each shear treatment ( and ) are a contribution of the agglomerate fraction values whether they are mixed with lactose or with Avicel. The excipient plays a role in the de-agglomeration of micronized APAP; however, the agglomerate fraction values were combined to facilitate the comparison among APAP grades.