Determining API domain sizes in pharmaceutical tablets and blends upon varying milling conditions by near-infrared chemical imaging

Abstract

A blend–mill–blend process is commonly used in tablet manufacturing. This process uses a screening mill to de-lump the agglomerates potentially present in the active pharmaceutical ingredient (API) and/or the excipients to promote better mixing and blend homogeneity. As a part of the study in which various process conditions were explored to better understand the manufacturing of a pharmaceutical formulation in development, two batches were manufactured using different mill screen sizes and were compared to an unmilled batch. Near-infrared (NIR) chemical imaging was used to provide information on API domains in these three samples. Both tablets and blends from the three batches were imaged and the results were compared with the content uniformity data of the tablets. The simplest imaging approach (univariate) was used for producing the API images. Experimentally, the importance and priority was given to the speed of the acquisition and the number of images acquired in order to provide sufficient evidence for the presence or lack of agglomeration. Significant API agglomeration was found in both blends and tablets in the samples from the unmilled batch, clearly differing from the occasional and much smaller lumps found in the blends and tablets in the batches utilizing the milling screens. This study demonstrates an efficient and feasible process analytical technology (PAT) offline application of chemical imaging to provide better process understanding and identify criticality of particular process steps to ensure content uniformity.