Melt Granulation Techniques as an Alternative Manufacturing Technology for the Generic Development of Apixaban 5 mg Immediate-Release Tablets: A Case Study

Abstract

Purpose

Apixaban (APX) is a poorly soluble drug; hence, a micronized active pharmaceutical ingredient (API) is widely used for manufacturing immediate-release (IR) tablets using the dry granulation method (DG). Melt granulation techniques (MGTS) are widely used for enhancing solubility by reducing the crystallinity and/or formation of in situ amorphous forms. The present investigation aims to manufacture APX IR tablets with non-micronized API by MGTS and compare the same with tablets using micronized API manufactured by DG.

Methods

APX 5 mg tablets were manufactured with a nonmicronized API particle size of 195 μm (D₉₀) by MGTS, such as hot melt granulation (HMG) and hot melt extrusion (HME). Slugging/deslugging was selected as a dry granulation method (DG) to manufacture the tablets using a micronized API with a particle size of 25 μm (D₉₀). Drug‒polymer miscibility studies were performed, and polyvinyl alcohol (PVA) was found to be a suitable polymer for MGTS. Both lubricated blends and tablets were characterized using different orthogonal analytical techniques including multi-media dissolution studies.

Results

All the quality attributes for the initial and stable samples were well within the specification limits. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) data of the reference (REF) and DG products showed the crystalline form of the API in the tablets, whereas the HMG and HME tablets showed an amorphous nature. In multimedia dissolution studies, all manufactured batches showed a dissolution efficacy of > 85% in 15 min and, hence dissolution profiles of DG batches were comparable with MGTS.

Conclusion

These findings suggest that MGTS could be adopted for the manufacturing of APX IR tablets using a nonmicronized API. The results show that MGTS is an alternative manufacturing process for DG in the production of APX IR tablets, especially to formulate surfactant-free tablets manufactured with non-micronized API. MGTS provide dissolution similarity with reference product that was due formation of an amorphous form during the manufacturing process. Moreover, MGTS are continuous manufacturing processes, which provide a high degree of manufacturing flexibility.