(M0930-01-06) Implementing Co-processed API to Enable High-Drug-Load Formulation for Direct Compression

Purpose: To facilitate a high-drug-load oral dose formulation, physical properties of drug substance such as particle size and bulk density must be optimized / increased. But this has been challenging as a large number of API molecules tend to have an acicular morphology and micronization of particles is sometimes necessary to maximize its bio-performance. Such APIs typically present very poor physical properties which make it significantly challenging to enable the high drug load formulation. Continuous direct compression (cDC) brings significant advantages including increased efficiency, reduced processing time, reduced development time and cost savings. Nevertheless, cDC for a high-drug load formulation typically requires API to present amenable physical properties such as high bulk density and good flowability. Given the high requirement on physical properties and short development timeline for API drug substance, developing a technique to improve API physical properties to enable direct compression and high drug load formulation have gained significant interests. Herein, we performed an industrial case study including three approaches to implement the co-processing of API with an excipient. The final composites (Co-processed API) present improved bulk density and flowability. The high drug load formulation has been demonstrated to be feasible, and the quality attributes of the tablets are discussed.

Methods: We implement three approaches to enable co-processed API, as shown in Table 1. In the initial assessment, we are aiming to evaluate the feasibility of high drug load direct compression formulation for all three co-processed API techniques, as shown in table 2. In a further assessment focusing on the API from ISG technique, we are aiming to explore the formulation space to enable the high-drug load immediate-release tablet, as shown in table 3. The following aspects are characterized and discussed: Co-processed API and final blends: Particle size distribution, Flowability by FT4 powder rheometer, bulk and tapped density, microscopy. Tablets: weight, thickness, hardness, disintegration, dissolution, punch picking/sticking potency. Both co-processed API and tablet stability are investigated under four conditions: 40°C/75% RH, 70°C/75% RH, 50°C/30% RH, 30°C/65% RH; for up to 180 days.

Results: The XRPD profiles (not shown here) suggest that the heterogeneous nucleation and Mesoporous carrier result in amorphous material while the crystalline API is obtained from In-situ granulation. As seen in figure 1, the initial API present small particle size, low bulk density and poor flowability. In contrast, the resulting co-processed APIs show nearly spherical morphology, significantly improved bulk density, and free-flowing behavior. As shown in figure 2, the results indicate that all three platform enable the tablets with high tensile strength at reasonable solid fraction and compression stress. Given the high-aqueous-solubility nature of the material, all three platforms enable the immediate release tablets. Note that, the API loaded onto mesoporous carrier needs significantly longer time to be released from the formulation. Table 4 shows the total impurities after 30 days and 120 days. The results suggest that heterogeneous nucleation and mesoporous carrier-based tablets have degeneration at high temperature and humidity after 30 days. Conversely, the In-situ granulation tablets are stable across all storage conditions up to 120 days. During the initial assessment of three co-processed API platforms, the API from the ISG technique demonstrated significant advantages in chemical stability over the other two platforms, attributed to its intact crystalline structure throughout the process. However, its large particle size raises potential segregation concerns during tablet manufacturing (segregation was not assessed in this study). With that, slurry mill as a particle-size control strategy was examined which results in the API with reduced particle size and narrow distribution (as shown in figure 3), while still displays significantly improved bulk density, and free-flowing behavior. We further explored typical direct compression formulations with varying drug load levels: 50% and 70% ISG API loading, using different categories of fillers. MCC was used as an insoluble/plastic filler and lactose monohydrate as a soluble/brittle filler. As shown in figure 4, it is clear that all the formulations enable the production of tablets with high strength ( >2 MPa at 0.85 solid fraction), which can withstand downstream processing such as coating, packaging, and distribution. Using MCC as a filler results in tablets with higher strength than those with lactose. Additionally, the reduced particle size of ISG API enhances tablet strength. However, the disintegration time of MCC-based tablets is significantly longer than that of lactose-based tablets, with an increasing trend in disintegration time as ISG API load increases.

Conclusion: In conclusion, the co-processed API presents promising physical properties and tableting performance to enable continuous direct compression. A high drug loading formulation is enabled in this study. Particularly, the co-processed API from in-situ granulation (co-precipitation) demonstrated superior stability in a formulation at stressed conditions. In order to enhance disintegration and dissolution of final product, formulating ISG API with soluble filler has been demonstrated as an effective path forward.


Co-processed API platforms and the formulations


Results of initial assessment of three co-processed APIs


Results of in-situ granulation APIs in high-drug-load formulation