(M1430-02-14) Application of Microstructure Quality by Design Approach in Optimizing Granulation and Tablet Physico-Mechanical Attributes

Purpose: Developing an optimized tablet dosage form requires careful control over the granulation and tableting process. Studying the microstructures of produced granulations can provide quantitative insights of material compactibility and the impact of process parameters. This approach, integrated with an understanding of tablet performance can provide a path to improve efficiency in of new development and scale up of tablet manufacturing. This work specifically focuses on the measurement of true density and structural quality attributes of granule samples, and the corresponding tablet performance, to establish a new set of tools to advance implementation of quality by design (QbD) approach at each step of drug product manufacturing.

Methods: As part of the process development, three wet granulation batches were manufactured where the amount of water as granulation fluid and wet massing time were varied. Batch # PD03-243, PD03-307, and PD03-304 were manufactured with 51, 58, and 58% w/w water, respectively and wet massing time of 4, 3.5, and 5.7 min, respectively. Narrow particle size cut of granules (180 to 250 um)were imaged using high resolution X-ray computed tomography (XRCT) at 1.6 µm/voxel to allow for precise elucidation of both the overall granules and the granule substructure. The individual granules were segmented using AI-based approaches whereby the granule solids, granule pores, and the whole granule were identified and characterized. Organic calibration phantoms were used to calibrate the XRCT intensity which allows for determination of the true density of the granules based on their greyscale pixel intensity. All images were analyzed using digiM I2S software to extract out the salient structural characteristics of the granules.

Results: Modest variations were observed in the size distributions of granules and fractions of solid material vs. pores there in among the batches as seen in Figure 2a-c. Comparison of the solid density for the batches shown in Figure 2c confirmed comparable density for the solid material (true density) of the granules. However, the granules of batch PD03-243 contained greater sub-resolution nanoscale porosity, suggesting in a relative term that the batch PD03-243 had less granule formation. Compactibility (tensile strength vs. solid fraction of tablets), tabletability (tensile strength of tablets vs. compaction pressure), and compressability (solid fraction of tablets vs. compression pressure) profiles of the three batches indicated differences of the granule properties. The granules (batch PD03-243) prepared with low amount of water and the least wet massing time yielded the lowest compactibilty profile indicating that the granules were sub-optimal to achieve tablet mechanical strength. While the granules (batch PD03-307) prepared with high amount of with similar wet massing time demonstrated highest compactability and tabletability (Figure 3). Interestingly, the granules (batch PD03-304) prepared using the same high water amount but with a longer wet masing time showed a drop in the mechanical properties suggesting a likelihood of over-granulation. The granule characterization from XRCT had revealed maximum nanoscale porosity in the PD03-243 granule agglomerates, which potentially indicated towards poor granule formation. Correlating the granule characterization from XRCT and tablet mechanical strength characterization helped to understand the impact of granulation process variables and identify the optimal working range. The work suggests the granule microstructure characterization by XRCT could be a valuable tool to understand changes at the granule level and how they correlate to the mechanical properties of tablets.

Conclusion: This work demonstrates the application of quantitative structural imaging in understanding the impact of wet granulation process variables like amount of granulation fluid and wet massing time on physico-mechanical properties of the granules and tablets obtained therefrom. True density and microstructure of granules which were determined using an innovative imaging-based calibration and X-ray imaging-based characterization techniques were leveraged in process wet granulation process development. Subsequent characterization of the tablet mechanical properties demonstrated correlation with the granule microstructure. This study demonstrated application of microstructure QbD approach in obtaining optimum granule properties for development of robust tablet dosage forms.

Figure 1. XRCT images of the three granule lots. Greyscale images are shown in (a-c), while the segmented granule images are shown in (d-f). The organic calibration phantoms can be seen as the multi-hued stripes.

Figure 2. (a-c) Size distributions for the (a) granule pores, (b) granule solid phase, and (c) the granules themselves. (d) True density of the granule solid phase and the density of granule agglomerates as a whole as measured from XRCT.

Figure 3. Compactibility, tabletability, and compressability of tablets.