(M1230-08-44) Case Study Approach for API Mechanical Properties Evaluation on Oral Solid Dosage Forms Development

Purpose: Dry granulation by Roller Compaction (RC) is becoming a technology of choice (cost, easier scale-up, simplicity, etc) when developing oral dosage forms for poorly flowable blends. When formulations have a highly drug loading, its behavior upon RC and tableting strongly depends on the active pharmaceutical ingredient (API) properties. This case study demonstrates the importance of evaluating API characteristics beyond the traditional Heckel analysis in view of RC and tableting process, showing the strong correlation between API mechanical properties and the drug product (DP) critical quality attributes (CQAs).

Methods: An immediate release formulation for a DP candidate for clinical studies was developed as follows: 60 % API, 35,5% Microcrystalline Cellulose; 3% hydroxypropylmethyl cellulose, 1% sodium croscarmellose and 0.5 % magnesium stearate. DP consisted of tablets made by RC. As part of a feasibility study for this project, two DP batches were manufactured on a Gerteis Mini-Pactor® roll compactor equipped with an in-line oscillating mill, followed by tableting on a Compaction Simulator (Styl’One®). DPs were manufactured using two different batches of the same active molecule. RC granules were made at different process parameters (PP) on both DP batches: RC (gap: 2mm; roll speed: 2 or 3 RPM; specific compaction forces: 3, 5 and 7 kN/cm; mill grid size: 800 µm) and tableting (compression pressure: 50, 100, 150, 200 and 250 MPa). During RC: DP Batch 1 was made at 2 RPM, while DP Batch 2 at 3 RPM. This minor roll speed difference is not expected to have an impact on final blend and DP properties. The two API batches were characterized using a Compaction Simulator (Phoenix®). First, a Heckel analysis was conducted to define their deformation behavior. Then, a more comprehensive study was performed, including:-Tablettability: tensile strength as a function of the compression pressure, -Compactibility: tensile strength as a function of the out-of-die solid fraction-Compressibility: out-of-die solid fraction as a function of the compression pressure

Results: The Heckel analysis classified both raw API batches as presenting moderately hard/brittle compression properties and being expected to deform predominantly by brittle fracture. Similar yield pressures: 113 and 122 MPa, were obtained for raw API batch 1 and 2, respectively; at a punch speed of 0,1 mm/s. However, DP tabletability curves (Fig. 1) displayed differences between both tablet batches, showing a significantly lower bondability for tablets from DP batch 2. The main difference between both DP batches was the raw API batch used (DP batch 1 made of raw API batch 1; and DP batch 2 made of API batch 2). The DP formulation, drug loading, as well as the manufacturing PP were kept constant. For this reason, a more detailed characterization on the mechanical properties of raw API was conducted. Both APIs revealed the same compressibility properties: equivalent compaction pressures resulted in compacts with identical ou-of-die solid fractions. However, Fig. 2 demonstrated that API batch 1 had a higher compactibility than API batch 2. This could explain that during the RC and tableting processes, even if the same solid fraction is targeted for both DP batches, ribbons/tablets from DP batch 1 would be more cohesive than the ones from DP batch 2. Consistently, Fig. 3 showed that API batch 1 had a significantly higher cohesion than API batch 2 through the whole pressure range tested. This indicates that tablets from DP batch 1 will have a higher tensile strength, as seen on Fig.1.

Conclusion: The compactibility and tabletability results on both raw API batches helped to understand the differences obtained in terms of DP properties between batches 1 and 2. They confirmed that the two API bathes had different mechanical properties despite having the same deformation behavior according to the Heckel analysis. This real case study highlights the importance of performing a comprehensive evaluation of the API properties, particularly in formulations having a high drug load. Here, an additional process step (milling) was applied during API batch 2 synthesis, which was also manufactured at a larger scale than batch 1. This was most probably the cause of the mechanical differences between both batches. Material sparing methods like compaction simulation are key tools during pharmaceutical development to build in-deep knowledge of the API and formulation, as well as better understand and anticipate issues during manufacturing.


Figure 1: DP Batch 1 and 2 Tabletability plots


Figure 2: Raw API Batch 1 and 2 Compactibility Plot


Figure 3: Raw API Batch 1 and 2 Tabletability Plot