(M1230-02-14) Optimization of Roller Compaction Process for Highly Unstable Drug Substance Susceptible to Degradation in Presence of Moisture, Oxygen and Magnesium Stearate

Purpose: The drug substance (API P) is an unstable substance that readily decomposes in presence of atmospheric moisture, oxygen as well as some common excipients.  The objective was to develop and optimize a stable formulation using a process that is robust and reproducible.

Methods: Roller compaction of pre-blend containing API P was performed using Fitzpatrick Roller Compactor (Model CCS320) attached with Fitz Mill (M3B).  The critical process parameters investigated were roller speed, force and gap. The granules and final blends for compression were characterized for particle size distribution (Advantech sonic shifter), bulk and tapped density (Pharma Test PT-TD300). Final blend was compressed using a Korsch XL 100 tablet press. The resultant tablets were evaluated for friability (Sotax), disintegration (Pharma Test DIST-3) and dissolution (Distek, USP II). Because of moisture sensitive nature of the drug substance, the roller compaction trials were performed under stringent room humidity-controlled environment by maintaining the room humidity below 30%RH. The final tablets were packaged in HDPE bottles with CRC caps. Prior to the induction sealing of the bottles, the bottles filled with tablets and desiccant were purged with nitrogen gas and the headspace oxygen level in sealed bottles were measured using benchtop O₂ analyzer (Ametek/Mocon) and confirmed to be below 4.0%.

Results: API P is not a free-flowing powder and so there was a need to granulate to improve processability properties such as powder flow and compressibility. Because of the tendency of the drug to undergo hydrolytic decomposition, wet granulation was not a viable option. Thus, a dry granulation process using a roller compactor was developed. Drug excipient compatibility study revealed that the drug was incompatible with magnesium stearate, a commonly used lubricant. Consequently, glyceryl dibehenate was chosen as a lubricant for the formulation. However, the low melting point of glyceryl dibehenate caused variations in granule density. This was overcome by maintaining the ribbon temperatures below 37ᵒC by internally circulating chilled water through roller compactor. Roller gap was identified as a critical in-process parameter that ultimately influenced the particle size and flowability of the granules generated. The impact of dwell time on granules properties was evaluated by varying roller speed and force. Experiments were performed with the objective to achieve maximum roller gap while minimizing the level of fines. This was because lower roller gap resulted in retardation of dissolution rate whereas increase in amount of fines resulted in poor powder flow and compressibility. Figures 1 and 2 show the effect of roller speed (rpm) and force (kN) on roller gap and %fines. These results indicated optimum value of 4.0 rpm roller speed and 4.5 kN roller force for the process. Particle size of the granules further controlled by optimizing the mill speed. Water activity was measured after each step to ensure product stability is not compromised at each step of the process.

Conclusion: Roller compaction is an excellent choice for APIs with poor flowability and are susceptible to degradation due to water. Roller compaction process was optimized to obtain the desired CQAs. The experimental design involved evaluation of input parameters such as roller speed and force on in-process parameters of roller gap and % fines. Ribbon quality was stabilized by maintaining the ribbon temperature below 37ᵒC. The oxidative and moisture related degradation was minimized through stringent environmental controls for storage and handling.

Acknowledgements: Authors are employees of CMIC CMO USA, Corporation.

Figure 1. Contour Plot of Roller Gap (mm) vs Roller Speed (rpm) and Roller Force (kN)

Figure 2. Contour Plot of % Fines vs Roller Speed (rpm) and Roller Force (kN)