(T1230-12-81) Development of a Fixed-Dose Combination Using Concurrent Twin-Screw Hot Melt Extrusion and Melt Granulation: Optimization of Polymer-Diluent Combinations for Enhanced Drug Delivery

Purpose: The present study aims to demonstrate the suitability of concurrent hot melt extrusion (HME) and melt granulation (MG) for a fixed-dose combination (FDC) of therapeutic drugs using a Twin Screw (TS) extruder for continuous processing. TS HME is a proven technique to impart amorphous character to an API. TS MG is a novel solid-state processing technique gaining interest for its solvent-free nature and compatibility with continuous processing [1]. FDCs comprise two drugs, typically with remarkably different physical and pharmacokinetic characteristics [2], and are of growing interest for patient convenience and therapeutic effect. Here, Ibuprofen (IBU) and Acetaminophen were selected as model FDC drugs to demonstrate the potential for concurrent ME and MG via TS extruder. The first drug was designed to undergo an amorphous transformation during TS MG, improving solubility and dissolution. The second drug was intentionally maintained in its crystalline state to preserve stability and properties. The study evaluates various BASF polymers and diluents and process parameters to determine their impact on crystallinity and dissolution.

Methods: This study involved screening various BASF polymers, diluents, and their combinations to assess their impact on the properties of granules produced using TSMG. Specifically, the focus was on identifying polymers and diluent combinations that led to the formation of brittle and hard granules. The influence of process parameters such as barrel temperature, screw speed, and the number of mixing zones on the granules was also investigated. The resulting granules were subjected to milling and compression using a single-station manual compression machine, followed by the evaluation of various granule and tablet characteristics. Differential scanning calorimetry (DSC) studies were conducted to determine the crystalline properties of both drugs. Then, solubility and dissolution studies were performed to evaluate the impact of the amorphous conversion of IBU on its release behavior.

Results: Various polymers and their combinations were tested to produce granules that possess hardness and brittleness, facilitating their flowability and compression into tablets. Since the melted ibuprofen acts as a plasticizer and when used in combination with low glass transition (Tg) polymers, it results in soft, plastic-like granules. Additionally, this combination affected the crystalline nature of acetaminophen. Consequently, Kollicoat® IR, a polymer with a high Tg of approximately 209°C, surpassing the melting points of both ibuprofen (Tm ~ 78°C) and acetaminophen (Tm ~ 170°C), was chosen. When Kollicoat® IR was used alone, the resulting granules were soft and unsuitable for milling. To address this, two diluents, Ludiflash® and Ludipress®, were added. The granules containing Ludipress® (lactose) turn soft and exhibit black discoloration after extrusion. On the other hand, the granules with Ludiflash® (mannitol) were hard, brittle, and free from any charring. Consequently, various Ludiflash® and Kollicoat® IR combinations were tested, and the 1:1 ratio yielded granules with the desired characteristics at a barrel temperature of 100°C with three mixing zones. DSC studies indicated the complete conversion of ibuprofen into an amorphous state while acetaminophen remained crystalline. Solubility studies revealed a significant improvement in the solubility of ibuprofen, with approximately a 16-fold increase at pH 1.2 and a 90-fold increase in water, while solubility remained unchanged at pH 7.2. From the dissolution studies, in pH 7.2 phosphate buffer, the release of IBU from the marketed product and the tablets from the extrudates exceeded 85% within 15 minutes, while the release was slower in directly compressed tablets. Conversely, the release of APAP from all formulations reached ≥ 85% within 15 minutes. In 0.1N HCl, the release of IBU from all tablets was less than 20%. However, the release of APAP from the directly compressed tablets and the marketed product exceeded 85% within 15 minutes, while the extrudate tablets released ≥ 85% in 30 minutes. The slower release in the case of IBU can be attributed to the strength and non-porous nature of the extruded granules. Additionally, the slower release may also be due to the formation of a matrix between melted IBU and polymer, resulting in reduced tablet wettability.

Conclusion: In conclusion, concurrent ME and MG could be achieved through TS MG, indicating the potential for continuous processing of FDCs. This approach effectively developed granules for tablet compression by combining appropriate polymer and diluent combinations. Among the trials, the Kollicoat® IR and Ludiflash® combination produced good quality granules. DSC tests confirmed the amorphous conversion of ibuprofen while acetaminophen remained crystalline. Ibuprofen solubility experiments showed significant improvements, while dissolution studies revealed good release patterns for both ibuprofen and acetaminophen. Overall, this comprehensive investigation sheds light on the selection of suitable polymers, diluents, and process parameters and provides insights into the crystalline characteristics, solubility improvement, and dissolution behavior of the granules when two drugs are used in combination. These findings contribute to the understanding and optimization of TS MG for developing pharmaceutical formulations with enhanced drug delivery properties.

References: 1. Nyavanandi D, Narala S, Mandati P, Alzahrani A, Kolimi P, Almotairy A, Repka MA. Twin Screw Melt Granulation: Alternative Approach for Improving Solubility and Permeability of a Non-steroidal Anti-inflammatory Drug Ibuprofen. AAPS PharmSciTech. 2023 26; 24(1): 47. doi: 10.1208/s12249-023-02512-z.
2. Althobaiti AA, Ashour EA, Almotairy A, Almutairi M, AlYahya M, Repka MA. Development and Characterization of Different Dosage Forms of Nifedipine/Indomethacin Fixed-Dose Combinations. J Drug Deliv Sci Technol. 2023; 80: 104117. doi: 10.1016/j.jddst.2022.104117.

Acknowledgements: The authors thank BASF Corporation, Pharma Solutions for supporting this project.

Figure 1: Dissolution profiles of the marketed product, directly compressed tablet (PM), and tablets from extrudates in pH 7.2 Phosphate buffer

Figure 2: Dissolution profiles of the marketed product, directly compressed tablet (PM), and tablets from extrudates in 0.1N HCl

Figure 3: DSC of IBU, APAP, Ludiflash®, Kollicoat® IR, PM, and extrudate