(M1030-02-08) Evaluation of Tableting Characteristics of Copovidone-Based ASDs Using CTC and Heckle Analysis

Purpose: Most newly developed drugs fall into Biopharmaceutics Classification System Class II category, which typically have very low solubility and bioavailability. Amorphous solid dispersion (ASD) is a popular technique to overcome dissolution challenges. However, if the drug loading (DL) exceeds limit of congruency (LoC), which is the maximum concentration that drug and polymer can achieve congruent release, it can lead to a decrease in the dissolution rate of the drug. This study examines the critical properties of ASDs at LoC during tablet compression.

Methods: Danazol (Coral Pharma) and copovidone (Kollidon^® VA 64) at 10% w/v in ethanol were spray-dried with a Buchi B-290 mini spray dryer under nitrogen. Assay was done via Pion’s UV-Vis spectroscopy. The melting point (T_m) and the glass transition temperature (Tg) were measured by DSC (Q2000, TA Instruments USA). For tablet compaction was planned according to Table 1. Roller compaction of pre-blend was performed using Medelpharm STYL´One Evo. The pre-blend was compressed into tablets according to Table 1. Based on the compactibility profile (Figure 1), a roll gap of 2.5 mm and roll speed of 3 rpm were selected for further evaluation. The granules were milled using Gerteis hand mill with 1.0 mm square screen. Prepared final-blend was compressed into tablets according to Table 1. Weights, thickness and hardness were measured using SOTAX MT50 to generate compressibility-tabletability-compactibility (CTC) profiles (Figure 1). Heckle analysis of final-blends from F1, F2 and F4 were performed to examine the compression properties. F3 was F2 with additional disintegrant and therefore was omitted.

Results: Copovidone was selected for ASD preparation because of its high Tg (104 °C), good ethanol solubility (up to 40% solids dissolved with danazol), and low solution viscosity ( < 300 mPa-s), which enable efficient spray drying. ASD assays showed DL at 21% ± 0.3% (n=3). High T_g (~102 °C) confirms a stable, amorphous form at room temperature. No T_m was observed in DSC indicating single-phase ASD formation. The pre-blend’s compactability showed tensile strength increase from 0.4 to 2.6 mPa and solid fraction (SF) increased from 0.61 to 0.72 when compression force increased from 2 to 8 kN. To examine the scenarios from both ends of spectrum, SF of 0.62 and 0.73 was selected as target for roller compaction (Figure 1). The CTC profile of the final-blends shows roller compacted blends have comparable compressibility with that of physical mixture. This is due to formulations incorporating large portions of copovidone based ASDs which have excellent dry binder functionality. F3 and F4 achieved tensile strength over 2 mPa (required for packaging of uncoated tablets) with only 6 kN compression force while F2 achieved 1.28 mPa. To achieve strength for coating (over 1.5 mPa), F3 and F4 need 6kN compression force while F2 need 8 kN. Therefore, CTC profiling facilitates the optimization of the production process and ensures final product complies with required quality standards. Heckle analysis (Figure 2a) of F1, F2, and F4 assessed the compression properties of the blends at both small and commercial scales. To evaluate strain rate sensitivity (%SRS), each blend was compressed at 5 mm/s (slow) and 300 mm/s (fast) to determine yield pressures (Py slow and Py fast). For the same blend, yield pressure (Py fast) was higher than Py (slow) because material demonstrates less plastic deformation during faster compression, which may reduce tablet strength in commercial production. Among the formulation, it was observed that F4's Py (fast) is lower than F2's, indicating F4 is less prone to plastic deformation and might be more suitable for high-speed compression process. The %SRS data (Figure 2b) shows that F2 has the highest %SRS at 27.64%, followed by F1 at 12.05%, and F4 at 9.93%. This indicates that F4’s flow stress is less sensitive to changes in the strain rate. In production settings, F4 can lead to better tablets because it would have consistent behavior under different compression speeds, leading to more uniform and reliable tablet properties. The combination of Py value and %SRS shows F4 material is moderately hard and brittle, and the mechanism of compaction would be fragmentation with some plastic flow at contact point [1]. Additionally, flow properties of roller compact material were found to be better than physical mixture (data not shown). Therefore, the results suggested that F4 is more suitable for commercial tablet production.

Conclusion: The results of this study show that danazol ASD with 21% DL formed tablets with tensile strengths ranging from 1.2 to 3.9 mPa under lower compression forces, due to the binding properties of spray-dried copovidone. Roller-compressed ASD formulations with high SF (F4) exhibited favorable flow characteristics, along with lower Py (fast) and %SRS values, which may support their suitability for commercial tablet manufacturing by maintaining consistent performance at high compression speeds. The analysis of CTC and Heckle plots yielded comprehensive insights into copovidone-based ASD materials, thereby informing potential possibilities for commercial tablet manufacturing processes.

References: 1. Roberts RJ, Rowe RC. The compaction of pharmaceutical and other model materials – a pragmatic approach. Chem Eng Sci 1987;42:903–911

Acknowledgements: No public funds supported this work. The authors have no conflicts of interest to disclose.

Table 1: Composition of danazol loaded tablets formulation

Figure 1: Compactability of Pre Blend and CTC Profile of 4 Final Blends

Figure 2 (a) Heckle Plot of F1, F2 and F4. (b) Material Property zone of F1, F2 and F4