(T1430-09-56) Impact of Dosage Form on Drug Release from Danazol-ASD at LoC: A Comparative Study

Purpose: Amorphous solid dispersion (ASD) is a well-established approach for addressing dissolution challenges associated with Biopharmaceutics Classification System Class II and IV drugs, which are known for their poor solubility in aqueous environments. However, if the drug loading (DL) exceeds the maximum loading when drug and polymer achieve congruent release (LoC), drug dissolution may decrease. This study seeks to compare the dissolution performance of two dosage forms when the ASD contains a high drug load near its LoC.

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. The melting point (T_m) and the glass transition temperature (Tg) were measured by DSC (Q2000, TA Instruments USA). For capsules, pure danazol and ASD were encapsulated in size "000" hard vegan capsules, each containing 80 mg of danazol. For tablet formulation, pre-blends (Table 1) underwent roller compaction using the Medelpharm STYL´One Evo system. Subsequently, tablets were compressed according to the specifications outlined in Table 1 utilizing a Carver Press. 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-blends were compressed into tablets (Table 1) to characterize for compressibility-tabletability-compactibility profiles (not discuss). Dissolution was performed with USP Apparatus II with sinkers, 100 rpm, in 1000 mL fasted state intestinal fluid at 37 ± 0.5°C. The drug release and assay were measured by UV-Vis spectroscopy.

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. Drug-ASD-filled capsules and compressed ASD tablets (with placebo) were compared to assess their dissolution performance in solid oral dosage forms. Placebo tablets were initially prepared using compositions with range of 30% to 80% copovidone ASD, MCC as filler (q.s.), and 5% crospovidone as disintegrant (including lubricant). The placebo tablets compressed at forces up to 15 kN exhibited good hardness and disintegration time (from 5 to 20 min) (Figure 1). Tablets with MCC and 5% crospovidone, which showed high strength and low disintegration time (Table 1), were chosen for danazol ASD at LoC tablet preparation at 9kN and 15kN. However, the dissolution of tablets showed less than 10% of API released in non-sink conditions (Figure 2). The tablets failed to disintegrate even after 24 h, whereas the placebo disintegrated within 20 minutes. Adding disintegrant (F3) compressed at lowest possible 3 KN force didn’t improve the dissolution performance. This indicates that the hollow or porous structure and dense outer layer of spray-dried particles containing very high (21% w/w) hydrophobic danazol collapsed and exacerbate the hydrophobic interaction during compression. This densification and interactions reduced wettability of drug matrix, which may in turn decrease the permeability to dissolution media and thus affect the drug's dissolution rate. It is also speculated that the mechanical energy imparted during compression can induced some crystallization of marginally stable amorphous drug. Therefore, compression-induced structural modifications in the ASD containing the high DL result in increased resistance to penetration of media within the tablet, as disintegration exceeded 24 h (outer layer wet but inside drug solid mass). This led to incomplete drug release even upon incorporating disintegrants in the formulation (i.e. 5% crospovidone). In comparison, capsules containing ASD powder disintegrated within 30 min and exhibited a drug release up to 70% in non-sink conditions (Figure 2). This observation indicates that the medium quickly permeated the high surface area provided by the hollow structure of the ASD particles.

Conclusion: The results of this study highlight the successful development of a single-phase ASD formulation containing 21% w/w danazol which is near to its LoC, with copovidone serving as the matrix polymer and prepared via spray drying. Capsules filled with this ASD achieved about 70% drug release under non-sink conditions, whereas tablets made from the same ASD showed only 10% release, even at the lowest compression force. This significant difference is likely due to fusion of spray dried particles and other structural changes in the ASD caused by compression, especially at higher concentrations of hydrophobic drug. It is important to consider dosage form selection in the early development of ASD formulations with high DL to achieve appropriate drug release and therapeutic outcomes. Further research on compression-induced changes in ASD performance at LOC using advanced analytical methods, such as Raman microscopy or Synchrotron X-ray diffraction, may yield information relevant to the development of improved drug delivery systems. Alternatively, consider using ASD-in-capsule forms instead of tablets.

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: Disintegration and hardness of placebo tablets containing copovidone ASD (30 to 80%) compressed at 9kN and 15 kN

Figure 2: In vitro drug release from danazol ASD at LoC-filled capsules and compressed danazol ASD tablets at LoC (F2 and F3).