(T1530-09-48) Copovidone-Based Spray Dried Amorphous Solid Dispersions: Investigation of Drug Loadings and the Limit of Congruency

Purpose: Most newly developed drugs fall into Biopharmaceutics Classification System (BCS) Class II category, which typically have very low solubility and bioavailability. Amorphous solid dispersion (ASD) is a popular technique to overcome dissolution challenges However, there is a limit to the amount of drug that can be incorporated into the polymer matrix while maintaining the desired amorphous state. If the drug concentration exceeds this limit of congruency (LoC), it can lead to a decrease in the solubility and dissolution rate of the drug. This study demonstrates the robustness of generating ASDs with a spray drying technique using copovidone as a matrix polymer by determining the LoC of drugs.

Methods: Various Danazol and copovidone mixtures were dissolved in ethanol (5% w/v) and spray dried with a Buchi B-290 mini spray dryer under nitrogen environment. The spray drying conditions were: inlet air temperature 68 ºC; aspirator 100 %, and pump feed rate 2-3 mL/min. The outlet air temperature was around 41 ºC. The ASDs were formulated at drug loadings of 15%, 20%, 30% and 40% w/w and vacuum dried (at 30 °C for 12 h) before further characterization. For drug assay, the formulation was dissolved in ethanol and analyzed by UV-Vis absorption spectroscopy (Pion’s fiber optic UV detection system). The melting point (Tm) of pure Danazol and the glass transition temperature (Tg) of ASDs were measured with Differential Scanning Calorimetry (DSC). To test the dissolution performance, the pure Danazol and each ASD were filled into hard gelatin capsules of size “00” at the 80mg strength. USP Apparatus II with sinkers, 1000 mL fasted state intestinal fluid (FaSSIF) at 37 °C with 100 rpm was used. The drug release from the formulations were measured by UV-Vis absorption spectra. To characterize the ASDs, they were compressed into pellets using a Carver Press and then analyzed by Raman mapping using a HORIBA Scientific XploRA Series Confocal Raman Microscope. A 100 x 100 micron area was mapped of each ASD, using 5 micron step sizes.

Results: For spray drying, ethanol was selected as solvent because the solubility of copovidone (up to 40% solids content) and Danazol; and sprayable viscosity of solution ( < 300 mPas). The ASD formulations at drug loadings of 15%, 21%, 31% and 39% w/w (Table 1A) were characterized using scanning electron microscopy (SEM), DSC, and polarized microscopy (data not shown). The DSC showed Tg of ASDs at ~141 °C. Additionally, no melting temperature (Tm) of Danazol was observed in the thermogram at drug loading up to 39%, indicating the formation of homogenous single -phase ASD (Table 1B). The dissolution data showed a significant improvement in dissolution performance of ASDs at 15% and 21% drug loadings, reaching 67% and 76% release within 6 h, respectively, compared to API alone, which drug release was only 16%. The dissolution performance dropped significantly at 31% and 39% drug loading, resulting in only 21% and 19% release within 6 h, respectively (Figure 1). These results indicate LoC has been reached at a drug loading of 21% to 31% w/w of drug loading. To further establish and optimize the LoC, the performance of the ASD formulation at 25% drug loading is currently being evaluated along with characterization studies to evaluate the presence of Danazol crystallinity at molecular level, interactions between drugs and polymers, and media in ASDs. The Raman mapping revealed a change in the 1607 cm^-1 crystalline peak of the Danazol reference spectrum. Spectra from the Raman maps exhibited a broadening of the peak and a shift to higher wavenumbers (1611 cm^-1). These changes are due to the amorphous character of the Danazol in the ASD and are indicative of bonding between the Danazol and the polymer. The visualization of these changes can be accentuated by creating mapping profiles that compare the relative intensities at 1607 and 1611 cm^-1 at each point in the maps. Figure 2 compares the relative peak intensities in the 30% DL ASD to the 20% DL ASD. Red indicates higher relative intensity whereas blue indicates less. The relative intensity at 1607 cm^-1 is more prevalent in the 30% DL ASD than in the 20% DL ASD, indicating that the 30% DL ASD is less amorphous.

Conclusion: The results of this study indicated successful Danazol ASD formulations using Copovidone as a matrixing polymer by spray drying method. Drug loading had a significant impact on the drug dissolution performance with drug loading >31%w/w resulting in a significantly slower drug release, however homogeneous single phase ASDs were achieved up to a drug loading of 39% w/w. The LOC of these formulations was observed to be in the range of 21%- 31% w/w for copovidone spray dried formulations indicating suitability of formulating Danazol as ASDs for enhancing dissolution performance. Further optimization of the dissolution performance can be archived using suitable salts/ surfactants or filler excipients below the limit of congruency.

Table 1 A) Assay of Danazol -copovidone ASDs; B) Melting point of Danazol and glass transition temperature of ASDs

Figure 1 Dissolution data of Danazol ASDs vs pure Danazol

Figure 2 Raman mapping profiles comparing Danazol peak positions for 30% and 20% DL ASDs