(M1330-07-41) Improving Dissolution Performance and Drug Loading of Amorphous Dispersions Through a Hierarchical Particle Approach

Purpose: The pharmaceutical industry generally either uses spray-drying with organic solvents or hot melt extrusion to manufacture amorphous formulations. These two manufacturing processes are not without limitations, as they are ill-suited for drugs with poor solubility in volatile solvents or high melting points (and thermal degradation), respectively. Co-precipitation has been explored as a commercially viable alternative technique to prepare amorphous dispersions. The preparation of a co-precipitated amorphous dispersion (cPAD) involves rapid mixing of a solvent containing dissolved drug and polymer with an anti-solvent in a high-shear environment to enable rapid precipitation of the amorphous solid dispersion. While cPAD is a promising strategy for drugs that cannot be spray dried or hot melt extruded, one challenge associated with cPAD materials is that they present wettability challenges, complicating assessment of in vitro drug release. Incorporating the cPAD material into a water-soluble matrix such as hypromellose (HPMC) in ordered mixtures generated via evaporative isolation routes to produce hierarchical cPAD materials was shown to be effective at managing this phenomenon. However, it is not known if and to what extent this approach could remediate the suppression of drug release generally observed in amorphous solid dispersion (ASD) formulations with high drug loads. Herein, traditional (binary) and hierarchical cPAD materials (cPAD incorporated into water-soluble matrix) were prepared using grazoprevir as the model drug and hypromellose acetate succinate (HPMCAS) as the primary polymer to assess upper limits of drug load that could be achieved without dissolution slow down. Binary grazoprevir–HPMCAS ASDs were also prepared via solvent evaporation for comparison.

Methods: Grazoprevir–HPMCAS binary ASDs were prepared by solvent evaporation. The cPADs were prepared by anti-solvent precipitation method on a homogenizer running at a speed ranging from 6000–12000 rpm over the course of a few seconds. Grazoprevir and HPMCAS were dissolved in tetrahydrofuran, followed by precipitation into acidified water (0.001 N HCl). In case of the hierarchical cPAD particles, the secondary water-soluble polymer, HPMC, was pre-dissolved in the acidified water at a requisite amount in order to make the overall DL 60%, with a 20% each of HPMCAS and the secondary water-soluble polymer. For the hierarchical cPAD formulation, methyl tert-butyl ether (MTBE) containing HPMC was also used as an anti-solvent to precipitation of grazoprevir and HPMCAS. Release performance of the cPADs and solvent evaporated ASDs was evaluated through two-stage dissolution.

Results: In general, negligible grazoprevir release was observed during the first 30 min of dissolution. Once pH was adjusted from 1.2 to 6.5, release was observed across all the solvent evaporated ASDs. Complete release was observed for the 5% DL ASD, while the 10 and 15% ASDs showed ~80% drug release at 90 min (Figure 1). The amount of drug released at 90 min showed a decline as DL was increased. The drug release profiles for the 50, 60 and 75% DL ASDs were similar, where ~ 30% of drug release was observed at 90 min. With binary cPADs, drug release was less than 20% regardless of the anti-solvent used (Figure 2). One problem observed with the traditional cPAD was that they did not wet very well in the dissolution media, which could have resulted in the poor drug release performance observed. In comparison, cPAD particles that were prepared using the hierarchical approach showed improved wettability in the dissolution media and better release performance, where ~50% of grazoprevir was released after 90 min. With HPMC dissolved in the anti-solvent, the surface of the binary cPAD will be coated by HPMC during the precipitation process to form a continuous polymer coat. To further explore the influence of the secondary polymer on drug release, MTBE was also used as an anti-solvent for precipitation of grazoprevir and HPMCAS. Unlike with acidified water, HPMC is insoluble in MTBE. Therefore, it was postulated that the HPMC will form a discrete particle coat, which do not facilitate particle wetting as well as a continuous coat generated with acidified water as the anti-solvent. As shown in Figure 2, the hierarchical cPAD prepared with MTBE as the anti-solvent did not show improved drug release and even micronization of the HPMC did not help improve dissolution performance when hierarchical particles were generated from this system – suggesting a uniform coat is necessary. This result further illustrated the influence of the morphology of the secondary polymer on particle wetting and drug release.

Conclusion: Grazoprevir–HPMCAS amorphous dispersions prepared using the hierarchical approach were shown to have better release performance compared to binary cPAD, as well as ASDs prepared using solvent evaporation at the same DL. In the preparation of hierarchical cPAD, the morphology of the secondary polymer, whether forming a continuous coat or an ordered mixture comprised of discrete particles, was found to have an influence on drug release behavior. This study shows that hierarchical cPAD holds great promise in producing amorphous formulations with high DL while ensuring good particle wettability for improved dissolution.

Acknowledgments: This study is funded by Merck & Co. Inc.

Figure 1. Two-stage dissolution of grazoprevir–HPMCAS solvent evaporated ASDs.



Figure 2. Two-stage dissolution of grazoprevir binary and hierarchical cPADs.