(M1130-01-01) The Importance of Surface Composition and Wettability on the Dissolution Performance of High Drug Loading Amorphous Dispersion Formulations

Purpose: Amorphous solid dispersion (ASD) is an enabling formulation strategy aimed at enhancing the bioavailability of poorly soluble drugs. One challenge, low drug loadings, is the inherent limitation posed by hydrophobic drugs, necessitating a substantial amount of polymer to stabilize the amorphous phase and facilitate its release. The constraints of drug loading result in a considerable pill burden for patients, especially with high dose drugs. Consequently, there has been substantial interest in developing strategies to increase the drug loading of ASD formulations. Previous studies have shown that surface modification of ASDs with a hydrophilic polymer can be achieved through co-precipitation and subsequent coating. This strategy to produce a hierarchical co-precipitated amorphous dispersion (cPAD) led to a significant increase in drug release at 70% drug loading, surpassing the limits of typical binary ASDs without compromising dissolution. However, it was found that not all hydrophilic polymers could enhance drug release when used to dilute the surface of ASD particles. Therefore, the objective herein was to understand why some polymers are more effective than others in promoting drug release in surface-diluted high drug loading ASD formulations.

Methods: The interplay between particle surface composition, particle wettability, and drug release performance was investigated using grazoprevir and hypromellose acetate succinate (HPMCAS) as the model drug and polymer, respectively. Seven different hydrophilic secondary excipients (i.e., polymer or wetting agent) were used to prepare high drug loading surface-modified ASD particles. These excipients are hypromellose (HPMC), povidone (PVP), polyethylene glycol (PEG), poloxamer 407, gelatin, sodium dodecyl sulfate (SDS) and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS). The high drug loading surface-modified ASD particles were prepared either by dispersing milled binary ASD particles in acidified water containing dissolved polymer to form a polymer coat around the particles, or through co-precipitation to produce a hierarchical cPAD. The generation of hierarchical cPADs involved dissolving an additional polymer in the anti-solvent during precipitation, leading to the deposition of the polymer on the cPAD particles during isolation and drying. The surface-modified particles were characterized for drug release, wettability, morphology, and surface composition using two-stage biorelevant dissolution studies, contact angle measurements, scanning electron microscopy, and X-ray photoelectron spectroscopy (XPS), respectively.

Results: HPMC and SDS as secondary excipients were the most promising for improving dissolution (Figure 1a). However, one observation with the HPMC-based cPAD material was that the particles did not wet very well, while SDS is known to promote wetting. Therefore, a mixture of the two excipients was used to prepare hierarchical cPAD. This cPAD outperformed the cPADs prepared with only one secondary excipient and was comparable to the 30% drug loading binary ASD in terms of drug release (Figure 1b), suggesting that HPMC and SDS may have synergistic impact on dissolution enhancement for cPAD materials. Surface modification of binary ASDs prepared via solvent evaporation also changed drug release behavior. The application of HPMC onto the ASD particles resulted in an increase in the amount of grazoprevir released (Figure 2a). When a high amount of HPMC was used to modify the surface of ASD particles, the amount of grazoprevir released after 90 min was similar to a 20% drug loading binary ASD without coating applied. Scanning electron micrographs showed that HPMC in the anti-solvent was primarily deposited on the particle surfaces to form a uniform coat (Figure 2c). Despite surface modification with hydrophilic polymers, hierarchical cPAD particles did not consistently exhibit good release performance. XPS-measured surface drug concentration was not a good predictor for release across the different surface modifying polymers but was predictive within a given polymer. For example, while hierarchical cPADs prepared with PVP and poloxamer 407 had similar surface grazoprevir concentrations to cPADs prepared with HPMC as the secondary polymer, the former two cPADs had poorer release performance. However, particles with different amounts of HPMC on the surface had different release profiles. Contact angle measurements showed that the cPADs prepared with SDS and HPMC as the secondary excipients were hydrophilic (contact angle ≤ 90°), while cPADs prepared with PVP and poloxamer 407 were hydrophobic (contact angle > 90°) (Figure 3). These observations suggest that contact angle is a reasonable indicator of wetting behavior and drug release for these samples.

Conclusion: Surface modification of high drug loading ASDs and cPADs was shown to improve drug release. By using different polymers and surfactants as the secondary excipient, it was observed that not all hydrophilic polymers or surfactants were equally effective. HPMC- and SDS-based particles consistently demonstrated better performance in terms of drug release. Particles with good wettability showed improved drug release relative to particles that did not wet well, even with similar drug loadings. The observations herein underscore the intricate interplay between particle wettability and performance in amorphous dispersion formulations and illustrate a promising hierarchical particle approach to formulate high drug loading amorphous dispersions with improved dissolution performance.

Acknowledgements: The authors gratefully acknowledge Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA for funding this study.


Figure 1. (a) Two-stage dissolution of hierarchical cPADs prepared with different constituents as the secondary excipient. (b) Two-stage dissolution of hierarchical cPAD prepared with both HPMC and SDS . The amount of drug released at 90 min for solvent evaporated (SE) samples prepared at 20, 30, and 75%, SE-20, SE-30, and SE-75 are provided as reference for comparison.


Figure 2. (a) Two -stage dissolution of SE ASDs that were further mixed with 72.5 mg/mL or 10 mg/mL HPMC. (b) and (c) are scanning electron micrographs of 75% drug loading binary SE ASDs before and after coating with 72.5 mg/mL HPMC, respectively. The amount of drug released at 90 min for uncoated SE samples prepared at 20, 30, and 75%, SE-20, SE-30, and SE-75 are provided as reference for comparison.


Figure 3. Fasted-state simulated intestinal fluid contact angles on selected cPAD samples.