(W0930-01-05) Impact of Spray-Dried Dispersion Formulation and Composition of Physiological Fluid on Micellar and Colloidal Speciation

Purpose: Spray dried dispersions (SDDs) are recognized as a key technology for enhancing bioavailability of poorly water-soluble compounds. SDD formulations enable increased intestinal absorption through two primary mechanisms: (1) increasing concentration of solvated drug leading to a higher driving force for passive diffusion through the intestinal epithelium, and (2) formation of colloidal species leading to increased rates of diffusion through the unstirred water layer at the epithelial surface and a rapid resupply of solvated drug at the surface of epithelial cells. While the former is achieved through the amorphous form, the latter is dependent on the formation and nature of colloidal species that are characteristic of SDD formulations. During formulation screening, polymers are chosen, in part, based on their compatibility with the API and their ability to preserve supersaturation in solution. Basic selection criteria typically include highest achievable apparent concentrations and the ability to sustain supersaturation during in vitro dissolution studies, as they are practical metrics that can be correlated with in vivo pharmacokinetic (PK) studies. While there has been some work in the field to understand the mechanisms by which speciation in solution occurs, little work has been done to understand how the species vary with respect to polymer chemistry and concentration and as a function of physiological properties such as bile-salt concentration and pH.

Methods: The goal of this study is to systematically evaluate how formulation and biorelevant factors influence the size and distribution of colloidal species industry standard polymer excipients as a baseline for comparison of speciation for these systems in the presence of API. The polymers evaluated are HPMCAS-H, HPMCAS-M, HPMCAS-L, HPMC E3, Eudragit L100, PVP-VA, and Soluplus, which all have precedented usage in amorphous solid dispersions. A range of polymer concentrations are examined, corresponding to 10, 25, and 40 wt% drug-loading SDDs in a 130 mg API dose, as well as a polymer-only control. Bile salt concentrations were chosen for their relevance to typical pre-clinical models used in pharmaceutical development – 0 % as control, 0.224 wt% representative of human FaSSIF, 0.5 wt% representative of dog FaSSIF, and 1 wt% representative of rat Fe/FaSSIF. Finally, three pH conditions are used, each of which pertain to the range of adult human FaSSIF. They are pH = 5.5, and 6.5. Additionally, evaluation in a system representing the typical pH shift from gastric to intestinal fluid in a fasted human: transferring from pH = 2 to 6.5. In the current body of work, dynamic light scattering (DLS) is used to evaluate the presence and relative ratios of the solution species.

Results: Our results indicate that there are distinct differences in speciation as a result of both biorelevant factors and formulation factors. For instance, without the presence of bile salt micelles, HPMCAS-M forms species from 10 nm to 10 µm. As the concentration of HPMCAS-M increases, the prevalence of small ( < 100 nm) species decreases, while large, 100-1000 nm, species become more prevalent (Figure 1). However, in the presence of 0.224 wt% bile salts, the size distribution of observed species remains constant regardless of the polymer identity, its concentration, or the pH of the media and is consistent with the bile salt micelles known to form in this media. However, at 0.5 wt% and 1 wt% bile salts, larger species are detected in the presence of polymers and vary with respect to formulation. These results confirm that there are considerable differences in the solution state of dissolved SDDs as a result of polymer content and bile salt levels. In turn, this underscores the need to better understand speciation with different formulation and biorelevant conditions so that better in vitro experiments can be designed and in vivo experiments can be better interpreted and translated from animals to humans. Our results also demonstrate that there are distinct differences in colloidal species formed by the different polymer excipients (Figure 2) even without bile salt interactions. Within the HPMCAS derivatives, the transition from higher relative acetyl content (HPMCAS-H) to higher relative succinyl content (HPMCAS-L) is marked by a transition from a narrow distribution of sizes to a broad distribution. This is an intuitive result as the higher acetyl content renders the polymer more hydrophobic, forcing more intramolecular interactions in an aqueous media and resulting in more consistent colloid sizes. In contrast, higher succinyl content results in greater hydrophilicity and increases polymer solvation, resulting in a broader distribution of colloid sizes. The other polymers examined showed similar distributions to HPMCAS-H - narrow and generally smaller than 1 µm.

Conclusion: This study establishes a novel and strong baseline understanding of how industry-relevant polymers exist in biorelevant media. In future work, we will complement our DLS measurements using microfluidic particle measuring and then evaluate these same conditions with a variety of model APIs with varied pKa, acid/base characteristic, and logP values to understand how speciation is influenced by API.


Figure 1. DLS results for HPMCAS-M at a variety of polymer concentrations and bile salt concentrations at pH 6.5. The top row corresponds to baseline bile salt solutions that do not contain polymer. Columns increase bile salt concentration left-to-right as 0, 0.224, 0.5, and 1 wt%. Rows increase in polymer concentration top-to-bottom as 0, 0.75, 1.5, and 4.5 mg/mL.


Figure 2. DLS results of each polymer in this study at 1.5 mg/mL in a pH 6.5 phosphate buffer that does not contain bile salts.