(T1430-08-54) Influence of Particle Morphology on Amorphous Solid Dispersion Drug Product Design

Purpose: Amorphous solid dispersions (ASDs) have emerged over the past decade as the leading formulation technology for low solubility compounds. ASD formulations enhance bioavailability 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 drug-polymer colloids, that lead to increased rates of diffusion through the unstirred water layer and a rapid resupply of solvated drug at the epithelial surface. While the former is achieved through sustainment of the amorphous form and inhibition of precipitation, the latter is dependent on the formation and nature of colloidal species, as well as the extent of intermolecular interactions between the drug and polymer. In this work, we characterized the colloids formed by polymers traditionally used in ASDs and identified intrinsic differences in size and density as a result of chemistry, hydrophobicity, and polymer concentration in biorelevant media. Building off of these results, we evaluated the degree to which model drug compounds spontaneously partition into polymer colloids and measured their effect on the nature of colloidal species. The 4 model compounds were selected to have a range of physicochemical properties. After gathering these baseline measurements, we produced spray dried dispersion (SDD) and hot melt extrusion (HME) formulations for one of the model compounds, itraconazole, and compared the extent of solubilization and colloidal species formation of itraconazole as both neat ASD powders and as formulated tablets in biorelevant dissolution. These results allowed insights into the impact of particle size and density on colloidal speciation, in addition to formulation strategies in industry.

Methods: Colloidal species were evaluated through dynamic light scattering, in combination with varied centrifugation conditions. In order to measure the solubilized drug as free drug and in the colloids, both PION and HPLC were used. HPLC was primarily used during biorelevant dissolution experiments, while PION was used primarily during initial baseline measurements. SDDs were sprayed on a custom spray drier and HMEs were produced using the MeltPrep system. Tablets were granulated and compressed using the Medelpharm STYL’One Nano system and milling was performed on a Korsch Hand Mill. Biorelevant dissolution was performed in human fasted conditions with the first stage comprising 0.01N HCl, pH = 2, and the second stage comprising FaSSIF V1, pH = 6.5.

Results: Initial measurements of the polymer colloids show that colloidal size, polydispersity, and density are strongly dependent on the hydrophilicity of the polymers, with more hydrophilicity yielding smaller, less dense, more monodisperse colloids. Upon adding crystalline API to pre-existing colloids, it was seen that the model compounds do not strongly partition into polymer colloids, regardless of molecular weight, logP, and pKa of the compounds. However, the number of hydrogen bond acceptors the model compounds contain did correspond to an increase of partitioning into the pre-existing polymer colloids. Additionally, we observed that colloid density and size is impacted by drug partitioning and noted that colloids formed from hydrophilic polymers showed the biggest change in hydrodynamic radius upon partitioning of drug into the colloid. In characterizing the itraconazole ASDs by biorelevant dissolution, there were clear effects for both the neat powders and for the ASDs formulated as tablets. Namely, the extent of colloidal species formation correlated with initial solubilization in the gastric media. This initial solubilization appears related to particle surface area and density, suggesting that congruent dissolution of API and polymer can be affected not only by formulation, as established in literature, but also by particle characteristics.

Conclusion: The performance of ASDs is dependent on many factors. It is critical to consider the effects of formulation and processing as early as possible. Knowledge of the final target product profile needs to inform not only the design and formulation of the oral dosage form, but also the ingoing ASD. The ability of the ASD to promote colloidal speciation can be enhanced or diminished by the many aspects of formulation. Knowledge of the intrinsic polymer properties, intermolecular interactions with the API, and dependence on dissolution rate are critical to creating robust, advanceable, and scalable oral dosage forms.

References: [1] Mol. Pharmaceutics 2022, 19, 9, 3412-3428
[2] Mol. Pharmaceutics 2022, 19, 9, 3085-3099
[3] Mol. Pharmaceutics 2021, 18, 5, 2066-2081
[4] Mol. Pharmaceutics 2023, 20, 4, 2217-2234

Hydrodynamic Radii of stable ASD polymers, compared to measured micelle radii for physiologically relevant concentrations of bile salts.

Effect of API partitioning into staple ASD polymer colloids.

Biorelevant dissolution results of ITZ formulations. Solid lines with diamonds are HME, while dashed lines with circles are SDDs. Both neat ASD powders and fully formulated tablets are compared for two ASD formulations - 25% ITZ in HPMCAS-M or PVP-VA K64 (orange or blue, respectively).