(T1530-10-57) Impact of Counterions on the Performance of Spray-Dried Dispersions of Weak Base Drugs

Purpose: Salt formulations are commonly used in pharmaceutical formulations to enhance the solubility, stability, and bioavailability of poorly water-soluble drugs. By forming salts, the physicochemical properties of these drugs can be optimized, improving their performance in the oral dosage forms. Similarly, spray-dried dispersions (SDDs) have also been widely utilized over the past two decades to improve the solubility, dissolution, and bioavailability of such drugs. Several researchers have found that adding salts to the SDD can significantly impact their physicochemical properties and dissolution performance.^1-5 However, the impact and role of salts in SDDs have not been fully understood. This study investigated the impact of counterions on the properties of SDDs with poorly water-soluble weak base drugs. The primary objective is to understand how methanesulfonic acid (MSA) and hydrochloride (HCl) in SDD formulations influence the dissolution and diffusion flux of Dipyridamole and Itraconazole. By exploring these effects, we aim to enhance the dissolution and diffusion flux by incorporating suitable salts into the SDD formulation, ultimately improving their bioavailability. The findings from this study will provide valuable insights into optimizing the formulation of SDDs with salt for better drug delivery performance. Additionally, this research will enhance our overall understanding of the roles of counterion in pharmaceutical sciences, supporting future advancements in SDD.

Methods: The two model drugs, Dipyridamole (pKa 6.4) and Itraconazole (pKa 3.7), were formulated with and without a 1:1 molar ratio of MSA (pKa -1.9) and a 1:1; 1:2 molar ratio of HCl (pKa -6) in a polymer matrix. The mixtures, containing 25% drug and 75% hydroxypropyl methylcellulose acetate succinate (HPMCAS-MG), were spray-dried using a Bend mini spray dryer under controlled conditions to produce SDDs. Characterization techniques for these SDDs included polarized light microscopy and scanning electron microscopy (SEM) to analyze morphology, differential scanning calorimetry (DSC) to assess thermal properties, and X-ray powder diffraction (XRPD) to evaluate crystallinity. Additionally, the SDDs were formulated into a suspension vehicle to conduct the MicroDISS flux studies using the Pion MicroDISS Profiler. The dissolution and flux behaviors of the SDDs were measured via ultra-performance liquid chromatography (UPLC). All studies were conducted in triplicate, ensuring the reliability and reproducibility of the results.

Results: Scanning electron microscopy (SEM) and polarized light microscopy revealed that the spray-dried dispersions (SDDs) of Dipyridamole and Itraconazole, both with and without salts, produced spherical particles. Differential scanning calorimetry (DSC) analysis showed that SDDs with MSA had a relatively lower glass transition temperature (Tg) in both Dipyridamole and Itraconazole, whereas those with HCl had a relative higher Tg in Dipyridamole but almost the same Tg in Itraconazole with and without HCl. X-ray powder diffraction (XRPD) confirmed that these SDDs were amorphous. Both SDDs were stable in a suspension vehicle containing 5% PVPVA-64 35% PEG-400 65% Water over 24 hours. The particle size distribution in the suspension vehicle was consistent across all SDDs. In the Pion MicroDISS flux studies, the donor dissolution was significantly improved in the presence of MSA in the Dipyridamole SDD, which also translated into a higher diffusion flux rate. The SDDs with HCl exhibited slightly enhanced dissolution; however, the flux rate was almost the same compared to the free base SDD. This suggests that while HCl can improve the initial dissolution rate, it does not significantly impact the overall flux rate of the drug compared to MSA. These results highlight the importance of selecting appropriate counterions in optimizing the performance of SDD formulations.

Conclusion: This study demonstrates that incorporating MSA as a counterion significantly enhances the dissolution and diffusion flux of Dipyridamole SDDs, which can potentially lead to improved bioavailability. While HCl slightly improves dissolution rates, it does not substantially affect the flux rate compared to the free base SDD. These findings highlight the potential of using counterions like MSA and HCl to optimize the formulation of SDDs. These findings also highlight the critical role of counterion selection in optimizing SDD formulations for better drug delivery performance. The choice of counterion in SDD critically affects the physical and chemical properties of the final product. Further research could explore the long-term stability and in vivo performance of these formulations to fully understand their performance and non-clinical benefits.

References: 1. Tu Van Duong, Hanh Thuy Nguyen, Lynne S. Taylor. "Combining enabling formulation strategies to generate supersaturated solutions of delamanid: In situ salt formation during amorphous solid
dispersion fabrication for more robust release profiles." European Journal of Pharmaceutics and Biopharmaceutics, 2022, 174, 131–143.
2. Tze Ning Hiew , Lynne S. Taylor "Combining drug salt formation with amorphous solid dispersions – a double edged sword." Journal of Controlled Release, 2022, 352, 47–60.
3.Yinshan Chen, Joseph W. Lubach, Shijia Tang, Ajit S. Narang. "Effect of Counterions on Dissolution of Amorphous Solid Dispersions Studied by Surface Area Normalized Dissolution." Molecular Pharmaceutics, 2021, 18, 3429-2438.
4. Helen J. Zhang, Cheng W. Chiang, Tristan Maschmeyer-Tombs, Breanna Conklin, Jose G. Napolitano,
Joseph W. Lubach, Karthik Nagapudi, Chen Mao, Yinshan Chen. "Generality of Enhancing the Dissolution Rates of Free Acid Amorphous Solid Dispersions by the Incorporation of Sodium Hydroxide." Molecular Pharmaceutics, 2024, 21, 7, 3395–3406
5. Sumit Mukesh, Prachi Joshi, Arvind K. Bansal, Mahesh Chand Kashyap, Sanjay K. Mandal, Vasant Sathe, Abhay T. Sangamwar "Amorphous Salts Solid Dispersions of Celecoxib: Enhanced
Biopharmaceutical Performance and Physical Stability." Molecular Pharmaceutics, 2021, 18, 2334−2348.