(M1330-10-59) Dissolution Method Development for Amorphous Solid Dispersions-Based Oral Drug Products

Purpose: Dissolution methods are developed to reflect the performance of drug product. However, developing an appropriate in vitro dissolution test able to attain sink conditions, proper discriminatory capability and complete API release can be challenging. This difficulty increases when dealing with amorphous solid dispersions (ASDs) containing BCS Class II or IV API, polymer and eventually surfactants. This introduces many additional factors not considered in the equilibrium API solubility testing commonly carried out during dissolution method development. Furthermore, conditions such as  pH and dissolution medium composition have a great impact on the API solubility and therefore dissolution profile. The aim of this study was to understand the impact of key dissolution method conditions such as dissolution media pH and molarity, and surfactant and infer on how they impact the solubility behavior of a neutral API (Celecoxib, CLX; BCS Class II). For this study, solubility studies were carried out to both crystalline CLX and ASDs of CLX prepared with polyvinylpyrrolidone (PVPVA) at 50:50 ratio. This interplay aims at understanding what should be the method’s CQAs, that should be studied upfront, everytime a QC Dissolution method is required. This understanding will guide and improve the robustness of these type of methods as well as be a thorough support for CMC teams, throughout the product lifecycle.

Methods: ASD of CLX and PVPVA were prepared by spray-drying (SD) and its amorphous form confirmed by XRPD. Solubility of crystalline CLX and CLX ASD was measured in 0.1N Hydrochloric acid (HCl) pH=1.2, Acetate Buffer (AB) pH=4.5 and Sodium Phosphate Buffer (SPB) pH=6.8. Different molarities (25, 50 and 150 mM) and surfactants were evaluated (Sodium Lauryl Sulphate (SLS), Cetyltrimethylammonium bromide (CTAB), Tween 20 and Triton X-100 (TX-100)) at different Critical Micelle Concentrations (CMC) – 1 and 5x (%w/w), using a shake flask methodology. The solubility tests were carried out at 37 ºC and aliquots were collected at 1, 4, and 24 hours and centrifuged at 13 400 rpm for 15 minutes. The experiments were performed in triplicate.

Results: Crystalline CLX showed to have the highest equilibrium solubility in 0.1N HCl medium (0.05 SI) and lowest solubility in 150 mM SPB and 25 mM AB (0.02 SI). In solubility studies carried out to the ASD, pH of the buffers did not play any role, but molarity did. In detail, CLX amorphous solubility with SPB prepared with 150 mM showed the lowest solubility (0.05 SI versus 0.07-0.09 SI obtained for the other buffers pHs and molarities). Nevertheless, the obtained SI were too low for both crystalline CLX and ASD and therefore, the inclusion of surfactants to develop a QC dissolution test for this API is crucial. In dissolution media with surfactants at 1x CMC, the impact of the surfactant on increasing crystalline API solubility showed the following ranking order SLS > CTAB > TX-100 > Tween 20, regardless of the buffer’s pH. On the other hand, in amorphous CLX, the highest solubility was obtained for 50 mM SPB + SLS (0.7 SI), followed by 0.1N HCl medium + CTAB (0.6 SI), showing that surfactants had different performances in different buffer’s pH. This observation may be related with the different type of interactions between the polymer in ASD, the media pH and type of micelles formed with the surfactant [1,2]. When increasing the CMC of SLS and CTAB surfactants to 5x the CMC, the impact of the buffer pH was diluted by the improvement of solubility enhancement promoted by the surfactants. At these CMC, SLS showed to improve solubility of both crystalline and amorphous API at the same level (3.0 SI). This similar value for both crystalline API and ASD CLX solubility may lead to a non-discriminatory dissolution method between the ASD and crystalline API formulations. On the other hand, CTAB promoted a solubility increase of crystalline CLX to 2.0 SI in 50 mM SPB and 3.5 SI in amorphous ASD, which is a 1.7-fold increase.

Conclusion: This study allowed to confirm the different impact of pH, molarity and surfactants on crystalline and amorphous solubility and that the presence of the polymer in the CLX ASD may play a role in dissolution media choice. Amorphous and crystalline CLX in CTAB at 5 x CMC in SPB perform differently which may allow the ASDs to have a discriminatory power to its crystalline counterpart but also achieve a plateau at about 100% release due to sink conditions that were achieved at these conditions.

References: [1] Indulkar AS, Mo H, Gao Y, Raina SA, Zhang GGZ, Taylor LS. Impact of Micellar Surfactant on Supersaturation and Insight into Solubilization Mechanisms in Supersaturated Solutions of Atazanavir. Pharm Res. 2017 Jun;34(6):1276-1295. doi: 10.1007/s11095-017-2144-0. Epub 2017 Mar 28. PMID: 28352994.
[2] Yang R, Zhang GGZ, Kjoller K, Dillon E, Purohit HS, Taylor LS. Phase separation in surfactant-containing amorphous solid dispersions: Orthogonal analytical methods to probe the effects of surfactants on morphology and phase composition. Int J Pharm. 2022 May 10;619:121708. doi: 10.1016/j.ijpharm.2022.121708. Epub 2022 Mar 29. PMID: 35364219.