(M0930-07-46) Enhancing the Solubility of Sotorasib (AMG-510) with the Acid-Base Supersolubilization (ABS) Approach to Formulate ASDs by Hot Melt Extrusion

Purpose: Sotorasib, STR (AMG-510), is the first in class, small-molecule inhibitor of KRAS^G12C, approved by the FDA for treating certain non-small cell lung cancer (NSCLC), with a recommended dose of 960 mg/day. Sotorasib is a weakly basic BCS class IV compound with a high molecular weight of 560.06 g/mol and a high melting point of 290 °C. It has a pK_a of 4.56, showing high pH-dependent solubility of 1.3 mg/mL at pH 2.0 to 0.03 mg/mL at pH 6.8. Although the solubility is considerably high in gastric pH, as it transits to the small intestine, it causes precipitation and reduces the absorption of the drug (Zhang et al., 2022). To address these challenges, amorphous solid dispersions (ASDs) can be developed using hot melt extrusion (HME), a solvent-free continuous manufacturing technique. However, HME faces limitations with high melting point drugs like Sotorasib due to polymer thermal instability above 200°C (Huang et al., 2019). We are implementing acid-base super solubilization (ABS) strategy using a non-salt forming weak acid, glutaric acid (GA), to create high-energy amorphous systems through molecular interactions. This approach lowers the melting point, reduces extrusion temperature during HME processing while enhancing the drug’s supersaturation and dissolution kinetics across the pH range of the gastrointestinal tract. This concept of ABS was successfully employed in our previous studies to enhance the solubility of weakly basic drugs like Haloperidol (Singh et al., 2013). This approach can enhance aqueous solubility beyond the expected maximum, leading to supersolubilization, forming an amorphous system. Thus, it helps to achieve the goal of this study to develop a pH-independent oral formulation for Sotorasib by leveraging the ABS approach with GA as a super-solubilizing agent and employing HME for the ASD preparation. The resulting ASDs were evaluated for solubility and dissolution improvement.

Methods: Solubility of Sotorasib was performed in the presence of glutaric acid as a function of increasing acid concentration using the shake flask method. Later, a miscibility study was conducted of different molar ratios of 1:10, 1:20, and 1:40 (Sotorasib: GA) using hot stage microscopy (HSM) equipped with polarized light microscopy (PLM) with a heating rate of 5°C/ min to identify the temperature for complete amorphization of the drug. Further, solid state characterization of the melt-processed samples was milled, and solid-state characterization was performed to determine the amorphous or crystalline nature using DSC (differential scanning calorimetry) and powder X-ray diffraction (PXRD). The in vitro dissolution testing was performed using the USP dissolution apparatus II, in a flat-bottom dissolution bowl at 50 RPM and 37°C, with 25 mg drug equivalents in 250 mL of dissolution media of pH 6.8.

Results: The preliminary solubility of Sotorasib in water was observed to be ~40 mg/g of GA by applying the ABS concept. Further, the HSM-PLM microscopic qualitative evaluation was performed, and a complete melting of STR was observed at 190 °C for a 1:10 molar ratio of drug to GA. Interestingly, upon an increase in the molar ratio of GA, a drastic reduction in the melting of the drug was observed at 120 °C for a 1:20 molar ratio, as shown in Figure 2. Based on these preliminary findings, the drug was processed by the melt and mold method along with HPMC AS L-grade to obtain ASDs with a 5% drug load. The amorphous nature of these ASDs was confirmed via DSC and PXRD, as shown in Figure 3. The 1:40 showed GA peaks, indicating that an excess of GA is present in the ASDs. These ASDs were milled using the analytical mill, and a 25 mg drug equivalent dose was evaluated by in vitro dissolution, showing a linear release of ~70% (17.5 mg) of the drug. However, with fasted simulated conditions, having 3 mM bile salt provided ~100% release (25mg). These results demonstrate the potential of the ABS approach using GA for lowering the processing temperature to produce ASDs for Sotorasib using HME for improved solubility and oral bioavailability.

Conclusion: The ABS is a promising approach for weakly basic drug Sotorasib by using a weak acid such as glutaric acid. The ABS principle offers a potential advantage for developing amorphous solid dispersions (ASDs) using HME for high-melting-point drugs like Sotorasib. The oral formulation developed using this approach also demonstrated pH-independent solubility across the gastrointestinal pH range (1.2- 6.8), effectively enhancing the solubility of weakly basic drugs like Sotorasib.

References: Huang, D., Xie, Z., Rao, Q., Liamas, E., Pan, P., Guan, S., Zhang, Z.J., Lu, M., Li, Q., 2019. Hot melt extrusion of heat-sensitive and high melting point drug: Inhibit the recrystallization of the prepared amorphous drug during extrusion to improve the bioavailability. Int. J. Pharm. 565, 316–324. https://doi.org/10.1016/j.ijpharm.2019.04.064
Singh, S., Parikh, T., Sandhu, H.K., Shah, N.H., Malick, A.W., Singhal, D., Serajuddin, A.T.M., 2013. Supersolubilization and amorphization of a model basic drug, haloperidol, by interaction with weak acids. Pharm. Res. 30, 1561–1573. https://doi.org/10.1007/s11095-013-0994-7
Zhang, L., Griffin, D.J., Beaver, M.G., Blue, L.E., Borths, C.J., Brown, D.B., Caille, S., Chen, Y., Cherney, A.H., Cochran, B.M., Colyer, J.T., Corbett, M.T., Correll, T.L., Crockett, R.D., Dai, X.-J., Dornan, P.K., Farrell, R.P., Hedley, S.J., Hsieh, H.-W., Huang, L., Huggins, S., Liu, M., Lovette, M.A., Quasdorf, K., Powazinik, W.I., Reifman, J., Robinson, J.A., Sangodkar, R.P., Sharma, S., Kumar, S.S., Smith, A.G., St-Pierre, G., Tedrow, J.S., Thiel, O.R., Truong, J.V., Walker, S.D., Wei, C.S., Wilsily, A., Xie, Y., Yang, N., Parsons, A.T., 2022. Development of a Commercial Manufacturing Process for STR, a First-in-Class KRASG12C Inhibitor. Org. Process Res. Dev. 26, 3115–3125. https://doi.org/10.1021/acs.oprd.2c00249


Schematic representation of Sotorasib solubility limitations and its enhancement through acid-base supersolubilization to formulate as ASDs with Hot Melt Extrusion (HME) for improved oral bioavailability.


HSM-PLM images of physical mixtures of Sotorasib and glutaric acid with molar ratios of (a)1:10 (STR: GA), exposed with a temperature range of 30 to 190 °C, and (b)1:20 (STR: GA), exposed with a temperature range of 30 to 120 °C.


Represents (A) DSC scans from a temperature range of 50 to 325 °C and (B) PXRD patterns for a 2 Theta range of 10-40 degrees of pure Sotorasib and melt processed (STR: GA ) with molar ratios of 1:10, 1:20, 1:40.