(M1130-12-80) Preparation and Characterization of Alectinib Amorphous Solid Dispersion Using a Novel Polymer Apinovex™ to Enhance Solubility and Dissolution

Purpose: Alectinib (ALB) is a kinase inhibitor prescribed to treat patients diagnosed with metastatic non-small cell lung cancer that is anaplastic lymphoma kinase (ALK)-positive and who have either experienced cancer progression while taking crizotinib or have poor tolerance to crizotinib. ALB has low permeability, low solubility (BCS-Class IV), and bioavailability of 36.9% with food. The current formulation consists of 150 mg capsules, with a recommended dosage of 600 mg taken twice daily. This implies that patients would need to consume 8 capsules/day, which can be burdensome. The reason for this relatively high dosage recommendation is attributed to the compound's limited solubility, resulting in reduced bioavailability. Therefore, to decrease the necessary dosage, it is imperative to address the solubility issue, and one potential method to enhance solubility involves making amorphous solid dispersions (ASDs). Apinovex™, developed by Lubrizol, is a polymeric excipient composed of high molecular weight polyacrylic acid that are designed to offer advantages in both processing and formulation when creating ASDs. This polymer was selected for producing ALB ASDs as it holds promise in enhancing the solubility of BCS Class II and IV APIs while allowing for higher and stable drug loading. The objective of this project is to utilize different ratios of ALB to Apinovex™ to optimize a stable formulation with maximum drug loading with the goal of improving ALB solubility.

Methods: The ASDs were prepared at drug loadings of 10, 20, 30, 40, 60, 70, and 80% in polymer, using a mixture of methanol and chloroform as a solvent system. The solvent was evaporated on a rotary evaporator leaving a solid mass that was made into a powder (Fig. 1). Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction (PXRD) techniques were used to assess the extent of drug amorphization of prepared formulations. The drug loadings that yielded successful ASDs were assessed for solubility using the shake-flask method, which comprised adding excess amount of ASDs in various media, including 0.1 N HCl, pH 6.8 phosphate buffer, FaSSGF, FaSSIF-V2, and FeSSIF-V2 for 24 hours. The stability studies of ASDs were performed as per ICH stability guidelines (i.e., 25±2˚C/ 60±5% RH and 40±2 ˚C/ 75±5% RH).

Results: DSC and PXRD studies were carried out for the prepared ASDs and there was no endothermic and crystalline peak corresponding to crystalline ALB observed (Fig. 2) in 10, 20, 30, 40, and 60% ASDs, which indicates a conversion to an amorphous state from crystalline state. However, endothermic and crystalline peaks were observed in the 70& 80% ASDs, which may be ascribed to the presence of crystalline drug implying that the polymer could not hold all the drug. The solubility studies of 20, 40 & 60% ASDs and ALB pure drug showed an increase in solubility in various dissolution media (Fig. 3). The solubility of ASDs increased significantly with an increase in polymer content. ALB pure drug solubility was determined in 0.1 N HCl, pH 6.8 phosphate buffer, FaSSGF, FaSSIF-V2, and FeSSIF-V2, where solubilities were, 0.00, 1.02, 4.61, 0.16, and 8.81 µg/mL, respectively. As for the ASDs, the solubility of the 20% formulation was found to be 21.90, 7.94, 23.52, 8.03, 393.91 µg/mL, in 0.1 N HCl, pH 6.8 phosphate buffer, FaSSGF, FaSSIF-V2, FeSSIF-V2 media, respectively. The solubility of the 40% ASDs demonstrated a comparable increase to that of the 20% ASDs, resulting in a concentration of 347.92 µg/mL in FeSSIF-V2 media. However, the 60% ASDs showed an insignificant improvement in drug solubility in any of the media with only 4.86, 0.05, 5.68, 1.6, 32.66 µg/mL, in 0.1 N HCl, pH 6.8 phosphate buffer, FaSSGF, FaSSIF-V2, FeSSIF-V2 media, respectively. There was no crystallization of ALB in 20, 40 & 60% of ASDs exposed to 25˚C/60%RH and 40˚C/75%RH for 2 months as there were no endotherms in DSC scans and drug content analysis revealed that there was no degradation of ALB. Preliminary dissolution studies in FeSSIF-V2 indicate 75% drug release for 40% ASD in 2 hours that maintained saturation for 1.5 hours before any precipitation was visible. Ongoing studies include testing the 20% and 60% ASD for dissolution and investigating the particle size in dissolution media.

Conclusion: Amorphous solid dispersions of ALB were successfully developed by solvent evaporation technique. The developed formulation presented ALB in a stable amorphous state which resulted in increased drug solubility. It was observed that with an increase in the concentration of Apinovex ™ in the formulation, the solubility of ALB increased. 20% ASD exhibited the highest solubility among other ASD’s in all the media. The solubility of the developed formulations was improved; therefore, the dissolution and bioavailability can potentially be improved.

Figure 1. ASD preparation and optimization. a. Schematic representation of ASD preparation (Created with BioRender.com). b. Composition of amorphous solid dispersions prepared by rotary evaporator.

Figure 2. Solid state characterization a. Differential scanning calorimetry (DSC) thermograms b. Powder X-Ray Diffraction (PXRD) diffractograms of various ASDs.

Figure 3. Saturation solubility of API, 20% ASD, 40% ASD & 60% ASD. a. Saturation solubility in 0.1 N HCl b. Saturation solubility in phosphate buffer -pH 6.8 c. Saturation solubility in FaSSGF d. Saturation solubility in FaSSIF-V2. e. Saturation solubility in FeSSIF-V2 f. Mean saturation solubility table