Enhanced solubility and dissolution of Alectinib via amorphous solid dispersion with a novel polymer, Apinovex™

Abstract

Alectinib (ALB) is a kinase inhibitor typically used for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer. The objective of the current study was to improve the solubility and dissolution of ALB, a poorly water-soluble drug, by formulating into an amorphous solid dispersion (ASD) using Apinovex^TM, a novel high molecular weight polyacrylic acid polymer. ASDs were prepared by the rotary evaporation technique with varying weight ratios of ALB and Apinovex™. Samples with up to 60 % ALB in ASDs displayed amorphous state of ALB in the formulation when analyzed via powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). Further, 40 % ALB ASD showed increased solubility and dissolution in FaSSGF, FaSSIF-V2, and FeSSIF-V2 media. Stability studies for 40 % ALB ASD formulation were conducted at room temperature (25 ± 2 ˚C/ 60 ± 5 % RH) and accelerated conditions (40 ± 2 ˚C/ 75 ± 5 % RH), and results showed stability up to 6 months, as demonstrated by drug content, DSC, PXRD, and dissolution. The observed increase in solubility and dissolution in bio-relevant media suggests potential for improved in vivo absorption, especially in the fed-state. These findings support the use of solid dispersion as a strategy to enhance the bioavailability of ALB.

Introduction

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 (Larkins et al., 2016, Parrott et al., 2016, Morcos et al., 2017c). ALB is a weakly basic molecule with a pKa value of 7.05 (Parrott et al., 2016), a molecular weight of 482.62 g/mol (Zhao et al., 2020), and a log P value of 1.96 (Parrott et al., 2016). It is a BCS-Class IV drug with low aqueous solubility across the gastrointestinal pH range of 1–8 and low permeability (Parrott et al., 2016). Alectinib solubility is higher in fed-state simulated intestinal fluid (FeSSIF) than the fasted-state simulated intestinal fluid (FaSSIF), indicating a potential food effect (Parrott et al., 2016). Alecensa® is a commercially approved 150 mg ALB-containing oral capsule with a recommended therapeutic dose of 600 mg twice daily with food (four 150 mg capsules) (Larkins et al., 2016, Morcos et al., 2017c, Parrott et al., 2016). To improve ALB’s low solubility and bioavailability (about 36.9 %), particle size is controlled (4 μm) and sodium lauryl sulfate (SLS) is added as a solubilizing agent (Morcos et al., 2017b). Administration of daily dose results in an ingestion of 600 mg SLS, which is higher than the daily intake of SLS in other oral products previously approved by the Food and Drug Administration, raising safety concerns (Larkins et al., 2016). The labeling of Alecensa® recommends that it be taken with food to improve GI tolerability for SLS and bioavailability (Morcos et al., 2017a). Despite this, the commonly reported side effects are constipation and irritation in the GI tract due to its high SLS content (Larkins et al., 2016). Considering these challenges and the drugs’ low bioavailability, there is a compelling necessity for alternate formulations that potentially increase ALB solubility and reduce or eliminate SLS.

A significant obstacle in creating oral dosage forms for poorly water-soluble drugs is improving the low aqueous solubility (Siriwannakij et al., 2021). Toward this, a multitude of novel techniques have been developed, such as salts, co-crystals, lipid formulations, complexation, nanoparticles, co-solvents, and amorphous solid dispersions (ASDs) (Jackson, 2015, Siriwannakij et al., 2021). Among these techniques, formulating ASDs is more popular (Iyer et al., 2021). An ASD is a system where one or more active pharmaceutical ingredients (APIs) are molecularly dispersed in an amorphous polymeric carrier (Huang and Dai, 2014, Siriwannakij et al., 2021). Combining amorphous drugs with a suitable polymer raises the glass transition temperature (Tg), thereby decreasing molecular mobility, preventing nucleation and crystal growth (Huang and Dai, 2014, Iyer et al., 2021). In addition, ASDs prevent drug recrystallization during the dissolution process (Ilevbare et al., 2013a). ASDs generate a stable, long-lasting supersaturated solution upon mixing with the gastrointestinal fluid that, in turn, creates a higher flux across the intestinal membrane. ASD formulations exhibit a phenomenon known as liquid–liquid phase separation (LLPS), which occurs when the drug’s amorphous solubility is exceeded, resulting in excess drug separating from the solution and forming nanosized amorphous drug-rich droplets (Ilevbare et al., 2013a). During in vivo drug absorption, these drug-rich droplets can serve as a drug reservoir, replenishing dissolved drug in the intestinal lumen that has been absorbed, thereby maintaining the solute activity and, hence, maximum flux across the membrane and high bioavailability (Frank et al., 2012, Ilevbare et al., 2013a, Ilevbare et al., 2013b). Several studies have outlined that preparing ASDs can significantly increase the solubility and bioavailability of poorly water-soluble drugs. Wilson et al. demonstrated that the ASDs prepared using CPHPC-106 polymer (5-Carboxypent-1-yl Hydroxypropyl Cellulose) improved the bioavailability of enzalutamide by 5-fold compared to its crystalline form (Wilson et al., 2020). In addition, in vitro dissolution studies of electrosprayed ASD formulations exhibited ≥ 7.7-fold improved dissolution over those of crystalline celecoxib (Fan et al., 2025).

Previous formulation strategies to improve the solubility and dissolution of ALB have employed both ASDs and suspended self-nanoemulsifying drug delivery systems (Su-SNEDDS). For instance, Saha et al. developed a third-generation ASD using ALB: Soluplus® at a 1:5 ratio with 5 % poloxamer 407, achieving a drug loading of 15.83 % and this formulation showed approximately a 2-fold increase in dissolution in FaSSIF media compared to the pure ALB (Saha et al., 2023). In another approach, Park et al. formulated a Su-SNEDDS using 10 % Capmul MCM C8 and 90 % Kolliphor HS 15 with a drug loading of 10 % and achieved a 20-fold increase in dissolution compared to the free drug in 1 % SLS pH 1.2 buffer (Park et al., 2022). Despite these improvements, the low drug loading in both systems requires a large amount of excipient, which increases dosage size, making it difficult for the patient to swallow the oral dosage form. Therefore, enhancing ALB drug loading is essential to reduce the pill burden and improve the practicality of oral dosage forms.

To address this challenge, the present study explores the use of Apinovex™, a novel polymeric excipient developed by Lubrizol. Apinovex™ is a high molecular weight polyacrylic acid (PAA) (Marino, 2024) with a high glass transition temperature (Tg) , which enhances the overall Tg of the drug-polymer mixture (Lubrizol). PAA is an acidic polymer with a pKa of 4.5 (Yu et al., 2022). The carboxylic acid groups of PAA function as proton donors, facilitating pH-dependent solubility and interactions with the drug molecule (Mistry et al., 2015, Yu et al., 2022). These interactions enhance the solubility and stability of the drug in the amorphous state (Mistry et al., 2015). Notably, Apinovex™ has demonstrated the capability to support drug loading up to 80 % (Lubrizol). Accordingly, the present study aims to develop an ASDs of ALB using Apinovex™. Various ratios of ALB to Apinovex™ were formulated and characterized to identify a stable formulation with maximum drug loading and improved solubility.

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Materials

Alectinib anhydrous (ALB) was purchased from LC Laboratories (MA, USA). The API was characterized by Differential Scanning Calorimetry upon receipt, showing a melting point of 205 °C, corresponding to a specific polymorphic form of the free base. Apinovex™ polymer was generously gifted by Lubrizol Life Sciences (PA, USA). Fig. 1 shows the chemical structures of ALB and Apinovex™ polymer. Ortho-phosphoric acid (OPA), hydrochloric acid, potassium phosphate monobasic anhydrous, sodium phosphate.

Parasharamulu Kommarajula, Vasudha Prithipaul, Nitesh K. Kunda, Enhanced solubility and dissolution of Alectinib via amorphous solid dispersion with a novel polymer, Apinovex™, International Journal of Pharmaceutics, Volume 690, 2026, 126551, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.126551.

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