(M1030-09-57) Investigation of Nintedanib Formulation Development: Systematic Screening from pH Solubility Assessment to Sodium Fatty Acid Salt-Polymer Optimization

Purpose: The aim of this study was to develop a formulation for nintedanib, a poorly water-soluble drug whose solubility drastically decreases at pH 6.8 and in water. We systematically screened sodium fatty acid salt or organic acid with polymer combinations to improve formulation solubility. The study established an optimized ternary formulation that enhances solubility and inhibits gelation, and evaluated its solubility and dissolution performance.

Methods: Initial solubility screening was performed at various pH conditions (1.2, 4.0, 6.8, 7.4) to identify the pH-dependent solubility problem. Excipient screening was performed in 1% w/v solutions at pH 6.8. All formulations were prepared by solvent evaporation method and dried in an oven at 75°C. Binary formulation (F1) of nintedanib (50 mg) and sodium decanoate (250 mg) was evaluated. Polymer screening formulations (F2-F10) were prepared with nintedanib (50 mg), sodium decanoate (250 mg), and various polymers (600 mg) including Poloxamer 188, Poloxamer 407, Kolliphor SLS, PVA 80-89%, HPMCP HP50, Eudragit S100, Eudragit L100, HPMCP_HP50. Poloxamer 188 ratio optimization formulations (F11-F15) were prepared at various concentrations (600, 500, 400, 300, 200, 100 mg) with nintedanib (50 mg) and sodium decanoate (250 mg). Sodium fatty acid screening formulations (F16-F19) were prepared with varying sodium fatty acids salt(decanoate, octanoate, oleate, propionate, hexanoate, myristate) at 50:250:200 mg ratio with poloxamer 188. Organic acid screening formulations (F20-F24) were prepared with varying fatty acid salts (L(+)-ascorbic acid 99.5%, fumaric acid 99%, DL-malic acid 99.0%, citric acid anhydrous 99.5%, L(+)-tartaric acid 99.5%) at 50:250:200 mg ratio with poloxamer 188. Solubility evaluation was performed at pH 6.8 for all formulations. Visual assessment was performed to evaluate formulation appearance and physical stability after drying. Optimal formulation was selected based on solubility performance and physical characteristics. Physicochemical characterization was performed using DSC, PXRD, FT-IR, and FE-SEM. Tablets were prepared by direct compression for manufacturability assessment. Dissolution testing was performed using the paddle method in pH 6.8 medium (900 mL, 50 rpm) with sampling at 5, 10, 15, 30, 60, 90, and 120 minutes. Dissolution release profiles were compared between the optimized formulations containing either organic acid or fatty acid salts (F18, F24) with synergistic effects, nintedanib API in gelatin capsules, and the reference drug product soft capsules. The release patterns of the reference drug product and nintedanib capsules were thoroughly examined in four dissolution media for equivalence testing. Gelation was evaluated by swelling and erosion.

Results: Initial pH solubility screening confirmed intestinal pH issue, with nintedanib showing good solubility at acidic pH but no detectable solubility at pH 6.8 and 7.4. Excipient screening at pH 6.8 identified sodium decanoate as the most effective solubilizer (537.33 ± 152.69 µg/mL). Binary formulation (F1) of nintedanib and sodium decanoate alone showed no detectable solubility, necessitating polymer addition. Polymer screening (F2-F10) identified Poloxamer 188 as the most suitable carrier among tested polymers (755.36 ± 25.61 µg/mL) (Fig. 2). Poloxamer 188 optimization (F11-F15) revealed that 200 mg provided the highest solubility among tested concentrations (600-100 mg) with 1010.90 ± 32.94 µg/mL, establishing the optimal 50:250:200 mg ratio (Fig. 1). Using this optimized ratio, sodium fatty acid screening formulations (F16-F19) and organic acid screening formulations (F20-F24) were prepared to identify the optimal combination through comprehensive screening. Solubility evaluation showed that F16 (sodium decanoate) maintained the highest solubility performance among all tested formulations. Visual assessment after drying revealed that some organic acid-based formulations (F22-F24) formed gel-like structures unsuitable for further development, while sodium fatty acid formulations (F16-F19) and other organic acid formulations (F20-F21) maintained suitable solid dispersion characteristics (Fig. 3). Although other organic acids were also evaluated, F16 formulation demonstrated the optimal combination of superior solubility performance and suitable physical characteristics, making it the most suitable candidate. The optimized F16 formulation maintained high solubility performance, showing excellent solubility enhancement and complete resolution of the intestinal pH solubility challenge. Visual evaluation confirmed no gelation or precipitation occurred with F16 dispersion. Solid-state analysis confirmed complete amorphization of nintedanib with absence of crystalline peaks (PXRD), increased glass transition temperature (DSC), and hydrogen bonding between drug and excipients (FT-IR). Surface morphology analysis (FE-SEM) showed uniform distribution. Dissolution testing of existing formulations revealed that reference drug product showed no detectable release while nintedanib API achieved only 3.81% release at 2 hours in pH 6.8 medium, confirming the poor performance of current options. The F16 formulation maintained physicochemical stability and showed excellent tabletability with consistent tablet properties (diameter 9.0 mm, height 7.84 ± 0.10 mm, weight 512.32 ± 5.49 mg).

Conclusion: The optimized fatty acid salt-polymer combination formulation composed of nintedanib, sodium decanoate, and poloxamer 188 resolved the intestinal pH solubility challenge, achieving superior solubility compared to existing formulations that showed poor dissolution performance. The formulation demonstrated excellent physicochemical stability, effective gelation inhibition, and practical manufacturability. This ternary dispersion offers a clinically relevant strategy for enhancing oral bioavailability of poorly water-soluble drugs exhibiting pH-dependent precipitation, potentially improving therapeutic outcomes for nintedanib therapy.

References: Qin, Yuling, et al. "Enteric polymer–based amorphous solid dispersions enhance oral absorption of the weakly basic drug Nintedanib via stabilization of Supersaturation." Pharmaceutics 14.9 (2022): 1830.
Liu, Shuyin, et al. "Preparation, Characterization and Evaluation of Nintedanib Amorphous Solid Dispersions with Enhanced Oral Bioavailability." AAPS PharmSciTech 25.6 (2024): 183.
Zhang, Jie, et al. "Advances in the development of amorphous solid dispersions: The role of polymeric carriers." Asian journal of pharmaceutical sciences 18.4 (2023): 100834.

Acknowledgements: This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education (RS-2023-00245029).

Figure 1. Effect of different polymers on solubility of solid dispersions at pH 6.8.
Various solid dispersions (F1–F10) were prepared using nintedanib esylate (50 mg) and sodium decanoate (250 mg) with different polymers (600 mg each), including Poloxamer 188, Poloxamer 407, Kolliphor SLS, and enteric polymers. The solubility at pH 6.8 was significantly improved in F2 (Poloxamer 188) with 755.36 µg/mL, while other formulations exhibited poor solubility or complete precipitation.


Figure 2. Solubility optimization of solid dispersions by adjusting Poloxamer 188 content at pH 6.8.
Formulations F11–F15 were prepared with fixed amounts of nintedanib esylate (50 mg) and sodium decanoate (250 mg), while Poloxamer 188 content was varied from 600 mg to 100 mg. The highest solubility (1010.90 µg/mL) was observed in F14, containing 200 mg of Poloxamer 188, indicating that this ratio (50:250:200) is optimal for enhancing solubility at pH 6.8.

Figure 3. Acid used in each formulation (F14–F24): Each formulation contains nintedanib esylate (50 mg), acid (250 mg), and Poloxamer 188 (200 mg). The acids used are:Sodium Decanoate (F14), Sodium Octanoate (F15), Sodium Oleate (F16), Sodium Propionate (F17), Sodium Hexanoate (F18), Sodium Myristate (F19), L(+)-Ascorbic acid (F20), Fumaric acid (F21), DL-Malic acid (F22), Citric acid anhydrous (F23), and L(+)-Tartaric acid (F24).