Abstract
Tolterodine tartrate (TOTA) is associated with adverse effect, high hepatic access, varied bioavailability, slight aqueous solubility, and short half-life after oral delivery. Hansen solubility parameters (HSP, HSPiP program), experimental solubility (T = 298.2 to 318.2 K and p = 0.1 MPa), computational (vanʼt Hoff and Apelblat models), and thermodynamic models were used to the select solvent(s). HSPiP predicted PEG400 as the most suitable co-solvent based on HSP values (δd = 17.88, δp = 4.0, and δh = 8.8 of PEG400) and comparable to the drug (δd = 17.6, δp = 2.4, and δh = 4.6 of TOTA). The experimental mole fraction solubility of TOTA was maximum (xe = 0.0852) in PEG400 confirming the best fit of the prediction. The observed highest solubility was attributed to the δp and δh interacting forces. The activity coefficient (ϒi) was found to be increased with temperature. The higher values of r2 (linear regression coefficient) and low RMSD (root mean square deviation) indicated a good correlation between the generated “xe” data for crystalline TOTA and the explored models (modified Apelblat and vanʼt Hoff models). TOTA solubility in “PEG400 + water mixture” was endothermic and entropy-driven. IR (immediate release product) formulation can be tailored using 60% PEG400 in buffer solution for 2 mg of TOTA in 0.25 mL (dosing volume). The isotonic binary solution was associated with a pH of 7.2 suitable for sub-Q delivery. The approach would be a promising alternative with ease of delivery to children and aged patients.
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The authors extend their appreciation to King Saud University for funding this work through research supporting project (RSP2024R376), Riyadh, Saudi Arabia.
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The authors received funding from the King Saud University through research supporting project (RSP2024R376), Riyadh, Saudi Arabia.
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AM: conceptualization, funding acquisition, and methodology, TK: writing, review, and editing, and software, MUMS: validation, analysis, and methodology, AF: review and editing, AKS: software and data analysis, ZRB: editing and review.
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Malik, A., Khan, T., Siddique, M.U.M. et al. HSPiP, Computational, and Thermodynamic Model–Based Optimized Solvents for Subcutaneous Delivery of Tolterodine Tartrate and GastroPlus-Based In Vivo Prediction in Humans: Part I. AAPS PharmSciTech 25, 93 (2024). https://doi.org/10.1208/s12249-024-02800-2
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DOI: https://doi.org/10.1208/s12249-024-02800-2