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 (δ_d = 17.88, δ_p = 4.0, and δ_h = 8.8 of PEG400) and comparable to the drug (δ_d = 17.6, δ_p = 2.4, and δ_h = 4.6 of TOTA). The experimental mole fraction solubility of TOTA was maximum (x^e = 0.0852) in PEG400 confirming the best fit of the prediction. The observed highest solubility was attributed to the δ_p and δ_h 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.

By Abdul Malik, Tasneem Khan, Mohd Usman Mohd Siddique, Abdul Faruk, Ashwani Kumar Sood & Zahid Rafiq Bhat