Skip to main content
SpringerLink
Log in

HSPiP, Computational, and Thermodynamic Model–Based Optimized Solvents for Subcutaneous Delivery of Tolterodine Tartrate and GastroPlus-Based In Vivo Prediction in Humans: Part I

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

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.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Shaik RP, Puttagunta SB, Kothapalli CB, Awen BZS, Challa BR. A validated LC–MS/MS method for the determination of tolterodine and its metabolite in rat plasma and application to pharmacokinetic study. Journal of Pharmaceutical Analysis. 2013;3(6):489–99.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Librach SL. Chapter 13: Urinary incontinence. Palliative Care. 2011;176–185. https://doi.org/10.1016/b978-1-4377-1619-1.00013-5.

  3. Maggiore ULR, Salvatore U, Alessandri S, Remorgida F, Origoni V, Candiani M, Venturini M, Ferrero PLS. Pharmacokinetics and toxicity of antimuscarinic drugs for overactive bladder treatment in females. Expert Opin Drug Metab Toxicol. 2012;8(11):1387–408.

    Article  CAS  Google Scholar 

  4. Jones LH, Randall A, Napier C, Trevethick M, Sreckovic S, Watson J. Design and synthesis of a fluorescent muscarinic antagonist. Bioorg Med Chem Lett. 2008;18(2):825–7.

    Article  CAS  PubMed  Google Scholar 

  5. Brynne N, Stahl MM, Hallen B, Edlund PO, Palmér L, Höglund P, Gabrielsson J. Pharmacokinetics and pharmacodynamics of tolterodine in man: a new drug for the treatment of urinary bladder overactivity. Int J Clin Pharmacol Ther. 1997;35:287–95.

    CAS  PubMed  Google Scholar 

  6. Byeon JY, Kim YH, Kim SH, Lee CM, Choi CI, Bae JW, Jang CG, Lee SY, Lee YJ. Inhibition of salivary secretion by tolterodine transdermal patch. Arch Pharm Res. 2017;40:1455–63.

    Article  CAS  PubMed  Google Scholar 

  7. Elshafeey AH, Kamel AO, Fathallah MM. Utility of nanosized microemulsion for transdermal delivery of tolterodine tartrate: ex-vivo permeation and in-vivo pharmacokinetic studies. Pharm Res. 2009;26(11):2446–53.

    Article  CAS  PubMed  Google Scholar 

  8. Kitak T, Dumicic A, Planinsek O, Sibanc R, Srcic S. Determination of solubility 10 parameters of ibuprofen and ibuprofen lysinate. Molecules. 2015;20:21549–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hansen CM. Hansen solubility parameters: a user’s handbook. 2nd ed. CRC Press. 2007. https://doi.org/10.1201/9781420006834.

  10. Basu N, Chakraborty A, Ghosh R. Carbohydrate derived organogelators and the corresponding functional gels developed in recent time. Gels. 2018;4(2):52. https://doi.org/10.3390/gels4020052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kumar CB, Narayanan BL, Chandrasekar M, Malairajan P, Kumar EP. Development and validation of RP-HPLC method for the quantitative estimation of tolterodine tartrate in capsule formulation. RGUHS J Pharm Sci. 2013;3(3):58–64.

    Google Scholar 

  12. Taymouri S, Mostafavi A, Talabaki H. Formulation and evaluation of taste-masked oral disintegrating tablet containing tolterodine-loaded montmorillonite. Research in Pharmaceutical Sciences. 2023;18(5):528–40.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hussain A, Alshehri S, Ramzan M, Afzal O, Altamimi ASA, Alossaimi MA. Biocompatible solvent selection based on thermodynamic and computational solubility models, in-silico GastroPlus prediction, and cellular studies of ketoconazole for subcutaneous delivery. Journal of Drug Delivery Science and Technology. 2021;65: 102699. https://doi.org/10.1016/j.jddst.2021.102699.

    Article  CAS  Google Scholar 

  14. Soltanpour S, Nazemi V. Solubility of ketoconazole in binary and ternary solvents of polyethylene glycols 200, 400 or 600 with ethanol and water at 298.2 K. Data Report and Analysis. J Solution Chem. 2018;47:65–79.

    Article  CAS  Google Scholar 

  15. Prakash L, Himaja M, Vasudev R. Isolation, identification, and characterisation of degradation products and the development and validation of a stability-indicating method for the estimation of impurities in the tolterodine tartrate formulation. Sci Pharm. 2014;83(1):65–83.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Burke CMJ. Solubility parameters: theory and applications. AIC Book and Paper Group Annual. 1984;3:13–58.

    Google Scholar 

  17. Hildebrand JH, Scott RL. The solubility of nonelectrolytes. New York: Reinhold Pub. Corp.; 1950. pp. 514.

  18. Van Krevelen DW. Properties of polymers: their correlation with chemical structure; their numerical estimation and prediction from additive group contributions. Amsterdam: Elsevier; 2009. pp. 956–1004.

  19. Ruidiaz MMA, Rodríguez DSJ, Neita RPC, Cristancho BDM, Martínez RM. Performance of the Jouyban-Acree Model for correlating the solubility of indomethacin and ethylhexyl triazone in ethyl acetate + ethanol mixtures. Vitae, Revista de La Facultad de Química Farmacéutica. 2010;17(3):2145–660.

    Google Scholar 

  20. Apelblat A, Manzurola E. Solubilities of o-acetylsalicylic, 4-aminosalicylic, 3,5-dinitrosalicylic and p-toluic acid and magnesium-DL-aspartate in water from T = 20 (278–348) K. J Chem Thermodyn. 1999;31:85–91.

    Article  CAS  Google Scholar 

  21. Manzurola E, Apelblat A. Solubilities of L-glutamic acid, 3-nitrobenzoic acid, acetylsalicylic, p-toluic acid, calcium-L-lactate, calcium gluconate, magnesium-DL- aspartate, and magnesium-L-lactate in water. J Chem Thermodyn. 2002;34:1127–36.

    Article  CAS  Google Scholar 

  22. Yu S, Xu X, Xing W, Xue F, Cheng Y. Solubility, thermodynamic parameters, and dissolution properties of gliclazide in seventeen pure solvents at temperatures from 278.15 to 318.15 K. Journal of Molecular Liquids. 2020;312:113425. https://doi.org/10.1016/j.molliq.2020.113425.

    Article  CAS  Google Scholar 

  23. Bhesaniya KD, Chavda KV, Sadhu CH, Baluja S. Thermodynamic characteristics of solutions of ornidazole in different organic solvents at different temperatures. J Mol Liq. 2014;191:124–7.

    Article  CAS  Google Scholar 

  24. Jim M, Kim K-J. Solubility of forms I and II of clopidogrel hydrogen sulfate in formic acid, N-methylpyrrolidone, and N, N-dimethylformamide. J Chem Eng Data. 2012;57(2):598–602.

    Article  CAS  Google Scholar 

  25. Krug RR, Hunter WG, Grieger RS. Enthalpy-entropy compensation. 2. Separation 5 of the chemical from the statistic effect. J Phys Chem. 1976;80:2341–51.

    Article  CAS  Google Scholar 

  26. Shen Y, Liu W, Bao Z. Solubility measurement and thermodynamic modeling of doxycycline hyclate two binary solvent systems at 276.95–323.75K. J Mol Liq. 2019;289:111138.

    Article  CAS  Google Scholar 

  27. Reddy MB, Bolger MB, Fraczkiewicz G, Del Frari L, Luo L, Lukacova V, Mitra A, Macwan JS, Mullin JM, Parrott N, Heikkinen AT. PBPK modeling as a tool for predicting and understanding intestinal metabolism of uridine 5’-diphospho-glucuronosyltransferase substrates. Pharmaceutics. 2021;13(9):1325. https://doi.org/10.3390/pharmaceutics13091325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kim J, Gao Y, Zhao Z, Rodrigues D, Tanner EEL, Ibsen K, Sasmal PK, Jaladi R, Alikunju S, Mitragotri S. A deep eutectic-based, self-emulsifying subcutaneous depot system for apomorphine therapy in Parkinson’s disease. PNAS. 2022;119(9): e2110450119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Al-Shdefat R. Solubility determination and solution thermodynamics of olmesartan medoxomil in (PEG-400 + water) cosolvent mixtures. Drug Dev Ind Pharm. 2020;46(12):2098–104.

    Article  CAS  PubMed  Google Scholar 

  30. Dibrov G, Kagramanov G, Sudin V, Molchanov S, Grushevenko E, Yushkin A, Volkov V. Influence of draw ratio and take-up velocity on properties of ultrafiltration hollow fiber membranes from polyethersulfone. Fibers. 2022;10:29. https://doi.org/10.3390/fib10030029.

    Article  CAS  Google Scholar 

  31. Jankovic S, Tsakiridou G, Ditzinger F, Koehl NJ, Price DJ, Ilie A-R, Kalantzi L, Kimpe K, Holm R, Nair A, Griffin B, Saal C, Kuentz M. Application of the solubility parameter concept to assist with oral delivery of poorly water-soluble drugs - a PEARRL review. J Pharm Pharmacol. 2019;71(4):441–63.

    Article  CAS  PubMed  Google Scholar 

  32. Gade R, Nama S, Avula P. Formulation development and evaluation of modified oral drug delivery system of tolterodine tartrate microsponges. J Res Pharm. 2022;26(5):1138–55.

    CAS  Google Scholar 

  33. Reddy BP, Reddy KR, Reddy RR, Reddy DM, Reddy KSC. Polymorphs of tolterodine tartrate. United States Patent, US 7,393,874B2; 2008. pp. 1–4.

  34. Johnson EJ, Duan JE, Srirattana K, Venkitanarayanan K, Tulman ER, Tian XC. Effects of intramuscularly injected plant-derived antimicrobials in the mouse model. Sci Rep. 2022;12(1):5937. https://doi.org/10.1038/s41598-022-09705-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hussain A, Altamimi MA, Afzal O, Altamimi ASA, Ali A, Ali A, Martinez F, Siddique MUM, Acree WE Jr, Jouyban A. Preferential solvation study of the synthesized aldose reductase inhibitor (SE415) in the PEG 400 (1) + water (2) cosolvent mixture and GastroPlus-based prediction. ACS Omega. 2022;7(1):1197–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Grepioni F, Braga D, Chelazzi L, Shemchuk O, Maffei P, Sforzini A, Viscomi GC. Improving solubility and storage stability of rifaximin via solid-state solvation with transcutol®. CrystEngComm. 2019;21:5278–83.

    Article  CAS  Google Scholar 

  37. Paik D, Lee H, Kim H, Choi J-M. Thermodynamics of π–π interactions of benzene and phenol in water. Int J Mol Sci. 2022;23:9811. https://doi.org/10.3390/ijms23179811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Etman MA, Nada AH. Hydrotropic and cosolvent solubilisation of indomethacin. Acta Pharm. 1999;49(4):291–8.

    CAS  Google Scholar 

  39. Liu L, Li H, Chen D, Zhou X, Huang Q, Yang H. Solubility of 1,1-diamino-2,2-dinitroethylene in different pure solvents and binary mixtures (dimethyl sulfoxide + water) and (N, N-dimethylformamide + water) at different temperatures. Fluid Phase Equilibria. 2018;460:95–104.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors extend their appreciation to King Saud University for funding this work through research supporting project (RSP2024R376), Riyadh, Saudi Arabia.

Funding

The authors received funding from the King Saud University through research supporting project (RSP2024R376), Riyadh, Saudi Arabia.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia

    Abdul Malik

  2. Department of Pharmaceutics, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi, 110062, India

    Tasneem Khan

  3. Department of Pharmaceutical Chemistry, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy Dhule, Dhule, MH, 424001, India

    Mohd Usman Mohd Siddique

  4. Department of Pharmaceutical Sciences, HNB Garhwal University (A Central University), Srinagar - Garhwal, 246174, Uttarakhand, India

    Abdul Faruk

  5. Department of Chemistry, Guru Nanak Dev University, Amritsar, 143005, Punjab, India

    Ashwani Kumar Sood

  6. Department of Molecular and Cellular Oncology, MD Anderson Cancer Centre, Houston, Texas, USA

    Zahid Rafiq Bhat

Authors
  1. Abdul Malik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tasneem Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohd Usman Mohd Siddique
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Abdul Faruk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ashwani Kumar Sood
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zahid Rafiq Bhat
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Tasneem Khan.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 72 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-024-02800-2

Keywords

Search

Navigation