Solubility Enhancement Strategies for Poorly Soluble Drugs: Recent Trends
Abstract
Pharmaceutical development is severely hampered by poor drug solubility; over 40% of medications on the market and about 90% of drugs in development pipelines have inadequate solubility. Which also reduces bioavailability and therapeutic effectiveness. This review thoroughly investigates a range of methods, including physical alterations, chemical approaches, and innovative formulation techniques, for enhancing the solubility of poorly soluble drugs. Important techniques are covered in detail, including lipid-based formulations, solid dispersions, complexation with cyclodextrins, particle size reduction, and nanotechnology-based carriers. The mechanisms behind solubility enhancement, the benefits and drawbacks of each strategy, and their effects on drug absorption and clinical outcomes are also highlighted in the review. Recent developments and cutting-edge technologies that present viable ways to get around solubility-related obstacles in drug delivery are highlighted. For researchers and formulators looking to maximize drug solubility and enhance therapeutic results, this synthesis offers a useful framework.
Keywords: Solubility, Poor Soluble drugs, Bioavailability, Solid Dispersion, Nanotechnology, Solubility Enhancement.
Keywords:
Solubility, Poorly Soluble Drugs, Bioavailability, Solid Dispersion, Nano technology, Solubility EnhancementDOI
https://doi.org/10.22270/jddt.v16i3.7623References
1. Ainurofiq A, Putro DS, Ramadhani DA, Putra GM, Do Espirito Santo LDC. A review on solubility enhancement methods for poorly water-soluble drugs. Journal of Reports in Pharmaceutical Sciences. Wolters Kluwer Medknow Publications; 2021. p. 137–47. doi:10.4103/jrptps.JRPTPS_134_19
2. Jagtap M. Recent Trends in Solubility Enhancement Techniques for Poorly Water-Soluble Drugs. International Journal of Scientific Research and Technology. 2025 Aug 11.
3. Kumari L, Choudhari Y, Patel P, Gupta G Das, Singh D, Rosenholm JM, et al. Advancement in Solubilization Approaches: A Step towards Bioavailability Enhancement of Poorly Soluble Drugs. Life. MDPI; 2023. doi:10.3390/life13051099
4. Bhalani D V., Nutan B, Kumar A, Singh Chandel AK. Bioavailability Enhancement Techniques for Poorly Aqueous Soluble Drugs and Therapeutics. Biomedicines. MDPI; 2022. doi:10.3390/biomedicines10092055
5. Jagtap S, Magdum C, Jadge D, Jagtap R. Solubility enhancement technique: a review. Journal of pharmaceutical sciences and Research. 2018 Sep 1;10(9):2205-11.
6. Gajanan Bajait M, Ghatmale R, mundhe B. IMPORTANCE OF SOLUBILITY AND SOLUBILITY ENHANCEMENT TECHNIQUES. Journal of Medical Pharmaceutical and Allied Sciences [Internet]. 2019;6:2403–16. Available from: www.jmpas.com
7. Godase CB, Babar AL, Gopal AB. A concise review on methods of solubility enhancement. Int Pharm Sci 2020; 11: 109. doi: 10.31531/2231. 2020;5896(2).
8. Nurul Batrisyia R, Kumar Janakiraman A, Chiau Ming L, Helal Uddin A, Islam Sarker Z, Kai Bin L. A Review On The Solubility Enhancement Technique For Pharmaceutical Formulations. Volatiles & Essent. Oils. 2021. Report.
9. Aiassa V, Garnero C, Zoppi A, Longhi MR. Cyclodextrins and Their Derivatives as Drug Stability Modifiers. Pharmaceuticals. Multidisciplinary Digital Publishing Institute (MDPI); 2023. doi:10.3390/ph16081074
10. Deshmukh AS, Tiwari KJ, Mahajan VR. Solubility Enhancement Techniques for Poorly Water-Soluble Drugs. International Journal of Pharmaceutical Sciences and Nanotechnology. 2017 May 31;10(3):3701–8. doi:10.37285/ijpsn.2017.10.3.1
11. Chettri A, Subba A, Singh GP, Bag PP. Pharmaceutical co-crystals: A green way to enhance drug stability and solubility for improved therapeutic efficacy. Journal of Pharmacy and Pharmacology. Oxford University Press; 2024. p. 1–12. doi:10.1093/jpp/rgad097 PubMed PMID: 37934904.
12. Sapra K, Sapra A, Singh SK, Kakkar S. Self Emulsifying Drug Delivery System: A Tool in Solubility Enhancement of Poorly Soluble Drugs. Indo Global Journal of Pharmaceutical Sciences. 2012. Report.
13. Yadav KS, Soni G, Choudhary D, Khanduri A, Bhandari A, Joshi G. Microemulsions for enhancing drug delivery of hydrophilic drugs: Exploring various routes of administration. Medicine in Drug Discovery. Elsevier B.V.; 2023. doi:10.1016/j.medidd.2023.100162
14. dos Santos Lima B, Shanmugam S, de Souza Siqueira Quintans J, Quintans-Júnior LJ, de Souza Araújo AA. Inclusion complex with cyclodextrins enhances the bioavailability of flavonoid compounds: a systematic review. Phytochemistry Reviews. Springer; 2019. p. 1337–59. doi:10.1007/s11101-019-09650-y
15. Kim DH, Lee SE, Pyo YC, Tran P, Park JS. Solubility enhancement and application of cyclodextrins in local drug delivery. Journal of Pharmaceutical Investigation. Springer; 2020. p. 17–27. doi:10.1007/s40005-019-00434-2
16. Saha S, Roy A, Roy K, Roy MN. Study to explore the mechanism to form inclusion complexes of β-cyclodextrin with vitamin molecules. Sci Rep. 2016 Oct 20;6. doi:10.1038/srep35764 PubMed PMID: 27762346.
17. Abhijeet S, Ganesh S, Jadhav P, Atish V, Ashish B, kumar Redasani V. A Review on Solid Dispersion and Polymers Used For Solubility Enhancement Through Lyophilization Technique. Asian Journal of Pharmaceutical Research and Development. 2025;13(3):108–13. doi:10.22270/ajprd.v13i3.1563
18. Tekade AR, Yadav JN. A review on solid dispersion and carriers used therein for solubility enhancement of poorly water soluble drugs. Advanced Pharmaceutical Bulletin. Tabriz University of Medical Sciences; 2020. p. 359–69. doi:10.34172/apb.2020.044 PubMed PMID: 32665894.
19. Losada-Barreiro S, Celik S, Sezgin-Bayindir Z, Bravo-Fernández S, Bravo-Díaz C. Carrier Systems for Advanced Drug Delivery: Improving Drug Solubility/Bioavailability and Administration Routes. Pharmaceutics. Multidisciplinary Digital Publishing Institute (MDPI); 2024. doi:10.3390/pharmaceutics16070852
20. Sharma A, Chaudhary A, Singh B. A Review on Solubility Enhancement by Solid Dispersion Technique. J Pharm Res Int. 2021 Dec 29;77–87. doi:10.9734/jpri/2021/v33i63a35217
21. Malkawi R, Malkawi WI, Al-Mahmoud Y, Tawalbeh J. Current Trends on Solid Dispersions: Past, Present, and Future. Advances in Pharmacological and Pharmaceutical Sciences. Hindawi Limited; 2022. doi:10.1155/2022/5916013
22. Verma S. Solid Dispersion: Different methods of enhancing solubility and classification of solid dispersion. International Journal of Advance Research [Internet]. 2019. Report. Available from: www.IJARIIT.com
23. Sareen S, Joseph L, Mathew G. Improvement in solubility of poor water-soluble drugs by solid dispersion. Int J Pharm Investig. 2012;2(1):12. doi:10.4103/2230-973x.96921
24. Patil H, Vemula SK, Narala S, Lakkala P, Munnangi SR, Narala N, et al. Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation—Where Are We Now? AAPS PharmSciTech. Springer Science and Business Media Deutschland GmbH; 2024. doi:10.1208/s12249-024-02749-2 PubMed PMID: 38355916.
25. Wang B, Liu F, Xiang J, He Y, Zhang Z, Cheng Z, et al. A critical review of spray-dried amorphous pharmaceuticals: Synthesis, analysis and application. International Journal of Pharmaceutics. Elsevier B.V.; 2021. doi:10.1016/j.ijpharm.2020.120165 PubMed PMID: 33309835.
26. Dhondale MR, Thakor P, Nambiar AG, Singh M, Agrawal AK, Shastri NR, et al. Co-Crystallization Approach to Enhance the Stability of Moisture-Sensitive Drugs. Pharmaceutics. MDPI; 2023. doi:10.3390/pharmaceutics15010189
27. Patole T, Deshpande A. CO-CRYSTALLIZATION-A TECHNIQUE FOR SOLUBILITY ENHANCEMENT. Int J Pharm Sci Res. 2014;5(9):3566. doi:10.13040/IJPSR.0975-8232.5(9).3566-76
28. Dumda AK, Tidke VN, Rawat S, Tigote RM. Advanced co-crystal technologies for effective solubility enhancement in BCS Class II and IV drugs. PEXACY International Journal of Pharmaceutical Science. 2024 Feb 15;3(02):86-106.
29. Serajuddin ATM. Salt formation to improve drug solubility. Advanced Drug Delivery Reviews. 2007. p. 603–16. doi:10.1016/j.addr.2007.05.010 PubMed PMID: 17619064.
30. Vishwanath Doke V, Sunder Kunwarpuriya A, Gupta K, Khutle NM. CO-SOLVENCY AND ANTI-SOLVENT METHOD FOR THE SOLUBILITY ENHANCEMENT: AN OVERVIEW. World J Pharm Res. 2020;9. doi:10.20959/wjpr20205-17317
31. Sharma M, Sharma R, Jain DK. Nanotechnology Based Approaches for Enhancing Oral Bioavailability of Poorly Water Soluble Antihypertensive Drugs. Scientifica. Hindawi Limited; 2016. doi:10.1155/2016/8525679
32. Patel VR, Agrawal YK. Nanosuspension: An approach to enhance solubility of drugs. Journal of advanced pharmaceutical technology & research. 2011 Apr 1;2(2):81-7.
33. Liu Y, Liang Y, Yuhong J, Xin P, Han JL, Zhu R, et al. Advances in Nanotechnology for Enhancing the Solubility and Bioavailability of Poorly Soluble Drugs. Drug Design, Development and Therapy. Dove Medical Press Ltd; 2024. p. 1469–95. doi:10.2147/DDDT.S447496 PubMed PMID: 38707615.
34. Kim JY, Kim S, Papp M, Park K, Pinal R. Hydrotropic solubilization of poorly water-soluble drugs. J Pharm Sci. 2010;99(9):3953–65. doi:10.1002/jps.22241 PubMed PMID: 20607808.
35. Pignatello R, Corsaro R, Bonaccorso A, Zingale E, Carbone C, Musumeci T. Soluplus® polymeric nanomicelles improve solubility of BCS-class II drugs. Drug Deliv Transl Res. 2022 Aug 1;12(8):1991–2006. doi:10.1007/s13346-022-01182-x PubMed PMID: 35604634.
36. Tran P, Park JS. Application of supercritical fluid technology for solid dispersion to enhance solubility and bioavailability of poorly water-soluble drugs. International Journal of Pharmaceutics. Elsevier B.V.; 2021. doi:10.1016/j.ijpharm.2021.121247 PubMed PMID: 34740762.
37. Priya C, Kumari R, Ankita K. LIQUISOLID TECHNIQUE: AN APPROACH FOR ENHANCEMENT OF SOLUBILITY INTRODUCTION. Journal of Drug Delivery & Therapeutics [Internet]. 2011;2013(3):131–7. Available from: http://jddtonline.info
38. Chauhan J, Gupta D, Shah C, Upadhyay U. SOLUBILITY ENHANCEMENT TECHNIQUES. European Journal of Biomedical and Pharmaceutical Sciences [Internet]. 2024. Report. Available from: www.ejbps.com
39. Kureshi JB, Gupta VP, Tiwari B. FORMULATION AND EVALUATION OF RAPID RELEASE SYSTEM OF IRBESARTAN BY LIQUISOLID TECHNOLOGY. Current Research in Pharmaceutical Sciences. 2024 Oct 8;14(3):36–40. doi:10.24092/CRPS.2024.140302
40. NAIR HA, GADHIRAJU G, SUNNY G. DEVELOPMENT OF ORODISPERSIBLE TABLETS OF LORATADINE CONTAINING AN AMORPHOUS SOLID DISPERSION OF THE DRUG IN SOLUPLUS® USING DESIGN OF EXPERIMENTS. Int J Pharm Pharm Sci. 2023 Aug 1;19–27. doi:10.22159/ijpps.2023v15i8.47750
41. Islam N, Khan NU, Razzaq A, Menaa F, Khan ZU, Hussain A, et al. Loratadine oral bioavailability enhancement via solid dispersion loaded oro-dispersible films: Formulation, characterization and pharmacokinetics. Colloids Surf B Biointerfaces. 2023 Oct 1;230. doi:10.1016/j.colsurfb.2023.113526 PubMed PMID: 37647750.
42. Rao MRP, Pawar JA. Solubility Enhancement of Nevirapine Using Β-Cyclodextrin Nanosponges. Int J Pharm Investig. 2023 Jul 8;13(3):496–502. doi:10.5530/ijpi.13.3.061
43. Chauhan N, Patel A, Patel R. Solubility Enhancement of Brexpiprazole for Schizophrenia using HPβ Cyclodextrin Ternary Complexation. Ars Pharmaceutica (Internet). 2025 Mar 19;66(2):126–38. doi:10.30827/ars.v66i2.32043
44. Sharma A, Park YR, Garg A, Lee BS. Deep Eutectic Solvents Enhancing Drug Solubility and Its Delivery. Journal of Medicinal Chemistry. American Chemical Society; 2024. p. 14807–19. doi:10.1021/acs.jmedchem.4c01550 PubMed PMID: 39185938.
45. Javed S, Mangla B, Sultan MH, Almoshari Y, Sivadasan D, Alqahtani SS, et al. Pharmaceutical applications of therapeutic deep eutectic systems (THEDES) in maximising drug delivery. Heliyon. Elsevier Ltd; 2024. doi:10.1016/j.heliyon.2024.e29783
46. Zhuo Y, Zhao YG, Zhang Y. Enhancing Drug Solubility, Bioavailability, and Targeted Therapeutic Applications through Magnetic Nanoparticles. Molecules. Multidisciplinary Digital Publishing Institute (MDPI); 2024. doi:10.3390/molecules29204854 PubMed PMID: 39459222.
47. Rusdin A, Mohd Gazzali A, Ain Thomas N, Megantara S, Aulifa DL, Budiman A, et al. Advancing Drug Delivery Paradigms: Polyvinyl Pyrolidone (PVP)-Based Amorphous Solid Dispersion for Enhanced Physicochemical Properties and Therapeutic Efficacy. Polymers. Multidisciplinary Digital Publishing Institute (MDPI); 2024. doi:10.3390/polym16020286
48. Zhang H, Wu H, Wang L, Gao Y, Galarza LM, Zhao Y, et al. Preparation and characterization of ASDs improves the solubility and dissolution performance of a PROTAC drug. J Drug Deliv Sci Technol. 2025 May 1;107. doi:10.1016/j.jddst.2025.106837
49. Shelke R, Velagacherla V, Nayak UY. Recent advances in dual-drug co-amorphous systems. Drug Discovery Today. Elsevier Ltd; 2024. doi:10.1016/j.drudis.2023.103863 PubMed PMID: 38141778.
50. Chen C. Artificial Intelligence aided pharmaceutical engineering: Development of hybrid machine learning models for prediction of nanomedicine solubility in supercritical solvent. J Mol Liq. 2024 Mar 1;397. doi:10.1016/j.molliq.2024.124127
Published
Abstract Display: 237 
PDF Downloads: 271 PDF Downloads: 65 How to Cite
Issue
Section
Copyright (c) 2026 Tanishq Sudhir Varma , Yogeshkumar Nanasaheb Gavhane, Prashant Babarao Shamkuwar
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
How to Cite
.