Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Radiopharmaceuticals
  4. Volume 18, Issue 2
  5. Article
Volume 18, Issue 2
  • ISSN: 1874-4710
  • E-ISSN: 1874-4729

Abstract

Background

In the pharmaceutical sciences, the solubility profile of therapeutic molecules is crucial for identifying and formulating drugs and evaluating their quality across the drug discovery pipeline based on factors like oral bioavailability, metabolic transformation, biodistribution kinetics, and potential toxicological implications. The investigation aims to enhance the solubility parameters of ketoprofen (BCS-II class), which exhibits low solubility and high permeability.

Methods

In this method, hydrotrope blends of aromatic sodium benzoate and electrolyte sodium acetate were employed to enhance the solubility parameter of ketoprofen. Several batches of solid dispersion of ketoprofen were made using a solvent evaporation method, and the response surface method 32 factorial design was used to find the best one. The optimised formulation, KSD9, underwent drug dissolution, DSC, pXRD, and SEM studies.

Results

The optimized batch demonstrated substantial improvement in ketoprofen solubility, attributed to mixed hydrotropy. The results indicated that both solubility and %CDR improved when hydrotropes were employed, suggesting a direct proportionality between the rise in solubility and % CDR. Formulations KSD1-KSD9 exhibited solubility enhancements ranging from 2.23 to 5.77-fold, along with an elevation in % CDR from 72.28% to 94.76%. This implies that the % CDR was modulated by the hydrotropes, specifically influenced by the concentration levels of the independent variables. An increase in hydrotrope levels corresponded to an increase in % CDR. The positive coefficients in the quadratic equation for % CDR underscored the significant role of these independent variables in augmenting the release of Ketoprofen. Similarly, during a comparative dissolution investigation, the optimized KSD9 formulation exhibited remarkable solubility and drug content compared to conventional Ketoprofen dispersible tablets.

Conclusion

The synergistic effect of combining two hydrotropic agents significantly increased the solubility of ketoprofen by up to 58 times. The results indicated that the independent variables exerted a positive influence on solubility and % CDR. Furthermore, the responses were contingent on the specific hydrotropes selected, which functioned as the independent variables. Analyzing the r2 and ANOVA results suggested that the dependent variables aligned well with the chosen model. Visual representations, such as the 3D response surface plot and contour plot, demonstrated the impact of each hydrotrope individually and when combined. Overall, employing hydrotropes led to improved solubility and % CDR, highlighting a direct proportionality between the rise in solubility and % CDR. Mixed hydrotropic lessens the toxicity associated with individual hydrotrope concentrations while also offering a sustainable and eco-friendly alternative. This study paves the way for future research aiming to improve the solubility of low- solubility drugs, broadening their clinical applications.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/crp/10.2174/0118744710311951241018054453
2024-10-24
2025-04-23

  • From This Site

    /content/journals/crp/10.2174/0118744710311951241018054453
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. AliH.A. OmerH.K. Research article solubility enhancement of a poorly water-soluble drug using hydrotropy and mixed hydrotropy-based solid dispersion techniques.Adv. Pharmacol. Pharmaceut. Sci.2022202216
     [Google Scholar]
  2. SunX. VilarS. TatonettiN.P. High-throughput methods for combinatorial drug discovery.Sci. Transl. Med.20135205300666710.1126/scitranslmed.3006667
     [Google Scholar]
  3. DahlgrenD. LennernäsH. Intestinal permeability and drug absorption: predictive experimental, computational and in vivo approaches.Pharmaceutics201911841110.3390/pharmaceutics11080411 31412551
     [Google Scholar]
  4. VinarovZ. AbdallahM. AgundezJ.A.G. AllegaertK. BasitA.W. BraeckmansM. CeulemansJ. CorsettiM. GriffinB.T. GrimmM. KeszthelyiD. KoziolekM. MadlaC.M. MatthysC. McCoubreyL.E. MitraA. ReppasC. StappaertsJ. SteenackersN. TrevaskisN.L. VanuytselT. VertzoniM. WeitschiesW. WilsonC. AugustijnsP. Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review.Eur. J. Pharm. Sci.202116210581210.1016/j.ejps.2021.105812 33753215
     [Google Scholar]
  5. PatelM.S.N. AhmedM.H. SaqibM. ShaikhS.N. Chemical Modification: A unique solutions to Solubility problem.J. Drug Deliv. Ther.20199254254610.22270/jddt.v9i2.2432
     [Google Scholar]
  6. JatwaniS. RanaA.C. SinghG. AggarwalG. An overview on solubility enhancement techniques for poorly soluble drugs and solid dispersion as an eminent strategic approach.Int. J. Pharm. Sci. Res.201234942
     [Google Scholar]
  7. JagtapS. MagdumC. JadgeD. JagtapR. Solubility enhancement technique: A review.J. Pharmaceut. Sci. Res.201810922052211
     [Google Scholar]
  8. KaleA.R. KakadeS. BhosaleA. A Review on: Solubility Enhancement Techniques.J. Curr. Pharm. Res.202010236303647
     [Google Scholar]
  9. AbranchesD.O. BenficaJ. ShimizuS. CoutinhoJ.A.P. The perspective of cooperative hydrotropy on the solubility in aqueous solutions of cyrene.Ind. Eng. Chem. Res.20205941186491865810.1021/acs.iecr.0c02346
     [Google Scholar]
  10. DixitC. ChauhanI. VermaM. Hydrotropy- A brief insight into the Solubility Enhancement Technique.Int. J. Res. Educ. Scient. Meth.20219613
     [Google Scholar]
  11. de Oliveira JuniorH. BorgesB.A. BarbosaT.W.L. BatistaA. BragaM.T.L. de AraújoM.B. BonfilioR. A New Crystalline Ketoprofen Sodium Salt: Solid-State Characterization, Solubility, and Stability.J. Pharm. Sci.202211161674168110.1016/j.xphs.2021.11.011 34808219
     [Google Scholar]
  12. Abou-TalebH.A. ShomanM.E. MakramT.S. Abdel-AleemJ.A. AbdelkaderH. Exploration of the Safety and Solubilization, Dissolution, Analgesic Effects of Common Basic Excipients on the NSAID Drug Ketoprofen.Pharmaceutics202315271310.3390/pharmaceutics15020713 36840035
     [Google Scholar]
  13. AbranchesD.O. BenficaJ. SoaresB.P. Leal-DuasoA. SintraT.E. PiresE. PinhoS.P. ShimizuS. CoutinhoJ.A.P. Unveiling the mechanism of hydrotropy: Evidence for water-mediated aggregation of hydrotropes around the solute.Chem. Commun. (Camb.)202056527143714610.1039/D0CC03217D 32462150
     [Google Scholar]
  14. KhanA.D. TabishM. KaushikR. SaxenaV. KesharwaniP. GuptaS. Hydrotropy: Recent advancements in enhancement of drug solubility and formulation development.Int. J. Drug Deliv. Technol.2021202111
     [Google Scholar]
  15. MalkawiR. MalkawiW.I. Al-MahmoudY. TawalbehJ. Current trends on solid dispersions: Past, present, and future.Adv. Pharmacol. Pharmaceut. Sci.202220221710.1155/2022/5916013
     [Google Scholar]
  16. PadiyarA. AgrawalO.P. RajpootK. TekadeR.K. Hydrotropy, mixed hydrotropy, and mixed solvency as trending concept for solubilization of lipophilic drugs. The Future of Pharmaceutical Product Development and Research.Elsevier2020145178
     [Google Scholar]
  17. PaulR. ChattarajK.G. PaulS. Role of hydrotropes in sparingly soluble drug solubilization: Insight from a molecular dynamics simulation and experimental perspectives.Langmuir202137164745476210.1021/acs.langmuir.1c00169 33853331
     [Google Scholar]
  18. TripathiD. ChaudharyN. WalP. RaiA.K. SahooJ. Green Hydrotropes-Assisted Route: An Alternative Approach for Extracting Phytoconstituents and Associated Drug Delivery Systems.Drug Deliv. Lett.202111322023210.2174/2210303111666210712100722
     [Google Scholar]
  19. RajakA. Solubility Enhancement of a Poorly Water-Soluble Drug, Amlodipine Besylate and its Formulation Development into Solid Dispersion using Mixed Solvency Concept and Evaluation of Prepared Solid Dispersions.Asian J. Pharm.2023171
     [Google Scholar]
  20. SharmaU. SarohaK. A Review of Hydrotropic Solubilization Techniques for Enhancing the Bioavailability of Poorly Soluble Drugs.Int. J. Toxicol.2023202310915818231216414 37999970
     [Google Scholar]
  21. ShenY. XiaoY. EdkinsR.M. YoungsT.G.A. HughesT.L. TellamJ. EdkinsK. Elucidating the hydrotropism behaviour of aqueous caffeine and sodium benzoate solution through NMR and neutron total scattering analysis.Int. J. Pharm.202364712352010.1016/j.ijpharm.2023.123520 37858637
     [Google Scholar]
  22. TripathiD. ChaudharyN. SharmaD.K. SahooJ. Insightful Investigative Account on Hydrotropic Solubilization Practice Utilized for Solubility Management of Poorly Dissolvable Drugs.Curr. Drug Ther.202116539340810.2174/1574885516666210914105024
     [Google Scholar]
  23. ZakharovaL.Y. VasilievaE.A. MirgorodskayaA.B. ZakharovS.V. PavlovR.V. KashapovaN.E. GaynanovaG.A. Hydrotropes: Solubilization of nonpolar compounds and modification of surfactant solutions.J. Mol. Liq.202337012092310.1016/j.molliq.2022.120923
     [Google Scholar]
  24. YadavN.K. ShuklaT. UpmanyuN. PandeyS.P. KhanM.A. Novel application of mixed hydrotropic solubilization technique in the formulation and evaluation of solid dispersion of flupirtine maleate.J. Drug Deliv. Ther.20188548148810.22270/jddt.v8i5.1911
     [Google Scholar]
  25. MadubalaP. Formulation and Evaluation of Floatting Drug Delivey System of Famotidine.Thesis, PGP College of Pharmaceutical Science and Research Institute2020
     [Google Scholar]
  26. TripathiD. ChaudharyN. Kumar SharmaD. SahooJ. An attempt to applying hydrotropy technique for titrimetric estimation of ketoprofen using sodium salicylate as hydrotrope.Res. J. Pharm. Technol.20211442277227910.52711/0974‑360X.2021.00402
     [Google Scholar]
  27. TripathiD. SahooJ. SharmaD.K. RamanS.K. Ecologically validated UV method for etodolac estimation in pharmaceutical formulation using green hydrotropic solution and forced degradation study for stability detection.Lett. Appl. Nano. Bio. Sci.202213113
     [Google Scholar]
  28. TripathiD. SharmaD.K. SahooJ. RamanS.K. Enhanced Solubility of Meloxicam with Sodium Benzoate Hydrotrope: Ecofriendly Approach for Improved Topical Drug Delivery.Indian J. Pharmceut. Edu. Res.20225641052106210.5530/ijper.56.4.186
     [Google Scholar]
  29. TripathiD. SharmaD.K. SahooJ. Analytical Applications of Mefenamic Acid By Hydrotrope Approach: Titrimetric Estimation and Ultraviolet Method Validation.Asian J. Pharm. Clin. Res.2021147404410.22159/ajpcr.2021.v14i7.41682
     [Google Scholar]
  30. Manohar ChouhanD.M.C. Formulation And Optimization Dispersible Tablets Using Of Solid Dispersions Of Poorly Water-Soluble Drug Etoricoxib.J. Pharm. Negat. Results20211218092
     [Google Scholar]
  31. MansukA.G. DeshmukhD. MaheshwariR.K. PachputeT. Formulation optimization and characterization of solid dispersion of piroxicam prepared by novel application of mixed solvency concept.Pharm. Res.2020224146
     [Google Scholar]
  32. LiuX. WuT. YangJ. LiH. YangW. Improved Bioavailability of Repaglinide by Utilizing Hydrotropy-Solid Dispersing Techniques and Prepared Its Dropping Pills.J. Pharm. Innov.20221741259126710.1007/s12247‑021‑09615‑9
     [Google Scholar]
  33. KumarA. GhoshM.K. BithyM.B.A. KhanM.R.I. HuqM.M. WahedM.I.I. BarmanR.K. Development and evaluation of stable paracetamol loaded solid dispersion with enhanced analgesic and hepatoprotective property.Pharmacol. Pharm.202314412314310.4236/pp.2023.144010
     [Google Scholar]
  34. BajwaN. SinghM. NaryalS. MahalS. MehtaS. MadanJ. BaldiA. Formulation Development and Assessment of Solid Dispersion and Hydrotropy for BCS Class II Drug Solubility Enhancement.Lett. Drug Des. Discov.202421230531910.2174/1570180819666220822115049
     [Google Scholar]
  35. Nazrul IslamM. Abdul RubM. Rafikul IslamM. Abdul GoniM. RanaS. KumarD. AsiriA.M. AlghamdiY.G. Anamul HoqueM. KabirS.E. Physico-chemical study of the effects of electrolytes and hydrotropes on the clouding development of TX-100 and ceftriaxone sodium drug mixture.J. Mol. Liq.202337912160110.1016/j.molliq.2023.121601
     [Google Scholar]
  36. TripathiD. MishraS. RaiA.K. SahooJ. SharmaD.K. SinghY. Curcumin-loaded Hydrotropic Solid Dispersion Topical Gel Development and Evaluation: A Greener Approach Towards Transdermal Delivery of Drugs.Curr. Green Chem.202291263910.2174/2213346110666221020121020
     [Google Scholar]
  37. TripathiD. MPB. SahooJ. KumariJ. Navigating the Solution to Drug Formulation Problems at Research and Development Stages by Amorphous Solid Dispersion Technology.Rec. Adv. Drug Deliv. Formul.2023
     [Google Scholar]
  38. RiveraM.E.M. Development and characterization of ketoprofen solid dispersions with hydrophilic polymers.PhD thesis, University of Puerto Rico Medical Sciences (Puerto Rico)2022
     [Google Scholar]
  39. DeviS. KumarS. VermaV. KaushikD. VermaR. BhatiaM. Enhancement of ketoprofen dissolution rate by the liquisolid technique: optimization and in vitro and in vivo investigations.Drug Deliv. Transl. Res.202212112693270710.1007/s13346‑022‑01120‑x 35178670
     [Google Scholar]
  40. IqbalA. HossainS. ShamimA. IslamM. SiddiqueA.T. Formulation, in vitro evaluation and characterization of atorvastatin solid dispersion.Trop. J. Pharm. Res.20201961131113810.4314/tjpr.v19i6.2
     [Google Scholar]
  41. InamS. IrfanM. LaliN. Khalid SyedH. AsgharS. KhanI.U. KhanS.U.D. IqbalM.S. ZaheerI. KhamesA. Abou-TalebH.A. AbourehabM.A.S. Development and characterization of eudragit® EPO-based solid dispersion of rosuvastatin calcium to foresee the impact on solubility, dissolution and antihyperlipidemic activity.Pharmaceuticals (Basel)202215449210.3390/ph15040492 35455489
     [Google Scholar]
  42. PandiP. BulusuR. KommineniN. KhanW. SinghM. Amorphous solid dispersions: An update for preparation, characterization, mechanism on bioavailability, stability, regulatory considerations and marketed products.Int. J. Pharm.202058611956010.1016/j.ijpharm.2020.119560 32565285
     [Google Scholar]
  43. SabooS. MosesonD.E. KesturU.S. TaylorL.S. Patterns of drug release as a function of drug loading from amorphous solid dispersions: A comparison of five different polymers.Eur. J. Pharm. Sci.202015510551410.1016/j.ejps.2020.105514 32810579
     [Google Scholar]
  44. KumarV.S. RajaC. JayakumarC. A review on solubility enhancement using hydrotropic phenomena.Int. J. Pharm. Pharm. Sci.20146617
     [Google Scholar]
  45. JoshiJ. NainwalN. SaharanV.A. Review on hydrotropy: A potential approach for the solubility enhancement of poorly soluble drug.Asian J. Pharm. Clin. Res.201912192610.22159/ajpcr.2019.v12i10.34811
     [Google Scholar]
  46. Mahendra PawarB. GoswamiA. Nazrin Ruhina RahmanS. SreeA. ShunmugaperumalT. On the use of linear model-based optimization to obtain optimum solubility permeability balance (OSPB) in cinnarizine-hydrotropic blends.J. Mol. Liq.202338112181710.1016/j.molliq.2023.121817
     [Google Scholar]
  47. SaharawatA. Deepali NainwalN. Natural plus synthetic hydrotropic solubilization using response surface methodology to optimize the solid dispersion of hydrochlorothiazide.Comb. Chem. High Throughput Screen.202225230732310.2174/1386207323666201218115149 33353534
     [Google Scholar]
  48. ShirsathN.R. GoswamiA.K. Design and development of solid dispersion of valsartan by a lyophilization technique: A 32 factorial design approach.Micro Nanosyst.20211319010210.2174/1876402912666200206155430
     [Google Scholar]
  49. JainA. Solubilization of indomethacin using hydrotropes for aqueous injection.Eur. J. Pharm. Biopharm.200868370171410.1016/j.ejpb.2007.06.013 17716879
     [Google Scholar]
  50. SolankiS.S. SoniL.K. MaheshwariR.K. Study on mixed solvency concept in formulation development of aqueous injection of poorly water soluble drug.J. Pharmaceut.2013201367813210.1155/2013/678132
     [Google Scholar]
  51. BhatiaM. DeviS. Development, characterisation and evaluation of PVP K-30/PEG solid dispersion containing ketoprofen.ACTA Pharmaceut. Sci.202058117
     [Google Scholar]
  52. RubM.A. Effect of additives on the aggregation phenomena of amphiphilic drug and hydrotrope mixtures.J. Mol. Liq.202029811204910.1016/j.molliq.2019.112049
     [Google Scholar]
  53. AkhterS. UddinA.K.M.S. NathA.K. Md Salahuddin KadirM.F. IslamM.S. Preparation, physicochemical characterization and in-vitro dissolution studies of ketoprofen solid dispersion with PEG 6000 and HPMC 6 cps.Bangladesh Pharmaceut. J.2020231445310.3329/bpj.v23i1.45319
     [Google Scholar]
  54. SalmanA. NasrulE.L. RivaiH.A. BenE.S. ZainiE.R. Physicochemical characterization of amorphous solid dispersion of ketoprofen–Polyvinylpyrrolidone K-30.Int. J. Pharm. Pharm. Sci.201572
     [Google Scholar]
  55. YadavP.S. KumarV. SinghU.P. BhatH.R. MazumderB. Physicochemical characterization and in vitro dissolution studies of solid dispersions of ketoprofen with PVP K30 and d-mannitol.Saudi Pharm. J.2013211778410.1016/j.jsps.2011.12.007 24109206
     [Google Scholar]
  56. SavardekarR.Y. SherikarA.S. Screening of Ketoprofen-Poloxamer and Ketoprofen-Eudragit solid dispersions for improved physicochemical characteristics and dissolution profile.Braz. J. Pharm. Sci.202056e1864110.1590/s2175‑97902019000318641
     [Google Scholar]
  57. DeyA. SandreV. MarangoniD.G. GhoshS. Interaction between a nonsteroidal anti-inflammatory drug (ibuprofen) and an anionic surfactant (AOT) and effects of salt (NaI) and hydrotrope (4-4-4).J. Phys. Chem. B2018122143974398710.1021/acs.jpcb.8b00687 29513995
     [Google Scholar]
  58. NainwalN. JawlaS. SinghR. BanerjeeS. SaharanV.A. Solubility-permeability interplay of hydrotropic solubilization of piroxicam.Drug Dev. Ind. Pharm.202450648149410.1080/03639045.2024.2349576 38717346
     [Google Scholar]
  59. SharmaS. SharmaR. KokaS.S. DarwhekarG.N.A. Review: “Hydrotropy” Techniques to increase the solubility of Drug.J. Pharm. Negat. Results2023202316111618
     [Google Scholar]
  60. VittalG.V. DeveswaranR. BharathS. BasavarajB.V. MadhavanV. Development of an analytical method for spectrophotometric estimation of ketoprofen using mixed co solvency approach.Int. J. Pharm. Sci. Res.20123410531056
     [Google Scholar]
/content/journals/crp/10.2174/0118744710311951241018054453
Loading
Enhancing Ketoprofen Solubility: A Strategic Approach Using Solid Dispersion and Response Surface Methodology
Current Radiopharmaceuticals 18, 100 (2025); https://doi.org/10.2174/0118744710311951241018054453
/content/journals/crp/10.2174/0118744710311951241018054453
/content/journals/crp/10.2174/0118744710311951241018054453
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): Hydrotropy; mixed hydrotropes; optimization; solid dispersion; solubilization; surface response methodology

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test