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image of Determination of pH-Solubility Profile and Development of Prediction Models for pH-Dependent Solubility of Atorvastatin Calcium

Abstract

Background

Aqueous solubility is a key parameter in understanding drug transport in the body and also in the development of analytical methods. Determination of a complete pH-solubility profile is essential during the pre-formulation stage, and it is also required to define the class of drug according to the biopharmaceutical classification system.

Objectives

This study aimed to generate solubility data to obtain a complete pH-solubility profile for Atorvastatin calcium using the spectrophotometric method and to develop models for the prediction of aqueous solubility of Atorvastatin calcium at a given combination of the pH and temperature.

Methods

The developed pH independent spectrophotometric method was applied to determine the pH solubility profile of the drug at three different temperatures. Models for the prediction of solubility were generated by using a full factorial design and validated by determining solubility experimentally at some combinations of pH and temperature within the design spaces.

Results

Solubility of Atorvastatin calcium was found to increase gradually with pH within a range of pH 1.2-4.0 and pH 9.0-12.0 while increasing drastically with pH within a range of pH 4.0-9.0 at all three temperatures. Experimental values of solubility of Atorvastatin calcium were found to be in good agreement with predicted values from models.

Conclusion

Predictive models generated from the experimental values are good indicative of the solubility of Atorvastatin calcium with respect to temperature and pH of the medium and can be used for accurate prediction of aqueous solubility within the design space of the models.

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2024-10-10
2024-11-26

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References

  1. Bhattachar S.N. Deschenes L.A. Wesley J.A. Solubility: it’s not just for physical chemists. Drug Discov. Today 2006 11 21-22 1012 1018 17055411
    [Google Scholar]
  2. Hite M. Turner S. Federici C. Part 1: Oral delivery of poorly soluble drugs. Pharmaceutical Manufacturing and Packing Sourcer Samedan 2003 1 3
    [Google Scholar]
  3. Savjani K.T. Gajjar A.K. Savjani J.K. Drug solubility: importance and enhancement techniques. ISRN Pharm. 2012 2012 195727 22830056
    [Google Scholar]
  4. Cassens J. Prudic A. Ruether F. Sadowski G. Solubility of pharmaceuticals and their salts as a function of pH. Ind. Eng. Chem. Res. 2013 52 2721 2731
    [Google Scholar]
  5. Goldberg A.H. Gibaldi M. Kanig J.L. Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures II: Experimental evaluation of a eutectic mixture: urea‐acetaminophen system. J. Pharm. Sci. 1966 55 482 487
    [Google Scholar]
  6. Goldberg A.H. Gibaldi M. Kanig J.L. Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures. I. Theoretical considerations and discussion of the literature. J. Pharm. Sci. 1965 54 8 1145 1148 5882218
    [Google Scholar]
  7. Goldberg A.H. Gibaldi M. Kanig J.L. Mayersohn M. Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures. IV. Chloramphenicol--urea system. J. Pharm. Sci. 1966 55 6 581 583 5924122
    [Google Scholar]
  8. Sugano K. Okazaki A. Sugimoto S. Tavornvipas S. Omura A. Mano T. Solubility and dissolution profile assessment in drug discovery. Drug Metab. Pharmacokinet. 2007 22 4 225 254 17827779
    [Google Scholar]
  9. Lucero-Borja D. Castilla Ò. Barbas R. Subirats X. Ràfols C. Solubility-pH profiles of a free base and its salt: Sibutramine as a case study. ADMET DMPK 2017 5 253 256
    [Google Scholar]
  10. Sieger P. Cui Y. Scheuerer S. pH-dependent solubility and permeability profiles: A useful tool for prediction of oral bioavailability. Eur. J. Pharm. Sci. 2017 105 82 90 28478135
    [Google Scholar]
  11. Ohyama M. Kudo S. Amari S. Takiyama H. Production of crystalline particles with high homogeneity in reaction crystallization by using pH-solubility-profile. J. Ind. Eng. Chem. 2019 75 38 43
    [Google Scholar]
  12. Shah J.C. Maniar M. pH-Dependent solubility and dissolution of bupivacaine and its relevance to the formulation of a controlled release system. J. Control. Release 1993 23 261 270
    [Google Scholar]
  13. Madlool D.T. Al-Ani I. Ata T. Dayyih W.A. Solubility, pH-Solubility Profile, pH-Rate Profile, and Kinetic Stability of the Tyrosine Kinase Inhibitor, Alectinib. Pharmaceuticals (Basel) 2024 17 6 776 38931444
    [Google Scholar]
  14. Hamed R. Awadallah A. Sunoqrot S. Tarawneh O. Nazzal S. AlBaraghthi T. Al Sayyad J. Abbas A. pH-dependent solubility and dissolution behavior of carvedilol—case example of a weakly basic BCS class II drug. AAPS PharmSciTech 2016 17 2 418 426 26202065
    [Google Scholar]
  15. Shoghi E. Fuguet E. Bosch E. Ràfols C. Solubility-pH profiles of some acidic, basic and amphoteric drugs. Eur. J. Pharm. Sci. 2013 48 1-2 291 300 23178441
    [Google Scholar]
  16. Volkova T.V. Simonova O.R. Levshin I.B. Perlovich G.L. Physicochemical profile of new antifungal compound: pH-dependent solubility, distribution, permeability and ionization assay. J. Mol. Liq. 2021 336 116535
    [Google Scholar]
  17. Völgyi G. Baka E. Box K.J. Comer J.E.A. Takács-Novák K. Study of pH-dependent solubility of organic bases. Revisit of Henderson-Hasselbalch relationship. Anal. Chim. Acta 2010 673 1 40 46 20630176
    [Google Scholar]
  18. Marković O.S. Pešić M.P. Shah A.V. Serajuddin A.T.M. Verbić T.Ž. Avdeef A. Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates. Eur. J. Pharm. Sci. 2019 133 264 274 30914359
    [Google Scholar]
  19. NINGSIH BW SUWALDI S, NUGROHO AK. Effects of pH and Ionic Strength on the Solubility Profile of Ofloxacin. Jurnal Ilmu Kefarmasian Indonesia. 2014 12 25 31
    [Google Scholar]
  20. Butcher G. Comer J. Avdeef A. pKa-critical interpretations of solubility–pH profiles: PG-300995 and NSC-639829 case studies. ADMET DMPK 2015 3 131 140
    [Google Scholar]
  21. Wang Z. Burrell L.S. Lambert W.J. Solubility of E2050 at various pH: a case in which apparent solubility is affected by the amount of excess solid. J. Pharm. Sci. 2002 91 6 1445 1455 https://www.sciencedirect.com/science/article/pii/S0022354916310152 [Internet]. 12115844
    [Google Scholar]
  22. Wu Z. Razzak M. Tucker I.G. Medlicott N.J. Physicochemical characterization of ricobendazole: I. Solubility, lipophilicity, and ionization characteristics. J. Pharm. Sci. 2005 94 5 983 993 https://www.sciencedirect.com/science/article/pii/S0022354916317701 [Internet]. 15793800
    [Google Scholar]
  23. Hansen N.T. Kouskoumvekaki I. Jørgensen F.S. Brunak S. Jónsdóttir S.O. Prediction of pH-dependent aqueous solubility of druglike molecules. J. Chem. Inf. Model. 2006 46 6 2601 2609 17125200
    [Google Scholar]
  24. Jorgensen W.L. Duffy E.M. Prediction of drug solubility from structure. Adv. Drug Deliv. Rev. 2002 54 3 355 366 11922952
    [Google Scholar]
  25. Yan A. Gasteiger J. Prediction of aqueous solubility of organic compounds by topological descriptors. QSAR Comb. Sci. 2003 22 821 829
    [Google Scholar]
  26. Blake J.F. Chemoinformatics - predicting the physicochemical properties of ‘drug-like’ molecules. Curr. Opin. Biotechnol. 2000 11 1 104 107 10679344
    [Google Scholar]
  27. Huuskonen J. Estimation of aqueous solubility for a diverse set of organic compounds based on molecular topology. J. Chem. Inf. Comput. Sci. 2000 40 3 773 777 10850781
    [Google Scholar]
  28. Huuskonen J. Estimation of aqueous solubility in drug design. Comb. Chem. High Throughput Screen. 2001 4 3 311 316 11375745
    [Google Scholar]
  29. Delaney J.S. ESOL: estimating aqueous solubility directly from molecular structure. J. Chem. Inf. Comput. Sci. 2004 44 3 1000 1005 15154768
    [Google Scholar]
  30. Wegner J.K. Zell A. Prediction of aqueous solubility and partition coefficient optimized by a genetic algorithm based descriptor selection method. J. Chem. Inf. Comput. Sci. 2003 43 3 1077 1084 12767167
    [Google Scholar]
  31. Hou T.J. Xia K. Zhang W. Xu X.J. ADME evaluation in drug discovery. 4. Prediction of aqueous solubility based on atom contribution approach. J. Chem. Inf. Comput. Sci. 2004 44 1 266 275 14741036
    [Google Scholar]
  32. Liu R. Sun H. So S-S. Development of quantitative structure-property relationship models for early ADME evaluation in drug discovery. 2. Blood-brain barrier penetration. J. Chem. Inf. Comput. Sci. 2001 41 6 1623 1632 11749589
    [Google Scholar]
  33. Klopman G. Wang S. Balthasar D.M. Estimation of aqueous solubility of organic molecules by the group contribution approach. Application to the study of biodegradation. J. Chem. Inf. Comput. Sci. 1992 32 5 474 482 1400663
    [Google Scholar]
  34. Ran Y. Jain N. Yalkowsky S.H. Prediction of aqueous solubility of organic compounds by the general solubility equation (GSE). J. Chem. Inf. Comput. Sci. 2001 41 5 1208 1217 11604020
    [Google Scholar]
  35. Huuskonen J. Salo M. Taskinen J. Aqueous solubility prediction of drugs based on molecular topology and neural network modeling. J. Chem. Inf. Comput. Sci. 1998 38 3 450 456 9611785
    [Google Scholar]
  36. McFarland J.W. Avdeef A. Berger C.M. Raevsky O.A. Estimating the water solubilities of crystalline compounds from their chemical structures alone. J. Chem. Inf. Comput. Sci. 2001 41 5 1355 1359 11604037
    [Google Scholar]
  37. Klamt A. Eckert F. Hornig M. Beck M.E. Bürger T. Prediction of aqueous solubility of drugs and pesticides with COSMO-RS. J. Comput. Chem. 2002 23 2 275 281 11924739
    [Google Scholar]
  38. Tetko I.V. Tanchuk V.Y. Kasheva T.N. Villa A.E.P. Estimation of aqueous solubility of chemical compounds using E-state indices. J. Chem. Inf. Comput. Sci. 2001 41 6 1488 1493 11749573
    [Google Scholar]
  39. Lennernäs H. Clinical pharmacokinetics of atorvastatin. Clin. Pharmacokinet. 2003 42 13 1141 1160 14531725
    [Google Scholar]
  40. Colhoun H.M. Betteridge D.J. Durrington P.N. Hitman G.A. Neil H.A.W. Livingstone S.J. Thomason M.J. Mackness M.I. Charlton-Menys V. Fuller J.H. CARDS investigators Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004 364 9435 685 696 15325833
    [Google Scholar]
  41. Lennernäs H. Human jejunal effective permeability and its correlation with preclinical drug absorption models. J. Pharm. Pharmacol. 1997 49 7 627 638 9255703
    [Google Scholar]
  42. Wu X. Whitfield L.R. Stewart B.H. Atorvastatin transport in the Caco-2 cell model: contributions of P-glycoprotein and the proton-monocarboxylic acid co-transporter. Pharm. Res. 2000 17 2 209 215 10751037
    [Google Scholar]
  43. Corsini A. Bellosta S. Baetta R. Fumagalli R. Paoletti R. Bernini F. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol. Ther. 1999 84 3 413 428 10665838
    [Google Scholar]
  44. Cilla D.D. Jr Whitfield L.R. Gibson D.M. Sedman A.J. Posvar E.L. Multiple-dose pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an inhibitor of HMG-CoA reductase, in healthy subjects. Clin. Pharmacol. Ther. 1996 60 6 687 695 8988072
    [Google Scholar]
  45. Kearney A.S. Crawford L.F. Mehta S.C. Radebaugh G.W. The interconversion kinetics, equilibrium, and solubilities of the lactone and hydroxyacid forms of the HMG-CoA reductase inhibitor, CI-981. Pharm. Res. 1993 10 10 1461 1465 8272408
    [Google Scholar]
  46. Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) 2009 Available from: https://www.who.int/teams/health-product-policy-and-standards/standards-and-specifications/norms-and-standards-for-pharmaceuticals/expert-committee-on-specifications-for-pharmaceutical-preparations(accessed on 28-9-2024)
  47. Ahirwar K. Shukla R. Preformulation studies: A versatile tool in formulation design. Drug Formulation Design Intech Open 2023
    [Google Scholar]
  48. Jones T.M. Preformulation studies. Pharmaceutical Formulation: The Science and Technology of Dosage Forms The Royal Society of Chemistry 2018
    [Google Scholar]
  49. Tong W.Q. Practical Aspects of Solubility Determination in Pharmaceutical Preformulation Solvent Systems and Their Selection in Pharmaceutics and Biopharmaceutics. Augustijns P. Brewster M.E. New York, NY Springer New York 2007 137 149
    [Google Scholar]
  50. Bodiwala K.B. Shah J. Sureja D.K. Dhameliya T.M. Khadela A. Generation of predictive models for oxidative degradation kinetics of dapagliflozin with the applications of DOE and stability indicating HPLC method. Int. J. Chem. Kinet. 2022 54 712 725
    [Google Scholar]
  51. Marolia B.P. Prajapati P.B. Bodiwala K.B. Vaghela M.P. Shah S.A. Suhagia B.N. Hydrolytic Degradation Kinetic Study of Balofloxacin by Stability Indicating Reversed Phase High Performance Liquid Chromatography Method. Pharm. Methods 2016 ••• 7
    [Google Scholar]
  52. Bodiwala K.B. Shah S. Thakor J. Marolia B. Prajapati P. Degradation kinetics study of alogliptin benzoate in alkaline medium by validated stability-indicating HPTLC Method. J. AOAC Int. 2016 99 6 1505 1512 27608919
    [Google Scholar]
  53. Canbay H.S. Spectrophotometric determination of acid dissociation constants of some arylpropionic acids and arylacetic acids in acetonitrile-water binary mixtures at 25o C. Braz. J. Pharm. Sci. 2023 58 1 11 [Internet]. 10.1590/s2175‑97902022e20740
    [Google Scholar]
  54. Şanlı S. Başaran F. Şanlı N. Akmeşe B. Bulduk İ. Determination of Dissociation Constants of Some Antifungal Drugs by Two Different Methods at 298 K. J. Solution Chem. 2013 42 1976 1987 [Internet]. 10.1007/s10953‑013‑0083‑x
    [Google Scholar]
  55. Sanjeev R. Jagannadham V. Vrath R.V. Implications of a novel interpretation of the isosbestic point. Chem. New Zealand 2012 2012 133 135
    [Google Scholar]
  56. Lotfy H.M. Saleh S.S. Hassan N.Y. Salem H. A comparative study of novel spectrophotometric methods based on isosbestic points; application on a pharmaceutical ternary mixture. Spectrochim. Acta A Mol. Biomol. Spectrosc. 2014 126 112 121 https://www.sciencedirect.com/science/article/pii/S1386142514001607 [Internet]. 24589996
    [Google Scholar]
  57. Salgado L.E.V. Vargas-Hernández C. Spectrophotometric determination of the pKa, isosbestic point and equation of absorbance vs. pH for a universal pH indicator. Am. J. Anal. Chem. 2014 5 1290
    [Google Scholar]
  58. Bodiwala K. Prajapati P.B. Marolia B.P. Rathod I.S. Shah S.A. Development and validation of pH independent spectrophotometric method for determination of pravastatin sodium in dosage forms. Journal of Pharmacy And Applied Sciences [Internet] 2014 1 23 28 https://www.researchgate.net/profile/Kunjan-Bodiwala/publication/299452347_Development_and_Validation_of_pH_Independent_Spectrophotometric_Method_for_Determination_of_Pravastatin_Sodium_in_Dosage_Forms/links/56f8c56008ae95e8b6d36678/Development-and-Validation-of-pH-Independent-Spectrophotometric-Method-for-Determination-of-Pravastatin-Sodium-in-Dosage-Forms.pdf
    [Google Scholar]
  59. Lu Y. Tang N. Qi J. Wu W. Phase solubility behavior of hydrophilic polymer/cyclodextrin/lansoprazole ternary system studied at high polymer concentration and by response surface methodology. Pharm. Dev. Technol. 2012 17 2 236 241 [Internet]. 10.3109/10837450.2010.531738 21067338
    [Google Scholar]
  60. Izadiyan Z. Basri M. Fard Masoumi H.R. Abedi Karjiban R. Salim N. Kalantari K. Improvement of physicochemical properties of nanocolloidal carrier loaded with low water solubility drug for parenteral cancer treatment by Response Surface Methodology. Mater. Sci. Eng. C 2019 94 841 849 https://www.sciencedirect.com/science/article/pii/S092849311830119X [Internet]. 30423770
    [Google Scholar]
/content/journals/cpa/10.2174/0115734129314568241009053724
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Determination of pH-Solubility Profile and Development of Prediction Models for pH-Dependent Solubility of Atorvastatin Calcium
Bentham Science Publishers ; https://doi.org/10.2174/0115734129314568241009053724
/content/journals/cpa/10.2174/0115734129314568241009053724
/content/journals/cpa/10.2174/0115734129314568241009053724
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  • Article Type:     Research Article
Keywords: dissociation constant ; solubility ; pH-solubility profile ; atorvastatin calcium ; predictive models

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