Skip to main content
SpringerLink
Log in

pH-Induced Precipitation Behavior of Weakly Basic Compounds: Determination of Extent and Duration of Supersaturation Using Potentiometric Titration and Correlation to Solid State Properties

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

To examine the precipitation and supersaturation behavior of ten weak bases in terms of the relationship between pH-concentration-time profiles and the solid state properties of the precipitated material.

Methods

Initially the compound was dissolved at low pH, followed by titration with base to induce precipitation. Upon precipitation, small aliquots of acid or base were added to induce slight subsaturation and supersaturation respectively and the resultant pH gradient was determined. The concentration of the unionized species was calculated as a function of time and pH using mass and charge balance equations.

Results

Two patterns of behavior were observed in terms of the extent and duration of supersaturation arising following an increase in pH and this behavior could be rationalized based on the crystallization tendency of the compound. For compounds that did not readily crystallize, an amorphous precipitate was formed and a prolonged duration of supersaturation was observed. For compounds that precipitated to crystalline forms, the observed supersaturation was short-lived.

Conclusion

This study showed that supersaturation behavior has significant correlation with the solid-state properties of the precipitate and that pH-metric titration methods can be utilized to evaluate the supersaturation behavior.

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
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Li S, He H, Parthiban LJ, Yin H, Serajuddin ATM. IV-IVC considerations in the development of immediate-release oral dosage form. J Pharm Sci. 2005;94(7):1396–417.

    Article  CAS  PubMed  Google Scholar 

  2. Hillery AM, Lloyd AWS, J. Drug delivery and targeting: for pharmacists and pharmaceutical scientists. 1 edition ed: CRC Press; 2001.

  3. Mullin JW. Crystallization. 4th edition. Oxford: Elsiever Butterworth-Heinemann; 2001.

  4. Vandecruys R, Peeters J, Verreck G, Brewster ME. Use of a screening method to determine excipients which optimize the extent and stability of supersaturated drug solutions and application of this system to solid formulation design. Int J Pharm. 2007;342(1–2):168–75.

    Article  CAS  PubMed  Google Scholar 

  5. Gao P, Rush BD, Pfund WP, Huang T, Bauer JM, Morozowich W, et al. Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability. J Pharm Sci. 2003;92(12):2386–98.

    Article  CAS  PubMed  Google Scholar 

  6. Yang S, Gursoy RN, Lambert G, Benita S. Enhanced oral absorption of paclitaxel in a novel self-microemulsifying drug delivery system with or without concomitant use of P-Glycoprotein inhibitors. Pharm Res. 2004;21(2):261–70.

    Article  CAS  PubMed  Google Scholar 

  7. DiNunzio JC, Miller DA, Yang W, McGinity JW, Williams RO. Amorphous compositions using concentration enhancing polymers for improved bioavailability of itraconazole. Mol Pharm. 2008;5(6):968–80.

    Article  CAS  PubMed  Google Scholar 

  8. Miller DA, DiNunzio JC, Yang W, McGinity JW, Williams RO. Enhanced in vivo absorption of itraconazole via stabilization of supersaturation following acidic-to-neutral pH transition. Drug Dev Ind Pharm. 2008;34(8):890–902.

  9. Curatolo W, Nightingale J, Herbig S. Utility of Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS) for initiation and maintenance of drug supersaturation in the GI Milieu. Pharm Res. 2009;26(6):1419–31.

    Article  CAS  PubMed  Google Scholar 

  10. Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm Sci. 2009;98(8):2549–72.

    Article  CAS  PubMed  Google Scholar 

  11. Box KJ, Völgyi G, Baka E, Stuart M, Takács-Novák K, Comer JEA. Equilibrium versus kinetic measurements of aqueous solubility, and the ability of compounds to supersaturate in solution - a validation study. J Pharm Sci. 2006;95(6):1298–307.

    Article  CAS  PubMed  Google Scholar 

  12. Stuart M, Box K. Chasing equilibrium: measuring the intrinsic solubility of weak acids and bases. Anal Chem. 2005;77(4):983–90.

    Article  CAS  PubMed  Google Scholar 

  13. Baird JA, Van Eerdenbrugh B, Taylor LS. A classification system to assess the crystallization tendency of organic molecules from undercooled melts. J Pharm Sci. 2010;99(9):3787–806.

    CAS  PubMed  Google Scholar 

  14. Van Eerdenbrugh B, Baird JA, Taylor LS. Crystallization tendency of active pharmaceutical ingredients following rapid solvent evaporation—classification and comparison with crystallization tendency from undercooled melts. J Pharm Sci. 2010;99(9):3826–38.

    PubMed  Google Scholar 

  15. Miyajima M, Koshika A, Okada J, Ikeda M, Nishimura K. Effect of polymer crystallinity on papaverine release from poly (l-lactic acid) matrix. J Controlled Release. 1997;49(2–3):207–15.

    Article  CAS  Google Scholar 

  16. Allen RI, Box KJ, Comer JEA, Peake C, Tam KY. Multiwavelength spectrophotometric determination of acid dissociation constants of ionizable drugs. J Pharm Biomed Anal. 1998;17(4–5):699–712.

    Article  CAS  PubMed  Google Scholar 

  17. Avdeef A, Comer JEA, Thomson SJ. pH-Metric log P. 3. Glass electrode calibration in methanol–water, applied to pKa determination of water-insoluble substances. Anal Chem. 1993;65(1):42–9.

    Google Scholar 

  18. Takács-Novák K, Box KJ, Avdeef A. Potentiometric pKa determination of water-insoluble compounds: validation study in methanol/water mixtures. Int J Pharm. 1997;151(2):235–48.

    Article  Google Scholar 

  19. Avdeef A. pH-metric log P. II: Refinement of partition coefficients and lonization constants of multiprotic substances. J Pharm Sci. 1993;82(2):183–90.

    Article  CAS  PubMed  Google Scholar 

  20. Oh D-M, Curl RL, Amidon GL. Estimating the fraction dose absorbed from suspensions of poorly soluble compounds in humans: a mathematical model. Pharm Res. 1993;10(2):264–70.

    Google Scholar 

  21. Kostewicz ES, Brauns U, Becker R, Dressman JB. Forecasting the oral absorption behavior of poorly soluble weak bases using solubility and dissolution studies in biorelevant media. Pharm Res. 2002;19(3):345–9.

    Article  CAS  PubMed  Google Scholar 

  22. Bevernage J, Forier T, Brouwers J, Tack J, Annaert P, Augustijns P. Excipient-mediated supersaturation stabilization in human intestinal fluids. Mol Pharm. 2010;8(2):564–70.

    Article  Google Scholar 

  23. Yalkowsky SH, He Y. Handbook of aqueous solubility data. 1 edition. CRC Press; 2003.

  24. Avdeef A. pH-metric solubility. 1. Solubility-pH profiles from Bjerrum plots. Gibbs buffer and pKa in the solid state. Pharm Pharmacol Commun. 1998;4:165–78.

    CAS  Google Scholar 

  25. Berbenni V, Marini A, Bruni G, Maggioni A, Cogliati P. Thermoanalytical and spectroscopic characterization of solid state dipyridamole. J Therm Anal Calorim. 2002;68(2):413–22.

    Article  CAS  Google Scholar 

  26. Hoffman JD. Thermodynamic driving force in nucleation and growth processes. J Chem Phys. 1958;29(5):1192–3.

    Article  CAS  Google Scholar 

  27. Murdande SB, Pikal MJ, Shanker RM, Bogner RH. Solubility advantage of amorphous pharmaceuticals: I. A thermodynamic analysis. J Pharm Sci. 2009;99(3):1254–64.

    Article  Google Scholar 

  28. Murdande S, Pikal M, Shanker R, Bogner R. Solubility advantage of amorphous pharmaceuticals: II. Application of quantitative thermodynamic relationships for prediction of solubility enhancement in structurally diverse insoluble pharmaceuticals. Pharm Res. 2010;27(12):2704–14.

    Article  CAS  PubMed  Google Scholar 

  29. DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.

  30. Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colo: THOMSON REUTERS (Healthcare) Inc. Updated periodically.

  31. Russell TL, Berardi RR, Barnett JL, O’Sullivan TL, Wagner JG, Dressman JB. pH-related changes in the absorption of dipyridamole in the elderly. Pharm Res. 1994;11(1):136–43.

    Article  CAS  PubMed  Google Scholar 

  32. Zhou R, Moench P, Heran C, Lu X, Mathias N, Faria TN, et al. pH-dependent dissolution in vitro and absorption in vivo of weakly basic drugs: development of a canine model. Pharm Res. 2005;22(2):188–92.

    Article  CAS  PubMed  Google Scholar 

  33. Alonzo D, Zhang G, Zhou D, Gao Y, Taylor L. Understanding the behavior of amorphous pharmaceutical systems during dissolution. Pharm Res. 2010;27(4):608–18.

    Article  CAS  PubMed  Google Scholar 

  34. Tung H-H, Paul EL, Midler M, McCauley JA. Critical issues in crystallization practice. Crystallization of Organic Compounds: John Wiley & Sons, Inc.; 2008. p. 101–16.

  35. Bonnett PE, Carpenter KJ, Dawson S, Davey RJ. Solution crystallisation via a submerged liquid-liquid phase boundary: oiling out. Chem Commun. 2003;6:698–9.

    Article  Google Scholar 

  36. Veesler S, Lafferrère L, Garcia E, Hoff C. Phase transitions in supersaturated drug solution. Org Process Res Dev. 2003;7(6):983–9.

    Article  CAS  Google Scholar 

  37. Codan L, Bäbler MU, Mazzotti M. Phase diagram of a chiral substance exhibiting oiling out in cyclohexane. Cryst Growth Des. 2010;10(9):4005–13.

    Article  CAS  Google Scholar 

  38. Derdour L. A method to crystallize substances that oil out. Chem Eng Res Des. 2010;88(9):1174–81.

    Article  CAS  Google Scholar 

  39. Svärd M, Gracin S, Rasmuson ÅC. Oiling out or molten hydrate—liquid–liquid phase separation in the system vanillin–water. J Pharm Sci. 2007;96(9):2390–8.

    Article  PubMed  Google Scholar 

  40. He G, Tan RBH, Kenis PJA, Zukoski CF. Metastable States of Small-Molecule Solutions. J Phys Chem B. 2007;111(51):14121–9.

    Google Scholar 

  41. Roelands CPM, ter Horst JH, Kramer HJM, Jansens PJ. Precipitation mechanism of stable and metastable polymorphs of L-glutamic acid. AICHE J. 2007;53(2):354–62.

    Article  CAS  Google Scholar 

  42. Lafferrère L, Hoff C, Veesler S. Study of liquid-liquid demixing from drug solution. J Cryst Growth. 2004;269(2–4):550–7.

    Article  Google Scholar 

  43. Groen H, Roberts KJ. Nucleation, growth, and pseudo-polymorphic behavior of citric acid as monitored in situ by attenuated total reflection fourier transform infrared spectroscopy. J Phys Chem B. 2001;105(43):10723–30.

    Article  CAS  Google Scholar 

  44. Maeda K, Aoyama Y, Fukui K, Hirota S. Novel phenomena of crystallization and emulsification of hydrophobic solute in aqueous solution. J Colloid Interface Sci. 2001;234(1):217–22.

    Article  CAS  PubMed  Google Scholar 

  45. Lai SM, Yuen MY, Siu LKS, Ng KM, Wibowo C. Experimental determination of solid–liquid-liquid equilibrium phase diagrams. AICHE J. 2007;53(6):1608–19.

    Article  CAS  Google Scholar 

  46. Box KJ, Comer JEA. Using measured pK(a), LogP and solubility to investigate supersaturation and predict BCS class. Curr Drug Metab. 2008;9(9):869–78.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments & Disclosures

The authors would like to thank Eli Lilly and Company for providing the Sirius instrument. Pfizer Inc. is acknowledged for providing a fellowship for YLH. BVE is a Postdoctoral Researcher of the 'Fonds voor Wetenschappelijk Onderzoek', Flanders, Belgium.

Author information

Authors and Affiliations

  1. Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA

    Yi-Ling Hsieh, Grace A. Ilevbare, Bernard Van Eerdenbrugh & Lynne S. Taylor

  2. Laboratory for Pharmacotechnology and Biopharmacy, K.U. Leuven, Leuven, Belgium

    Bernard Van Eerdenbrugh

  3. Sirius Analytical, Sussex, UK

    Karl J. Box

  4. Eli Lilly and Company, Indianapolis, Indiana, USA

    Manuel Vincente Sanchez-Felix

  5. 575 Stadium Mall Dr., West Lafayette, Indiana, 47907, USA

    Lynne S. Taylor

Authors
  1. Yi-Ling Hsieh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Grace A. Ilevbare
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bernard Van Eerdenbrugh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Karl J. Box
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Manuel Vincente Sanchez-Felix
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lynne S. Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lynne S. Taylor.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hsieh, YL., Ilevbare, G.A., Van Eerdenbrugh, B. et al. pH-Induced Precipitation Behavior of Weakly Basic Compounds: Determination of Extent and Duration of Supersaturation Using Potentiometric Titration and Correlation to Solid State Properties. Pharm Res 29, 2738–2753 (2012). https://doi.org/10.1007/s11095-012-0759-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-012-0759-8

KEY WORDS

Search

Navigation