Skip to main content
SpringerLink
Log in

Effect of Formulation and Process Parameters on the Disproportionation of Indomethacin Sodium in Buffered Lyophilized Formulations

  • Research Paper
  • Theme: Formulation and Manufacturing of Solid Dosage Forms
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

(i) To investigate buffer salt crystallization and the consequent pH shifts during the freezing stage of the lyophilization of indomethacin sodium (IMCNa) in aqueous sodium phosphate buffer. (ii) To determine the effect of pH shift on the disproportionation of IMCNa in lyophilized formulations.

Methods

Prelyophilization solutions containing IMCNa in sodium phosphate buffer, at initial buffer concentrations ranging from 10 to 100 mM (pH 7.0), and at IMCNa concentrations of 5, 10 & 15 mg/ml, were investigated. Their phase behavior during cooling was monitored by low temperature X- ray diffractometry (XRD), differential scanning calorimetry (DSC) and pH measurements. The final lyophiles were characterized by infrared spectroscopy (IR) and XRD.

Results

Upon cooling to −25°C, pronounced pH shifts were observed only in IMCNa buffered solutions containing high initial buffer concentration (100 mM), due to crystallization of Na2HPO4.12H2O. In the final lyophiles, disproportionation of IMCNa to the free acid (IMC) was observed in systems with buffer concentrations ≥50 mM, but not low buffer concentration (10 mM). At intermediate buffer concentrations (35 & 20 mM) the disproportionation depended on IMCNa concentration. The initial concentrations of both buffer and IMCNa influenced the buffer crystallization.

Conclusions

During freeze drying, selective crystallization of a buffer component and the consequent pH shift can cause disproportionation of IMCNa. This can prolong the reconstitution time or retain particles of the poorly soluble free acid in the reconstituted solution.

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.
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Abbreviations

API:

Active pharmaceutical ingredient

DI:

Deionized water

DSC:

Differential scanning calorimetry

EMF:

Electromotive force

FT-IR:

Fourier-transform infrared spectroscopy

IMC:

Indomethacin

IMCNa:

Indomethacin sodium

IR:

Infrared spectroscopy

NaP:

Sodium phosphate buffer

XRD:

Powder x-ray diffractometry

REFERENCES

  1. Bross PF, Kane R, Farrell AT, Bross PF, Kane R, Farrell AT, et al. Approval Summary for Bortezomib for Injection in the Treatment of Multiple Myeloma. Clin Cancer Res. 2004;10(12):3954–64.

    Article  CAS  PubMed  Google Scholar 

  2. Thakral S, Suryanarayanan R. Salt formation during freeze-drying - an approach to enhance indomethacin dissolution. Pharm Res. 2015;32(11):3722–31.

    Article  CAS  PubMed  Google Scholar 

  3. van den Berg L, Rose D. Effect of freezing on the pH and composition of sodium and potassium phosphate solutions: the reciprocal system KH2PO4-Na2HPO4-H2O. Arch Biochem Biophys. 1959;81(2):319–29.

    Article  Google Scholar 

  4. Gomez G, Pikal MJ, Rodriguez-Hornedo N. Effect of initial buffer composition on pH changes during far-from-equilibrium freezing of sodium phoaphate buffer solutions. Pharm Res. 2001;18(1):90–7.

    Article  CAS  PubMed  Google Scholar 

  5. Szkudlarek BA. Selective crystallization of phosphate buffer components and pH changes during freezing: Implication to protein stability. Ph.D. Thesis, University of Michigan. 1997.

  6. Sundaramurthi P, Shalaev E, Suryanarayanan R. “pH Swing” in Frozen Solutions—Consequence of Sequential Crystallization of Buffer Components. J Phys Chem Lett. 2010;1(1):265–8.

    Article  CAS  Google Scholar 

  7. Sundaramurthi P, Shalaev E, Suryanarayanan R. Calorimetric and Diffractometric Evidence for the Sequential Crystallization of Buffer Components and the Consequential pH Swing in Frozen Solutions. J Phys Chem B. 2010;114(14):4915–23.

    Article  CAS  PubMed  Google Scholar 

  8. Pikal-Cleland KA, Carpenter JF. Lyophilization-induced protein denaturation in phosphate buffer systems: Monomeric and tetrameric β-galactosidase. J Pharm Sci. 2001;90(9):1255–68.

    Article  CAS  PubMed  Google Scholar 

  9. Hora MS, Rana RK, Smith FW. Lyophilized formulations of recombinant tumor necrosis factor. Pharm Res. 1992;9(1):33–6.

    Article  CAS  PubMed  Google Scholar 

  10. Hill JP, Dickinson MF. Enzyme storage—to freeze or not to freeze? Biochem Soc Trans. 1989;17(6):1079–80.

    Article  CAS  PubMed  Google Scholar 

  11. Lam XM, Costantino HR, Overcashier DE, Nguyen TH, Hsu CC. Replacing succinate with glycolate buffer improves the stability of lyophilized interferon-gamma. Int J Pharm. 1996;142(1):85–95.

    Article  CAS  Google Scholar 

  12. Larsen SS. Studies on stability of drugs in frozen systems. IV. The stability of benzylpenicillin sodium in frozen aqueous solutions. Dan Tidsskr Farm. 1971;45(9):307–16.

    CAS  PubMed  Google Scholar 

  13. te Booy MPWM, de Ruiter RA, de Meere ALJ. Evaluation of the Physical Stability of Freeze-Dried Sucrose-Containing Formulations by Differential Scanning Calorimetry. Pharm Res. 1992;9(1):109–14.

    Article  Google Scholar 

  14. Stephenson GA, Aburub A, Woods TA. Physical Stability of Salts of Weak Bases in the Solid-State. J Pharm Sci. 2011;100(5):1607–17.

    Article  CAS  PubMed  Google Scholar 

  15. Zannou EA, Ji Q, Joshi YM, ATM S. Stabilization of the maleate salt of a basic drug by adjustment of microenvironmental pH in solid dosage form. Int J Pharm. 2007;337(1):210–8.

    Article  CAS  PubMed  Google Scholar 

  16. Merritt JM, Viswanath SK, Stephenson GA. Implementing Quality by Design in Pharmaceutical Salt Selection: A Modeling Approach to Understanding Disproportionation. Pharm Res. 2012;30(1):1–15.

    Google Scholar 

  17. Rohrs B, Thamann T, Ping G, Stelzer D, Bergren M, Chao R. Tablet Dissolution Affected by a Moisture Mediated Solid-State Interaction Between Drug and Disintegrant. Pharm Res. 1999;16(12):1850–6.

    Article  CAS  PubMed  Google Scholar 

  18. Williams AC, Cooper VB, Thomas L, Griffith LJ, Petts CR, Booth SW. Evaluation of drug physical form during granulation, tabletting and storage. Int J Pharm. 2004;275(1):29–39.

    Article  CAS  PubMed  Google Scholar 

  19. Unger EF. Weighing Benefits and Risks — The FDA ’ s Review of Prasugrel. N Engl J Med. 2009;361(10):942–5.

    Article  CAS  PubMed  Google Scholar 

  20. Koranne S, Govindarajan R, Suryanarayanan R. Investigation of spatial heterogeneity of salt disproportionation in tablets by synchrotron X-ray diffractometry. Mol Pharm. 2017;14(4):1133–44.

    Article  CAS  PubMed  Google Scholar 

  21. Guo Y, Byrn SR, Zografi G. Effects of Lyophilization on the Physical Characteristics and Chemical Stability of Amorphous Quinapril Hydrochloride. Pharm Res. 2000;17(8):930–5.

    Article  CAS  PubMed  Google Scholar 

  22. Brien MO, Mccauley J, Cohen E. Indomethacin. In: Florey K, editor. Analytical profiles of drug substances, Vol. 13. New York: Academic Press; 1984. p. 211–8.

  23. James AR. Crystalline sodium and potassium indomethacin and their trihydrates, process for preparing and pharmaceutical compositions containing the same. 1980;EP 0006223 A1. https://www.google.com/patents/EP0006223A1?cl=en

  24. De Marzi S, Morini V. Use of meglumine indomethacin in the treatment of pain due to neoplastic disease. Clin Ter. 1972;62(2):175–80.

    PubMed  Google Scholar 

  25. Indocin IV. Product Information, Merck, Whitehouse Station, NJ. 2002. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018878s027lbl.pdf

  26. Siddiqui A, Rahman Z, Khan SR, Awotwe-otoo D, Khan MA. Root cause evaluation of particulates in the lyophilized indomethacin sodium trihydrate plug for parenteral administration. Int J Pharm. 2014;473(1):545–51.

    Article  CAS  PubMed  Google Scholar 

  27. Jain AK. Solubilization of indomethacin using hydrotropes for aqueous injection. Eur J Pharm Biopharm. 2008;68(3):701–14.

    Article  CAS  PubMed  Google Scholar 

  28. Taylor LS, Zografi G. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm Res. 1997;14(12):1691–8.

    Article  CAS  PubMed  Google Scholar 

  29. Tong P, Zografi G. Solid-state characteristics of amorphous sodium indomethacin relative to its free acid. Pharm Res. 1999;16(8):1186–92.

    Article  CAS  PubMed  Google Scholar 

  30. Aceves-Hernandez JM, Nicolás-Vázquez I, Aceves FJ, Hinojosa-Torres J, Paz M, Castañ OVM. Indomethacin polymorphs: Experimental and conformational analysis. J Pharm Sci. 2009;98(7):2448–63.

    Article  CAS  PubMed  Google Scholar 

  31. Surwase SA, Boetker JP, Saville D, Boyd BJ, Gordon KC, Peltonen L, et al. Indomethacin: New polymorphs of an old drug. Mol Pharm. 2013;10(12):4472–80.

    Article  CAS  PubMed  Google Scholar 

  32. Gomez G. Crystallization-related pH changes during freezing of sodium phosphate buffer solutions. Ph.D. Thesis, University of Michigan. 2000.

  33. Lin S-Y. Isolation and Solid-state Characteristics of a New Crystal Form of lndomet haci n. J Pharm Sci. 1991;81(6):572–6.

    Article  Google Scholar 

  34. Borka L. The polymorphism of indomethacine. New modifications, their melting behavior and solubility. Acta Pharm Suec. 1974;11(3):295–303.

    CAS  PubMed  Google Scholar 

  35. Tong P, Zografi G. A study of amorphous molecular dispersions of indomethacin and its sodium salt. J Pharm Sci. 2001;90(12):1991–2004.

    Article  CAS  PubMed  Google Scholar 

  36. Varshney DB, Kumar S, Shalaev EY, Kang SW, Gatlin LA, Suryanarayanan R. Solute crystallization in frozen systems-use of synchrotron radiation to improve sensitivity. Pharm Res. 2006;23(10):2368–74.

    Article  CAS  PubMed  Google Scholar 

  37. Tong P, Zografi G. Effects of Water Vapor Absorption on the Physical and Chemical Stability of Amorphous Sodium Indomethacin. AAPS PharmSciTech. 2004;5(2):1–8.

    Article  Google Scholar 

  38. Sundaramurthi P, Suryanarayanan R. The effect of crystallizing and non-crystallizing cosolutes on succinate buffer crystallization and the consequent pH shift in frozen solutions. Pharm Res. 2011;28(2):374–85.

    Article  CAS  PubMed  Google Scholar 

  39. Trissel LA. Indomethacin sodium trihydrate. In: Handbook on injectable drugs. 11th ed. Bethesda: American Society of Health-System Pharmacists; 2001. p. 745–6.

  40. Kumar L, Baheti A, Mokashi A, Bansal AK. Effect of counterion on the phase behaviour during lyophilization of indomethacin salt forms. Eur J Pharm Sci. 2011;44(1):136–41.

    Article  CAS  PubMed  Google Scholar 

  41. Nail SL, Jiang S, Chongprasert S, Knopp SA. Fundamentals of freeze-drying. In: Nail SL, Akers MJ, editors. Development and manufacture of protein pharmaceuticals. New York: Kluwer Academic/Plenum Publisher; 2002.

  42. Cavatur RK, Suryanarayanan R. Characterization of Frozen Aqueous Solutions by Low Temperature X-ray Powder Diffractometry. Pharm Res. 1998;15(2):194–9.

    Article  CAS  PubMed  Google Scholar 

  43. Suzuki T, Franks F. Solid–liquid phase transitions and amorphous states in ternary sucrose–glycine–water systems. J Chem Soc Faraday Trans. 1993;89(17):3283–8.

    Article  CAS  Google Scholar 

  44. Pikal-Cleland KA, Cleland JL, Anchordoquy TJ, Carpenter JF. Effect of glycine on pH changes and protein stability during freeze-thawing in phosphate buffer systems. J Pharm Sci. 2002;91(9):1969–79.

    Article  CAS  PubMed  Google Scholar 

  45. Wu C, Shamblin S, Varshney D, Shalaev E. Advance understanding of buffer behavior during lyophilization. In: Varshney D, Singh M, editors. Lyophilized biologics and vaccines. New York: Springer; 2015. p. 25–41.

Download references

Acknowledgments and Disclosures

SK was partially funded by the 3 M Science and Technology Fellowship. The project was partially supported by the William and Mildred Peters endowment fund. The XRD studies in this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC program. We thank Vishard Ragoonanan, PhD for helping with the low temperature pH experiments.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 9-177 WDH, 308 Harvard Street S.E, Minneapolis, Minnesota, 55455, USA

    Sampada Koranne, Seema Thakral & Raj Suryanarayanan

Authors
  1. Sampada Koranne
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seema Thakral
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Raj Suryanarayanan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raj Suryanarayanan.

Additional information

Guest Editors: Tony Zhou and Tonglei Li

Electronic supplementary material

ESM 1

(DOCX 718 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Koranne, S., Thakral, S. & Suryanarayanan, R. Effect of Formulation and Process Parameters on the Disproportionation of Indomethacin Sodium in Buffered Lyophilized Formulations. Pharm Res 35, 21 (2018). https://doi.org/10.1007/s11095-017-2310-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11095-017-2310-4

KEY WORDS

Search

Navigation