Skip to main content

Advertisement

SpringerLink
Log in

Ultrasonication as a Potential Tool to Predict Solute Crystallization in Freeze-Concentrates

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

Abstract

Purpose

We hypothesize that ultrasonication can accelerate solute crystallization in freeze-concentrates. Our objective is to demonstrate ultrasonication as a potential predictive tool for evaluating physical stability of excipients in frozen solutions.

Methods

The crystallization tendencies of lyoprotectants (trehalose, sucrose), carboxylic acid buffers (citric, tartaric, malic, and acetic) and an amino acid buffer (histidine HCl) were studied. Aqueous solutions of buffers, lyoprotectants and mixtures of the two were cooled from room temperature to −20°C and sonicated to induce solute crystallization. The crystallized phases were identified by X-ray diffractometry (laboratory or synchrotron source).

Results

Sonication accelerated crystallization of trehalose dihydrate in frozen trehalose solutions. Sonication also enhanced solute crystallization in tartaric (200 mM; pH 5), citric (200 mM pH 4) and malic (200 mM; pH 4) acid buffers. At lower buffer concentrations, longer annealing times following sonication were required to facilitate solute crystallization. The time for crystallization of histidine HCl progressively increased as a function of sucrose concentration. The insonation period required to effect crystallization also increased with sucrose concentration.

Conclusions

Sonication can substantially accelerate solute crystallization in the freeze-concentrate. Ultrasonication may be useful in assessing the crystallization tendency of formulation constituents used in long term frozen storage and freeze-drying.

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

Similar content being viewed by others

References

  1. Singh SK, Kolhe P, Wang W, Nema S. Large-scale freezing of biologics. Bio Proc Int. 2009;7:32–44.

    CAS  Google Scholar 

  2. Jameel F, Padala C, Randolph TW. Strategies for bulk storage and shipment of proteins. Formulation and process development strategies for manufacturing biopharmaceuticals. John Wiley & Sons, Inc., 2010, pp. 677-704.

  3. Piedmonte D, Summers C, McAuley A, Karamujic L, Ratnaswamy G. Sorbitol crystallization can lead to protein aggregation in frozen protein formulations. Pharm Res. 2007;24:136–46.

    Article  CAS  PubMed  Google Scholar 

  4. Singh S, Kolhe P, Mehta A, Chico S, Lary A, Huang M. Frozen state storage instability of a monoclonal antibody: aggregation as a consequence of trehalose crystallization and protein unfolding. Pharm Res. 2011;28:873–85.

    Article  CAS  PubMed  Google Scholar 

  5. Sundaramurthi P, Shalaev E, Suryanarayanan R. Calorimetric and diffractometric evidence for the sequential crystallization of buffer components and consequent pH swing in frozen solutions. J Phys Chem Lett. 2010;114:4915–23.

    Article  CAS  Google Scholar 

  6. Pikal-Cleland KA, Rodríguez-Hornedo N, Amidon GL, Carpenter JF. Protein denaturation during freezing and thawing in phosphate buffer systems: monomeric and tetrameric [beta]-Galactosidase. Arch Biochem Biophys. 2000;384:398–406.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Ni P, Ding J, Rao B. In situ cryogenic Raman spectroscopic studies on the synthetic fluid inclusions in the systems H2O and NaCl-H2O. Chin Sci Bull. 2006;51:108–14.

    Article  CAS  Google Scholar 

  9. Cho H, Shepson PB, Barrie LA, Cowin JP, Zaveri R. NMR Investigation of the quasi-brine layer in ice/brine mixtures. J Phys Chem B. 2002;106:11226–32.

    Google Scholar 

  10. Murase N, Franks F. Salt precipitation during the freeze-concentration of phosphate buffer solutions. Biophys Chem. 1989;34:293–300.

    Google Scholar 

  11. Kim AI, Akers MJ, Nail SL. The physical state of mannitol after freeze-drying: effects of mannitol concentration, freezing rate, and a noncrystallizing cosolute. J Pharm Sci. 1998;87:931–5.

    Article  CAS  PubMed  Google Scholar 

  12. Sundaramurthiand P, Suryanarayanan R. Influence of crystallizing and non-crystallizing cosolutes on trehalose crystallization during freeze-drying. Pharm Res. 2010;27:2384–93.

    Article  Google Scholar 

  13. Carless JE. Accelerated tests for physical stability of pharmaceutical products. Pestic Sci. 1970;1:270–3.

    Article  CAS  Google Scholar 

  14. Fischer P, Eugster A, Windhab EJ, Schuleit M. Predictive stress tests to study the influence of processing procedures on long term stability of supersaturated pharmaceutical o/w creams. Int J Pharm. 2007;339:189–96.

    Article  CAS  PubMed  Google Scholar 

  15. Lucas TI, Bishara RH, Seevers RH. A stability program for the distribution of drug products. Pharm Technol. 2004;28:68–73.

    Google Scholar 

  16. Ferreira C, Crespo R, Martins PM, Gales L, Rocha F, Damas AM. Small temperature oscillations promote protein crystallization. Cryst Eng Comm. 2011;13:3051–6.

    Article  CAS  Google Scholar 

  17. Kordylla A, Koch S, Tumakaka F, Schembecker G. Towards an optimized crystallization with ultrasound: effect of solvent properties and ultrasonic process parameters. J Cryst Growth. 2008;310:4177–84.

    Article  CAS  Google Scholar 

  18. Kordylla A, Krawczyk T, Tumakaka F, Schembecker G. Modeling ultrasound-induced nucleation during cooling crystallization. Chem Eng Sci. 2009;64:1635–42.

    Article  CAS  Google Scholar 

  19. Ichitsubo T, Matsubara E, Yamamoto T, Chen HS, Nishiyama N, Saida J, et al. Microstructure of fragile metallic glasses inferred from ultrasound-accelerated crystallization in Pd-based metallic glasses. Phys Rev Lett. 2005;95:245501.

    Article  CAS  PubMed  Google Scholar 

  20. Zheng L, Sun D-W. Innovative applications of power ultrasound during food freezing processes—a review. Trends Food SciTechnol. 2006;17:16–23.

    Article  CAS  Google Scholar 

  21. Ruecroft G, Hipkiss D, Ly T, Maxted N, Cains PW. Sonocrystallization: the use of ultrasound for improved industrial crystallization. Org Proc Res Dev. 2005;9:923–32.

    Article  CAS  Google Scholar 

  22. Kim S, Wei C, Kiang S. Crystallization process development of an active pharmaceutical ingredient and particle engineering via the use of ultrasonics and temperature cycling. Org Proc Res Dev. 2003;7:997–1001.

    Article  CAS  Google Scholar 

  23. Nakagawa K, Hottot A, Vessot S, Andrieu J. Influence of controlled nucleation by ultrasounds on ice morphology of frozen formulations for pharmaceutical proteins freeze-drying. Chem Eng Proc : Process Intensific. 2006;45:783–91.

    Article  CAS  Google Scholar 

  24. Powder Diffraction File. histidine HCl monohydrate, Card # 00-054-1737; DL-malic acid, Card # 00-031-1776; Na hydrogen malate, Card # 00-051-2464, Na citrate monohydrate, Card # 00-043-1524; Na acetate trihydrate, Card # 00-028-1030., International Centre for Diffraction Data, Newtown Square, PA, 2004.

  25. Varshney D, Kumar S, Shalaev E, Sundaramurthi P, Kang S-W, Gatlin L, et al. Glycine crystallization in frozen and freeze-dried systems: effect of pH and buffer concentration. Pharm Res. 2007;24:593–604.

    Article  CAS  PubMed  Google Scholar 

  26. Beyer KD, Schroeder JR, Pearson CS. Solid/Liquid phase diagram of the ammonium Sulfate/Maleic Acid/Water System. J Phys Chem A. 2011;115:13842–51.

    Article  CAS  PubMed  Google Scholar 

  27. Banker GS, Siepmann J, Rhodes C. Modern pharmaceutics, CRC Press, 2002.

  28. Green W. The “melting-point” of hydrated sodium acetate: solubility curves. J Phys Chem. 1908;12:655–60.

    Article  Google Scholar 

  29. Dahms A. Nachträge und Bemerkungen zu der Arbeit über Gefrierpunkte binärer Gemenge. Annalen der Physik. 1896;296:119–23.

    Article  Google Scholar 

  30. Izutsu K-i, Yoshioka S, Terao T. Decreased protein-stabilizing effects of cryoprotectants due to crystallization. Pharm Res. 1993;10:1232–7.

    Article  CAS  PubMed  Google Scholar 

  31. Crowe LM, Reid DS, Crowe JH. Is trehalose special for preserving dry biomaterials? Biophys J. 1996;71:2087–93.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Coutinho C, Bernardes E, Félix D, Panek AD. Trehalose as cryoprotectant for preservation of yeast strains. J Biotechnol. 1988;7:23–32.

    Article  CAS  Google Scholar 

  33. Akers MJ. Excipient–drug interactions in parenteral formulations. J Pharm Sci. 2002;91:2283–300.

    Article  CAS  PubMed  Google Scholar 

  34. Sundaramurthiand P, Suryanarayanan R. Trehalose crystallization during freeze-drying: implications on lyoprotection. J Phys Chem Lett. 2010;1:510–4.

    Article  Google Scholar 

  35. Miller DP, de Pablo JJ, Corti H. Thermophysical properties of trehalose and its concentrated aqueous solutions. Pharm Res. 1997;14:578–90.

    Article  CAS  PubMed  Google Scholar 

  36. Sundaramurthi P, Patapoff TW, Suryanarayanan R. Crystallization of trehalose in the frozen solutions and its phase behavior during drying. Pharm Res. 2010;27:2374–83.

    Article  CAS  PubMed  Google Scholar 

  37. Luque de Castro MD, Priego-Capote F. Ultrasound-assisted crystallization (sonocrystallization). Ultrason Sonochem. 2007;14:717–24.

    Article  CAS  PubMed  Google Scholar 

  38. Young FE, Jones FT. Sucrose hydrates. The sucrose–water phase diagram. J Physic Coll Chem. 1948;53:1334–50.

    Article  Google Scholar 

  39. Roos YH. Chapter 5 - food components and polymers. San Diego: Phase Transitions in Foods, Academic Press; 1995. p. 109–56.

    Google Scholar 

  40. Sundaramurthiand P, Suryanarayanan R. Thermophysical properties of carboxylic and amino acid buffers at subzero temperatures: relevance to frozen state stabilization. J Phys Chem B. 2011;115:7154–64.

    Article  Google Scholar 

  41. Kolhe P, Amend E, Singh SK. Impact of freezing on pH of buffered solutions and consequences for monoclonal antibody aggregation. Biotechnol Prog. 2010;26:727–33.

    Article  CAS  PubMed  Google Scholar 

  42. Nail SL, and Gatlin LA. Freeze-drying: Principles and practice. Pharmaceutical Dosage Forms: Parenteral Medications, pp. 353-382.

  43. Gómez G, Pikal MJ, Rodríguez-Hornedo N. Effect of initial buffer composition on pH changes during far-from-equilibrium freezing of sodium phosphate buffer solutions. Pharm Res. 2001;18:90–7.

    Article  PubMed  Google Scholar 

  44. Cho H, Shepson PB, Barrie LA, Cowin JP, Zaveri R. NMR investigation of the Quasi-Brine layer in Ice/Brine Mixtures. J Phys Chem B. 2002;106:11226–32.

    Article  CAS  Google Scholar 

  45. Muraseand N, Franks F. Salt precipitation during the freeze-concentration of phosphate buffer solutions. Biophys Chem. 1989;34:293–300.

    Article  Google Scholar 

  46. Sundaramurthiand 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;28:374–85.

    Article  Google Scholar 

  47. van den Bergand 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;81:319–29.

    Article  Google Scholar 

  48. Varshney D, Kumar S, Shalaev E, Kang S-W, Gatlin L, Suryanarayanan R. Solute crystallization in frozen systems–use of synchrotron radiation to improve sensitivity. Pharm Res. 2006;23:2368–74.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments and Disclosures

The work was partially supported by the William and Mildred Peters endowment fund. Parts of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC program. Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357.

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

    Vishard Ragoonanan & Raj Suryanarayanan

Authors
  1. Vishard Ragoonanan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raj Suryanarayanan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raj Suryanarayanan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ragoonanan, V., Suryanarayanan, R. Ultrasonication as a Potential Tool to Predict Solute Crystallization in Freeze-Concentrates. Pharm Res 31, 1512–1524 (2014). https://doi.org/10.1007/s11095-013-1257-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-013-1257-3

Key words

Search

Navigation