Salt formation during freeze-drying - An approach to enhance indomethacin dissolution

Seema Thakral, Raj Suryanarayanan

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Purpose: (i) Prepare a freeze-dried injectable indomethacin (IMC) dosage form. (ii) Convert IMC to its tris salt during freeze-drying so as to facilitate rapid dissolution (reconstitution). (iii) Modulate salt crystallinity by annealing the frozen solution. Methods: Aqueous IMC solutions buffered with tris were freeze dried, with or without annealing the frozen solutions. The lyophiles were characterized by X-ray diffractometry, differential scanning calorimetry and infra-red spectroscopy and also subjected to water sorption and dissolution studies. Results: Based on IR spectroscopy, the final lyophile was confirmed to contain the IMC tris salt. In the absence of annealing, the lyophile was X-ray amorphous with a glass transition temperature of 19°C. Annealing the frozen solutions caused a substantial increase in lyophile crystallinity. Interestingly, both the amorphous and partially crystalline lyophiles dissolved "instantaneously" and completely in the dissolution medium. In contrast, the crystalline IMC as well as its physical mixture with tris exhibited much slower dissolution with ∼ 50% drug dissolved in 30 min. Conclusion: In situ IMC tris salt formation resulted in an elegant lyophile with a very short reconstitution time. Tris served two roles - as a buffer in the prelyophilization solution and as the counterion for the salt in the final lyophile. This approach for solubility enhancement could be extended to other acidic drugs wherein salt formation was observed during freeze-drying.

Original languageEnglish (US)
Pages (from-to)3722-3731
Number of pages10
JournalPharmaceutical research
Issue number11
StatePublished - Nov 1 2015

Bibliographical note

Funding Information:
ST was partially supported by the William and Mildred Peters Endowment fund. We thank Tanmoy Sadhukha, PhD for suggesting the use of tris buffer. The critical comments of Naveen Thakral, PhD and Pinal Mistry are appreciated. Parts of this work were carried out in the Characterization Facility, University of Minnesota, a member of the NSF-funded Materials Research Facilities Network ( ).

Publisher Copyright:
© 2015 Springer Science+Business Media New York.


  • IR spectroscopy
  • annealing
  • freeze-drying
  • indomethacin
  • salt
  • tris


Dive into the research topics of 'Salt formation during freeze-drying - An approach to enhance indomethacin dissolution'. Together they form a unique fingerprint.

Cite this