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

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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.

Original languageEnglish (US)
Article number21
JournalPharmaceutical research
Volume35
Issue number1
DOIs
StatePublished - Jan 1 2018

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

  • buffer crystallization
  • lyophilization
  • pH shift
  • salt disproportionation
  • salt stability

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