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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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

Keywords

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

Fingerprint Dive into the research topics of 'Effect of Formulation and Process Parameters on the Disproportionation of Indomethacin Sodium in Buffered Lyophilized Formulations'. Together they form a unique fingerprint.

Cite this