Physicochemical stability of lipid injectable emulsions: Correlating changes in large globule distributions with phase separation behavior

Single particle optical sensing (SPOS) and visual inspection were used to characterize a series of lipid injectable emulsions ( n = 21) featuring three lipid types, two electrolyte conditions, and three pH levels (7.0, 4.75, and 2.5). Seven of the twenty-one sample conditions exhibited phase separation instability by visual inspection within 98 h of emulsion preparation. The phase instability was driven by electrolyte type and pH, and “cracking” phenomena were independent of lipid type despite the base lipids ranging almost two orders of magnitude in PFAT 5 levels. Logistic regression analysis showed that the PFAT 5 level determined 1 h after admixture preparation was not correlated with phase separation behavior. However, PFAT 5 measured at later times showed much improved correlations with emulsion instability. PFAT 5 was highly correlated with neighboring cumulative distributions termed PFAT X where X = 2–10 μm. Although the admixtures studied were not clinically relevant, the data demonstrate some limitations of developing empirical correlations between single-point SPOS measurements and emulsion instability. An alternative limit test for emulsion stability based on the rate of change in the large globule counts is proposed to mitigate inherent deficiencies in the current USP Chapter 〈729〉 limit test based on single-point determination of PFAT 5 values.