Ethyl Lactate as a Pharmaceutical-Grade Excipient and Development of a Sensitive Peroxide Assay - Pharmaceutical Technology

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Ethyl Lactate as a Pharmaceutical-Grade Excipient and Development of a Sensitive Peroxide Assay
The authors investigate whether the addition of an antioxidant could be used to stabilize the solvent ethyl lactate by preventing the formation of peroxides.

Pharmaceutical Technology
Volume 33, Issue 5, pp. 74-84

Results and discussion

Figure 3: Results of the stability study of ethyl lactate of pharmaceutical grade (ELPG) performed at 40 C. Each antioxidant was added at 3% w/v into ELPG. The antioxidants studied were ascorbic acid (AA), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid (CA), methionine (METH), sodium ascorbate (SA), sucrose (SU), and tocopherol (vitamin E [VE]). C1 and N2 represent the control groups. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
ELPG stability study. At 25 C, it is apparent that all the antioxidant additives reduced the concentration of peroxides in the ELPG, and several showed reduced levels of peroxide for some period of time (see Figure 2). The best performing additives were AA, BHT, SA, and VE because the peroxide concentrations did not exceed 30 mg/L for at least six months. BHA, CA, and SU displayed an initial reduced concentration of peroxides for up to one month, but then there was a rapid increase in levels, so these additives were considered to be ineffective at the concentrations used. At 40 C, there is a similar display of effectiveness (see Figure 3). The profiles for BHA, CA, and SU, however, showed a rapid increase in peroxide concentrations after three days. This observation indicated that these additives were only effective for a limited period and so could be eliminated as potential stabilizing antioxidants. The control groups with no additives showed similar degradation at 25 and 40C, and 100 mg/L peroxide levels were observed after seven days. A rapid rise and fall of peroxide levels were observed within the control group containing the purged nitrogen blanket head. This phenomenon was observed within several groups during the course of the study, but it is not an accurate indication of the actual peroxide levels within the container. The sharp rise and fall in peroxide quantification was merely an artifact of the test-strip determination method, as this method relies on the operator's assessment of a colorimetric change observed on the test strip when exposed to peroxide levels. This type of assessment is generally a guide and may be subject to individual interpretation. For the ELPG sample that contained METH, the results indicated a lag time in the reduction of peroxide concentration that lasted for up to three to four days at 25 C. This lag time was observed to be more rapid at 40 C and was probably because of the solubility of METH within the ELPG. (The METH was more soluble at this elevated temperature and therefore had increased antioxidant capacity within the ELPG.)

Table II. Observed colorimetric change of stability vials upon storage at 25 C.*
Observing the vials upon storage revealed another issue with the long-term stability of the samples. Although the peroxide levels had been deemed low, in some cases, degradation occurred during the stability study. The numbers assigned to a yellowish colorimetric change for samples stored at 25 C are specified in Table II. No discernible color change was visible in the ELPG containing AA, BHT, CA, or SU in addition to the control samples C1 and N2. The samples containing BHA and VE showed only a moderate change to a pale straw yellow color. The samples of METH and SA stored at 25 C showed a strong change to a deep yellow color that occurred more rapidly in the sample containing SA. The same trend in yellowing was observed for the samples when stored at 40 C (see Table III). The onset of discoloration, however, was much more rapid and turned to a darker yellowish-brown color at this temperature.


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