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

Table III. Observed colorimetric change of stability vials upon storage at 40 C.
Taking into account the peroxide concentration data obtained from the stability studies at the two temperatures, it was clear that the most effective antioxidants were AA, BHT, METH, and SA. By observing the vials for any colorimetric change, METH and SA could be further eliminated because they displayed some yellowing during the tests. Elimination of those two antioxidant additives prompted further investigation of AA and BHT as potential stabilizers for ELPG.

Solubility of AA in ELPG . As previously described, the proposed antioxidants were added to ELPG to obtain a 3% w/v mixture. In some instances, the antioxidant was completely dissolved in the ELPG. In the case of AA, however, excess powder was observed at the bottom of the sealed scintillation vial. This situation is highly undesirable from a commercial point of view because the presence of excess powder within a solvent vehicle has the potential to interfere with formulation design and can severely limit the diversity of manufacturing processes.

After reaction of a 5% v/v solution of the I3PC stock solution with an AA solution (5 mg/mL), the resultant I2PC absorption at 510 nm reached a maximum value after 10 min and was stable for up to 20 min. As a result, the authors decided that 10 min of developing time was needed to allow for full conversion of I3PC to I2PC and to maintain maximum absorption.

After determining the calibration curve for the various concentrations of AA, the solubility of AA in ELPG was determined. This was only 33 5 mg/L at 25 C and 42 mg/L at 37 C. Because this stability group was observed to have excess AA powder within the ELPG throughout the entire course of the stability study, it is safe to assume that the ELPG maintained a saturated solution of AA at approximately 33 mg/L. Furthermore, the solubilized AA was the active component that was able to act as an antioxidant within the ELPG. Because the amount of AA was such a low concentration, it was hypothesized that solubilized AA was constantly being removed from the solution after reacting with the oxygen radicals, thus allowing more of the excess AA to be dissolved and to maintain a constant saturated solution of AA. This hypothesis could be further investigated by monitoring the stability of a 33 mg/L solution of AA in ELPG.

Solubility of BHT in ELPG . In the case of BHT, no excess powder was observed with a 3% w/v solution in ELPG, so it was clear that a nonsaturated solution had been formed within the solvent. The absence of excess powder within a solvent vehicle is desirable from a commercial point of view to prevent potential cross-contamination during processing. Additionally, the absence of powder in the ELPG may negate the need for a "settling" period (where the antioxidant powder is able to settle out of the ELPG after shipping and before use.

It may be assumed that the only component of BHT that is active in limiting the degree of oxidation that can occur within the ELPG is that which is in solution. It was relevant, therefore, to determine the solubility of BHT in the ELPG (not previously reported in the literature). At 25 C, the solubility of BHT in ELPG was 0.311 0.004 g/mL, and at 37 C, the solubility was 0.378 0.002 g/mL. These results reveal that BHT demonstrated an extremely high degree of solubility within ELPG. BHT can be solubilized to a maximum level of approximately 30% w/v, which is considerably higher than the initial 3% w/v used throughout the stability study. Considering the extended stability allowed by using a 3% w/v solution of BHT within ELPG, it is reasonable to assume that higher concentrations of BHT would allow for even longer stability by reducing the potential of solvent oxidation. This aspect of the research warrants further investigation to determine the optimal levels of BHT required for stabilization of ELPG over specific time periods.

Figure 4: Calibration curve used for the accurate determination of peroxide in ethyl lactate of pharmaceutical grade using a reverse–absorption method.
Accurate determination of peroxide concentration in ELPG. A calibration curve obtained for the standard peroxide concentration using the reverse-absorbance method is shown in Figure 4. The curve displays good linearity (R2 value = 0.9994) with an absorbance intercept of 4.2 10-3 and a slope of 1 10-4, in accordance with the Beer–Lambert law. The initial concentration of peroxides within the partially oxidized sample of ELPG was 42 8 mg/L ( standard deviation). This peroxide concentration is comparable to a value of 30 mg/L obtained from the peroxide test-strip analysis. Although the standard deviation of the analysis is relatively high, it may be considered an improvement in detection compared with the peroxide test-strip method. The biggest problems encountered while using the test strips were operator-dependent variability and variation in the uniformity of the colorimetric change associated with the developing time of the test strips. The second problem has the potential to cause great variation in the data as observed in the stability study data (see Figures 2 and 3). It is an artifact that appears with the peroxide concentrations in the control samples when the concentration peaks at 100 mg/L and suddenly drops to 30 mg/L. This type of observed observation is the biggest variability that can occur because the color change on the test strip is rapid within this concentration range. It was also highly likely that this fluctuation in concentration also occurred at the low range of analysis, but was less obvious from the data range under investigation during these studies.


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