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

The use of organic solvents for coating solid oral dosage forms has diminished over the past decade because many harmful effects are associated with exposure to these solvents. Acute effects of solvent inhalation in humans and animals include narcosis, anesthesia, central-nervous-system depression, and respiratory problems (1). As a result, the industry has shifted from organic-based systems to aqueous-based technologies. Tablet coating is a prime example of this change.

Advantages and properties of ethyl lactate

Ethylcellulose and acrylic polymers, which traditionally used either acetone or isopropyl alcohol (IPA), have been replaced by popular latex and pseudolatex systems such as the Eudragit (Evonik, Darmstadt, Germany) and Aquacoat (FMC BioPolymer, Philadelphia) product lines of coating dispersions. The advantages of these systems include a reduced health risk for the operator, a reduction in environmental contamination, low cost, and low risk of combustion or explosion. A disadvantage of aqueous coating systems is that they generally require more energy because of the low vapor pressure of water. Also, an increased quantity of plasticizer is required in an aqueous-based system to obtain a coating finish that is comparable with a coating finish in an organic-based system. Assuming appropriate equipment is used, organic-based systems are limited because of toxicity or environmental issues. A novel approach for pharmaceutical applications would be a user-friendly organic solvent that is environmentally friendly and poses little health risk. An example is ethyl lactate of pharmaceutical grade (ELPG) (2).

Crude ethyl lactate is prepared by the esterification of lactic acid and ethanol (3). Lactic acid and ethanol are from renewable sources and may be obtained by fermenting corn starches, an environmentally acceptable process (4). Ethyl lactate can be manufactured from a continuous process (3). Enhanced yields of ethyl lactate may be prepared by using an acid-catalyzed preparation step, and zeolites may be used to remove water from the reaction vessel, a byproduct of the esterification process (5). The pharmaceutical grade is prepared by purifying raw ethyl lactate (2).

Ethyl 2-hydroxypropionate (ethyl lactate) is used in many applications, including inks, flavorings, coatings, silicone oil and grease removal, and in the semiconductor industry (6). It is a replacement solvent for N-methylpyrrolidone, toluene, acetone, and xylene (7). As a "green" solubilizing agent, ethyl lactate has many advantages compared with other organic-based solubilizing agents. It may be readily purified because it is prepared from natural and renewable sources. It is completely biodegradable to carbon dioxide and water. It is easy and inexpensive to recycle (7). It is approved by the US Food and Drug Administration as an adjuvant solubilizing ingredient for flavors and pharmaceutical dyes. (8). It is a nonozone-depleting chemical, poses no hazard as an air pollutant, and is noncarcinogenic and noncorrosive (7). The authors propose that this ultrapure pharmaceutical grade of ethyl lactate is suitable in various pharmaceutical applications.

Figure 1: The basic steps of degradation of ethyl lactate of pharmaceutical grade: (a) the mechanism of hydrolysis to form acid and alcohol and (b) oxidation forming an unstable pyruvate intermediate and water. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
Ethyl lactate is susceptible to degradation by hydrolysis and oxidation, and as such is packaged under an inert blanket (e.g., nitrogen or argon) (9). It is highly recommended that it be stored under inert conditions to prevent oxidation. The main routes of degradation are summarized in Figures 1(a) and 1(b). Under dry conditions, degradation because of oxidation is most prevalent. Peroxides are formed during or after the oxidation process and may be monitored as a direct indication of the extent of oxidation of ethyl lactate that has occurred. Previous efforts used antioxidant materials to stabilize a similar organic solvent, ethyl oleate, a nonaqueous solvent used for injections (10, 11). The focus of the research in this article deals with the stabilization of ELPG by the inclusion of various generally recognized as safe (GRAS) excipients with certain antioxidant properties. The authors also present an improved method for determining peroxide levels within ethyl lactate solutions.


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