Fixed-Oil Excipient Monographs: Development of USP Fixed-Oil Reference Standards - Pharmaceutical Technology

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Fixed-Oil Excipient Monographs: Development of USP Fixed-Oil Reference Standards
This article summarizes the development and modernization of the United States Pharmacopeia-National Formulary (USP-NF) fixed-oil excipient monographs. This article contains bonus online-exclusive material.

Pharmaceutical Technology
Volume 37, Issue 4, pp. 102-108

Modernization strategy

Table IV: A strategic analytical test plan recommended in fixed oil monographs.
USP staff and EM2 EC have developed an analytical test plan to fulfill the current regulatory requirements and keep abreast of current industry developments.

The analytical test plan for fixed oils is summarized in Table IV. The tests recommended in Table IV are critical control measures that ensure the identity, strength, quality, and purity of fixed oils. Further explanation and rationale to justify these recommendations are presented below.

Figure 2: Fourier transform infrared (FTIR) spectrum for olive oil.
Identification tests. Spectroscopic identification and laboratory results. In the USP 2005–2010 revision cycle, USP staff and EM2 EC identified excipient monographs that lacked an identification test and recommended introducing an infrared (IR) spectroscopy or similar spectroscopic identification test in preference to wet chemistry or colorimetric tests. Generally, spectroscopic procedures provide a good identification for highly purified single-molecular compounds. This approach is similar to that adopted in a number of existing USP monographs for highly purified drug substances. These monographs usually specify a high-performance liquid chromatography (HPLC) identification test—HPLC peak agreement between the drug substance sample and a corresponding USP Reference Standard—in addition to the use of IR identification as an orthogonal test. An HPLC analytical procedure alone, depending on the separation mechanism of the compounds studied, is unable to provide information about the chemical structure of the components separated, whereas IR does provide information about the basic chemical structure of the components studied or their functional groups. In general, spectroscopic methodology and separation science are complementary. Separately, neither spectroscopic nor separation procedures is likely to be sufficient for unique identification, but when used together they provide a greater assurance of uniquely identifying an excipient.

Figure 3: 1H nuclear magnetic resonance (1H NMR) spectra for seven oils.
The USP Research and Development laboratory performed suitability studies for inclusion of an IR identification test in several fixed-oil monographs such as cottonseed oil, olive oil, peanut oil, safflower oil, and soybean oil. The results indicated that IR could not be used as a suitable identification test for these fixed oils because their IR spectra were indistinguishable from each other. IR was unable to uniquely identify fixed oils by visual comparison because of the similarities in their functional groups. For example, general functional group assignments for IR analyses of olive oil (Figure 2) and peanut oil are presented in Table V, and their IR spectra are similar. The IR spectrum shown in Figure 2 is representative of a fatty ester. In contrast, the five fixed oil spectra could be differentiated from those of other oils, (e.g., mineral oil [a petrochemical oil] and polyoxyl 35 castor oil [a derivative of fixed oil]).

Table V: IR spectral analyses for fixed oils.
The laboratory further investigated liquid 1H nuclear magnetic resonance (NMR) spectroscopy for identification of seven vegetable oils—corn oil, cottonseed oil, olive oil, palm oil, peanut oil, safflower oil, and soybean oil—using a 300-MHz NMR instrument. Their 1H NMR spectra were distinguishable from each other, and analysts observed significant differences between 0.8 and 2.8 ppm (Figure 3). Liquid 1H NMR could uniquely identify each of the seven oils studied. These results confirmed published findings (20). General information about 1H NMR signals vs. functional protons (Figure 3) for 1H NMR analysis of the seven fixed oils is summarized in Table VI. Table VI lists notable differences observed in the four 1H NMR signal ranges for the oils studied.

Figure 4: Chemical structure of ricinoleic acid.
Although 1H NMR was capable of distinguishing the seven fixed oils studied, EM2 EC did not recommend the 1H NMR test be included as a compendial identification test because no assurance could be provided to ensure that mixtures of fixed oils could not unequivocally be identified as such and thus the samples could be identified—erroneously—as pure oils. In this regard, it should be emphasized that distinguishing between oils was entirely different from identification of a particular oil. Furthermore, there were concerns related to cost, lack of NMR instruments in most quality-control laboratories in industry, and a lack of personnel training for the NMR procedure. Currently, 1H NMR use typically is limited to research and development laboratories. It is, however, a necessary analytical tool used to qualify USP reference standards.

Table VI: NMR analysis for seven fixed oils studied (NMR signal 0.8–2.8 ppm).
Some non-oil excipient monographs do incorporate 1H NMR testing, although not explicitly for identification testing, and have done so for several decades (e.g., the Polyoxyl 10 Oleyl Ether and the Polyoxyl 20 Cetostearyl Ether monographs that use 1H NMR to determine the average polymer chain length). In the Poloxamer NF monograph, 1H NMR test helps to determine the percentage of oxyethylene in the polymer sample. More recently, the 1H NMR test increasingly is being introduced into NF monographs for complex excipients such as Hydroxypropyl Betadex, Chitosan, hydroxypropyl starches of different botanical origins, and corresponding pregelatinized species because it is the only suitable method to appropriately characterize these complex excipients.


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