Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Reexamination Certificate
2000-09-08
2002-05-28
Carr, Deborah D. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
C554S191000
Reexamination Certificate
active
06395915
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
The present invention relates generally to a method of producing commercially feasible amounts of purified tocotrienols, tocopherols and isomers thereof or crude stocks enriched in tocotrienols or tocopherols using reverse phase liquid chromatography.
2. Description of Prior Art
Tocopherol is used widely as an antioxidant with applications in the cosmetic, pharmaceutical. nutraceutical, food and fine chemical industries. The four main isomers of tocopherol (alpha, beta, delta, and gamma) are generally referred to individually and as a group as “Vitamin E.” Tocotrienols are structurally very similar to tocopherols and also have four main isomers (alpha, beta, delta, and gamma). Tocotrienols have been shown to provide a significant increase in antioxidant activities over tocopherols. Recent studies have indicated that tocotrienols, and to a somewhat lesser extent tocopherols, provide certain health benefits, including reduction in serum cholesterol levels and prevention of coronary heart disease due to their antioxidant properties. When produced or otherwise isolated, tocotrienoIs and tocopherols, due to their similarity, can be found together. Therefore, separation of these two classes of chemical compounds is necessary to evaluate or produce individual classes of these materials.
There are several methods known in the art that can be used to concentrate and/or purify tocotrienols and tocopherols from crude mixtures containing them. Common chemical separation methods include extraction, distillation (fractional distillation and molecular distillation), membrane filtration and chromatography. Within chromatography, there are several general subcategories including adsorption chromatography, partition chromatography, ion exchange chromatography, and size exclusion chromatography that can be applied.
The prior art contains several previously developed and published liquid chromatography methods directed toward the separation of tocotrienols and tocopherols. Some of these methods are designed only for the qualitative and quantitative analysis of tocotrienols and tocopherols and are not suitable for process cliromatography (the use of chromatography to isolate and recover substantial amounts of pure material from a mixture on a commercial scale). Other methods are designed for preparative work but do not provide a discrete separation between all of the isomers of tocotrienols and all of the isomers of tocopherols into two different groups of eluting material.
Prior art liquid chromatography methods, particularly those described below, can thus be broken into two categories: analytical liquid chromatography methods designed to resolve the different components at very low levels to permit analysis with bench top analytical HPLC equipment; and preparative (process) liquid chromatography methods designed for the commercial purification of specific components out of a crude feedstock. The priori art does not describe a reverse-phase partition liquid chsomatography method which can be used commercially to purify tocotrienols and/or tocopherols, or further, to provide one simple method to separate all of the tocopherol isomers n d all o f the tocotrienol isomers at the same time.
U.S. Pat. No. 4,122,094 to Woziwodzki detail s a method of separating the isomers of tocopherol by liquid/solid chromatography. The method of Woziwodzki is directed to analytical separations of tocopherol isomers through the use of normal phase media rather than large-scale separations useful for commercial production. Woziwodzki also does not discuss using the disclosed methods to separate tocopherols from tocotrienols or separating the isomers of tocotrienol.
U.S. Pat. No. 5,157,132 to Tan et al. describes an integrated process for recovery of carotenoid and tocotrienols from vegetable oils. This method uses normal phase absorption chromatography in which components in the crude material bind, sometimes irreversibly, to the stationary phase. The lifetime of normal phase media is generally much shorter than that of reversed phased media. As Such, the economics of larger scale processes can be significantly affected because the stationary phase must be replaced frequently and additional man-hours are expended. Furthermore, the surface of underivatized silica, which is typically used for normal phase chromatography, is very sensitive to water (from air, solvents and crude material) which deactivates the stationary phase surface resulting in non uniform elution profiles. This can make automation difficult and production unpredictable. The method of U.S. Pat. No. 5,157,132 also uses hexane as the mobile phase. These solvents are more hazardous and more expensive (including the cost of disposal) than other mobile phase solvents, such as ethanol and water. Finally, this reference does not teach a method of separating tocopherols from tocotrienols.
Top et al. teach a method of production of high concentration tocopherols and tocotrienols from palm-oil by-products through ion-exchange chromatography in U.S. Pat. No. 5,190,618. Ion-exchange chromatography separates based on the retention of charged molecules on a charged stationary phase rather than on the attraction of molecules to an aromatic and/or hydrophobic stationary phase. The major shortcoming of the method outlined in this patent is that it does not provide a high degree of resolution and further does not even show separation between the tocopherols and tocotrienols in the crude material.
U.S. Pat. No. 5,908,940 discloses a process for recovering tocotrienols, tocopherols and tocotrienol-like compounds. The method taught utilizes chemical extractions. While likely useful for small-scale applications, the patent does not discuss how the method can be used for large scale recovery needed in commercial operations. The patent also does not teach use of the disclosed method for separation of the separate isomers of tocotrienols and tocopherols.
It is therefore one object of the present invention to provide a method to isolate, with high purity if required, all of the different isomers of tocotrienols and tocopherols. It is a further object of the present invention to isolate, on any required scale (grams, kilograms, tons), the desired products. It is yet another object of the invention to provide a method of “class separation” of tocotrienols from tocopherols on a commercial scale through the use of either a single column reverse phase chromatography process or a multiple column simulated moving bed (SMB) reverse phase chromatography process due to the binary nature of separation which is amenable to SMB. It is an additional object of the present invention to provide a separation method which utilizes inexpensive and safe mobile phase solvents.
REFERENCES:
patent: 4122094 (1978-10-01), Woziwozki
patent: 5157132 (1992-10-01), Tan et al.
patent: 5190618 (1993-03-01), Top et al.
patent: 5908940 (1999-06-01), Lane et al.
patent: 0 333 472 (1989-09-01), None
patent: 083174 (2001-03-01), None
patent: WO 99/38859 (1999-08-01), None
patent: WO 99/38860 (1999-08-01), None
patent: WO 00/43095 (2000-07-01), None
European Patent Office—Search Report—Jan. 25, 2001.
Publication: Barrie Tan and Linda Brzuskiewicz Separation of Tocopherol and Tocotrienol Isomers Using Normal and Reverse Phase Liquid Chromatography.
Hoehler et al., Journal of Agric. Food Chem., vol. 46, pp. 973-978, 1998.
Bellafiore Louis
Henretta Kevin
Carr Deborah D.
Piper Marbury Rudnick & Wolfe
Rifkin William T.
Ryan Thomas W.
Technikrom, Inc.
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