Zone refining method for nutraceuticals

Abstract

Disclosed is a method for purifying an organic compound, comprising the steps of (i) providing a crystalline sample of organic compound having a first impurity level, (ii) adding a catalyst to the sample, (iii) heating a portion of the sample to a temperature at or above melting point of the organic compound so as to create a molten zone of the sample, (iv) moving application of heat down the length of the sample, such that the molten zone is moved along the length of the sample, (v) collecting molten material at an end of the sample, (vi) optionally grinding the sample back to a powder, (vii) repeating steps (i)-(iv) at least two more times, and (viii) obtaining a purified sample having a second impurity level, which is lower than the first impurity level, wherein the organic compound is a nutraceutical selected from the group consisting of vinpocetine, huperzine, astragalosides, HEPPS buffer, curcumin, piperine, uridine, capsaicin and kinetin.

Claims

1. A method for purifying an organic compound, comprising the following steps: (i) providing a crystalline sample of organic compound having a first impurity level, (ii) adding a catalyst to the sample, (iii) heating a portion of the sample to a temperature at or above melting point of the organic compound so as to create a molten zone of the sample, (iv) moving application of heat down the length of the sample, such that the molten zone is moved along the length of the sample, (v) collecting molten material at an end of the sample, (vi) optionally grinding the sample back to a powder, (vii) repeating steps (i)-(iv) at least two more times, and (viii) obtaining a purified sample having a second impurity level, which is lower than the first impurity level, wherein the organic compound is a nutraceutical selected from the group consisting of vinpocetine, huperzine, astrazaloside IV, HEPPS buffer, curcumin, piperine, uridine, capsaicin and kinetin.

2. The method of claim 1, wherein the catalyst is an oxide, oxychloride or chloride of copper, vanadium, or cobalt, or a mixture thereof.

3. The method of claim 2, wherein the catalyst is copper oxychloride, cuprous choride, cupric chloride, or a mixture thereof.

4. The method of claim 1, wherein the concentration of catalyst used is about 5-100 ppm.

5. The method of claim 4, wherein the concentration of catalyst used is about 5-10 ppm.

6. The method of claim 5, wherein the concentration of catalyst used is about 10 ppm.

7. The method of claim 1, wherein the catalyst is a fine powder having a particle size of about 10 microns or less.

8. The method of claim 7, wherein the catalyst has a particle size of less than about 10 microns.

9. The method of claim 1, wherein steps (i)-(iv) are repeated at least four times.

10. The method of claim 1, wherein steps (i)-(vi) are repeated at least twice.

11. The method of claim 10, wherein steps (i)-(vi) are repeated at four times.

12. The method of claim 1, further comprising a step of analyzing the sample to determine purity level of the sample.

13. The method of claim 1, wherein steps (i), (ii) and/or (iii) are performed at a temperature of at least 100 C.

14. The method of claim 13, wherein steps (i), (ii) and/or (iii) are performed at a temperature of about 200 C. or above.

15. The method of claim 1, wherein movement of heat application in step (iv) is vertical.

16. The method of claim 1, wherein movement of heat application in step (iv) is horizontal.

17. A purified sample of organic compound obtained by the method of claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1: illustrates a prior art zone melting technique to purify a metal rod.

DETAILED DESCRIPTION

(2) This invention provides a method for purifying an organic compound, comprising the steps of (i) providing a crystalline sample of organic compound having a first impurity level, (ii) adding a catalyst to the sample, (iii) heating a portion of the sample to a temperature at or above melting point of the organic compound so as to create a molten zone of the sample, (iv) moving application of heat down the length of the sample, such that the molten zone is moved along the length of the sample, (v) collecting molten material at an end of the sample, (vi) optionally grinding the sample back to a powder, (vii) repeating steps (i)-(iv) at least two more times, and (viii) obtaining a purified sample having a second impurity level, which is lower than the first impurity level, wherein the organic compound is a nutraceutical selected from the group consisting of vinpocetine, huperzine, astragalosides, HEPPS buffer, curcumin, piperine, uridine, capsaicin and kinetin.

(3) In one embodiment of the method described herein, the catalyst is an oxide, oxychloride or chloride of copper, vanadium, or cobalt, or a mixture thereof. In another embodiment, the catalyst is copper oxychloride, cuprous choride, cupric chloride, or a mixture thereof.

(4) In one embodiment, the concentration of catalyst used is about 5-100 ppm. In another embodiment, the concentration of catalyst used is about 5-10 ppm. In yet another embodiment, the concentration of catalyst used is about 10 ppm.

(5) In one embodiment, the catalyst is a fine powder having a particle size of about 10 microns or less. In another embodiment, catalyst has a particle size of less than about 10 microns.

(6) In one embodiment, steps (i)-(iv) are repeated at least four times. In another embodiment, steps (i)-(vi) are repeated at least twice. In yet another embodiment, steps (i)-(vi) are repeated at four times.

(7) In one embodiment, the method further comprises a step of analyzing the sample to determine purity level of the sample.

(8) In one embodiment, steps (i), (ii) and/or (iii) are performed at a temperature of at least 100 C. In another embodiment, steps (i), (ii) and/or (iii) are performed at a temperature of about 200 C. or above.

(9) In one embodiment, movement of heat application in step (iv) is vertical. In another embodiment, movement of heat application in step (iv) is horizontal.

(10) Finally, also provided is a purified sample of organic compound obtained by the various embodiments of the method as described herein.

Terms

(11) As used herein, and unless stated otherwise, each of the following terms shall have the definition set forth below.

(12) As used herein, about in the context of a numerical value or range means10% of the numerical value or range recited or claimed. By any range disclosed herein, it is meant that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention. Accordingly, about a recited value specifically includes that recited value. For example, about 10 ppm refers to all sizes within the range of 10% of 10 ppm including 10 ppm.

(13) As used herein, the term nutraceutical refers to any high purity, standardized grade of fortified or concentrated food substance, herbal, vitamin, mineral, amino acid, ayurvedic or dietary supplement which when administered can or have been known to provide health or medical benefits in addition to its basic nutritional value. Examples of nutraceuticals in accordance with the inventive method described herein include but are not limited to vinpocetine, huperzine, astragalosides, HEPPS buffer, curcumin, piperine, uridine, capsaicin and kinetin.

(14) An embodiment of the disclosed method comprises. (i) providing a (optionally solid and/or powder) crystalline sample of nutraceutical having a first (e.g., standard) impurity level, (ii) adding a catalyst, optionally selected from the group consisting of an oxide, oxychloride or chloride of copper, vanadium, or cobalt, or a mixture thereof, wherein the catalyst preferably having cations with valences of the -ous or -ic suffix. (iii) heating a portion of the sample to a temperature at or above the melting point of the nutraceutical so as to create a molten zone of the sample, (iv) moving application of heat down the (preferably full) length of the sample, such that the molten zone is moved along the (preferably full) length of the sample, (v) collecting molten material at an end of the sample and optionally analyzing the sample to determine purity level of the sample, (vi) optionally grinding the sample back to a powder and optionally analyzing the sample to determine purity level of the sample, (vii) repeating steps (i)-(iv) at least two more times (passes), or repeating steps (i)-(v) at least two more times (passes), or repeating steps (i)-(vi) at least two more times (passes), and (viii) obtaining a purified sample having a second impurity level, which is lower than the first impurity level, and optionally analyzing the sample to determine purity level of the sample.

(15) In an embodiment of the inventive method as described herein, the sample is analyzed to determine purity level of the sample after each pass, after every 2 passes, or after every 3 passes, etc. Appropriate analytical methods are known to those having ordinary skill in the art. Examples of such analytical methods include, but are not limited to, high-performance liquid chromatography (HPLC), mass spectrometry (MS), thin-layer chromatography (TLC), and nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy.

(16) Finally, the combination of any embodiment or feature mentioned herein with one or more of any of the other separately mentioned embodiments or features is contemplated to be within the scope of the instant invention.

EXPERIMENTS

(17) The below described series of experiments were conducted using the Instrolec 300 Zone Refiner, which was a vertical research and development (R&D) unit capable of reaching temperatures of up to 300 C. Nutraceuticals were zone refined in accordance with method steps substantially as that described hereinabove, catalyzed with the following catalysts at levels of 5-10 ppm: copper oxychloride, cuprous chloride or cupric chloride.

(18) The Instrolec 300 Zone Refiner was originally produced in the United Kingdom but is no longer available. However, similar results are expected by using other commercial low temperature zone refiners for organic chemicals, such as the MiniZone zone refiner available from Design Scientific (Holland, Mich.), modified by attaching a radio frequency (RF) induction heating system to increase temperature capabilities. An appropriate cooling system should also be attached because too high a temperature will tend to decompose the containers for the organic chemicals. Additional zone refiners for organic chemicals such as that made by SMART Laboratories of Kansas State University (KSU), by Bhabha Atomic Research Centre (BARC) of Mumbai, India, by State Research and Design Institute of the Rare Metal Industry (GIREDMET) of Russia, or the flat bed/horizontal unit described in U.S. Pat. No. 6,030,588, are expected to be similarly useful by modifying the low temperature unit to increase the maximum temperature reachable from 200 C. to 300 C. or higher.

Experiment 1: Zone Refining of Nutraceuticals Using Instrolec 300 Zone Refiner

(19) Results from the first set of runs are shown in Table 1 below.

(20) TABLE-US-00001 TABLE 1 Zone refining of nutraceuticals using Introlec 300 Zone Refiner Ending Starting Catalyst Catalyst Process catalyst Ending MP purity level particle Temp level Nutraceutical Nutraceutical ( C.) (%) Catalyst (ppm) size (m) Passes ( C.) (ppm) purity (%) Inventive Vinpocetine 149 95 CuOCl 10 1-10 3 200 0.36 99.995+ Ex.1 Inventive Huperzine 213 93 CuOCl 10 1-10 3 250 0.5 99.995+ Ex. 2 Inventive Astragaloside 290 97 CuOCl 10 1-10 2 300 0.58 99.98+ Ex. 3 IV Inventive HEPPS 237 99 CuOCl 10 1-10 3 275 0.28 99.999+ Ex.4 Buffer Inventive Curcumin 184 95 CuCl.sub.2 10 1-10 3 250 0.44 99.995+ Ex. 5 Inventive Piperine 130 97 CuOCl 10 1-10 3 200 0.35 99.998+ Ex.6 Inventive Uridine 167 99 CuOCl 10 1-10 3 200 0.45 99.999+ Ex.7 Inventive Kinetin 270 98 CuCl.sub.2 10 1-10 2 300 4.1 99.97+ (also Ex. 8 sublimes) Inventive Capsaicin 65 98 CuOCl 10 1-10 1 200 2.2 99.97 Ex.9* *For Inventive Example 9, the zone refiner collapsed after the first pass. The starting purity was ~98%. Only one pass of the zone refiner resulted in a purity of 99.97%. The inventors expect that purities of 99.995-99.999% would have been possible with additional passes.

Experiment 2: Comparative Testing without Catalysts

(21) Additional runs were performed where catalysts were not used. Without catalysts, vinpocetine was purified from 95% to 97%, huperzine was purified from 93% to 96%, astragaloside IV and capsaicin stayed at the same purity (no purification), and kinetin decomposed. Accordingly, when catalysts were not used, the zone refining did not work or did not work as well (e.g., the nutraceuticals either decomposed or was not purified, or was purified to a level which is below an acceptable or desirable level).

Experiment 3: Comparative Testing with Additional Catalysts

(22) Additional runs were performed using different catalysts, including copper, vanadium and cobalt along with their oxides, oxychlorides and chlorides. When manganese chloride or zirconium oxychloride were used instead, the zone refining did not work or did not work as well (e.g., the nutraceuticals either decomposed or was not purified, or was purified to a level which is below an acceptable or desirable level).

Experiment 4: Comparative Testing to Vary Catalyst Amount

(23) Additional runs were performed wherein the catalyst particle size in each case exceeds 10 m. Specifically, catalysts with particle sizes ranging from 30-50 m were used. When particle sizes of the catalyst used exceed 10 m, the zone refining did not work or did not work as well (e.g., the nutraceuticals either decomposed or was not purified, or was purified to a level which is below an acceptable or desirable level). When the catalysts were air milled down to 1-10 m, the zone refining worked better in comparison.

(24) Experiments 1-4: Discussion

(25) Experiments 1-4 and Table 1 demonstrate that catalysts are required for the zone purification process to work or work well. Further, the inventor has determined that catalysts with particle sizes below 10 microns work best. The catalysts are ultimately zone refined out to levels of 0.1-0.5 ppm's. Most nutraceuticals according to Table 1 below were zone refined to purities ranging from 99.995+% to 99.999+%.

(26) In sum, the inventor surprisingly found that zone refining of nutraceuticals catalyzed with certain catalysts enables one to obtain nutraceuticals of very high purity levels. The high purity nutraceuticals are useful as analytical standards, or as high purity premium starting materials.

Experiment 5: Comparative Testing to Vary Catalyst Level (ppm)

(27) Additional runs can be performed to vary catalyst level. It is expected that when the catalyst level exceeds 100 ppm, the catalyst themselves would likely break down during the zone refining process causing the run to fail. 10-100 ppm is being considered the acceptable catalyst level to be used in the inventive methods described herein.