FIELD OF THE INVENTION
The present invention relates to purification of curcumin 95% with a very low amount of residual solvents to
a very low amount of total residual solvents less than 50 ppm so that it can be safely used in
pharmaceutical, nutraceutical and food/ feed applications. The present invention describes process for
making such low residual solvent curcumin involve dissolution of curcumin 95% in alkaline aqueous
solution (in which normally curcumin degradation occurs) in presence of an antioxidant and later
precipitation of pure curcumin in an acidic media.
BACKGROUND OF THE INVENTION
Curcumin is a diarylheptanoid, it is the principal curcuminoid of the popular South Asian spice turmeric,
which is a member of the ginger family (Zingiberaceae). The curcuminoids are natural phenols that are
responsible for the yellow color of turmeric. Curcumin can exist in several tautomeric forms, including a 1,3-
diketo form and two equivalent enol forms. The enol form is more energetically stable in the solid phase
and in solution. Curcumin is a bright-yellow color and may be used as a food coloring.
Curcumin has been isolated from turmeric rhizomes through various solvent extraction process which
normally yield a product with residual solvent about 5000ppm. The residual solvent present in curcumin is
trapped inside the crystals of curcumin and it is practically not possible to remove the residual solvents to
50ppm level by drying or vacuum or any other process.
To remove the entrapped residual solvents from curcumin crystals, it should be dissolved in a solvent. If
curcumin is dissolved in any other solvent like iso propanol, methanol, acetone, ethyl acetate or ethanol
and crystallize, the alternate solvent in which crystallization occur getting entrapped in curcumin crystals
and finally the same residual solvent results. To get rid of residual solvents from curcumin, the only solution
is to crystallize curcumin in water.
Curcumin is practically insoluble in water at acidic and neutral pH. (Humphrey, 1980, Tonnesen, 2002).
Curcumin gets hydrolysed at pH above 1. The kinetics of hydrolytic degradative reactions of curcumin
3
(diferuloylmethane ) was studied and reported by Tonnesen and Karlsen, (1985). At pH above 1, aqueous
solutions of diferuloylmethane have a red colour which indicates the protonated form. In the pH range 1-7,
the majority of diferuloylmethane species are in the neutral form. Water solubility is very low in this pH
range and solutions are yellow. At pH>7.5, the colour changes to red.
Curcumin is relatively stable at acidic pH, but they rapidly decompose at pHs above neutral. In a study of
alkaline degradation of curcumin products of decomposition ie. ferulic acid and feruloylmethane were
determined by HPLC at pH 7-10. The initial degradation products are formed after 5 minutes.
Feruloylmethane rapidly forms coloured (mostly yellow to brownish-yellow) condensation products.
Degradation products formed by hydrolysis of feruolylmethane are vanillin and acetone and their amount
increase with incubation time (Tonnesen and Karlsen, 1985).
Curcumin incubated in slightly alkaline pH 7.2 with 0.1 M phosphate buffer was 90 percent decomposed
within 30 min. Trans-6-(4-hydroxy-3-methoxyphenyl)-2,4-dioxo-5-hexenal was predicted as major
degradation product and vanillin, ferulic acid, feruloyl methane were identified as minor degradation
products (Wang et al, 1997).
As curcumin is insoluble in water at neutral or acidic pH and in alkaline aqueous media, although curcumin
is soluble, it degrade in to its degradation products ferulic acid and feruloylmethane, none of the prior art
was adapted to process curcumin in water. Inventors of the present invention have developed a process to
dissolve curcumin in aqueous alkaline media in presence of an antoxidant and recovered the product
without decomposition and precipitated in acidic media to get Curcumin with 95% assay and residual
solvent lower than 50ppm. About 90 to 95% of the Curcumin is recovered in the purification process after
removing the residual solvents.
Although WO20120023128 A1 discloses curcumin with low residual solvents, but the process used in this
document is entirely different.
The process of the prior art provides residual free turmeric oleo resin i.e. 30 to 80% curcumin only, on the
other hand, process of the present invention involves residual solvent removal from curcumin powder with
assay 95%.
4
The process of the prior art involves dissolution in acetone whereas process of the present invention is
water based. As Curcumin is not stable in alkaline media, the inventors of the present invention processed
in presence of an antioxidant to get the curcumin in its pure from with 95% assay and residual solvents less
than 50 ppm.
CN103130629 describes that the extraction of crude curcumin was carried out using alkaline water and
precipitating in acid, further purification was described using alcohol and crystallization in solvents so that
the final product is not claimed as residual free curcumin.
None of the prior art documents discloses Curcumin with residual solvent level up to <50ppm
SUMMARY
The present invention relates to purification process of curcumin 95% with a very low amount of
residual solvents to a very low amount of total residual solvents less than 50 ppm so that it can be
safely used in pharmaceutical, nutraceutical and food/ feed applications. The process comprising
the steps of:
(a) dissolving the isolated curcumin 95% in aqueous alkali solution in presence of 2% antioxidant;
(b) filtering the solution of step (a) and collecting a clear filtrate ;
(c) preparing an aqueous acidic solution wherein the acid is dissolved in water in the range of 1 to
5%;
(d) adding the clear filtrate of step (b) to the said aqueous acidic solution, continuously stirring for
30 min to 1 hour leading to formation of curcumin precipitate;
(e) filtering the precipitate;
(f) washing thoroughly the precipitate of step (e) with water and drying the precipitate to obtain
residual solvent free Curcumin and
(g) analysing the residual solvent free Curcumin using Headspace Gas chromatography (GC-HS).
DEFINITIONS
5
Unless defined otherwise, all technical and scientific terms used herein have the same meaning
as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
In describing the present invention, the following terms will be employed, and are intended to be
defined as indicated below.
For purpose of this invention, the term “LOD” means “Loss On Drying”. It determine the
moisture, solvent and any other volatile impurities in the product.
For purposes of this invention, “Curcumin solution” mean the solution of curcumin 95%
dissolved in aqueous alkaline solution.
For purpose of this invention, the term pH defines the acidity or alkalinity of a solution on a
logarithmic scale on which 7 is neutral, lower values are more acid and higher values more
alkaline.
For purpose of this invention, the term Curcumin 95% refers to the mixture of three
curcuminoids, Curcumin, Demothxy curcumin and is Bisdemethoxy curcumin.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to process for making low residual solvent curcumin. The process of the
present invention is based on crystallization of curcumin in aqueous media without using any solvents.
Present invention for the first time describes this principle of crystallizing 95% curcumin in aqueous media.
Based on this principle, working examples 1 to 7 describes the preparation of low solvent turmeric oleoresin
compositions with very low amounts of residual solvents.
The process starts with a curcumin 95% that comprises significant amounts of residual organic solvent(s)
trapped within the curcuminoid crystals present in the oleoresin up to maximum level of 50000ppm.
The prior art describe the residual solvent removal from turmeric oleoresin which comprises of curucmin
content from 30% to 80% only, whereas our invention describe the process for obtaining residual free
curcumin 95%.
In step (b), curcuminoid crystals are dissolved in an aqueous media using 1 to 5% alkali sodium or
potassium hydroxide in the presence of antioxidant
6
The residual solvents are entrapped inside the crystalline structure of curcumin. It could not be removed to
a very low level simply by drying or evaporation under vacuum. It is essential that it is important to dissolve
the crystals of curcumin in order to remove the trapped solvents.
In the prior arts where curcumin was dissolved in organic solvents like acetone, and crystallized, the
solvent in which it was crystallized was again trapped inside the crystals and the final residual solvent level
in curcumin was still on the higher side.
The principle aim of the inventors of the present invention is not to use any solvent for dissolving curcumin
and crystallize in pure aqueous medium. As curcumin is practically insoluble in acidic or neutral pH, it is
essential that it has to be dissolved in an alkaline medium only.
The stability of curcumin in alkaline medium is a challenge. Generally curcumin degrade in ferulic acid and
feruloylmethane within 5 minutes. Feruloylmethane rapidly forms coloured (mostly yellow to brownishyellow)
condensation products and hydrolysed in to vanillin and acetone.
It was discovered that the antioxidant addition during dissolution in alkaine medium has improved the
stability of curcumin for a certain time in which it can be processed further to obtain in pure form i.e.
curcumin >95%. The antioxidant was chosen as natural antioxidants of polyhydric alcohols or acids.
It is apparent that the conditions should be so that essentially all crystals are dissolved completely in
alkaine aqueous medium to effectively remove the residual solvents. The operation has to be conducted in
ambient temperature 20 to 30 deg C.
Once the curcumin is dissolved in alkaline medium, it should be processed immediately to prevent the
degradation of curcumin. It should not be kept more than 30 minutes.
In the next step an aqueous media is prepared by dissolving suitable organic or mineral acids in water in
the range of 0.5% to 5% for precipitation of curcumin.
For precipitation of curcumin, aqueous alkaline medium is added to the acidic medium immediately under
continuous stirring at ambient temperature 20 to 30 deg C. The reverse addition of an acid solution to
aqueous alkaline curcumin solution will not yield the desired product quality. The mass has to be
continuously stirred for 30 min to 1 hr for the complete precipitation of curcumin.
7
The crystallized mass is filtered through a nutch filter or by centrifuge to collect all the solids and then the
solid mass is washed with water to remove the acidity completely by checking the mother liquor, by keeping
pH almost neutral.
The filtered and washed mass is suck dried in the nutch filter and then dried in a hot air oven at
temperature ranging from 70 to 90 deg C until the LOD is < 0.2%.
The yield of product ranges from 90 to 95% in the purification process after removing the residual solvents.
The process of the present invention comprises the following steps:
􀂾 Starting with curcumin 95% with a high residual solvent level up to 50000ppm;
􀂾 Dissolving curcumin in aqueous sodium hydroxide solution in presence of 2% antioxidant;
􀂾 Filtering out the clear filtrate of curcumin solution;
􀂾 Preparing an aqueous acidic solution 1 to 5%;
􀂾 Adding the alkaline solution of curcumin to the acidic water and precipitating the curcumin;
􀂾 Filtering the mass and collecting the solids;
􀂾 Removing all the entrapped residual solvents in the product in the mother liquor;
􀂾 90 to 95% of curcumin was precipitated as powder;
􀂾 Washing thoroughly the end product with water and dried completely in hot over oven at 90oC;
􀂾 Analysing the assay of the dried product as >95%; and
􀂾 Residual solvents were analysed as per the enclosed procedure using Headspace Gas
chromatography (GC-HS), the results are tabulated below.
EXAMPLES:
Example 1
The starting material for the process is Curcumin >95% powder was obtained through solvent
extraction/isolation process. The powder (1 Kg) was taken in a stainless steel vessel and 10L of 10%
sodium hydroxide solution and 2% antioxidant was added and stirred for 1.0 h. 10 - 30 deg C;
a) The Curcumin was dissolved in the sodium hydroxide solution completely;
b) the solution was filtered and clear filtrate (a) was collected;
c) Weighed 0.5 kg of hydrochloric acid in a glass lined vessel & dissolved to 10 L with water (5%)
8
d) the clear filtrate of aqueous Curcumin solution (a) was added in to Citric acid solution (b) under
continuous stirring, yellow colour precipitate was appeared;
e) The precipitate was filtered in nutch filter; and
f) The precipitate was washed with water thoroughly & finally the material was dried using tray drier
at 60-70oC;
The resultant product, called as residual solvent free Curcumin - orange - yellow in colour (yield,
86.50 %, assay 95.4%, total residual solvents 49ppm).
Example-2
a) Curcumin >95% powder (1 Kg) was taken in a stainless steel vessel and 10L of 5% sodium
hydroxide solution and 2% antioxidant was added and stirred for 1.0 h. 10 - 30 deg C;
b) The Curcumin was dissolved in the sodium hydroxide solution completely;
c) Solution was filtered and clear filtrate was collected(a);
d) 0.5 L of hydrochloric acid was weighed in a glass lined vessel & diluted to 10 L with water (5%);
e) Clear filtrate of aqueous Curcumin solution (a) was added in to hydrochloric acid solution (b) under
continuous stirring, yellow color precipitate was appeared;
f) The precipitate was filtered by nutch filter;
g) The precipitate was washed with water thoroughly & finally material was dried using tray drier at
60-70oC.
The resultant product, called as residual solvent free Curcumin - orange - yellow in colour (yield,
90.13 %, assay 95.6%, total residual solvents 49ppm).
Example-3
a) Curcumin >95% powder (1 Kg) was taken in a stainless steel vessel and 10L of 5% sodium
hydroxide solution and 2% antioxidant was added and stirred for 1.0 h. 10 - 30 deg C;
b) The Curcumin was dissolved in the sodium hydroxide solution completely;
c) Solution was filtered and clear filtrate was collected (a)
d) 1.0 L of hydrochloric acid was weighed in a glass lined vessel & diluted to 10 L with water (1%)
9
e) Clear filtrate of aqueous Curcumin solution (a) was added in to hydrochloric acid solution (b) under
continuous stirring yellow colour precipitate was appeared;
f) The precipitate was filtered in nutch filter;
g) The precipitate was washed with water thoroughly & finally material was dried using tray drier at
60-70oC.
The resultant product, called as residual solvent free Curcumin - orange - yellow in colour (yield,
90.40 %, assay 95.2%, total residual solvents 48ppm).
Example-4
a) Curcumin>95% powder (1 Kg) was taken in a stainless steel vessel and 10L of 1.0% sodium
hydroxide solution and 2% antioxidant was added and stirred for 1.0 h. 10 - 30 deg C;
b) The Curcumin was dissolved in the sodium hydroxide solution completely;
c) Solution was filtered and clear filtrate (a) was collected;
d) 5 L of glacial acetic acid was weighed in a glass lined vessel & diluted to 10 L with water (5%);
e) Clear filtrate of aqueous Curcumin solution (a) was added in to acetic acid solution (b) under
continuous stirring yellow colour precipitate was appeared
f) The precipitate was filtered in nutch filter;
g) The precipitate was washed with water thoroughly & finally material was dried using tray drier at
60-70oC.
The resultant product, called as residual solvent free Curcumin - orange - yellow in colour (yield,
89.5 %, assay 95.9%, total residual solvents 48ppm).
Example-5
a) Curcumin >95% powder (1 Kg) was taken in a stainless steel vessel and 10L of 1.0% sodium
hydroxide solution and 2% antioxidant was added and stirred for 1.0 h. 10 - 30 deg C;
b) The Curcumin was dissolved in the sodium hydroxide solution completely;
c) Solution was filtered and clear filtrate (a) was collected;
d) 2 L of glacial acetic acid was weighed in a glass lined vessel & diluted to 10 L with water (2%);
10
e) Clear filtrate of aqueous Curcumin solution (a) was added in to acetic acid solution (b) under
continuous stirring yellow colour precipitate was appeared;
f) The precipitate was filtered in nutch filter;
g) The precipitate was washed with water thoroughly & finally material was dried using tray drier at
60-70oC.
The resultant product, called as residual solvent free Curcumin - orange - yellow in colour (yield,
90.87 %, assay 96.3%, total residual solvents 47ppm).
Example-6
a) Curcumin >95% powder (0.5 Kg) was taken in a stainless steel vessel and 10L of 0.5% sodium
hydroxide solution and 2% antioxidant was added and stirred for 1.0 h. 10 - 30 deg C;
b) The Curcumin was dissolved in the sodium hydroxide solution completely;
c) Solution was filtered and clear filtrate (a) was collected;
d) 1 L of glacial acetic acid was weighed in a glass lined vessel & diluted to 10 L with water (1%);
e) Clear filtrate of aqueous Curcumin solution (a) was added in to acetic acid solution (b) under
continuous stirring yellow colour precipitate was appeared;
f) The precipitate was filtered in nutch filter
g) The precipitate was washed with water thoroughly & finally material was dried using tray drier at
60-70oC.
The resultant product, called as residual solvent free Curcumin - orange - yellow in colour (yield,
91.20 %, assay 96.6%, total residual solvents 47ppm).
Example-7
a) Curcumin >95% powder (0.5 Kg) was taken in a stainless steel vessel and 10L of 0.5%
potassium hydroxide solution and 2% antioxidant was added and stirred for 1.0 h. 10 - 30 deg C;
b) The Curcumin was dissolved in the potassium hydroxide solution completely;
c) Solution was filtered and clear filtrate (a) was collected;
d) 1 L of glacial acetic acid was weighed in a glass lined vessel & diluted to 10 L with water (1%);
11
e) Clear filtrate of aqueous Curcumin solution (a) was added in to acetic acid solution (b) under
continuous stirring yellow colour precipitate was appeared;
f) The precipitate was filtered in nutch filter;
g) The precipitate was washed with water thoroughly & finally material was dried using tray drier at
60-70oC.
The resultant product, called as residual solvent free Curcumin - orange - yellow in colour (yield,
91.20 %, assay 96.6%, total residual solvents 47ppm).
Example-8
a) Curcumin >95% powder (0.5 Kg) was taken in a stainless steel vessel and 10L of 0.5% sodium
hydroxide solution and 2% antioxidant was added and stirred for 1.0 h. 10 - 30 deg C;
b) The Curcumin was dissolved in the sodium hydroxide solution completely;
c) Solution was filtered and clear filtrate (a) was collected;
d) 2 L of glacial acetic acid was weighed in a glass lined vessel & diluted to 10 L with water (2%);
e) Clear filtrate of aqueous Curcumin solution (a) was added in to acetic acid solution (b) under
continuous stirring yellow colour precipitate was appeared;
f) The precipitate was filtered in nutch filter;
g) The precipitate was washed with water thoroughly & finally material was dried using tray drier at
60-70oC.
The resultant product, called as residual solvent free Curcumin - orange - yellow in colour (yield,
95.10 %, assay 96.8%, total residual solvents <08 ppm).
Analytical method to measure residual free organic solvent(s) trapped within the curcumin crystals
METHOD 1
The analytical method of the examples as providedis based on GC-HS well known standard described
analytical methods as below –
12
Standard Preparation: Weigh about 50mg of reference standard dissolved in 50ml of Dimethyl
formamide (DMF).Take 5ml of this solution into GC vial crimp & put into the head space tray.
Sample Preparation: Weigh 200mg of test sample in GC HS vial, add 5ml diluent & sonicate for
dissolution and crimp the vial put it in the head space tray.
Blank Preparation: Take 5ml of diluent and crimp the vial put in the Head Space tray.
System Suitability: RSD of replicate injection of each solvent in standard solution should not be
more than 15%.
Chromatographic Condition:
Column :DB-624,30m X 0.32mm X 3μm
Carrier Gas : Nitrogen
Split ratio : 7:1
Total flow : 25ml/per min
Column flow : 2ml/per min
H2 : 40ml/per min
Air : 400ML/per min
Make up gas N2 : 20ml/per Min
GC Parameters and Conditions:
Front inlet Temp. : 150°C
Detector FID Temp. : 220°C
Initial Oven Temp. : 40°C
Initial hold Time. : 10.0 min
Ramp I : 10.0°C/Min
Oven Temp.II : 140°C
Hold Time II : 10.0Min
Final Ramp : 20.0°C/Min
Final Oven Temp. : 200.0°C
Final Hold Time : 10.0min
Injection volume : 1.0ml
Run Time : 30.0 Min
Head Space Sampler Conditions:
Vial temp. : 105.0°C
13
Loop temp. : 95.0°C
Transfer line temp. : 125.0°C
GC cycle time : 35Min.
Vial Equilibration time : 15 Min.
Pressurization time : 0.5 Min.
Loop fill time : 0.2 Min.
Loop equilibration time : 0.05min
Injection time : 1.0 min
Shake : 1 (Low)
Calculation (Residual solvent in ppm)
Area of solvent in sample x standard dilution x purity of standard
= ---------------------------------------------------------------------------------------- X 10000
Area of solvent in standard X Dilution of sample
RESULTS:
Analysis of residual solvents in commercial batches of Curcumin 95% produced by our invented
process are analysed by the analytical method 1.
The results are shown in table-1 below. The term "powder" in the table refers to turmeric curcumin
crystal powder composition.
TABLE 1 –DMF was used as solvent
Sampl
e no
Type Hexan
e
(ppm)
Acetone
(ppm)
Ethyl
acetate
(ppm)
Methan
ol
(ppm)
Isopropy
l alcohol
(ppm)
Ethyl
alcohol
(ppm)
n-
Butanol
(ppm)
EDC
(ppm)
Total
residua
l
solvent
(ppm)
14
1 powder 0 0 32 0 08 09 0 0 49
2 powder 0 0 31 0 09 09 0 0 49
3 powder 0 0 33 0 08 07 0 0 48
4 powder 0 0 33 0 05 10 0 0 48
5 powder 0 0 20 0 12 15 0 0 47
6 powder 0 0 19 0 14 14 0 0 47
7 powder 0 0 21 0 12 14 0 0 47
8 powder <1 <1 <1 <1 <1 <1 <1 <1 <08
Note: Test report from SGS Labs for sample No.8 enclosed Report No.:GG14-004506-001 dated
28/05/2014
Conclusion-
The term "powder" in the table refers to Turmeric curcumin crystal powder composition starting from
example (1) by GC HS method, amounts of residual organic solvents trapped within the curcumin crystals
present in commercially available was measured and analysis of residual solvents in commercial curcumin
sample was carried out.
Residual solvent free turmeric curcumin crystal powder composition was achieved as described herein.
References:
Humphrey, A.M. 1980. Chlorophyll. Food. Chem. 5: 57
Tonnesen, H. H., 2002. Solubility, chemical and photochemical stability of curcumin in surfactant solutions,
Pharmazie 57 (12): 820-824
Tonnesen, H.H. & Karlsen, J. 1985. Studies of curcumin and curcuminoids: VI. Kinetics of curcumin
degradation in aqueous solutions. Z. Lebensm. Unters. Forsch. 180: 402-404
Wan, Y.J., Pan, M.H., Cheng, A.L., Lin, L.I., Ho, Y.S., Hsieh, C.Y., & Lin, J.K. 1997. Stability of curcumin
in buffer solutions and characterization of its degradation products. J. Pharm. Biomed. Anal.,15(12): 1867-
1876.
WO 2010023128 A1 Turmeric curcumin compositions with low residual solvent
K.V. Balakrishnan (Indian Journal of Technology, 21 , 247 (1983)
J. Verghese; Flavour and Fragnance Journal, Vol. 8, 315-319 (1993).

We claim:-
1) A process for the purification of the isolated Curcumin 95% , the process comprising the steps of:
(a) dissolving the isolated curcumin 95% in aqueous alkali solution in presence of 2% antioxidant;
(b) filtering the solution of step (a) and collecting a clear filtrate ;
(c) preparing an aqueous acidic solution wherein the acid is dissolved in water in the range of 1 to
5%;
(d) adding the clear filtrate of step (b) to the said aqueous acidic solution, continuously stirring for
30 min to 1 hour leading to formation of curcumin precipitate;
(e) filtering the precipitate;
(f) washing thoroughly the precipitate of step (e) with water and drying the precipitate to obtain
residual solvent free Curcumin;
(g) analysing the residual solvent free Curcumin using Headspace Gas chromatography (GC-HS).
wherein the curcumin crystals have residual solvent less than 50 ppm.
2) The process as claimed in claim 1, wherein the alkali is selected from sodium hydroxide or
potassium hydroxide.
3) The process as claimed in claim 1, wherein the acid is selected from the group consisting of citric
acid, hydrochloric acid and glacial acetic acid.
4) The process as claimed in claim 1, wherein the isolated curcumin 95% in aqueous alkali solution in
presence of 2% antioxidant is stirred for 1 hour at 10oC to 30oC.
5) The process as claimed in claim 1, wherein the precipitate is filtered using nutch filters.
6) The process as claimed in claim 1, wherein the precipitate is dried using a hot air oven or tray drier.
7) The process as claimed in claim 6, wherein the temperature ranges between 70oC to 90oC and
LOD is less than 0.2%.
16
8) A low residual solvent curcumin crystal powder composition that comprises at least 95% curcumin
by weight of the composition, characterized by that the turmeric curcumin crystal powder
comprises from 1 ppm to 50 ppm of residual organic solvent(s) trapped within the curcumin crystals
present in the powder and wherein the amount of trapped residual organic solvent(s) are measured
by the analytical method as described in example 1 herein, wherein the amount of residual organic
solvents are measured by making two separate measurements - one using water as solvent and in
the second N,N-dimethyl-formanide (DMF) as solvent - and the amount of residual organic
solvent(s) trapped within the curcumin crystals present in the powder is then the difference
between the amount measured by using DMF as solvent minus the amount measured by using
DMF as solvent.