KR20000055129A - Supercritical extraction solvent composition for removing polaric imparities from oral compound - Google Patents

Abstract

PURPOSE: A supercritical extractant composite for removing polar impurities of a compound for oral use composite is provided to mix carbon monoxide ,which is effective to remove a resident solvent of solid compound for oral use, with a polar solvent, which is not harmful for human health. CONSTITUTION: A supercritical extractant composite for removing polar impurities of a compound for oral use is processed to mix carbon monoxide under 90 volume percent with a polar solvent or with more than two solvents which are liquid phase at room temperature and which has boiling point under 200°C. The composite is manufactured to maintain at 74-800 atm and at 32-200°C. The polar solvent is selected from methanol, ethanol, other alcohol groups and acetic acid, formic acid, organic acid groups and water.

Description

SUPERCRITICAL EXTRACTION SOLVENT COMPOSITION FOR REMOVING POLARIC IMPARITIES FROM ORAL COMPOUND

The present invention relates to a solvent composition that can effectively remove the residual solvent remaining in the solid compounds used directly in the human body, such as food and pharmaceutical use, and more particularly, remains in a compound synthesized for oral use, etc. The present invention relates to a supercritical extraction solvent composition for removing polar impurities of an oral compound composed of carbon dioxide and a small amount of polar solvent which is harmless to the human body.

Generally in chemical synthesis, saturated or unsaturated hydrocarbons such as hexane and hexene, aromatic hydrocarbons such as toluene, ketones such as methyl ethyl ketone (MEK), alcohols such as isobutyl alcohol, or dimethyl formamide (DMF) and dimethyl sulfoxide One or more organic solvents harmful to the human body are used, such as heter atom compounds such as DMSO. Therefore, in order to use the prepared compound for oral use, a process of removing or extracting impurities including residual solvents in the product is necessary.

Purification of a solid oral compound uses a method of washing out impurities by using a difference in solubility between impurities containing a residual solvent contained in a solid and a solid. In this case, for example, a volatile organic solvent may be used. However, it is limited to those which are easy to be processed after treatment such as organic solvents or water which are harmless to the human body or have little effect on the human body even if they remain in the product.

U.S. Patent 4,683,299 has a similar solubility in water and organic solvents, such as oral fatty acid sugar ester compounds or cellulose compounds, and is therefore used for the purification of compounds used as emulsifiers for food dispersants or medicines. In this process, the process of washing out impurities or residual solvents with water is adopted, but in this process, the loss of the product is severe, and the composition of the product is changed or a separate process of recovering the residual product from the recovered water is required. In addition to this, there are secondary problems such as contamination by another compound in the purification process and a large amount of waste water, which is not preferable to actually apply to the process.

In addition to the above method, there is a method of purifying using a supercritical fluid, where the supercritical fluid refers to a fluid that appears when the gas is maintained above a critical temperature. These supercritical fluids, which are neither liquids nor gases, can easily manipulate the polarity of the fluids through changes in temperature or pressure, and have impurities that contain residual solvents in the medium because they have a high penetration force into a medium made of a general solid. There is an advantage that can be effectively removed. The case for such a supercritical fluid to extract the solvent extraction purification of the impurities "Design and Control of a CO2 extraction plant _{(Design and Control of CO 2 Extraction} Plants)" ( , May 20-22, 1991 days. The main mesa Massachusetts Massachusetts Stone, presented at the 2nd International Symposium on Critical Fluids) and U.S. Patents 5,281,406, 5,550,211, 5,417,795, 5,439,861, 5,478,921, 4,703,105, and others.

Table 1 shows the supercritical fluids generally used as extraction solvents, and in particular, the reason why these materials are applied as extraction solvents is that they are prepared as supercritical extraction solvents because the critical point is relatively low at the critical temperature of 100 ° C. and below the critical pressure of 100 atm. It is because it has economic value.

Critical Temperature (℃) Critical Pressure (bar) Boiling Point (℃) Carbon dioxide (CO ₂ ) Nitrogen oxide (N ₂ O) Ethane (C ₂ H ₆ ) Ethylene (C ₂ H ₄ ) 31.2 74.0 -73.8 96.8 72.7 -88.8 32.4 48.9 -88.4 9.8 51.2 -48.0

In Table 1, carbon dioxide has an advantage of being inert, harmless to the human body, and having a low critical point. However, since carbon dioxide is nonpolar, it is somewhat difficult to use as an extraction solvent for purifying polar impurities.

In US Pat. No. 5,478,921, supercritical carbon dioxide is separated and purified from a bioabsorable polymer using polar monomers such as glycolic acid by increasing the polarity with increasing pressure. The extraction solvent was not economically desirable because it must use a supercritical fluid made by maintaining the pressure of carbon dioxide above 300 atm.

An object of the present invention is to solve the conventional problems as described above, to provide a solution composition made by mixing a small amount of a polar solvent harmless to the human body with carbon dioxide effective to remove the residual solvent in the solid compound used for oral use.

That is, the present invention is prepared by mixing liquid carbon dioxide with one selected from alcohols such as methanol, ethanol, organic acids such as acetic acid and formic acid, and polar compounds such as water, which are harmless to the human body within 90% of the volume of carbon dioxide. A supercritical extractant composition for removing polar impurities of a compound.

Hereinafter, the present invention will be described in more detail.

The oral compound applied to the use of the supercritical extractant composition of the present invention refers to a compound having a molecular weight of 500 or more and a solid at room temperature having a food or pharmaceutical use that can be directly or indirectly ingested by humans. In addition, the impurity containing the residual solvent present in the oral compound means a polar or mesopolar compound having a molecular weight of less than 1,000 and liquid at room temperature, more specifically organic acids such as glycolic acid, alcohols such as butanol, Aromatic alcohols such as phenol, ketones such as methyl ethyl ketone (MEK), and mixed with two or more kinds of harmful solvents such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and tetrahydrofuran (THF) It means that it exists in an oral compound.

In the supercritical fluid used in the present invention, the liquid carbon dioxide is mixed within 90% of the liquid polar solvent in a volume ratio, using a high pressure pump, the pressure of the mixing tank with a heater is 74 to 800 atm, and the temperature is 32 to 200 ° C. It is a fluid prepared by holding, more preferably a liquid composition prepared by mixing a liquid polar solvent in a liquid carbon dioxide at a volume ratio of 30% or less and maintaining the pressure at 80 to 300 atm and a temperature of 35 to 80 ° C.

Here, the polar solvents added to the carbon dioxide is a liquid at room temperature, boiling point of 200 ℃ or less and a high polarity compound, for example selected from the group consisting of alcohols such as methanol, ethanol and the like, organic acids such as acetic acid, formic acid and water Among them, most preferably, ethanol or formic acid, acetic acid, and the like, which are harmless polar compounds, are used alone or in combination of two or more thereof.

The method of applying the supercritical extractant of the present invention thus prepared to the extraction of the residual solvent from the oral solid compound may be carried out as follows.

First, the static extraction method that contains a certain amount of the sample in the extractor made of durable material at high pressure, supply the supercritical extraction solvent of the present invention and leave it for a certain time and then remove the residual solvent dissolved in the supercritical extraction solvent (Static Extraction) Repeatedly perform a dynamic extraction (Dynamic Extraction) method to remove the residual solvent dissolved in the supercritical extraction solvent while passing a certain amount of supercritical solvent for a predetermined time until a target content is obtained. In this case, the extraction efficiency depends on the amount of supercritical extraction solvent used, the extraction time and the number of times of extraction depending on the type of sample present in the sample, the amount of initial residual solvent, and the amount of target residual solvent.

In one embodiment of the present invention, in the case of a particulate synthetic emulsifier in which DMSO is mixed, a supercritical fluid is supplied after the sample is filled with 10-50% of the sample using the supercritical extractant composition of the present invention and left for 30 minutes. Static extraction and repetitive extraction in one cycle of dynamic extraction flowing a supercritical extraction solvent corresponding to 0.1 times (0.7 ml / min) to 1 times (7 ml / min) of the reactor volume per minute within 30 minutes As the supercritical extraction solvent, the extraction efficiency is improved by more than 100% compared to the case of using carbon dioxide alone.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by the following Examples.

Examples 1-8, Comparative Examples 1-2

The apparatus used in this embodiment and the comparative example is divided into a fluid supply unit and an extractor unit, and when supplying carbon dioxide mixed with liquefied carbon dioxide alone or a small amount of polar solvent through a high pressure pump, It turns into a critical extraction solvent. The supercritical extraction solvent was prepared using a stainless steel tube, penetrated the sample through an extractor with a 10 μm stainless steel filter attached to an internal volume of 7 ml, a fluid inlet and an outlet, and extracted polar impurities through a nozzle. Exhausted in gaseous state.

At this time, extraction was repeated with 1 cycle of static extraction and dynamic extraction, where static extraction was stopped for about 20 minutes after filling the fluid in the extractor, and dynamic extraction was performed for 1.4 ml / min of fluid 5 Extracted while flowing for 20 minutes.

The sample was prepared by using a powder containing 1000 ppm of butanol and dimethyl sulfoxide in a synthetic sugar ester (mono ester content: 75%). For extraction, put 0.998 to 1.002 g of sample into the extractor and use the extraction conditions shown in Table 2 to determine the sample composition change (mono / di / triester composition) before and after extraction by gel permeation chromatography (Gel Permeation Chromatograpy, GPC). ) And the butanol and dimethyl sulfoxide contents contained in the samples are shown in Tables 2 and 3 after the analysis using the chromatographic method.

division DMSO content before extraction (ppm) Polar solvent type and content (type /%) ¹⁾ Extraction pressure (atmospheric pressure) Extraction temperature (℃) Extraction time (minutes) Repeated extraction DMSO content after extraction (ppm) Extraction efficiency (%) ²⁾ silence dynamic Comparative Example 1 1000 not used 200 60 20 20 One 350 ＞ 98 Example 1 1000 Acetic acid / 0.5 200 60 20 20 One 42 ＞ 98 Example 2 1000 Acetic acid / 5.0 200 60 20 20 One ＞ 1 ＞ 98 Example 3 1000 Ethanol / 0.5 200 60 20 20 One 85 ＞ 98 Example 4 1000 Ethanol / 5.0 200 60 20 20 One ＞ 1 ＞ 98

division Butanol content (ppm) before extraction Polar solvent type and content (type /%) ¹⁾ Extraction pressure (atmospheric pressure) Extraction temperature (℃) Extraction time (minutes) Repeated extraction Butanol content after extraction (ppm) Extraction efficiency (%) ²⁾ silence dynamic Comparative Example 2 1000 not used 200 60 20 20 One 259 ＞ 98 Example 5 1000 Acetic acid / 0.5 200 60 20 20 One 57 ＞ 98 Example 6 1000 Acetic acid / 5.0 200 60 20 20 One 2 ＞ 98 Example 7 1000 Ethanol / 0.5 200 60 20 20 One 14 ＞ 98 Example 8 1000 Ethanol / 5.0 200 60 20 20 One ＞ 1 ＞ 98

^{1) The} content is volume ratio,

²⁾ Extraction efficiency (%) = (weight of sample after extraction) / (weight of sample before extraction) x 100

The removal of dimethyl sulfoxide (DMSO) in Examples 1 to 4 was remarkably superior to Comparative Example 1, and appeared to be effective when mixed a large amount of polar solvents such as acetic acid and ethanol, even more when using acetic acid rather than ethanol It was effective.

Butanol removal in Examples 5 to 8 was also significantly superior to Comparative Example 2, and appeared to be effective in the case of mixing a large amount of polar solvents such as acetic acid and ethanol, where ethanol is used as opposed to dimethyl sulfoxide More effectively.

In addition, it can be seen that the extraction efficiency measured by the weight of the sample changed before and after the extraction is less than 2% of the sugar esters lost due to the exhibitor of Examples 1 to 8 showing 98% or more.

As described above, a super ester extract solvent composition of the present invention prepared by mixing a small amount of a polar solvent that is harmless to the human body to carbon dioxide is added to an oral solid compound such as food or medicine to remove residual organic solvent. The extraction efficiency is improved by more than about 100% compared to the critical solvent using carbon dioxide alone, and the recovery rate of the sample is more than 98%. But it is much more effective in terms of fairness.

Claims (2)

In the supercritical extraction solvent used to remove the residual solvent-containing polar impurities present in the solid compound for oral use, the polar solvent alone or two or more thereof, which is liquid at room temperature and has a boiling point of 200 ° C. or less, is mixed at 90% or less with respect to the carbon dioxide volume. And a pressure of 74 to 800 atm and a temperature of 32 to 200 ° C. to maintain the polar impurity of the oral compound, characterized in that the preparation of a supercritical extraction solvent composition. The supercritical extractant composition for removing polar impurities of the oral compound according to claim 1, wherein the polar solvent is selected from methanol, ethanol alcohols, organic acids such as acetic acid and formic acid, and water.