CN111057130B

CN111057130B - High-purity micafungin or salt thereof, and preparation method and application thereof

Info

Publication number: CN111057130B
Application number: CN201911262804.8A
Authority: CN
Inventors: 陈敏; 王园圆; 李严; 季晓铭
Original assignee: Shanghai Techwell Biopharmaceutical Co Ltd
Current assignee: Shanghai Techwell Biopharmaceutical Co Ltd
Priority date: 2019-12-11
Filing date: 2019-12-11
Publication date: 2023-06-30
Anticipated expiration: 2039-12-11
Also published as: CN111057130A

Abstract

The invention discloses high-purity micafungin or salt thereof, a preparation method and application thereof, wherein the content of residual organic solvent in the micafungin or salt thereof is lower than 1.8%. The preparation method comprises introducing air with certain humidity into a drying oven, adding raw materials containing micafungin or its salt, and vacuum drying with water system, and stopping introducing air when the humidity of the drying oven reaches above 70%. The preparation method disclosed by the invention has the advantages of mild conditions, simple operation process, high yield, good product stability and convenience in transportation, and reduces the process operation difficulty coefficient to a great extent and the production cost. The micafungin or the salt thereof can be used for preparing medicines for preventing or treating diseases caused by fungal infection.

Description

High-purity micafungin or salt thereof, and preparation method and application thereof

Technical Field

The invention relates to the field of organic compounds, in particular to high-purity micafungin or pharmaceutically acceptable salt thereof, and a preparation method and application thereof.

Background

Fungal infections have become a major cause of increased morbidity and mortality in immunocompromised patients. The incidence of mold infections has increased significantly over the last 20 years. The high risk group for fungal infections includes critically ill patients, surgical patients and those suffering from HIV infection, leukemia and other neoplastic diseases. Those patients undergoing organ transplantation are also at high risk for fungal infection.

Echinocandins are a novel class of antifungal agents that are effective in the treatment of infections caused by candida or aspergillus. Such agents are in turn represented by micafungin and caspofungin. Echinocandins inhibit fungi by inhibiting the formation of 1, 3-beta glycosidic bonds, thereby better reducing injury to the human body, and reducing side effects as much as possible while being highly effective, so that they are safer than traditional antifungal agents in use.

FK463, also known as micafungin sodium, developed by japan rattan corporation (Japan Fujisawa Toyama co., ltd, takaoka Plant), under the trade name micafungin (Mycamine), is currently marketed in various countries as an intravenous antifungal agent. The chemical structure is shown as formula 1:

residual solvents in pharmaceuticals are defined at ICH (international human drug registry and pharmaceutical technology consortium) as organic volatile compounds that are produced or used in the manufacture of bulk drugs or excipients, and which are not completely removed in the process. The guidelines classify the residual solvents according to the degree of hazard and formulate acceptable amounts, i.e., limits, of the residual solvents under conditions that ensure human safety, providing some toxicologically acceptable levels of the residual solvents.

The current processes for the production of micafungin use basically involve a variety of solvents among methanol, isobutanol, ethyl acetate and ethanol. Whereas micafungin products prepared using the conventional methods reported so far fail to meet the ICH specifications for solvent residues (see ICH Q3C for details). If the equipment investment is high, the production scale is easy to limit, the operation difficulty is high, the industrial production is obviously unfavorable, meanwhile, the stability of the obtained product is poor, the product is required to be stored below-70 ℃, the difficulty of product transportation is brought, the difficulty of industrial production is certainly increased, and the industrial production scale is severely limited.

Therefore, further research on a preparation method of micafungin or its salt, which can effectively remove the organic solvent residue in the product and prevent degradation thereof, is suitable for industrial production, so as to obtain the stable micafungin or its salt with low solvent residue, which meets the pharmaceutical standard, is urgently needed.

Disclosure of Invention

The present invention aims to provide a high purity micafungin or a salt thereof.

It is another object of the present invention to provide a process for preparing micafungin or a salt thereof in high purity.

It is a further object of the present invention to provide the use of high purity micafungin or a salt thereof.

In the first aspect of the invention, the mass percentages of ethyl acetate, ethanol, methanol and isobutanol in the high-purity low-solvent-residue micafungin or the salt thereof are respectively lower than 0.5%, 0.3% and 0.5%, preferably lower than 0.25%, 0.1% and 0.25%, more preferably lower than 0.01%, 0.01% and 0.20%; the optimal mass percent is 0%, wherein the other solvent content accords with the limit regulation of ICH on residual solvent.

In a preferred embodiment of the present invention, the micafungin or a salt thereof is in a crystalline form.

In one embodiment of the present invention, the method for obtaining low solvent residual and low salt micafungin or a salt thereof comprises the steps of:

(1) Firstly, introducing air with a certain humidity, and putting a raw material containing micafungin or salt thereof into the water system to be dried in vacuum for a certain time.

(2) When the humidity of the drying oven reaches more than 70%, air is stopped from being introduced, and the PH of the product is raised from 5.1 to 5.8 after the drying is finished. And continuing to vacuum-dry the raw material of the micafungin or the salt thereof to obtain the micafungin or the salt thereof.

In another preferred embodiment, in the step a, the air with a certain humidity is introduced to be more than 80%.

In a further preferred embodiment, it is characterized in that in step a, the aeration time is 1-5h.

In a further preferred embodiment, it is characterized in that in step b, the drying time is from 0 to 24h.

In another preferred embodiment, the composition is used for preparing a medicament for preventing or treating diseases caused by fungal infection.

In a second aspect of the invention, there is provided the use of the low solvent residue and low salt micafungin or a salt thereof provided by the invention for the preparation of a medicament for the prevention or treatment of a disease caused by fungal infection.

The invention has the main advantages that:

1. the invention provides a novel low-solvent-residue and low-salt micafungin or pharmaceutically acceptable salt thereof.

2. The invention provides a novel preparation method of micafungin or salt thereof with low solvent residue and low salt.

3. The method has the advantages of mild conditions, simple operation process, high yield, good product stability and convenient transportation, reduces the process operation difficulty coefficient to a great extent, and reduces the production cost.

Detailed Description

The inventors have discovered a simple process for preparing micafungin or a salt thereof with low solvent residue and low salt. Through intensive research, it is found that the micafungin or its salt in an amorphous form can be dissolved by aqueous solution of methanol, then isobutanol and ethyl acetate are added for crystallization, raw materials containing the micafungin or its salt in the formula 1 are obtained, and then the micafungin or its salt with low solvent residue and low salt is obtained by vacuum drying together with an aqueous system.

As used herein, a chemical formula or name shall include all optical and stereoisomers, as well as the racemic mixtures of such isomers.

Low solvent residue and low salt micafungin or salt thereof.

The inventor has conducted intensive studies on the existing documents, respectively, and found that the nitrogen drying method, the freeze drying method and the spray drying method are difficult to dry and remove the organic solvent, so that the organic solvent residue exceeds the standard, the vacuum drying method (without adding water system for drying) cannot well remove the organic solvent, and the degradation of the product is quite obvious. The inventors have conducted intensive analysis on the reasons why the solvent residue in the dried product by the above methods exceeds the standard, and found that: the nitrogen drying method, the freeze drying method and the vacuum drying method (without adding the water system for drying) are easy to remove under the condition of vacuum drying or nitrogen flow in the earlier stage of sample drying, but the crystal lattice of the sample is gradually closed with the decrease of the residual solvent, so that the solvent still remains in the crystal lattice. In the latter stage of drying, the sample lattice is completely closed, and the solvent is permanently embedded in the lattice and cannot be removed under vacuum drying or nitrogen flow.

The inventors have surprisingly found that placing a substance capable of releasing water vapor in a vacuum dryer not only results in a low solvent residue, even no solvent residue, of micafungin or a salt thereof, but also no change in the purity of micafungin or a salt thereof.

The inventors have conducted intensive studies on the principle of drying micafungin or a salt thereof with low solvent residue and low salt. A substance capable of releasing water vapor is placed in a vacuum dryer in order to control the water content of the sample. In the early stages of sample drying, a significant amount of the organic solvent has been removed. In the middle stage of drying the sample, water in the sample continuously forms water vapor, and the water vapor forms hydrogen bonds with residual organic solvent in the sample, so that the organic solvent is dried and removed together in vacuum. However, the moisture content in the sample is limited, in order to maintain the balance and prevent the lattice of the sample from being completely closed, a substance capable of releasing water vapor is put into a drying system, and under the condition of vacuum, the substance continuously generates water vapor, and the sample itself contains a large amount of nitrogen and oxygen atoms and can form hydrogen bonds with water vapor to combine with water, so that the lattice closure of the sample can be avoided, and the exchange balance is maintained. In the other wet nitrogen drying method in the prior art, although the water content of the sample is controlled, under the condition of positive pressure, water in the sample cannot form water vapor, solvents cannot be dried and removed together in vacuum, a large amount of nitrogen is consumed, and equipment investment is high.

The inventors have conducted intensive studies on the drying process of micafungin or a salt thereof with low solvent residue and low salt, and have surprisingly found that the concentration of isobutanol can be effectively reduced by controlling the humidity of the drying oven. The drying process of the invention is divided into two stages, wherein the first stage is to introduce more than 80% of air into a drying box, then to dry the sample and the water system together in vacuum for a certain time, and the second stage is to stop introducing air when the humidity of the drying box reaches more than 70%, and to continue vacuum drying until the water content of the sample is qualified, so that the PH of the compound is raised from 5.1 to 5.8, thus being beneficial to volatilization of acetic acid and reducing the content of isobutanol. Unlike the drying methods reported in patent CN 104861044B and CN 104861043B.

Low solvent residue and low salt micafungin or salt purity and solvent residue determination.

The inventors have further studied the purity and solvent residue of micafungin or a salt thereof with respect to each other by using a high performance liquid phase and a gas after obtaining micafungin or a salt thereof with low solvent residue.

The invention adopts HPLC to measure the purity of micafungin or salt thereof (compound of formula 1 or salt thereof) in the sample prepared by the method of the invention, and is used for the stability study of the sample, and the HPLC detection method is as follows:

chromatographic column: a 4.6X250mm 5 μm C18 column;

mobile phase: a:0.1% perchloric acid and 0.075% sodium chloride solution; b: acetonitrile;

gradient elution conditions: a: b=65.5:34.5, 14.5 minutes; a: b=65.5:34.5 to 50:50, 21.5 minutes; a: b=50:50 to 35:65, 10 minutes; a: b=35:65 to 20:80, 5 minutes; a: b=20: 80,2 minutes; a: b=20:80 to 65.5: 34.5,1 minutes; a: b=65.5:34.5, 13 minutes;

flow rate: 1 ml/min; sample injection amount: 10 μl;

column temperature: 35 ℃ +/-5 ℃; detection wavelength: 220nm; run time: 60 minutes;

main peak retention time: about 27 minutes.

The invention also adopts GC to measure the solvent residue in the sample prepared by the method, and the GC detection method comprises the following steps:

chromatographic column: HP-INNOWAX

Column specification: 30 m.times.0.53 mm.times.1 μm

Sample inlet temperature: 200 DEG C

Detector temperature: 260 DEG C

Flow rate: 2ml/min

Furnace temperature: the initial temperature was 40℃for 5min, raised to 60℃at a rate of 5℃per minute, and raised to 240℃at a rate of 30℃per minute for 3 min.

Carrier gas: high purity nitrogen

Split ratio: 7:1 (soap film flowmeter measurement)

Air flow rate: 400 ml/min

Hydrogen flow rate: 40 ml/min

Tail blow flow rate: 25 ml/min (Nitrogen)

Headspace injector conditions:

temperature (temperature)	Equilibrium temperature: 120 DEG C	Quantitative ring temperature: 130 DEG C	Transmission line temperature: 140 DEG C
				Time	Equilibration time: 20min	Sample introduction time: 1min	GC cycle time: 30min

As used herein, "starting material containing micafungin or a salt thereof" refers to micafungin or a salt thereof in a crystalline state, which can be obtained by the steps of:

a'. Mixing crude micafungin or micafungin salt with methanol and water to obtain a homogeneous solution 1;

b'. Mixing the homogeneous solution 1 with isobutanol to obtain a homogeneous solution 2; mixing the homogeneous solution 2 with ethyl acetate to obtain a starting material containing micafungin or a salt thereof.

The steps a ' to b ' to c ' can be repeated 1, 2 or 3 times to obtain recrystallized micafungin or salt thereof, wherein the mass percent of the organic solvent in the crystalline micafungin or salt thereof is more than or equal to 1.8%; the organic solvent is isobutanol, methanol, ethyl acetate or ethanol. .

In the process of obtaining a starting material containing micafungin or a salt thereof, once step (c') is completely crystallized, the crystals may be isolated by filtration, decanting the solvent, or other means, preferably by filtration.

In the method for obtaining the micafungin or the salt thereof with low solvent residue and low salt provided by the invention, the step of vacuum drying the raw material containing the micafungin or the salt thereof together with the water system means that the raw material containing the micafungin or the salt thereof is placed in a place where a sample is usually placed in a vacuum dryer, and an open container containing a substance capable of releasing water vapor is placed around (e.g. at the bottom of) the vacuum dryer, wherein the substance capable of releasing water vapor is selected from tap water, pure water, crushed ice or an ice-water mixture.

The above-mentioned features of the invention or of the embodiments may be combined in any desired manner. All of the features of this specification may be used in combination with any form of micafungin, and the various features disclosed in this specification may be substituted for any alternative feature that may provide the same, or equivalent, or similar purposes. Thus, unless expressly stated otherwise, the disclosed features are merely general examples of equivalent or similar features.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, not specifically stated in the examples below, are generally carried out in accordance with conventional conditions, or in accordance with the conditions recommended by the manufacturer, except as otherwise indicated, percentages and parts are by weight.

The units in weight volume percent in the present invention are well known to those skilled in the art and refer, for example, to the weight of solute in 100ml of solution.

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. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.

Example 1

Preparation of micafungin with low solvent residue and low salt

The compound (2.0 g) of the formula 1 was dissolved in a system of methanol (0.13 ml) and water (2.2 ml) at 15℃and isobutanol (25 ml) was added after the dissolution, followed by stirring uniformly, ethyl acetate (27.4 ml) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at 12℃for 12 hours. The mixture was filtered, washed several times with a mixture of methanol and ethyl acetate (1.7:1) and the solids were collected by centrifugation. Introducing air with humidity of more than 85%, placing the sample in a vacuum drying oven, placing a tray of tap water at the bottom of the vacuum drying oven, drying at 15 ℃ under vacuum for 2 hours, and continuing to vacuum-dry at 15 ℃ for 14 hours when the humidity of the drying oven is 75%, so as to obtain micafungin sodium (1.50 g, mass yield 75%). HPLC shows 99.90% purity, less than 0.1% for single impurity, and 0.03%, 0.0%, 0.01% and 0.06% for isobutanol, methanol, ethyl acetate and ethanol, respectively.

Example 2

Preparation of micafungin with low solvent residue and low salt

The compound (2.0 g) of the formula 1 was dissolved in a system of methanol (0.13 ml) and water (2.2 ml) at 10℃and isobutanol (25 ml) was added after the dissolution, followed by stirring uniformly, ethyl acetate (27.4 ml) was slowly added dropwise, and after the completion of the dropping, stirring was carried out at 8℃for 2 hours. The mixture was filtered, washed several times with a mixture of methanol and ethyl acetate (1.7:1) and the solids were collected by centrifugation. Introducing air with humidity of above 82%, placing the sample in a vacuum drying oven, placing a tray of tap water at the bottom of the vacuum drying oven, drying at 10deg.C under vacuum for 4h, and vacuum drying at 10deg.C for 10h when the humidity of the drying oven is 78% to obtain micafungin sodium (1.50 g, mass yield 75%). HPLC shows 99.90% purity, less than 0.1% for single impurities, and 0.02%, 0.05%, 0.02% and 0.01% for isobutanol, methanol, ethyl acetate and ethanol, respectively.

Example 3

Preparation of micafungin with low solvent residue and low salt

A raw material (2.0 g) containing the compound of formula 1 was dissolved in a system of methanol (0.25 ml) and water (2.2 ml) at 15℃and isobutanol (25 ml) was added after the dissolution, followed by stirring uniformly, ethyl acetate (30 ml) was slowly added dropwise, and after the addition, stirring was carried out at 15℃for 2 hours. The mixture was filtered, washed several times with a mixture of methanol and ethyl acetate (1.7:1) and the solids were collected by centrifugation. Introducing air with humidity of more than 88%, placing the sample in a vacuum drying oven, placing a disc of pure water at the bottom of the vacuum drying oven, drying at 15 ℃ under vacuum condition for 6h, and continuing vacuum drying at 15 ℃ for 12h when the humidity of the drying oven is 80%, thereby obtaining micafungin sodium (1.70 g, mass yield 85%). HPLC showed 99.91% purity. The mass percentages of the isobutanol, the methanol, the ethyl acetate and the ethanol are respectively 0.07%, 0.01% and 0.0%.

Example 4

Preparation of micafungin with low solvent residue and low salt

A raw material (2.0 g) containing the compound of formula 1 was dissolved in a system of methanol (0.13 ml) and water (4.2 ml) at 20℃and isobutanol (25 ml) was added after the dissolution, followed by stirring uniformly, ethyl acetate (88.2 ml) was slowly added dropwise, and after the addition, stirring was carried out at 20℃for 1 hour. The mixture was filtered, washed several times with a mixture of methanol and ethyl acetate (1.7:1) and the solids were collected by centrifugation. Introducing air with humidity of more than 90%, placing the sample in a vacuum drying oven, placing an ice-water mixture at the bottom of the vacuum drying oven, drying for 4 hours at 20 ℃ under vacuum, and continuing to vacuum-dry for 9 hours at 20 ℃ when the humidity of the drying oven is 76%, so as to obtain micafungin sodium (1.95 g, quality yield is 97.5%). HPLC showed 99.92% purity with 0.06%, 0.0%, 0.02% and 0.0% mass% of isobutanol, methanol, ethyl acetate and ethanol respectively.

Example 5

Preparation of micafungin with low solvent residue and low salt

The compound (2.0 g) of the formula 1 was dissolved in a system of methanol (0.25 ml) and water (2.2 ml) at 10℃and ethanol (25 ml) was added after the dissolution, followed by stirring, ethyl acetate (30 ml) was slowly added dropwise, and after the completion of the dropping, the mixture was stirred at 10℃for 2 hours. The mixture was filtered, washed several times with a mixture of ethanol and ethyl acetate (1.7:1) and the solids were collected by centrifugation. Introducing air with humidity of more than 84%, placing the sample in a vacuum drying oven, placing an ice-water mixture at the bottom of the vacuum drying oven, drying at 10 ℃ under vacuum for 3 hours, and continuing to vacuum-dry at 10 ℃ for 24 hours when the humidity of the drying oven is 73%, so as to obtain micafungin sodium (1.55 g, mass yield 77.5%). HPLC showed 99.90% purity with 0.05%, 0.0% and 0.0% mass% of isobutanol, methanol, ethyl acetate and ethanol respectively.

Example 6

Preparation of micafungin with low solvent residue and low salt

The compound (2.0 g) of the formula 1 was dissolved in a system of methanol (0.13 ml) and water (2.3 ml) at 0℃and isobutanol (36 ml) was added after the dissolution, and ethyl acetate (38.4 ml) was slowly added dropwise with stirring, and after the addition, the mixture was stirred at 0℃for 1 hour. The mixture was filtered, washed several times with a mixture of ethanol and ethyl acetate (1.7:1) and the solids were collected by centrifugation. Introducing air with humidity of more than 88%, placing the sample in a vacuum drying oven, placing an ice-water mixture at the middle bottom of the vacuum drying oven, drying at 0 ℃ and under vacuum for 2 hours, and continuing to vacuum-dry at 0 ℃ for 12 hours when the humidity of the drying oven is 78%, so as to obtain micafungin sodium (1.80 g, mass yield 90%). HPLC showed 99.88% purity with 0.10%, 0.01% and 0.0% mass% of isobutanol, methanol, ethyl acetate and ethanol.

Example 7

Preparation of micafungin with low solvent residue and low salt

A raw material (2.0 g) containing the compound of formula 1 was dissolved in a system of methanol (0.50 ml) and water (3.3 ml) at 5℃and isobutanol (36 ml) was added after the dissolution, and ethyl acetate (60 ml) was slowly added dropwise after stirring, followed by stirring at 5℃for 1 hour. The mixture was filtered, washed several times with a mixture of ethanol and ethyl acetate (1.7:1) and the solids were collected by centrifugation. Introducing air with humidity of more than 83%, placing the sample in a vacuum drying oven, placing a disc of crushed ice at the bottom of the vacuum drying oven, drying at 5 ℃ under vacuum for 3 hours, and continuing to vacuum-dry at 5 ℃ for 7 hours when the humidity of the drying oven is 74%, so as to obtain micafungin sodium (1.88 g, mass yield 94.0%). HPLC showed 99.86% purity with 0.11%, 0.01%, 0.0% and 0.02% mass% of isobutanol, methanol, ethyl acetate and ethanol.

Example 8

Preparation of micafungin with low solvent residue and low salt

Firstly, introducing air with the humidity of more than 87%, placing the raw materials containing the compound of the formula 1 into a vacuum drying box, placing a disc of crushed ice at the bottom of the vacuum drying box, drying for 4 hours, and continuing to vacuum-dry at the temperature of 0 ℃ for 10 hours until the humidity of the drying box is 74%. HPLC showed 99.50% purity with 0.13%, 0.10%, 0.07% and 0.20% mass% of isobutanol, methanol, ethyl acetate and ethanol.

Example 9

Preparation of micafungin with low solvent residue and low salt

Introducing air with humidity of above 93%, placing the raw materials containing the compound of formula 1 in a vacuum drying oven, placing a tray of crushed ice at the bottom of the vacuum drying oven, drying for 3 hours until the humidity of the drying oven is 80%, and drying at 10deg.C under vacuum for 12 hours. HPLC showed 99.50% purity with 0.22%, 0.08%, 0.02% and 0.18% mass% of isobutanol, methanol, ethyl acetate and ethanol.

In the GC analysis control chart of various solvents according to the invention, the retention times and peak areas of the various solvents are listed in the following table:

retention time	Peak area	Solvent species
			9.113	285.1	Methanol
9.961	627.6	Ethanol
			12.263	452.8	Isobutanol
8.729	1629.5	Acetic acid ethyl ester

In the GC analysis chart of the low-solvent-residue and low-salt micafungin or the salt thereof, which is prepared by the embodiment of the invention, the retention time, the peak area and the mass content of various solvents are listed in the following table:

retention time	Peak area	Mass content (%)	Solvent species
				9.113	0	0	Methanol
9.961	0	0	Ethanol
				12.263	32.0	0.03	Isobutanol
8.729	21.8	0.01	Acetic acid ethyl ester

Claims

1. A process for the preparation of high purity micafungin or a salt thereof, said process comprising the steps of:

a. introducing air with humidity of more than 80% into a drying box, and vacuum drying the raw materials containing micafungin or salt thereof and the water system for 1-5h;

b. when the humidity of the drying oven reaches more than 70%, stopping introducing air; continuously vacuum drying the raw material of micafungin or salt thereof for 0-24h, and raising the PH of the product from 5.1 to 5.8 after the drying is finished to obtain high-purity micafungin or salt thereof;

the high-purity micafungin or the salt thereof is in a crystalline state, and the mass percentage of the residual organic solvent is lower than 1.8%; the organic solvent is methanol, ethyl acetate, isobutanol or ethanol; the mass percentages of the methanol, the ethyl acetate, the isobutanol and the ethanol are respectively lower than 0.3 percent, 0.5 percent and 0.5 percent; the salt is a pharmaceutically acceptable salt.

2. The method of claim 1, wherein the salt is a sulfonate salt.

3. The preparation method according to claim 1, wherein the mass percentages of methanol, ethyl acetate, isobutanol and ethanol are respectively lower than 0.1%, 0.25% and 0.1%.

4. The method of claim 3, wherein the percentages of methanol, ethyl acetate, isobutanol and ethanol are less than 0.01%, o.10% and 0.01%, respectively.

5. The method of claim 4, wherein the methanol, ethyl acetate, isobutanol and ethanol are each 0.

6. The preparation method according to claim 1, wherein the solvents other than methanol, isobutanol, ethyl acetate and ethanol are contained in amounts conforming to the limit regulations of ICH with respect to residual solvents.

7. The method of claim 1, wherein the salt is a sodium salt.