Metformin manufacturing method

Abstract

To provide a process for the preparation of metformin that is free from the disadvantages of traditional preparation processes.SOLUTION: The present invention relates to an improved process for the preparation of metformin hydrochloride, an important drug in the first selective treatment of Type II Diabetes.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an improved process for the preparation of metformin hydrochloride, an important drug in the first-line treatment of type 2 diabetes. [Background technology]

[0002] Metformin can be prepared by the condensation of dimethylammonium chloride with dicyanodiamide as shown below. [ka]

[0003] Generally, the reaction is usually carried out at elevated temperatures in a hydrocarbon or alcohol solvent.

[0004] Examples of prior art that disclose the selection of hydrocarbons such as xylene as solvents include German Patent No. 1023757, Indian Patent Application No. 1350 / MUM / 2007, Indian Patent Application No. 1346 / MUM / 2008 and French Patent Application No. 2322860.

[0005] Prior art examples of selecting an alcohol solvent include CN105481726, CN100391939 and CN106795104.

[0006] Anvar Shalmashi (Molbank, 2008, M564) discloses a synthetic route to metformin hydrochloride by microwave irradiation on thin layer chromatography (TLC) plates.

[0007] All of the methods disclosed in the prior art must consider the removal of the solvent to ensure the purity of the final product, in addition to safety considerations regarding protection from flammable organic solvents. Furthermore, residual amounts of solvent in the final product cannot be completely removed, which is significant from a toxicological point of view. In principle, reactions in the absence of organic solvents are desirable and are the preferred and safer option.

[0008] A solvent-free synthesis of metformin hydrochloride is disclosed in Indian Patent Application No. 189077. According to such teachings, dicyanodiamide and dimethylammonium chloride (reactants) are mixed with wet metformin hydrochloride (product) in a ratio of from 1:1 to 1.3:1-3 and reacted at a temperature below 150° C. To achieve sufficient conversion of the reactants to the product, an equimolar or greater amount of metformin hydrochloride must be added to the reaction mixture.

[0009] In order to add at least an equimolar amount of metformin hydrochloride to the reactants, the reactor must be made larger and the energy input must be increased, resulting in a reduced output of the reaction product relative to the reactants (only a portion of the metformin hydrochloride in the product is newly synthesized). Furthermore, the metformin hydrochloride fed into the reaction may be decomposed when the reaction mixture is heated, which increases the content of impurities in the final product and must be removed from the reaction product after the reaction. In addition to further increasing costs, the overall reaction time becomes extremely long. Summary of the Invention [Problem to be solved by the invention]

[0010] Therefore, the object of the present invention is to provide a method for preparing metformin that does not cause the above-mentioned disadvantages of the conventional preparation methods, in particular, the method should avoid the use of organic solvents and should not require the addition of at least an equimolar amount of metformin hydrochloride. [Means for solving the problem]

[0011] These objectives have been achieved by a method for producing metformin hydrochloride, which comprises the steps of: (a) heating a mixture of dimethylammonium chloride, dicyanodiamide, and 0 to 20% by mass of water and 0 to 50% by mass of metformin hydrochloride, based on the total amounts of dimethylammonium chloride and dicyanodiamide present in the mixture, to a temperature in the range of 70°C to 250°C, and maintaining the temperature in that range for 0.1 minutes to 20 hours; and (b) cooling the reacted mixture and recovering the resulting crystalline metformin hydrochloride.

[0012] Therefore, the present invention relates to a method for producing metformin hydrochloride, comprising the steps of: (a) heating a mixture of dimethylammonium chloride, dicyanodiamide, and 0 to 20% by mass of water and 0 to 50% by mass of metformin hydrochloride, respectively, based on the total amounts of dimethylammonium chloride and dicyanodiamide present in the mixture, to a temperature in the range of 70°C to 250°C and maintaining the temperature in that range for 0.1 minutes to 20 hours; and (b) cooling the reacted mixture and recovering the resulting crystalline metformin hydrochloride. DETAILED DESCRIPTION OF THE INVENTION

[0013] Because the reaction and crystallization are exothermic, a slow temperature increase allows for better control of the heat dissipated in the batch reactor.

[0014] Preferably, all reaction steps are carried out under stirring, preferably under constant stirring.

[0015] The above process is a batch process. As used herein, the term "batch process" refers to a process in which the raw materials are combined in a reactor or vessel and the product is removed at the end of the reaction.

[0016] Alternatively, the method can be carried out as a continuous process. As used herein, the term "continuous process" refers to a process in which raw materials flow in and products flow out continuously. Such a continuous process provides a platform in which a series of operations, beginning with an initial starting material, can be fully continuous to synthesize a final product. In some cases, the final product can be produced by a synthesis that combines batch and flow processes.

[0017] Conducting the process as a continuous process is advantageous for increasing productivity and providing a safe, rapid, and scalable route to meet future demand for metformin hydrochloride. Such a method for producing metformin hydrochloride comprises the steps of: (a) continuously feeding dimethylammonium chloride, dicyanodiamide, and 0-20% by weight of water and 0-50% by weight of metformin hydrochloride, respectively, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture, into a reactor while continuously stirring and continuously heating the mixture to a temperature in the range of 70°C to 250°C; and (b) cooling the reacted mixture and recovering the resulting crystalline metformin hydrochloride. Therefore, the present invention also relates to a method for producing metformin hydrochloride, comprising the steps of: (a) continuously stirring dimethylammonium chloride, dicyanodiamide, and 0 to 20% by mass of water and 0 to 50% by mass of metformin hydrochloride, respectively, based on the total amounts of dimethylammonium chloride and dicyanodiamide present in the mixture, and continuously feeding the mixture into a reactor while continuously heating the mixture to a temperature in the range of 70°C to 250°C; and (b) cooling the reacted mixture and recovering the resulting crystalline metformin hydrochloride.

[0018] In an advantageous embodiment of the process of the invention, metformin hydrochloride can be present in an amount of 0-20% by weight, preferably 0-10% by weight, more preferably about 5% by weight, and most preferably 0% by weight, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture, both in batch as well as continuous processes. The present invention therefore also relates to a process characterized in that metformin hydrochloride is present in an amount of 0-20% by weight, preferably 0-10% by weight, more preferably about 5% by weight, and most preferably 0% by weight, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture.

[0019] In step (a) of the continuous or batch process, the mixture can be heated stepwise to one or more different temperatures, i.e., in one, two or more stages. In an advantageous embodiment, in step (a), the mixture is heated in two stages, where the mixture is heated to a first temperature in the range of 70°C to 120°C, maintained at that temperature for a certain period of time, and then heated to a second temperature in the range of 120°C to 250°C and maintained at that temperature for a certain period of time. Thus, the present invention also relates to a process characterized in that in step (a), the mixture is heated to a first temperature in the range of 70°C to 120°C, maintained at that temperature for a certain period of time, and then heated to a second temperature in the range of 120°C to 250°C and maintained at that temperature for a certain period of time.

[0020] The continuous treatment can be carried out in one continuous reactor or in several continuous reactors connected in series. Accordingly, the present invention further relates to a process characterized in that it is carried out in one continuous reactor or in several continuous reactors connected in series.

[0021] According to an advantageous embodiment of the continuous process, the mixture is heated to a first temperature in the range of 70°C to 120°C in a first reactor and maintained at that temperature for a certain period of time, then heated to a temperature in the range of 110°C to 160°C in a second reactor and maintained at that temperature for a certain period of time, and then heated to a third temperature in the range of 140°C to 250°C in a third reactor and maintained at that temperature for a certain period of time. Thus, the present invention also relates to a continuous process for producing metformin hydrochloride, characterized in that in step (a), the mixture is heated to a first temperature in the range of 70°C to 120°C in a first reactor and maintained at that temperature for a certain period of time, then heated to a second temperature in the range of 110°C to 160°C in a second reactor and maintained at that temperature for a certain period of time, and then heated to a third temperature in the range of 140°C to 250°C in a third reactor and maintained at that temperature for a certain period of time. The temperature and residence time of each step depend on the type of reactor technology selected.

[0022] The heating time required for melting and reacting the raw materials to obtain the product can vary over a wide range depending on the type and size of the equipment used for continuous or batch processing, the applied production parameters such as the feed rate and stirring rate of the raw materials, and the heating temperature. When the method is carried out under normal conditions, the total time for maintaining the heating temperature is in the range of 0.1 minutes to 10 hours. Therefore, the present invention further relates to a method characterized in that the total time for maintaining the heating temperature is in the range of 0.1 minutes to 10 hours.

[0023] In one embodiment of the present invention, the method is a continuous process, and heating is carried out in three stages. In such an embodiment, it is advantageous to maintain the heating temperatures at the first temperature for 0.1 minutes to 2 hours, at the second heating temperature for 0.1 minutes to 3 hours, and at the third heating temperature for 0.1 minutes to 5 hours. Accordingly, the present invention also relates to a continuous process for producing metformin, in which the first heating temperature is maintained for 0.1 minutes to 2 hours, the second heating temperature is maintained for 0.1 minutes to 3 hours, and the third heating temperature is maintained for 0.1 minutes to 5 hours.

[0024] In a particularly preferred embodiment, the method for producing metformin hydrochloride comprises the steps of: (a) continuously feeding anhydrous dimethylammonium chloride, dicyanodiamide, and 0 to 20% by mass of water, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture, into a continuous reactor; heating the mixture to a first heating temperature in the range of 70°C to 120°C; maintaining the heating temperature for 0.1 to 2 hours; then increasing the temperature to a second temperature in the range of 110°C to 160°C; maintaining the temperature in that range for 0.1 minutes to 3 hours; and then increasing the temperature to a third temperature in the range of 140°C to 250°C; and maintaining the temperature for 0.1 minutes to 5 hours; and (b) cooling the reacted mixture; and recovering the resulting crystalline metformin hydrochloride.

[0025] As used herein, "about" refers to numerical values, including integers, fractions, percentages, etc., whether explicitly stated or not. The term "about" generally refers to a range of numbers (e.g., ±1-3% of the stated value) that one of ordinary skill in the art would consider equivalent to the stated value (e.g., providing a similar function or result). In some cases, the term "about" may include numbers that are rounded to the nearest significant figure.

[0026] Generally, in this application, when the term "method" is used without further elaboration, the disclosure relates to both batch and continuous processes. When the term "method" is used in conjunction with the term "continuous," i.e., "continuous processing," the disclosure relates only to continuous processing and does not apply to batch processing. Vice versa, when the term "method" is used in conjunction with "batch," i.e., "batch processing," the disclosure relates only to batch processing and does not apply to continuous processing.

[0027] In principle, any known continuous reactor suitable for melt handling can be used in the process according to the invention. Suitable continuous reactors that can be used to carry out the process include continuous stirred tank reactors, single or twin screw extruders, single or twin screw kneaders or combinations of continuous stirred tank reactors, single or twin screw extruders and single or twin screw kneaders. Thus, the present invention also relates to a process characterized in that the continuous reactor is a continuous stirred tank reactor, a single or twin screw extruder, a single or twin screw kneader or combinations of continuous stirred tank reactors, single or twin screw extruders and single or twin screw kneaders.

[0028] According to a suitable embodiment of the present invention, dimethylammonium chloride and dicyanodiamide are present in a mixture with each other in a molar ratio of 1.0 to 2.0: 1, preferably in a molar ratio of about 1.15: 1. Thus, the present invention also relates to a process characterized in that dimethylammonium chloride and dicyanodiamide are present in a mixture with each other in a molar ratio of 1.0 to 2.0: 1, preferably in a molar ratio of about 1.15: 1.

[0029] As mentioned above, the mixture of dimethylammonium chloride, dicyanodiamide, and, if present, metformin hydrochloride used in step (a) of the method of the present invention contains up to 20% by weight of water, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture. According to a preferred embodiment, the amount of water in this step is 0-10% by weight, preferably 0-5% by weight, and more preferably about 3% by weight, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture. Thus, the present invention also relates to a method in which the mixture treated in step (a) contains 0-10% by weight, preferably 0-5% by weight, and more preferably about 3% by weight, of water, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture.

[0030] According to an advantageous embodiment, the reaction mixture may contain an additive that increases the reaction selectivity and / or viscosity of the molten mixture. The term "reaction selectivity" as used herein refers to the ratio of metformin hydrochloride to by-products obtained by the reaction. High reaction selectivity reduces or suppresses impurities derived from by-products. An increase in the viscosity of the molten mixture reduces backflow in the flow direction, which is particularly advantageous when the process is carried out as a continuous process (e.g., in an extruder or kneader). Therefore, the present invention also relates to a process characterized in that the mixture treated in step (a) further contains an additive that increases the reaction selectivity and / or viscosity of the molten mixture.

[0031] Any solid additive that increases the reaction selectivity and / or viscosity of the melt can be used. Additives particularly suitable for the process of the present invention include sodium chloride, celite, silica, or a mixture of two or more of these substances. A preferred additive is celite. Therefore, the present invention further relates to a process characterized in that the additive is sodium chloride, celite, or silica, preferably metformin hydrochloride, celite, or a mixture of two or more of these substances.

[0032] In an exemplary embodiment, the amount of additive present in the mixture is 0.001 to 50% by weight, preferably 0.01 to 10% by weight, and more preferably 0.1 to 5% by weight, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture. Accordingly, the present invention also relates to a method, wherein the amount of additive present in the mixture is 0.001 to 50% by weight, preferably 0.01 to 10% by weight, and more preferably 0.1 to 5% by weight, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture.

[0033] According to a preferred embodiment of the method, the reaction mixture comprises about 1% by weight of Celite as an additive, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture. Thus, the present invention also relates to a method, characterized in that the reaction mixture comprises about 1% by weight of Celite as an additive, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture.

[0034] Because solid dimethylammonium chloride is hygroscopic, large-scale shipping and handling tends to be difficult, which can adversely affect the robustness of the method. To reduce this risk, dimethylammonium chloride can be supplied as an aqueous solution containing 20-50% water by mass and concentrated to the required water content before mixing with dicyanodiamide to form a molten mixture.

[0035] Therefore, the present invention also relates to a method of preparing a solution of dimethylammonium chloride containing 20 to 50% by mass of water, concentrating the solution so that the solution contains 0.1 to 20% by mass of water, preferably 0.1 to 10% by mass of water, and more preferably about 0.1 to 6% by mass of water, based on the total amount of dimethylammonium chloride and water, to prepare a mixture, and adding dimethylammonium chloride as a mixture with water.

[0036] The mixture of dimethylammonium chloride and water can be used in a batch process (wherein a mixture of dimethylammonium chloride and dicyanodiamide is prepared by mixing a mixture of dimethylammonium chloride and water with dicyanodiamide) as well as a continuous process (wherein the dimethylammonium chloride is fed as a mixture of dimethylammonium chloride and water). [Example]

[0037] The examples illustrate the invention without limiting it.

[0038] Example 1 (batch process, one heating step) 250 g of dicyanodiamide, 315.22 g of dimethylammonium chloride, and 16.96 mL of water were added to a 1 L reactor. The reactor was heated to 145° C. for 3 hours. As the reaction proceeded, metformin hydrochloride precipitated from the mixture. The reactor was cooled to room temperature, demineralized water was added to the reactor, and the resulting slurry was removed. Metformin hydrochloride was obtained with a purity of 89%.

[0039] Example 2 (batch process, two heating steps) 3432 g of dicyanodiamide, 4320 g of dimethylammonium chloride, and 232.5 mL of water were added to a reactor. The reactor was heated to 105°C until a homogeneous melt was formed. The molten mixture was transferred to a 12 L twin-screw co-rotating batch mixer and heated at 130°C for 1 hour, then at 145°C for 2.5 hours. As the reaction proceeded, metformin hydrochloride precipitated from the mixture. The reactor was cooled to room temperature, demineralized water was added to the reactor, and the resulting slurry was removed. Metformin hydrochloride was obtained with a purity of 94%.

[0040] Example 2 (continuous processing) Dicyanodiamide and dimethylammonium chloride in a molar ratio of 1:1.15 and water (3% by weight based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture) were continuously fed into a 6 L stirred vessel heated to 100°C. The molten mixture was transferred to a stirred reactor at a rate of 4 kg / h and heated to 135°C for a residence time of 15 minutes. The partially reacted material was continuously discharged into a twin-screw kneader and fully converted by stirring at 175°C for 45 minutes. The product was continuously discharged from the second kneader at a rate of 4 kg / h via a vertical twin-screw conveyor into a recovery flask. The recovered solid mixture contained metformin with a purity of 89%.

[0041] Example 3 (Batch Treatment Using a Mixture of Dimethylammonium Chloride and Water) 450 g of 70% aqueous dimethylammonium chloride solution was added to a reactor equipped with a distillation column. The mixture was concentrated at 130°C for 2.5 hours until the water content was approximately 5%. To this mixture, 250 g of dicyanodiamide was added. The reactor was heated to 145°C for 3 hours. As the reaction proceeded, metformin hydrochloride precipitated from the mixture. The reactor was cooled to room temperature, demineralized water was added to the reactor, and the resulting slurry was removed. Another aspect of the present invention may be as follows. [1] A method for producing metformin hydrochloride, comprising: (a) heating a mixture of dimethylammonium chloride, dicyanodiamide, and 0 to 20% by mass of water and 0 to 50% by mass of metformin hydrochloride, based on the total amounts of dimethylammonium chloride and dicyanodiamide present in the mixture, to a temperature in the range of 70°C to 250°C and maintaining the temperature for 0.1 minutes to 20 hours; (b) cooling the reacted mixture and recovering the resulting crystalline metformin hydrochloride. [2] A method for producing metformin hydrochloride, comprising: (a) continuously feeding dimethylammonium chloride, dicyanodiamide, and 0-20% by mass of water and 0-50% by mass of metformin hydrochloride, respectively, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture, into a reactor while continuously stirring and continuously heating the mixture to a temperature in the range of 70°C to 250°C; (b) cooling the reacted mixture and recovering the resulting crystalline metformin hydrochloride. [3] The method according to [1] or [2], wherein metformin hydrochloride is present in an amount of 0 to 20% by mass, preferably 0 to 10% by mass, more preferably about 5% by mass, and most preferably 0% by mass, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture. [4] The method according to any one of [1] to [3] above, wherein in step (a), the mixture is heated to a first temperature in the range of 70°C to 120°C, maintained at that temperature for a certain period of time, and then heated to a second temperature in the range of 120°C to 250°C, and maintained at that temperature for a certain period of time. [5] The method according to any one of [2] to [4] above, characterized in that the method is carried out in one continuous reactor or a plurality of continuous reactors connected in series. [6] The method according to [5], characterized in that the method is carried out using a plurality of continuous reactors connected in series, and in step (a), the mixture is heated in a first reactor to a first heating temperature in the range of 70°C to 120°C and maintained at that temperature for a certain period of time, then heated in a second reactor to a second heating temperature in the range of 110°C to 160°C and maintained at that temperature for a certain period of time, and then heated in a third reactor to a third temperature in the range of 140°C to 250°C and maintained at that temperature for a certain period of time. [7] The method according to any one of [1] to [6] above, wherein the total time for maintaining the heating temperature is in the range of 0.1 minutes to 10 hours. [8] The method according to [6], characterized in that the first heating temperature is maintained for 0.1 minutes to 2 hours, the second heating temperature is maintained for 0.1 minutes to 3 hours, and the third heating temperature is maintained for 0.1 minutes to 5 hours. [9] The method according to any one of the above [2] to [7], wherein the continuous reactor is a continuous stirred tank reactor, a single-screw or twin-screw extruder, a single-screw or twin-screw kneader, or a combination of a continuous stirred tank reactor, a single-screw or twin-screw extruder, and a single-screw or twin-screw kneader.

[10] The method according to any one of [1] to [9] above, characterized in that dimethylammonium chloride and dicyanodiamide are present in the mixture in a molar ratio of 1.0 to 2.0:1, preferably in a molar ratio of about 1.15:1.

[11] The method according to any one of [1] to

[10] above, wherein the mixture treated in step (a) contains water in an amount of 0 to 10 mass%, preferably 0 to 5 mass%, and more preferably about 3 mass%, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture.

[12] The method according to any one of [1] to

[11] above, wherein the mixture treated in step (a) further contains an additive that increases the reaction selectivity and / or viscosity of the molten mixture.

[13] The method according to

[12] above, wherein the additive is sodium chloride, celite or silica, preferably celite or a mixture of two or more of these substances.

[14] The method according to

[12] or

[13] , wherein the amount of the additive present in the mixture is 0.001 to 50% by mass, preferably 0.01 to 10% by mass, and more preferably 0.1 to 5% by mass, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture.

[15] The method according to any one of

[11] to

[12] above, wherein the mixture contains about 1 mass % of celite as an additive, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture.

[16] The method according to any one of the above [1] to

[15] , characterized in that a solution of dimethylammonium chloride containing 20 to 50 mass% of water is prepared, and the solution is concentrated to contain 0.1 to 20 mass% of water, preferably 0.1 to 10 mass% of water, and more preferably about 0.1 to 6 mass% of water, based on the total amount of dimethylammonium chloride and water, to prepare a mixture, and dimethylammonium chloride is added as a mixture with water.

Claims

1. 1. A method for producing metformin hydrochloride, comprising: (a) continuously feeding dimethylammonium chloride, dicyanodiamide, and 0-20% by weight of water and 0-50% by weight of metformin hydrochloride, respectively, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture, into a reactor while continuously stirring and continuously heating the mixture to a temperature in the range of 70° C. to 250° C.; (b) cooling the reacted mixture and recovering the resulting crystalline metformin hydrochloride; a method for producing metformin hydrochloride, the method being carried out in a plurality of continuous reactors connected in series, wherein in step (a), the mixture is heated in a first reactor to a first heating temperature in the range of 70°C to 120°C and maintained at that temperature for 0.1 minutes to 2 hours, then heated in a second reactor to a second heating temperature in the range of 110°C to 160°C and maintained at that temperature for 0.1 minutes to 3 hours, and then heated in a third reactor to a third heating temperature in the range of 140°C to 250°C and maintained at that temperature for 0.1 minutes to 5 hours.

2. 2. The method of claim 1, wherein 0 to 20% by weight of metformin hydrochloride is present, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture.

3. 3. The method according to claim 1 or 2, characterized in that in step (a), the mixture is heated stepwise to two different temperatures, a first temperature in the range of 70°C to 120°C and a second temperature in the range of 120°C to 250°C.

4. 4. The method according to claim 1, wherein the total time for maintaining the heating temperature is in the range of 0.1 minutes to 10 hours.

5. The method according to any one of claims 1 to 4, characterized in that the continuous reactor is a continuous stirred tank reactor, a single-screw or twin-screw extruder, a single-screw or twin-screw kneader or a combination of a continuous stirred tank reactor, a single-screw or twin-screw extruder and a single-screw or twin-screw kneader.

6. 6. The process according to claim 1, wherein the dimethylammonium chloride and the dicyanodiamide are present in a mixture with one another in a molar ratio of 1.0 to 2.0:

1.

7. 7. The method according to claim 1, wherein the mixture treated in step (a) contains 0 to 10% by weight of water, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture.

8. 8. The method according to any one of claims 1 to 7, characterized in that the mixture treated in step (a) further contains an additive that increases the reaction selectivity and / or the viscosity of the molten mixture.

9. 9. The method according to claim 8, wherein the amount of additive present in the mixture is from 0.001 to 50% by weight, based on the total amount of dimethylammonium chloride and dicyanodiamide present in the mixture.

10. 10. The method according to any one of claims 1 to 9, characterized in that a solution of dimethylammonium chloride containing 20 to 50% by weight of water is prepared, and such a solution is concentrated to produce a mixture containing 0.1 to 20% by weight of water, based on the total amount of dimethylammonium chloride and water, and dimethylammonium chloride is added as a mixture with water.

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