EP3164378A1 - Process for making microcrystalline dimethyl fumarate - Google Patents

Process for making microcrystalline dimethyl fumarate

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Publication number
EP3164378A1
EP3164378A1 EP15731943.5A EP15731943A EP3164378A1 EP 3164378 A1 EP3164378 A1 EP 3164378A1 EP 15731943 A EP15731943 A EP 15731943A EP 3164378 A1 EP3164378 A1 EP 3164378A1
Authority
EP
European Patent Office
Prior art keywords
dimethyl fumarate
process according
solution
water
particle size
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP15731943.5A
Other languages
German (de)
French (fr)
Inventor
Libor Vyklicky
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synthon BV
Original Assignee
Synthon BV
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Filing date
Publication date
Application filed by Synthon BV filed Critical Synthon BV
Publication of EP3164378A1 publication Critical patent/EP3164378A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds

Definitions

  • the present invention relates to an improved process for making the compound dimethyl fumarate in a finely crystalline (microcrystalline) form.
  • Dimethyl fumarate is an extremely potent allergen and is generally banned for use in consumer products with the exception of pharmaceuticals (EU Commission Decision 2009/251 of 17 March 2009). Special precautions have to be assured in the manufacture, storage and handling of both the active substance and the final pharmaceutical forms comprising it, to prevent a human body against contacting it by aspiration or via skin or mucosa.
  • WO 2013/076216 discloses particles of dimethyl fumarate coated by at least one layer of a pH- dependent entero-resistant polymer, which minimizes such direct contacting.
  • dimethyl fumarate may be produced by esterification of fumaric acid with methanol under catalysis by an acid, preferably by a strong acid such as sulfuric acid. It is also well known in the art that the acid-catalyzed esterification is an equilibrium reaction so that the desired dimethyl fumarate produced by the reaction comprises certain amount of intermediated monomethyl fumarate and starting fumaric acid.
  • the known methods for isolation of dimethyl fumarate from a reaction mixture after the esterification provide the compound in a form of relatively large crystals.
  • the desirably small particle size may be obtained by conventional milling of the obtained product. Milling is however always associated with forming a relatively large portion of dust, and, because of the specific nature of the product as a potent allergen, special and costly technical precautions must be applied to prevent contacting the dust of dimethyl fumarate with humans.
  • a process for making high purity and crystalline dimethyl fumarate has been disclosed in WO 2012/170923. It provides a process comprising reacting fumaric acid with methanol in the presence of sulfuric acid and reducing the particle size of the dimethyl fumarate.
  • the document suggests that the raw dimethyl fumarate may be recrystallized from a solvent, e.g., from a mixture of methanol and water.
  • a solvent e.g., from a mixture of methanol and water.
  • no further details were provided.
  • the only disclosed technique of crystallization is a standard crystallization, i.e. providing a solution of dimethyl fumarate in the said solvent mixture, followed by cooling such solution.
  • the present invention relates to the discovery of a process for making solid state dimethyl fumarate in desirably low particle size without need of milling.
  • a process of making dimethyl fumarate in a micro-crystalline form comprising: a. Providing a clear solution of dimethyl fumarate in methanol of a temperature of at least 50°C;
  • micrometers and/or D90 150+ 10 micrometers.
  • the solution of dimethyl fumarate in the step a) is provided by reacting fumaric acid with a molar excess of methanol in the presence of an acid, preferably hydrochloric acid, optionally followed by a filtration of the reaction mixture.
  • an acid preferably hydrochloric acid
  • the solution of dimethyl fumarate is provided by dissolving raw dimethyl fumarate in methanol, optionally followed by a filtration.
  • the solution from the step a) is combined with water by pouring water thereto, preferably followed by cooling the formed mixture.
  • the solution from the step a) is combined with water by pouring it into water, preferably followed by cooling the formed mixture.
  • the process of the present invention based on a technique in which a hot solution of dimethyl fumarate in a selected solvent is brought into a contact with a selected anti-solvent (i.e. with a liquid in which the dimethyl fumarate is practically insoluble) at well defined and controllable conditions disclosed herein below, allows to form crystals of dimethyl fumarate of the desired particle size.
  • a selected anti-solvent i.e. with a liquid in which the dimethyl fumarate is practically insoluble
  • the process of the present invention is particularly useful for making the dimethyl fumarate in a micro-crystalline form.
  • the "micro-crystalline form", as defined for purpose of the present invention is a population of crystals characterized by a mean particle size of 80 ⁇ and less based, e.g., on measurement by Malvern MasterSizer.
  • the "micro -crystalline form” comprises a population of crystals with a mean particle size of equal or less than 60 micrometers, more preferably equal or less than 50 micrometers.
  • the D50 also known as the median diameter or the medium value of the particle size distribution
  • the value of D90 is defined the same way, showing that 90% of particles in the population is smaller than the stated value.
  • the values D50 and D90 may be measured by a sieve analysis or by optical technologies.
  • a clear solution of dimethyl fumarate in methanol of a temperature at least 50°C is provided. In one embodiment, the temperature of the solution is at least 55 °C, in yet another embodiment, the temperature is at least 60°C.
  • the solution is represented by the reaction mixture resulting from a process of making dimethyl fumarate.
  • the reaction mixture is obtained after esterification of fumaric acid with a molar excess of methanol.
  • esterification is typically performed by heating the solution of fumaric acid in methanol in the presence of an acid, preferably a strong acid.
  • the strong acid is typically sulfuric acid but, advantageously, also hydrochloric acid, e.g. methanolic HCl or concentrated aqueous hydrochloric acid, can be used.
  • HCl instead of sulfuric acid eliminates the risk of forming genotoxic dimethyl sulfate as a side product in the esterification reaction, and is accordingly preferred in the present invention.
  • the suitable amount of HCl is between 0.1 - 0.2 molar %, in respect to fumaric acid.
  • the course of the esterification reaction can be advantageously monitored by a suitable analytical method, e.g. by HPLC, and the reaction can be terminated after obtaining at least 80%, advantageously at least 85% conversion.
  • a suitable analytical method e.g. by HPLC
  • the process of the further treatment of the reaction mixture according to the present invention allows also for a very effective separation of the desired dimethyl fumarate from the undesired monomethyl fumarate and the unreacted fumaric acid. Accordingly, it is not necessary to focus on the complete conversion of fumaric acid and to prolong the esterification reaction. In further, it is not necessary to neutralize the used acid prior to further treatment of the reaction mixture, although such possibility is not excluded.
  • the solution of dimethyl fumarate in methanol of a temperature at least 50°C can be provided by dissolving raw dimethyl fumarate in methanol.
  • the dimethyl fumarate raw material useful for making the solution is an isolated solid dimethyl fumarate, which can be obtained by any known synthetic process.
  • the raw starting material has a mean particle size of higher than 80 micrometers.
  • the raw starting material obtainable according to the process disclosed in WO2012/170923 has a mean particle size of about 450 micrometers.
  • the process of the present invention is especially useful as a tool for a recrystallization of a material with too large, pharmaceutically not suitable, medium particle size.
  • the concentration of dimethyl fumarate in methanol is not particularly limited.
  • it may be from 100 to 300 g/1, preferably from 150 to 250 g/1.
  • the solution of dimethyl fumarate in methanol may be optionally filtered to assure that the solution is clear.
  • the absence of solid particles in the solution is important for obtaining population of crystals of the desirable particle size in the next step.
  • the filtration may be optionally performed in the presence of a surface active material, e.g. activated carbon.
  • the clear solution of dimethyl fumarate in methanol from the first step of a temperature at least 50°C, is combined, rapidly and under stirring, with water of a temperature not exceeding 30°C.
  • the temperature of water is less than 25°C, in some preferred embodiments less than 20°C.
  • the relative amount of water, in respect to the volume of the methanolic solution is advantageously from 0.5 : 1 to 2 : 1 (v/v) , preferably from 0.6 : 1 to 1.5 :1 (v/v), yet preferably from 0.7 : 1 to 1.2 : 1 (v/v).
  • the "combining” may be performed by pouring water, rapidly and under stirring, into the hot methanolic solution. In another embodiment, the “combining” is performed by pouring the hot methanolic solution, rapidly and under stirring, into water pre-equilibrated at a temperature not exceeding 30°C.
  • the "rapid" mixing is advantageously performed in a time not exceeding 10 minutes, preferably not exceeding 5 minutes.
  • the temperature of the mixture after combining both liquids is from about 35 °C to about 45 °C.
  • the mixture is then cooled, or allowed to cool, to room temperature under stirring.
  • the formed suspension is then filtered, preferably at room temperature, to separate the formed solid material from the mother liquor.
  • the filtration may be performed by any conventional filtration or centrifugation technique.
  • the solid may be washed, preferably by water and then by cold methanol, and dried until the desired low content of volatiles is obtained. The drying and further handling must be performed under careful protection against a contact with the operator, in particular by aspiration of dust.
  • the dimethyl fumarate solid product prepared by the process of the present invention typically corresponds to particle size limits prescribed in the tabletting procedures. Accordingly, it can be formulated and used in pharmaceutical compositions.
  • a suitable pharmaceutical composition may comprise the dimethyl fumarate and at least one
  • excipients include carriers, diluents, fillers, binders, lubricants, disintegrants, glidants, colorants, pigments, taste masking agents, sweeteners, flavorants, plasticizers, and any acceptable auxiliary substances.
  • excipients include various polymers, waxes, calcium phosphates, sugars, etc.
  • Polymers include cellulose and cellulose derivatives such as HPMC, hydroxypropyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, and ethylcellulose;
  • Waxes include white beeswax, microcrystalline wax, carnauba wax, hydrogenated castor oil, glyceryl behenate, glycerylpalmito stearate, and saturated
  • Calcium phosphates include dibasic calcium phosphate, anhydrous dibasic calcium phosphate, and tribasic calcium phosphate.
  • Sugars include simple sugars, such as lactose, maltose, mannitol, fructose, sorbitol, saccharose, xylitol, isomaltose, and glucose, as well as complex sugars (polysaccharides), such as maltodextrin, amylodextrin, starches, and modified starches.
  • the compositions are preferably formulated for oral administration. The above lists of excipients and forms are not exhaustive.
  • the dimethyl fumarate prepared by the process of the present invention is useful as pharmaceutically active agent, by administering an effective amount thereof to a patient in need thereof.
  • it is useful in the treatment of dermatological diseases, e.g. of psoriasis, as well as in treatment of autoimmune diseases, e.g., multiple sclerosis.
  • the effective doses may be determined by a skilled medical doctor in accordance with the limits in the marketing
  • Fumaric acid 50 g, 431 mmol was placed in a 500 ml three neck flask equipped with magnetic stir bar and reflux condenser and methanol (200 ml, 4937 mmol) was added. The mixture was heated to reflux (internal temp ca 68°C) and 37% aq. hydrochloric acid (5.70 ml, 64.6 mmol) was added. The reaction mixture was maintained at reflux (int. temp. 68.5-70°C) for 3 hours taking aliquots at specified intervals to monitor conversion.
  • Fumaric acid (5 g, 43.1 mmol) and methanol (30 ml, 740 mmol) were charged into a 50 ml three neck flask equipped with magnetic stir bar and reflux condenser.
  • the mixture was heated to reflux (ca. 68°C int. temp.) and 37% aq. hydrochloric acid (0.570 ml, 6.46 mmol) was added. Heating was continued for 3 hours.
  • the reaction mixture was cannulated into water (30 ml) that was pre -equilibrated at 25 °C. During the transfer no clogging was observed.
  • the cannula used was PTFE diameter 1/16 ID. The suspension was then stirred for 1 hour at room temperature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a process for making a microcrystalline dimethyl fumarate comprising a step of providing a solution of dimethyl fumarate in methanol and combining the solution with water under precipitation of microcrystalline dimethyl fumarate.

Description

PROCESS FOR MAKING MICROCRYSTALLINE DIMETHYL FUMARATE
BACKGROUND OF THE INVENTION
The present invention relates to an improved process for making the compound dimethyl fumarate in a finely crystalline (microcrystalline) form.
Dimethyl ester of fumaric acid, i.e. dimethyl fumarate of the formula (1)
H3COOC^COOCH3 (1 )
is a well known compound disclosed hundred years ago. However, quite recently, a novel pharmaceutical use of dimethyl fumarate was discovered. Since 1994, a mixture of dimethyl fumarate and salts of monoethylfumarate has been marketed as Fumaderm for treatment of psoriasis. Such composition has been disclosed, i.a., in US 4,959,389 and US 6,355,676. Tablets comprising dimethyl fumarate as the single active substance are in clinical development for the treatment of psoriasis as well. Furthermore, dimethyl fumarate was proven to be effective in the treatment of multiple sclerosis and is being marketed for said use under brand name Tecfidera. The marketed pharmaceutical form comprises microtablets packed in capsules. Microtablets and pellets formulations for use in treatment of autoimmune diseases including multiple sclerosis have been disclosed in EP 1131065 (US 7,320,999).
Dimethyl fumarate is an extremely potent allergen and is generally banned for use in consumer products with the exception of pharmaceuticals (EU Commission Decision 2009/251 of 17 March 2009). Special precautions have to be assured in the manufacture, storage and handling of both the active substance and the final pharmaceutical forms comprising it, to prevent a human body against contacting it by aspiration or via skin or mucosa. For instance, WO 2013/076216 discloses particles of dimethyl fumarate coated by at least one layer of a pH- dependent entero-resistant polymer, which minimizes such direct contacting.
As well known in the art, dimethyl fumarate may be produced by esterification of fumaric acid with methanol under catalysis by an acid, preferably by a strong acid such as sulfuric acid. It is also well known in the art that the acid-catalyzed esterification is an equilibrium reaction so that the desired dimethyl fumarate produced by the reaction comprises certain amount of intermediated monomethyl fumarate and starting fumaric acid.
It was found by the present inventor that the known methods for isolation of dimethyl fumarate from a reaction mixture after the esterification provide the compound in a form of relatively large crystals. Indeed, the desirably small particle size (required for pharmaceutical formulations) may be obtained by conventional milling of the obtained product. Milling is however always associated with forming a relatively large portion of dust, and, because of the specific nature of the product as a potent allergen, special and costly technical precautions must be applied to prevent contacting the dust of dimethyl fumarate with humans. Thus, it is desirable to have a way, in which the solid dimethyl fumarate can be isolated from the reaction mixture in such particle size, which will be directly useful in pharmaceutical applications without a need of milling.
No literature data are known, which would successfully provide a solution of this particular technical problem.
A process for making high purity and crystalline dimethyl fumarate has been disclosed in WO 2012/170923. It provides a process comprising reacting fumaric acid with methanol in the presence of sulfuric acid and reducing the particle size of the dimethyl fumarate. The document suggests that the raw dimethyl fumarate may be recrystallized from a solvent, e.g., from a mixture of methanol and water. However, no further details were provided. When considering the disclosure, the skilled person understands that the only disclosed technique of crystallization is a standard crystallization, i.e. providing a solution of dimethyl fumarate in the said solvent mixture, followed by cooling such solution.
It was shown in the same document that dimethyl fumarate can be easily isolated after esterification by cooling the reaction mixture, wherein the product precipitates. However, as disclosed in the Example 5, the rate of cooling does not affect the particle size. In any case, the mean particle size of the product so produced was 448-475 micrometers. The only process how to reduce the particle size to the desired values disclosed in this prior art document is a jet milling.
In a document CN 1103398A the hot reaction mixture comprising dimethyl fumarate in methanol was combined with hot water and the hot mixture so obtained was cooled. After repetition in house, it was found out that also this process provides large crystals.
Thus, it would be desirable to find a process of precipitation of dimethyl fumarate from a solvent providing the precipitate in a form of small crystals.
SUMMARY OF THE INVENTION
The present invention relates to the discovery of a process for making solid state dimethyl fumarate in desirably low particle size without need of milling.
According to the main aspect of the present invention, there is provided a process of making dimethyl fumarate in a micro-crystalline form comprising: a. Providing a clear solution of dimethyl fumarate in methanol of a temperature of at least 50°C;
b. Combining, under stirring, the solution from the step a) with water of a temperature not exceeding 30°C;
c. Separating the crystals by filtration, preferably at room temperature.
In a preferred embodiment the population of crystals have a mean particle size of equal or less than 80 micrometers, preferably equal or less than 60 micrometers, more preferably equal or less than 50 micrometers, most preferred having the particle size value D50 = 40+ 10
micrometers and/or D90 = 150+ 10 micrometers.
In a particular aspect, the solution of dimethyl fumarate in the step a) is provided by reacting fumaric acid with a molar excess of methanol in the presence of an acid, preferably hydrochloric acid, optionally followed by a filtration of the reaction mixture.
In an alternate particular aspect, the solution of dimethyl fumarate is provided by dissolving raw dimethyl fumarate in methanol, optionally followed by a filtration.
In yet a particular aspect, the solution from the step a) is combined with water by pouring water thereto, preferably followed by cooling the formed mixture. Alternately, the solution from the step a) is combined with water by pouring it into water, preferably followed by cooling the formed mixture.
DETAILED DESCRIPTION OF THE INVENTION
The known processes of making the crystalline dimethyl fumarate by a "classical" crystallization, i.e. by a process characterized by providing a solution of dimethyl fumarate of an enhanced temperature and cooling the solution until a crystalline solid starts to precipitate therefrom, have the principal disadvantage in that the process provides large crystals regardless of cooling rate, agitation power, final temperature and stirring time.
The process of the present invention, based on a technique in which a hot solution of dimethyl fumarate in a selected solvent is brought into a contact with a selected anti-solvent (i.e. with a liquid in which the dimethyl fumarate is practically insoluble) at well defined and controllable conditions disclosed herein below, allows to form crystals of dimethyl fumarate of the desired particle size. The process is easily applicable in industrial scale, which is particularly important in a large scale production.
The process of the present invention is particularly useful for making the dimethyl fumarate in a micro-crystalline form. The "micro-crystalline form", as defined for purpose of the present invention, is a population of crystals characterized by a mean particle size of 80 μπι and less based, e.g., on measurement by Malvern MasterSizer. Preferably, the "micro -crystalline form" comprises a population of crystals with a mean particle size of equal or less than 60 micrometers, more preferably equal or less than 50 micrometers. The most advantageous "micro- crystalline form" for purpose of the present invention comprises a population of crystals having the values D50 = 40+ 10 micrometers and/or D90 = 150+ 10 micrometers. Such population is especially useful for pharmaceutical compositions, e.g. for tablet compositions.
For clarity, the D50 (also known as the median diameter or the medium value of the particle size distribution), it is the value of the particle diameter at 50% in the cumulative distribution. For example, if D5o=40 um, then 50% of the particles in the sample are larger than 40um, and 50% are smaller than 40um. The value of D90 is defined the same way, showing that 90% of particles in the population is smaller than the stated value. The values D50 and D90 may be measured by a sieve analysis or by optical technologies. In the first step of the process of the present invention, a clear solution of dimethyl fumarate in methanol of a temperature at least 50°C is provided. In one embodiment, the temperature of the solution is at least 55 °C, in yet another embodiment, the temperature is at least 60°C.
In the first option, the solution is represented by the reaction mixture resulting from a process of making dimethyl fumarate. Typically, the reaction mixture is obtained after esterification of fumaric acid with a molar excess of methanol. Such esterification is typically performed by heating the solution of fumaric acid in methanol in the presence of an acid, preferably a strong acid. The strong acid is typically sulfuric acid but, advantageously, also hydrochloric acid, e.g. methanolic HCl or concentrated aqueous hydrochloric acid, can be used. Using of HCl instead of sulfuric acid eliminates the risk of forming genotoxic dimethyl sulfate as a side product in the esterification reaction, and is accordingly preferred in the present invention. The suitable amount of HCl is between 0.1 - 0.2 molar %, in respect to fumaric acid.
The course of the esterification reaction can be advantageously monitored by a suitable analytical method, e.g. by HPLC, and the reaction can be terminated after obtaining at least 80%, advantageously at least 85% conversion. It should be noted in advance that the process of the further treatment of the reaction mixture according to the present invention allows also for a very effective separation of the desired dimethyl fumarate from the undesired monomethyl fumarate and the unreacted fumaric acid. Accordingly, it is not necessary to focus on the complete conversion of fumaric acid and to prolong the esterification reaction. In further, it is not necessary to neutralize the used acid prior to further treatment of the reaction mixture, although such possibility is not excluded. In a second option, the solution of dimethyl fumarate in methanol of a temperature at least 50°C can be provided by dissolving raw dimethyl fumarate in methanol. The dimethyl fumarate raw material useful for making the solution is an isolated solid dimethyl fumarate, which can be obtained by any known synthetic process. Advantageously, the raw starting material has a mean particle size of higher than 80 micrometers. For instance, the raw starting material obtainable according to the process disclosed in WO2012/170923 has a mean particle size of about 450 micrometers. In such case, the process of the present invention is especially useful as a tool for a recrystallization of a material with too large, pharmaceutically not suitable, medium particle size.
The concentration of dimethyl fumarate in methanol is not particularly limited.
Advantageously, it may be from 100 to 300 g/1, preferably from 150 to 250 g/1.
Once the solution of dimethyl fumarate in methanol is obtained, it may be optionally filtered to assure that the solution is clear. The absence of solid particles in the solution is important for obtaining population of crystals of the desirable particle size in the next step. The filtration may be optionally performed in the presence of a surface active material, e.g. activated carbon.
In the second step of the process of the present invention, the clear solution of dimethyl fumarate in methanol from the first step, of a temperature at least 50°C, is combined, rapidly and under stirring, with water of a temperature not exceeding 30°C. Preferably the temperature of water is less than 25°C, in some preferred embodiments less than 20°C. The relative amount of water, in respect to the volume of the methanolic solution, is advantageously from 0.5 : 1 to 2 : 1 (v/v) , preferably from 0.6 : 1 to 1.5 :1 (v/v), yet preferably from 0.7 : 1 to 1.2 : 1 (v/v).
The "combining" may be performed by pouring water, rapidly and under stirring, into the hot methanolic solution. In another embodiment, the "combining" is performed by pouring the hot methanolic solution, rapidly and under stirring, into water pre-equilibrated at a temperature not exceeding 30°C.
The "rapid" mixing is advantageously performed in a time not exceeding 10 minutes, preferably not exceeding 5 minutes.
In some embodiments, the temperature of the mixture after combining both liquids is from about 35 °C to about 45 °C.
The mixture is then cooled, or allowed to cool, to room temperature under stirring.
The formed suspension is then filtered, preferably at room temperature, to separate the formed solid material from the mother liquor. The filtration may be performed by any conventional filtration or centrifugation technique. The solid may be washed, preferably by water and then by cold methanol, and dried until the desired low content of volatiles is obtained. The drying and further handling must be performed under careful protection against a contact with the operator, in particular by aspiration of dust.
The dimethyl fumarate solid product prepared by the process of the present invention typically corresponds to particle size limits prescribed in the tabletting procedures. Accordingly, it can be formulated and used in pharmaceutical compositions. For instance, a suitable pharmaceutical composition may comprise the dimethyl fumarate and at least one
pharmaceutically acceptable solid excipient.
Pharmaceutically acceptable excipients are known in the art and include carriers, diluents, fillers, binders, lubricants, disintegrants, glidants, colorants, pigments, taste masking agents, sweeteners, flavorants, plasticizers, and any acceptable auxiliary substances. Examples of common types of excipients include various polymers, waxes, calcium phosphates, sugars, etc. Polymers include cellulose and cellulose derivatives such as HPMC, hydroxypropyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, and ethylcellulose;
polyvinylpyrrolidones; polyethylenoxides; polyalkylene glycols such as polyethylene glycol and polypropylene glycol; and polyacrylic acids including their copolymers and crosslinked polymers thereof, e.g., Carbopol® (B.F. Goodrich), Eudragit® (Rohm), polycarbophil, and chitosan polymers. Waxes include white beeswax, microcrystalline wax, carnauba wax, hydrogenated castor oil, glyceryl behenate, glycerylpalmito stearate, and saturated
polyglycolyzed glycerate. Calcium phosphates include dibasic calcium phosphate, anhydrous dibasic calcium phosphate, and tribasic calcium phosphate. Sugars include simple sugars, such as lactose, maltose, mannitol, fructose, sorbitol, saccharose, xylitol, isomaltose, and glucose, as well as complex sugars (polysaccharides), such as maltodextrin, amylodextrin, starches, and modified starches. The compositions are preferably formulated for oral administration. The above lists of excipients and forms are not exhaustive.
The dimethyl fumarate prepared by the process of the present invention is useful as pharmaceutically active agent, by administering an effective amount thereof to a patient in need thereof. In particular, it is useful in the treatment of dermatological diseases, e.g. of psoriasis, as well as in treatment of autoimmune diseases, e.g., multiple sclerosis. The effective doses may be determined by a skilled medical doctor in accordance with the limits in the marketing
authorization.
The invention will be further described with reference to the following non-limiting examples. Example 1
Fumaric acid (50 g, 431 mmol) was placed in a 500 ml three neck flask equipped with magnetic stir bar and reflux condenser and methanol (200 ml, 4937 mmol) was added. The mixture was heated to reflux (internal temp ca 68°C) and 37% aq. hydrochloric acid (5.70 ml, 64.6 mmol) was added. The reaction mixture was maintained at reflux (int. temp. 68.5-70°C) for 3 hours taking aliquots at specified intervals to monitor conversion.
After 3 hours, water (150 ml) of the room temperature was added rapidly and under stirring to the hot reaction mixture and the resulting thick suspension was allowed to cool to room temperature over 1 h while stirring at ca. 1000 rpm. After ca. 50 min the temperature reached ca.39°C, therefore the mixture was placed in a water bath for 10 min reaching 25°C.
The mixture was filtered, the solid washed with water (150 ml) followed by MeOH (60 ml), sucked on the filter (until flow of liquid stopped) and vacuum dried at 150 mbar for 18 hours. Dimethyl fumarate (49.5 g, 343 mmol, 80 % yield) was obtained as white microcrystalline powder. Mean particle size is ca. 48 μπι.
Example 2
Fumaric acid (5 g, 43.1 mmol) and methanol (30 ml, 740 mmol) were charged into a 50 ml three neck flask equipped with magnetic stir bar and reflux condenser. The mixture was heated to reflux (ca. 68°C int. temp.) and 37% aq. hydrochloric acid (0.570 ml, 6.46 mmol) was added. Heating was continued for 3 hours. Then the reaction mixture was cannulated into water (30 ml) that was pre -equilibrated at 25 °C. During the transfer no clogging was observed. The cannula used was PTFE diameter 1/16 ID. The suspension was then stirred for 1 hour at room temperature. The solids were filtered off, filter cake washed with water (30 ml) and suction dried for 1 hour affording dimethyl fumarate (5.03 g, 34.6 mmol, 80 % yield) as white microcrystalline material. Mean particle size is ca. 40 μπι.
Example 3
2g of course-crystalline dimethyl fumarate (mean particle size ca. 280 μπι) was dissolved in methanol (8 ml) at 65-68°C and water (6 ml) of the room temperature was added. The resulting thick suspension was allowed to cool to room temperature over 1 hour while stirring. Filtration, washing with water (30 ml), MeOH (15 ml) and suction drying on the filter for 30 min gave dimethyl fumarate (1.41 g, 9.78 mmol, 70.5 % yield) as white microcrystalline powder with mean particle size ca. 44 μπι.
The invention having been described it will be obvious that the same may be varied in many ways and all such modifications are contemplated as being within the scope of the invention as defined by the following claims.

Claims

A process for making dimethyl fumarate in a micro-crystalline form comprising a. Providing a clear solution of dimethyl fumarate in methanol of a temperature of at least 50°C;
b. Combining, under stirring, the solution from the step a) with water of a temperature not exceeding 30°C;
c. Separating the crystals by filtration.
The process according to claim 1 , wherein the population of crystals has the mean particle size of equal or less than 80 micrometers.
The process according to claim 1 , wherein the population of crystals has the mean particle size of equal or less than 60 micrometers.
The process according to claim 1 , wherein the population of crystals has the mean particle size of equal or less than 50 micrometers.
The process according to any one of claims 1 to 4 wherein the population of crystals has the particle size value D50 = 40+ 10 micrometers and/or D90 = 150+ 10 micrometers.
The process according to any one of claims 1 to 5 wherein the solution of dimethyl fumarate in the step a) is provided by reacting fumaric acid with a molar excess of methanol in the presence of an acid, optionally followed by a filtration of the reaction mixture.
The process according to claim 6 wherein the acid is hydrochloric acid.
The process according to any one of claims 1 to 7, wherein the solution of dimethyl fumarate is provided by dissolving raw dimethyl fumarate in methanol, optionally followed by a filtration.
9. The process according to any one of claims 1 to 8 wherein the concentration of the dimethyl fumarate in methanol is from 100 to 300 g/1.
10. The process according to any one of claims 1 to 9 wherein the methanolic solution of dimethyl fumarate is combined with water by pouring water into the methanolic solution.
11. The process according to any one of claims 1 to 9, wherein the methanolic solution of dimethyl fumarate is combined with water by pouring it into water.
12. The process according to any one of claims 1 to 11, wherein the relative amount of water, in respect to the volume of the methanolic solution is from 0.5:1 to 2:1 (v/v).
EP15731943.5A 2014-07-03 2015-06-26 Process for making microcrystalline dimethyl fumarate Withdrawn EP3164378A1 (en)

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PCT/EP2015/064564 WO2016001093A1 (en) 2014-07-03 2015-06-26 Process for making microcrystalline dimethyl fumarate

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WO2017013672A1 (en) * 2015-07-23 2017-01-26 Natco Pharma Ltd Process for the preparation of pharmaceutical grade dimethyl fumarate
RU2616605C1 (en) * 2016-04-07 2017-04-18 Олег Ростиславович Михайлов Crystal beta-modification of (e)-dimethyl butenedioate, method for its preparation and pharmaceutical composition on its basis

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CN1426994A (en) * 2001-12-10 2003-07-02 茂名学院科技开发公司 Method of synthesizing dimethyl fumarate by rectification
CN103649041A (en) * 2011-06-08 2014-03-19 比奥根艾迪克Ma公司 Process for preparing high purity and crystalline dimethyl fumarate
CN102766050A (en) * 2012-08-10 2012-11-07 太仓市运通化工厂 Method for synthesizing dimethyl fumarate

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