WO2016001093A1 - Procédé de préparation de diméthylfumarate microcristallin - Google Patents

Procédé de préparation de diméthylfumarate microcristallin Download PDF

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Publication number
WO2016001093A1
WO2016001093A1 PCT/EP2015/064564 EP2015064564W WO2016001093A1 WO 2016001093 A1 WO2016001093 A1 WO 2016001093A1 EP 2015064564 W EP2015064564 W EP 2015064564W WO 2016001093 A1 WO2016001093 A1 WO 2016001093A1
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WO
WIPO (PCT)
Prior art keywords
dimethyl fumarate
process according
solution
water
particle size
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Ceased
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PCT/EP2015/064564
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English (en)
Inventor
Libor Vyklicky
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Synthon BV
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Synthon BV
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Filing date
Publication date
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Priority to EP15731943.5A priority Critical patent/EP3164378A1/fr
Publication of WO2016001093A1 publication Critical patent/WO2016001093A1/fr
Anticipated expiration legal-status Critical
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    • 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

L'invention concerne un procédé de préparation d'un diméthylfumarate microcristallin comprenant une étape consistant à fournir une solution de diméthylfumarate dans du méthanol et à combiner cette solution avec de l'eau de manière à produire une précipitation du diméthylfumarate microcristallin.
PCT/EP2015/064564 2014-07-03 2015-06-26 Procédé de préparation de diméthylfumarate microcristallin Ceased WO2016001093A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP15731943.5A EP3164378A1 (fr) 2014-07-03 2015-06-26 Procédé de préparation de diméthylfumarate microcristallin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP14175667 2014-07-03
EP14175667.6 2014-07-03

Publications (1)

Publication Number Publication Date
WO2016001093A1 true WO2016001093A1 (fr) 2016-01-07

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PCT/EP2015/064564 Ceased WO2016001093A1 (fr) 2014-07-03 2015-06-26 Procédé de préparation de diméthylfumarate microcristallin

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EP (1) EP3164378A1 (fr)
WO (1) WO2016001093A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017013672A1 (fr) * 2015-07-23 2017-01-26 Natco Pharma Ltd Procédé de préparation de fumarate de diméthyle de qualité pharmaceutique
RU2616605C1 (ru) * 2016-04-07 2017-04-18 Олег Ростиславович Михайлов Кристаллическая бета - модификация (Е)-диметилбутендиоата, способ её получения и фармацевтическая композиция на её основе

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1426994A (zh) * 2001-12-10 2003-07-02 茂名学院科技开发公司 ＂精馏分水一锅法＂合成富马酸二甲酯的方法
CN102766050A (zh) * 2012-08-10 2012-11-07 太仓市运通化工厂 一种富马酸二甲酯的合成方法
WO2012170923A1 (fr) * 2011-06-08 2012-12-13 Biogen Idec Ma Inc. Procédé de préparation de fumarate de diméthyle cristallin de grande pureté

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1426994A (zh) * 2001-12-10 2003-07-02 茂名学院科技开发公司 ＂精馏分水一锅法＂合成富马酸二甲酯的方法
WO2012170923A1 (fr) * 2011-06-08 2012-12-13 Biogen Idec Ma Inc. Procédé de préparation de fumarate de diméthyle cristallin de grande pureté
CN102766050A (zh) * 2012-08-10 2012-11-07 太仓市运通化工厂 一种富马酸二甲酯的合成方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017013672A1 (fr) * 2015-07-23 2017-01-26 Natco Pharma Ltd Procédé de préparation de fumarate de diméthyle de qualité pharmaceutique
RU2616605C1 (ru) * 2016-04-07 2017-04-18 Олег Ростиславович Михайлов Кристаллическая бета - модификация (Е)-диметилбутендиоата, способ её получения и фармацевтическая композиция на её основе

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