FORM - 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION (S. 10 and rule 13)
1. TITLE OF THE INVENTION: Process of making salts of metoprolol
2 APPLICANTS
NAME: Polydrug Laboratories Pvt. Ltd.
NATIONALITY: Indian Company registered under the Companies Act,
1956
ADDRESS: 201, Navbharat Estates, Zakaria Bunder Road,
Sewri (West), Mumabi 400 015., Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION: The following specification describes the invention:
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FIELD OF INVENTION:
The invention relates to a process of making non toxic dicarboxylic acid salts of metoprolol.
BACK GROUND DEFINITION:
Metoprolol salts, both the succinate and tartarate are drugs that belong to the group called beta-adrenergic blockers, and is used in the treatment of several diseases and ailments of the cardio vascular system. Beta-blockers are used to treat the heart and blood circulation, to treat angina and hypertension.
Metoprolol selectively blocks the action of the sympathetic nervous system, a portion of the involuntary nervous system. The sympathetic nervous system stimulates the pace of the heart beat. By blocking the action of these nerves, metoprolol reduces the heart rate and is useful in treating abnormally rapid heart rhythms or irregular heart beat conditions (eg. atrial fibrillation) Metoprolol is primarily used ( alone or in combination) to reduce the force of heart muscle contraction and lower blood pressure. By reducing the heart rate and the force of muscle contraction, metoprolol reduces heart muscle oxygen demand. Since angina occurs when oxygen demand of the heart exceeds supply, metoprolol is helpful in treating angina. It works by slowing the heart rate and relaxing the blood vessels so the heart does not have to pump as hard
It is a prescription drug and is prescribed for patients with high blood pressure.
Patients who are prescribed metoprolol are required to be on this medication for extended periods of time, and in most cases for their entire life time.
The use of this drug being so extensive, new and novel cost effective methods of manufacture of high yeild and purity of metoprolol are constantly sought, to make the price of this drug more competitive, and more easily accessible to the end user.
Several processes are used in the manufacture of this drug.
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ES 2011585 describes a method of manufacture of Metoprolol, where in 4(2-Methoxy ethyl phenol) i.e. MEP is reacted with Epichlorohydrin (EPCH) in the presence of aqueous alkaline solution, at a temperature of 0° to 25°C, for over 15 hours and the epoxide so formed is reacted with Isopropyl amine in an aqueous medium. This method though extensively used, results in relatively low yields and higher percentage of impurities. Further the process of making tartarate salt as described in the invention involves a recrystallization process using n-heptane at 47° C. N-heptane is highly explosive, and is safety hazard in any industrial process.
US 6252113 also describes a method of manufacture of Metoprolol, where in the [MEP] is reacted with Epichlorohydrin in water as solvent, at elevated temperatures from 50 to 70°C. The use of elevated temperatures results in impurities and lower yield, although high temperatures accelerate the reaction process.
In 1185/mum/2003, yet another industrial process for the manufacture of Metoprolol is described where MEP is reacted with epichlorohydrin in aqueous alkaline solution. This process also uses elevated temperature, and requires some amount of heating. Since a fairly high concentration of Sodium hydroxide is used in the alkaline solution, the aqueous and organic phase separate out with the formation of an emulsion layer between the two phases, as a result of which some amount of epoxide in the emulsion layer is lost. In addition the high concentration of caustic soda used also results in higher impurity levels. Further this invention describes a method of forming the dicarboxylic non toxic acid salts namely the succinate and tartarate by dissolving the crude metoprolol base in acetone followed by carbon treatment at 45°C and adding a solution of the dicarboxylic acid (succinate or tartarate) in acetone solution. The acid solution reacts with the metoprolol base to form the corresponding dicarboxylic acid salt. This method uses very large volumes of acetone for making the salt. Large volumes of acetone are required to keep the salt in a dissolved form. Acetone has a low boiling point and hence solvent loss in this process of manufacture is higher, which adds to the cost. Further, the flash point of acetone is also low, and use of this solvent in such large volumes can be an industrial hazard. The process also involves repurification of the salt, with methanol for succinate and large volumes of isopropyl alcohol in case of tartarate which adds to the cost. The present process also eliminates carbon treatment for purification, which is a time consuming and laborious process.
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An industrial process of manufacturing any drug has to take in to consideration all aspects and stages of production, the cost of reactants and solvents, to evaluate and trim the cost of production, and at the same time ensure optimum purity and yield.
Unlike the inventions described in the above referred patents, the present invention describes a process where in the first stage of the reaction proceeds at ambient temperature, to produce an epoxide with minimal impurities. The concentration of the aqueous alkaline solution used also minimises the loss of epoxide in the reaction process, since an emulsion layer is not formed, and an organic solvent is used to extract the epoxide, having high purity and high yield.
The invention also describes for the first time a process wherein, the salt of the metoprolol is manufactured using an aliphatic alcohol as a solvent, to dissolve the crude metoprolol base. The use of aliphatic alcohol allows for the crystalline form of the dicarboxylic acid to be used to manufacture the dicarboxylic acidic salt and hence a one pot reaction is possible in the industrial process. As compared to large volumes of acetone solvent used in PATENT APPLICATION NO.:1185/MUM/2003, relatively small volumes of alcohol is sufficient to keep the metoprolol salt in a dissolved state. The flash point of alcohol is higher (as compared to acetone or n-heptane used in the above cited patents) and thus enhances the safety levels in any industrial process. Because of the high levels of the purity of the metoprolol base and salts obtained, the disclosed process does not require a repurification process or recrystallisation process as described in the earlier patents.
In all the above patents the reactants are the same .The benefit realised is in the yeild and purity obtained as a result of the concentrations of reactant medium, molar ratios used, the solvents used, temperature used and the length of reaction time.
The present invention seek to address the issues of yield and purity as well as energy considerations so as to make the process give an yield of over 97% with a drug purity of 99%., with reduced energy consumption, and enhancing ease of production, by avoiding multiple purification and multiple recrystallisation procedures.
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DESCRIPTION:
Following is a brief description of the process for manufacturing non-toxic dicarboxylic acid salts of METOPROLOL
The process involves 4 steps: (i). Obtaining the sodium salt of 4(2-Methoxy ethyl phenol) MEP, (ii). Producing the epoxide, (iii). Producing the metoprolol base, (iv). Producing the pure metoprolol non toxic dicarboxylic organic acid salts.
4(2-Methoxy ethyl phenol) i.e. MEP is reacted with a clear monobasic aqueous alkaline solution, at ambient temperature to form a MEP basic salt. Preferably aqueous sodium hydroxide solution, at a concentration of less than 4 % is used to form the MEP sodium salt. A clear homogenous solution of the MEP sodium salt is obtained. The formation of the salt and obtaining of a homogenous solution facilitates the reaction forming the epoxide to progress at ambient temperatures.
The solution of the MEP sodium salt is reacted with Epichlorohydrin (EPCH) which forms the epoxide i.e. (3-(4-(2-methoxyethyl)phenoxyl)-1.2-epoxypropane and the chloro compound i.e. ( l-(4-2-methoxy ethyl ) phenoxyl )-3-chloro-2-propanol ) For optimum results of the reaction, EPCH is added slowly over an extended period of time, at ambient temperature. Completion of the reaction is determined by gas chromatography.
The excess EPCH is stripped by vacuum distillation.. An aprotic aromatic solvent is added to extract the epoxide and the chlorocompound. The organic layer is washed with water. Repeated extraction with the solvent, ensures complete extraction of the epoxide. The solvent is removed by distillation under vacuum below 100°C. , leaving behind the epoxide mass with minimal impurities. The epoxide mass is cooled and checked for purity.
The epoxide obtained is of 99% purity. The process also gives an yield of 99%.
The epoxide is reacted with Isopropyl amine (MIPA) in an aqueous medium at 38 to 42 C for 10-12 hours to give the metoprolol base. MIPA is used in the ratio of l:17 to l:19 of epoxide to MIPA.
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Excess MIPA is distilled off at normal conditions. Water is added to the solution, and remainder MIPA is distilled of by distillation under vacuum at temperatures below 85°C. The dimer, trimer impurities of epoxides of metoprolol, unreacted epoxide and traces of MIPA are removed by acid wash followed by an alkaline wash. An inorganic acid, preferably a monovalent acid like dilute HC1 (3 to 4%) is added to the residue till a pH of 6 to 6.5 is attained, to form a clear metoprolol hydrochloric acid salt solution. The hydrochloric acid salt of metoprolol is extracted using a aprotic aromatic solvent This helps to remove the traces of dimers and trimers of epoxides of metoprolol and any unreacted epoxide. Caustic soda is added to the Metoprolol hydrochloric acid salt to form the metorprolol base, which is again extracted by using an aprotic aromatic solvent, preferably toluene. The toluene is distilled out to isolate metoprolol base having purity of 99% and yield of 86-90%.
The non - toxic dicarboxylic acid salts are produced from the isolated metoprolol base. The base is dissolved in aliphatic alcohol in the ratio of 1: 4.5 to 1: 5.5 by weight. Preferably a mixture of Isopropyl alcohol (IPA) and methanol in the ratio of 2:1 to 3:1 or Isopropyl Alcohol alone is used. Once dissolved, the solution is gradually heated, preferably up to 50 to 60° C. Solid non-toxic dicarboxylic acid is added to the solution until an appropriate slightly acidic pH is attained. Use of an aliphatic alcohol allows the process to be conducted as a one pot reaction, since crystalline acid can be added, instead of acid solution Mixture is refluxed for an extended period of time, till a clear solution of the dicarboxylic acid salt is formed. The solution is purified by a process of filtration, and cooled to ambient temperature for 1 to 2 hours, to obtain crystals of metoprolol salts. The product namely metoprolol salt is isolated by filtration, and washed with acetone to remove any protic solvents. The product is dried at 60 to 70°C, preferably in a fluid bed drier, to yield the metoprolol non-toxic dicarboxylic acid salt. The acids used include oxalic acid, malic acid, succinic acid, tartaric acid, fumaric acid or lactic acid to yield the corresponding metoprolol salt. .
The following examples demonstrate the disclosed invention.
Example:
Stage I: l-(2, 3-epoxypropoxy)-4-(2-methoxyethyl) benzene (Epoxide)
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4(2-methoxy ethyl phenol)(MEP) 0.7 to 0.75 mole) is reacted with 3% to 4% sodium hydroxide solution (0.75 to 0.80 mole) at 30° to 35° to form sodium salt. To the sodium salt of MEP, epichlorohydrin (EPCH) (1.6 to 1.7 mole) is added slowly at 26° to 28 °C (over 2 to hours) and then the reaction mixture is maintained for 12 - 15 hours at 26° to 35°C, to obtain an epoxide. Excess Epichlorohydrin is then removed by distillation under vacuum The epoxide is extracted twice in toluene, 16 to 18 v/v of reaction mixture each time. The combined organic layer is washed with water. Toluene is removed by distillation under vacuum below 100°C and the resulting epoxide mass is cooled to about 40° C, and checked for purity. Yield is 96-99%.
Stage II: Forming the Metoprolol base.
Epoxide (.9 to 1 mole) is added to 16 to 18 Moles Mono isopropyl amine (MIPA) having water, 1 .5-1.9 wt/wt of epoxide at ambient temperature. The temperature is raised to 38 to 42°C and maintained for 12-15 hours. Excess MIPA is then removed by distillation at normal reflux condition and then under vacuum below 85°C. Add water 3.0 wt/wt of epoxide. The residue of crude metoprolol base is acidified with HCL to form Metoprolol hydrochloride solution at pH 6-6.5. The aqueous is extracted with toluene in the ratio of 5:1 by volume, leaving behind impurities. The Metoprolol hydrochloride solution is basified up to pH 9-10.5 with caustic soda solution. The metoprolol base is extracted with toluene from the aqueous (in ratio of .8:1 v/v of toluene is to water). The organic layer is washed with water in the ratio of 1: 1 v/v of toluene is to water. Toluene is removed by distillation under vacuum below 100 °C. The metoprolol base mass is cooled to 40°C, and checked for purity. Purity obtained is 99% and yield is 95-98%.
Stage HI (a) METOPROLOL TARTARATE SALT:
Metoprolol base is added slowly to MIPA (5-5.2 V/wt of Metoprolol base), with gradual increase in temperature to 50 to 60°C. Solid L(+) tartaric acid is added slowly (.28kg - .3kg per kg of metoprolol base). The pH of reaction mixture is adjusted to 5.5 to 6. Reaction mixture is refluxed and checked for clarity-). The clear solution is filtered through micron filter and the product is cooled to 25-35°. The crystal of metoprolol tartarate is isolated by
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filtration and finally washed with small quantity of acetone. The product is dried at 60-70° C. Yield is 75 to 80% and purity is above 99%.
Stage III (B) METOPROLOL SUCCINATE SALT
Metoprolol base is dissolved in a mixture of MIPA and methanol (in the ratio of 2:1 to 3:1), where in the mixture is 4.7 v/wt of the base. Temperature is raised gradually to 50 to 60°C. Solid succinic acid is added slowly (.22kg -.25kg per kg of metoprolol base). The pH of reaction mixture is adjusted to 6 to 6.5. Reaction mixture is refluxed and checked for clarity. The clear solution is filtered through micron filter and the product is cooled to 25-35°. The crystal of metoprolol tartarate is isolated by filtration and finally washed with small quantity of acetone. The product is dried at 60-70° C.
The theoretical yield of the salt by this method is 75-80%, and the purity obtained is a minimum of 99%.
Dated this 25th day of April 2007 at Mumbai For Polydrug Laboratories Pvt. Ltd.

To,
The Controller Of Patents,
The Patent Office, Mumbai.
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