WO2014041566A2

WO2014041566A2 - An improved process for the preparation of metformin hydrochloride

Info

Publication number: WO2014041566A2
Application number: PCT/IN2013/000558
Authority: WO
Inventors: Satyanarayana Chava; Seeta Ramanjaneyulu Gorantla; Venkata Sunil Kumar Indukuri; Narasimha Rao Ketavarapu; Veeraiah Chowdary GORANTLA
Original assignee: Laurus Labs Private Limited
Priority date: 2012-09-17
Filing date: 2013-09-17
Publication date: 2014-03-20
Also published as: WO2014041566A3

Abstract

The present invention relates to an improved process for the preparation of Metformin hydrochloride by removing solvent from a solution comprising metformin hydrochloride using agitated thin film dryer.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF METFORMIN HYDROCHLORIDE

PRIORITY

This application claims the benefit under Indian Provisional Application No. 3847/CHE/2012 filed on 17 September 2012 and entitled "AN IMPROVED PROCESS FOR THE PREPARATION OF METFORMIN HYDROCHLORIDE", the content of which is incorporated by reference herein.

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Metformin hydrochloride also known as Ν,Ν-dimethyl imidodicarbonimidic diamide is generally adrninistered as its hydrochloride salt is represented by the following structure:

Metformin hydrochloride is currently marketed in the United States under the brand name of Glucophage^® by Bristol Myers Squibb Company. Metformin is the first-line drug of choice for the treatment of type 2 diabetes, particularly in overweight and obese people and those with normal kidney function. It is also known for its efficiency in gestational diabetes and in the treatment of polycystic ovary syndrome. Each GLUCOPHAGE^® tablet contains 500, 850 or 1000 mg of Metformin Hydrochloride.

The preparation of dimethyl biguanide for use in dyeing of textile fibers has been disclosed in US Patent No 2448448 by reacting dicyandiamide with dimemylainine. DE Patent Application No 1023757 discloses preparation of metformin hydrochloride by reacting dicyandiamide with dimethylamine hydrochloride in xylene at reflux temperature, followed by decantation of xylene and crystallization from water to obtain metformin hydrochloride with a moderate yield of 47%. U.S. Patent Application No 2011/021634 discloses preparation of metformin hydrochloride substantially free from dimethylamine wherein an aqueous solution of metformin hydrochloride is concentrated to remove water completely under vacuum at 65°C and further involves pulverization technique. ΓΝΙ 89077 patent disclosed a solvent-less process of preparing metformin hydrochloride via the condensation of dicyandiamide with dimethylamine hydrochloride in the presence of wet metformin hydrochloride, extracting the product into water followed by evaporation of water, crystallization and isolation of metformin hydrochloride crystals.

Indian Patent Application No. 1350/MUM/2007 publication discloses preparation of highly pure metformin hydrochloride substantially free from melamine and cyanoguanidine impurities by condensation of dimethylamine hydrochloride with dicyandiamide in xylene; extracting the product into water followed by distillation of water under vacuum at 65-72°C and crystallizing metformin hydrochloride from methanol or a mixture of water and methanol.

Indian Patent Application No. 1346/MUM/2008 publication discloses a one-pot process for preparation of highly pure metformin hydrochloride substantially free from melamine and cyanoguanidine impurities by reacting dimethylamine hydrochloride solution prepared insitu with cyanoguanidine in xylene, extracting metformin hydrochloride in to water, and distillation of around 50% of water followed by isolation.

The methods known in the art for the preparation of metformin hydrochloride involve removal of water by distillation under vacuum prior to isolation of the product. The main disadvantage with the known processes involve prolonged period of water distillation and repeated purifications of the product rendering the process quite expensive and cumbersome on commercial scale.

Further, metformin hydrochloride rapidly emits from solution during water distillation under vacuum and high temperatures at commercial scale. This rapid emission of metformin hydrochloride jams the reactor agitator and severely reduces pace of distillation. Such distillation often leads to high residues of water in the distillate (semi- dry metformin hydrochloride, i.e.). Metformin hydrochloride obtained in this fashion contains higher amounts of water-content than desired and therefore leads to lower quality, for example the solution obtained may not be clear and hazy when product emitted with higher amounts of water during the isolation and eventually lower yield as further purification/drying is necessitated.

To overcome the difficulties associated with the vacuum distillation to isolate metformin hydrochloride from water medium, mild vacuum at lower temperatures is preferred, but this again takes longer periods of time.

Accordingly, there remains a need in the art for preparation of highly pure metformin hydrochloride that circumvents the aforementioned difficulties in cost effective and commercially viable methods. The main objective of the present invention is to provide an improved process for the preparation of metformin hydrochloride which is cost effective and commercially viable by employing Agitated Thin Film Dryer (ATFD) for removal of water instead of the techniques of evaporation or distillation under vacuum thus rendering the process amenable on large scale.

SUMMARY OF THE INVENTION

The present invention encompasses an improved process for the preparation of metformin hydrochloride. In accordance with one embodiment, the present invention provides a process for preparing metformin hydrochloride, comprising removing solvent from a solution comprising metformin hydrochloride using agitated thin film dryer.

In accordance with a second embodiment, the present invention provides a process for the preparation of metformin hydrochloride, comprising:

a) providing a solution of metformin hydrochloride in a solvent;

b) subjecting the metformin hydrochloride solution to agitated thin film dryer c) slurrying the obtained wet material in an alcohol; and

d) isolating the metformin hydrochloride. In accordance with a third embodiment, the present invention provides a process for the preparation of metformin hydrochloride, comprising:

a) reacting dicyandiamide with dimemylamine hydrochloride in one or more hydrocarbon solvents;

b) extracting the reaction mass with another solvent;

c) subjecting the resultant solution to agitated thin film dryer

d) slurrying the obtained wet material in an alcohol; and

e) isolating the metformin hydrochloride.

In accordance with a fourth embodiment, the present invention provides a pharmaceutical composition comprising metformin hydrochloride prepared by the process of the present invention and at least one pharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF THE INVENTION The present invention encompasses an improved process for the preparation of metformin hydrochloride using agitated thin film dryer, which avoids the use of conventional distillation techniques there by process more convenient and economical, particularly on commercial scale. In one embodiment, the present invention provides an improved process for the preparation of metformin hydrochloride comprising: removing solvent from a solution comprising metfoimin hydrochloride using agitated thin film dryer. In another embodiment, the present invention provides a process for the preparation of Metformin hydrochloride comprising:

a) providing a solution of metfonnin hydrochloride in a solvent;

b) subjecting the metformin hydrochloride solution to agitated thin film dryer;

c) slurrying the obtained wet material in alcohol; and

d) isolating metformin hydrochloride from the slurry.

The solvent for use herein may be any solvent that can be able to form a solution with metformin hydrochloride, preferably water.

Metformin hydrochloride used in the present invention can be obtained by any of the methods known in the art or it may be obtained as a solution directly from a reaction mixture in which metformin hydrochloride is formed and used as such without isolation.

Alternatively, the metforrriin hydrochloride can be prepared by reacting dicyandiamide with dimethylamine hydrochloride in one or more hydrocarbon solvents and extracting the reaction mass with a solvent.

Dicyandiamide and dimemylamine hydrochloride are either commercially available or can be prepared from processes known in the art.

The suitable hydrocarbon solvent includes but is not limited to ethylbenzene, toluene, xylene and the like. Preferably the hydrocarbon solvent is xylene, more preferably o- xylene.

The reaction may be carried out at a temperature within the range from about 100°C to about 150°C; preferably at about 130°C to about 140°C and for a period of time ranging from 5 hrs to about 10 hrs.

After completion of the reaction, the reaction mass can be extracted with another solvent, preferably water at a temperature ranging from about 40°C to about 100°C and the resulting product layer can be subjected to ATFD to isolate the metformin hydrochloride of the present invention.

Agitated thin film drying is a drying technique involves separating the volatile component using indirect heat transfer coupled with mechanical agitation of the flowing film under controlled condition. The starting solution is fed from the top into a cylindrical space between a centered rotary agitator and an outside heating jacket. The rotor rotation agitates the downside-flowing solution while the heating jacket heats it. During operation, the rotor revolves at high speed and the feed distributor spreads the incoming feed uniformly over the cylinder top periphery. The rotor blades pick up the material spread it over heated surface in a thin film and agitate the film intensely, as it rapidly travels down. The material transforms from solution to slurry, wet cake, wet powder and finally dry powder as it travels from top to bottom.

The ATFD technique uses high vacuum along with elevated temperatures which allows operation at lower temperatures. This allows for a short residence time for the product in the drier. The required evaporation can be achieved in a single pass, avoiding product recirculation and possible degradation. The operating pressures are from atmospheric down to 1 mbar. The equipment can be operated at a wide range of temperatures, such as 25°C to 350° C or more.

The concentrations, solvent type, temperature, vacuum, and feeding rate is set to combinations where the metformin hydrochloride coming from the inlet precipitates essentially instantly.

Step a) of the foregoing process may include providing a solution of metformin hydrochloride in a solvent, preferably water at a temperature of about room temperature to about 100°C. Alternatively, such a solution may be obtained directly from a reaction in which metformin hydrochloride is formed.

Step b) of the aforementioned process involves feeding the metformin hydrochloride solution into an agitated thin film dryer. The temperature, feed rate, vacuum and speed of the ATFD rotor can be adjusted to optimize the output and particle size distribution.

In another embodiment, the drying process is carried out at temperatures that are below the atmospheric pressure and boiling point of the solvent, such as about 35°C to about 95°C, under a reduced pressure such as about 400 to about 740 mm Hg. The temperature and pressure conditions can vary depending on properties of the solvent that is being removed, and can be higher or lower than the ranges mentioned.

The solution of metformin hydrochloride may be added slowly or continuously to the drying chamber. The rate of flow may vary depending upon the size, capacity of the ATFD; preferably range from about 10 to about 350 ltr/hour. These and other parameters are well known to a person skilled in the art of drying using ATFD, and will vary depending upon characteristics of the actual apparatus being used.

The yield of metformin hydrochloride obtained using this technique is superior to those obtained using other techniques/equipments and controls moisture to below 2%, inevitably producing better yields and quality.

The resulting metformin hydrochloride may further be purified through a solvent slurry and the product can be recovered by conventional techniques such as filtration. The product may optionally be further dried in any conventional drier. The suitable solvent used herein for solvent slurry may be one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like and mixtures thereof. It has been observed that solubility and impurity profile of the metformin hydrochloride API is dependent on the content of moisture present in the crude stage obtained after removal of the solvent. The inventors of the present invention have performed repetition (Example 3) by solvent removal using conventional technique such as atmospheric distillation or distillation under vacuum results product containing higher amounts of moisture content of about 5% as a result final product contain substantial amounts of undesired guanidine impurity of Formula A and hazy solutions obtained even after repeated purifications.

Formula A

In contrast, the present invention provides crystalline metformin hydrochloride, obtained by the process described above, wherein the resultant residual mass after subjecting to ATFD has moisture content of below 2% inevitably producing better yields and substantially free of Formula A. The present invention provides metformin hydrochloride substantially free of guanidine impurity of Formula A, where in the word "substantially free" refers to metformin hydrochloride contain less than 0.1% of guanidine impurity of Formula A as measured by HPLC; preferably less than 0.05% of Formula A as measured by HPLC. Advantages of ATFD over conventional distillation include but not limited to cost reduction, minimization of operational time, high evaporation ratios, reduction in reactor occupancy time, and increase in batch size and yield improvement.

The invention further encompasses a process for preparing a pharmaceutical composition comprising combining metformin hydrochloride of the present invention, with at least one pharmaceutically acceptable excipient.

EXAMPLES

The present invention is further illustrated by the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention. The drying of solution of metformin hydrochloride can be performed using agitated thin film dryer with the following specifications:

Capacity: 3.5 m², Operating temperature: Shell: 30 - 70°C Jacket: 0 - 120°C; Rotor Speed: Agitator RPM: 325; Motor HP/RPM: 12.5/ 1440; Condenser: 3.6 m² Heat Transfer Area.

EXAMPLE 1:

Preparation of metformin hydrochloride (distillation using ATFD)

Metformin hydrochloride (137kgs) was dissolved in DM water (410 Its) in a reactor at room temperature. The solution was filtered to remove any extraneous material and the aqueous solution was subjected to ATFD under 720-740mm/Hg vacuum and a flow rate of 1 lOLts/Hr with outlet temperature of about 90°C to 95°C. To the obtained solid (138kgs; moisture content 0.6%) was charged methanol (1631ts) at room temperature and the slurry was stirred for 60 minutes at same temperature. The solid so obtained was collected by filtration, washed with methanol (601ts) and suck dried for 60mins. Metformin hydrochloride thus obtained was dried in a tray drier at 60°C to 65 °C to obtain the title compound.

Yield: 132.6kgs

LOD: 0.2%

Purity: 99.99%

Formula A: 0.01%

EXAMPLE 2:

Preparation of metformin hydrochloride (distillation using ATFD)

To a 1.0 KL SSR was charged O-Xylene (600Lts),l^stportion of dicyandiamide (40Kgs) and dimethylamine hydrochloride (232.6Kgs) at room temperature. The reaction mass was stirred for 10 mins at same temperature and slowly raised the temperature to 50°c to 55°C. At this temperature, charged 2^nd portion of dicyandiamide (160Kgs) and heated the reaction mass to 135°C to 140°C. The reaction mass was stirred for 8 hrs at same temperature and the reaction completion was monitored by HPLC. After the reaction completion, reaction mass was allowed to cool to 90°C to 95°C and DM Water (500Lts) was charged. The reaction mass was stirred for 30 min at 90°C to 95°C and the aqueous layer was separated. The aqueous layer was treated with charcoal 70°C to 75°C and separated the charcoal. The clear filtrate was subjected to ATFD under 720-740mm/Hg vacuum and a flow rate of 1301ts/Hr. To the obtained wet solid material (370kgs; moisture content 1.6%) was charged methanol (4001ts) at room temperatureand the slurry was stirred for 60 minutes at same temperature. The solid so obtained was collected by filtration, washed with methanol (60 Its) and suck dried for 60mins. Metformin hydrochloride thus obtained was dried in a tray drier at 60°C to 65°C to obtain the title compound.

Yield: 338kgs

LOD: 0.3%.

Purity: 99.94%

Formula A: 0.03%

EXAMPLE 3:

Preparation of metformin hydrochloride (distillation under vacuum)

To a 1.0 L RBF was charged O-Xylene (300 ml),l^stportion of dicyandiamide (20gms) and dimemylamine hydrochloride (116.3 gms) at room temperature. The reaction mass was stirred for 10 mins at same temperature and slowly raised the temperature to 50°C to 55°C. At this temperature, charged 2^nd portion of dicyandiamide (80 gms) and heated the reaction mass to 135°C to 140°C. The reaction mass was stirred for 8 hrs at same temperature and the reaction completion was monitored by HPLC. After , the reaction completion, reaction mass was allowed to cool to 90°C to 95°C and DM Water (250 ml)) was charged. The reaction mass was stirred for 30 min at 90°C to 95°C and the aqueous layer was separated. The aqueous layer was treated with charcoal 70°C to 75°C and separated the charcoal. The clear filtrate was distilled completely under vacuum at below 60°C. To the obtained wet solid material (moisture content 5.57%) was charged methanol (200 ml) at room temperature and the slurry was stirred for 60 minutes at same temperature. The solid so obtained was again slurred in 120 ml methanol and filtered. The solid was collected by filtration, washed with methanol (30 ml) and suck dried for 60mins. Metformin hydrochloride thus obtained was dried in a tray drier at 60°C to 65°C to obtain the title compound.

Yield: 145 gms

LOD: 0.5%.

Purity: 99.62%

Formula A: 0.16%

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.

Claims

WE CLAIM

Claim 1 : A process for preparing metformin hydrochloride, comprising removing solvent from a solution comprising metformin hydrochloride using Agitated thin film dryer. Claim 2: The process of claim 1, wherein the solution of metformin hydrochloride is prepared by mixing metformin hydrochloride with a solvent.

Claim 3: The process of claim 2, wherein the solvent is water.

Claim 4: The process of claim 1, wherein the solvent is removed at temperatures of about 35°C to about 95°C. Claim 5: The process of claim 1, wherein the solvent is removed at a reduced pressure of about 400 to about 740 mm Hg.

Claim 6: A process for the preparation of metformin hydrochloride, comprising: a) providing a solution of metformin hydrochloride in a solvent,

b) subjecting the metformin hydrochloride solution to agitated thin film dryer, c) slurrying the obtained wet material in an alcohol, and

d) isolating the metformin hydrochloride.

Claim 7: The process of claim 6, wherein the solvent is water. Claim 8: The process of claim 6, wherein the solution of metformin hydrochloride is prepared at a temperature from about room temperature to about 100°C.

Claim 9: The process of claim 6, wherein the agitated thin film drying is carried out at a temperature of about 35°C to about 95°C.

Claim 10: The process of claims 6, wherein the agitated thin film drying is carried out at a reduced pressure of about 400 to about 740 mm Hg.

Claim 11 : The process of claim 6, wherein the alcohol solvent, is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and mixtures thereof. Claim 12: The process of claim 11, wherein the alcohol solvent is methanol.

Claim 13: Metformin hydrochloride contains less than 0.05% of guanidine impurity of Formula A as measured by HPLC.