PREPARATION OF METFORMIN HYDROCHLORIDE FREE FROM GENOTOXIC IMPURITY

Abstract

A high purity metformin hydrochloride, having a purity equal to or greater than 99% by area percentage of LCMS and no detectable amount of N-Nitrosodimethylamine (NDMA), wherein the LCMS method for the determination of NDMA content in Metformin hydrochloride has a Limit of detection of 0.004 ppm and a Limit of quantification of 0.009 ppm.

Claims

1. A high purity metformin hydrochloride, having a purity equal to or greater than 99% by area percentage of LCMS and no detectable amount of N-Nitrosodimethylamine (NDMA), wherein the LCMS method for the determination of NDMA content in Metformin hydrochloride has a Limit of detection of 0.004 ppm and a Limit of quantification of 0.009 ppm.

2. The high purity metformin hydrochloride according to claim 1, having a purity equal to or greater than 99% by area percentage of LCMS and NDMA in an amount less than 0.035 ppm.

3. The high purity metformin hydrochloride according to claim 1 prepared by a process comprising: (h) reacting dicyanodiamide of Formula (III) with dimethylamine hydrochloride of Formula (IV) in one or more hydrocarbon solvents; ##STR00010## (i) extracting reaction mass with water to obtain a solution; (j) treating the solution with carbon; (k) removing the water to obtain a residue; (l) treating the residue with one or more C.sub.1-C.sub.4 alcohols to obtain a slurry; (m) pulverizing the slurry; and (n) drying at 60-85° C. to obtain the metformin hydrochloride having no detectable amount of NDMA.

4. The process according to claim 3, wherein the hydrocarbon at step (a) comprises one or more of toluene, xylene, ethylbenzene, cyclohexane, hexane, cyclopentane, pentane, and heptane.

5. The process according to claim 3, wherein the carbon at step (c) is highly active carbon having a surface area between 1200 to 1800 m.sup.2/gm and pore volume in the range of 0.5 to 1.8 cc/gm.

6. The process according to claim 3, wherein the C.sub.1-C.sub.4 alcohols at step (e) comprises one or more of methanol, ethanol, propanol, isopropanol, butanol and isobutanol.

7. The process according to claim 5, wherein the highly active carbon is selected from one or more of PF457, 31 AL, 31 HW, Pentacarb, New carb (N) and 21 HW or equivalents having pore volume in the range of 0.5 to 1.8 cc/gm.

8. The process according to claim 3, wherein the drying at step (g) comprises drying at 60-85° C. under vacuum (Not less than 700 mm Hg) to obtain the metformin hydrochloride having no detectable amount of NDMA.

9. A pharmaceutical composition comprising metformin hydrochloride having a purity equal to or greater than 99% by area percentage of LCMS and NDMA in an amount less than threshold of toxicological concern limit (TTC) 0.035 ppm, prepared by the process according to claim 3.

10. A pharmaceutical composition comprising metformin hydrochloride having a purity equal to or greater than 99% by area percentage of LCMS and NDMA in an amount less than TTC 0.035 ppm and one or more pharmaceutically acceptable carriers, excipients or diluents.

11. A pharmaceutical composition comprising metformin hydrochloride having a purity equal to or greater than 99% by area percentage of LCMS and NDMA in an amount less than TTC 0.035 ppm, alone or in combination with at least another therapeutic agent in the presence of a pharmaceutically acceptable carrier.

12. The pharmaceutical composition according to claim 11, wherein the therapeutic agent comprises one or more of DPP IV inhibitors, SGLT2 inhibitors or glipizide, glyburide, repaglinide pioglitazone, rosiglitazone and glimepiride.

13. A method for treating diabetes in patients comprising administering a therapeutically effective amount of a pharmaceutical composition comprising metformin hydrochloride having a purity equal to or greater than 99% by area percentage of HPLC and NDMA in an amount less than TTC 0.035 ppm, alone or in combination with at least another therapeutic agent in the presence of a pharmaceutically acceptable carrier.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0039] As used herein the term “obtaining” may include filtration, filtration under vacuum, centrifugation, and decantation for isolation of the product. The product may be preceded for further steps with or without isolation and with or without drying in case of the product was isolated.

[0040] The term “treating” means mixing, stirring, slurring, keeping that at any temperature or conditions.

[0041] The term “cooling” herein means the reaction mixture is cooled at temperature from about 0° C. to about 35° C., In particular, from about 5° C. to about 30° C., More particularly, from about 5° C. to about 25° C., after the reaction mixture is being heated.

[0042] The term “free from NDMA” herein means metformin hydrochloride having NDMA less than TTC 0.035 ppm by area percentage of LCMS. In particular, less than about 0.010 ppm by area percentage of LCMS, and less than about 0.004 ppm. More particular, not in detectable amount by area percentage of LCMS.

Abbreviations:

LOQ: Limit of Quantification

LOD: Limit of Detection

HPLC: High Performance Liquid Chromatography

API: Active Pharmaceutical Ingredient

Hrs: Hours

MRM: Multiple Reaction Monitoring

APCI: Atmospheric Pressure Chemical Ionization

LCMS: Liquid Chromatography Mass Spectrometry

ppm: Parts Per Million

[0043] In general, the solvents may be removed from the reaction mixture in order to obtain solid or precipitate. The solvents may be removed by one or more of filtration, filtration under vacuum, centrifugation, decantation, distillation and distillation under vacuum.

[0044] The product(s) obtained may further be converted to any other physical forms thereof which includes but not specifically limited to salt(s), solvate(s), hydrate(s), co-crystal(s) and solid dispersion(s) in either crystalline or amorphous forms.

[0045] In one general aspect, there is provided high purity metformin hydrochloride free from NDMA.

[0046] In another general aspect, there is provided a high purity metformin hydrochloride, having a purity equal to or greater than 99% by area percentage of LCMS and no detectable amount of NDMA, wherein the LCMS method for the determination of NDMA content in Metformin hydrochloride has a Limit of detection of 0.004 ppm and a Limit of quantification of 0.009 ppm.

[0047] In another general aspect, there is provided high purity metformin hydrochloride, having a purity equal to or greater than 99% by area percentage of LCMS and NDMA in an amount less than 0.035 ppm.

[0048] In another general aspect, there is provided a process for the preparation of high purity metformin hydrochloride, the process comprising: [0049] (a) reacting dicyanodiamide of Formula (III) with dimethylamine hydrochloride of Formula (IV) in one or more hydrocarbon solvents;

##STR00004## [0050] (b) extracting reaction mass with water to obtain a solution; [0051] (c) treating the solution with carbon; [0052] (d) removing the water to obtain a residue; [0053] (e) treating the residue with one or more C.sub.1-C.sub.4 alcohols to obtain a slurry; [0054] (f) pulverizing the slurry; and [0055] (g) drying at 60-85° C. to obtain the metformin hydrochloride having no detectable amount of NDMA.

[0056] In general, the reaction of dicyanodiamide of Formula (III) with dimethylamine hydrochloride of Formula (IV) may be carried out in one or more hydrocarbon solvents.

[0057] The hydrocarbon solvent may be selected from one or more of toluene, xylene, ethylbenzene, cyclohexane, hexane, cyclopentane, pentane, and heptane. In particular, toluene and xylene may be used. The reaction mixture may be heated at a temperature from about 50° C. to about 150° C.

[0058] After the completion of the reaction, the reaction mass may be extracted with water at an ambient temperature to reflux temperature, for example, at about 80° C. to about 95° C. The solution may be purged with nitrogen gas for about 15 minutes to one hour.

[0059] The solution can be treated with highly active carbon to remove colored and other suspended matters and impurities.

[0060] In general, the carbon at step (c) is highly active carbon having a surface area between 1200 to 1800 m.sup.2/gm and pore volume in the range of 0.5 to 1.8 cc/gm.

[0061] The highly active carbon used according to the invention is having pore volume in the range of 0.5 to 1.8 cc/gm, preferably 0.55-1.2 cc/gm and surface area between 1200 to 1800 m.sup.2/gm, preferably 1400-1600 m.sup.2/gm.

[0062] The highly active carbon is selected from one or more of PF457, 31 AL, 31 HW, Pentacarb, New carb (N) and 21 HW or equivalents having pore volume in the range of 0.5 to 1.8 cc/gm.

[0063] The following are the grades of activated carbon which effectively removes the traces level of NDMA present in drug substance during crystallization

TABLE-US-00001 Grade No. Pore Volume PF457 1.2 cc/gm 31 AL 0.52 cc/gm 31 HW 0.62 cc/gm 21 HW 0.55 cc/gm

[0064] The water may be removed from the solution by a technique which includes, for example, distillation, distillation under vacuum, and evaporation.

[0065] The residue obtained may be treated with one or more of C.sub.1-C.sub.4 alcohols to obtain slurry.

[0066] The C.sub.1-C.sub.4 alcohols at step (e) comprises one or more of methanol, ethanol, propanol, isopropanol, butanol and isobutanol.

[0067] The drying at step (g) comprises drying at 60-85° C. under vacuum (Not less than 700 mm Hg) to obtain the metformin hydrochloride having no detectable amount of NDMA.

[0068] Certain manufacturing conditions using the solvent N, N-Dimethylformamide (DMF), gave rise to this class of impurities in drug substance. NDMA is a carcinogenic risk substance and for which the acceptable intake (i.e. permissible daily exposures—PDE) is 0.0959 μg/day. Maximum daily dose of Metformin HCl is 2.55 g./day

[0069] Concentration (μg/g)=PDE (μg/day)/Daily amount of drug product (g./day)=0.0959/2.55=0.03761 in ppm≈0.038 in ppm

[0070] TTC=Threshold of Toxicological Concern (TTC)

[0071] NDMA forms by the reaction of nitrous acid with dimethylamine:

HONO+(CH.sub.3).sub.2NH.fwdarw.(CH.sub.3).sub.2NNO+H.sub.2O

[0072] NDMA can form by following routes also:

##STR00005##

Or

[0073] ##STR00006##

[0074] The present invention does not involve N,N-Dimethylformamide as a solvent and sodium nitrite during the process. Preparation of metformin hydrochloride in the present invention involves reaction of cyano guanidine with dimethylamine hydrochloride. Other materials used in process are xylene, methanol, activated carbon and water. As there is no scope of generation of the NDMA and other nitrosamines although dimethylamine is used. Therefore, there is no possibility of NDMA and other Nitrosamines.

[0075] The starting materials for the preparation of metformin are prepared as per the procedure described herein below.

Preparation of Compound (III):

[0076] ##STR00007##

Preparation of Compound (IV):

[0077] ##STR00008##

[0078] As during the synthesis of metformin hydrochloride and starting compounds-III and IV, neither sodium nitrite, nor dimethyl formamide is used in the process, therefore NDMA and other Nitrosamines are not possible in the process.

[0079] Usage of water, after analysing for NDMA before its use in the process for preparation of metformin hydrochloride:

[0080] As per WHO Guidelines, NDMA and Nitrite were analysed in water to be used for the synthesis of metformin hydrochloride.

TABLE-US-00002 Test Guideline Result (ppm) Nitrite Max 3.0 Not Detected (<0.01 ppm) NDMA Max 0.1 Not Detected (<0.01 ppm)

[0081] In another general aspect, there is provided a pharmaceutical compositions comprising metformin hydrochloride free from NDMA for the treatment of diabetes.

[0082] In another general aspect, there is provided a pharmaceutical composition comprising metformin hydrochloride having a purity equal to or greater than 99% by area percentage of LCMS and NDMA in an amount less than 0.035 ppm.

[0083] In another general aspect, there is provided a pharmaceutical composition comprising metformin hydrochloride having a purity equal to or greater than 99% by area percentage of LCMS and NDMA in an amount less than 0.035 ppm and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0084] The determination of NDMA content in Metformin Hydrochloride API by LCMS:

Experimental:

[0085] In general, the following LCMS methods for the determination of NDMA in metformin may be used.

[0086] LCMS Chromatograph Mass Spectrometry Approach:

[0087] NDMA from Synzeal batch No. SRL-255-111 having purity of 99.96% was used as standard. The method is highly sensitive to detected NDMA in metformin upto the level of 0.004 ppm with respect to metformin.

Chromatographic condition:
Equipment: HPLC System 1260 or equivalent

Column: ACE 3 PFP C18

Detector: Mass

[0088] Flow rate: 0.7 mL/min

Injection Volume: 50 μL

[0089] Column temperature: 30° C.
Run time: 10 mins

Mass Parameters:

[0090] Equipment: Q trap 4500
Scan type: MRM

Polarity: Positive

[0091] Curtain gas (N.sub.2): 30 mL/min

Temperature: 400° C.

[0092] Dwell time: 200 msec

[0093] The following are the results of the batches tested using LCMS method for the determination of NDMA content in metformin.

TABLE-US-00003 Batch No. Results of NDMA in ppm MFH2019001 Not Detected MFH2019002 Not Detected MFH2019003 Not Detected MFH2019004 Not Detected

[0094] In another general aspect, there is provided a pharmaceutical composition comprising high purity metformin hydrochloride having a purity equal to or greater than 99% by area percentage of HPLC and NDMA in an amount, less than TTC 0.035 ppm.

[0095] The Impact of carbon treatment and drying at different temperature is as shown in below table:

1. Limit of NDMA=0.035 ppm

[0096] 2. Limit of detection=0.004 ppm
3. Limit of quantification=0.009 ppm

TABLE-US-00004 Carbon NDMA Batch No. grade Sample details Imp. ppm MFH210661AFP — As such As such aq. 0.833 aq. Mass Mass MFH210661AFP — — Before carbon 0.295 treatment aq. Mass MFH210661AFP — — After carbon 0.441 treatment aq. Mass Carbon Drying NDMA Batch No. grade Sample temperature Impurity RD/MF/0011/20/022 Pentacarb Sample-01 60-65° C. Not Detected Sample-02 70-75° C. Not Detected Sample-03 80-85° C. Not Detected RD/MF/0011/20/023 Exemed Sample-01 60-65° C. 0.004 carbon Sample-02 70-75° C. Not Detected Sample-03 80-85° C. Not Detected RD/MF/0011/20/024 PF 457 Sample-01 60-65° C. 0.004 Sample-02 70-75° C. Not Detected Sample-03 80-85° C. Not Detected RD/MF/0011/20/025 New carb Sample-01 60-65° C. Not (N) Detected Sample-02 70-75° C. Not Detected Sample-03 80-85° C. Not Detected

[0097] In another general aspect, there is provided a pharmaceutical composition comprising metformin hydrochloride having a purity equal to or greater than 99% by area percentage of LCMS and NDMA in an amount less than TTC 0.035 ppm, prepared by the process as mentioned herein above.

[0098] In another general aspect, there is provided a pharmaceutical composition comprising metformin hydrochloride having a purity equal to or greater than 99% by area percentage of LCMS and NDMA in an amount, less than TTC 0.035 ppm and one or more pharmaceutically acceptable carriers, excipients or diluents.

[0099] In another general aspect, there is provided a pharmaceutical composition comprising metformin hydrochloride having a purity equal to or greater than 99% by area percentage of LCMS and NDMA in an amount, less than TTC 0.035 ppm alone or in combination with at least another therapeutic agent in the presence of a pharmaceutically acceptable carrier.

[0100] The therapeutic agent comprises one or more of DPP IV inhibitors, SGLT2 inhibitors or glipizide, glyburide, repaglinide pioglitazone, rosiglitazone and glimepiride.

[0101] In another general aspect, there is provided a pharmaceutical composition comprising metformin hydrochloride having a purity equal to or greater than 99% by area percentage of LCMS and NDMA in an amount, less than TTC 0.035 ppm and one or more SGLT2 inhibitors or one or more DPP IV inhibitors.

[0102] In another general aspect, there is provided a method for treating diabetes in patients comprising administering a therapeutically effective amount of a pharmaceutical composition comprising metformin hydrochloride having a purity equal to or greater than 99% by area percentage of HPLC and NDMA in an amount, less than TTC 0.035 ppm, alone or in combination with at least another therapeutic agent in the presence of a pharmaceutically acceptable carrier.

[0103] In general, the pharmaceutically acceptable carriers may be used for example lactose, sucrose, mannitol, sorbitol; cornstarch, tapioca starch and potato starch; cellulose, sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose, calcium phosphates, dicalcium phosphate, tricalcium phosphate, sodium sulfate, calcium sulfate, polyvinyl pyrrolidone, polyvinyl alcohol, stearic acid, magnesium stearate, calcium stearate, stearic acid, peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, ethylene glycol betacyclodextrin, fatty alcohols, and hydrolyzed cereal solids, as well as other non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, flavoring agents which are commonly used in formulations.

[0104] The examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications.

EXAMPLES

Example-1: Preparation of Metformin Hydrochloride Free from NDMA Impurity Using PF457 Grade Carbon

[0105] ##STR00009##

[0106] Xylene (400 mL) and dicyanodiamide (100 g) were taken in a round-bottom flask. The reaction mixture was heated at 80° C. Dimethylamine hydrochloride (117 g) was added portion-wise within 2 hours. The reaction mass was stirred for 3 hours. The reaction mixture was further heated to 100° to 105° C. followed by heating to 140° C. The reaction mass was stirred for 4 hours and cooled to 95° C. The reaction mass was treated with water (200 mL) and layers were separated. The organic layer was again extracted with water (50 mL). The combined aqueous layer was treated with carbon PF457 grade (3 g) and stirred for 20 minutes. The reaction mass was filtered through a hyflo bed and washed with water (50 mL). The filtrate was taken in a round-bottom flask at 50° C. and N.sub.2 gas was purged for 30 minutes. The filtrate was distilled to remove water completely under vacuum at 65° C. The residue thus obtained was treated with methanol (110 mL) at 40° C. to 45° C. and cooled to 20° C. to 25° C. The product was filtered and washed with chilled methanol (50 mL). The wet-cake thus obtained was treated with water at 50° C. along with N.sub.2 gas purging for 30 minutes. The solution was distilled to remove water completely under vacuum at 65° C. The residue thus obtained was treated with methanol (80 mL) at 40° C. to 45° C. to prepare the slurry. The slurry was pulverized under high-speed grinder for wet grinding for 25 minutes. The reaction mass was filtered and dried. The wet-cake was washed with chilled methanol (30 mL). The product was dried at 65° C. to 70° C. to obtain 160 g metformin hydrochloride having NDMA content—Not detected.

Example-2: Preparation of Metformin Hydrochloride Free from NDMA Impurity Using 31HW Grade Carbon

[0107] Toluene (500 mL) and dicyanodiamide (100 g) were taken in a round-bottom flask at 25° C. to 35° C. The reaction mixture was heated at 80° C. Dimethylamine hydrochloride (117 g) was added portion-wise within 2 hours. The reaction mass was stirred for 3 hours. The reaction mixture was further heated to 100° to 105° C. followed by heating to reflux temperature. The reaction mass was stirred for 4 hours and cooled to 95° C. The reaction mass was treated with water (200 mL) and layers were separated. The organic layer was extracted with water (50 mL). The combined aqueous layer was treated with carbon 31HW (3 g) and stirred for 20 minutes. The reaction mass was filtered through hyflo bed and washed with water (50 mL). The filtrate was taken in a round-bottom flask at 50° C. and N.sub.2 gas was purged for 30 minutes. The filtrate was distilled to remove water completely under vacuum at 65° C. The residue thus obtained was treated with methanol (110 mL) at 40° C. to 45° C. and cooled to 20° C. to 25° C. The product was filtered and washed with chilled methanol (50 mL). The wet-cake thus obtained was treated with water at 50° C. along with N.sub.2 gas purging for 30 minutes. The solution was distilled to remove water completely under vacuum at 65° C. The residue thus obtained was treated with methanol (80 mL) at 40° C. to 45° C. to prepare the slurry. The slurry was pulverized under high-speed grinder for wet grinding for 25 minutes. The reaction mass was filtered and dried. The wet-cake was washed with chilled methanol (30 mL). The product was dried at 65° C. to 70° C. to obtain 155 g metformin hydrochloride having NDMA content—Not detected.

Example-3: Preparation of Metformin Hydrochloride Free from NDMA Impurity Using Pentacarb Grade Carbon

[0108] After the reaction of Dicyanodiamide with Dimethylamine hydrochloride as explained in example 1 and 2, the product was extracted in aqueous layer. The aqueous layer (175 mL) was treated with Pentacarb grade carbon (0.1 g) and stirred at 90-100° C. for 30 minutes. The reaction mass was filtered through a hyflo bed and washed with water (25 mL). The filtrate was taken in a round-bottom flask at 50° C. and N.sub.2 gas was purged for 30 minutes. The filtrate was distilled to remove water completely under vacuum at 65° C. The residue thus obtained was treated with methanol (55 mL) at 40-45° C. and cooled to 25-35° C. The product was filtered and washed with chilled methanol (50 mL). The wet-cake thus obtained was treated with methanol (45 mL) at 25-35° C. to prepare the slurry. The reaction mass was filtered and suck dried. The wet-cake was washed with methanol (15 mL). The product was dried under vacuum (Not less than 700 mm Hg) at temperature 80-85° C. to obtain metformin hydrochloride having NDMA content—Not detected (below 0.004 ppm).

Example-4: Preparation of Metformin Hydrochloride Free from NDMA Impurity Using PF 457 Grade Carbon

[0109] After the reaction of Dicyanodiamide with Dimethylamine hydrochloride as explained in example 1 and 2, the product was extracted in aqueous layer. The aqueous layer (175 mL) was treated with PF 457 grade carbon (0.1 g) and stirred at 90-100° C. for 30 minutes. The reaction mass was filtered through a hyflo bed and washed with water (25 mL). The filtrate was taken in a round-bottom flask at 50° C. and N.sub.2 gas was purged for 30 minutes. The filtrate was distilled to remove water completely under vacuum at 65° C. The residue thus obtained was treated with methanol (55 mL) at 40-45° C. and cooled to 25-35° C. The product was filtered and washed with chilled methanol (50 mL). The wet-cake thus obtained was treated with methanol (45 mL) at 25-35° C. to prepare the slurry. The reaction mass was filtered and suck dried. The wet-cake was washed with methanol (15 mL). The product was dried under vacuum (Not less than 700 mm Hg) at temperature 70-75° C. to obtain metformin hydrochloride having NDMA content—Not detected (below 0.004 ppm).

Example-5: Preparation of Metformin Hydrochloride Free from NDMA Impurity Using New Carb (N) Grade Carbon

[0110] After the reaction of Dicyanodiamide with Dimethylamine hydrochloride as explained in example 1 and 2, the product was extracted in aqueous layer. The aqueous layer (175 mL) was treated with new carb (N) grade carbon (0.1 g) and stirred at 90−100° C. for 30 minutes. The reaction mass was filtered through a hyflo bed and washed with water (25 mL). The filtrate was taken in a round-bottom flask at 50° C. and N.sub.2 gas was purged for 30 minutes. The filtrate was distilled to remove water completely under vacuum at 65° C. The residue thus obtained was treated with methanol (55 mL) at 40-45° C. and cooled to 25-35° C. The product was filtered and washed with chilled methanol (50 mL). The wet-cake thus obtained was treated with methanol (45 mL) at 25-35° C. to prepare the slurry. The reaction mass was filtered and suck dried. The wet-cake was washed with methanol (15 mL). The product was dried under vacuum (Not less than 700 mm Hg) at temperature 80-85° C. to obtain metformin hydrochloride having NDMA content—Not detected (below 0.004 ppm).

[0111] While the present invention has been described in terms of a few specific embodiments, modifications and equivalents thereof, in light of teaching and disclosure of the present invention that are apparent of the skilled artisan, are to be construed as included within the scope of the invention.