FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"IMPROVED PROCESS FOR PREPARATION OF METFORMIN HYDROCHLORIDE FREE OF DMA HCL"
2. APPLICANT (S):
(a) NAME: WANBURY LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: B- Wing, 10th Floor, BSEL Tech Park, Sector 30 A,
Plot no.39/5 & 39/5A, Opp. Vashi Railway Station, Navi Mumbai- 400 703, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

Related application:
This application is Complete Cognate for the Provisional Patent Application No. 1409/MUM/2010 dated 03/05/2010, Provisional Patent Application No. 1708/MUM/20I0 dated 03/06/2010 and Provisional Patent Application No. 1737/MUM/2010 dated 07/06/2010.
Technical field:
The present invention relates to process for preparation of highly pure metformin hydrochloride substantially free from DMA-HCI impurity to obtain uniform particle size distribution and particle size reduction using in situ grinding technology during the crystallization of metformin hydrochloride in metformin hydrochloride. The present invention particularly relates to a process for insitu grinding of Metformin Hydrochloride during crystallization from mother liquor in which nucleation and growth of the nuclei are controlled and are crystallized out by concentration under vacuum and the crystals are separated from the mother liquor. This invention also relates to particle size reduction assembly which includes a reactor and homogenizer pump that can be easily disassembled for cleaning and to process for preparation of metformin hydrochloride with better compact ability.
Background and prior art:
Metformin is a typical biguanide, chemically known as (N, N- dimethyl imidocarbonimidic diamide), is an oral antihyperglycemic drug used in the management of non-insulin-dependent diabetes mellitus (NIDDM). It is typically used as pharmaceutical^ acceptable salt preferably hydrochloride salt. Metformin hydrochloride, currently marketed as GLL)COPHAGE(R) tablets by Bristol-Myers Squibb Co. Each GLUCOPHAGE(R) tablet contains 500, 850 or 1000 mg of metformin hydrochloride. There is no fixed dosage regimen for the management of hyperglycemia in diabetes mellitus with GLUCOPHAGE(R). Dosage of GLUCOPHAGE(R) is individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended dose of 2550 mg per day.

Metformin hydrochloride is a white to off white crystalline compound with a molecular formula C4H11N5 HCL and with molecular wt of 65.63. Metformin HCL is freely soluble in water and practically insoluble in acetone, ether and chloroform.
US3174901 disclose composition containing dimethyl biguanide used in the form of hydrochloride salt wherein it is used for treating diabetes by oral administration. (Merck index details).
Metformin hydrochloride (N, N-dimethylimidodicarbonimidic diamide hydrochloride) of formula I is a member of the biguanide class of oral antihyperglycemics which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose.
Metformin is commercially manufactured by condensation of dimethyl amine (Formula II) in the form of hydrochloride and Dicyanodiamide, also called as Cyanoguanidine (Formula III) as shown in scheme 1.
Scheme-1

During this condensation number of impurities are formed which are present in metformin hydrochloride along with unreacted starting materials. Major impurity so far detected even after successive crystallizations of metformin hydrochloride in commercial metformin hydrochloride is dimethyl amine hydrochloride (DMA HCI), which is potentially hazardous to human health. Literature references related to toxicological studies of this impurity is as below:
Dimethyl amine is the immediate precursor of dimethylnitrosamine, a known potent carcinogen in a wide variety of animal species (Food and Chemical Toxicology 36, 923-927, (1998)) Olfactory sensory cells are highly sensitive to the toxic effects of dimethyl

amine (Buckley et al Toxicol. Sci. 5, 541-352 (1985)). Limit of this impurity in BP and Ph Eur are 0.05% (500 ppm).
Thus it was necessary to develop a technology that meets the virtual demand in producing metformin hydrochloride, which will contain DMA HCI impurity level well below permissible limit.
In conventional process for producing Metformin hydrochloride (N, N- dimethyl imidocarbonimidic diamide) is prepared by condensation of dimethyl amine (Formula II) in the form of hydrochloride and Dicyanodiamide, also called as Cyanoguanidine (Formula III) in a reactor at a temperature of about 100-degree. to 150.degree. C. for about \ to 8 hours to form metformin hydrochloride To remove impurity and unreacted raw material is extracted in water and is usually crystallized by concentration under vacuum/atmosphere, cooled and centrifuged to separated metformin hydrochloride from mother liquor which is generally performed in perforated-screen centrifuge baskets. The common form of crystallizer used in the crystallization of Metformin Hydrochloride is a horizontal cylindrical tank fitted with an agitator, cooling jacket, and distillation assembly.
Until now, the particle size reduction is carried by milling, and or pulverizing of dry Metformin Hydrochloride obtained from dryer and the time required between 10 to 30 hours for total micronisation or milling. In these known processes, material loss due to dusting and extra manpower and power cost is involved. Moreover, metformin is hygroscopic in nature and after micronisation, it absorbs moisture and forms lump and thus great difficulty in handling.
Crystallization is the main separation and purification step for the manufacturing of drug substances. The particle size distribution (PSD) obtained during crystallization is influenced by a combination of various mechanisms that occur during crystallization, such as nucleation, growth, aggregation, attrition, breakage, etc. Control of PSD during crystallization is critical to achieve the desired product properties. When the particle size cannot be consistently controlled during crystallization to meet the desired specifications,

an extra processing step such as dry milling is required, which incur additional cost in manufacturing the API.
The PSD of a material can be important in understanding its physical and chemical properties. The particle size of the drug powder might be an important physical parameter in the dissolution rate. The way PSD is expressed usually defined by the method by which it is determined.
Therefore, the main object of the invention is to produce remarkably pure metformin hydrochloride with high throughput with exceptionally low amount of impurity, DMA-HC1 & an improved process for crystallization of Metformin hydrochloride from mother liquor in which the powder processing time is significantly reduced and a narrower and better defined particle distribution is achieved which has characteristics, which are more suitable for handling.
Summary of the invention:
In accordance with objective, the present invention provides a process for the preparation of metformin hydrochloride, with effective removal of impurity DMA HC1 using in situ grinding technology during crystallization.
In an aspect, the present invention provides a process for insitu particle size reduction of metformin hydrochloride during crystallization from mother liquor in which nucleation and growth of the nuclei are controlled and crystallized out by concentration under vacuum.
Accordingly, the process for the preparation of high throughput crystalline Metformin HCL having better compact ability, uniform particle size distribution and particle size reduction, with effective removal of impurity, DMA-HC1 using Insitu grinding technology comprises the steps of;
a. Obtaining a solution of metformin HC1 (having DMA HC1 content of
1000-2000ppm) in water,
b. Distilling out water under vacuum and then carrying out Insitu
grinding/homogenization of the reaction mass during crystallization/slow
cooling crystallization , both in the nucleation zone and in metastable

zone, in presence of solvent at a temperature range of 65°C to 90°C for about 2 to 6 hrs, cooling to 35-45°C followed by addition of methanol to obtain a slurry,
c. Centrifuging the slurry obtained in step (b) in presence of a solvent for
about 3 hours, drying in FBD to obtain Metformin-HCI: and
d. Optionally milling, grinding etc as per formulation requirements.
In yet another aspect, the invention provides metformin oral solid dosage form with enhanced tablet strength, where metformin is provided with better compact ability obtained by modified crystallization process, i.e. slow cooling crystallization method.
Accordingly, the invention provides a process for metformin hydrochloride tablet with enhanced hardness, and with better compact ability involving modified crystallization process, which comprises;
a) dissolving the crude Metformin HCI in warer at 75-90 oC & fitecing the
reaction mass on Charcoal followed by Highflow;
b) distilling out water under vacuum below 75 °C followed by cooling the mass
from 74 °C to 50 °C in 3 hours; further cooling the mass from 50 °C to 35 °C in 6
hours;
c) centrifuging the slurry containing metformin hydrochloride in methanol to obtain wet cake;
d) milling the dried cake to achieve 60 meshes passing as per formulation requirements;
e) adding excipients (as per specifications) to the milled API (94 wt%) followed by granulating to form 20 mesh passing granules and
f) compressing the granules to form tablets.
In another aspect, the crude metformin is obtained by reacting DCDA and DMA-HC1 in Xylene at 110°C, followed by maintaining the reaction at 136-138°C under reflux for 8 hours. Water is added to the mass; maintained the reaction at 90°C and separated the aqueous layer followed by distilling out maximum water under vacuum. The Reaction mass is cooled to 35 - 40 °C, added CH30H; filtered the wet cake and suck dried under vacuum to obtain crude product.

Brief Description of the Drawings:
Fig 1 depicts the flow diagram of the process for insitu particle size reduction of metformin hydrochloride during crystallization from mother liquor.
Fig 2 is a front schematic view showing setup for use with a homogenizer pump in metformin hydrochloride wherein homogenizer pump is connected to bottom of the reactor for inlet of feed from bottom and outlet of homogenizer is connected at the top of the reactor used in metformin hydrochloride crystallization
Fig 3 is a perspective view of a particle size reduction setup consisting of crystallizer and homogenizer for the purpose of this invention.
Disclosure of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The phrase "in situ grinding" is used to indicate the grinding process during the crystallization of metformin hydrochloride.
The phrase "substantially free" as used herein is in the context that the final product, metformin hydrochloride is free from contamination of the impurity DMA HC1 that is present in the final product, not more than 500 ppm, preferably less than 200 ppm and most preferably less than 180 ppm.
The phrase 'particle size reduction set up' means and includes a reactor and homogenizer pump, and the connection of homogenizer to the reactor.
The phrase 'particle size reduction assembly' and 'grinding assembly' are used interchangeably throughout the text and person skilled in the art may be appreciated as such.
The phrase 'mother liquor/feeding liquor' are used interchangeably throughout the text.

In accordance with the above object, the present invention relates to a process for the preparation of pure metformin hydrochloride with high throughput with exceptionally low amount of impurity, DMA-HCI & to obtain uniform particle size distribution and particle size reduction during crystallization process using real-time INS1TU GRINDING TECHNOLOGY.
In an embodiment, the present invention provides a process for insitu particle size reduction of metformin hydrochloride during crystallization from mother liquor in which nucleation and growth of the nuclei are controlled and are crystallized out by concentration under vacuum and the crystals are separated from the mother liquor.
As discussed in the preceding paragraphs, DMA HCl is one of the starting materials used in the preparation of metformin hydrochloride. After the crystallization of metformin hydrochloride, the impurity, DMA-HCI content remains in the final product in an amount of approximately up to 1500 ppm, whereas, the required specification for DMA-HCI content in final product is less than 180 ppm. However, by using conventional methods, this DMA-HCI content in Metformin-HCI can be further reduced to 180 ppm by multiple re-processing and re-crystallization methods, but at the cost of time and overall yield. Multiple re-processing also involves wastage of energy, solvents (water and alcohols) thereby putting extra pressure on the ecology system. Therefore, the present invention aims to provide a novel technology that eliminates one or more problems associated with DMA-HCI impurity in the preparation of metformin hydrochloride. The inventors have observed that the impurity, DMA-HCI is weakly bound to final product, metformin hydrochloride.
Accordingly, in a preferred embodiment, the invention provides an INSITU-GRINDING technology during the crystallization process of metformin hydrochloride, which breaks the Metformin-HCI crystals into smaller particles thus freeing the bound impurity, DMA-HCI.
Further, in the prior art methods, the crystalline product has to be milled to achieve the desired specification having a particle size specification of 95% passing through 60 mesh. Also, while milling the product, the heat is generated, wear and tear of the product takes place and a lot of energy and utility gets wasted. The milling process also reduces the

bulk density of the product which is undesirable for formulations/dosage forms. The milled product is also electro statically charged during the process which leads to lumping while packing of the product.
Thus in a preferred embodiment, the process for the preparation of high throughput crystalline Metformin HCL having better compact ability, uniform particle size distribution and particle size reduction, with effective removal of impurity, DMA-HCI using Insitu grinding technology comprises the steps of;
a. Obtaining a solution of metformin HCI ( having DMA HC1 content of
1000-2000ppm) in water,
b. Distilling out water under vacuum and then carrying out Insitu
grinding/homogenization of the reaction mass during crystallization/slow cooling crystallization, both in the nucleation zone and in metastable zone, in presence of solvent at a temperature range of 65°C to 90°C for about 2 to 6 hrs, cooling to 35-45°C followed by addition of methanol to obtain a slurry,
c. Centrifuging the slurry obtained in step (b) in presence of a solvent for
about 3 hours, drying in FBD to obtain Metformin-HCI; and
d. Optionally milling, grinding etc as per formulation requirements.
In another preferred embodiment, there is provided a process for insitu particle size reduction of metformin hydrochloride during crystallization, said process comprises;
a) obtaining a solution of metformin HCI ( having DMA HCI content of 1000- 2000ppm) in water,
b) distilling out (till nucleation point) water under vacuum in crystalliser;
c) starting the homogenizer and re-circulating the slurry back to reactor;
d) continuing the re-circulation while remaining water is distilled under vacuum;
e) adding methanol to the reaction mass and striped off to remove water traces, with methanol;
f) releasing the vacuum followed by adding methanol and continue running the pump till filtration;

g) centrifuging the slurry followed by washing with methanol and
centrifuged; and
h) drying the wet cake in FBD.
In accordance with the present invention, the distilled concentrated liquor created by the distillation process has a certain degree of super saturation which, as such, should be sufficient to produce nucleation after a sufficient period of time. Passing of the concentrated liquor through homogenizer improves nucleation conditions and control the crystal growth. Moreover, recirculation time of the feeding liquor formed from the concentrated liquor through the homogenizer, allows nucleation to take place and growth control.
The strong shearing forces in the homogenizer, because of the geometrics of the tools with the numerous pressure-creating and pressure-releasing sequences, cause reduction of particle size in smallest volumes of the type which is also known from the effect of ultrasonic in other crystallization processes and thereby further super saturation. A large number of homogeneous, that is to say nuclei of uniform size as a basis of uniform-crystal-size, are formed.
By the process of the present invention, a special and time saving particle size control, objective of the crystallization steps are achieved. Specifically, there is an increase in degree of super saturation to form more of nucleation during the crystal growth phases, and in a preferred embodiment of the invention there is a reduction of crystal size in crystal-growth phases. The process of the present invention not only results in a considerable reduction in the particle size, but also in particular, effective nucleation occurs as a result of the high shear force created and therefore creation of super saturation in the homogenizer, in turn leads to a homogeneous grain size distribution for the metformin hydrochloride crystal. This uniform particle size distribution reduces the powder processing load (milling and pulverizing operation).
Running the homogenizer pump in between the evaporative crystallization and during the crystallization is an important set up in controlling metformin hydrochloride particle size.

Therefore, it is imperative that the running of homogenizer pump is carried according to particle size requirement during use. Furthermore, since a variety of particle size distribution can be achieved within a single size reduction machine to produce metformin having a wide range of particle sizes, it additionally becomes important to be able to consistently adjust running of homogenizer to control product particle size and/or particle size distribution of metformin hydrochloride.
The setup for use in insitu grinding according to the invention essentially comprises homogenizer pump, the inlet of which is connected to bottom of the reactor for receiving the feed from bottom and outlet of homogenizer is connected at the top of the reactor used in metformin hydrochloride crystallization.
The perspective view of a particle size reduction assembly (Fig 3) consisting of crystallizer and homogenizer for the purpose of this invention, comprises 4KL glassline reactor (Crystallizer)(1) having propeller Agitator (2) with maximum RPM % (Variable drive) flush bottom valve (3), with reflux cum distillation assembly (4). Crystallizer (1) is connected with 40NB SS316 line (5) and ball valve (6) to homogenizer.
Homogenizer pump (7) includes an impeller associated with an impeller drive shaft with a drive mechanism to rotate impeller shaft with maximum flow rate of 5000 liters/hr using 20 Hp.motor.
Homogenizer outlet (8) is connected to reactor using reflux line by 25NB SS316 pipe (9) to the reactor. In between ball valves (10) are provided to segregate vacuum distillation and reflux. This arrangement enables to circulate slurry under vacuum distillation and run system under vacuum.
15NB sample cum drain point (11) with ball valve is provided near the feed point (inlet) of the pump to draw sample as well as to drain the system. 1/4 inch cooling line connection (12) is provided to the homogenizer seal to remove heat.
Accordingly, in yet another preferred embodiment, the invention provides a method of running the grinding assembly which method comprises:

a) closing the reflux line valve followed by opening the outlet of the homogenizer pump to run the homogenizer first;
b) opening the bottom valve of the reactor followed by starting the cool water circulation to the seal of the homogenizer pump; and
c) opening the ball valve of feed line to the pump followed by starting the pump and circulating under vacuum.
In the present invention, the concentrated liquor is taken through bottom of the reactor and re-circulated back into the reactor under atmospheric/vacuum conditions through homogenizer pump. The insitu grinding process can be carried out between the nucleation stages of crystallization till the end of crystallization process. The recirculation time and homogenizer spacing i.e. clearance between casing and impeller for variation of shear force can be varied to achieve the desired particle size distribution.
Sampfe from the sampfe collection point at the inlet of the grinder pump is taken to ensure the particle size distribution is as required.
The steam temperature in the jacket is maintained such that the grinded particles are not re-dissolved at that concentration (determined by solubility curve). The flow of the pump is maintained to 2000 to 5000 liters/hr such that a narrow particle size distribution is achieved in the reactor.
The concentrated liquor generally has a temperature of about 50degree to 90degree C.
In the present invention, the feeding liquor at different concentrations is sent to a homogenizer where it is subjected to shearing. The feeding liquor preferably passes through the homogenizer for a period of 1 to 12 hrs.
In one embodiment of the present invention, feeding/mother liquor from the beginning of the concentration operation is sent to the homogenizer during entire concentration operation.
In an alternate embodiment of the present invention, mother liquor is concentrated to 90 % under vacuum till no further evaporation is observed, further traces of water is stripped

with methanol, the residue thus obtained is slurried in methanol, then started the homogenizer and re-circulate the slurry back to reactor for 4 hours; stopped the homogenizer; filtered and dried.
In still another embodiment of the present invention, distilled out mother liquor till nucleation point under vacuum and started the homogenizer (with lesser clearance between casing and rotor) and re-circulated the slurry back to reactor. Continue the r-circulation while remaining water is distilled. Further methanol was added to the mass and striped off to remove water traces, slurried in Methanol and continue running the pump, filtered and dried.
In the present invention, the crystals that are produced by passing the mother liquor through the homogenizer, particle size and distribution is controlled to desired level. The process of the present invention operates under vacuum as well as in atmospheric condition.
Still further, the invention provides metformin oral solid dosage form with enhanced tablet strength, wherein, metformin is provided with better compact ability which can be obtained by modified crystallization process, i.e. slow cooling crystallization method. The slow cooling crystallization process involves various factors like change in crystallization pattern; temperature profile during crystallization; change in concentration gradient in crystallization.
In another embodiment, the invention provides a process for metformin hydrochloride tablet with enhanced hardness and with better compact ability involving modified crystallization process, which comprises;
a. dissolving the crude Metformin HC1 in water at 75-90 °C & filtering the reaction
mass on charcoal followed by Highflow;
b. distilling out water under vacuum below 75 °C followed by cooling the mass from
74 °C to 50 °C in 3 hours; further from 74 °C to 50 °C in 3 hours; further
cooling the mass from 50 °C to 35 °C in 6 hours;
c. centrifuging the slurry containing metformin hydrochloride in methanol to obtain
wet cake; and drying the wet cake.

d. milling the dried cake to achieve 60 meshes passing as per formulation
requirements;
e. adding excipients (as per specifications) to the milled API (94 wt%) followed by
granulating to form 20 mesh passing granules and
f. compressing the granules to form tablets.
The crude metformin is obtained by reacting DCDA and DMA-HCI in Xylene at 110°C, followed by maintaining the reaction at 136-138 °C under reflux for 8 hours. Water is added to the mass; maintained the reaction at 90°C and separated the aqueous layer followed by distilling out maximum water under vacuum. The Reaction mass is cooled to 35 - 40 °C, added CH30H; filtered the wet cake and suck dried under vacuum to obtain crude product.
To assess the improvement in tablet properties, Hardness & Friability tests for the Tablet prepared have been taken as main study tests. A rugged formulation with following composition has been taken common for all the APIs developed in different batches:
Metformin Hydrochloride 93 %
Polyvinyl pyrrolidone K-90 6 %
Magnesium Stearate 1%
Wet Granulation Process with standard quantity of water as granulating fluid adopted for all Trials. The LOD & particle size distribution for all experiments were in tolerance limits. Hardness of the tablets was ascertained with Schleunger Hardness tester & Friability using Standard Tester as per USP.
Thus, the in situ grinding technology during crystallization itself in the present invention surprisingly leads to several other advantages such as desired particle size, particle strength, time, high process throughput and improvement in particle size distribution. The metformin hydrochloride prepared by conventional methods transforms into a 'solid rocky block' during the transport and storage, On the contrary, the pure metformin hydrochloride obtained using insitu grinding technology completely eliminates powder processing and hence the bulk density of the product is also high and no lumping is observed in the packed product. Moreover, particles obtained by the current process

remains free flowing during its transport and storage and hence user friendly up to the end user.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
EXAMPLES:
Example 1: Conventional process for preparation of Metformin:
A - Reaction Step: Charged 1500 liters of Xylene into Reactor-1 followed by the
addition of 700 Kg of DCDA and 800 Kg of DMA-HC1. The reaction mass is heated by
steam and an exotherm (temperature increase) is observed at 110 °C. Reaction
temperature is maintained at 136-138 °C with Xylene under reflux for 8 hours followed
by addition of 1500 liters of water. Maintained the reaction at 90°C and separated the
aqueous layer and transferred into Reactor-2. Filtered the reaction mass on Charcoal (2
Kg) followed by Highflow into Reactor-3 in 2 hours.
B - Crystallization Step: In Reactor-3, distilled out 1200 liters of water at 600 mm Hg
vacuum for 4 hours; added 300 liters of CH30H and striped off remaining water and
methanol. Distilled out 200 liters of water at 600 mm Hg vacuum for 2 hours; released
vacuum; and added 500 liters of CH30H to prepare slurry.
C -Centrifuging Step: Centrifuged the slurry in 5 lots for 2 hrs each; washed each lot in
centrifuge with 50 liters of CH30H and centrifuged for 3 hrs.
D - Drying: Unloaded the wet cake from centrifuge and dried in FBD for 6 hrs to obtain
crystalline material.
E- Milling and Pulverization; Milled or pulverized the crystalline material as per
requirement for particle size.
Results:
DCDA (DicyanoDiamide): less than 200 ppm
Single highest Impurity: less than 500 ppm
DMA-HC1: 1500 ppm
Particle size: 5% passing through 60 mesh

Sieving: required before milling/pulverization
Milling/Pulverization: required
Lumping: observed after milling/ pulverization on storage
Example-2
A - Reaction Step: same as provided in Example 1.
B - Crystallization Step: Started vacuum in Reactor-3 and distilled out 300 liters of
water at 650 mm Hg vacuum & at 50-90 Deg C temperature for 4 hours to reach
nucleation stage of Metformin-HCI. Then the vacuum was removed & started the in situ
Grinding pump/ Homogenizer for 2-3 Hrs (Nucleation stage), stopped the circulation and
again applied vacuum & distilled out the total of 1000-1100 Lit of water. Again vacuum
was removed and started circulation by Insitu grinding pump / Homogenizer for 2-3 Hrs
(Metastable stage), stopped the pump & removed the remaining water by applying
vacuum at 60-90 Deg C Added 300 liters of CH30H and stripped off remaining water
and methanol and released the vacuum and added 500 liters of CH30H to prepare slurry;
and cooled to 25-45 Deg C.
C -Centrifuging Step: Centrifuged the slurry in 5 lots for I hrs each; washed each lot in
centrifuge with 20% solution of 40 liters CH30H and 10 liters H20 centrifuged for I hr;
washed each lot in centrifuge with 50 liters CH30H and centrifuged for 3 hrs.
D - Drying: Unloaded the wet cake from centrifuge and dried in FBD for 6 hrs.
E - Milling and Pulverization: Not required.
Results:
DCDA: less than 200 ppm;
Single highest Impurity: less than 500 ppm;
DMA-HC1: 160 ppm;
Particle size: 95% passing through 60 mesh;
Sieving: required before packing;
Milling/Pulverization: Not required;
Lumping: Not observed during storage.
Example-3
A-Reaction Step: same as provided in Example 1

B - Crystallization Step: Started vacuum in Reactor-3: distilled 300 liters of water at
650 mm Hg vacuum & at 50-90 Deg C temperature for 4 hours to reach nucleation stage
of Metformin-HCl. Removed the vacuum & started the Insitu Grinding pump /
Homogenizer for 2-3 Hrs ( Nucleation stage), stopped the circulation and again applied
vacuum & distilled out the total 1000-1100 Lt of water. Again vacuum was removed and
started circulation by Insitu grinding pump / Homogenizer for 2-3 Hrs (Metastable stage),
stopped the pump & removed the remaining water by applying vacuum at 50-90 Deg C.
Added 300 liters of CH30H and stripped off remaining water and methanol; released the
vacuum and added 500 liters of CH30H to prepare slurry; and cooled to 25-45 Deg C.
C -Centrifuging Step: Centrifuged the slurry in 5 lots for 1 hrs each; washed each lot in
centrifuge with 30% solution of 35 liters CH30H and 15 liters of H20 and centrifuged
for 1 hrs; washed each lot in centrifuge with 50 liters CH30H and centrifuged for 3 hrs.
D - Drying: Unloaded the wet cake from centrifuge and dried in FBD for 6 hrs.
E - Milling and Pulverization: Not required.
Results:
DCDA: less than 200 ppm;
Single highest Impurity: less than 500 ppm;
DMA-HC1: 150 ppm;
Particle size: 95% passing through 60 mesh;
Sieving: required before packing;
Milling/Pulverization: Not required
Lumping: Not observed on storage.
Example-4
A-Reaction Step: same as provided in Example 1
B - Crystallization Step: Started vacuum in Reactor-3; distilled out 300 liters of water at
600 mm Hg vacuum & at 60-90 Deg C temperature for 4 hours to reach nucleation stage
of Metformin-HCI. The vacuum was removed & started the Insitu Grinding pump /
Homogenizer for 2-3 hrs (Nucleation stage), stopped the circulation and again applied
vacuum & distilled out the total 1000-1100 Lt of water. Again vacuum was removed and
started circulation by Insitu grinding pump / Homogenizer for 2-3 Hrs (Metastable stage),
stopped the pump & removed the remaining water by applying vacuum at 60-90 Deg C

Added 300 liters of CH30H and stripped off remaining water and methanol. Released the
vacuum and added 500 liters of CH30H to prepare slurry; and cooled to 25-45 Deg C.
C -Centrifuging Step: Centrifuged the slurry in 5 lots for 1 hrs each; washed each lot in
centrifuge with 50% solution of 50 liters CH30H & 50 liters H20, centrifuged for 1 hr;
washed each lot in centrifuge with 50 liters CH30H and centrifuged for 3 hrs.
D - Drying; Unloaded the wet cake from centrifuge and dried in FBD for 6 hrs.
E - Milling and Pulverization: Not required.
Results:
DCDA: less than 200 ppm;
Single highest Impurity: less than 500 ppm;
DMA-HC1: 100 ppm;
Particle size: 95% passing through 60 mesh;
Sieving: required before packing;
Milling/Pulverization: Not required;
Lumping: Not observed during the storage.
Example-5
A-Reaction Step: same as Example 1
B - Crystallization Step: Started vacuum in Reactor-3; Distill 300 liters of water at 600
mm Hg vacuum & 60-90 Deg C Temperature for 4 hours to reach nucleation stage of
Metformin-HCI. Vacuum was released & started the Insitu Grinding pump /
Homogenizer for 2-3 Hrs ( Nucleation stage), stopped the circulation and again applied
the vacuum & distilled out the total 1000-1100 Lt of water. Again vacuum was released
and started circulation by Insitu grinding pump / Homogenizer for 2-3 Hrs (Metastable
stage), stopped the pump & removed the remaining water by applying vacuum at 60-90
Deg C Added 300 liters of CH30H and stripped off remaining water and methanol;
released vacuum and added 500 liters of CH30H to prepare slurry; and cooled to 25-45
deg C.
C -Centrifuging Step: Centrifuged the slurry in 5 lots for I hrs each; washed each lot in
centrifuge with 100% solution of 50 liters H20, centrifuge for 1 hr and washed each lot in
centrifuge with 50 liters CH30H and centrifuge for 3 hrs.
D - Drying: Unloaded the wet cake from centrifuge and dried in FBD for 6 hrs.
E - Milling and Pulverization: Not required.

Results:
DCDA: less than 200 ppm
Single highest Impurity: less than 500 ppm
DMA-HC1: 90 ppm
Particle size: 95% passing through 60 mesh
Sieving: required before packing
Milling/Pulverization: Not required
Lumping: Not observed during the storage.
Example-6
A-Reaction Step: same as Example 1
B - Crystallization Step: Started the Aqueous layers circulation through slurry pump and started vacuum in Reactor-3; distilled 300 liters of water at 600 mm Hg vacuum for 4 hours to reach nucleation stage of metformin-HCl. Added 300 liters of CH30H and stripped off remaining water and methanol. Distilled out 220 liters of water at 600 mm Hg vacuum for 2 hours; released vacuum and added 500 liters of CH30H to prepare slurry. The recirculation was continued for I hr and stopped slurry pump and clear the recirculation line.
C -Centrifuging Step: Centrifuged the slurry in 5 lots for 1 hr each; washed each lot in centrifuge with 50 Lt of 20%-100 % water in CH30H, centrifuged for 1 hrs; washed each lot in centrifuge with 50 liters of CH30H and centrifuged for 3 hrs. D - Drying: Unloaded the wet cake from centrifuge and dried in FBD for 6 hrs to achieve fine particles.
E - Milling and Pulverization: Not required. Results:
DCDA: less than 200 ppm; Single highest Impurity: less than 500 ppm; DMA-HCI:70ppm;
Particle size: 95% passing through 60 mesh; Sieving: required before packing; Milling/Pulverization: Not required; Lumping: Not observed.

Example-7
A - Reaction Step: same as Example 1.
B - Crystallization Step: Started the Aqueous layers circulation through insitu grinding
slurry pump and started vacuum in Reactor-3; distilled off water as much as possible by
vacuum at temperature 60-90 Deg C. Released vacuum and continued the insitu grinding
slurry pump and added 500 liters of CH30H to prepare slurry. The recirculation was
further continued for 1 hr and stopped slurry pump and clear the recirculation line.
C -Centrifuging Step: Centrifuged the slurry in 5 lots for lhr each; washed each lot in
centrifuge with 50 Lt of CH30H.
D - Drying: Unloaded the wet cake from centrifuge and fried in FBD for 6 hrs to achieve
fine particles.
E - Milling and Pulverization: Not required.
Results:
DCDA: less than 200 ppm;
Single highest Impurity: less than 500 ppm;
DMA-HC1: 90 ppm;
Particle size: 95% passing through 60 mesh;
Sieving: required before packing;
Milling/Pulverization: Not required;
Lumping: Not observed.
Example 8:
Modified Crystallization to achieve higher strength of Metformin tablets:
A - Reaction Step: Charged 1500 liters of Xylene into Reactor-1 followed by the
addition of 700 Kg of DCDA and 775 Kg of DMA-HCI- The reaction mass is heated by
steam and an exotherm (temperature increase) is observed at 110 C. Reaction
temperature is maintained at 136-138°C with Xylene under reflux for 8 hours followed by
addition of 1500 liters of water. Maintained the reaction at 90°C and separated the
aqueous layer and transferred into Reactor-2.
B - Crude Crystallization Step: In Reactor-2, distilled out maximum water under
vacuum. Cool the Reaction mass to 35 - 40 °C. Added 500 liters of CH30H to the
reaction mass.

C - Filtration Step: Filtered the crude Metformin-HCl and suck-dried the wet cake
under vacuum.
D - Dissolution and Charcoalization: Dissolved the crude Metformin HC1 of step-C in
Reactor-3 with 1200 liters of water at 75-90 °C. Filtered the reaction mass on Charcoal (2
Kg) followed by Highflow into Reactor-4.
E - Pure Crystallization Step: In Reactor-4, distilled out 400-450 liters of water under
vacuum below 75 °C. Cool the Reaction mass from 74 °C to 50 °C in 3 hours. Again cool
the reaction mass from 50 °C to 35 °C in 6 hours. Added 500 liters of CH30H to the
reaction mass.
F - Centrifuging & Drying Step: Centrifuged the slurry; washed with methanol and
centrifuged. Wet cake dried in FBD.
G - Milling and Pulverization: Crystalline material to be milled to achieve 60 meshes
passing as per formulation requirements.
H-Granulation and Compaction: Excipients and binder are added (as per
specifications) to the milled API (94 wt%) and granulated to form 20 mesh passing
granules. These granules are then compacted to form tablets.
Results:
Tablet hardness: 20-21 Kpa Friability: 100rpm:0.2% 200 rpm : 0.3 %
Example-9:
Particle size characterization to achieve higher strength of Metformin tablets
A - Reaction Step: same as in Example 8.
B - Crude Crystallization Step: same as in Example 8.
C - Filtration Step: same as in Example 8.
D - Dissolution and Charcoalization: same as in Example 8.
E - Pure Crystallization Step: In Reactor-4, distilled out 400-450 liters of water under
vacuum below 75 °C. Cool the Reaction mass from 74 °C to 50 °C in 3 hours. Again cool
the reaction mass from 50°C to 35°C in 6 hours. Added 500 liters of CH30H to the
reaction mass.
F - Centrifuging & Drying Step: same as in Example 8.

G - Milling and Pulverization: same as in Example 8. Sieve the milled material through
200 Mesh and 200 mesh oversize taken for tableting.
H - Granulation and Compaction: same as in Example 8.
Results:
Tablet hardness: 25-26 Kpa Friability: 100 Revolutions : 0.18 % 200 Revolutions: 0.23 %
ADVANTAGES OF THE METHODOLOGY:
The in situ grinding of the reaction mass during crystallization has the following advantages:
a) The reaction mixture is taken through bottom and re-circulated back into the reactor under atmospheric conditions.
b) Sample from the sample collection point at the inlet of the grinder pump is taken to ensure the particle size distribution as required.
c) The steam temperature in the jacket is maintained such that the grinded particles are not re-dissolved at that concentration (determined by solubility curve).
d) The flow of the pump is maintained such that a narrow particle size distribution is achieved in the reactor.
Industrial applicability:
The present inventive process involving INSITU GRINDING TECHNOLOGY leads to
improved particle size, particle strength, time and utility saving, improvement in particle
size distribution of the final product, metformin hydrochloride.
Product particle size ex-crystallizer without powder processing; 90% passing through 60
MESH with Insitu grinding whereas only 5% passing through 60 MESH by conventional
method.
• Utility saving: no powder processing required.
• Particle strength: high temperatures and shear & tear of product are avoided
during powder processing thus improving the particle strength.

* Improved particle size distribution: due to uniform grinding of the reaction
mixture narrow particle size distribution is attained.
• No lumping observed during long storage: as powder processing is avoided
which changes the intermolecular bonding.
The present invention is susceptible to various modifications, changes and adaptations, and the same are intended to be comprehended within the meaning and range of equivalents of the appended claims.

We claim,
1. A process for the preparation of high throughput crystalline metformin hydrochloride having better compact ability, uniform particle size distribution and particle size reduction, with effective removal of impurity, DMA-HC1 using realtime INSITU GRINDING TECHNOLOGY during crystallization process from mother liquor.
2. The process for the preparation of high throughput crystalline Metformin HCL using Insitu grinding technology according to claim 1, comprising the steps of;
a. Obtaining a solution of metformin HC1 ( having DMA HC1 content of
1000-2000ppm) in water,
b. Distilling out water under vacuum and then carrying out Insitu
grinding/homogenization of the reaction mass during crystallization/slow
cooling crystallization, both in the nucleation zone and in metastable zone,
in presence of solvent at a temperature range of 65 C to 90°C for about 2
to 6 hrs, cooling to 35-45°C followed by addition of methanol to obtain a
slurry,
c. Centrifuging the slurry obtained in step (b) in presence of a solvent for
about 3 hours, drying in FBD to obtain Metformin-HCl; and
d. Optionally milling, grinding etc as per formulation requirements.
3. The process of insitu grinding according to claims 1 and 2, wherein the isolated metformin HCI contains DMA-HCI less than I80ppm.
4. The process of insitu grinding according to claims 1 and 2, wherein crystalline metformin hydrochloride obtained is having a particle size of 95% passing through 60 mesh.
5. The process for the preparation of crystalline Metformin HCL using Insitu grinding technique having uniform particle size distribution and particle size reduction according to claims 1 and 2, comprising the steps of;

a. obtaining a solution of metformin HC1( having DMA HCI content of 1000-
2000ppm) in water,
b. distilling out of water (till nucleation point) under vacuum in crystallizer;
c. starting the homogenizer and re-circulating the slurry back to reactor;
d. continuing the re-circulation while remaining water is distilled under
vacuum;
e. adding methanol to the reaction mass and striped off to remove water
traces with methanol;
f. releasing the vacuum followed by adding methanol and continue running
the pump till filtration;
g. centrifuging the slurry followed by washing with methanol and
centrifuged; and
h. drying the wet cake in FBD.
6. The process of insitu grinding according to claim 5, wherein crystalline metformin hydrochloride obtained is having a particle size of 95% passing through 60 mesh.
7. The process for metformin hydrochloride tablet with enhanced hardness and with better compact ability according to claim I and 2, comprises;

a) dissolving the crude Metformin HCI in water at 75-90 °C & filtering the reaction mass on charcoal followed by Highflow;
b) distilling out water under vacuum below 75 °C followed by cooling the mass from 74 °C to 50 °C in 3 hours; further cooling the mass from 50 °C to 35 °C in 6 hours; and
c) centrifuging the slurry containing metformin hydrochloride in methanol to obtain wet cake; and drying the wet cake.
d) milling the dried cake to achieve 60 meshes passing as per formulation requirements;
e) adding excipients (as per specifications) to the milled API (94 wt%) followed by granulating to form 20 mesh passing granules and
f) compressing the granules to form tablets.

8. The process for preparation of metformin hydrochloride tablet according to claim
7, wherein the tablet hardness is in the range of 20-26kpa.
9. The process for preparation of metformin hydrochloride tablet according to claim
8, wherein the metformin hydrochloride obtained is having a particle size passing
through 20 meshes.