FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION "ISOLATION OF CROSS-LINKED POLYMER SALTS"
Emcure Pharmaceuticals Limited.
an Indian Company, registered under the Indian Company's Act 1957
and having its Registered Office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to an improved process for isolation and drying of cross-linked polymers and its pharmaceutically acceptable salts. Specifically, the invention relates to a process for isolation and drying of cross-linked polymers and its salts by utilizing a nutsche filter having an agitator and a dryer.
BACKGROUND OF THE INVENTION
Cross-linked polymers are alkylated amine polymers with one or more hydrophobic substitutents and optionally, one or more quaternary ammonium containing substituents, these cross-linked polymers are employed in medicine for lowering the phosphate and lipid level and also for helping in controlling blood sugar in people with type 2 diabetes. The level of cross-linking in these polymers makes it completely insoluble and thus limits the activity of the alkylated reaction product to the gastrointestinal tract only. Thus, the compositions of cross-linked alkylated allyl amine polymers are non-systemic in their activity and lead to reduced side-effects in the patient.
The pharmaceutically acceptable cross-linked polymers are sevelamer hydrochloride, sevelamer carbonate, colesevelam hydrochloride etc. Sevelamer, marketed as its hydrochloride or carbonate salt and first disclosed in SU 417441 (assigned to Tashkent Polytechnic Institute, U.S.S.R) is a phosphate binding drug used to prevent hyperphosphatemia in patients with chronic renal failure while Colesevelam hydrochloride is a non-absorbing, polymeric, lipid-lowering and glucose-lowering agent intended for oral administration.
Sevelamer is prepared by reacting allylamine with concentrated hydrochloric acid to form allylamine hydrochloride followed by removal of water under vacuum, adding an aqueous solution of catalyst azobis (amidonopropane) dihydrochloride and stirring the reaction mixture at a temperature between 50°C and 55°C for about 60 hours, after the addition of catalyst. Water is added to the reaction mixture and the pH adjusted to 10.0-11.0 with an aqueous solution of an inorganic base followed by addition of

epichlorohydrin to the reaction mixture and stirring at room temperature for 15 to 20 hours. The product is isolated by quenching the reaction mass with an organic solvent to separate Sevelamer hydrochloride. Optionally Sevelamer hydrochloride is converted to carbonate salts by the process disclosed in the art.
Colesevelam hydrochloride is prepared according to the general method disclosed in Polymer Preprints 2000, 41(1), 753, by alkylation of sevelamer hydrochloride with 6-bormohexyl trimethyl ammonium bromide and 1-bromodecane in methanol as solvent. The mixture is then refluxed to get the desired product, which is then filtered and washed with solvents to obtain a gel which is bound to 90% of water. Sevelamer hydrochloride, in turn is prepared by a cross-linking reaction between polyallyl amine hydrochloride and epichlorohydrin.
A common problem that is encountered during the preparation of these cross-linked polymers like sevelamer and colesevelam is that the filtration of the gels in prior art methods is quite slow and these gels have a tendency to degrade in colour or assay due to prolonged exposure to atmosphere during filtering. Further, the removal of these gels from the filtration bed for tray drying is quite tedious due to the cohesive nature of these gels.
According to the prior art, the drying of the moist gel which has approximately 90% of water bound is carried out, for example, by contact drying. Further, the immense reduction in the volume of the polymer gel during drying has an adverse effect on the product/heating surface heat transfer, as the entire heating surface is no longer available for the energy transfer. Additionally, longer residence time in the dryer has an adverse effect on the product quality and the unloading of the semi-dried gel for drying in a vacuum oven is quite tedious and cumbersome due to the cohesive nature of the gel.
Further, the disadvantage associated with contact drying is that, incrustation of the product surface occurs as a result of which the product quality is adversely affected due to the higher temperature. In addition, the heat transfer worsens with increasing

incrustation, as a result of which the drying efficiency falls. Further, the circulating air ovens (drying chambers) as disclosed in US 5,693,675 are only suitable for laboratory scale and not suitable for use on an industrial scale.
Further, rotary dryers may also be employed for drying, however, the drying process due to localized contact during drying and small batch size is suitable only for laboratory scale.
US 7,057,010 dispose the utilization of Fluidized Bed Dryer (FBD) for drying polymer gel under normal or over pressure. However, we have found that the main disadvantages of fluid bed dryer lies in difficulty in fluidizing certain wet feeds i.e. moist polymer gel, saturation of the exhaust gas near the inlet and the potential overheating of dry solids near the outlet; which has adverse effect on the product quality. If the material, during the course of drying, goes through a molten or liquid state, extreme cars should be exercised in the selection of fluid bed dryer (FBD).
However, the fluidized bed dryer (FBD) does not take care of the difficulties arising in the removal of solvents during centrifuging as there is a tendency for the removal of solvents to become sluggish during centrifuging after initial feeding.
Therefore, it was imperative for the synthetic chemist to overcome such drawbacks/disadvantages, which could hamper the physical characteristic and assay of the product due to possible formation of impurities during prolonged filtration/centrifuging followed by drying.
Hence, to overcome the prior art drawbacks, the present inventors developed an improved process for the isolation of cross-linked polymers and its pharmaceutically acceptable salts.

The present inventors found that Agitated Nutsche Filter cum Dryer (ANFD) or a Spin Flash Dryer (SFD) was able to solve the prior art disadvantages to provide the final product conforming to regulatory specifications.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide an industrially viable method for isolation of cross-linked polymers having therapeutic value wherein the steps of filtration and drying are carried out in a single step to obtain a product which conforms to regulatory specifications.
Another object of the invention is to avoid a fluidized bed dryer for drying a cross-linked polymer.
SUMMARY OF THE INVENTION
An aspect of the present invention relates to a process for isolation of polymers containing N or amino, ammonium or spirobicyclic ammonium groups, comprising cationic N-containing groups and suitable counter-ions, which comprises passing a slurry containing the polymer in a closed vessel equipped with a sintered bottom and a stirrer, which can be raised or lowered about its axis, removing the mother liquor under pressure and/or vacuum; slurry washing the gel with solvents and drying the semi-dry cake in the same vessel, at the desired temperature in an inert atmosphere.
Another aspect of the present invention relates to a process for isolation of colesevelam hydrochloride, sevelamer hydrochloride or sevelamer carbonate which comprises filtration of a slurry containing the polymer through a closed vessel equipped with a sintered bottom and a stirrer, which can be raised or lowered about its axis, removing the mother liquor under pressure and/or vacuum; slurry washing the gel with solvents and drying the semi-dry cake in the same vessel, at the desired temperature in an inert atmosphere.

Yet another aspect of the invention relates to a process for isolation of polymers containing N or amino, ammonium or spirobicyclic ammonium groups, comprising cationic N-containing groups, and suitable counter-ions, which comprises addition of the semi-dry cake containing the polymer into spin flash dryer system equipped with hot air and mechanical dispersion and obtaining the dry product conforming to regulatory specifications through a orifice.
DRAWINGS
Figure-1: Agitated nutsche filter and dryer (ANFD),
Figure 2: Schematic diagram of Agitated nutsche filter and dryer (ANFD) and
Figure-3: Spin flash dryer (SFD).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the isolation of polymers containing N or amino, ammonium or spirobicyclic ammonium groups, comprising cationic N-containing groups and suitable counter-ions, by employing nutsche filter dryer and a spin flash dryer.
The present inventors have found that cross-linked polymers such as colesevelam hydrochloride, sevelamer hydrochloride, sevelamer carbonate etc., which are quite cohesive in nature, need to be isolated and dried with care for avoiding possible degradation of the product during filtration and drying.
The present inventors found that their objective could be achieved by employing filtering and drying vessels like Agitated nutsche filter and dryer (ANFD) or a Spin flash dryer (SFD).
The agitated nutsche filter is a closed vessel designed to separate solid and liquid by filtration under pressure or vacuum or combination of both. An agitated nutsche filter consists of a cylindrical shell with a welded dished end at the top and a flat welded end at the bottom. The vessel is divided into two compartments by means of a perforated

plate, provided with suitable filter cloth. The base plate has an arrangement of bolting bar to hold the filter cloth. Suitable support mesh is provided under filter cloth to facilitate the flow of filtrate. It is further provided with an "S" curve inside the vessel to perform the movements of vertical and rotational directions simultaneously and to take the high torque generated during solid discharge and re-slurring operation.
Slurry is fed into the top compartment from where filtrate passes into the lower chamber en route to the receiver. Solids are deposited on the filtering media in the top compartment and take the shape of cake with uniform thickness. The agitator pushes the solid content in the slurry upwards by keeping it under suspension till maximum possible filtrate passes through the filter bed. It then seals the cracks in the cake, which develops after most of the filtrate has passed through, by smoothening the top surface of the cake.
Agitated nutsche filter and dryer also squeezes out some of the moisture in the cake by slightly pressing the cake uniformly with the help of blades. After the separation of solvent/mother liquor and if the cake requires washing, then wet cake can be re-slurried and washed thoroughly with water or solvent at desired temperature and under agitation so that all the particles forming the cake can be treated with fresh solvent and be thoroughly washed through the specially designed agitator. This improves quality of the finished products. After washing and removal of wash liquor, the cake can be discharged through a quick opening side discharge door, by rotating and lowering agitator in the discharge direction.
Further, the closed system during filtration and slurring ensures odorless contamination and non-polluting working condition thereby maintaining the product quality and purity.
The discharge of the wet cake although automatic is optional. The wet cake however can also be dried in the same system at the desired temperature and at reduced pressure, without resorting to the tedious task of unloading the cohesive product.

Optionally, spin flash dryer is used to dry the filtered material at different temperatures. The spin flash dryer consist of double shaft screw followed by mono screw to feed homogenous material. The cakes from the filter press are manually conveyed to the dryer. Hot air is supplied by a temperature controlled heater and as speed controlled fan, entering the dryer at a tangent in order to establish a turbulent, whirling air flow. Drying takes place in a matter of seconds.
In an embodiment, the present invention for preparation of the cross linked polymer and its salts comprises the steps of treating either polyallylamine or Sevelamer with a cross-linking or an alkylating agent respectively in presence of organic solvent and water. The polymeric gel thus obtained is filtered through a nutsche filter and suck dried. The wet cake is washed, filtered and dried under reduced pressure at temperature between 40°C to 80°C for 15 to 50 hours.
The filtration of polymeric gel preferably carried out at a temperature between 25°C to 35°C, and preferably under vacuum.
Wet cake from the nutsche was washed with sodium chloride solution followed by water and then with an organic solvent under agitation at a desired temperature. The preferable temperature for washing ranges from 25°C to 55°C.
The organic solvent was selected from the group comprising of alcohols, esters, ketones, halogenated hydrocarbons etc. The alcohol was preferably methanol, ethanol, propyl alcohol, the ester was ethyl acetate and the ketone was acetone, methyl isobutyl ketone and methyl ethyl ketone while the halogenated hydrocarbon was selected from methylene dichloride and ethylene dichloride.
A preferred embodiment of the present invention relates to colesevelam and its salts, which comprises the steps of alkylation of sevelamer salt with an alkylating agent in presence of methanol and water as solvents. The polymeric gel obtained after alkylation was filtered through nutsche filter and the wet cake slurry washed with an organic

solvent in the agitated nutsche filter, filtered and dried in the same system with partial agitation under reduced pressure at temperature between 40°C to 80°C for 15 to 50 hours.
The filtration of polymeric gel was preferably carried out at a temperature between 25°C to 35°C and preferably under vacuum.
Wet cake from the nutsche was washed with sodium chloride solution water and with organic solvent respectively at desired temperature. The preferably temperature for washing is in the range of 25°C to 55°C. The organic solvent was selected form alcohols like methanol, ethanol isopropyl alcohol.
Another embodiment of the present invention wherein sevelamer hydrochloride or sevelamer carbonates were prepared by the steps comprising reaction of polyallylamine and epichlorohydrin in a mixture of acetonitrile and water at ambient temperature; sevelamer hydrochloride polymer gel thus obtained was filtered through nutsche filter and the wet cake was slurry washed with water followed by organic solvent with stirring, filtered and dried with mild agitation under reduced pressure at 25-80°C.
The wet cake from the nutsche was washed with isopropyl alcohol or mixture of water and isopropyl alcohol to eliminate the impurity (like monomers, oligomers, inorganic salts etc) associated with sevelamer salts under the agitation or stirring at desired temperature
An important feature of the agitation nutsche filtration process involves efficient slurry washing of the entire cake with agitation at the desired temperature, without unloading the cake to a reactor.
Another feature relates to drying of the wet cake on the nutsche filter at temperature 25°C to 80°C and under reduced pressure. Since the drying is carried out under stirring, therefore, the time required for drying is reduced and it is quite effective and facile.

In yet another embodiment of the invention wherein wet cake is dried in spin flash dryer. The temperature for drying is in the range of 50°C to 80°C.
The main advantage of utilizing the agitated nutsche filter cum dryer for isolating cross-linked polymers and its pharmaceutically acceptable salts, is that the dried product is obtained directly from nutsche filter as filtration and drying are carried out in one system and in a single operation. This is in stark comparison to the conventional process which requires multiple equipments such as reaction vessel, centrifuge/vacuum filter and a dryer.
The present invention has the following advantages over prior art methods:
* Efficient filtration and washing due to stirring and axial up / down movement of stirrer,
* Washings can be done thoroughly and economically with rriinimal solvent/ water,
* Efficient drying due to better heat transfer as a result of simultaneous stirring,
* Operation time and cost are minimized and
* The closed system ensures no contamination and provides a non-polluting working environment.
The principles, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
The present invention is described herein below with reference to examples, which are illustrative only and should not be construed to limit the scope of the present invention in any manner.

EXAMPLES:
EXAMPLE 1
Preparation of colesevelam hydrochloride (I)
Sevelamer hydrochloride (25 kg), 1-bromodecane (27.5 kg) and 6-(bromohexyl) trimethylammonium bromide (37.5 kg) was suspended in methanol (1000 liter) with stirring and the mixture refluxed for 30 minutes. Sodium hydroxide solution (12.5 kg / 12.5 liter water) was added to the reaction mixture and stirred for 18 hours at same temperature. The reaction mixture was cooled to 25°C to 30°C and the pH was adjusted to 6.5 to 7.5 with hydrochloric acid (6N). The reaction mass was filtered through an agitated nutsche filter and washed with saturated sodium chloride solution (1250 liter) and with water (1250 liter), and isopropyl alcohol (500 liter) at 25°C to 30°C. After all the solvent was sucked properly, the material was dried in the agitated nutsche filter and dryer (ANFD) under stirring at 60°C to 70°C for 10 to 12 hours. Bile binding capacity: 0.52 g/g. Yield: 55 kg.
EXAMPLE 2
Preparation of colesevelam hydrochloride (I)
Sevelamer hydrochloride (5 kg), 1-bromodecane (5.5 kg) and 6-(bromohexyl) trimethylammonium bromide (7.5 kg) were suspended in methanol (200 liter) with stirring and the mixture was heated to reflux for 30 minutes. Sodium hydroxide solution (2.5 kg / 2.5 liter water) was added to the reaction mixture and stirred for 18 hours at reflux temperature. The reaction mixture was cooled to 25°C to 30°C and the pH was adjusted between pH 6.5 and 7.5 with hydrochloric acid (6 N). The reaction mass was filtered through agitated nutsche filter and washed with saturated sodium chloride solution (250 liter) and water (250 liter) and isopropyl alcohol (100 liter) at 25°C to 30°C. The material was dried in the spin flash dryer (SFD). Bile binding capacity: 0.57 g/g; Yield: 10 kg.

EXAMPLE 3
Preparation of sevelamer hydrochloride (II)
Polyallyl amine hydrochloride (100 kg; 50% aqueous) and water (135 liters) solution were added to a vessel and neutralized with sodium hydroxide (50% aqueous) solution to pH about 10.4. The solution obtained was stirred for 60 minutes and further diluted with acetonitrile (318 liters) and stirred for 30 minutes. Epichlorohydrin (3.51 kg) was added to the reaction mixture and stirring for 21 hours at 25-30°C. After gelling and curing time of 21 hrs, the gel was filtered through agitated nutsche filter and suck dried under vacuum. The wet gel was washed successively with water (1600 liters) to remove all impurities. The resulting gel was then washed with mixture of water and isopropyl alcohol. The wet gel was dried under vacuum at about 50-70°C. Yield: 34 kg
EXAMPLE 4
Preparation of sevelamer carbonate (III)
Polyallyl amine hydrochloride (100 kg; 50% aqueous) and water (135 liters) solution were added to a vessel and neutralized with sodium hydroxide (50% aqueous) solution to a pH of about 10.4. Acetonitrile (318 liters) was added to the solution and stirred for 90 minutes. Epichlorohydrin (3.51 kg) was added to the reaction mixture and stirring for 21 hours at 25-30°C. After gelling and curing time of 21 hrs, the gel was filtered through agitated nutsche filter and suck dried under vacuum. The wet gel was slurry washed successively with water (1600 liters).
The wet gel of sevelamer hydrochloride was charged in reactor with water (1650 liters) and neutralized with sodium hydroxide (50% aqueous) solution to a pH between 12 and 13. The gel was transferred to agitated nutsche filter for filtration and suck dried under vacuum. The wet gel was washed with water (1850 liters) to remove free chloride. Wet sevelamer free base was charged to the reactor along with water (1480 liters). Carbon dioxide gas was purged to the reaction mass to obtain pH between 8.7 and 9.3. The gel was collected by filtration and suck dried under vacuum, the resulting wet gel was

washed with water (1480 liters). The resulting gel was then washed with isopropyl alcohol and dried in the agitated nutsche filter under vacuum at about 50-70°C. Yield: 33 Kg.

We Claim,
1. A process for isolation of cross-linked polymers and its pharmaceutically acceptable salts comprising addition of slurry containing the polymer to a vessel, filtering, washing and drying the cross-linked polymer with agitation at the desired temperature and reduced pressure.
2. The method as claimed in claim 1, wherein the said vessel is an agitated nutsche filter cum dryer (ANFD).
3. The method as claimed in claim 1, wherein the said vessel is a spin flash dryer (SFD).
4. The method as claimed in claim 1, wherein filtration is carried out at atmospheric pressure or under reduced pressure.
5. The method as claimed in claim 1 and 2, wherein washing includes slurry washing of the cake with a solvent and with agitation at a temperature between 25°C and 95°C.
6. The method as claimed in claim 5, wherein solid cake is washed with a solvent selected from organic solvent and / or water; wherein organic solvent is selected from alcohols, esters, ketones and halogenated hydrocarbons.
7. The method as claimed in claim 1, 2 and 3, wherein said filtering and drying are under air or nitrogen gas.
8. The method as claimed in claim 1 and 2, wherein the slurry is either the reaction mixture or a cross-linked polymer suspended in a solvent or water.

9. The method as claimed in claim 1, wherein the cross-linked polymer is colesevelam, sevelamer and its pharmaceutically acceptable salts thereof.