WO2011154977A1 - 'process for the preparation of colesevelam hydrochloride" - Google Patents

'process for the preparation of colesevelam hydrochloride" Download PDF

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Publication number
WO2011154977A1
WO2011154977A1 PCT/IN2011/000382 IN2011000382W WO2011154977A1 WO 2011154977 A1 WO2011154977 A1 WO 2011154977A1 IN 2011000382 W IN2011000382 W IN 2011000382W WO 2011154977 A1 WO2011154977 A1 WO 2011154977A1
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colesevelam
chloride
hydrochloride
process according
formula
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PCT/IN2011/000382
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French (fr)
Inventor
Shekhar Bhaskar Bhirud
Perminder Singh Johar
Ekta Sharma
Veerender Sharma
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Ind-Swift Laboratories Limit
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/02—Polyamines
    • C08G73/0206—Polyalkylene(poly)amines
    • C08G73/0213—Preparatory process
    • C08G73/022—Preparatory process from polyamines and epihalohydrins

Definitions

  • the present invention relates to an industrially advantageous and efficient process for the preparation of colesevelam hydrochloride, a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent using a new source of chloride ion.
  • Colesevelam hydrochloride of formula I is a crosslinked polyallylamine polymer having many therapeutic applications and having high capacity to bind with bile acids and is chemically known as 1- chloro-2,3-epoxypropane, [6-(allylamino)-hexyl]trimethylammonium chloride and N-allyldecylamine, hydrochloride.
  • (a) represents allyl amine monomer units that have neither been alkylated by either of the 1- bromodecane or (6-bromohexyl)-trimethylammonium bromide alkylating agents nor cross-linked by epichlorohydrin;
  • (b) represents allyl amine units that have undergone crosslinking with epichlorohydrin;
  • (c) represents allyl amine units that have been alkylated with a decyl group;
  • (d) represents allyl amine units that have been alkylated with a (6-trimethylammonium) hexyl group, and
  • m represents a number >100 to indicate an extended polymer network.
  • Colesevelam hydrochloride is a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent used as oral administrative. It reduces the blood cholesterol levels by reducing reabsorption of bile acids.
  • Colesevelam has been first disclosed in US patent 5,693,675.
  • the process disclosed for preparation of colesevelam comprises crosslinking of polyallylamine hydrochloride with epichlorohydrin, followed by alkylation of resulting crosslinked poly(allylamine) with (6-bromohexyl) trimethylammonium _ .
  • Colesevelam was dried in a vacuum oven at 50 °C and ground to pass through an 80 mesh sieve and have particle size of about 179 ⁇ .
  • Above patent is silent about the conversion of colesevelam in to colesevelam hydrochloride, which is used as an API for formulation.
  • US patent 5,607,669 discloses process for alkylating cross linked poly-(allylamine) using 6- bromohexyl trimethylammonium bromide and 1 -bromodecane in presence of aqueous base or methanolic solution of base.
  • alkylation is carried out on gelled crosslinked amine polymer which is prepared in situ and further alkylated with alkylating agents. After complete alkylation, resulting polymer was washed several times with methanol, 2M sodium chloride solution in water and deionized water.
  • Above patent is also silent about formation of colesevelam hydrochloride salt from colesevelam.
  • An article Polymer Preprints, 2000, 41(1), 735-736 discloses process for preparation of colesevelam hydrochloride by the alkylation of poly-(allylamine) using 6-bromohexyl trimethylammonium bromide and 1 -bromodecane followed by treatment with concentrated hydrochloric acid with in situ preparation of colesevelam.
  • concentrated hydrochloric acid may lead to formation of undesired level of impurities. It is found on our hand that colesevelam hydrochloride prepared by the above process shows inconsistent results of chloride content, which shows that process is not reproducible at industrial level.
  • US patent 7, 148,319 discloses process for preparation of colesevelam by deprotonation of cross linked gelled polymers by addition of a base, followed by washing with water, an organic solvent or an organic solvent/water mixture, then alkylation by adding one or more alkylators at atmospheric or elevated pressure at a temperature between 5- l 60°C in the presence of base to give a gel suspension. Thereafter, suspension of gel is reprotonated by means of concentrated hydrochloric acid to form colesevelam hydrochloride. Use of concentrated hydrochloric acid during reprotonation may form undesired amount of chloride content in final API.
  • US patent 7, 105,63 1 discloses preparation of colesevelam by cross linking polyallylamine hydrochloride with epichlorohydrin to give cross linked polymer gel which is then cut into defined shape and washed the crosslinked polymer gel with methanol.
  • the obtained moist crude gel was then alkylated in methanol by adding one or/and more alkylators at 5-90°C and under pressure of 1 -3 bar in presence of base followed by reprotonation using concentrated hydrochloric acid to give colesevelam hydrochloride, which was washed several times with methanol, 2M sodium chloride solution in water during preparation of colesevelam hydrochloride.
  • PCT publication WO 2010/029579 discloses process for the preparation of colesevelam hydrochloride by neutralizing polyallylamine hydrochloride to polyallylamine followed by cross-linking with epichlorohydrin in non aqueous medium to obtain cross-linked polymer. Thus obtained cross linked polymer is then alkylated to give colesevelam hydrochloride.
  • the patent is completely silent about the reaction conditions for the synthesis of colesevelam hydrochloride such as solvent, source of hydrochloric acid used for the reaction.
  • PCT publication WO 2010/041268 discloses process for the preparation of colesevelam hydrochloride by the alkylation of sevelamer hydrochloride using 6-bromohexyltrimethylammonium bromide and 1 - bromodecane in the presence of methanol in sodium hydroxide to give colesevelam which in wet form is treated with dilute hydrochloric acid to form colesevelam hydrochloride.
  • colesevelam hydrochloride prepared by these methods may not be of consistent quality. Chloride content and bile binding capacity vary from batch to batch. In addition to this, we have not found any reference wherein reagents other than hydrochloric acid have been employed during preparation of colesevelam hydrochloride.
  • present invention provides a process that overcomes disadvantages of the prior art and provides an industrially advantageous and efficient process for the preparation of colesevelam hydrochloride, which produces reproducible results.
  • the principal objective of the present invention is to provide an industrially advantageous, efficient and reproducible process for the preparation of colesevelam hydrochloride.
  • Another objective of the present invention is to provide colesevelam free base having particle size less ratio less than 1 .25 and/or compressibility index less than 20 so that resulting colesevelam hydrochloride is free flowing and efficient in easy formulation.
  • Still another objective of the present invention is to provide colesevelam hydrochloride having swell index between 4.5 to 10.0.
  • present invention provides a novel, industrially advantageous and efficient process for the preparation of colesevelam hydrochloride of formula I.
  • the process comprises the steps of:
  • present invention provides a process for the preparation of colesevelam hydrochloride, comprises the steps of:
  • present invention provides colesevelam having particle size less than 150 ⁇ .
  • present invention provides colesevelam hydrochloride having Hausner ratio less than 1 .25. , . _
  • present invention provides colesevelam hydrochloride having swell index between 4.5 to 10.0
  • the present invention provides a process for the preparation of colesevelam hydrochloride of formula I, which gives reproducible results, free flowing product and will be efficient for easy formulation.
  • process involves neutralization of acid addition salt of polyallylamine using a suitable base followed by cross linking using a suitable cross linking agent such as epichlorohydrin.
  • Base employed for the neutralization can be inorganic base, which includes alkali or alkaline metal hydroxides, carbonates, bicarbonates, alkoxides thereof such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, lithium bicarbonate and the like; or organic base includes aliphatic amines, aromatic amines and ammonia and the like.
  • acid addition salt of polyallylamine used is hydrochloride.
  • a cross linking agent such as epichlorohydrin can be added to the reaction mixture at a temperature of 0- 100 °C, preferably at a temperature of I 0°C to ambient temperature till completion of cross-linking reaction.
  • cross-linking reaction completes in 30 hours, preferably in 20 hours. It is advantageous to agitate the reaction mixture slowly in order to achieve desired level of cross-linking because fast agitation leads to improper gel formation.
  • cross linked polymer can be isolated from reaction mixture by conventional methods. It is preferable to add water or a mixture of water with water miscible solvent to the reaction mixture to provide easy isolation of material there from. Water miscible solvent includes C
  • Cross-linked polymer can be isolated from . . .
  • crosslinked polymer It is highly advantageous to pulverize cross linked polymer to attain desired particle size less than 300 ⁇ , preferably less than 195 ⁇ , more preferably less than 100 ⁇ .
  • Use of crosslinked polymer having particle size less than 300 ⁇ have a great impact on further alkylation reaction as particle of lower size provides desired degree of alkylation and give alkylated product in high yield and having less amount of by products.
  • Lower particle size ensures completion of alkylation reaction and avoids formation of by products.
  • Cross-linked polymer thus prepared is found to have swell index > 8.5, preferably swell index of cross linked polymer is 12.6.
  • Cross linked polymer is found to have bulk density in range of 0.50 to 0.80 g/ml, more preferably 0.65 g/ml.
  • Cross linked polymer thus prepared also shows loss on drying up to 10 % w/w, preferably less than 7.0 % w/w, more preferably 6.9 % w/w.
  • Cross linked polymer display infra-red spectrum as shown in Figure 1.
  • Crosslinked polymer is then alkylated in the presence of suitable alkylating agent in a suitable solvent to give colesevelam or its hydrochloride thereof.
  • alkylation reaction involves addition of a suitable alkylating agent to cross-linked polymer in a suitable solvent at ambient temperature to 80°C for few minutes to few hours.
  • the alkylation reaction is carried out in the presence of a suitable base at a temperature of 25 to 70°C for few minutes to few hours, preferably till the completion of the reaction.
  • Suitable solvent includes Ci -4 alcohol such as methanol, ethanol, isopropanol and the like or mixture thereof.
  • Suitable base employed for the reaction can be inorganic base, which includes alkali or alkaline metal hydroxides, carbonates, bicarbonates, alkoxides thereof such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; or organic base includes aliphatic amines, aromatic amines and ammonia and the like.
  • Alkylating agent used for the synthesis of colesevelam are 6-bromohexyl trimethyl ammonium bromide and 1 -bromodecane. Usually, alkylation reaction is carried out at 50 to 70 °C for 20 to 30 hours; preferably it takes about 22 hours for complete alkylation.
  • colesevelam can be isolated from the reaction mixture using conventional techniques such as filtration or centrifugation or irtsitu converted to colesevelam hydrochloride. It is preferable to wash the colesevelam with a suitable solvent and/or sodium chloride solution in either order. Suitable , , , ,
  • washing can be repeated with same or different solvent and/or with aqueous sodium chloride solution.
  • wet colesevelam thus obtained can be dried or can be converted as such to colesevelam hydrochloride without drying by the methods known in the art or by the method as specified in the present invention.
  • Colesevelam thus prepared have particle size less than 1 50 ⁇ , preferably less than 100 ⁇ , more preferably less than 65 ⁇ and loss on drying up to 10 % w/w, preferably 9.5 % w/w. For instance, in different experiments dried colesevelam having a particle size 1 50 ⁇ , 100 ⁇ , 64 ⁇ , and 59 ⁇ were obtained.
  • the conversion of colesevelam having particle size less than 1 50 ⁇ to colesevelam hydrochloride is highly advantageous with respect to consistent chloride content, swell index and/or bile acid binding.
  • Colesevelam thus prepared is found to have swell index between 5.0 to 8.0, preferably 7.4.
  • Colesevelam thus prepared by the present invention is free flowing in nature which can be attributed to its particle size less than 1 50 ⁇ and having bulk density between 0.50 - 0.80 g/ml, preferably 0.65 g/ml.
  • Colesevelam thus prepared is also characterized by infrared spectroscopy which display infra-red spectrum as shown in Figure 2.
  • present invention provides novel method for the preparation of colesevelam hydrochloride.
  • process involves the reaction of a suspension of colesevelam with a suitable source of chloride ion for a time sufficient for the formation of hydrochloride salt.
  • a suspension of colesevelam can be provided by suspending dried solid or wet form of colesevelam in a suitable solvent; or can be provided directly from the reaction mixture (containing colesevelam) where in insitu conversion of colesevelam to its hydrochloride take place.
  • Suitable solvent includes water, alcohol such as methanol, ethanol, isopropanol; ether such as tetrahydrofuran; nitriles such as acetonitrile; ketones such as acetone and the like or mixture thereof.
  • Suitable source of chloride ion can be selected from hydrogen chloride gas, solvent saturated with hydrogen chloride gas; (wherein solvent includes ethers such as isopropyl ether, methyl tertiary butyl ether; alcohols such as methanol, ethanol, isopropanol; water; ketones such as acetone and the like); hydrochloride salt of a suitable amine having formula N Rj R 2 R 3 . HCI (wherein R R 2 and R 3 can be , .
  • alkyl or aryl or alkaryl, aralkyl, heteroaryl) such as ammonium chloride
  • sulfur compounds such as thionyl chloride; sulfuryl chloride; carboxylic acid chloride having formula RiCOCl (wherein R / is as defined above) such as acetyl chloride
  • silyl chloride of formula Ri R 2 R SiCl such as trimethyl silyl chloride
  • metal chlorides such as TiCl 4 ; TiCl 3 ; BC1 ; A1C1 3 ; PC1 3 ; PC1 5 ; or alkali metal chloride such sodium chloride, potassium chloride in combination with a sulfuric acid and the like or in combination thereof.
  • colesevelam hydrochloride can be isolated from the reaction mixture using conventional methods known in the art. Specifically, colesevelam hydrochloride can be isolated from the reaction mixture using filtration, centrifugation or decantation and the like.
  • Colesevelam hydrochloride thus obtained can optionally be purified with a suitable solvent.
  • colesevelam hydrochloride of formula I can be stirred in a suitable solvent at a temperature of 0 to 50 °C for few minutes to several hours, preferably at a temperature of 20 to 35 °C up to 4 hours.
  • Suitable solvent includes water, alcohol such as methanol, ethanol, isopropanol and the like or mixture thereof.
  • Colesevelam hydrochloride can be isolated from the mixture using conventional techniques such as filtration, centrifugation or decantation and the like and then dried. The washing of colesevelam hydrochloride can be repeated with same or different solvent.
  • Colesevelam hydrochloride shows loss on drying up to 10 % w/w, preferably 9.9 % w/w.
  • Colesevelam hydrochloride thus prepared have particle size less than 100 ⁇ , preferably less than 73 ⁇ ⁇ , more preferably less than 45 ⁇ .
  • Free flowing nature of colesevelam hydrochloride can be attributed to its particle size and/or other characteristics such as Hausner ration less than 1.25 and/or compressibility index less than 20.
  • Hausner ratio and compressibility index are the properties that provides the nature of compound.
  • Colesevelam hydrochloride thus prepared is found to have chloride content in range from 22.0 to 28.0 % w/w, preferably between 22.5 % to 26.0 % w/w and bromide content less than 0.5% w/w, preferably less than 0.2 % w/w, more preferably less than 0.1 % w/w, most preferably less than 0.06 % w/w.
  • Product has water soluble amines ⁇ 0.50%w/w and bile acid binding capacity 1.8 to 2.6 g/g, preferably 1 .9 to 2.4 g/g.
  • Colesevelam hydrochloride has swell index in between 4.5 to 10.0.
  • Swell index can be calculated by using two part centrifuge tube, centrifuge device, magnetic stirrer and magnetic stir bar. A known amount of the test sample (cross linked polymer or colesevelam or colesevelam hydrochloride) is transferred to upper par of centrifuge tube followed by addition of known volume of buffer solution (herein buffer solution having 0.03 M NN-bis(hydroxyethyl)2-aminoethane sulphonic acid and 0.01 M sodium chloride is prepared). The centrifuged tube was inverted and then stirred, preferably for 30 minutes at about 3500 rpm - 4000 rpm. Swell index is then calculated by following equation:
  • is weight of the centrifuge tube (without cap) along with magnetic stir bar
  • W 2 is weight of the centrifuge tube (without cap) along with magnetic stir bar and test sample after the stirring.
  • Bile acid binding capacity is calculated by using sodium glycocholate method by high pressure liquid chromatography instrument.
  • intermediate as well as final API i.e. colesevelam hydrochloride can be dried after the isolation from the reaction mixture using conventional methods such as air or standard tray dryer; vacuum tray dryer, fluidized bed dryer or rotatory evaporator at suitable temperature.
  • the order and manner of combining the reactants at any stage of the process are not important and may be varied.
  • the reactants may be added to the reaction mixture as solids, or may be dissolved individually and . ,
  • Main advantage of the present invention is use of new source of chloride ion for synthesis of colesevelam hydrochloride either from dried colesevelam or from wet material.
  • Other advantage of the invention is that is provides a colesevelam having particle size less than 150 ⁇ which proved highly advantageous in yielding the final product with consistent results.
  • the process of the present invention is efficient, reproducible as well as industrially advantageous.
  • the solid wet cake was rinsed three times by suspending in water ( 12.5L, 18.75L, 25L), stirring the suspension for 1 hour, and collecting the solid each time by centrifugation followed by spin drying. Isopropanol (21 .25 L) was added to the resulting solid, stirring the mixture for 1 hour, centrifuged and spin dried. The solid was dried , after which the solid was dried in at 45-50 °C for 72-100 hours to give 825 g of the title compound as a granular, brittle, white solid. The resulting product was pulverized.
  • Example 2 Preparation of colesevelam n e po y a y am ne g , me ano . » " r mc y ammonium brom ide (844 g) and 1 -bromodecane (504 g) was heated at 65 °C and aqueous sodium hydroxide (480 ml) was added to the reaction mass in lots and stirred at 65 °C for 20 hours. The reaction mixture was cooled to ambient temperature, centrifuged and spin dried. Methanol (53.33 L) was added to the resulting wet solid, stirred at ambient temperature for 30 minutes, centri fugcd and spin dried.
  • the solid was twice rinsed by suspending in 2M aqueous sodium chloride (3.43 kg in 29.28 L water), stirred for 30 minutes and filtered.
  • the resulting solid was thrice rinsed by suspending in deminerali ed water (2 1 .28 L), stirred for 30 minutes, filtered and dried at 45-50 °C for 72- 100 hours to give 1 .02 kg of title compound.
  • the resulting product was pulverized to attain the particle si/.e of 1 50 pm.
  • the solid was twice rinsed by suspending in 2M aqueous sodium chloride (343 g in 2.93 L water), stirred for 30 minutes and filtered.
  • the resulting solid was thrice rinsed by suspending in demineralized water (2. 13 L), stirred for 30 minutes, filtered and dried at 45-50 °C for 72- 100 hours to give 100 g of title compound.
  • the resulting product was pulverized to attain the particle size of 59 ⁇ .
  • the solid was twice rinsed by suspending in 2M aqueous sodium chloride ( 1 7 1 g in 1 .47 L water), stirred for 30 minutes and fi ltered.
  • the resulting solid was thrice rinsed by suspending in dem ineralized water (400 ml x 3), stirred for 30 minutes, filtered and dried at 45-50 °C for 72- 100 o .
  • Method A Colesevelam (1 kg) and 2N hydrochloric acid ( 12L) were stirred at ambient temperature for 2 hours. The product was centrifuged, washed with demineralized water (3 L) at ambient temperature, re-centrifuged and spin dried. The resulting solid was dried at 45-50 °C for 72- 100 hours to give 1.1 kg title compound as an off-white solid. The product was pulverized to attain the particle size of 62 ⁇ .
  • Method B Colesevelam ( 100 g) and 2N hydrochloric acid (1 .2 L) were stirred at ambient temperature for 2 hours. The product was centrifuged, washed with demineralized water (300 ml) at ambient temperature, re-centrifuged and spin dried. The solid was dried at 45-50 °C for 72- 100 hours to give 105 g of title compound as an off-white solid. The product was pulverized to attain the particle size of
  • Chloride content 22.3% w/w; swell index: 5.2, bile acid binding capacity: 1 .9 g/g.
  • Method C To a stirred suspension of colesevelam (30 g) and water (300 ml) was added concentrated hydrochloric acid (70 ml) and stirred at ambient temperature for 2 hours. The product was centrifuged, washed with demineralized water (60 ml) at ambient temperature, re- centrifuged and spin dried. The solid was dried at 45-50 °C for 72-100 hours to give 30 g of title compound as an off-white solid. The product was pulverized to attain the particle size of 34 ⁇ .
  • Method D To a suspension of colesevelam (30 g) and methanol (300 ml) was added concentrated hydrochloric acid (70 ml) and stirred at ambient temperature for 2 hours. The product was centrifuged, washed with demineralized water (60ml), re centrifuged and spin dried. The solid was then dried at 45- 50 °C for 72- 100 hours to give 3 1 g of title compound as an off-white solid. The product was pulverized to attain the particle size of 61 ⁇ .
  • Chloride content 22.9% w/w; swell index: 4.2, bile acid binding capacity: 2.0 g/g.
  • Method E To colesevelam (30 g) was added 6N hydrochloric acid (360 ml) and stirred together at ambient temperature for 2 hours. The product was centrifuged, washed with demineralized water (60 ml), re-centrifuged and spin dried. The solid was then dried at 45-50 °C for 72- 100 hours to give 30.5 g of title compound as an off-white solid. The product was pulverized to attain the particle size of 74 ⁇ . Chloride content: 22.8% w/w; swell index: 5.1 , bile acid binding capacity: 2.1 g/g. chloride (30 ml) and stirred at ambient temperature for 4 hours.
  • the product was centrifuged, washed successively with demineralized water (60 ml), methanol (60 ml) and demineralized water (60ml) at ambient temperature, centrifuged each time and spin dried. The solid was then dried at 45-50 °C for 72- 100 hours to give 30 g of title compound as an off-white solid.
  • the product was pulverized to attain the particle size of 80 ⁇ .
  • Chloride content 23.0% w/w; swell index: 6.8, bile acid binding capacity: 2.1 g/g, loss on drying: 7.1 % w/w.
  • Method G To a stirred suspension of colesevelam (30 g) and water (210 ml, ammonium chloride (35 g) was added and stirred at ambient temperature for 12 hours. The product was centrifuged, washed with demineralized water (60 ml), re-centrifuged and spin dried. The solid was then dried at 45-50 °C for 72- 100 hours to give 3 1 g of title compound as an off-white solid. The product was pulverized to attain the particle size of 40 ⁇ .
  • Chloride content 22.8% w/w; swell index: 7.3, bile acid binding capacity: 2.2 g/g.
  • Method H To stirred suspension of colesevelam (30 g) and water (210 ml) was added thionyl chloride ( 17 ml) and stirred at ambient temperature for 4 hours. The product was centrifuged, washed successively with demineralized water (60 ml), methanol (60ml) and demineralized water (60ml) at ambient temperature, centrifuged each time and spin dried. The solid was then dried at 45-50 °C for 72- 100 hours to give 29 g of title compound as an off-white solid. The product was pulverized to attain the particle size of 46 ⁇ .
  • Method I To a stirred suspension of colesevelam (30 g) and water (210 ml) was added acetyl chloride (30 ml) and stirred at ambient temperature for 4 hours. The product was centrifuged, washed successively with demineralized water (60 ml), methanol (60 ml) and demineralized water (60ml) at ambient temperature, centrifuged each time and spin dried. The solid was then dried at 45-50 °C for 72- 100 hours to give 29.7 g of title compound as an off-white solid. The product was pulverized to attain the particle size of 60 ⁇ .
  • Method A Mixture of crosslinked poly(allylamine) (80g), methanol (2.13 L), (6-bromohexyl) trimethyl ammonium bromide (84 g) and 1 -bromodecane (50 g) was heated at 65 °C with stirring for 2 hours. 50 % Aqueous sodium hydroxide (48 ml) was added to the reaction mass in lots and stirred at 65 °C for 20 hours. The reaction mixture was cooled to ambient temperature for 1 hour, centrifuged . . . ,
  • Chloride content 22.8% w/w; swell index: 4.2, bile acid binding capacity: 2.0 g/g.
  • Method B Mixture of crosslinked poly(allylamine) (80g), methanol (2. 13 L), (6-bromohexyl) trimethyl ammonium bromide (84 g) and 1 -bromodecane (50 g) was heated at 65 °C with stirring for 2 hours. 50 % Aqueous sodium hydroxide (48 ml) was added to the reaction mass in lots and stirred at 65 °C for 20 hours. The reaction mixture was cooled to ambient temperature for 1 hour, centrifuged and spin dried. Methanol (5.3 L) was added to the resulting wet solid, stirred at ambient temperature for 30 minutes, centrifuged and spin dried.
  • the solid was twice, rinsed by suspending in 2M aqueous sodium chloride (343 g in 2.93 L water), stirred for 30 minutes and filtered. The resulting solid was thrice rinsed by suspending in demineraiized water (2. 13 L), stirred for 30 minutes, filtered. 8 N Hydrochloric acid ( 1.2 L) was added to the resulting wet cake and stirred together at ambient temperature for 2 hours. The product was centrifuged, washed with demineraiized water (200ml) at ambient temperature; re- centrifuged and spin dried. The solid was then dried at 45-50 °C for 72- 100 hours to give 103g of title compound as an off-white solid. The product was pulverized to attain the particle size of 60 ⁇ .
  • Chloride content 22.9% w/w; swell index: 5.2, bile acid binding capacity: 2. 1 g/g; loss on drying: 7.3 % w/w.
  • Method C Mixture of crosslinked poly(allylamine) (80g), methanol (2.13 L), (6-bromohexyl) trimethyl ammonium bromide (84 g) and 1 -bromodecane (50 g) was heated at 65 °C with stirring for 2 hours. 50 % Aqueous sodium hydroxide (48 ml) was added to the reaction mass in lots and stirred at 65 °C for 20 hours. The reaction mixture was cooled to ambient temperature for 1 hour, centrifuged and spin dried. Methanol (5.3 L) was added to the resulting wet solid, stirred at ambient temperature for 30 minutes, centrifuged and spin dried. The solid was twice, rinsed by suspending in 2M aqueous . . . ,
  • Chloride content 22.8% w/w; swell index: 6.7, bile acid binding capacity: 2.1 g/g.
  • Method D Mixture of crosslinked poly(allylamine) (80g), methanol (2.13 L), (6-bromohexyl) trimethyl ammonium bromide (84 g) and 1 -bromodecane (50 g) was heated at 65 °C with stirring for 2 hours. 50 % Aqueous sodium hydroxide (48 ml) was added to the reaction mass in lots and stirred at 65 °C for 20 hours. The reaction mixture was cooled to ambient temperature for 1 hour, centrifuged and spin dried. Methanol (5.3 L) was added to the resulting wet solid, stirred at ambient temperature for 30 minutes, centrifuged and spin dried.
  • the solid was twice, rinsed by suspending in 2M aqueous sodium chloride (343 g in 2.93 L water), stirred for 30 minutes and filtered. The resulting solid was thrice rinsed by suspending in demineralized water (2.13 L), stirred for 30 minutes, filtered. Water (700 ml) and ammonium chloride ( 1 17 g) were added to the resulting wet cake and stirred at ambient temperature for 12 hours. The product was centrifuged, washed with demineralized water (200 ml) at ambient temperature; re- centrifuged and spin dried. The solid was then dried at 45-50 °C for 72- 100 hours to give 100 g of title compound as an off-white solid. The product was pulverized to attain the particle size of 85 ⁇ .
  • Chloride content 22.9% w/w; swell index: 7.2, bile acid binding capacity: 2.2 g/g.
  • Method E Mixture of crosslinked poly(allylamine) (80g), methanol (2.13 L), (6-bromohexyl) trimethyl ammonium bromide (84 g) and 1 -bromodecane (50 g) was heated at 65 °C with stirring for 2 hours. Aqueous sodium hydroxide (48 ml) was added to the reaction mass in lots and stirred at 65 °C for 20 hours. The reaction mixture was cooled to ambient temperature for 1 hour, centrifuged and spin dried. Methanol (5.3 L) was added to the resulting wet solid, stirred at ambient temperature for 30 minutes, centrifuged and spin dried.
  • the solid was twice, rinsed by suspending in 2M aqueous sodium chloride (343 g in 2.93 L water), stirred for 30 minutes and filtered. The resulting solid was thrice rinsed by suspending in demineralized water (2. 13 L), stirred for 30 minutes, filtered. Water (700 ml) . . for 4 hours. The product was centrifuged, washed with demineralized water (200 ml) at ambient temperature; re- centrifuged and spin dried. The solid was then dried at 45-50 °C for 72-100 hours to give 103 g of title compound as an off-white solid. The product was pulverized to attain the particle
  • Method F Mixture of crosslinked poly(allylamine) (80g), methanol (2.13 L), (6-bromohexyl) trimethyl ammonium bromide (84 g) and 1 -bromodecane (50 g) was heated at 65 °C with stirring for 2 hours. Aqueous sodium hydroxide (48 ml) was added to the reaction mass in lots and stirred at 65 °C for 20 hours. The reaction mixture was cooled to ambient temperature for 1 hour, centrifuged and spin dried. Methanol (5.3 L) was added to the resulting wet solid, stirred at ambient temperature for 30 minutes, centrifuged and spin dried.
  • the solid was twice, rinsed by suspending in 2M aqueous sodium chloride (343 g in 2.93 L water), stirred for 30 minutes and filtered. The resulting solid was thrice rinsed by suspending in demineralized water (2.13 L), stirred for 30 minutes, filtered. Water (700 ml) and acetyl chloride ( 100 ml) were added to the resulting wet cake and stirred at ambient temperature for 4 hours. The product was centrifuged, washed with demineralized water (200 ml) at ambient temperature; re- centrifuged and spin dried. The solid was then dried in at 45-50 °C for 72- 100 hours to give 102 g of title compound as an off-white solid. The product was pulverized to attain the particle

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Abstract

The present invention provides an industrially advantageous and efficient process for the preparation of colesevelam hydrochloride using dried colesevelam and a source of chloride ion which includes hydrogen chloride gas, solvent saturated with hydrogen chloride gas; hydrochloride salt of a suitable amine having formula NR1 R2R3. HCl (wherein R 1 R 2 and R 3 can be same or different and can be individually selected amongst hydrogen, substituted or unsubstituted alkyl or aryl or alkaryl, aralkyl, heteroaryl); sulfur compounds; carboxylic acid chloride having formula R1COCI (wherein R 1 is as defined above; silyl chloride of formula R1 R2R3SiC1 (wherein R 1 R 2 and R 3 are as defined above); metal chlorides such as TiCI4; TiCl3; BCI3; AlCl3; PCI3; PCl5; or alkali metal chloride in combination with a sulfuric acid and the like or in combination thereof.

Description

'PROCESS i UK 1 HE PREPARATION OF COLESEVELAM HYDROCHLORIDE"
FIELD OF THE INVENTION:
The present invention relates to an industrially advantageous and efficient process for the preparation of colesevelam hydrochloride, a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent using a new source of chloride ion.
BACKGROUND OF THE INVENTION:
Colesevelam hydrochloride of formula I is a crosslinked polyallylamine polymer having many therapeutic applications and having high capacity to bind with bile acids and is chemically known as 1- chloro-2,3-epoxypropane, [6-(allylamino)-hexyl]trimethylammonium chloride and N-allyldecylamine, hydrochloride.
Figure imgf000002_0001
wherein (a) represents allyl amine monomer units that have neither been alkylated by either of the 1- bromodecane or (6-bromohexyl)-trimethylammonium bromide alkylating agents nor cross-linked by epichlorohydrin; (b) represents allyl amine units that have undergone crosslinking with epichlorohydrin; (c) represents allyl amine units that have been alkylated with a decyl group; (d) represents allyl amine units that have been alkylated with a (6-trimethylammonium) hexyl group, and m represents a number >100 to indicate an extended polymer network.
Colesevelam hydrochloride is a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent used as oral administrative. It reduces the blood cholesterol levels by reducing reabsorption of bile acids.
Colesevelam has been first disclosed in US patent 5,693,675. The process disclosed for preparation of colesevelam comprises crosslinking of polyallylamine hydrochloride with epichlorohydrin, followed by alkylation of resulting crosslinked poly(allylamine) with (6-bromohexyl) trimethylammonium _ . Colesevelam was dried in a vacuum oven at 50 °C and ground to pass through an 80 mesh sieve and have particle size of about 179μηι. Above patent is silent about the conversion of colesevelam in to colesevelam hydrochloride, which is used as an API for formulation.
US patent 5,607,669 discloses process for alkylating cross linked poly-(allylamine) using 6- bromohexyl trimethylammonium bromide and 1 -bromodecane in presence of aqueous base or methanolic solution of base. In this patent alkylation is carried out on gelled crosslinked amine polymer which is prepared in situ and further alkylated with alkylating agents. After complete alkylation, resulting polymer was washed several times with methanol, 2M sodium chloride solution in water and deionized water. Above patent is also silent about formation of colesevelam hydrochloride salt from colesevelam.
An article Polymer Preprints, 2000, 41(1), 735-736 discloses process for preparation of colesevelam hydrochloride by the alkylation of poly-(allylamine) using 6-bromohexyl trimethylammonium bromide and 1 -bromodecane followed by treatment with concentrated hydrochloric acid with in situ preparation of colesevelam. The use of concentrated hydrochloric acid may lead to formation of undesired level of impurities. It is found on our hand that colesevelam hydrochloride prepared by the above process shows inconsistent results of chloride content, which shows that process is not reproducible at industrial level.
US patent 7, 148,319 discloses process for preparation of colesevelam by deprotonation of cross linked gelled polymers by addition of a base, followed by washing with water, an organic solvent or an organic solvent/water mixture, then alkylation by adding one or more alkylators at atmospheric or elevated pressure at a temperature between 5- l 60°C in the presence of base to give a gel suspension. Thereafter, suspension of gel is reprotonated by means of concentrated hydrochloric acid to form colesevelam hydrochloride. Use of concentrated hydrochloric acid during reprotonation may form undesired amount of chloride content in final API.
US patent 7, 105,63 1 discloses preparation of colesevelam by cross linking polyallylamine hydrochloride with epichlorohydrin to give cross linked polymer gel which is then cut into defined shape and washed the crosslinked polymer gel with methanol. The obtained moist crude gel was then alkylated in methanol by adding one or/and more alkylators at 5-90°C and under pressure of 1 -3 bar in presence of base followed by reprotonation using concentrated hydrochloric acid to give colesevelam hydrochloride, which was washed several times with methanol, 2M sodium chloride solution in water during preparation of colesevelam hydrochloride.
PCT publication WO 2010/029579 discloses process for the preparation of colesevelam hydrochloride by neutralizing polyallylamine hydrochloride to polyallylamine followed by cross-linking with epichlorohydrin in non aqueous medium to obtain cross-linked polymer. Thus obtained cross linked polymer is then alkylated to give colesevelam hydrochloride. The patent is completely silent about the reaction conditions for the synthesis of colesevelam hydrochloride such as solvent, source of hydrochloric acid used for the reaction.
PCT publication WO 2010/041268 discloses process for the preparation of colesevelam hydrochloride by the alkylation of sevelamer hydrochloride using 6-bromohexyltrimethylammonium bromide and 1 - bromodecane in the presence of methanol in sodium hydroxide to give colesevelam which in wet form is treated with dilute hydrochloric acid to form colesevelam hydrochloride.
Most of prior art references are either silent about formation of colesevelam hydrochloride from colesevelam or uses hydrochloric acid with wet colesevelam.
It has been observed that colesevelam hydrochloride prepared by these methods may not be of consistent quality. Chloride content and bile binding capacity vary from batch to batch. In addition to this, we have not found any reference wherein reagents other than hydrochloric acid have been employed during preparation of colesevelam hydrochloride.
In the view of above, there is need in the art to develop a process that will produce consistent quality, results and proves to be industrially advantageous for the synthesis of colesevelam hydrochloride. Thus, present invention provides a process that overcomes disadvantages of the prior art and provides an industrially advantageous and efficient process for the preparation of colesevelam hydrochloride, which produces reproducible results.
OBJECTIVE OF THE INVENTION:
The principal objective of the present invention is to provide an industrially advantageous, efficient and reproducible process for the preparation of colesevelam hydrochloride.
Another objective of the present invention is to provide colesevelam free base having particle size less
Figure imgf000004_0001
ratio less than 1 .25 and/or compressibility index less than 20 so that resulting colesevelam hydrochloride is free flowing and efficient in easy formulation.
Still another objective of the present invention is to provide colesevelam hydrochloride having swell index between 4.5 to 10.0.
SUMMARY OF THE INVENTION:
Accordingly, present invention provides a novel, industrially advantageous and efficient process for the preparation of colesevelam hydrochloride of formula I.
The process comprises the steps of:
a), neutralizing poly(allylamine) hydrochloride using a base; b) . crosslinking of poly(allylamine) with epichlorohydrin to form cross linked polymer;
c) . alkylating the resulting polymer using 6-bromohexyl trimethyl ammonium bromide and 1 - bromodecane in the presence of base to form .colesevelam; d) . isolating colesevelam from the reaction mixture;
e) . optionally, drying colesevelam; and
f) . converting colesevelam in to colesevelam hydrochloride of formula 1.
According to another embodiment, present invention provides a process for the preparation of colesevelam hydrochloride, comprises the steps of:
a) , providing a suspension of colesevelam in a solvent;
b) . adding a suitable source of chloride ion;
c) . isolating colesevelam hydrochloride there from; and
d) . optionally, purifying colesevelam hydrochloride.
According to another embodiment, present invention provides colesevelam having particle size less than 150 μιη.
According to another embodiment, present invention provides colesevelam hydrochloride having Hausner ratio less than 1 .25. , . _
compressibility index less than 20.
According to another embodiment, present invention provides colesevelam hydrochloride having swell index between 4.5 to 10.0
BRIEF DESCRIPTION OF DRAWINGS:
Figure 1 : Infrared (IR) spectrum of cross linked polymer
Figure 2: Infrared (IR) spectrum of colesevelam
Figure 3: Infrared (IR) spectrum of colesevelam hydrochloride
Figure 4: Powder X-ray diffraction pattern of colesevelam hydrochloride
DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides a process for the preparation of colesevelam hydrochloride of formula I, which gives reproducible results, free flowing product and will be efficient for easy formulation.
Generally, process involves neutralization of acid addition salt of polyallylamine using a suitable base followed by cross linking using a suitable cross linking agent such as epichlorohydrin. Base employed for the neutralization can be inorganic base, which includes alkali or alkaline metal hydroxides, carbonates, bicarbonates, alkoxides thereof such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, lithium bicarbonate and the like; or organic base includes aliphatic amines, aromatic amines and ammonia and the like. Preferably acid addition salt of polyallylamine used is hydrochloride. After neutralization of amine, a cross linking agent such as epichlorohydrin can be added to the reaction mixture at a temperature of 0- 100 °C, preferably at a temperature of I 0°C to ambient temperature till completion of cross-linking reaction. Usually cross-linking reaction completes in 30 hours, preferably in 20 hours. It is advantageous to agitate the reaction mixture slowly in order to achieve desired level of cross-linking because fast agitation leads to improper gel formation. After completion of the reaction, cross linked polymer can be isolated from reaction mixture by conventional methods. It is preferable to add water or a mixture of water with water miscible solvent to the reaction mixture to provide easy isolation of material there from. Water miscible solvent includes C |.4 alcohol such as methanol, ethanol, isopropanol; ethers such as tetrahydrofuran; nitriles such as acetonitrile; ketones such as acetone and the like or mixture thereof. Cross-linked polymer can be isolated from . . .
with water or water miscible solvent and dried.
It is highly advantageous to pulverize cross linked polymer to attain desired particle size less than 300 μηι, preferably less than 195 μηι, more preferably less than 100 μιη. Use of crosslinked polymer having particle size less than 300 μηι have a great impact on further alkylation reaction as particle of lower size provides desired degree of alkylation and give alkylated product in high yield and having less amount of by products. Lower particle size ensures completion of alkylation reaction and avoids formation of by products.
Further reduction in particle size is also advantageous to provide free flowing crosslinked polymer having improved characteristics. Cross-linked polymer thus prepared is found to have swell index > 8.5, preferably swell index of cross linked polymer is 12.6. Cross linked polymer is found to have bulk density in range of 0.50 to 0.80 g/ml, more preferably 0.65 g/ml. Cross linked polymer thus prepared also shows loss on drying up to 10 % w/w, preferably less than 7.0 % w/w, more preferably 6.9 % w/w. Cross linked polymer display infra-red spectrum as shown in Figure 1.
Crosslinked polymer is then alkylated in the presence of suitable alkylating agent in a suitable solvent to give colesevelam or its hydrochloride thereof.
Generally, alkylation reaction involves addition of a suitable alkylating agent to cross-linked polymer in a suitable solvent at ambient temperature to 80°C for few minutes to few hours. The alkylation reaction is carried out in the presence of a suitable base at a temperature of 25 to 70°C for few minutes to few hours, preferably till the completion of the reaction. Suitable solvent includes Ci-4 alcohol such as methanol, ethanol, isopropanol and the like or mixture thereof. Suitable base employed for the reaction can be inorganic base, which includes alkali or alkaline metal hydroxides, carbonates, bicarbonates, alkoxides thereof such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; or organic base includes aliphatic amines, aromatic amines and ammonia and the like. Alkylating agent used for the synthesis of colesevelam are 6-bromohexyl trimethyl ammonium bromide and 1 -bromodecane. Usually, alkylation reaction is carried out at 50 to 70 °C for 20 to 30 hours; preferably it takes about 22 hours for complete alkylation. After completion of the reaction, colesevelam can be isolated from the reaction mixture using conventional techniques such as filtration or centrifugation or irtsitu converted to colesevelam hydrochloride. It is preferable to wash the colesevelam with a suitable solvent and/or sodium chloride solution in either order. Suitable , , , ,
mixture thereof. Washing can be repeated with same or different solvent and/or with aqueous sodium chloride solution.
Wet colesevelam thus obtained can be dried or can be converted as such to colesevelam hydrochloride without drying by the methods known in the art or by the method as specified in the present invention.
However, it is highly advantageous to dry as well as pulverize colesevelam so that product of improved characteristics can be obtained. Colesevelam thus prepared have particle size less than 1 50 μιτι, preferably less than 100 μιη, more preferably less than 65 μιη and loss on drying up to 10 % w/w, preferably 9.5 % w/w. For instance, in different experiments dried colesevelam having a particle size 1 50 μιη, 100 μιη, 64 μπι, and 59 μιη were obtained. The conversion of colesevelam having particle size less than 1 50 μιη to colesevelam hydrochloride is highly advantageous with respect to consistent chloride content, swell index and/or bile acid binding. Consistency in above-mentioned characteristic is necessary for effective formulation and for its activity as lipid lowering agent. Colesevelam thus prepared is found to have swell index between 5.0 to 8.0, preferably 7.4. Colesevelam thus prepared by the present invention is free flowing in nature which can be attributed to its particle size less than 1 50 μπι and having bulk density between 0.50 - 0.80 g/ml, preferably 0.65 g/ml. Colesevelam thus prepared is also characterized by infrared spectroscopy which display infra-red spectrum as shown in Figure 2.
According to another embodiment, present invention provides novel method for the preparation of colesevelam hydrochloride.
Generally, process involves the reaction of a suspension of colesevelam with a suitable source of chloride ion for a time sufficient for the formation of hydrochloride salt. A suspension of colesevelam can be provided by suspending dried solid or wet form of colesevelam in a suitable solvent; or can be provided directly from the reaction mixture (containing colesevelam) where in insitu conversion of colesevelam to its hydrochloride take place. Suitable solvent includes water, alcohol such as methanol, ethanol, isopropanol; ether such as tetrahydrofuran; nitriles such as acetonitrile; ketones such as acetone and the like or mixture thereof.
Suitable source of chloride ion can be selected from hydrogen chloride gas, solvent saturated with hydrogen chloride gas; (wherein solvent includes ethers such as isopropyl ether, methyl tertiary butyl ether; alcohols such as methanol, ethanol, isopropanol; water; ketones such as acetone and the like); hydrochloride salt of a suitable amine having formula N Rj R2R3. HCI (wherein R R2 and R3 can be , . alkyl or aryl or alkaryl, aralkyl, heteroaryl) such as ammonium chloride; sulfur compounds such as thionyl chloride; sulfuryl chloride; carboxylic acid chloride having formula RiCOCl (wherein R/ is as defined above) such as acetyl chloride; silyl chloride of formula Ri R2R SiCl (wherein R R2 an Rs are as defined above) such as trimethyl silyl chloride; metal chlorides such as TiCl4; TiCl3; BC1 ; A1C13; PC13; PC15; or alkali metal chloride such sodium chloride, potassium chloride in combination with a sulfuric acid and the like or in combination thereof.
Usually, salt formation can be carried out at 0 to 40 °C for few minutes to few hours, preferably till completion of reaction. After completion of reaction, colesevelam hydrochloride can be isolated from the reaction mixture using conventional methods known in the art. Specifically, colesevelam hydrochloride can be isolated from the reaction mixture using filtration, centrifugation or decantation and the like.
Colesevelam hydrochloride thus obtained can optionally be purified with a suitable solvent. Specifically, colesevelam hydrochloride of formula I can be stirred in a suitable solvent at a temperature of 0 to 50 °C for few minutes to several hours, preferably at a temperature of 20 to 35 °C up to 4 hours. Suitable solvent includes water, alcohol such as methanol, ethanol, isopropanol and the like or mixture thereof. Colesevelam hydrochloride can be isolated from the mixture using conventional techniques such as filtration, centrifugation or decantation and the like and then dried. The washing of colesevelam hydrochloride can be repeated with same or different solvent.
It is highly advantageous to dry as well as pulverize colesevelam hydrochloride to obtain free flowing colesevelam hydrochloride . Colesevelam hydrochloride shows loss on drying up to 10 % w/w, preferably 9.9 % w/w. Colesevelam hydrochloride thus prepared have particle size less than 100 μιη, preferably less than 73 μιη, more preferably less than 45 μιτι. Free flowing nature of colesevelam hydrochloride can be attributed to its particle size and/or other characteristics such as Hausner ration less than 1.25 and/or compressibility index less than 20. Hausner ratio and compressibility index are the properties that provides the nature of compound. Compounds having Hausner ration less than 1 .25 are considered to be free flowing in nature and similarly compound having compressibility index less than 20 are free flowing in nature. Above these limits for Hausner ration as well as compressibility index, product is considered to have poor flowability. Colesevelam hydrochloride thus prepared by the present invention have Hausner ratio and compressibility index within above specified limit, which are the characteristic value for free flowing compounds. Colesevelam hydrochloride has bulk density in range of 0.40- 0.70 g/ml and tapped density in range of 0.50 - 0.80 g/ml. Colesevelam hydrochloride . , _ .
formulation. Colesevelam hydrochloride display infra-red spectrum and powered X-ray diffraction pattern as shown in Figures 3 and 4.
Colesevelam hydrochloride thus prepared is found to have chloride content in range from 22.0 to 28.0 % w/w, preferably between 22.5 % to 26.0 % w/w and bromide content less than 0.5% w/w, preferably less than 0.2 % w/w, more preferably less than 0.1 % w/w, most preferably less than 0.06 % w/w. Product has water soluble amines < 0.50%w/w and bile acid binding capacity 1.8 to 2.6 g/g, preferably 1 .9 to 2.4 g/g.
Colesevelam hydrochloride has swell index in between 4.5 to 10.0. Swell index can be calculated by using two part centrifuge tube, centrifuge device, magnetic stirrer and magnetic stir bar. A known amount of the test sample (cross linked polymer or colesevelam or colesevelam hydrochloride) is transferred to upper par of centrifuge tube followed by addition of known volume of buffer solution (herein buffer solution having 0.03 M NN-bis(hydroxyethyl)2-aminoethane sulphonic acid and 0.01 M sodium chloride is prepared). The centrifuged tube was inverted and then stirred, preferably for 30 minutes at about 3500 rpm - 4000 rpm. Swell index is then calculated by following equation:
(W2-W|)- Weight of sample taken in g
Swell index = —
Weight of sample taken in g
wherein W| is weight of the centrifuge tube (without cap) along with magnetic stir bar,
W2 is weight of the centrifuge tube (without cap) along with magnetic stir bar and test sample after the stirring.
Bile acid binding capacity is calculated by using sodium glycocholate method by high pressure liquid chromatography instrument.
As used herein intermediate as well as final API i.e. colesevelam hydrochloride can be dried after the isolation from the reaction mixture using conventional methods such as air or standard tray dryer; vacuum tray dryer, fluidized bed dryer or rotatory evaporator at suitable temperature.
The order and manner of combining the reactants at any stage of the process are not important and may be varied. The reactants may be added to the reaction mixture as solids, or may be dissolved individually and . ,
solutions may be combined in any order. Wherever required, progress of the reaction is monitored by suitable chromatographic techniques such as High performance liquid chromatography (HPLC) or thin layer chromatography (TLC). Isolation and purification of final compound and intermediates described here in the present invention can be effected, if desired, by any suitable separation or purification procedure.
Main advantage of the present invention is use of new source of chloride ion for synthesis of colesevelam hydrochloride either from dried colesevelam or from wet material. Other advantage of the invention is that is provides a colesevelam having particle size less than 150 μιτι which proved highly advantageous in yielding the final product with consistent results. The process of the present invention is efficient, reproducible as well as industrially advantageous.
Having described the invention with reference to certain preferred aspects, other aspects will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES
Example 1: Preparation of poly(allylamine) hydrochloride crosslinked with epichlorohydrin
To a stirred mixture of 50% aqueous poly(allylamine) hydrochloride (2.5 kg) and water (3.75 L) was added sodium hydroxide (355 g) at ambient temperature to 40 °C. The reaction mixture was stirred at ambient temperature for I hour and cooled to 15-25 °C followed by addition of epichlorohydrin (50 ml) with stirring. The resulting mixture was stirred gently for 45 minutes. The resulting gel was stirred for an additional 18 hours at 25-30 °C. Demineralized water ( 12.5 L) was added to the reaction mixture, stirred for 1 hour, centrifuged and spin dried. The solid wet cake was rinsed three times by suspending in water ( 12.5L, 18.75L, 25L), stirring the suspension for 1 hour, and collecting the solid each time by centrifugation followed by spin drying. Isopropanol (21 .25 L) was added to the resulting solid, stirring the mixture for 1 hour, centrifuged and spin dried. The solid was dried , after which the solid was dried in at 45-50 °C for 72-100 hours to give 825 g of the title compound as a granular, brittle, white solid. The resulting product was pulverized.
Example 2: Preparation of colesevelam n e po y a y am ne g , me ano . » " r mc y ammonium brom ide (844 g) and 1 -bromodecane (504 g) was heated at 65 °C and aqueous sodium hydroxide (480 ml) was added to the reaction mass in lots and stirred at 65 °C for 20 hours. The reaction mixture was cooled to ambient temperature, centrifuged and spin dried. Methanol (53.33 L) was added to the resulting wet solid, stirred at ambient temperature for 30 minutes, centri fugcd and spin dried. The solid was twice rinsed by suspending in 2M aqueous sodium chloride (3.43 kg in 29.28 L water), stirred for 30 minutes and filtered. The resulting solid was thrice rinsed by suspending in deminerali ed water (2 1 .28 L), stirred for 30 minutes, filtered and dried at 45-50 °C for 72- 100 hours to give 1 .02 kg of title compound. The resulting product was pulverized to attain the particle si/.e of 1 50 pm.
Example 3: Preparation of colcsevelam
Mixture of crosslinked poly(al lylamine) (80 g), methanol (2. 13 L) (6-bromohexyl) trimcthyl ammonium bromide (84 g) and 1 -bromodecane (50 g) was heated at 65 °C and aqueous sodium hydroxide (480 ml) was added to the reaction mass in lots and stirred at 65 °C for 20 hours. The reaction mixture was cooled to ambient temperature for I hour, centrifugcd and spin dried. Methanol (5.3 1.) was added to the resulting wet solid, stirred at ambient temperature for 30 minutes, centri fugcd and spin dried. The solid was twice rinsed by suspending in 2M aqueous sodium chloride (343 g in 2.93 L water), stirred for 30 minutes and filtered. The resulting solid was thrice rinsed by suspending in demineralized water (2. 13 L), stirred for 30 minutes, filtered and dried at 45-50 °C for 72- 100 hours to give 100 g of title compound. The resulting product was pulverized to attain the particle size of 59 μιη.
Example 4: Preparation of colcsevelam
Mixture of crosslinked poly(allylamine) (40 g), methanol (560 ml), (6-bromohexyl) trimcthyl ammonium bromide (46.42 g) and 1 -bromodecane (25.2 g) was heated at 65 °C and aqueous sodium hydroxide (24 ml) was added to the reaction mass in lots and stirred at 65 °C for 20 hours. The reaction mixture was cooled to ambient temperature for I hour, centrifuged and spin dried. Methanol (400 ml x 2) was added to the resulting wet solid, stirred at ambient temperature for 30 minutes, centri fuged and spin dried. The solid was twice rinsed by suspending in 2M aqueous sodium chloride ( 1 7 1 g in 1 .47 L water), stirred for 30 minutes and fi ltered. The resulting solid was thrice rinsed by suspending in dem ineralized water (400 ml x 3), stirred for 30 minutes, filtered and dried at 45-50 °C for 72- 100 o .
64 μιη.
Example 5: Preparation of colesevelam hydrochloride
Method A: Colesevelam (1 kg) and 2N hydrochloric acid ( 12L) were stirred at ambient temperature for 2 hours. The product was centrifuged, washed with demineralized water (3 L) at ambient temperature, re-centrifuged and spin dried. The resulting solid was dried at 45-50 °C for 72- 100 hours to give 1.1 kg title compound as an off-white solid. The product was pulverized to attain the particle size of 62μιτι.
Method B: Colesevelam ( 100 g) and 2N hydrochloric acid (1 .2 L) were stirred at ambient temperature for 2 hours. The product was centrifuged, washed with demineralized water (300 ml) at ambient temperature, re-centrifuged and spin dried. The solid was dried at 45-50 °C for 72- 100 hours to give 105 g of title compound as an off-white solid. The product was pulverized to attain the particle size of
Chloride content: 22.3% w/w; swell index: 5.2, bile acid binding capacity: 1 .9 g/g.
Method C: To a stirred suspension of colesevelam (30 g) and water (300 ml) was added concentrated hydrochloric acid (70 ml) and stirred at ambient temperature for 2 hours. The product was centrifuged, washed with demineralized water (60 ml) at ambient temperature, re- centrifuged and spin dried. The solid was dried at 45-50 °C for 72-100 hours to give 30 g of title compound as an off-white solid. The product was pulverized to attain the particle size of 34μιη.
Method D: To a suspension of colesevelam (30 g) and methanol (300 ml) was added concentrated hydrochloric acid (70 ml) and stirred at ambient temperature for 2 hours. The product was centrifuged, washed with demineralized water (60ml), re centrifuged and spin dried. The solid was then dried at 45- 50 °C for 72- 100 hours to give 3 1 g of title compound as an off-white solid. The product was pulverized to attain the particle size of 61 μιη.
Chloride content: 22.9% w/w; swell index: 4.2, bile acid binding capacity: 2.0 g/g.
Method E: To colesevelam (30 g) was added 6N hydrochloric acid (360 ml) and stirred together at ambient temperature for 2 hours. The product was centrifuged, washed with demineralized water (60 ml), re-centrifuged and spin dried. The solid was then dried at 45-50 °C for 72- 100 hours to give 30.5 g of title compound as an off-white solid. The product was pulverized to attain the particle size of 74μιη. Chloride content: 22.8% w/w; swell index: 5.1 , bile acid binding capacity: 2.1 g/g. chloride (30 ml) and stirred at ambient temperature for 4 hours. The product was centrifuged, washed successively with demineralized water (60 ml), methanol (60 ml) and demineralized water (60ml) at ambient temperature, centrifuged each time and spin dried. The solid was then dried at 45-50 °C for 72- 100 hours to give 30 g of title compound as an off-white solid. The product was pulverized to attain the particle size of 80μιη.
Chloride content: 23.0% w/w; swell index: 6.8, bile acid binding capacity: 2.1 g/g, loss on drying: 7.1 % w/w.
Method G: To a stirred suspension of colesevelam (30 g) and water (210 ml, ammonium chloride (35 g) was added and stirred at ambient temperature for 12 hours. The product was centrifuged, washed with demineralized water (60 ml), re-centrifuged and spin dried. The solid was then dried at 45-50 °C for 72- 100 hours to give 3 1 g of title compound as an off-white solid. The product was pulverized to attain the particle size of 40μηι.
Chloride content: 22.8% w/w; swell index: 7.3, bile acid binding capacity: 2.2 g/g.
Method H: To stirred suspension of colesevelam (30 g) and water (210 ml) was added thionyl chloride ( 17 ml) and stirred at ambient temperature for 4 hours. The product was centrifuged, washed successively with demineralized water (60 ml), methanol (60ml) and demineralized water (60ml) at ambient temperature, centrifuged each time and spin dried. The solid was then dried at 45-50 °C for 72- 100 hours to give 29 g of title compound as an off-white solid. The product was pulverized to attain the particle size of 46μιη.
Method I: To a stirred suspension of colesevelam (30 g) and water (210 ml) was added acetyl chloride (30 ml) and stirred at ambient temperature for 4 hours. The product was centrifuged, washed successively with demineralized water (60 ml), methanol (60 ml) and demineralized water (60ml) at ambient temperature, centrifuged each time and spin dried. The solid was then dried at 45-50 °C for 72- 100 hours to give 29.7 g of title compound as an off-white solid. The product was pulverized to attain the particle size of 60μιη.
Example 6: Preparation of colesevelam hydrochloride
Method A: Mixture of crosslinked poly(allylamine) (80g), methanol (2.13 L), (6-bromohexyl) trimethyl ammonium bromide (84 g) and 1 -bromodecane (50 g) was heated at 65 °C with stirring for 2 hours. 50 % Aqueous sodium hydroxide (48 ml) was added to the reaction mass in lots and stirred at 65 °C for 20 hours. The reaction mixture was cooled to ambient temperature for 1 hour, centrifuged . . . ,
for 30 minutes, centrifuged and spin dried. The solid was twice, rinsed by suspending in 2M aqueous sodium chloride (343 g in 2.93 L water), stirred for 30 minutes and filtered. The resulting solid was thrice rinsed by suspending in demineraiized water (2.13 L), stirred for 30 minutes, filtered. Methanol ( 1 L) and concentrated hydrochloric acid (235 ml) was added to the resulting wet cake and stirred together at ambient temperature for 2 hours. The product was centrifuged, washed with demineraiized water (200ml) at ambient temperature, re- centrifuged and spin dried. The solid was then dried at 45-50 °C for 72- 100 hours to give 102g of title compound as an off-white solid. The product was pulverized to attain the particle size of 48μηι.
Chloride content: 22.8% w/w; swell index: 4.2, bile acid binding capacity: 2.0 g/g.
Method B: Mixture of crosslinked poly(allylamine) (80g), methanol (2. 13 L), (6-bromohexyl) trimethyl ammonium bromide (84 g) and 1 -bromodecane (50 g) was heated at 65 °C with stirring for 2 hours. 50 % Aqueous sodium hydroxide (48 ml) was added to the reaction mass in lots and stirred at 65 °C for 20 hours. The reaction mixture was cooled to ambient temperature for 1 hour, centrifuged and spin dried. Methanol (5.3 L) was added to the resulting wet solid, stirred at ambient temperature for 30 minutes, centrifuged and spin dried. The solid was twice, rinsed by suspending in 2M aqueous sodium chloride (343 g in 2.93 L water), stirred for 30 minutes and filtered. The resulting solid was thrice rinsed by suspending in demineraiized water (2. 13 L), stirred for 30 minutes, filtered. 8 N Hydrochloric acid ( 1.2 L) was added to the resulting wet cake and stirred together at ambient temperature for 2 hours. The product was centrifuged, washed with demineraiized water (200ml) at ambient temperature; re- centrifuged and spin dried. The solid was then dried at 45-50 °C for 72- 100 hours to give 103g of title compound as an off-white solid. The product was pulverized to attain the particle size of 60μιη.
Chloride content: 22.9% w/w; swell index: 5.2, bile acid binding capacity: 2. 1 g/g; loss on drying: 7.3 % w/w.
Method C: Mixture of crosslinked poly(allylamine) (80g), methanol (2.13 L), (6-bromohexyl) trimethyl ammonium bromide (84 g) and 1 -bromodecane (50 g) was heated at 65 °C with stirring for 2 hours. 50 % Aqueous sodium hydroxide (48 ml) was added to the reaction mass in lots and stirred at 65 °C for 20 hours. The reaction mixture was cooled to ambient temperature for 1 hour, centrifuged and spin dried. Methanol (5.3 L) was added to the resulting wet solid, stirred at ambient temperature for 30 minutes, centrifuged and spin dried. The solid was twice, rinsed by suspending in 2M aqueous . . . ,
thrice rinsed by suspending in demineralized water (2.13 L), stirred for 30 minutes, filtered. Water (210 ml) and trimethylsilyl chloride ( 100 ml) were added to the resulting wet cake and stirred together at ambient temperature for 4 hours. The product was centrifuged, washed successively with demineralized water (200ml), methanol (200 ml), demineralized water (200ml) at ambient temperature; re- centrifuged and spin dried. The solid was then dried at 45-50 °C for 72- 100 hours to give 10 l g of title compound as an off-white solid. The product was pulverized to attain the particle size of 69μπι.
Chloride content: 22.8% w/w; swell index: 6.7, bile acid binding capacity: 2.1 g/g.
Method D: Mixture of crosslinked poly(allylamine) (80g), methanol (2.13 L), (6-bromohexyl) trimethyl ammonium bromide (84 g) and 1 -bromodecane (50 g) was heated at 65 °C with stirring for 2 hours. 50 % Aqueous sodium hydroxide (48 ml) was added to the reaction mass in lots and stirred at 65 °C for 20 hours. The reaction mixture was cooled to ambient temperature for 1 hour, centrifuged and spin dried. Methanol (5.3 L) was added to the resulting wet solid, stirred at ambient temperature for 30 minutes, centrifuged and spin dried. The solid was twice, rinsed by suspending in 2M aqueous sodium chloride (343 g in 2.93 L water), stirred for 30 minutes and filtered. The resulting solid was thrice rinsed by suspending in demineralized water (2.13 L), stirred for 30 minutes, filtered. Water (700 ml) and ammonium chloride ( 1 17 g) were added to the resulting wet cake and stirred at ambient temperature for 12 hours. The product was centrifuged, washed with demineralized water (200 ml) at ambient temperature; re- centrifuged and spin dried. The solid was then dried at 45-50 °C for 72- 100 hours to give 100 g of title compound as an off-white solid. The product was pulverized to attain the particle size of 85μιη.
Chloride content: 22.9% w/w; swell index: 7.2, bile acid binding capacity: 2.2 g/g.
Method E: Mixture of crosslinked poly(allylamine) (80g), methanol (2.13 L), (6-bromohexyl) trimethyl ammonium bromide (84 g) and 1 -bromodecane (50 g) was heated at 65 °C with stirring for 2 hours. Aqueous sodium hydroxide (48 ml) was added to the reaction mass in lots and stirred at 65 °C for 20 hours. The reaction mixture was cooled to ambient temperature for 1 hour, centrifuged and spin dried. Methanol (5.3 L) was added to the resulting wet solid, stirred at ambient temperature for 30 minutes, centrifuged and spin dried. The solid was twice, rinsed by suspending in 2M aqueous sodium chloride (343 g in 2.93 L water), stirred for 30 minutes and filtered. The resulting solid was thrice rinsed by suspending in demineralized water (2. 13 L), stirred for 30 minutes, filtered. Water (700 ml) . . for 4 hours. The product was centrifuged, washed with demineralized water (200 ml) at ambient temperature; re- centrifuged and spin dried. The solid was then dried at 45-50 °C for 72-100 hours to give 103 g of title compound as an off-white solid. The product was pulverized to attain the particle
Figure imgf000017_0001
Loss on drying: 7.3 %; bile acid binding capacity: 2.1 g/g.
Method F: Mixture of crosslinked poly(allylamine) (80g), methanol (2.13 L), (6-bromohexyl) trimethyl ammonium bromide (84 g) and 1 -bromodecane (50 g) was heated at 65 °C with stirring for 2 hours. Aqueous sodium hydroxide (48 ml) was added to the reaction mass in lots and stirred at 65 °C for 20 hours. The reaction mixture was cooled to ambient temperature for 1 hour, centrifuged and spin dried. Methanol (5.3 L) was added to the resulting wet solid, stirred at ambient temperature for 30 minutes, centrifuged and spin dried. The solid was twice, rinsed by suspending in 2M aqueous sodium chloride (343 g in 2.93 L water), stirred for 30 minutes and filtered. The resulting solid was thrice rinsed by suspending in demineralized water (2.13 L), stirred for 30 minutes, filtered. Water (700 ml) and acetyl chloride ( 100 ml) were added to the resulting wet cake and stirred at ambient temperature for 4 hours. The product was centrifuged, washed with demineralized water (200 ml) at ambient temperature; re- centrifuged and spin dried. The solid was then dried in at 45-50 °C for 72- 100 hours to give 102 g of title compound as an off-white solid. The product was pulverized to attain the particle
Figure imgf000017_0002
Loss on drying: 7.6 %; bile acid binding capacity: 2.2 g/g.

Claims

1). A process for the preparation of colesevelam hydrochloride, comprises the steps of: a) , neutralizing poly(allylamine) hydrochloride using a base; b) . crosslinking of poly(allylamine) with epichlorohydrin to form cross linked polymer; c). alkylating the resulting polymer using 6-bromohexyl trimethyl ammonium bromide and 1 - bromodecane in the presence of base to form colesevelam; d) . isolating colesevelam from the reaction mixture; e) . optionally, drying colesevelam; and f) . converting colesevelam in to colesevelam hydrochloride of formula I. 2). The process according to claim 1 , wherein in steps a) and c) suitable base is inorganic base or organic base.
3). The process according to claim 2, wherein inorganic base includes alkali or alkaline metal hydroxides, carbonates, bicarbonates, alkoxides and organic base includes aliphatic amines, aromatic amines and ammonia and the like. 4). The process according to claim 3, wherein base is preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like;
5). The process according to claim I , wherein in step e) colesevelam is not dried and used as wet product for the synthesis of colesevelam hydrochloride. 6). The process according to claim 1 , wherein in step e) colesevelam is dried and converted to colesevelam hydrochloride.
7) . Colesevelam having particle size < 150 μιη.
8) . A process for the preparation of colesevelam hydrochloride of formula I, a), providing a solution of colesevelam in a solvent; adding a suitable source of chloride ion; c) WO 2011/154?77jevelam hydrochloride there from; and PCT/IN2011/000382 d) . optionally, purifying colesevelam hydrochloride of formula I.
9). The process according to claim 8, wherein in step a) solvent includes water, alcohol; ether; nitriles; ketones and the like or mixture thereof. 10). The process according to claim 8, wherein in step a) solvent includes methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, and acetone.
11) .The process according to claim 8 wherein in step b) source of chloride ion includes hydrogen chloride gas, solvent saturated with hydrogen chloride gas; hydrochloride salt of a suitable amine having formula NR1 R2R3. HC1 (wherein Rf R2 and R3 can be same or different and can be individually selected amongst hydrogen, substituted or unsubstituted alkyl or aryl or alkaryl, aralkyl, heteroaryl) such as ammonium chloride; sulfur compounds such as thionyl chloride; sulfuryl chloride; carboxylic acid chloride having formula R| COCI (wherein Ri is as defined above) such as acetyl chloride; silyl chloride of formula Ri R2R3SiCI (wherein Rf R2 andR} are as defined above) such as trimethyl silyl chloride; metal chlorides such as TiCl4; TiCl3; BC13; A1C13; PC13; PCI5; or alkali metal chloride such sodium chloride, potassium chloride in combination with a sulfuric acid and the like or in combination thereof.
12) . The process according to claim 1 1 solvent saturated with hydrogen chloride gas includes ethers such as isopropyl ether, methyl tertiary butyl ether; alcohols such as methanol, ethanol, isopropanol; ketones such as acetone and the like) 13).The process according to claim 8, wherein colesevelam hydrochloride is purified by washing with a suitable solvent which includes water and alcohol or mixture thereof.
14) . The process according to claim 13, wherein alcohol includes methanol, ethanol, isopropanol and the like.
15) . Colesevelam hydrochloride having at least one of following: a). Hausner ratio less than 1.25 and/or b) . compressibility index less than 20 and/or c) . Swell index 4.5- 10.0
PCT/IN2011/000382 2010-06-11 2011-06-08 'process for the preparation of colesevelam hydrochloride" WO2011154977A1 (en)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
US20150080532A1 (en) * 2013-09-19 2015-03-19 Mahendra R. Patel Process For The Preparation Of Colesevelam Hydrochloride
CN104448139A (en) * 2014-11-21 2015-03-25 新发药业有限公司 Preparation method of colesevelam hydrochloride
WO2015092669A1 (en) * 2013-12-19 2015-06-25 Chemi Spa Process for the preparation of colesevelam
CN106008813A (en) * 2016-06-15 2016-10-12 新发药业有限公司 Method for preparing colesevelam through solution polymerization

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Publication number Priority date Publication date Assignee Title
US20150080532A1 (en) * 2013-09-19 2015-03-19 Mahendra R. Patel Process For The Preparation Of Colesevelam Hydrochloride
US9475891B2 (en) * 2013-09-19 2016-10-25 Navinta, Llc Process for the preparation of colesevelam hydrochloride
WO2015092669A1 (en) * 2013-12-19 2015-06-25 Chemi Spa Process for the preparation of colesevelam
CN104448139A (en) * 2014-11-21 2015-03-25 新发药业有限公司 Preparation method of colesevelam hydrochloride
CN104448139B (en) * 2014-11-21 2016-08-17 新发药业有限公司 A kind of preparation method of colesevelam hydrocholoride
CN106008813A (en) * 2016-06-15 2016-10-12 新发药业有限公司 Method for preparing colesevelam through solution polymerization

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