(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property

Organization I
International Bureau
(10) International Publication Number
(43) International Publication Date WO 2013/087238 Al
20 June 2013 (20.06.2013) PO PCT

(51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
C08F 6/00 (2006.01) C08G 73/02 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
A61K 31/785 (2006.01) C08J3/24 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
C08F 8/00 (2006.01) G01N 1/00 (2006.01) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
C08F 26/02 (2006.01) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW,
(21) International Application Number: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM,
PCT/EP2012/066473 TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM,
(22) International Filing Date: ZW.
24 August 2012 (24.08.2012)(84) Designated States (unless otherwise indicated, for every
(25) Filing Language: English kind of regional protection available): ARIPO (BW, GH,
GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ,
(26) Publication Language: English UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
(30) Priority Data: TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
PCT/EP201 1/072613 EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
13 December 201 1 (13. 12.201 1) EP MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM,
TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
(71) Applicant (for all designated States except US): SYN- ML, MR, NE, SN, TD, TG).
THON BV [NL/NL]; Microweg 22, NL-6545 CM Nijme-
gen (NL). Declarations under Rule 4.17 :
— as to applicant's entitlement to apply for and be granted a
(72) Inventor; and
patent (Rule 4.1 7(H))
(75) Inventor/Applicant (for US only): LUTEN, Jordy
[NL/NL]; Microweg 22, NL-6545CM Nijmegen (NL). — as to the applicant's entitlement to claim the priority of the
earlier application (Rule 4.1 7(in))
(74) Agent: STERREN-MOL VAN DER, Josephine E.M.;
P.O. Box 7071, NL-6503 GN Nijmegen (NL). Published:
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kind of national protection available): AE, AG, AL, AM,
AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,

00

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©
o (54) Title: PREPARATION OF SEVELAMER WITH REDUCED CONTENT OF ALLYL AMINE
(57) Abstract: The invention relates to a process of making polyallylamine with a reduced content of residual allylamine and, con
sequently, to the use of such product in making epichlorohydrin- crosslinked polyallylamine (a sevelamer polymer) of pharmaceutic
al quality.
 PREPARATION OF SEVELAMER WITH REDUCED CONTENT OF

ALLYLAMINE

BACKGROUND OF THE INVENTION

Sevelamer is a non-absorbed phosphate binding polymer used in the treatment for the

control of serum phosphorus in patients with Chronic Kidney Disease (CKD). It is a polymer

of poly(allylamine) crosslinked with epichlorohydrin. Its chemical structure is as follows:

= number of primary amine groups (a + b = 9)

number of crosslinking groups (c = 1)
=large number to indicate extended polymer network

The compound contains multiple amines that become partially protonated in the

intestine and interact with phosphate ions through ionic and hydrogen bonding. By binding

phosphate in the gastrointestinal tract facilitating phosphorus excretion in feces, sevelamer

lowers the plasma phosphorus concentration.

Sevelamer may form acid addition salts, in which a part of the amine groups has been

neutralized by an acid ion. In existing medicinal products, sevelamer is marketed as

sevelamer carbonate (Renvela®) or sevelamer hydrochloride (Renagel®).

Process of preparing a polyallylamine crosslinked with epichlorohydrin has been

disclosed in several patent documents, e.g. in US 5,496,545, EP 0716606, EP 0831857,

EP 1133989 and EP 1676581.

 In essence, the process of making sevelamer comprises two steps:

a] In the first step, polyallylamine hydrochloride of relatively high molecular weight

(around 15 000 Da ) is prepared by polymerization of allylamine in concentrated

HC1 using a suitable initiator of polymerization such as azobis(amidinopropane)

dihydrochloride.

b] The polyallylamine polymer reacts with epichlorohydrin in alkalinized water. The

formed gel is solidified in isopropanol, washed and dried to form the final product

as a granular solid.

As the sevelamer product has to comply with requirements of pharmaceutical quality, it

must be essentially free from residual allylamine, which is a toxic compound. As the

allylamine may be quite firmly bound in the network of the sevelamer molecule (the whole

sevelamer particle must be regarded as a single molecule), it is of utmost need to use

polyallylamine with a reduced content of residual allylamine.

US 5667775 discloses a process for reducing the allylamine content in poly(allylamine

hydrochloride) by precipitation in methanol and repeated washing of the poly(allylamine

hydrochloride) with methanol. The purification is not efficient as the polymer is produced in

a granulated mass in which the allylamine is easily entrapped. Consequently, the amount of

methanol necessary to purify 1 kg of poly(allylamine hydrochloride) in the first step is around

80 kg, which is undesirable in respect of cost of goods, environment, etc.

WO 01/18072 discloses a process in which the produced polyallylamine hydrochloride

is neutralized, at least partly, in water to form a polyallylamine base solution and the counter

ions are removed preferably by electrodialysis and ultrafiltration yielding a polyallylamine

solution with reduced salt content. Such product is, after optional concentration, crosslinked

with epichlorohydrin. The content of residual allylamine should also be decreased within the

removal of salt ions by the above procedures. However, while the above process has been
shown as efficient with respect to removal of inorganic salts, no effectivity in removal of

allylamine has been demonstrated in the document.

JP 63-286405 describes a process for purifying poly(allylamine hydrochloride)

containing 9.93% unreacted allylamine by using electrodialysis using ion-exchanging

membranes and 1% sodium chloride aqueous solution at 16- 17V for 1.5h to give a product

containing 0.3% monomers.

While the prior art documents deal with several processes of how to decrease the

content of the undesired allylamine in a process of making sevelamer, an improvement in the

art is still desirable. In particular, it is desired to have a simple and efficient process for

reducing the amount of allylamine in the starting polyallylamine to an acceptable low level,

which would lead to minimal need of purification of the final sevelamer polymer.

SUMMARY OF THE INVENTION

The present invention relates to a process of making polyallylamine with a reduced

content of residual allylamine and, consequently, to use such product in making

epichlorohydrin-crosslinked polyallylamine (a sevelamer polymer) of pharmaceutical quality.

In a first main aspect, the invention provides a process of making a high-molecular-

weight polyallylamine having a content of residual allylamine of less than 500 ppm,

preferably less than 100 ppm, and most preferably less than 50 ppm, comprising subjecting

an aqueous solution of a high-molecular-weight polyallylamine comprising more than 500

ppm of residual allylamine, said solution having a pH of between 8.0 and 13.0, preferably

between 8.5 and 11.0, and most preferably between 9.0 and 10.0, and a concentration of

about 5-50 weight %, preferably between 10-40 weight % of the polyallylamine, to a partial

evaporation of volatiles at a temperature of between 40 and 80°C and a pressure of between

0.1-10 mbar (10-1000 Pa).

 Advantageously, the evaporation is performed by a distillation of the solution,

advantageously by a fractional distillation using a distillation column.

Advantageously, the amount of volatiles removed by the evaporation is 20-75% of the

original volume.

Advantageously, the average evaporation speed corresponds to removal of 5-25% of

the original volume per hour.

Advantageously, the starting polyallylamine has a content of residual allylamine less

than 30,000 ppm.

In a particular aspect, the starting polyallylamine having a content of residual

allylamine higher than 30,000 ppm is subjected to a pre-purification to obtain a

polyallylamine having a content of residual allylamine between 500-30,000 ppm and the

obtained product is subjected to the above process.

In a particular aspect, the evaporation process is monitored by measuring the content of

residual amount of allylamine in the distillation residue and is terminated after the desired

concentration of the allylamine is obtained.

In a second main aspect the invention provides a process of making a sevelamer

polymer, preferably sevelamer carbonate polymer, comprising less than 1 ppm of

physiologically extractable residual allylamine, said process comprising crosslinking the

polyallylamine having the residual allylamine content of less than 500 ppm, preferably less

than 100 ppm, and most preferably less than 50 ppm, with epichlorohydrin in water at

alkaline pH, optionally treating the product with a carbonate buffer and washing the obtained

sevelamer hydrochloride or sevelamer carbonate with water.

In a particular aspect, the polyallylamine having the residual allylamine content of less

than 500 ppm, preferably less than 100 ppm, and most preferably less than 50 ppm, is

obtained by the above purification process.

 In a third main aspect, the invention provides a process for the determination of the

physiologically extractable residual allylamine in sevelamer and/or a salt of sevelamer, such

as sevelamer hydrochloride or sevelamer carbonate, comprising:

a] Treating, under agitation, a sample comprising sevelamer with an aqueous buffer

of pH higher than 5.0, preferably between 5.0 and 9.0, at 37°C;

b] Optionally, separating the solid substrate from the liquid phase, preferably at

ambient temperature; and

c] Subjecting the liquid phase to a determination of the content of allylamine by a

suitable analytical method.

In a particular aspect, the sample comprising sevelamer of step a] is extracted for a time

period ranging from 10 to 40 hours, preferably from 20 to 30 hours and most preferably of 24

hours.

The sevelamer polymer, preferably sevelamer carbonate, comprising less than 1 ppm of

physiologically extractable residual allylamine, as well as pharmaceutical compositions

comprising it, represent a fourth main aspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is focused to a sevelamer polymer, particularly to a sevelamer

carbonate polymer, comprising less than 1 ppm of physiologically extractable residual

allylamine. The objective of the invention is to provide a process of separating a high-

molecular-weight polyallylamine from residual allylamine to obtain a high-molecular-weight

polyallylamine having a content of less than 500 ppm, preferably less than 100 ppm, and

most preferably less than 50 ppm, of residual allylamine. Another objective of the invention

is the use of such high-molecular-weight allylamine with the reduced amount of residual
allylamine in a process for making a sevelamer polymer, preferably sevelamer carbonate,

having less than 1 ppm of physiologically extractable allylamine.

Polyallylamine is a cationic polymer comprising ionizable amino groups.

Consequently, at least part of these groups may be neutralized by an acid ion, such as a

chloride ion, to form a "salt" of the polyallylamine. The term "polyallylamine", as used

throughout the invention, relies also to such salts of polyallylamine, typically to

polyallylamine hydrochloride.

Within the present invention, the polyallylamine (and/or a salt thereof) is a high-

molecular- weight polyallylamine. The "high-molecular-weight polyallylamine" within the

invention typically has an average molecular weight greater than about 10.000 and more

preferably greater than about 15.000. Preferably the high-molecular-weight polyallylamine

polymer used in the invention typically has an average molecular weight less than 100.000.

Polyallylamine hydrochloride polymer, the product of polymerization of allylamine

hydrochloride, is the preferred polyallylamine polymer.

The "content" of residual allylamine, as used throughout this invention, is the relative

mass amount of allylamine in respect to:

• The total mass of the polyallylamine polymer, which comprises, if relevant, also the

mass of the polyallylamine salt; and/or

• The total mass of sevelamer or a sevelamer salt polymer.

Polyallylamine polymers are commercially available in various molecular weights,

including the high-molecular- weight polyallylamine as defined above. This one is typically

available in the form of an aqueous solution of a polyallylamine hydrochloride, i.e. having at

least a part of the amino-groups saturated by a chloride anion. The polyallylamine

hydrochloride can be typically prepared by a polymerization of allylamine hydrochloride in

the presence of an azo-type radical initiator by methods known in the art. Concentration,
nature and amount of the radical initiator, pH and temperature of polymerization affect the

molecular weight of the resulting polymer. The high-molecular-weight polyallylamine may

be obtained by a proper selection of these variables.

The high-molecular-weight polyallylamine hydrochloride is typically obtained in the

form of an aqueous solution after the polymerization. An isolated form of polyallylamine

hydrochloride may be obtained, e.g., by treatment of the solution with methanol, wherein the

polymer precipitates. For purpose of further use in making sevelamer polymer, i.e. for

purpose of the subsequent crosslinking reaction with epichlorohydrin, it is, however, not

necessary to isolate the polyallylamine from the aqueous solution. Instead, the original acidic

solution of polyallylamine hydrochloride may be neutralized to an alkaline pH and said

alkaline solution may be subjected to the reaction with epichlorohydrin.

In a polymerization process known in the art, the aqueous solution of high-molecular-

weight polyallylamine hydrochloride obtained after the polymerization reaction typically

comprises 1-5% (10000-50000 ppm) of residual allylamine. Known purification processes

focused to a further removal of the residual allylamine often do not lead to a proper result.

For instance, as shown above, a process of JP 63-286405 based on electrodialysis using ion-

exchanging membranes and 1% sodium chloride aqueous solution gives a product containing

0.3% (30000 ppm) of residual allylamine. The use of polyallylamine of such quality,

however, requires, after subjecting it to a crosslinking reaction with epichlorohydrin, a further

purification of the crosslinked product (the sevelamer polymer), wherein such purification

has a low degree of efficacy due to the gel-like nature of the sevelamer capable to a relatively

firm adsorption of the allylamine within the polymer network.

Now it was found that sevelamer polymer having an extraordinary low amount of

residual allylamine may be prepared by a simple process without need of a specific

purification step for the removal of residual allylamine from the crude sevelamer polymer.
The key step in the overall inventive process is a step of making the high-molecular-weight

allylamine polymer with a low content of residual allylamine; the amount of allylamine is so

low that, within the ordinary crosslinking and subsequent separation processes, the sevelamer

polymer product may be obtained with a pharmaceutically acceptable level of residual

allylamine. In particular, the process of the present invention may provide a sevelamer

hydrochloride or carbonate polymer comprising less than 1 ppm of physiologically

extractable residual allylamine. The "physiologically extractable residual allylamine" as used

within this invention is that portion of the total amount of residual allylamine actually present

in the sevelamer polymer, which is removable from the polymer under physiological

conditions, i.e. by an extraction with a buffer of physiological pH, which typically is a buffer

of pH between 5.0 and 9.0, preferably about 6.5, at 37°C (which corresponds to the

temperature of human body). The determination of physiologically extractable residual

allylamine shows how much of the toxic allylamine may interact with human body fluid and

thus affect the safety of the taken sevelamer medicine. It thus represents an important

parameter in the quality control of both the sevelamer active substance and the

pharmaceutical compositions comprising it.

In a first aspect of the present invention, an aqueous solution of high-molecular- weight

polyallylamine comprising more than 500 ppm of residual allylamine, said solution having a

pH of between 8.0 and 13.0, preferably between 8.5 and 11.0 and most preferably between

9.0 and 10.0, and a concentration of about 5-50 weight %, preferably between 10-40 weight

% of the polyallylamine, is subjected to a partial evaporation of volatiles at a temperature of

between 40-80°C and a pressure of between 0.1-10 mbar (10-1000 Pa).

The "aqueous solution" of the polyallylamine is substantially free from any other

solvent except water.

 The "temperature" of the evaporation is the temperature of the polyallylamine -

comprising solution.

In general, the starting aqueous solution of high-molecular-weight polyallylamine

comprising more than 500 ppm of residual allylamine is the solution obtained by a

conventional polymerization process, the conditions of which were adjusted to produce

polyallylamine of a molecular weight between 10.000 and 100.000. Typically, the initial

acidic pH of the solution after the polymerization is further adjusted to a pH range of between

8.0 and 13.0, preferably between 8.5 and 11.0 and most preferably between 9.0 and 10.0, by

ordinary processes; in addition, residual salt ions may be also removed, at least partly, by a

dialysis or similar methods. Typically, such solution after polymerization comprises from 1 to

5 weight % of residual allylamine. In an advantageous embodiment, the starting high-

molecular- weight polyallylamine comprises less than 3% (30000 ppm) and preferably less

than 2% (20.000 ppm) of residual allylamine; under this condition a single partial evaporation

process of the present invention is sufficient to yield the polyallylamine of the desired

quality. At higher concentrations of residual allylamine, the partial evaporation process has to

be often repeated; thus, any suitable pre-treatment of the polyallylamine solution leading to a

reduction of the content of residual allylamine to the range of between 500 and 30000 ppm,

may be performed instead.

The desired concentration of the polyallylamine solution prior to the evaporation step is

within the range of about 5-50 weight %, preferably between 10-40 weight % . If the solution

after the polymerization is not within these ranges, the volume may be adjusted by methods

known per se.

The step of partial evaporation of volatiles from the aqueous solution of a high-

molecular- weight polyallylamine may be performed, e.g., as a simple evaporation, e.g. on a

rotary vacuum evaporator. Advantageously however, the evaporation is performed by means

of a batch distillation with condensing and receiving the evaporated volatiles. The distillation

may be a simple distillation or, advantageously, a fractional distillation (a rectification) where

a part of the evaporated and condensed liquid has been returned back to the pot. For such

purpose, a suitable distillation column may be used.

Advantageously, the amount of volatiles removed by the evaporation corresponds to

20-75% of the original volume of the solvent. In some embodiments, the amount of volatiles

removed may exceed 75%. The advantageous speed of evaporation typically corresponds to a

removal of 5-25% of the original volume per hour.

In an advantageous embodiment, the course and effectivity of the evaporation process

may be monitored by measuring the content of the residual amount of allylamine in the

distillation residue. Any suitable method, for instance a GC method or an HPLC method, may

be employed. Accordingly, the evaporation process is terminated after the desired

concentration of the allylamine in the distillation residue is obtained.

The so obtained polyallylamine having a residual allylamine content of less than 500

ppm, preferably less than 100 ppm, and most preferably less than 50 ppm is obtained mainly

in the form of a free base. Typically, less than 10% of the amino-groups are protonated and

bound to an acid anion. According to a further aspect of the present invention, it is used for

making sevelamer polymer, typically sevelamer hydrochloride or carbonate, comprising less

than 1 ppm of physiologically extractable residual allylamine. In essence, said process of

making sevelamer polymer comprises a step of crosslinking the polyallylamine having a

residual allylamine content of less than 500 ppm, preferably less than 100 ppm, and most

preferably less than 50 ppm, with epichlorohydrin in water at alkaline pH, optionally

followed by treating the product with a carbonate buffer and washing the obtained sevelamer

hydrochloride or sevelamer carbonate with water.

 The crosslinking reaction with epichlorohydrin is typically performed with the

distillation residue obtained in the above process of removal of the residual allylamine. The

distillation residue is typically adjusted by water or by a water-miscible solvent, e.g. by

acetonitrile, to a concentration of between 10-40 weight %, preferably of between 15-30%, of

polyallylamine. No adjustment of pH is generally required.

The conditions of the reaction with epichlorohydrin are well known in the art.

Epichlorohydrin is preferably used in an amount of about 5-15% w/w of polyallylamine.

The sevelamer hydrochloride resulting from the crosslinking reaction is allowed to cure

and form a gel. Typically, curing takes about 16-36, about 18-30, or about 16-18 hours. The

gel is preferably washed, preferably with a water-miscible solvent, followed by water, to

obtain wet sevelamer hydrochloride. The preferred water-miscible solvent comprises an

alcohol, such as methanol, isopropanol, or a combination thereof.

The sevelamer hydrochloride may then undergo an anion exchange reaction with an

aqueous solution of a carbonate, typically with an alkali or alkaline earth metal carbonate to

form sevelamer carbonate. Preferably, the carbonate is ammonium carbonate, sodium

carbonate, or potassium carbonate. The concentration of the carbonate solution used is

preferably about 0.5-2.0 M . The contact time of the wet product with the carbonate solution is

preferably at least 2 hours; in some embodiments, a repeated contacting with fresh carbonate

solutions may be performed. The sevelamer carbonate is then washed with water, and

separated by filtration or centrifugation.

Alternately, the sevelamer hydrochloride may be converted to sevelamer carbonate by

an anion exchange reaction with carbon dioxide at alkaline pH.

Advantageously, the sevelamer carbonate is dried, preferably in an air tray dryer or a

fluidized bed dryer. Preferably, the drying temperature is about 40-100°C. The material can
be optionally milled after drying. Preferably, the sevelamer carbonate is milled to achieve an

average particle size of less than 100 microns.

Sevelamer carbonate obtained according to the process of the present invention

preferably has a chloride content of less than about 2% w/w, preferably less than about 1%

w/w, most preferably than about 0.5% w/w. Preferably the pH is about 8.0- 11.0 in a 1%

solution. LOD (Loss on Drying) of sevelamer carbonate obtained according to the above

processes is preferably not more than (NMT) 7% w/w, preferably below 5% w/w.

Preferably, the obtained sevelamer carbonate has a phosphate binding capacity of about

5.0-7.0 mmol/g.

Similarly, optionally, sevelamer hydrochloride may be prepared using the technique of

processing and drying described above.

In a particular aspect, the present invention provides sevelamer hydrochloride and/or

carbonate having a content of physiologically extractable residual allylamine (as explained

above) of less than 1 ppm. Such extraordinary low amount of residual allylamine is obtained

by crosslinking a polyallylamine, preferably high-molecular- weight polyallylamine, which

comprises less than 500 ppm, preferably less than 100 ppm, and most preferably less than 50

ppm of residual allylamine, and which is typically obtained by the above process of the

present invention, followed by isolation procedures disclosed above.

A confirmation of the actual content of the physiologically extractable residual

allylamine may be done by measuring it by a suitable analytical method. However, no such

method has been reported in the prior art.

A suitable process for the determination of the physiologically extractable residual

allylamine in sevelamer and/or a salt of sevelamer, such as sevelamer hydrochloride or

sevelamer carbonate, comprises:

 a] Treating, under agitation, a sample comprising sevelamer with an aqueous buffer

of pH higher than 5.0, preferably between 5.0 and 9.0, at 37°C;

b] Optionally, separating the solid substrate from the liquid phase, preferably at

ambient temperature; and

c] Subjecting the liquid phase to a determination of the content of allylamine by a

suitable analytical method.

Sub a]

Typically, a sample of sevelamer and/or a salt of sevelamer is stirred in a milligram

amount (typically 5 to 100 mg) in a flask comprising several milliliters (typically 1-10 ml) of

the buffer at 37 °C for a suitable time. The extraction time typically ranges from 10 to 40

hours, preferably from 20 to 30 hours and most preferably is 24 hours. The buffer is

advantageously a borate buffer, preferably of a concentration of between 1 to 50 mM, most

preferably between 5 and 25 mM. As allylamine is a volatile product, the extraction is

advantageously performed in a closed vial.

Sub b]

The separation step provides a liquid sample comprising the extracted residual

allylamine, which is not contaminated by the solid. Typically, the liquid phase may be

separated by filtration or centrifugation, and may be optionally diluted by water to a desired

volume. Alternately, the separation may be only partial, i.e. the solid is allowed to sediment

either spontaneously or in a centrifuge and a sample of the supernatant is taken for analysis.

Sub c]

The liquid extract can be analyzed by any appropriate analytical method developed in

the art for separation and quantification of allylamine, or of aliphatic amines or amino acids.
 Typically, a chromatographic method, such as high performance liquid chromatography

(HPLC) may be used. Advantageously, the allylamine in the sample may be subjected to a

derivatization to provide a derivative with better detectability, e.g. by increased absorbance,

or by fluorescence. Thus, in a particular aspect, the process of the present invention also

comprises a step of treating the liquid sample comprising allylamine with a derivatization

agent. For HPLC purposes, a suitable derivatization agent may be, e.g., 6-Aminoquinolyl-N-

hydroxysuccinimidyl carbonate (AccQ-Tag™, Waters), fluorenylmethylchloroformate

(FMOC), dimethylamino-naphthalensulphonyl chloride (Dansyl-Cl), phenylisothiocyanate

(PITC), ortho-phthaldialdehyde, etc.

In general, an HPLC method after a derivatization of allylamine in the sample prepared

by the above process is the most useful method for determining the content of the allylamine.

Proper stationary and mobile phase may be determined by experimentation; in general,

chromatographic columns and mobile phases useful for analyses of amino acids and their

derivatives may be used.

Other useful methods to separate, identify and quantify allylamine may be ion

chromatography, gas chromatography or capillary electrophoresis.

Advantageously, the useful analytical method should have a limit of detection of 0 . 1

ppm or lower.

In an advantageous way, the processes of determination of the content of the

physiologically extractable residual allylamine according to the present invention may be

used for the analysis of a sample of sevelamer hydrochloride or carbonate for use in

pharmaceutical applications. The sample of the sevelamer hydrochloride or carbonate may be

a sample of the active substance per se or a sample or the final pharmaceutical composition

comprising sevelamer hydrochloride or carbonate, for instance a tablet or a powder for oral

suspension.
 The invention will be further described with reference to the following non-limiting

examples.

Example 1 Process for making sevelamer carbonate

A 25% w/w solution of poly(allylamine).HCl, containing 1.5% of allylamine, was

prepared. The pH was adjusted with NaOH to pH 10 and the solution was divided equally

into four flasks in such a way that each flask contained 5 g of polyallylamine. Each flask was

subjected to evaporation at a certain temperature and pressure (see table below) for 2 hours.

Content of allylamine in flasks 1-3 was about 20 ppm.

The mass loss due to evaporation of water was compensated by adding water to obtain

a 25% solution and epichlorohydrin (0.5 ml) was added to each flask. The solutions were

stirred for 30 minutes (gel point) and then cured for 18 hr. The gel was cut into particles and

washed with carbonate buffer (70 ml, 1.0 M, pH 9.5), followed by washing three times with

water (70 ml) and then with isopropanol (120 ml). The resulting white material was dried

overnight at 40 C under vacuum and milled.

The content of physiologically extractable residual allylamine in the respective

samples 1-4, determined by HPLC, was as follows:

 Reactor Allylamine content

1 0.87 ppm

2 0.20 ppm

3 0.17 ppm

4 1.50 ppm

Example 2 Process for analyzing sevelamer carbonate

Extraction process for the drug substance

30 mg of sevelamer carbonate was weighed into a safe-lock tube of 2 mL and 1.5 mL

of 10 mM boric acid was added. The tube was vortexed until all powder was released from

the bottom of the tube. The tube was placed in a thermostated mechanical shaker for 24 hours

at 37°C at 1400 rpm. Subsequently, the tube was centrifuged for 10 minutes at 14,650 rpm.

Extraction process for 800 mg tablet

800 mg sevelamer carbonate tablet was transferred into a ball mill and grinded until

fine powder was obtained (30 hrs for 30 seconds). 42.5 mg of the powder was transferred into

a safe-lock tube of 2 mL and 1.5 mL of 10 mM boric acid was added. The tube was vortexed

until all powder was released from the bottom of the tube. The tube was placed in a

thermostated mechanical shaker for 24 hours at 37°C at 1400 rpm. Subsequently, the tube

was centrifuged for 10 minutes at 14,650 rpm.

Derivatization

Three milligram of commercially available AccQ-Tag reagent (6-aminoquinolyl-N-

hydroxysuccinimidyl carbamate) is dissolved in 1 mL acetonitrile and completely dissolved

by agitation and mildly heating. An appropriate amount of the extract from the extraction

process step (by preference \ µ 30 µ (the latter when there are low amounts of
allylamine present)) is mixed with 70 µ of AccQ-tag Ultra Borate buffer in an appropriate

vial. To this mixture 20 µ of the dissolved AccQ-Tag reagent is added, mixed immediately

and then placed for 5 minutes at 55 °C. The derivatized extract is ready for HPLC analysis.

Analysis

Analysis of the derivatized sample was performed by UPLC method on an AccQ-Tag

Ultra column (2.1 xlOO mm, dp 1.7 µιη) using conditions as prescribed by the manufacturer

of the column for analysis of derivatized amino acids.

The invention having been described it will be obvious that the same may be varied in

many ways and all such modifications are contemplated as being within the scope of the

invention as defined by the following claims.

 CLAIMS

1. A process of making a high-molecular-weight polyallylamine having a content of

residual allylamine of less than 500 ppm, preferably less than 100 ppm and most

preferably less than 50 ppm, comprising subjecting an aqueous solution of a high-

molecular-weight polyallylamine having a content of more than 500 ppm of residual

allylamine, said solution having a pH of between 8.0-13.0, preferably between 8.5-1 1.0

and most preferably between 9.0-10.0, and a concentration of about 5-50 weight %,

preferably between 10-40 weight % of the polyallylamine, to a partial evaporation of

volatiles at a temperature of between 40 and 80°C and a pressure of between 0.1-10

mbar.

2. The process according to claim 1, wherein the evaporation is performed by a distillation

of the solution, advantageously by a fractional distillation using a distillation column.

3. The process according to claims 1-2, wherein the amount of volatiles removed by the

distillation is 20-75% of the original volume.

4. The process according to claims 1-3, wherein the average evaporation speed

corresponds to removal of 5-25% of the original volume per hour.

5. The process according to claims 1-4, wherein the starting polyallylamine has a content

of residual allylamine less than 30,000 ppm.

6. The process according to claims 1-5, wherein the content of allylamine in the

distillation residue is monitored by an analytical method.

7. The process according to claims 1-6, wherein the high-molecular-weight

polyallylamine of a content of 500-30,000 ppm of residual allylamine is obtained by

subjecting a high-molecular-weight polyallylamine having a content higher than 30,000

ppm to a pre-purification step.

8. A process of making a sevelamer hydrochloride polymer comprising less than 1 ppm of

physiologically extractable residual allylamine, said process comprising crosslinking

the polyallylamine having a residual allylamine content of less than 500 ppm,

preferably less than 100 ppm, and most preferably less than 50 ppm, with

epichlorohydrin in water at alkaline pH, and washing the obtained sevelamer

hydrochloride with water.

9. A process of making a sevelamer carbonate polymer comprising less than 1 ppm of

physiologically extractable residual allylamine, said process comprising crosslinking

the polyallylamine having a residual allylamine content of less than 500 ppm,

preferably less than 100 ppm, and most preferably less than 50 ppm, with

epichlorohydrin in water at alkaline pH, treating the product with a carbonate buffer

and washing the obtained sevelamer carbonate with water.

10. The process according to claims 8-9, wherein the polyallylamine having the residual

allylamine content of less than 500 ppm, preferably less than 100 ppm and most

preferably less than 50 ppm, is obtained by the process of claims 1-7.

11. The process according to claims 8-10, further comprising a step of subjecting the

sevelamer to a process of determination of the content of the physiologically

extractable residual allylamine by an analytical method.

12. A process for the determination of the physiologically extractable residual

allylamine in sevelamer and/or a salt of sevelamer, such as sevelamer hydrochloride or

sevelamer carbonate, comprising:

a] treating, under agitation, a sample comprising sevelamer with an aqueous buffer

of pH higher than 5.0, preferably between 5.0 and 9.0, at 37°C;

b] optionally, separating the solid substrate from the liquid phase, preferably at

ambient temperature; and

 c] subjecting the liquid phase to a determination of the content of allylamine by a

suitable analytical method.

13. The process for determination of claim 12 in which the sample comprising sevelamer of

step a] is extracted for a time period ranging from 10 to 40 hours, preferably from 20 to

30 hours and most preferably of 24 hours.

14. A sevelamer polymer, preferably sevelamer carbonate, comprising less than 1 ppm of

physiologically extractable residual allylamine.

15. A pharmaceutical composition for oral administration of sevelamer comprising the

sevelamer polymer according to claim 14.

16. Use of a high-molecular-weight polyallylamine having a residual allylamine content of

less than 500 ppm, preferably less than 100 ppm and most preferably less than 50 ppm

in a process for making a sevelamer polymer, preferably sevelamer carbonate, having a

content of less than 1 ppm of physiologically extractable residual allylamine.

A . CLASSIFICATION O F SUBJECT MATTER
INV. C08F6/00 A61K31/785 C08F8/00 C08F26/02 C08G73/02
C08J3/24 GOlNl/00
ADD.
According to International Patent Classification (IPC) o r t o both national classification and IPC

B . FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
C08F A61K C08G C08J G01N

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

EPO-Internal , WPI Data

C . DOCUMENTS CONSIDERED TO B E RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

US 6 395 849 Bl (KATO TADASHI [JP] ET AL) 1-7

28 May 2002 (2002-05-28)
paragraph [0086] ; exampl e s 6 , 14, 17 8-16

0 2011/099038 A2 (SUN PHARMACEUTICAL IND 1-16

LTD [IN] ; JADAV KANKSINH JESINGBHAI [IN] ;
PATEL) 18 August 2011 (2011-08-18)
page 1, l i ne 13 - page 3 , l i ne 3
page 3 , l i ne 27 page 4 , l i ne 9
page 5 , l i ne 1 1 l i ne 14; c l aims 1-11 ;
exampl e s 1, 2
page 7 , l i ne 1 page 10, l i ne 14

US 2009/155368 Al (HOLMES-FARLEY STEPHEN 14-16

RANDALL [US] ET AL)
18 June 2009 (2009-06-18)
paragraphs [0307] , [0315] , [0432] ; 1-13
c l aims 1-39 ; tabl e 18

-/-
X| Further documents are listed in the continuation of Box C . XI See patent family annex.

* Special categories of cited documents :

"T" later document published after the international filing date o r priority
date and not in conflict with the application but cited to understand
"A" document defining the general state of the art which is not considered
the principle o r theory underlying the invention
to be of particular relevance
"E" earlier application o r patent but published o n o r after the international
"X" document of particular relevance; the claimed invention cannot be
filing date considered novel o r cannot b e considered to involve a n inventive
"L" documentwhich may throw doubts o n priority claim(s) orwhich is step when the document is taken alone
cited to establish the publication date of another citation o r other
"Y" document of particular relevance; the claimed invention cannot be
special reason (as specified)
considered to involve a n inventive step when the document is
"O" document referring to a n oral disclosure, use, exhibition o r other combined with one o r more other such documents, such combination
means being obvious to a person skilled in the art
"P" document published prior to the international filing date but later than
the priority date claimed "&" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

16 November 2012 23/11/2012

Name and mailing address of the ISA/ Authorized officer
European Patent Office, P.B. 5818 Patentlaan 2
NL - 2280 HV Rijswijk
Tel. (+31-70) 340-2040,
Fax: (+31-70) 340-3016 Gol d , Josef
C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

US 2005/239901 Al (CHANG HAN T [US] ET A L 14-16

CHANG HAN TING [US] ET AL)
2 7 October 2005 (2005-10-27)
c l aims 1-20 1-13

0 2008/062437 A2 (USV LTD [IN] ; HEDGE 14-16

DEEPAK ANANT [IN] ; CHOUDHARY VARSHA
SHASHANK [IN] ; ) 29 May 2008 (2008-05-29)
page 29 , l i ne 3 - l i ne 28; c l aims 36-39 1-13

W0 2008/005217 A2 (GENZYME CORP [US] ; 14-16

HUVAL CHAD C [US] ; DHAL PRADEEP K [US] ;
H0LMES-FARL) 10 January 2008 (2008-01-10)
c l aims 1-45 1-13

W0 2010/041274 A2 (SHASUN CHEMICALS AND 8-13

DRUGS LTD [IN] ; THAKASHINAMOORTY CHANDI RAN
[IN] ; ) 15 Apri l 2010 (2010-04-15)
page 2 , l i ne 2 7 - l i ne 34; c l aims 1-11 ; 1-7 ,
exampl e s 1-5 14-16
 Patent document Publication Patent family Publication
cited in search report date member(s) date

US 6395849 Bl 28-05-2002 AU 9184998 A 17-05-1999

P 3659404 B2 15-06-2005
US 6395849 Bl 28-05-2002
O 9921901 Al 06-05-1999

WO 2011099038 A2 18-08-2011 NONE

US 2009155368 Al 18-06-2009 AR 072652 Al 15-09-2010

EP 2222313 Al 01-09-2010
P 2011506448 A 03-03-2011
PA 8807201 Al 23-07-2009
PE 13312009 Al 18-09-2009
TW 200930384 A 16-07-2009
US 2009155368 Al 18-06-2009
UY 31530 A 14-12-2009
WO 2009078956 Al 25-06-2009

US 2005239901 Al 27-10-2005 NONE

W0 2008062437 A2 29-05-2008 CA 2661987 Al 29 -05 -2008

CA 2749074 Al 29 -05 -2008
EP 2064252 A2 03 -06 -2009
EP 2441779 Al 18 -04 -2012
P 2010502590 A 28 -01 -2010
KR 20090051240 A 2 1 -05 -2009
RU 2009111853 A 1 -10 -2010
US 2009280178 Al 12 -11 -2009
US 2010092421 Al 1 5 -04 -2010
WO 2008062437 A2 29 -05 -2008

W0 2008005217 A2 10-01-2008 EP 2043627 A2 08-04-2009

JP 2009542653 A 03-12-2009
US 2010135950 Al 03-06-2010
W0 2008005217 A2 10-01-2008

W0 2010041274 A2 15-04-2010 NONE