FORM2THE PATENTS ACT, 1970(39 of 1970)&The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10; rule 13)1. Title of the invention AN IMPROVED PROCESS FOR THE PREPARATION OF AN AMORPHOUS FORM OF PENTOSAN POLYSULFATE OR SALTS THEREOF.2. Applicant(s) (a) NAME : ALEMBIC LIMITED(b) NATIONALITY : An Indian Company.(c) ADDRESS : Alembic Campus, Alembic Road, Vadodara - 390 003, Gujarat, India.3. PREAMBLE TO THE DESCRIPTIONThe following specification particularly describes the invention and the manner in which it is to be performed:

Field of Invention
The present invention relates to an improved process for the preparation amorphous form of Pentosan polysulfate of formula (I)

or salt thereof, wherein R represents -SO3Y, and Y is at least one member selected from the group consisting of H and a pharmaceutically acceptable cation such as sodium and potassium.
Background of the invention
Pentosan polysulfate sodium is chemically known as b-D-Xylan, (1-4), 2, 3-bis (hydrogen sulphate) sodium salt having molecular weight range of 4000 to 6000 Dalton. The structural formula of Pentosan polysulfate sodium represents as below:


OS03Na

Pentosan Polysulfate sodium

The current pharmaceutical product containing Pentosan polysulfate sodium salt is being sold by Ortho McNeil under the tradename Elmiron® in the form of capsules which is used for the treatment of bladder infection, interstitial cystitis and tumors.
Pentosan polysulfate sodium [37319-17-8] is a semi-synthetically produced heparin-like macromolecular carbohydrate derivative which chemically and structurally resembles glycosaminoglycans. It is a white odorless powder, slightly hygroscopic and soluble in water.
Pentosan polysulfate sodium is a mixture of linear polymers of P-l -> 4-linked xylose, usually sulfated at the 2- and 3-positions and occasionally substituted at the 2-position with 4-0-methyl-a-D-glucuronic acid 2, 3-O-suflate.
Pentosan polysulfate is a semi-synthetic compound whose polysaccharide backbone, xylan is extracted from the bark of the beech tree or other plant sources and then treated with sulfating agents such as chlorosulfonic acid or sulfuryl chloride and acid. After sulfation, Pentosan polysulfate is usually treated with sodium hydroxide to yield the sodium salt.
Pentosan polysulfate is disclosed in US patent no. 2689848. The process wherein Xylan is treated with chlorosulfonic acid in the presence of pyridine to obtain sulfuric acid ester salt of xylan followed by oxidative depolymerisation in acidic or neutral aqueous medium to obtain depolymerised product which is dialyzed and followed the fractionation process to obtain desired product. However, this process does not provide end product with desired molecular weight. .
US patent 2689848 disclosed the process for the production of salts of sulfuric acid ester of Xylan, the steps which comprise oxidizing the aqueous solution of the a salt of a sulfuric acid ester of highly polymeric xylan in an aqueous solution of H2O2 and H2SO4 to depolymerize such highly polymeric xylan ester partially, dialyzing the depolymerized product and fractionating an aqueous solution of the dialyzate with an organic water
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miscible solvent to obtain a fraction having a Zh value between 0.0030 and 0.015 and sulfur content of 13.5 to 17%.
Moreover, the process as disclosed above for the preparation of Pentosan polysulfate is tedious, costly and provides low yield of final product. Moreover, the use of cellophane tubes for dialysis makes process inapplicable at industrial scale up.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes in solid state. The polymorphic and pseudopolymorphic solids display different physical properties, including those due to packing, and various thermodynamic, spectroscopic, interfacial and mechanical properties (See H. Brittain, Polymorphism in Pharmaceutical Solids, Marcel Dekker, New York, N.Y., 1999, pp. 1-2). It is known that the amorphous form of an individual pharmaceutical active substance has different dissolution characteristics and a different bioavailability in comparison to crystalline forms (Konno T., Chem. Pharm. Bull., 1990, 38:2003-2007). It is generally known that pharmaceutical active substances in amorphous form are better soluble, or dissolve more quickly than crystalline ones.
Therefore, it is necessary to develop an improved process for preparation of Pentosan polysulfate sodium which provides high yield as well as feasible at an industrial scale.
The present inventors has carried out spray drying of aqueous solution of crude Pentosan polysulfate of formula (I) or salt which provides unexpectedly high yield and high purity of an amorphous form of Pentosan polysulfate sodium having molecular weight of 4000 to 6000 Dalton.
Summary of the invention
The present invention relates to provide an improved process for preparation of an amorphous form of Pentosan polysulfate sodium, comprising steps of:
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i) dissolving crude Pentosan polysulfate sodium having molecular weight of
4000 to 6000 Dalton in water
ii) spray drying the solution obtained in step (i) to obtain amorphous form of
Pentosan polysulfate sodium
Object of the invention
It is therefore an object of the present invention is to provide an improved process for the preparation of an amorphous form of Pentosan polysulfate of formula (I) or salt thereof.
Another object of the present invention is to provide the process for the preparation of an amorphous form of Pentosan polysulfate of formula (I) or its salt which is operationally simple, easy to handle and applicable at an industrial scale.
A further object of the present invention is to provide an improved process for preparation of an amorphous form of Pentosan polysulfate of formula (I) or salt thereof, comprising steps of:
i) dissolving crude Pentosan polysulfate of formula (I) or its salt in water
ii) filtering the reaction mixture obtain in the step (i) with NF membrane system iii) concentrating filtrate obtained in step (ii) up to 1/10 of the original volume
iv) adjusting the pH of solution obtained in step (iii) at 6.5 to 7.0 with dilute
NaOH
v) spray drying the solution obtained in step (iv) to obtain amorphous form of Pentosan polysulfate of formula (I) or its salt
A further object of the present invention is to provide an improved process for
preparation of an amorphous form of Pentosan polysulfate sodium, comprising steps of:
i) dissolving crude Pentosan polysulfate sodium in water
ii) filtering the reaction mixture obtain in the step (i) with NF membrane system
iii) concentrating filtrate obtained in step (ii) up to 1/10 of the original volume
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iv) adjusting the pH of solution obtained in step (iii) at 6.5 to 7.0 with dilute
NaOH
v) spray drying the solution obtained in step (iv) to obtain amorphous form of
Pentosan polysulfate sodium
Yet another object of the invention is to provide an improved process for preparation of an amorphous form of Pentosan polysulfate sodium, comprising steps of:
iii) dissolving crude Pentosan polysulfate sodium having molecular weight of
4000 to 6000 Dalton in water
iv) spray drying the solution obtained in step (i) to obtain amorphous form of Pentosan polysulfate sodium
Brief description of the drawings
Fig-1 represents the powder X-ray diffraction (XRD) pattern of an amorphous form of Pentosan polysulfate sodium prepared by spray drying technique.
Detailed description of the invention
According to one aspect, present invention provides an improved process for the preparation of an amorphous form of Pentosan polysulfate of formula (I),

(I)
or salt thereof, wherein R represents -SO3Y, and Y is at least one member selected from the group consisting of H and a pharmaceutically acceptable cation such as sodium and potassium.
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According to another aspect, present invention provides an improved process for the preparation of an amorphous form of Pentosan polysulfate of formula (I) or salt thereof, which is operationally simple, easy to handle and applicable at an industrial scale.
Further aspect of the present invention is to provide an improved process for preparation of an amorphous form of Pentosan polysulfate of formula (I) or salt thereof, comprising steps of:
i) dissolving crude Pentosan polysulfate of formula (I) or its salt in water
ii) filtering the reaction mixture obtain in the step (i) with NF membrane
system
iii) concentrating filtrate obtained in step (ii) up to 1/10 of the original volume
iv) adjusting the pH of solution obtained in step (iii) at 6.5 to 7.0 with dilute
NaOH
v) spray drying the solution obtained in step (iv) to obtain amorphous form of
Pentosan polysulfate of formula (I) or its salt
A further object of the present invention is to provide an improved process for
preparation of an amorphous form of Pentosan polysulfate sodium, comprising steps of:
i) dissolving crude Pentosan polysulfate sodium in water
ii) filtering the reaction mixture obtain in the step (i) with NF membrane
system
iii) concentrating filtrate obtained in step (ii) up to 1/10 of the original volume
iv) adjusting the pH of solution obtained in step (iii) at 6.5 to 7.0 with dilute
NaOH
v) spray drying the solution obtained in step (iv) to obtain amorphous form of
Pentosan polysulfate sodium
According to present invention, Sodium salt of sulfuric acid ester of xylan dissolved in water at room temperature and pH of the reaction mixture was adjusted to 6.0-6.5 with acetic acid. The mixture of 5N sulfuric acid (2.62g sulfuric acid is diluted up to 10mL with DI water) was added in 30% hydrogen peroxide at 80°C. The temperature of
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reaction mixture was raised to 90-95°C and monitored with HPLC till molecular weight of the reaction mass was in range of 6000-4000D. After completion of reaction, it was cooled to 70-80°C over a period of 15 minutes. The pH was adjusted to 7.0-7.5 with 5N sodium hydroxide. The reaction mass was cooled to 25-30°C. The reaction mass was filtered and filtrate was diluted with water then charged the in to the feeding tank of N.F. membrane filtration system having 4000D molecular weight cut off membrane. The water was circulated by arranging concentrate flow on feeding tank. DM water was continuously filled up the feeding tank and the washing material was monitored with HPLC till the desired conversion came. After the completion of NF, the concentrate was collected and adjusted the pH to 6.5-7.0 with dilute sodium hydroxide solution. The concentrate was then subjected to the 0.2um filter. The filtrate was then subjected to spray drier. After spray drying, white amorphous powder was obtained having Zr\ value 0.006 and Molecular weight of 5100 Dalton. X-ray powder diffraction pattern is matching with Fig-1.
The processes of the present invention may preferably employ spray drying with an inlet temperature of from about 40°C to about 140°C. Most preferably the inlet temperature is at least about 110°C.
The spray drying may preferably be conducted with a feed pump speed about 4.0-4.5 RPM and aspirator speed is 1500 RPM.
The spray drying may preferably be conducted with an outlet temperature of below the inlet temperature, more preferably below about 90°C, and most preferably about 60°C-65°C.
In the present invention, the filtration step as discussed hereinabove is carried out by using NF Membrane system "PERMA" Pilot Membrane System manufactured by PERMIONIC Membranes Pvt. Ltd., 3/29, 4/19, B.I.D.C., Gorwa Estate, Vadodara-390016, Gujarat, India.
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The filtration of crude Pentosan polysulfate of formula (I) or its salt is carried out in following manner:
The crude Pentosan polysulfate of formula (I) or its salt is dissolved in water. Feeding the resultant solution and allow it to pass through micron filter membrane system and concentrate flow meter, thereby filtering out the Pentosan polysulfate of formula (I) or its salt with desired molecular weight in the range of 4000 to 6000 Dalton.
For the purpose of this specification, the meaning of the term "NF membrane system" is nano-filtration accompanied by membrane which is capable to pass the undesired product having molecular weight of at least 4000 Dalton.
For the purpose of this specification, the meaning of the term "Spray drying" broadly refers to processes involving breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture. In a typical spray drying apparatus, there is a strong driving force for evaporation of solvent from the droplets, which may be provided by providing a drying gas. Spray drying processes and equipment are described in Perry's Chemical Engineer's Handbook, pp. 20-54 to 20-57 (6th ed. 1984) and Remington: The Science and Practice of Pharmacy, 19th ed., vol. 11, pg. 1627, which are herein incorporated by reference.
By way of non-limiting example only, the typical spray drying apparatus comprises a drying chamber, atomizing means for atomizing a solvent-containing feed into the drying chamber, a source of drying gas that flows into the drying chamber to remove solvent from the atomized-solvent-containing feed, an outlet for the products of drying, and product collection means located downstream of the drying chamber. Examples of such apparatuses include Niro Models PSD-1, PSD-2 and PSD-4 (Niro A/S, Soeborg, Denmark). Typically, the product collection means includes a cyclone connected to the drying apparatus. In the cyclone, the particles produced during spray drying are separated from the drying gas and evaporated solvent, allowing the particles to be collected. A filter may also be used to separate and collect the particles produced by spray drying.
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Herein the instrument used for spray drying is manufactured by Jay Instruments and Services Pvt. Ltd., India.
Advantages of the present invention over prior art:
i) The present invention provides process which is economical, operationally
and industrially applicable,
ii) The present invention provides cheaper as well as less time consuming
process for the preparation of amorphous form of Pentosan polysulfate
sodium,
iii) The process is simple and easy to handle and does not require special handling
care or critical conditions,
iv) The process provides the desired Pentosan polysulfate sodium with molecular
weight of 4000 to 6000 Dalton specifically.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Example-1
In a three neck stirred round bottom flask charged sodium salt of sulfuric acid ester of xylan (100 gm) at room temperature. DI water (300 mL) was charged to it and the pH of the reaction mixture was adjusted to 6.0-6.5 with acetic acid. A solution of 5N sulfuric acid was added in 30% hydrogen peroxide at 80°C. The temperature of reaction mixture was raised to 90-95°C and monitored with HPLC till molecular weight of the reaction mass was in range of 6000-4000D. After completion of reaction it was cooled to 70-80°C. The pH was adjusted to 7.0-7.5 with 5N sodium hydroxide. The reaction mass was cooled to 25-30°C. The reaction mass was filtered and filtrate was diluted with water then charged the in to the feeding tank of N.F. membrane filtration system having 4000D molecular weight cut off membrane. After the completion of NF, the concentrate was collected and adjusted the pH to 6.5-7.0 with dilute sodium hydroxide solution. The
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concentrate was then subjected to the 0.2|.im filter. The filtrate was then subjected to spray drier by inlet temperature of air of 110°C. After spray drying, white amorphous powder was obtained.
Yield: 45.0 gm
Average molecular weight: 5100D
Low molecular weight content < 5.0%
Assay >98%
X-ray powder diffraction pattern is matching with Fig-1.
Example-2
Crude Pentosan polysulfate sodium 25 gm in 250 ml of water was dissolved in 20 ml of water to obtain a clear solution. This solution was spray dried in a Lab Plant Spray Drier ALV-FD-025 (Manufactured by Jay instrument & Services Pvt. Ltd.) with an inlet temperature of 100°C, outlet temperature of 60-65°C, aspirator speed of 1500 RPM and a feed pump speed of 4.0-4.5 RPM, to obtain 20 gm of the product.
The amorphous product was characterised by powder X-ray diffraction which is matching with Fig-1.
Example-3
Reaction mixture (300 ml) after oxidative depolymerisation of Pentosan polysulfate sodium was spray dried in a Lab Plant Spray Drier ALV-FD-025 (Manufactured by Jay instrument & Services Pvt. Ltd.) with an inlet temperature of 100°C, outlet temperature of 60-65°C, aspirator speed of 1500 RPM and a feed pump speed of 4.0-4.5 RPM, to obtain 50 gm of the product.
The amorphous product was characterised by powder X-ray diffraction which is matching with Fig-1.
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We claim
1. A process for preparation of an amorphous form of Pentosan polysulfate sodium,
comprising steps of:
i) dissolving crude Pentosan polysulfate sodium having molecular weight of
4000 to 6000 Dalton in water
ii) spray drying the solution obtained in step (i) to obtain amorphous form of
Pentosan polysulfate sodium
2. A process for preparation of an amorphous form of Pentosan polysulfate of
formula (I)

(I)
or salts thereof, wherein R represents -SO3Y, and Y is at least one member selected from the group consisting of H and a pharmaceutically acceptable cation such as sodium and potassium, comprising steps of:
i) dissolving crude Pentosan polysulfate of formula (I) or its salt in water
ii) filtering the reaction mixture obtain in the step (i) with NF membrane
system
iii) concentrating filtrate obtained in step (ii) up to 1/10 of the original volume iv) adjusting the pH of solution obtained in step (iii) at 6.5 to 7.0 with dilute
NaOH
v) spray drying the solution obtained in step (iv) to obtain amorphous form of
Pentosan polysulfate of formula (1) or its salt
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3. A process for the preparation of an amorphous form of Pentosan polysulfate
sodium, comprising steps of:
i) dissolving crude Pentosan polysulfate sodium in water
ii) filtering the reaction mixture obtain in the step (i) with NF membrane
system
iii) concentrating filtrate obtained in step (ii) up to 1/10 of the original volume iv) adjusting the pH of solution obtained in step (iii) at 6.5 to 7.0 with dilute
NaOH
v) spray drying the solution obtained in step (iv) to obtain amorphous form of
Pentosan polysulfate sodium
4. An amorphous form of Pentosan polysulfate sodium as prepared by the process
comprising steps of:
i) dissolving crude Pentosan polysulfate sodium having molecular weight of
4000 to 6000 Dalton in water
ii) spray drying the solution obtained in step (i) to obtain amorphous form of
Pentosan polysulfate sodium
Dated this 10th day of October 2007
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Title : AN IMPROVED PROCESS FOR THE PREPARATION OF AN
AMORPHOUS FORM OF PENTOSAN POLYSULFATE OR SALTS THEREOF
ABSTRACT
The present invention relates to provide an improved process for preparation of an amorphous form of Pentosan polysulfate sodium, comprising steps of:
i) dissolving crude Pentosan polysulfate sodium having molecular weight of
4000 to 6000 Dalton in water
ii) spray drying the solution obtained in step (i) to obtain amorphous form of
Pentosan polysulfate sodium