WO2009047699A1 - An improved process for the preparation of an amorphous form of pentosan polysulfate or salts thereof - Google Patents
An improved process for the preparation of an amorphous form of pentosan polysulfate or salts thereof Download PDFInfo
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- WO2009047699A1 WO2009047699A1 PCT/IB2008/054092 IB2008054092W WO2009047699A1 WO 2009047699 A1 WO2009047699 A1 WO 2009047699A1 IB 2008054092 W IB2008054092 W IB 2008054092W WO 2009047699 A1 WO2009047699 A1 WO 2009047699A1
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- WIPO (PCT)
- Prior art keywords
- pentosan polysulfate
- amorphous form
- sodium
- preparation
- polysulfate sodium
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 229940043138 pentosan polysulfate Drugs 0.000 title claims description 24
- 150000003839 salts Chemical class 0.000 title claims description 24
- QUCDWLYKDRVKMI-UHFFFAOYSA-M sodium;3,4-dimethylbenzenesulfonate Chemical compound [Na+].CC1=CC=C(S([O-])(=O)=O)C=C1C QUCDWLYKDRVKMI-UHFFFAOYSA-M 0.000 claims abstract description 37
- 229960003820 pentosan polysulfate sodium Drugs 0.000 claims abstract description 36
- 238000001694 spray drying Methods 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 239000012528 membrane Substances 0.000 claims description 14
- 239000011541 reaction mixture Substances 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- -1 sodium and potassium Chemical class 0.000 claims description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000000243 solution Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 229920001221 xylan Polymers 0.000 description 9
- 239000002904 solvent Substances 0.000 description 7
- 150000004823 xylans Chemical class 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 5
- 238000000634 powder X-ray diffraction Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- MSJQCBORNZDNDU-UHFFFAOYSA-D decasodium 3-methoxy-6-[2-(6-methoxy-4,5-disulfonatooxyoxan-3-yl)oxy-5-[5-(5-methoxy-3,4-disulfonatooxyoxan-2-yl)oxy-3,4-disulfonatooxyoxan-2-yl]oxy-4-sulfonatooxyoxan-3-yl]oxy-4,5-disulfonatooxyoxane-2-carboxylate Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].COC1COC(OC2COC(OC3COC(OC4COC(OC)C(OS([O-])(=O)=O)C4OS([O-])(=O)=O)C(OC4OC(C(OC)C(OS([O-])(=O)=O)C4OS([O-])(=O)=O)C([O-])=O)C3OS([O-])(=O)=O)C(OS([O-])(=O)=O)C2OS([O-])(=O)=O)C(OS([O-])(=O)=O)C1OS([O-])(=O)=O MSJQCBORNZDNDU-UHFFFAOYSA-D 0.000 description 2
- 238000005374 membrane filtration Methods 0.000 description 2
- WGLLPAPKWFDHHV-NRGGUMNKSA-N (2s,3s,4r,5r,6s)-4,5,6-trihydroxy-3-methoxyoxane-2-carboxylic acid Chemical compound CO[C@H]1[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]1C(O)=O WGLLPAPKWFDHHV-NRGGUMNKSA-N 0.000 description 1
- 229920000298 Cellophane Polymers 0.000 description 1
- 240000000731 Fagus sylvatica Species 0.000 description 1
- 235000010099 Fagus sylvatica Nutrition 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 229910003556 H2 SO4 Inorganic materials 0.000 description 1
- 208000005615 Interstitial Cystitis Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001719 carbohydrate derivatives Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940043249 elmiron Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 150000004676 glycans Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000001728 nano-filtration Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 235000020030 perry Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001180 sulfating effect Effects 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0057—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Xylans, i.e. xylosaccharide, e.g. arabinoxylan, arabinofuronan, pentosans; (beta-1,3)(beta-1,4)-D-Xylans, e.g. rhodymenans; Hemicellulose; Derivatives thereof
Definitions
- the present invention relates to an improved process for the preparation amorphous form of Pentosan polysulfate of formula (I)
- R represents -SO 3 Y
- Y is at least one member selected from the group consisting of H and a pharmaceutically acceptable cation such as sodium and potassium.
- Pentosan polysulfate sodium is chemically known as Beta-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:
- 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 Beta-1 — > 4-linked xylose, usually sulfated at the 2- and 3-positions and occasionally substituted at the 2-position with 4-O-methyl-alpha-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.
- 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.
- 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 H 2 O 2 and H 2 SO 4 to depolymerize such highly polymeric xylan ester partially, dialyzing the de- polymerized product and fractionating an aqueous solution of the dialyzate with an organic water miscible solvent to obtain a fraction having a Z ⁇ value between 0.0030 and 0.015 and sulfur content of 13.5 to 17%.
- 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.
- 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.
- the present invention relates to provide an improved process for preparation of an amorphous form of Pentosan polysulfate sodium, comprising steps of:
- step (i) spray drying the solution obtained in step (i) to obtain amorphous form of
- 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:
- step (iii) adjusting the pH of solution obtained in step (iii) at 6.5 to 7.0 with dilute NaOH
- step (iv) spray drying the solution obtained in step (iv) to obtain amorphous form of
- 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:
- step (iii) adjusting the pH of solution obtained in step (iii) at 6.5 to 7.0 with dilute NaOH
- step (iv) spray drying the solution obtained in step (iv) to obtain amorphous form of
- 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: [56] i) dissolving crude Pentosan polysulfate sodium having molecular weight of 4000 to
- Fig- 1 represents the powder X-ray diffraction (XRD) pattern of an amorphous form of Pentosan polysulfate sodium prepared by spray drying technique.
- XRD powder X-ray diffraction
- present invention provides an improved process for the preparation of an amorphous form of Pentosan polysulfate of formula (I), [64]
- R represents -SO 3 Y
- Y is at least one member selected from the group consisting of H and a pharmaceutically acceptable cation such as sodium and potassium.
- 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.
- 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:
- 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 0.2 ⁇ m filter. The filtrate was then subjected to spray drier. After spray drying, white amorphous powder was obtained having Z ⁇ 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 4O 0 C to about 14O 0 C. Most preferably the inlet temperature is at least about 11O 0 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 9O 0 C, and most preferably about 6O 0 C- 65 0 C.
- 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, India.
- 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.
- 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.
- 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.
- 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-I, PSD-2 and PSD-4 (Niro A/S, Soeborg, Denmark).
- 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.
- the instrument used for spray drying is manufactured by Jay Instruments and Services Pvt. Ltd., India.
- 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 concentrate was then subjected to the 0.2 ⁇ m filter. The filtrate was then subjected to spray drier by inlet temperature of air of 11O 0 C. After spray drying, white amorphous powder was obtained.
- the amorphous product was characterised by powder X-ray diffraction which is matching with Fig-1.
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- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
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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
Description
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF AN AMORPHOUS FORM OF PENTOSAN POL YSULF ATE OR
SALTS THEREOF
[i]
Field of Invention
[2] [3] The present invention relates to an improved process for the preparation amorphous form of Pentosan polysulfate of formula (I)
[5] 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.
[6]
Background of the invention
[7] [8] Pentosan polysulfate sodium is chemically known as Beta-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:
Pentosan Polysulfate sodium
[10] 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.
[H]
[12] 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.
[13]
[14] Pentosan polysulfate sodium is a mixture of linear polymers of Beta-1 — > 4-linked xylose, usually sulfated at the 2- and 3-positions and occasionally substituted at the 2-position with 4-O-methyl-alpha-D-glucuronic acid 2, 3-O-suflate.
[15]
[16] 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.
[17]
[18] 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.
[19]
[20] 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 H2 SO4 to depolymerize such highly polymeric xylan ester partially, dialyzing the de- polymerized product and fractionating an aqueous solution of the dialyzate with an organic water miscible solvent to obtain a fraction having a Zη value between 0.0030 and 0.015 and sulfur content of 13.5 to 17%.
[21]
[22] 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.
[23]
[24] 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.
[25]
[26] 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.
[27]
[28] 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.
[29]
Summary of the invention
[30]
[31] The present invention relates to provide an improved process for preparation of an amorphous form of Pentosan polysulfate sodium, comprising steps of:
[32] i) dissolving crude Pentosan polysulfate sodium having molecular weight of 4000 to
6000 Dalton in water
[33] ii) spray drying the solution obtained in step (i) to obtain amorphous form of
Pentosan polysulfate sodium
[34]
[35]
Object of the invention
[36]
[37] 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.
[38]
[39] 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.
[40]
[41] 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:
[42] i) dissolving crude Pentosan polysulfate of formula (I) or its salt in water
[43] ii) filtering the reaction mixture obtain in the step (i) with NF membrane system
[44] iii) concentrating filtrate obtained in step (ii) up to 1/10 of the original volume
[45] iv) adjusting the pH of solution obtained in step (iii) at 6.5 to 7.0 with dilute NaOH
[46] v) spray drying the solution obtained in step (iv) to obtain amorphous form of
Pentosan polysulfate of formula (I) or its salt [47] [48] 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:
[49] i) dissolving crude Pentosan polysulfate sodium in water
[50] ii) filtering the reaction mixture obtain in the step (i) with NF membrane system
[51] iii) concentrating filtrate obtained in step (ii) up to 1/10 of the original volume
[52] iv) adjusting the pH of solution obtained in step (iii) at 6.5 to 7.0 with dilute NaOH
[53] v) spray drying the solution obtained in step (iv) to obtain amorphous form of
Pentosan polysulfate sodium [54] [55] 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: [56] i) dissolving crude Pentosan polysulfate sodium having molecular weight of 4000 to
6000 Dalton in water [57] ii) spray drying the solution obtained in step (i) to obtain amorphous form of
Pentosan polysulfate sodium [58]
Brief description of the drawings [59] [60] Fig- 1 represents the powder X-ray diffraction (XRD) pattern of an amorphous form of Pentosan polysulfate sodium prepared by spray drying technique. [61]
Detailed description of the invention [62] [63] According to one aspect, present invention provides an improved process for the preparation of an amorphous form of Pentosan polysulfate of formula (I), [64]
[65] 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.
[66] [67] 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.
[68] [69] 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:
[70] i) dissolving crude Pentosan polysulfate of formula (I) or its salt in water [71] ii) filtering the reaction mixture obtain in the step (i) with NF membrane system [72] iii) concentrating filtrate obtained in step (ii) up to 1/10 of the original volume [73] iv) adjusting the pH of solution obtained in step (iii) at 6.5 to 7.0 with dilute NaOH [74] v) spray drying the solution obtained in step (iv) to obtain amorphous form of Pentosan polysulfate of formula (I) or its salt
[75] [76] 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:
[77] i) dissolving crude Pentosan polysulfate sodium in water [78] ii) filtering the reaction mixture obtain in the step (i) with NF membrane system [79] iii) concentrating filtrate obtained in step (ii) up to 1/10 of the original volume [80] iv) adjusting the pH of solution obtained in step (iii) at 6.5 to 7.0 with dilute NaOH [81] v) spray drying the solution obtained in step (iv) to obtain amorphous form of Pentosan polysulfate sodium
[82] [83] 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 1OmL with DI water) was added in 30% hydrogen peroxide at 8O0C. The temperature
of reaction mixture was raised to 90-950C 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 70-800C 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 25-3O0C. 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 0.2μm filter. The filtrate was then subjected to spray drier. After spray drying, white amorphous powder was obtained having Zη value 0.006 and Molecular weight of 5100 Dalton. X-ray powder diffraction pattern is matching with Fig-1.
[84]
[85] The processes of the present invention may preferably employ spray drying with an inlet temperature of from about 4O0C to about 14O0C. Most preferably the inlet temperature is at least about 11O0C.
[86]
[87] The spray drying may preferably be conducted with a feed pump speed about 4.0-4.5
RPM and aspirator speed is 1500 RPM.
[88]
[89] The spray drying may preferably be conducted with an outlet temperature of below the inlet temperature, more preferably below about 9O0C, and most preferably about 6O0C- 650C.
[90]
[91] 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.
[92]
[93] The filtration of crude Pentosan polysulfate of formula (I) or its salt is carried out in following manner:
[94]
[95] 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.
[96]
[97] 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.
[98]
[99] 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.
[100]
[101] 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-I, 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. Herein the instrument used for spray drying is manufactured by Jay Instruments and Services Pvt. Ltd., India.
[102]
[103] Advantages of the present invention over prior art:
[104] i) The present invention provides process which is economical, operationally and industrially applicable.
[105] ii) The present invention provides cheaper as well as less time consuming process for the preparation of amorphous form of Pentosan polysulfate sodium.
[106] iii) The process is simple and easy to handle and does not require special handling care or critical conditions.
[107] iv) The process provides the desired Pentosan polysulfate sodium with molecular weight of 4000 to 6000 Dalton specifically.
[108]
[109] 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.
[HO]
[111] Example-1
[112] 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 8O0C. The temperature of reaction mixture was raised to 90-950C 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 70-800C. The pH was adjusted to 7.0-7.5 with 5N sodium hydroxide. The reaction mass was cooled to 25-3O0C. 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 concentrate was then subjected to the 0.2μm filter. The filtrate was then subjected to spray drier by inlet temperature of air of 11O0C. After spray drying, white amorphous powder was obtained.
[113] Yield: 45.0 gm
[114] Average molecular weight: 510OD
[115] Low molecular weight content < 5.0%
[116] Assay >98%
[117] X-ray powder diffraction pattern is matching with Fig- 1.
[118]
[119] Example-2
[120] 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 1000C, outlet temperature of 60-650C, aspirator speed of 1500 RPM and a feed pump speed of 4.0-4.5 RPM, to obtain 20 gm of the product.
[121] The amorphous product was characterised by powder X-ray diffraction which is matching with Fig-1.
[122]
[123] Example-3
[124] 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 1000C, outlet tern-
perature of 60-650C, aspirator speed of 1500 RPM and a feed pump speed of 4.0-4.5
RPM, to obtain 50 gm of the product. [125] The amorphous product was characterised by powder X-ray diffraction which is matching with Fig-1. [126]
Claims
[i] We claim :
[2]
[3] 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
[4] [5] 2. A process for preparation of an amorphous form of Pentosan polysulfate of formula (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 (I) or its salt
[6]
[7] 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 poly sulfate sodium
[8]
[9] 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
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012114349A1 (en) | 2011-02-23 | 2012-08-30 | Cadila Healthcare Limited | An improved process for the preparation of pentosan polysulfate sodium |
| RU2518473C2 (en) * | 2009-12-21 | 2014-06-10 | Колгейт-Палмолив Компани | Kit containing photosensitising dyes |
| US9120877B2 (en) | 2008-07-04 | 2015-09-01 | Parnell Technologies Pty Ltd | Sulfated polysaccharide compound and the preparation and use thereof |
| WO2016191698A1 (en) * | 2015-05-27 | 2016-12-01 | Vanguard Therapeutics, Inc. | Pentosan polysulfate sodium for the treatment of sickle cell disease |
| WO2020039480A1 (en) | 2018-08-20 | 2020-02-27 | 株式会社レクメド | Novel pentosan polysulfate sodium preparation |
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|---|---|---|---|---|
| CH290145A (en) * | 1944-06-13 | 1953-04-15 | Kaulla Kurt Nikolai Dr Med Von | Process for the preparation of sulfuric acid esters of xylan. |
| FR2543145A1 (en) * | 1983-03-24 | 1984-09-28 | Sanofi Sa | NOVEL XYLANES SULFATES, PROCESS FOR PREPARING THEM AND ANTI-THROMBOTIC AND HYPOLIPEMIANT ACTIVITY |
| EP0184480A1 (en) * | 1984-11-07 | 1986-06-11 | Sanofi | Sulphated xylanes with a low molecular weight, process for their preparation and medicines containing them |
| WO2004078790A1 (en) * | 2003-03-06 | 2004-09-16 | The Procter & Gamble Company | Chitosan powder |
| WO2008107906A1 (en) * | 2007-03-06 | 2008-09-12 | Alembic Limited | Process for the preparation of pentosan polysulfate or salts thereof |
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2008
- 2008-10-07 WO PCT/IB2008/054092 patent/WO2009047699A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH290145A (en) * | 1944-06-13 | 1953-04-15 | Kaulla Kurt Nikolai Dr Med Von | Process for the preparation of sulfuric acid esters of xylan. |
| FR2543145A1 (en) * | 1983-03-24 | 1984-09-28 | Sanofi Sa | NOVEL XYLANES SULFATES, PROCESS FOR PREPARING THEM AND ANTI-THROMBOTIC AND HYPOLIPEMIANT ACTIVITY |
| EP0184480A1 (en) * | 1984-11-07 | 1986-06-11 | Sanofi | Sulphated xylanes with a low molecular weight, process for their preparation and medicines containing them |
| WO2004078790A1 (en) * | 2003-03-06 | 2004-09-16 | The Procter & Gamble Company | Chitosan powder |
| WO2008107906A1 (en) * | 2007-03-06 | 2008-09-12 | Alembic Limited | Process for the preparation of pentosan polysulfate or salts thereof |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9120877B2 (en) | 2008-07-04 | 2015-09-01 | Parnell Technologies Pty Ltd | Sulfated polysaccharide compound and the preparation and use thereof |
| RU2518473C2 (en) * | 2009-12-21 | 2014-06-10 | Колгейт-Палмолив Компани | Kit containing photosensitising dyes |
| US9211420B2 (en) | 2009-12-21 | 2015-12-15 | Colgate-Palmolive Company | Kit containing photosensitizing dyes |
| WO2012114349A1 (en) | 2011-02-23 | 2012-08-30 | Cadila Healthcare Limited | An improved process for the preparation of pentosan polysulfate sodium |
| WO2016191698A1 (en) * | 2015-05-27 | 2016-12-01 | Vanguard Therapeutics, Inc. | Pentosan polysulfate sodium for the treatment of sickle cell disease |
| WO2020039480A1 (en) | 2018-08-20 | 2020-02-27 | 株式会社レクメド | Novel pentosan polysulfate sodium preparation |
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| WO2009047699A8 (en) | 2009-05-28 |
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