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WO2009047699A1 - Procédé perfectionné pour la préparation d'une forme amorphe de polysulfate de pentosan ou de sels de celui-ci - Google Patents

Procédé perfectionné pour la préparation d'une forme amorphe de polysulfate de pentosan ou de sels de celui-ci Download PDF

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Publication number
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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WO
WIPO (PCT)
Prior art keywords
pentosan polysulfate
amorphous form
sodium
preparation
polysulfate sodium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2008/054092
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English (en)
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WO2009047699A8 (fr
Inventor
Keshav Deo
Ashok Prasad
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Alembic Ltd
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Alembic Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alembic Ltd filed Critical Alembic Ltd
Publication of WO2009047699A1 publication Critical patent/WO2009047699A1/fr
Publication of WO2009047699A8 publication Critical patent/WO2009047699A8/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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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  • Chemical & Material Sciences (AREA)
  • 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)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Processes Of Treating Macromolecular Substances (AREA)

Abstract

La présente invention porte sur un procédé perfectionné pour la préparation d'une forme amorphe de polysulfate de pentosan sodique, comprenant les étapes consistant à : i) dissoudre le polysulfate de pentosan sodique brut ayant une masse moléculaire de 4 000 à 6 000 daltons dans l'eau, ii) sécher par pulvérisation la solution obtenue à l'étape (i) pour obtenir une forme amorphe de polysulfate de pentosan sodique.
PCT/IB2008/054092 2007-10-10 2008-10-07 Procédé perfectionné pour la préparation d'une forme amorphe de polysulfate de pentosan ou de sels de celui-ci Ceased WO2009047699A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2023MU2007 2007-10-10
IN2023/MUM/2007 2007-10-10

Publications (2)

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WO2009047699A1 true WO2009047699A1 (fr) 2009-04-16
WO2009047699A8 WO2009047699A8 (fr) 2009-05-28

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012114349A1 (fr) 2011-02-23 2012-08-30 Cadila Healthcare Limited Procédé amélioré pour la préparation de pentosane polysulfate sodium
US9120877B2 (en) 2008-07-04 2015-09-01 Parnell Technologies Pty Ltd Sulfated polysaccharide compound and the preparation and use thereof
US9211420B2 (en) 2009-12-21 2015-12-15 Colgate-Palmolive Company Kit containing photosensitizing dyes
WO2016191698A1 (fr) * 2015-05-27 2016-12-01 Vanguard Therapeutics, Inc. Pentosane polysulfate de sodium pour le traitement de la drépanocytose
WO2020039480A1 (fr) 2018-08-20 2020-02-27 株式会社レクメド Nouvelle préparation de pentosane polysulfate sodique

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH290145A (de) * 1944-06-13 1953-04-15 Kaulla Kurt Nikolai Dr Med Von Verfahren zur Herstellung von Schwefelsäureestern des Xylans.
FR2543145A1 (fr) * 1983-03-24 1984-09-28 Sanofi Sa Nouveaux sulfates de xylanes, leur procede de preparation et leur activite anti-thrombotique et hypolipemiante
EP0184480A1 (fr) * 1984-11-07 1986-06-11 Sanofi Nouveaux sulfates de xylanes de bas poids moléculaires, leur procédé de préparation et médicaments les contenant
WO2004078790A1 (fr) * 2003-03-06 2004-09-16 The Procter & Gamble Company Poudre de chitosan
WO2008107906A1 (fr) * 2007-03-06 2008-09-12 Alembic Limited Processus de préparation de polysulfate de pentosane ou de ses sels

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH290145A (de) * 1944-06-13 1953-04-15 Kaulla Kurt Nikolai Dr Med Von Verfahren zur Herstellung von Schwefelsäureestern des Xylans.
FR2543145A1 (fr) * 1983-03-24 1984-09-28 Sanofi Sa Nouveaux sulfates de xylanes, leur procede de preparation et leur activite anti-thrombotique et hypolipemiante
EP0184480A1 (fr) * 1984-11-07 1986-06-11 Sanofi Nouveaux sulfates de xylanes de bas poids moléculaires, leur procédé de préparation et médicaments les contenant
WO2004078790A1 (fr) * 2003-03-06 2004-09-16 The Procter & Gamble Company Poudre de chitosan
WO2008107906A1 (fr) * 2007-03-06 2008-09-12 Alembic Limited Processus de préparation de polysulfate de pentosane ou de ses sels

Cited By (5)

* Cited by examiner, † Cited by third party
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
US9211420B2 (en) 2009-12-21 2015-12-15 Colgate-Palmolive Company Kit containing photosensitizing dyes
WO2012114349A1 (fr) 2011-02-23 2012-08-30 Cadila Healthcare Limited Procédé amélioré pour la préparation de pentosane polysulfate sodium
WO2016191698A1 (fr) * 2015-05-27 2016-12-01 Vanguard Therapeutics, Inc. Pentosane polysulfate de sodium pour le traitement de la drépanocytose
WO2020039480A1 (fr) 2018-08-20 2020-02-27 株式会社レクメド Nouvelle préparation de pentosane polysulfate sodique

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Publication number Publication date
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