WO2008046799A2 - Preparation of granules of hydrophilic vitamins - Google Patents

Preparation of granules of hydrophilic vitamins Download PDF

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Publication number
WO2008046799A2
WO2008046799A2 PCT/EP2007/060934 EP2007060934W WO2008046799A2 WO 2008046799 A2 WO2008046799 A2 WO 2008046799A2 EP 2007060934 W EP2007060934 W EP 2007060934W WO 2008046799 A2 WO2008046799 A2 WO 2008046799A2
Authority
WO
WIPO (PCT)
Prior art keywords
binder
granules
vitamin
hydrophilic vitamin
hydrophilic
Prior art date
Application number
PCT/EP2007/060934
Other languages
English (en)
French (fr)
Other versions
WO2008046799A3 (de
Inventor
Anisul Quadir
Charles Onyiuke
Kai Zhuang
Original Assignee
Basf Aktiengesellschaft
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 Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Publication of WO2008046799A2 publication Critical patent/WO2008046799A2/de
Publication of WO2008046799A3 publication Critical patent/WO2008046799A3/de

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a process for preparing granules of a hydrophilic vitamin comprising at least one binder in powder form composed of a copolymer of vinyl pyrrolidone and vinyl acetate by compacting the mixture of the hydrophilic vitamin and the binder to form pieces and comminuting the pieces to form granules of the hydrophilic vitamin and the binder.
  • the invention further relates to the granules of a hydro- philic vitamin obtained by said process and to tablets made with said granules of a hydrophilic vitamin.
  • the hydrophilic vitamin crystals obtained by synthesis or from natural sources have to be granulated.
  • the hydrophilic vitamin is granulated using roller compaction technique.
  • U.S. Pat. No. 4,800,086 describes a process for the preparation of ascorbic acid gran- ules for direct tabletting with polyvinylpyrrolidone as a binder by a compacting method. Soluble or insoluble homopolymers of vinyl pyrrolidone are used as binder.
  • copovidone which is a synthetic random copolymer of vinyl pyrrolidone and vinyl ace- tate, as binder in pharmaceutical tableting. It is shown that copovidone can be used as binder in the roller compaction of acetylsalicylic acid or hydrochlorothiazide.
  • Kollidon® VA 64 Fine was specifically tailored for the application in roller compaction. No example for roller compaction of an active compound is described.
  • EP 1 714 988 describes binders based on finely divided vinyllactam polymers in powder form, where the binders have an average particle size of up to 35 ⁇ m and an ap- parent density of up to 0.2 g/ml. A process for producing such binder particles and the use thereof for producing tablets with high strength is also described. No example for roller compaction of a hydrophilic vitamin is described.
  • Direct compression or direct tabletting means the compression of a powder mixture without previous granulation of the powder mixture. It is known that many hydrophilic vitamins, particu- larly L-ascorbic acid, have to be transformed to direct compressible vitamin granules as described in the above mentioned U.S. Pat. No. 4,800,086.
  • hydrophilic vitamin stands for thiamin (B1), riboflavin (B2), niotinamide, pantothenic acid, pyridoxine (B6), cobalamin (B12), folic acid, L- ascorbic acid (C) or biotin, preferably thiamin (B1), pyridoxine (B6), cobalamin (B12) or L-ascorbic acid, most preferably L-ascorbic acid.
  • L-ascorbic acid stands not only for the acid itself but also for its ascorbates, particularly its alkali metal salts or its alkaline earth metal salts.
  • L-ascorbic acid stands for the acid itself, its sodium salt or its calcium salt, most preferably for the acid itself.
  • the hydrophilic vitamin is used in crystalline form either as crystals themselves, which can be obtained directly from synthesis, or as crystal fragments wherein the later can be obtained from the crystals by controlled crushing e.g. by using mechanical comminuting means like suitable mills in order to form a powder of said vitamin.
  • step a) of the present invention not less than 90 %, preferably not less than 94 % by weight of crystals or crystal fragments of a hydrophilic vitamin, preferably L-ascorbic acid, are mixed with the binder.
  • the hydrophilic vitamin contains less than 0.3%, preferably less than 0.15% of water.
  • the hydrophilic vitamin is mixed with 0.5 to 10 %, preferably 2 to 6 % by weight of at least one, preferably of one binder in powder form composed of a copolymer of vinyl pyrrolidone and vinyl acetate, wherein said copolymer has a water content of less than 5%.
  • the copolymer of the binder is preferably obtained from vinyl pyrrolidone and vinyl acetate in a ratio of between 40 : 60 and 80 : 20 by weight, more preferably in a ratio of between 50 : 50 and 70 : 30 by weight, most preferably in a ration of 6 : 4.
  • Copolymers of vinyl pyrrolidone and vinyl acetate are commercially available in a ratio of 6 : 4, e. g. Kollidon® VA 64 or Plasdone® S 630.
  • the binder in powder form which is a copolymer of vinyl pyrrolidone and vinyl acetate, is preferably a finely divided binder having an average particle size of up to 35 ⁇ m, preferably less than 30 ⁇ m and particularly preferably less than 20 ⁇ m, with a lower limit for the average particle size of 2 ⁇ m.
  • the method used for determining the average particle size is the D(4,3) value derived from diffraction of light.
  • the binder of the present invention is preferably in the form of hollow spheres or parts of such hollow spheres having a wall thickness of less than 3.0 ⁇ m, in particular less than 2.5 ⁇ m and particularly preferably less than 2.0 ⁇ m, with a lower limit of 0.05 ⁇ m and the ratio of the diameter of the hollow sphere to the wall thickness is greater than 10:1 , preferably greater than 12:1 and particularly preferably greater than 15:1.
  • the apparent density of the binder is preferably less than 0.2 g/ml, in particular from 0.05 to 0.18 g/ml.
  • the apparent density is determined according to Pharm. Eur. 2.9.15.
  • the BET surface area of the binder is usually above 1 m 2 per gram and may be up to 50 m 2 /g.
  • step b) and c) of the present invention the mixture of step a) is compacted to a piece and subsequently the piece is comminuted to form granules of the hydrophilic vitamin comprising the binder.
  • the pieces which are obtained by the compaction step of the mixture of a hydrophilic vitamin and a binder, are also called solid compacts, sheets, strands, ribbons, strips or flakes.
  • the size and form of the pieces depend on the tools used in the compaction step. Usually the thickness of the pieces is less than the length or width of the pieces. The appearance of the surface of the pieces also depends on the tools used for compaction.
  • step b) and c) is known by a person skilled in the art as dry granulation, briquetting or compaction (V. B ⁇ hler, "Vademecum for vitamin formulations", Wiss. Verl.-Ges. Stuttgart, 1988, page 51 ).
  • dry granulation technology is the roller compaction technique. In a roller compactor a powder is compacted between two roll surfaces and the resulting pieces, which are often called ribbons or flakes, are comminuted to form granules in a granulator unit.
  • the person skill in the art is aware of the fact that the surface of the rolls, the compaction force, the gap between the rolls, the roller speed and the configuration of the granulator unit of the roller compactor have an influence on the properties of the produced granules.
  • the person skilled in the art routinely optimizes the machine parameter of a chosen roller compactor with respect to a certain powder mixture in order to obtain granules with optimal properties.
  • Another object of the present invention are granules of a hydrophilic vitamin produced by a process comprising: a) mixing not less than 90 % by weight of crystals or crystal fragments of a hydrophilic vitamin containing less than 0.3% of water, with from 0.5 to 10 % by weight of at least one binder in powder form composed of a copolymer of vinyl pyrrolidone and vinyl acetate, wherein said copolymer has a water content of less than 5%; b) compacting the mixture of the hydrophilic vitamin and the finely divided binder to form a piece, and c) comminuting the piece to form granules of the hydrophilic vitamin and the binder.
  • the granules of a hydrophilic vitamin are particularly L-ascorbic acid granules.
  • hydrophilic vitamin in particular of L-ascorbic acid granules, with respect to the amount of hydrophilic vitamin and its specification or the amount of binder and its specification are defined as described above.
  • the granules of a hydrophilic vitamin which are usually used for the preparation of tablets, have a particle diameter of from 100 to 1000 ⁇ m, preferably from 200 to 800 ⁇ m.
  • the roller compactor usually comprises devices that allow the separation of finer and coarser fractions from the desired fraction and that allow the reintroduction of said finer and coarser fractions in the compacting process.
  • Another object of the present invention are vitamin tablets produced by direct compression of the above-described granules of a hydrophilic vitamin, in particular L-ascorbic acid granules, which have been produced by the process of the present invention.
  • inventive granules of a hydrophilic vitamin in particular L-ascorbic acid granules, are mixed with common auxiliaries and eventually with additional active ingredients like other direct compressible vitamin powders in order to form a mixture, which is used in a process of direct tabletting.
  • Common vitamin C tablets comprise 500 or 1000 mg L-ascorbic acid.
  • the formulation of a 500 mg vitamin C tablet usually differs from the formulation of a 1000 mg vitamin C tablet.
  • inventive granules of a hydrophilic vitamin, in particular L-ascorbic acid granules are also useful for direct tabletting of 1000 mg vitamin tablets, in particular 1000 mg vitamin C tablets.
  • hydrophilic vitamin mixture for direct tabletting comprises besides the granulate of the hydrophilic vitamin more than two further excipients.
  • a mixture for direct tabletting consisting only of L-ascorbic acid granules, preferably the inventive L-ascorbic acid granules, comprising at least 90%, preferably at least 94%, in particular at least 96% by weight of L-ascorbic acid, from 0.25 to 0.75 %, preferably from 0.4 to 0.6 % by weight of the final mixture of stearic acid and from 8 to 20 %, preferably from 10 to 16 % by weight of the final mixture of a microcrystalline cellulose like Avicel ® PH 101 can be easily compressed to tablets that show good properties with respect to hardness and friability. No capping was observed.
  • Vitamin C fine powder 19.0 kg of Vitamin C fine powder and 1.0 kg Kollidon® VA 64 Fine (copovidone - 6 parts 1-vinyl-2-pyrrolidone and 4 parts vinyl acetate by mass) were blended in a free fall blender (Turbula blender) for 10 min.
  • This mixture was formulated into granules by using a roller compactor (Gerteis Minipactor) equipped with an integrated oszillating sieve granulator to fragment the compacted flakes into granules. Two smooth rolls of a diameter of 25 cm and a thickness of 25 mm were used.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

PF 58492 10 Summary The present invention relates to a process for preparing granules of a hydrophilic vita- min comprising at least one binder in powder form composed of a copolymer of vinyl 5 pyrrolidone and vinyl acetate by compacting the mixture of the hydrophilic vitamin and the binder to form pieces and comminuting the pieces to form granules of the hydro- philic vitamin and the binder. The invention further relates to the granules of a hydro- philic vitamin obtained by said process and to tablets made with said granules of a hy- drophilic vitamin.
PCT/EP2007/060934 2006-10-20 2007-10-15 Preparation of granules of hydrophilic vitamins WO2008046799A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US86231406P 2006-10-20 2006-10-20
US60/862,314 2006-10-20

Publications (2)

Publication Number Publication Date
WO2008046799A2 true WO2008046799A2 (de) 2008-04-24
WO2008046799A3 WO2008046799A3 (de) 2008-06-12

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PCT/EP2007/060934 WO2008046799A2 (de) 2006-10-20 2007-10-15 Preparation of granules of hydrophilic vitamins

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3740432A (en) * 1971-02-16 1973-06-19 Hoffmann La Roche Vitamin complexes of niacinamide,riboflavin and sodium ascorbate
EP0186090A2 (de) * 1984-12-24 1986-07-02 BASF Aktiengesellschaft Verfahren zur Herstellung von Ascorbinsäure-Granulat
DE19709663A1 (de) * 1997-03-10 1998-09-17 Basf Ag Verwendung von redispergierbaren Polymerpulvern oder Polymergranulaten als Bindemittel zur Herstellung von festen pharmazeutischen Darreichungsformen
US5994324A (en) * 1996-09-05 1999-11-30 Takeda Chemical Industries, Ltd. Water-soluble vitamin composition having excellent tablet properties and process for production thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3740432A (en) * 1971-02-16 1973-06-19 Hoffmann La Roche Vitamin complexes of niacinamide,riboflavin and sodium ascorbate
EP0186090A2 (de) * 1984-12-24 1986-07-02 BASF Aktiengesellschaft Verfahren zur Herstellung von Ascorbinsäure-Granulat
US5994324A (en) * 1996-09-05 1999-11-30 Takeda Chemical Industries, Ltd. Water-soluble vitamin composition having excellent tablet properties and process for production thereof
DE19709663A1 (de) * 1997-03-10 1998-09-17 Basf Ag Verwendung von redispergierbaren Polymerpulvern oder Polymergranulaten als Bindemittel zur Herstellung von festen pharmazeutischen Darreichungsformen

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ASKER ET AL.: "Investigation of some Materials as Dry Binders for Direct Compression in Tablet Manufacture" PHARMAZIE, vol. 30, no. H.7, 1975, pages 466-470, XP009097923 *
KOLTER K ET AL: "Structure and dry binding activity of different polymers, including KollidonVA 64" DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, NEW YORK, NY, US, vol. 26, no. 11, November 2000 (2000-11), pages 1159-1165, XP009097916 ISSN: 0363-9045 *
MORONI A: "A Novel Copovidone Binder for Dry Granulation and Direct-Compression Tableting" PHARMACEUTICAL TECHNOLOGY, ADVANSTAR COMMUNICATIONS, ISELIN, NJ, US, vol. 24, September 2001 (2001-09), pages 8-12, XP008083486 ISSN: 1543-2521 cited in the application *

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Publication number Publication date
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