WO1995020970A1 - A process for the preparation of bismuth complexes - Google Patents

A process for the preparation of bismuth complexes Download PDF

Info

Publication number
WO1995020970A1
WO1995020970A1 PCT/SE1995/000042 SE9500042W WO9520970A1 WO 1995020970 A1 WO1995020970 A1 WO 1995020970A1 SE 9500042 W SE9500042 W SE 9500042W WO 9520970 A1 WO9520970 A1 WO 9520970A1
Authority
WO
WIPO (PCT)
Prior art keywords
bismuth
water
process according
polyacrylic acid
carbomer
Prior art date
Application number
PCT/SE1995/000042
Other languages
French (fr)
Inventor
Lars Westfelt
Ingemar Ander
Christer Wallquist
Original Assignee
Nobel Chemicals Ab
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 Nobel Chemicals Ab filed Critical Nobel Chemicals Ab
Priority to AU17214/95A priority Critical patent/AU1721495A/en
Publication of WO1995020970A1 publication Critical patent/WO1995020970A1/en

Links

Classifications

    • 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
    • A61K31/28—Compounds containing heavy metals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/245—Bismuth; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin

Definitions

  • the present invention relates to an improved process for the preparation of complexes of bismuth and polyacrylic acid useful in pharmaceutical formulations. More specifically it relates to the preparation of such complexes, using an acrylic acid polymer of the carbomer type and a bismuth salt as starting compounds.
  • Bismuth salts thus have been used for the treatment of gastric and duodenal ulcers and of diarrhoea.
  • these salts are susceptible to precipitation in low pH environments such as those existing in the stomach, resulting in an impaired activity.
  • Rhodes et al in WO 92/01457 proposed to use water soluble complexes of bismuth and polyacrylic acid which are particularly well suited for the treatment of the gastrointestinal tract and moreover present a low absorptivity from the intestine.
  • Rhodes et al. in WO 92/01457 also describe a process for the preparation of these complexes of bismuth and polyacrylic acid, wherein a polyacrylic acid, suitably a carbomer such as Carbopol 974 P or 934 P, in the form of a dispersion, is reacted with a bismuth salt, suitably a salt with a weak inorganic or organic carboxylic acid, e.g. bismuth citrate.
  • the reaction medium is water, and this also is the reaction medium of the embodying examples.
  • Rhodes et al. further specify that an acid acceptor can be present and that it conveniently can be added at a later stage of the reaction, to combine with the acid liberated from the bismuth salt.
  • the acid acceptor preferably is added at the end of the reaction.
  • the purpose is to neutralize the liberated citric acid, increase the solubility of the carbomer-bismuth complex and maintain the pH required to obtain the desired viscosity of the carbomer solution.
  • reaction time is several days but that it can be reduced to less than 24 hours by heating and continuously stirring.
  • the resulting viscous solution can be used as such in certain pharmaceutical preparations.
  • its content of carbomer-bismuth complex can be isolated in solid form by conventional methods such as e.g. precipitating it with a water- miscible solvent such as methanol.
  • the present invention thus will provide a process for the preparation of a water soluble complex of bismuth and polyacrylic acid, process having a substantially improved productivity, with a lower solvent consumption, a shorter reaction time and a lower energy consumption.
  • the object of the invention is attained by a process for the preparation of a water soluble complex of bismuth and a polyacrylic acid, which is characterized in that a) the polyacrylic acid is dispersed in a solution of alkali or ammonia in a water-miscible organic solvent; b) a bismuth containing compound is added to the dispersion obtained according to a); and c) water and a water-miscible organic solvent are gradually added to the dispersion obtained according to b) .
  • the polyacrylic acid used in accordance with the invention is preferably a carbomer, most preferably Carbopol 974 P of pharmacological quality.
  • Carbopol 974 P of pharmacological quality. This is a polymer of acrylic acid, somewhat crosslinked with polyols, having the chemical formula of approximately (C 3 H 4 0 2 ) n . It dissolves in water, forming a viscous solution or a gel.
  • An alternative to Carbopol 974 P is Carbopol 934 P.
  • the bismuth containing compound is preferably a bismuth salt of a weak inorganic acid or a carboxylic acid, or bismuth hydroxide.
  • bismuth salts are bismuth citrate, bismuth salicylate or bismuth subgallate.
  • a preferred salt is bismuth citrate, e.g. the bismuth citrate sold by HEK GmbH of L ⁇ beck.
  • the water-miscible organic solvent is a lower alkanol such as methanol or ethanol, or a lower ketone such as acetone. Ethanol is preferred.
  • alkalis examples include potassium hydroxide and sodium hydroxide, and mixtures thereof.
  • the charging order indicated above as being first a), then b) and then c), and to perform c) in a gradual manner are essential features of the invention. Indeed, in contrast to the polyacrylic acid itself, the alkali or ammonium salt of the same does not swell or dissolve in the water-miscible organic solvent. Accordingly, when the polyacrylic acid particles are dispersed in the alkali or ammonium containing water-miscible organic solvent the molecules of the particle surfaces are converted to their insoluble salt form thus acting as a protective skin for the interior polyacrylic acid molecules.
  • the slurry was filtered and washed with 15 ml of 65% aqueous ethanol followed by 15 ml of ethanol.
  • the product was dried over night in a vacuum oven at 70-80°C.
  • the weight of the dried product was 9.1 g. This corresponds to a productivity, as defined herein above, of 47 kg/m 3 of reactor volume.
  • the product was freely soluble in water.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Processes Of Treating Macromolecular Substances (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
  • Inorganic Compounds Of Heavy Metals (AREA)

Abstract

A process for the preparation of a water soluble complex of bismuth and a polyacrylic acid, wherein a) the polyacrylic acid is dispersed in a solution of alkali or ammonia in a water-miscible organic solvent; b) a bismuth containing compound is added to the dispersion obtained according to a); and c) water and a water-miscible organic solvent are gradually added to the dispersion obtained according to b).

Description

A PROCESS FOR THE PREPARATION OF BISMUTH COMPLEXES
Area of the invention
The present invention relates to an improved process for the preparation of complexes of bismuth and polyacrylic acid useful in pharmaceutical formulations. More specifically it relates to the preparation of such complexes, using an acrylic acid polymer of the carbomer type and a bismuth salt as starting compounds.
Background of the invention
Since long bismuth compounds have had various medicinal applications. Bismuth salts thus have been used for the treatment of gastric and duodenal ulcers and of diarrhoea. However, these salts are susceptible to precipitation in low pH environments such as those existing in the stomach, resulting in an impaired activity. Furthermore, since the intestinal absorption of the bismuth compounds leads to undesired side effects, Rhodes et al in WO 92/01457 proposed to use water soluble complexes of bismuth and polyacrylic acid which are particularly well suited for the treatment of the gastrointestinal tract and moreover present a low absorptivity from the intestine.
Rhodes et al. in WO 92/01457 also describe a process for the preparation of these complexes of bismuth and polyacrylic acid, wherein a polyacrylic acid, suitably a carbomer such as Carbopol 974 P or 934 P, in the form of a dispersion, is reacted with a bismuth salt, suitably a salt with a weak inorganic or organic carboxylic acid, e.g. bismuth citrate. It is stated that the reaction medium is water, and this also is the reaction medium of the embodying examples. Rhodes et al. further specify that an acid acceptor can be present and that it conveniently can be added at a later stage of the reaction, to combine with the acid liberated from the bismuth salt. When the bismuth salt is bismuth citrate, it is stated that the acid acceptor preferably is added at the end of the reaction. The purpose is to neutralize the liberated citric acid, increase the solubility of the carbomer-bismuth complex and maintain the pH required to obtain the desired viscosity of the carbomer solution.
It is specified that the reaction time is several days but that it can be reduced to less than 24 hours by heating and continuously stirring. The resulting viscous solution can be used as such in certain pharmaceutical preparations. Alternatively, its content of carbomer-bismuth complex can be isolated in solid form by conventional methods such as e.g. precipitating it with a water- miscible solvent such as methanol.
The process of Rhodes et al. suffers from a number of drawbacks, one of which is related to the nature of the carbomer. This latter does not dissolve in water, but forms a slurry. However, for the reaction to occur the carbomer particles first must be induced to swell. Rhodes et al. propose to effect this by adding alkali to the suspension. The particles swell within a very narrow range of the alkali content. By a higher alkali concentration, i.e. when this range has been exceeded, the carbomer dissolves, forming a gel. For this gel to be manageable its viscosity must be lowered; Rhodes et al. accomplished this by dilution with a large amount of water, the volume of the reaction medium thus becoming very large. This very large volume of the reaction medium furthermore results in that the volume of solvent required for the product isolation becomes very important. As a consequence the productivity, expressed as the amount of product per reactor unit volume, is extremely and unusually low. As moreover the reaction time is quite long, and stirring as well as heating are required, the energy consumption is unreasonably high and this coupled with the low productivity and the substantial solvent consumption makes the process of Rhodes et al. economically quite disadvantageous.
Considering what has been said herein above, the present invention thus will provide a process for the preparation of a water soluble complex of bismuth and polyacrylic acid, process having a substantially improved productivity, with a lower solvent consumption, a shorter reaction time and a lower energy consumption.
Summary of the invention
The object of the invention is attained by a process for the preparation of a water soluble complex of bismuth and a polyacrylic acid, which is characterized in that a) the polyacrylic acid is dispersed in a solution of alkali or ammonia in a water-miscible organic solvent; b) a bismuth containing compound is added to the dispersion obtained according to a); and c) water and a water-miscible organic solvent are gradually added to the dispersion obtained according to b) .
Detailed description of the invention
The polyacrylic acid used in accordance with the invention is preferably a carbomer, most preferably Carbopol 974 P of pharmacological quality. This is a polymer of acrylic acid, somewhat crosslinked with polyols, having the chemical formula of approximately (C3H402)n. It dissolves in water, forming a viscous solution or a gel. An alternative to Carbopol 974 P is Carbopol 934 P.
The bismuth containing compound is preferably a bismuth salt of a weak inorganic acid or a carboxylic acid, or bismuth hydroxide. Examples of such bismuth salts are bismuth citrate, bismuth salicylate or bismuth subgallate. A preferred salt is bismuth citrate, e.g. the bismuth citrate sold by HEK GmbH of Lϋbeck.
The water-miscible organic solvent is a lower alkanol such as methanol or ethanol, or a lower ketone such as acetone. Ethanol is preferred.
Examples of alkalis are potassium hydroxide and sodium hydroxide, and mixtures thereof.
The charging order indicated above as being first a), then b) and then c), and to perform c) in a gradual manner are essential features of the invention. Indeed, in contrast to the polyacrylic acid itself, the alkali or ammonium salt of the same does not swell or dissolve in the water-miscible organic solvent. Accordingly, when the polyacrylic acid particles are dispersed in the alkali or ammonium containing water-miscible organic solvent the molecules of the particle surfaces are converted to their insoluble salt form thus acting as a protective skin for the interior polyacrylic acid molecules. Only when water is subsequently added, dissolution of this skin and thereby swelling will start to take place, and this can readily be limited and governed by a judicious choice of the amount of water added and the charging rate. The order and rate of charging as indicated above consequently eliminates the risk of forming a gel which would lead to an excessive viscosity, whereas the polyacrylic acid, in the form of a salt, still will be allowed to swell sufficiently to be able to react with the bismuth citrate. Since there is no tendency of gel formation, no large volumes of water and solvent for dilution are required.
The invention will now be illustrated by means of an example.
Example
2.25 g NaOH (54.9 mmoles) and 0.42 g KOH (6.4 mmoles) as well as 33.7 g of ethanol were charged to a three-necked round-bottomed flask. The hydroxides were dissolved by stirring.
To the stirred hydroxide solution 4.49 g (59.1 mmoles of carboxylic acid) of Carbopol 974 P was charged, followed by 2.5 g (6.2 mmoles) of bismuth citrate.
In the flask there now was a fine-grained and easily stirred particle dispersion. To this stirred dispersion there was charged 44.9 g (51 ml) of 65% aqueous ethanol at a reasonably steady rate during a period of 1.8 hours. During this time the particles swelled slightly at the same time as the reaction between the Carbopol and the bismuth citrate started.
After this, 49.9 g of water was charged at a steady rate during a period of 2 hours, and stirring was continued for 1 hour, to complete the reaction.
The slurry was filtered and washed with 15 ml of 65% aqueous ethanol followed by 15 ml of ethanol. The product was dried over night in a vacuum oven at 70-80°C.
The weight of the dried product was 9.1 g. This corresponds to a productivity, as defined herein above, of 47 kg/m3 of reactor volume. The product was freely soluble in water.

Claims

C L A I M S
1. A process for the preparation of a water soluble complex of bismuth and a polyacrylic acid, c h a r a c t e r i z e d in that a) the polyacrylic acid is dispersed in a solution of alkali or ammonia in a water-miscible organic solvent; b) a bismuth containing compound is added to the dispersion obtained according to a); and c) water and a water-miscible organic solvent are gradually added to the dispersion obtained according to b) .
2. The process according to claim 1, c h a r a c t e r i z e d in that the polyacrylic acid is a carbomer.
3. The process according to claim 2, c h a r a c t e r i z e d in that the carbomer is Carbopol.
4. The process according to claim 1, c h a r a c t e r i z e d in that the bismuth containing compound is a bismuth salt of a weak inorganic acid, a carboxylic acid or bismuth hydroxide.
5. The process according to claim 4, c h a r a c t e r i z e d in that the bismuth salt is selected from bismuth citrate, bismuth salicylate or bismuth subgallate.
6. The process according to any of claims 1 - 3, c h a r a c ¬ t e r i z e d in that the carbomer is Carbopol 974 P and the bismuth salt is bismuth citrate.
7. The process according to any of the preceding claims, c h a - r a c t e r i z e d in that the water-miscible organic solvent is a lower alkanol or a lower ketone.
8. The process according to claim 7, c h a r a c t e r i z e d in that the lower alkanol is ethanol.
9. The process according to claim 7, c h a r a c t e r i z e d in that the lower ketone is acetone.
10. The process according to claim 1, c h a r a c t e r i z e d in that the alkali is NaOH, KOH or a mixture thereof.
PCT/SE1995/000042 1994-02-04 1995-01-18 A process for the preparation of bismuth complexes WO1995020970A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU17214/95A AU1721495A (en) 1994-02-04 1995-01-18 A process for the preparation of bismuth complexes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9400382-9 1994-02-04
SE9400382A SE502628C2 (en) 1994-02-04 1994-02-04 Process for preparing a water-soluble complex of bismuth and a polyacrylic acid

Publications (1)

Publication Number Publication Date
WO1995020970A1 true WO1995020970A1 (en) 1995-08-10

Family

ID=20392822

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1995/000042 WO1995020970A1 (en) 1994-02-04 1995-01-18 A process for the preparation of bismuth complexes

Country Status (3)

Country Link
AU (1) AU1721495A (en)
SE (1) SE502628C2 (en)
WO (1) WO1995020970A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022116A1 (en) * 1996-11-15 1998-05-28 Medeva Europe Limited Pharmaceutical composition containing bismuth-polyacrylic acid compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992001457A1 (en) * 1990-07-20 1992-02-06 Slagel, David Products and processes for the treatment of the alimentary canal

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992001457A1 (en) * 1990-07-20 1992-02-06 Slagel, David Products and processes for the treatment of the alimentary canal

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022116A1 (en) * 1996-11-15 1998-05-28 Medeva Europe Limited Pharmaceutical composition containing bismuth-polyacrylic acid compounds
US6004546A (en) * 1996-11-15 1999-12-21 Medeva Europe Limited Pharmaceutical composition containing bismuth-polyacrylic acid compounds

Also Published As

Publication number Publication date
AU1721495A (en) 1995-08-21
SE9400382D0 (en) 1994-02-04
SE502628C2 (en) 1995-11-27
SE9400382L (en) 1995-08-05

Similar Documents

Publication Publication Date Title
KR100427005B1 (en) Spheroidally Agglomerated Basic Cobalt(II) Carbonate and Spheroidally Agglomerated Cobalt(II) Hydroxide, Process for Their Production and Their Use
US5021561A (en) Complexes of iron or other metals with sulphonated derivatives of chitosan
US5756715A (en) Process for making crystalline iron dextran
US4190716A (en) Polymeric agent for releasing 5-aminosalicylic acid or its salts into the gastrointestinal tract
CA1124714A (en) Saccharide derivative having ureido group
DE2813921C2 (en) Process for the production of ionic pullulangels and their use as molecular sieves for separation and purification
GB1565989A (en) Hydroxyalkyl cellulose ethers
WO1995020970A1 (en) A process for the preparation of bismuth complexes
USRE30362E (en) Process for preparing polyvinylamine and salts thereof
JPH0368447A (en) Production of nitrile hydration catalyst
US3962067A (en) Process for the production of an aqueous solution of silicoformic acid
US3514270A (en) Manufacture of bismuth magnesium aluminosilicate
US4275002A (en) Process for preparing polymeric colorants having a poly(vinylamine) backbone
US4035567A (en) Process for producing the methyl ester of amphotericin B
US3838150A (en) Disaccharide polysulfate ester hydroxyaluminum allantoinate-aluminum complex and process for preparing same
US3761465A (en) Preparation of water soluble derivatives of cellulose and compositions thereof
JPS6038401A (en) Novel production process for calcium cellulose glycolate
US2409291A (en) Chemotherapeutic sulfanilamide derivatives
WO1997017377A1 (en) Process for making crystalline iron dextran
DE3914428A1 (en) METHOD FOR PRODUCING GELATINE / CYCLODEXTRIN POLYMERS AND GELATINE / CYCLODEXTRIN COPOLYMERS
SU1098931A1 (en) Process for preparing 2,4,6-trinitrostyrene
KR940011152B1 (en) Process for the preparation of 2,2'-dihydroxy-4,4'-dimethoxy 5,5'-disulfobenzophenone salt
CA2032758C (en) Acrylamide copolymers containing (met)acrylamide benzene dicarboxylic units
JPS5823429B2 (en) Novel water-soluble polymer metal scavenger
SU729193A1 (en) Aminoalkylsalicylic acids as intermediates in azodyes synthesis

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU JP KE KG KP KR KZ LK LR LT LU LV MD MG MN MW MX NL NO NZ PL PT RO RU SD SE SI SK TJ TT UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE MW SD SZ AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase