WO1997016173A1 - New technology for wet granulation - Google Patents

New technology for wet granulation Download PDF

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Publication number
WO1997016173A1
WO1997016173A1 PCT/CA1996/000724 CA9600724W WO9716173A1 WO 1997016173 A1 WO1997016173 A1 WO 1997016173A1 CA 9600724 W CA9600724 W CA 9600724W WO 9716173 A1 WO9716173 A1 WO 9716173A1
Authority
WO
WIPO (PCT)
Prior art keywords
active ingredient
solubility
electrolyte
compound
wet granulation
Prior art date
Application number
PCT/CA1996/000724
Other languages
French (fr)
Inventor
Simon Bechard
Original Assignee
Merck Frosst Canada Inc.
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
Priority claimed from GBGB9604277.5A external-priority patent/GB9604277D0/en
Application filed by Merck Frosst Canada Inc. filed Critical Merck Frosst Canada Inc.
Priority to EP96934274A priority Critical patent/EP0859600A1/en
Priority to AU72741/96A priority patent/AU709301B2/en
Priority to JP9516946A priority patent/JPH11514382A/en
Publication of WO1997016173A1 publication Critical patent/WO1997016173A1/en

Links

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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • This invention is concerned with a novel method of wet granulation in the manufacture of tablets comprising a large dose of a highly soluble compound as active ingredient.
  • the novel method comprises the addition of a second compound having the capability of decreasing solubility of the active ingredient prior to agglomeration.
  • the invention is particularly concerned with the novel method wherein the active ingredient is a highly soluble ionic compound.
  • the novel method of this invention is a wet granulation of an active ingredient which is a highly soluble compound and is to be inco ⁇ orated in a relatively high concentration in compressed tablets which comprises the addition of a second compound to reduce the solubility of the active ingredient prior to the agglomeration step.
  • the solubility of the active ingredient is decreased and a signficant increase in the viscosity of the granulation is adequately suppressed.
  • This novel method is particularly useful wherein the active ingredient is ionic and has an aqueous solubility of about 10 to about 500 mg/ml, especially about 135 to about 235 mg/ml of water.
  • the second compound added during the novel process is ordinarily a soluble ionic compound that can suppress the solubility of the active ingredient especially an electrolyte having an ion in common with that of the active ingredient.
  • the tablet compositions prepared by the novel method of this invention are generally art recognized and employ standard excipients based on their compatibility with one another and with the active ingredient .
  • excipients are such as: microcrystalline cellulose, dextrates, calcium phosphates, or pregelatinized starch for their compactibility properties, lactose, mannitol, sorbitol, xylitol, sucrose or glucose because of their water solubility which improves the agglomeration process; hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinly pyrrolidone as binders or adhesives; Croscarmelose, crospovidone or sodium starch glycolate as disintegrants; and lastly, magnesium or calcium stearate, stearic acid, sodium stearyl fumarate, or polyethylene glycols as lubricants; and a granulating fluid such as water or ethanol: water mixtures.
  • the active agent is dry blended with the excipients, and an aqueous solution of the second compound is atomized onto the blend.
  • the blend is then granulated by spraying onto it an aqueous solution of the granulating fluid, which may or may not contain the binder. After drying, the granulation is sized, lubricated with magnesium stearate and then compressed to form the tablet cores.
  • the active ingredient in the following Example is identified as montelukast sodium. This name is listed in USAN and is used by T.R. Jones, et al in Can. J. Physiol. Pharmacol.. (1995) 73(2), 191-201. It has the name and absolute structural formula as follows:
  • Sodium chloride was dissolved in 540 g of water. Hydroxypropyl cellulose was dissolved in 1485 g of water. The microcrystalline cellulose, montelukast sodium, lactose hydrous and Croscarmellose were added together and blended for 5 minutes. The sodium chloride solution was added over 30 seconds and blended for 30 seconds. The hydroxypropylcellulose solution was sprayed onto the mixture over 1.5 minutes and mixed for 30 seconds. After drying, the granulation was sized and then lubricated by addition of the magnesium stearate. The lubricated blend was then compressed to form tablet cores.

Abstract

Wet granulation of a highly soluble compound is facilitated by addition of a solubility modulator before the agglomeration step.

Description

TITLE OF THE INVENTION
NEW TECHNOLOGY FOR WET GRANULATION
BACKGROUND OF THE INVENTION Wet granulation is a common procedure in the manufacture of compressed tablets. In the preparation of compressed tablets comprising a high dose of a relatively highly soluble active ingredient it has been necessary either to increase the ultimate tablet size or reduce the drug/excipient ratio to obtain a mixture suitable for agglomeration. Otherwise a significant increase in granulation viscosity and poor flow characteristics results from the formation of a gel.
Now, with the present invention, it has been found that wet granulation of a highly soluble compound is greatly facilitated if a solubility modulator is added to the mixture before agglomeration. By this method the solubility of the active ingredient is adequately suppressed and the problem of high viscosity is eliminated.
SUMMARY OF THE INVENΗON
This invention is concerned with a novel method of wet granulation in the manufacture of tablets comprising a large dose of a highly soluble compound as active ingredient. The novel method comprises the addition of a second compound having the capability of decreasing solubility of the active ingredient prior to agglomeration. The invention is particularly concerned with the novel method wherein the active ingredient is a highly soluble ionic compound.
It is even more concerned with the novel method where the solubility of the active ingredient is reduced by the addition of an electrolyte, especially wherein the electrolyte has an ion in commmon with that of the ionic active ingredient. DETAILED DESCRIPTION OF THE INVENTION
The novel method of this invention is a wet granulation of an active ingredient which is a highly soluble compound and is to be incoφorated in a relatively high concentration in compressed tablets which comprises the addition of a second compound to reduce the solubility of the active ingredient prior to the agglomeration step. By this procedure the solubility of the active ingredient is decreased and a signficant increase in the viscosity of the granulation is adequately suppressed. This novel method is particularly useful wherein the active ingredient is ionic and has an aqueous solubility of about 10 to about 500 mg/ml, especially about 135 to about 235 mg/ml of water.
The second compound added during the novel process is ordinarily a soluble ionic compound that can suppress the solubility of the active ingredient especially an electrolyte having an ion in common with that of the active ingredient.
The tablet compositions prepared by the novel method of this invention are generally art recognized and employ standard excipients based on their compatibility with one another and with the active ingredient . These excipients are such as: microcrystalline cellulose, dextrates, calcium phosphates, or pregelatinized starch for their compactibility properties, lactose, mannitol, sorbitol, xylitol, sucrose or glucose because of their water solubility which improves the agglomeration process; hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinly pyrrolidone as binders or adhesives; Croscarmelose, crospovidone or sodium starch glycolate as disintegrants; and lastly, magnesium or calcium stearate, stearic acid, sodium stearyl fumarate, or polyethylene glycols as lubricants; and a granulating fluid such as water or ethanol: water mixtures. The active agent is dry blended with the excipients, and an aqueous solution of the second compound is atomized onto the blend. The blend is then granulated by spraying onto it an aqueous solution of the granulating fluid, which may or may not contain the binder. After drying, the granulation is sized, lubricated with magnesium stearate and then compressed to form the tablet cores.
The active ingredient in the following Example is identified as montelukast sodium. This name is listed in USAN and is used by T.R. Jones, et al in Can. J. Physiol. Pharmacol.. (1995) 73(2), 191-201. It has the name and absolute structural formula as follows:
Sodium l-[[[(/?)- -[(£)-2-(7-chloro-2-quinolyl)vinyl]-α-[o-(l-hydroxy- l-methylethyl)phenethyl]benzyllthio]methyl] cyclopropaneacetate.
Figure imgf000005_0001
C35H35ClNθ3SNa
EXAMPLE
TABLET CORE COMPRISING MONTELUKAST SODIUM AS
ACTIVE INGREDIENT
INGREDIENT mg/tab g/batch
1. Montelukast Sodium 51.9 583.9
2. Hydroxypropylcellulose 10.0 112.5
3. Microcrystalline cellulose 200.0 2250.0 4. Lactose hydrous 112.0 1260.0
5. Croscarmellose 12.0 135.0 6. Water 2025.0
7. Magnesium stearate 2.0 22.5
8. Sodium chloride 12.0 135.0
Sodium chloride was dissolved in 540 g of water. Hydroxypropyl cellulose was dissolved in 1485 g of water. The microcrystalline cellulose, montelukast sodium, lactose hydrous and Croscarmellose were added together and blended for 5 minutes. The sodium chloride solution was added over 30 seconds and blended for 30 seconds. The hydroxypropylcellulose solution was sprayed onto the mixture over 1.5 minutes and mixed for 30 seconds. After drying, the granulation was sized and then lubricated by addition of the magnesium stearate. The lubricated blend was then compressed to form tablet cores.
Following the above directions but using amounts of active ingredient from about 20 to 200 mg/tablet in place of the 51.9 mg/tablet in the above Example similar results are obtained.

Claims

What is Claimed Is:
1. A method for the wet granulation of a highly soluble active ingredient comprising the addition of a second compound as a solubility modulator to decrease the solubility of the active ingredient prior to the agglomeration step of the granulation procedure in the manufacture of compressed tablets comprising about 20-200 mg of active ingredient per tablet.
2. The method of Claim 1 wherein the active ingredient has a solubility of about 10 to 500 mg/ml of water.
3. The method of Claim 2 wherein the solubility of the active ingredient is about 135 to 235 mg/ml of water.
4. The method of Claim 3, wherein the active ingredient is montelukast sodium.
5. The method of Claim 1, wherein the active ingredient is ionic and the second compound is an electrolyte.
6. The method of Claim 5 wherein the electrolyte has an ion in common with the active ingredient.
7. The method of Claim 6, wherein the active ingredient is montelukast sodium.
8. The method of Claim 2, wherein the active ingredient is ionic and the second compound is an electrolyte.
9. The method of Claim 8 wherein the electrolyte has an ion in common with the active ingredient.
10. The method of Claim 9 wherein the active ingredient is montelukast sodium.
11. The method of Claim 3, wherein the active ingredient is ionic and the second compound is an electrolyte.
12. The method of Claim 11, wherein the electrolyte has an ion in common with the active ingredient.
13. The method of Claim 12 wherein the active ingredient is montelukast sodium.
PCT/CA1996/000724 1995-11-02 1996-10-31 New technology for wet granulation WO1997016173A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP96934274A EP0859600A1 (en) 1995-11-02 1996-10-31 New technology for wet granulation
AU72741/96A AU709301B2 (en) 1995-11-02 1996-10-31 New technology for wet granulation
JP9516946A JPH11514382A (en) 1995-11-02 1996-10-31 New wet granulation method

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US616195P 1995-11-02 1995-11-02
US60/006,161 1995-11-02
GBGB9604277.5A GB9604277D0 (en) 1996-02-29 1996-02-29 New technology for wet granulation
GB9604277.5 1996-02-29

Publications (1)

Publication Number Publication Date
WO1997016173A1 true WO1997016173A1 (en) 1997-05-09

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA1996/000724 WO1997016173A1 (en) 1995-11-02 1996-10-31 New technology for wet granulation

Country Status (5)

Country Link
EP (1) EP0859600A1 (en)
JP (1) JPH11514382A (en)
AU (1) AU709301B2 (en)
CA (1) CA2236175A1 (en)
WO (1) WO1997016173A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035036A1 (en) * 2001-10-26 2003-05-01 Merck Frosst Canada & Co. Montelukast granule formulation
WO2007077135A1 (en) 2005-12-30 2007-07-12 Krka, Tovarna Zdravil, D.D., Novo Mesto Pharmaceutical composition containing montelukast
CZ298224B6 (en) * 2003-04-29 2007-07-25 Pliva Istrazivanje I Razvoj D.O.O. Pharmaceutical composition containing ribavirin as active substance and process for its preparation
WO2014012954A1 (en) 2012-07-18 2014-01-23 Takeda Gmbh Treatment of partly controlled or uncontrolled severe asthma
WO2015110394A1 (en) 2014-01-22 2015-07-30 Takeda Gmbh Treatment of partly controlled or uncontrolled severe asthma with a pde4 inhibitor (and in combination with a leukotriene modifier)
EP2949321A1 (en) 2014-05-26 2015-12-02 Sanovel Ilac Sanayi ve Ticaret A.S. Multilayer formulations of fexofenadine and montelukast
WO2017182641A1 (en) 2016-04-22 2017-10-26 Sanovel Ilac Sanayi Ve Ticaret A.S. Bilayer tablet formulations of montelukast and rupatadine
WO2017182644A1 (en) 2016-04-22 2017-10-26 Sanovel Ilac Sanayi Ve Ticaret A.S. Tablet formulations of montelukast sodium and rupatadine fumarate

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101278572B1 (en) * 2011-10-18 2013-06-25 주식회사 네비팜 Pharmaceutical combinations of leukotriene antagonist and epinastine and their preparing methods

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994000111A1 (en) * 1992-06-26 1994-01-06 Merck & Co., Inc. Spheronization process using charged resins

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994000111A1 (en) * 1992-06-26 1994-01-06 Merck & Co., Inc. Spheronization process using charged resins

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 123, no. 23, 4 December 1995, Columbus, Ohio, US; abstract no. 305952, XP002028053 *
D.F.SCHOORS ET AL.: "SINGLE DOSE PHARMACOKINETICS,SAFETY AND TOLERABILITY OF MK-0476,A NEW LEUKOTRIENE D4-RECEPTOR ANTAGONIST,IN HEALTHY VOLUNTEERS", BR. J. CLIN. PHARM., vol. 40, no. 3, 1995, pages 277 - 280 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035036A1 (en) * 2001-10-26 2003-05-01 Merck Frosst Canada & Co. Montelukast granule formulation
AU2002333134B2 (en) * 2001-10-26 2007-08-02 Merck Canada Inc. Montelukast granule formulation
US8007830B2 (en) 2001-10-26 2011-08-30 Merck Frosst Canada & Co. Granule formation
KR101094084B1 (en) * 2001-10-26 2011-12-15 머크 캐나다 인크. Montelukast granule formulation
HRP20040367B1 (en) * 2001-10-26 2012-07-31 Merck@Frosst@Canada@@@Co Montelukast granule formulation
CZ298224B6 (en) * 2003-04-29 2007-07-25 Pliva Istrazivanje I Razvoj D.O.O. Pharmaceutical composition containing ribavirin as active substance and process for its preparation
WO2007077135A1 (en) 2005-12-30 2007-07-12 Krka, Tovarna Zdravil, D.D., Novo Mesto Pharmaceutical composition containing montelukast
WO2014012954A1 (en) 2012-07-18 2014-01-23 Takeda Gmbh Treatment of partly controlled or uncontrolled severe asthma
WO2015110394A1 (en) 2014-01-22 2015-07-30 Takeda Gmbh Treatment of partly controlled or uncontrolled severe asthma with a pde4 inhibitor (and in combination with a leukotriene modifier)
EP2949321A1 (en) 2014-05-26 2015-12-02 Sanovel Ilac Sanayi ve Ticaret A.S. Multilayer formulations of fexofenadine and montelukast
WO2017182641A1 (en) 2016-04-22 2017-10-26 Sanovel Ilac Sanayi Ve Ticaret A.S. Bilayer tablet formulations of montelukast and rupatadine
WO2017182644A1 (en) 2016-04-22 2017-10-26 Sanovel Ilac Sanayi Ve Ticaret A.S. Tablet formulations of montelukast sodium and rupatadine fumarate

Also Published As

Publication number Publication date
AU709301B2 (en) 1999-08-26
AU7274196A (en) 1997-05-22
EP0859600A1 (en) 1998-08-26
CA2236175A1 (en) 1997-05-09
JPH11514382A (en) 1999-12-07

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