CA2236175A1 - New technology for wet granulation - Google Patents
New technology for wet granulation Download PDFInfo
- Publication number
- CA2236175A1 CA2236175A1 CA 2236175 CA2236175A CA2236175A1 CA 2236175 A1 CA2236175 A1 CA 2236175A1 CA 2236175 CA2236175 CA 2236175 CA 2236175 A CA2236175 A CA 2236175A CA 2236175 A1 CA2236175 A1 CA 2236175A1
- Authority
- CA
- Canada
- Prior art keywords
- active ingredient
- solubility
- electrolyte
- compound
- wet granulation
- 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.)
- Abandoned
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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Manufacturing Of Micro-Capsules (AREA)
Abstract
Wet granulation of a highly soluble compound is facilitated by addition of a solubility modulator before the agglomeration step.
Description
CA 0223617~ 1998-04-28 TITLE QF THE INVENTION
NEW TECHNOLOGY FOR VVET 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 gr~n~ tion 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 elimin~ted.
SUMMARY OF THE INVENTION
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.
CA 0223617~ 1998-04-28 DETAILED DESCRIPTION OF THE INVENTION
The novel method of this invention is a wet gr~n~ tion of an active ingredient which is a highly soluble compound and is to be incorporated in a relatively high concentration in compressed tablets 5 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/rnl, especially about 135 to about 235 mg/ml of water.
The second compound added during the novel process is or lin~rily 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 recogni7e-1 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 pregel~tini~ed 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 integrants; 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 gran~ tin~ fluid, which may or may not contain the binder. After CA 0223617~ 1998-04-28 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 identi~led 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-[[[(R)-m-[(E)-2-(7-chloro-2-quinolyl)vinyl]-a-[o-(1-hydroxy-1 -methylethyl)phenethyl]benzyl]thio]methyl]
cyclopropaneacetate.
S /2~ COO~Na+
C1 ~~ ¦
C35H35ClNO3SNa 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 CA 0223617~ 1998-04-28 4. Lactose hydrous 112.0 1260.0 5. Croscarmellose 12.0 135.0 5 6. Water 2025.0 7. Magnesium stearate 2.0 22.5 8. Sodium chloride 12.0 10 135.0 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 15 Croscarmellose were added together and blended for 5 rninutes. The sodium chloride solution was added over 30 seconds and blended for 30 seconds. ~e hydroxypropylcellulose solution was sprayed onto the mixture over 1.5 min~lte.s and mixed for 30 seconds. After drying, the grz~n~ tion was sized and then lubricated by addition of the magnesium 20 stearate. The lubricated blend was then compressed to forrn 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 ~imil~r results are obtained.
NEW TECHNOLOGY FOR VVET 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 gr~n~ tion 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 elimin~ted.
SUMMARY OF THE INVENTION
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.
CA 0223617~ 1998-04-28 DETAILED DESCRIPTION OF THE INVENTION
The novel method of this invention is a wet gr~n~ tion of an active ingredient which is a highly soluble compound and is to be incorporated in a relatively high concentration in compressed tablets 5 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/rnl, especially about 135 to about 235 mg/ml of water.
The second compound added during the novel process is or lin~rily 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 recogni7e-1 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 pregel~tini~ed 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 integrants; 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 gran~ tin~ fluid, which may or may not contain the binder. After CA 0223617~ 1998-04-28 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 identi~led 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-[[[(R)-m-[(E)-2-(7-chloro-2-quinolyl)vinyl]-a-[o-(1-hydroxy-1 -methylethyl)phenethyl]benzyl]thio]methyl]
cyclopropaneacetate.
S /2~ COO~Na+
C1 ~~ ¦
C35H35ClNO3SNa 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 CA 0223617~ 1998-04-28 4. Lactose hydrous 112.0 1260.0 5. Croscarmellose 12.0 135.0 5 6. Water 2025.0 7. Magnesium stearate 2.0 22.5 8. Sodium chloride 12.0 10 135.0 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 15 Croscarmellose were added together and blended for 5 rninutes. The sodium chloride solution was added over 30 seconds and blended for 30 seconds. ~e hydroxypropylcellulose solution was sprayed onto the mixture over 1.5 min~lte.s and mixed for 30 seconds. After drying, the grz~n~ tion was sized and then lubricated by addition of the magnesium 20 stearate. The lubricated blend was then compressed to forrn 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 ~imil~r results are obtained.
Claims (12)
1. A method for the wet granulation of an active ingredient having a solubility of about 10 to 500 ml/ml of water 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 solubility of the active ingredient is about 135 to 235 mg/ml of water.
3. The method of claim 2, wherein the active ingredient is montelukast sodium.
4. The method of claim 1, wherein the active ingredient is ionic and the second compound is an electrolyte.
5. The method of claim 4, wherein the electrolyte has an ion in common with the active ingredient.
6. The method of claim 5, wherein the active ingredient is montelukast sodium.
7. The method of claim 2, wherein the active ingredient is ionic and the second compound is an electrolyte.
8. The method of claim 7, wherein the electrolyte has an ion in common with the active ingredient.
9. The method of claim 8, wherein the active ingredient is montelukast sodium.
10. The method of claim 2, wherein the active ingredient is ionic and the second compound is an electrolyte.
11. The method of claim 10, wherein the electrolyte has an ion in common with the active ingredient.
12. The method of claim 11, wherein the active ingredient is montelukast sodium.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US616195P | 1995-11-02 | 1995-11-02 | |
| US60/006,161 | 1995-11-02 | ||
| GB9604277.5 | 1996-02-29 | ||
| GBGB9604277.5A GB9604277D0 (en) | 1996-02-29 | 1996-02-29 | New technology for wet granulation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2236175A1 true CA2236175A1 (en) | 1997-05-09 |
Family
ID=26308826
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2236175 Abandoned CA2236175A1 (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) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY148466A (en) * | 2001-10-26 | 2013-04-30 | Merck Frosst Canada Ltd | 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 |
| SI1976522T2 (en) | 2005-12-30 | 2019-11-29 | Krka Tovarna Zdravil D D Novo Mesto | Pharmaceutical composition containing montelukast |
| KR101278572B1 (en) * | 2011-10-18 | 2013-06-25 | 주식회사 네비팜 | Pharmaceutical combinations of leukotriene antagonist and epinastine and their preparing methods |
| WO2014012954A1 (en) | 2012-07-18 | 2014-01-23 | Takeda Gmbh | Treatment of partly controlled or uncontrolled severe asthma |
| CA2936332A1 (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 |
| EP3397285B1 (en) | 2016-04-22 | 2024-08-14 | Sanovel Ilac Sanayi ve Ticaret A.S. | Tablet formulations of montelukast sodium and rupatadine fumarate |
| WO2017182641A1 (en) | 2016-04-22 | 2017-10-26 | Sanovel Ilac Sanayi Ve Ticaret A.S. | Bilayer tablet formulations of montelukast and rupatadine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5350584A (en) * | 1992-06-26 | 1994-09-27 | Merck & Co., Inc. | Spheronization process using charged resins |
-
1996
- 1996-10-31 EP EP96934274A patent/EP0859600A1/en not_active Ceased
- 1996-10-31 WO PCT/CA1996/000724 patent/WO1997016173A1/en not_active Application Discontinuation
- 1996-10-31 CA CA 2236175 patent/CA2236175A1/en not_active Abandoned
- 1996-10-31 JP JP9516946A patent/JPH11514382A/en not_active Withdrawn
- 1996-10-31 AU AU72741/96A patent/AU709301B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| WO1997016173A1 (en) | 1997-05-09 |
| AU7274196A (en) | 1997-05-22 |
| JPH11514382A (en) | 1999-12-07 |
| AU709301B2 (en) | 1999-08-26 |
| EP0859600A1 (en) | 1998-08-26 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |