NEW TECHNOLOGY FOR WET GRANULATION

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. 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.

Inventors: BECHARD SIMON, BECHARD, SIMON
Applicants: BECHARD SIMON, MERCK FROSST CANADA INC, BECHARD, SIMON, MERCK FROSST CANADA INC.
Application year: 1996
Main classification: A61K9
IPC codes: A61K9, A61K31, A61K47