The present invention relates to a method of stabilizing amiodipine base and solid dosage forms obtained thereby.
The preparation of amiodipine base is described in US patent No. 4,572,909. Further, US patent No. 4,879,303 discloses that free base compositions comprising microcrystalline cellulose and dicalcium phosphate as diluent, suffer from excessive stickiness to the tablet punches and are not suitable in making solid dosage forms for peroral administration. Subsequently, US patent application No. 2003/0022922 discloses that to reduce the stickiness of the tablet, amiodipine free base should be incorporated into the tablet composition in the form of particulates having an average particle size of 150 - 350 urn; and preferred excipient is a combination of calcium phosphate and microcrystalline cellulose. This patent application also describes the preparation of crystalline amiodipine free base form II.
Amiodipine is highly hygroscopic and absorbs moisture leading to degradation. One of the major routes of degradation is via catalytic oxidative process, which is pH dependent. The major related substances produced are Impurity B ({3-ethyl 5-methyl (4RS) 4-(2- chlorophenyl)-6-methyl-2-[[2-[[2-(methylcarbamoyl) benzoyl] amino] ethoxy] methyl]-1,4-dihydropyridine-3,5 dicarboxylate}), D({3-ethyl-5-methyl-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-6-methylpyridine-3,5 dicarboxylate}) and A ({3-ethyl 5-methyl (4RS) 4-(2-chlorophenyl)-2[[2-(1,3-dioxo-dihydro-2H-isoindol-2-yl) ethoxy]methyl]-6-methyl-1,4-dihydropyridine-3,5 dicarboxylate}), along with some unknown impurities. Being an unstable compound it demands well-directed stability approaches to formulate pharmaceutical compositions with reasonable stability.
Till date all the prior art literature shows use of dicalcium phosphate as one of the preferred excipient for amiodipine formulations.
We have now discovered that presence of dicalcium phosphate in the amiodipine formulation triggers the degradation of amiodipine, which is more pronounced at pH below 6.0. Hence removal of dicalcium phosphate from the composition would provide stable pharmaceutical compositions of amiodipine.
We have now found out that it is possible to stabilize compositions containing amlodipine by replacing dicalcium phosphate with microcrystalline cellulose. The stability is further enhanced by addition of mannitol.
Dicalcium phosphate as used herein includes anhydrous calcium phosphate, anhydrous dicalcium phosphate, dibasic calcium phosphate as well as their hydrates and solvates thereof.
The use of microcrystalline cellulose has shown to be useful in preventing the decomposition of amlodipine in pharmaceutical compositions. The stability is enhanced with use of mannitol in the compositions. This is clearly evident from the stability data generated over a period of 1 month at 40°C and 75% relative humidity; listed herein for reference in Table 2, in terms of the % concentrations of related substances (w/w).
Accordingly, an aspect of the present invention is preparation of stable amlodipine solid dosage form, wherein the dosage form is free of dicalcium phosphate.
Another aspect of the present invention relates to a pharmaceutical solid dosage form comprising an effective amount of amlodipine and microcrystalline cellulose, wherein the dosage form is free of dicalcium phosphate.
Another aspect of the present invention relates to a solid dosage form comprising an effective amount of amlodipine, microcrystalline cellulose and mannitol, wherein the dosage form is free of dicalcium phosphate.
Another aspect of the present invention relates to a pharmaceutical tablet comprising an effective amount of amlodipine and microcrystalline cellulose and pharmaceutical acceptable excipients, wherein the tablet is free of dicalcium phosphate.
Another aspect of the present invention relates to a pharmaceutical tablet comprising an effective amount of amlodipine, microcrystalline cellulose, mannitol and pharmaceutical acceptable excipients, wherein the tablet is free of calcium phosphate.
Solid dosage forms as referred herein include tablet and capsules.
Amlodipine as used herein is the free base and can be of any form including crystalline form I, form II, amorphous or mixtures thereof. However it also encompass the pharmaceutically acceptable salts of amlodipine that are incompatible with dicalcium phosphate.
Microcrystalline cellulose is a white, odorless, tasteless, free flowing powder; widely accepted in pharmaceutical industry as a universal diluent. It is purified; partially depolymerized alpha cellulose derived from purified specialty grades of wood pulp. There are various grades, which differ in bulk density, particle size and moisture content. Some of the commercially available grades of microcrystalline cellulose are Avicel®, Vivapur® and Tabulose®.
Mannitol is a naturally occurring sugar alcohol having a cool taste and 50% sweetness compared to sucrose. It is non-hygroscopic, chemically inert and does not undergo the Maillard reaction, and therefore does not discolor in the presence of free amines. Mannitol is available as powder and free flowing granules, and used widely in pharmaceutical preparations. The granular form is particularly useful in direct compression technique of preparing tablets. Some of the commercial grades are Mannogem®, Pearlitol® and Partech M®. The concentration of mannitol may vary from about 5 % to about 80%, in particular it may vary from 20% to 60% by weight of the total uncoated tablet weight.
The pharmaceutically inert excipients as used herein may be selected from substances known in the art as diluents, binders, desiccants, disintegrants, coloring agents, flavoring agents, stabilizers, surfactants, lubricants/glidants, plasticizers and preservatives for pharmaceutical compositions. The excipients are selected based on the desired physical aspects of the final tablets; e.g., obtaining a tablet with desired hardness and friability, being rapidly dispersible and easily swallowed, etc. further, the inert excipients may be so selected to provide slow and controlled release of amlodipine from the tablets.
Disintegrants of the present invention may be selected from sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose and the like.
Binders of the present invention may be selected from methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, and the like.
Diluents of the present invention may be selected from cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and mixtures thereof.
Lubricants and glidants of the present invention may be selected from magnesium stearate, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated caster oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax and the like.
Desiccants of the present invention may be selected from colloidal silicon dioxide, silicon dioxide and the like.
Surfactants of the present invention may be selected from both non-ionic and ionic (Cationic, Anionic and Zwitterionic) surfactants suitable for use in pharmaceutical compositions. These include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides for example glyceryl ricinoleate; Sterol and sterol derivatives, for example sitosterol; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene -
polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl filmarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and the like.
Plasticizers of the present invention may be selected from polyethylene glycol, triethyl citrate, triacetin, diethyl phthalate, dibutyl sebacate and the like.
Stabilizers of the present invention may be selected from antioxidants, buffers, alkalizers, chelating agents and the like.
The coloring agents of the present invention may be selected from any FDA approved colors for oral use.
Tablets of the present invention may be prepared by: blending amlodipine, microcrystalline cellulose, mannitol and disintegrant(s); mixing with a lubricant/glidant; directly compressing the blend in a suitable tabletting machine; and optionally coating with a film forming polymer(s), if desired.
Alternatively, dry granulation and wet granulation techniques may also be used for preparing tablets.
Coating may be performed by applying film forming polymer(s) with or without other pharmaceutically inert excipients, as solution/suspension using any conventional coating technique known in the prior art such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating.
The following examples illustrate the invention but should not be construed as limiting the scope of the invention.
EXAMPLES 1 - 3
Amiodipine tablets of examples 1-3 were prepared as per the composition listed in Table 1, using the following steps -
1. Appropriate amounts of amiodipine and all other ingredients were separately passed through suitable sized sieves.
2. Amiodipine, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and dicalcium phosphate (only for Example 1) or mannitol (only for Example 3) were mixed together to form a uniform blend.
3. The blend of step 2 was lubricated by mixing with magnesium stearate.
4. The compression machine was adjusted to a fill weight of 400 mg.
5. The final lubricated blend of step 3 was directly compressed using suitable size punches to obtain compressed tablets.
Table 1. Composition of amiodipine tablets (Examples 1- 3)

(Table Removed)
The tablets obtained above were subjected to stability evaluation over a period of 1 month at 40°C and 75% relative humidity, the results of which are listed as percentage
(w/w) related substances in Table 2. These results clearly indicate the role of dicalcium phosphate in the degradative reactions of amiodipine and use of microcrystalline cellulose and mannitol in stabilization of amiodipine.
Table 2. Results of stability evaluation of amiodipine tablets (Examples 1 - 3) as percentage (w/w) related substances, over a period of 1 month at 40°C and 75% relative humidity.

(Table Removed)
While several particular formulations have been described above, it will be apparent that various modifications and combinations of the formulations detailed in the text can be made without departing from the spirit and scope of the invention. For example although the tablet dosage form has been prepared, other conventional solid dosage forms like capsule can also be prepared using the similar compositions.
Similarly, though a direct compression method has been used in preparing tablets of example 1-3, other conventional methods can also be used. For example, appropriately sieved amlodipine may be blended with other ingredients and a part of magnesium stearate, and compacted in a roller compacter to produce granules. The granules may then be seived and lubricated with the remaining amount of magnesium stearate and compressed into suitable sized tablets. Alternatively, appropriately seived amlodipine and other ingredients (except magnesium stearate) may be blended into a wet mass using a granulating fluid. Suitable sized granules can then be prepared in granulator. The granules may be dried, lubricated by mixing with magnesium stearate and compressed into suitable sized tablets.
Similarly, although amlodipine base has been used in preparing tablet of example 1-3, tablets of pharmaceutical acceptable salts of amlodipine such as amlodipine besylate and amlodipine mesylate wherein the tablet is free of dicalcium phosphate may also be prepared using compositions described for amlodipine base.

CLAIM:
1. A method for the preparation of stable amlodipine solid dosage form, wherein the dosage form is free of dicalcium phosphate.
2. The method according to claim 1 wherein the dosage form comprises microcrystalline cellulose.
3. The method according to claim 2 wherein the dosage form further comprises mannitol.
4. The method according to claim 2 or 3 wherein the dosage form further comprises of one or more pharmaceutically inert excipients.
5. The method according to claim 4 wherein pharmaceutically inert excipient is selected from the group consisting of diluents, binders, desiccants, disintegrants, coloring agents, flavoring agents, stabilizers, surfactants, lubricants/glidants, plasticizers and preservatives.
6. The method according to claim 5 wherein disintegrant is selected from the group consisting of sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxy propyl cellulose and the like.
7. The method according to claim 6 wherein disintegrant is sodium starch glycolate.
8. The method according to claim 5 wherein diluent is selected from the group consisting of cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and mixtures thereof.
9. The method according to claim 5 wherein binder is selected from the group consisting of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
10.The method according to claim 5 wherein lubricant/glidant is selected from the group consisting of colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated caster oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax and the like.
11.The method according to claim 10 wherein lubricant is magnesium stearate.
12.The method according to claim 5 wherein desiccant is selected from the group consisting of colloidal silicon dioxide, silicon dioxide and the like.
13.The method according to claim 12 wherein desiccant is colloidal silicon dioxide.
14.The method according to claim 1 wherein the solid dosage form is tablet or a capsule.
15.The method according to claim 14 wherein the solid dosage form is a tablet.
16. The method according to claim 14 wherein the solid dosage form is a capsule.
17. The method according to claim 15 wherein the tablet is prepared by wet granulation method.
18. The method according to claim 15 wherein the tablet is prepared by dry granulation method.
19.The method according to claim 15 wherein the tablet is prepared by direct compression method.
20.A method for the preparation of stable pharmaceutical tablet comprising amlodipine, microcrystalline cellulose and mannitol, wherein the tablet is free of dicalcium phosphate as described and illustrated by the examples herein.