Title of Invention

A PROCESS FOR MAKING A STABEL PHARMACEUTICAL FORMULATIONS FOR S (-) AMLODIPINE BESILATE

Abstract

A process of making stable pharmaceutical formulation of tablet, comprising an effective amount of S (-) Amlodipine besilate together with a pharmaceutically acceptable and chemically compatible diluents or carrier admixture with excipients which on & during shelf life minimizes the inter conversion of S (-) isomer to R (+) isomer less than 0.01% & not more than 0.15% of the total dose thereby reducing or nullifying the side effects caused by the R (+) isomer and shows the best in vitro dissolution profile studies even up to 6 months studied at 40°C ± 2 °C / 75%+ 5% RH accelerated conditions as per ICH guidelines & showing excellent tableting and machinability in production scale, wherein Dicalcium Phosphate anhydrous is used as a chemically compatible, stabilizing, inert tableting aid.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) PROVISIONAL SPECIFICATION A Process for Making a Pharmaceutical Stable Formulation for S (-) Amlodipine Besilate & its Combinations there of Assignee- Aristo Pharmaceutical Ltd, 23-A, Shah Industrial Estate, Off Veera Desai road, Andheri (w), Mumbai 400 053. Name of the inventors- 1) Mr. Manutosh Manohar. Acharya, Indian, residing at 4/7, Amaltas Parisar Shahpura, Bhopal (MP), India. 2) Mr. Abhay Shivajirao Pawar, Indian, residing at 1561, Ganesh nagar Opp. Sangam Ice Cream factory Sangli - 416416 Maharashtra, India. 3) Mr. Suresh Kumar Paswan, Indian, residing at QTR -790/5, Balconagar Dist. - Korba, Chattishgarh, India. The following provisional Specification describes the nature of this invention ORIGINAL 755/MUMNP/2003 GRANTED 28/9/2004 Page 2 of 7 ABSTRACT The present invention is concerned with stable pharmaceutical formulation of tablet comprising an effective amount of S (-) amlodipine besilate salt with pharmaceutically acceptable & compatible (physical & chemical) excipients. S (-) amlodipine besilate find utility as anti-ischaemic and anti-hypertensive activity and formulation having combination with group consisting of angiotensin-converting-enzyme inhibitor, an angiotensin II inhibitor, a calcium inhibitor, beta -adrenergic antagonists. BACKGROUND OF THE INVENTION Amlodipine is calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. Amlodipine is described in U.S. Pat. No. 4,572,909. With regard to the enantiomers of amlodipine, the individual enantiomers of amlodipine have been identified as R (+) and S(-) (J. Med. Chem. 35, 3341-3344 (1992), Goldmann et al). The separation Page 3 of 7 and analysis of enantiomers are well described on "Hand book of HPLC" and the isolation of these are disclosed in Arrowsmith et al. J. Med. Chem., 29: 1696-1702 (1986). Further, European Patent Application No.0331315 disclosed the use of cinchonidine salts of acid for the resolution of intermediates to eventually give enantiomerically pure amiodipine isomers. Amiodipine is chemically described as (RS) 3-ethyl-5-methyl-2- (2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5 pyridinedicarboxylate. (U.S. Pat. No. 4,572,909) Its empirical formula is: C2OH25CIN2O5. Amiodipine is a dihydropyridine with an asymmetric centre at the 4-position. The symbol "*" denotes the chiral carbon. The present commercial formulation of amiodipine disclosed contains the drug as the salt of racemic mixture of amiodipine besilate. The term "amiodipine" herein refers to amiodipine & its pharmaceutically suitable salts and esters including amiodipine besilate. The terms "S (-) amiodipine" and "S (-) isomer of amiodipine" as used further in this patent application includes substantially optically pure salt of S (-) isomer of amiodipine besilate. Page 4 of 7 The S (-) amiodipine besilate is useful for the treatment of angina and it is an effective antihypertensive agent for both systolic and diastolic hypertension, particularly in mild to moderate disease and such other conditions as may be related to the activity as a calcium channel antagonist without the concomitant liability of adverse effects which includes edema of extremities, headache and dizziness associated with the administration racemic mixture of amiodipine (U S Pat No. 6,057,344) The angiotensin converting enzyme blocks conversion of the decapeptide angiotensin I to angiotensin II. The principal pharmacological and clinical effects of angiotensin converting enzyme inhibitors arise from suppression of synthesis of angiotensin II. Angiotensin II is a potent pressor substance and, therefore, blood pressure lowering can result from inhibition of its biosynthesis, especially in animals and humans whose hypertension is angiotensin II related. ACE inhibitors and the angiotensin II receptor antagonist are effective antihypertensive agents in a variety of animal models and are clinically useful for the treatment of hypertension in humans. The angiotensin II inhibitor use in our invention is losartan potassium, and Candesartan. US. Patent 5,098,910 discloses pharmaceutical compositions containing a combination of angiotensin II antagonist (Ramipril, trandolapril, quinapril) and a calcium channel blocker (felodipine) for use in the treatment of hypertension and congestive heart failure. The publication states that the particular compositions can further contain antihypertensives and/or diuretics and/or angiotensin converting enzyme inhibitors. The angiotensin-converting-enzyme inhibitor use in our invention is Ramipril and Quinapril Hydrochloride. Page 5 of 7 Beta adrenergic blocking agents in the combination with the calcium channel blocker have an additive effect in treatment of hypertension, (Am J Cardiol, 81(2): 128-132 (1998) Dunselman P. H. et al). The beta-adrenergic receptor blockers use in our invention is Atenolol. Amiodipine besilate is patented in U.S. Pat. No. 4,879,303 and it discloses the formulation of amiodipine besilate, this patent is basically for the besilate salt of amiodipine, and it doesn't claim for formulation of the pure S (-) enantiomer of Amiodipine besilate. Novalitv Since there is no disclosure of the pharmaceutically stable formulations composition of tablet of optically pure S (-) enantiomer of amiodipine besilate to a human, which is having better pharmacological property then the amiodipine besilate without the concomitant liability of adverse effects which includes edema of extremities, headache and dizziness associated with the administration racemic mixture of amiodipine (U S Pat No. 6,057,344). Our invention provides a pharmaceutically stable tablet formulations comprising of the besilate salt of S (-) amiodipine together with a pharmaceutically acceptable and compatible diluent or a carrier which includes the developmental pharmaceutics studies with proper compatibility (physical & Chemical) studies as per ICH guidelines providing stable formulation composition of tablet with the drug and the excipients. Page 6 of 7 The present invention provides the stable formulation for the S (-) amiodipine besilate in which has the excipients such as microcrystalline cellulose, anhydrous dibasic calcium phosphate, lake of quinoline yellow, colloidal Silicon dioxide, sodium starch glycolate and magnesium stearate, however formulations in example 1,2,3 are physically and chemically stable as per the stability studies in ICH conditions. With lower dose tablets the need for good compressibility and uniform distribution of active drug is crucial and critical factor and selection of proper and suitable excipients and process is very essential microcrystalline cellulose is a commonly used compression aid and wacking agent. The dibasic calcium phosphate gives stability to the S (-) amiodipine. Disintegrants helps in breakup of tablet after the administration, as the active material must be released from the tablet matrix as efficiently as possible to allow rapid dissolution and availability of the drug through formulation to the body system, sodium starch glycolate is used here as disintegrant. Colloidal silicon dioxide helps in increasing the flow property of the granules and has a excellent glidant properties. The adhesion of the drug to the punches of the tablet machine must be avoided. When drug accumulates on the punch surfaces this causes the tablet surface to become pitted and therefore unacceptable. Also sticking of the drug in this way results in high ejection forces when removing the tablet from the machine. In practice it is possible to reduce sticking by wet-massing, careful selection of excipients and the use of high levels of anti-adherents, e.g. magnesium stearate. Thus our process offers the best stability of drug with respect to besilate salt of S-isomer of amiodipine and a convenient process for making a tablet dosage form which is fast, economical and having minimum exposure time to the environment, and a process formulae which can be run on high speed tableting machine having the good desired tablet properties both physical as well as chemical. Page 7 of 7 The invention further relates to a stable combination comprising of S (-) Amiodipine besilate with beta-adrenergic receptor blockers, Atenolol, angiotensin-converting-enzyme inhibitor Ramipril, Quinapril Hydrochloride the angiotensin II inhibitor as losartan potassium, and Candesartan, in tablet formulation as above and bilayer tablet formulation having the excipient as above. Dated this 17th day of July 2003 (1) Mr. Manutosh Manohar Acharya (2) Mr. Abhay Shivajirao Pawa (3) Mr. Suresh Kumar Paswan, To The Controller of Patents, The Patent Office, Mumbai. Complete Specifications Description BACKGROUND OF THE INVENTION (1) Amlodipine is calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extra cellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. (2) Amlodipine is chemically described as (R, S) 3-ethyl-5-methyl-2- (2-aminoethoxymethyl)-4-(2-chlorophenyl)-l,4-dihydro-6-methyl-3,5 - pyridinedicarboxylate. (U.S. Pat. No. 4,572,909) Its empirical formula is: C2OH25CIN2O5. Amlodipine is a dihydropyridine with an asymmetric centre at the 4-position. The symbol "*" denotes the chiral carbon. (003) (4) The present commercial formulation of amlodipine disclosed contains the drug as the salt of racemic mixture of amlodipine besilate. The term "amlodipine" herein refers to amlodipine & its pharmaceutically suitable salts and esters including amlodipine besilate. The terms "S (-) amlodipine" and "S (-) isomer of amlodipine" as used further in this patent application includes substantially optically pure salt of S (-) isomer of amlodipine besilate. (5) Amlodipine is described in U.S. Pat. No. 4,572,909. With regard to the enantiomers of amlodipine, the individual enantiomers of amlodipine have been identified as R (+) and S (-) (J. Med. Chem. 35, 3341-3344 (1992), Goldmann et al). The separation and analysis of enantiomers are well described on "Hand book of HPLC" and the isolation of these are disclosed in Arrowsmith et al. J. Med. Chem., 29: 1696-1702 (1986). Further, European Patent Application No.0331315 disclosed the use of cinchonidine salts of acid for the resolution of intermediates to eventually give enantiomerically pure amlodipine isomers. (6) The S (-) amlodipine besilate is useful for the treatment of angina and it is an effective antihypertensive agent for both systolic and diastolic hypertension, particularly in mild to moderate disease and such other conditions as may be related to the activity as a calcium channel antagonist without the concomitant liability of adverse effects associated with racemic mixture amlodipine salts are edema of the extremities including peripheral edema headache, dizziness flushing/hot flashes, vertigo, muscle cramps, palpitation, fatigue, nausea, abdominal pain and somnolence (U S Pat No. 6,476,058, U S Pat No. 6,291,490). (7) The angiotensin converting enzyme blocks conversion of the decapeptide angiotensin I to angiotensin II. The principal pharmacological and clinical effects of angiotensin converting enzyme inhibitors arise from suppression of synthesis of angiotensin II. Angiotensin II is a potent pressor substance and, therefore, blood pressure lowering can result from inhibition of its biosynthesis, especially in animals and humans whose hypertension is angiotensin II related. ACE inhibitors and the angiotensin II receptor antagonist are effective antihypertensive agents in a variety of animal models and are clinically useful for the treatment of hypertension in humans. The angiotensin II inhibitor used in our invention is losartan potassium, and Candesartan celexitil. (8) US. Patent 5,098,910 discloses pharmaceutical compositions containing a combination of angiotensin II antagonist (Ramipril, trandolapril, Quinapril) and a calcium channel blocker (felodipine) for use in the treatment of hypertension and congestive heart failure. The publication states that the particular compositions can further contain antihypertensives and/or diuretics and/or angiotensin converting enzyme inhibitors. The angiotensin-converting-enzyme inhibitor use in our invention is Ramipril and Quinapril Hydrochloride. (9) Beta-adrenergic blocking agents in the combination with the calcium channel blocker have an additive effect in treatment of hypertension, (Am J Cardiol, 81(2): 128-132 (1998) Dunselman P. H. et al). The beta-adrenergic receptor blockers use in our invention is Atenolol. (10) Amlodipine besilate is patented in U.S. Pat. No. 4,879,303 and it discloses the formulation of amlodipine besilate, this patent is basically for the besilate salt of amlodipine, and it doesn't claim for formulation of the pure S (-) enantiomer of Amlodipine besilate & its stability. (11) The US patent 6,333,342 discloses the process of making S (-) isomer of Amlodipine Substantially free of its R (+) isomer. The patent mentions & claims for pharmaceutical compositions comprising of S (-) Amlodipine & its salts with pharmaceutically acceptable carrier, where in various dosage forms including tablets is mentioned, but it lists only the excipients which it proposes to use, however it does not describe in details the process of making any of the listed or mentioned dosage forms including tablets, the percentage composition of excipients to be used in individual dosage form. The excipient list includes Lactose as excipient along, but does not mention the specific dosage form in which it is to be included. The excipient Di calcium phosphate (dihydrate or anhydrous) is not used or claimed in the patent. The stability studies of the dosage form & the impact of stressed condition on the inter conversion of S (-) isomer to R (+) isomer & in vitro dissolution data is not detailed. (012) The patent no. WO 03043989 discloses and claims hydrophilic S (-) Amlodipine salts & their hydrates with high bio availability which can be prepared in the forms of various delivery devices including tablets & capsules along with ACE Inhibitors, ATI Antagonist, diuretics, calcium channel blockers and antihyperlipidemic drugs, however it does not disclose the exact process for making a specific delivery device, also the stability study aspect of the delivery device in contest to inter conversion of S (-) isomer to R(+) isomer till shelf life. It mentions lactose, microcrystalline cellulose & other many excipients but does not disclose the percentage composition formula using these excipients for a particular delivery device. Di Calcium Phosphate is not used in the invention. (13) The US patent 6,524,615 discloses, controlled release pharmaceutical composition, in the form comprising a hard shell capsule & a formulation comprising water insoluble medicament, high melting fatty ester etc. & lists amplodipine along with other water insoluble medicaments for controlled release formulation, but does not individually discloses the process for making tablet or a capsule dosage form. Amplodipine here may be a racemic mixture as it does not specify whether it is an S (-) isomer or R (+) isomer. (14) The US patent 6,451,826 discloses, a optically pure (-) amplodipine compositions, claims use of (-) amplodipine & its pharmaceutically acceptable salts free from (+) Stereo isomer adopted for oral, intravenous, transdermal delivery but does not claims the limit of percentage of (+) isomer quantitatively, it discloses the tablet and capsule formulations using lactose, pre-gelatinized starch, starch and magnesium sterarate with different composition formula, it does not list use of Di Calcium Phosphate in the formulation, also it does not reveals the stability of such formulation under stress and the conversion of S(-) isomer to R(+) isomer on storage , also it does not list any studies pertaining to compatibility of excipients used with the S(-) isomer of amplodipine nor the developmental pharmaceutics for process of making the either of the dosage forms. (15) The Canadian patent CA02215234 discloses composition containing amplodipine, or a salt, or felodipine and an ACE inhibitor, the use of racemic Amlodipine besilate, in combination with ACE inhibitor & diuretics, however it does not detail about the stereoisomers & formulation excipients details. (16) The US patent application 2003/0050328 discloses, administration of optically pure (-) isomer of amplodipine free from (+) isomer reducing adverse effects of raecemic amplodipine by intravenous transdermal or orally as a tablet or a capsule. It claims amount of (-) amplodipine & its pharmaceutically acceptable salt is grater than approx 90% by weight of total amount of amplodipine for formulation with suitable carriers for oral, intravenous & transdermal administration, but does not reveal the increase or change in the (+) isomer on storage, also does not claim the excipients used for making a suitable formulations & its quantity. In detailed description it defines " Substantially free of its (+) isomer" meaning at composition at least 90% of the weight of (-) amplodipine and 10% by weight or less of (+) amplodipine preferably 99% by weight (-) amplodipine & 1 % or less of (+) amplodipine but further it does not describe the level changes of (-) & (+) isomer after processing it to the desired formulation & its stability to remain " substantially free of its (+) isomer" during the shelf life, also it does not discloses the process & excipient details for the formulation to oral dosage form. (17) The US patent 6,602,902 discloses methods for selectively targeting pharmaceutical agents to desired tissues, targeted to Non-CNS active agents which lists racemic amplodipine classified under antihypertensive drugs, using a carrier cis-docosahexanoic acid along with pharmaceutically acceptable carrier to form conjugates with various drugs. Our patent relates to formulation of S(-) Amlodipine besilate salt, as described in the detailed description of this patent. (18) The US patent 6,576,636 discloses, to provide conjugates of fatty acids and antiviral agents useful in treating liver disorders. It claims the use of conjugate for various categories of drugs, Amplodipine & its salt is mentioned along with other categories of drugs. (19) The US patent 6,331,289 discloses, targetable diagnostic & or therapeutically active agent being conjugated to different targets on the same or different cells. SUMMARY OF THE INVENTION (20) The present invention there is provided benzene sulphonate (besilate) salt of S (-) Amlodipine. (21) The invention provides a pharmaceutically stable tablet formulations comprising of the besilate salt of S (-) amlodipine together with a pharmaceutically acceptable and compatible diluent or a carrier. (22) The invention further provides tablet formulations comprising the besilate salt of S (-) amlodipine in admixture with excipients. The drug excipients, compatibility studies, with microcrystalline cellulose, lactose, dibasic calcium phosphate and starch, disintegrant such as sodium starch glycollate, croscarmellose and binders, such as polyvinylpyrrolidone, gelatin, glidant like colloidal silicon dioxide, lubricating agents such as magnesium stearate, stearic acid and talc was done with the help of differential scanning calorimeter (make Mettler Toledo DSC8226). It was performed with the suitable blending of drug-excipient ratio with each individual excipient. (23) The S (-) amlodipine besilate had shown interaction with lactose. Colour change in blend of experiment vials seen at physical observation and its study is been described in detailed description of example 5, formulation nol 1 & 12. (24) The U.S. Pat. No. 4,879,303 discloses the benzene sulfonate (besilate) salt of amlodipine has a number of advantage over the known salts of amlodipine on good formulation properties but does not discloses formulation using S (-) Amlodipine besilate. There is no disclosure of the pharmaceutically stable formulations composition of tablet of optically pure S (-) enantiomer of amlodipine besilate to a human, which is having better pharmacological property then the amlodipine besilate (U S Pat No. 6,057,344). The present invention also relates in controlling the level of R (+) isomer of amlodipine below 0.15%, during the storage and shelf life, to eliminate the adverse effects associated with the R (+) isomer, which is present in the racemic mixture of amlodipine. The adverse effects associated with racemic mixture amlodipine salts are edema of the extremities including peripheral edema headache, dizziness flushing/hot flashes, vertigo, muscle cramps,palpitation, fatigue, nausea, abdominal pain and somnolence (U S Pat No. 6,476,058, U S Pat No. 6,291,490). (25) The preferred formulations includes the besilate salt of S (-) amlodipine, a compression aid such as microcrystalline cellulose, an additive to provide sheen to the tablet such as anhydrous dibasic calcium phosphate, a binder such as polyvinylpyrrolidione a disintegrant such as sodium starch glycolate, a glidant such as colloidal silicon dioxide and a lubricant such as magnesium stearate. (26) The invention further relates to process of co-administering of a combination comprising of S (-) Amlodipine besilate with beta-adrenergic receptor blockers, Atenolol, Nebivilol, angiotensin-converting-enzyme inhibitor Ramrpril, Quinapril Hydrochloride, the angiotensin II inhibitor as losartan potassium, and Candesartan celexitil. (27) The invention further relates to the combination of the most probable compatible excipient in the proper ratio blended to yield a tablet formulations of desired tableting for commercial scale & desired tableting properties such as appearance, disintegration time, dissolution rate. The tablet formulations stability studies were done at accelerated stability testing as per ICH Guidelines. The monitoring of impurities, related substances with special emphasis on R (+) isomer impurity of amlodipine besilate were done at accelerated stability condition as per ICH guidelines. (28) The invention further relates to the developmental pharmaceutics of S (-) Amlodipine besilate tablet formulations. DETAILED DESCRIPTION OF THE INVENTION (029) The S (-) isomer of amlodipine is also useful for the treatment of angina and such other conditions as may be related to the activity of S (-) amlodipine as a calcium channel antagonist without the concomitant liability of adverse effects associated with the racemic mixture of amlodipine. Amlodipine have a chiral center at C4 in the dihydropyridine ring, and thus can exist as optical isomers. The isomers may be separated by various methods, for example enantiomers of amlodipine via their diastereomeric tartrates (U.S. Pat. No. 5,750,707) or by a combination of separation and chiral synthesis. Optical isomers of compounds are specified (+) or (-), indicating the direction the chiral center rotates a plane of polarized light. (030) The compatibility (physical & chemical) study was done taking suitable ratio of S (-) amlodipine besilate with the individual excipients and the combination drugs. The sample mixtures where blended and triturated gently in glass mortar and pestle and these where filled in glass vials and sealed with high-density polyethylene closures. Few pinholes where made on the cap for maintaining the relative humidity and the vials where placed on 40°C ± 2°C/ 75% ± 5% RH. Samples were analyzed on differential scanning calorimeter & visually for initially, and at the interval of 15 days for one month. The results were compared to check the compatibility (physical & chemical) of the drug with excipients. It was found that there was change in appearance of the blended drug with lactose to the extent of light brown shade than the control sample at 25°C ± 2° C & 60% ± 5% RH and the rest of vials containing drug and excipients blend triturate were satisfactory in appearance as compared to individual control samples. (031) In order to screen for formulation stability we have formulated five different types of process for the tablet compression. We tried to formulate the tablet by different formulation processes and the analysis was done by HPLC (make Shimadzu Class VP) using the Ultron ES OVM ovomucoid chiral column using buffer and Acetonitrile as mobile phase in ratio of 78: 22 respectively and detection was done at 360 nm. We have specially checked the interconversion of the S (-) isomer of the amlodipine besilate to R (+) isomer during the compression and the stability studies. The stability studies were done as per ICH guidelines for 6 months. We found that the conversion of S (-) isomer to the R (+) isomer was in limit of less than 0.15% after 6 months accelerated stability studies are as per ICH guidelines in all the formulations. Example 1 (32) Formulation of Tablets Containing Besilate Salt of $ (-) Amlodipine by non-aqueous granulation. (33) S (-) Amlodipine besilate sieved through 60 mesh and geometrically mixed with lake of quinoline yellow (used in formulation 2 & 3), sodium starch glycolate and anhydrous dibasic calcium phosphate and blended for 5 minutes (all the ingredients were previously sieved through 60 mesh). This mixture was then sieved through 60 mesh, geometrically mixed and reblended with microcrystalline cellulose and passed through 40 mesh. Polyvinyl Pyrrolidone K 30 was dissolved in Isopropyl alcohol (5% w/v solution) and the above blend was granulated. The granules were passed from 8 mesh, air dried and then dried at 40°C till the loss on drying (LOD) of desired value reached of NMT 2% (make Mettler Toledo LJ16 moisture analyzer) at 60°C. The dried granules were sieved through 20 mesh. Finally sodium starch glycolate, colloidal silicon dioxide and magnesium stearate were passed from 60 mesh was added and the whole mixture blended for 5 minutes. The blend was then compressed into tablets using 16 & 27-station rotatory tablet machine (make - Cadmach). The whole procedure was carried out in control condition of temperature (25°C ± 2° C), relative humidity (40%±5% RH) & dark condition, protected from direct exposure to light. (034) Table 1. TABLET COMPOSITIONS Ingredient Quantity / tablet (mg) Formulation 1 Formulation 2 Formulation 3 S (-) Amlodipine Besilate 1.736 3.472 6.944 Microcrystalline Cellulose 50 50 77.056 Anhydrous dibasic calcium phosphate 35.264 32.528 45 Polyvinyl Pyrrolidione K 30 3 3 5 Lake of quinoline yellow - 1 1 Sodium starch glycolate 6 6 9 Colloidal Silicon dioxide 2 2 3 Magnesium stearate 2 2 3 Isopropyl Alcohol QS QS QS Tablet weight 100 100 150 (35) The above formulation 1, 2 and 3 granules were compressed using 6.3 mm circular Flat faced beveled edge (FFBE), 6.3 mm circular FFBE and 8mm triangle shaped toolings respectively. (36) It was observed that the tablet formulation 1,2 and 3 has, excellent disintegration properties, with very low friability and good hardness and good dissolution rate done in USP type 2 dissolution apparatus, to the limit of not less than (NLT) 75% (Q) in 30 min. (37) The compression of the above formulation 1,2 and 3 were run at different speeds from 16 to 25 rpm & the formulation parameters did not change by standard deviation of NMT 1.00 % (38) The tablets were place on accelerated stability studies according to the ICH guidelines on 40° C ± 2° C / 75% ± 5% relative humidity (RH), 30° C ± 2° C / 60% + 5% RH, controlled room temperature (CRT). Six months studies have been done for the assay, dissolution and impurity conversions to R (+) isomers. (039) The formulation 1, 2 and 3 has shown good stability at CRT, 30° C ± 2° C / 60% ± 5% RH and accelerated stability at 40° C ± 2° C/ 75% ± 5% RH. The assay of the tablet and dissolution was within limit as observed till 6 month. The R (+) isomer was 0.02% at initial and was 0.03% of the formulations 1,2 and 3 after 6 months. Example 2 (40) Formulation of Tablets Containing Besilate Salt of S (-) Amlodipine by aqueous granulation. (41) S (-) Amlodipine besilate (60 mesh pass) was geometrically mixed with Lake of quinoline yellow (used in formulation 5 &16), sodium starch glycolate and anhydrous dibasic calcium phosphate and blended for 5 minutes (all the ingredients were previously sieved through 60 mesh). This mixture was then sieved through 60 mesh, geometrically mixed and reblended with microcrystalline cellulose and passed through 40 mesh. Polyvinyl Pyrrolidone K 30 was dissolved in water (5% solution) and the above blend was granulated. The granules were passed from 8 mesh and dried on tray drier at 50°C till the loss on drying (LOD) of desired value reached of NMT 2% (make Mettler Toledo LJ16 moisture analyzer) at 60°C. The dried granules were sieved through 20 mesh. Finally sodium starch glycolate, colloidal silicon dioxide and magnesium stearate were passed from 60 mesh was added and the whole mixture blended for 5 minutes. The blend was then compressed into tablets using 16 & 27-station rotatory tablet machine (make - Cadmach). The whole procedure was carried out in control condition of temperature (25°C ± 2° C), relative humidity (40%±5% RH)& dark condition, protected from direct exposure to light. (042) Table 2. TABLET COMPOSITIONS Ingredient Quantity / tablet (mg) Formulation 4 Formulation 5 Formulation 6 S (-) Amlodipine Besilate 1.736 3.472 6.944 Microcrystalline Cellulose 50 50 77.056 Anhydrous dibasic calcium phosphate 35.264 32.528 45 Polyvinyl Pyrrolidione K 30 3 3 5 Lake of quinoline yellow - 1 1 Sodium starch glycolate 6 6 9 Colloidal Silicon dioxide 2 2 3 Magnesium stearate 2 2 3 Water QS QS QS Tablet weight 100 100 150 (43) The above formulation 4,5 and 6 granules were compressed using 6.3 mm circular FFBE, 6.3 mm circular FFBE and 8mm triangle shaped tooling respectively. (44) It was observed that the tablet formulations 4, 5 and 6 has, excellent disintegration properties, with very low friability and good hardness and good dissolution rate done in USP type 2 dissolution apparatus, to the limit of not less than (NLT) 75% (Q) in 30 min. (45) The compression of the above formulations 4, 5 and 6 were run at different speeds from 16 to 25 rpm & the formulation parameters did not change by standard deviation of NMT 1.00% . (046) The tablets were place on accelerated stability studies according to the ICH guidelines on 40° C ± 2° C / 75% ± 5% RH, 30° C + 2° C / 60% ± 5% RH and CRT. Six -month studies have been done for the assay, dissolution and impurity conversions to R (+) isomers. (047) The formulation 4,5 and 6 has shown good stability at CRT, 30° C ± 2° C / 60% + 5% RH and at accelerated stability at 40° C + 2° C/ 75% ± 5% RH. The assay of the tablet and dissolution was within limit as observed till 6 month. The R (+) isomer was 0.02% at initial and was 0.02%, 0.03 %, and 0.03 % of the formulation 4, 5 and 6 respectively after 6 months. Example 3 (48) Formulation of Tablets Containing Besilate Salt of S (-) Amlodipine besilate added at the time of lubrication in dummy granules. (49) Anhydrous dibasic calcium phosphate was blended with lake of quinoline yellow, sodium starch glycolate, and microcrystalline cellulose for 5 minutes (all the ingredients were previously sieved through 60 mesh). This mixture was then sieved through 40 mesh. Polyvinyl Pyrrolidone K 30 was dissolved in Isopropyl alcohol (5% w/v solution) and the above blend was granulated. The granules were passed from 8 mesh, air dried and then dried at 60°C till the loss on drying (LOD) of desired value reached of NMT 2% (make Mettler Toledo LJ16 moisture analyzer) at 60°C. The dried granules were sieved through 20 mesh. Finally S (-) amlodipine besilate was sieved through 60 mesh and mixed with the above dummy granules. Sodium starch glycolate, colloidal silicon dioxide and magnesium stearate were sieved through 60 mesh and added to the above dummy granules and the whole mixture blended for 5 minutes. The blend was then compressed into tablets using 16 & 27-station rotatory tablet machine (make - Cadmach). The whole procedure was carried out in control condition of temperature (25°C ± 2° C), relative humidity (40%±5%RH) & dark condition, protected from direct exposure to light. (050) Table 3. TABLET COMPOSITIONS Ingredient Quantity / tablet (mg) Formulation 7 S (-) Amlodipine Besilate 6.944 Microcrystalline Cellulose 29.556 Anhydrous dibasic calcium phosphate 45 Polyvinyl Pyrrolidione K 30 3 • Lake of quinoline yellow 0.5 Sodium starch glycolate 6 Colloidal Silicon dioxide 2 Magnesium stearate 2 Isopropyl alcohol QS Tablet weight 95 (51) The above formulation granules were compressed using 6.3 mm circular FFBE shaped toolings. (52) It was observed that the tablet formulation 7 has, excellent disintegration properties, with very low friability and good hardness and good dissolution rate done in USP type 2 dissolution apparatus, to the limit of not less than (NLT) 75% (Q) in 30 min. (53) The compression of the above formulation 7 was run at different speeds from 16 to 25 rpm & the formulation parameters did not change by standard deviation of NMT 1.00%. (54) The tablets were place on accelerated stability studies according to the ICH guidelines on 40° C ± 2° C/ 75% ± 5% RH, 30° C ± 2° C / 60% ± 5% RH and CRT. Six -month studies have been done for the assay, dissolution and impurity conversions to R (+) isomers (055) The formulation 7 have shown good stability at CRT, 30° C ± 2° C / 60% ± 5% RH and at accelerated stability at 40° C + 2° C/ 75% + 5% RH. The assay of the tablet and dissolution was within limit as observed till 6 month. The R (+) isomer was 0.02% at initial and was 0.03% after 6 months. Example 4 (56) Formulations of Tablets Containing Besilate Salt of S (-) Amlodipine by direct compression (57) S (-) Amlodipine besilate (60 mesh pass) was geometrically mixed with lake of quinoline (used in formulation 9 &10) yellow, sodium starch glycolate and anhydrous dibasic calcium phosphate and blended for 5 minutes (all the ingredients were previously sieved through 60 mesh). This mixture was then sieved through 60 mesh, geometrically mixed and reblended with microcrystalline cellulose. The resultant mixture was then sieved again through 40 mesh and blended for a further 10 minutes. Finally colloidal silicon dioxide and magnesium stearate were passed from 60 mesh was added and the whole mixture blended for 5 minutes. The blend was then compressed into tablets using 16 & 27-station rotatory tablet compression machine (make - Cadmach). The whole procedure was carried out in control condition of temperature (25°C + 2° C), relative humidity (40%±5% RH) & dark condition, protected from direct exposure to light. (058) Table 4. TABLET COMPOSITIONS Ingredient Quantity / tablet (mg) Formulation 8 Formulation 9 Formulation 10 S (-) Amlodipine Besilate 1.73 3.45 6.944 Microcrystalline Cellulose 53 53.55 87.056 Anhydrous dibasic calcium phosphate 28.27 25 50 Lake of quinoline yellow - 1 1 Sodium starch glycolate 8 8 9 Colloidal Silicon dioxide 2 2 3 Magnesium stearate 2 2 3 Tablet weight 95 95 160 (59) The above formulation 8, 9 and 10 granules were compressed using 6.3 mm circular Flat FFBE, 6.3 mm circular FFBE and 8mm triangle shaped toolings respectively. (60) It was observed that the tablet formulation 8, 9 and 10 has, excellent disintegration properties, with very low friability and good hardness and good dissolution rate done in USP type 2 dissolution apparatus, to the limit of not less than (NLT) 75% (Q) in 30 min. (61) The compression of the above formulation 8, 9 and 10 was run at different speeds from 16 to 25 rpm & the formulation parameters did not change by standard deviation of NMT 1.00 %. (62) It was observed that the tablet formulations 8, 9 and 10 have, excellent disintegration properties, with very low friability and good hardness. The tablets were place on accelerated stability studies according to the ICH guidelines on 40° C ± 2° C/ 75% ± 5% RH, 30° C + 2° C / 60% ± 5% RH and at CRT. Six -month studies have been done for the assay, dissolution and impurity conversions to R (+) isomers (063) The formulation 8, 9 and 10 have shown good stability at CRT, 30° C ± 2° C / 60% + 5% RH and at accelerated stability at 40° C ± 2° C/ 75% ± 5% RH, the assay of the tablet and dissolution was within limit for 6 months. The R (+) isomer was 0.02% at initial and was 0.03%, 0.04%, and 0.02% of the formulation 8,9and 10 respectively after 6 months. Example 5 (064) Formulations of Tablets Containing Besilate Salt of S (-) Amlodipine by non-aqueous granulation using Lactose. (065) S (-) Amlodipine besilate (60 mesh pass) was geometrically mixed with, lactose and sodium starch glycolate (all the ingredients were previously sieved through 60 no mesh) for 5 minutes. This mixture was then again sieved through 60 mesh, geometrically mixed and reblended with microcrystalline cellulose and passed through 40 mesh. Polyvinyl Pyrrolidone K 30 was dissolved in Isopropyl alcohol (5% w/v solution) and the above blend was granulated. The granules were passed from mesh 8, air dried and then dried at 40°C till the loss on drying (LOD) of desired value reached of NMT 2% (make Mettler Toledo LJ16 moisture analyzer) at 60°C. The dried granules were sieved through 20 mesh. Finally sodium starch glycolate, colloidal silicon dioxide and magnesium stearate (60 mesh passed) were added and the whole mixture was blended for 5 minutes were passed from 60 mesh. The blend was then compressed into tablets using 16 & 27-station rotatory tablet machine (make - Cadmach). The whole procedure was carried out in control condition of temperature (25°C ± 2° C), relative humidity (40%±5% RH) & dark condition, protected from direct exposure to light. (066) Table 5. TABLET COMPOSITIONS Ingredient Quantity / tablet (mg) Formulation 11 Formulation 12 S (-) Amlodipine Besilate 3.45 6.944 Lactose 33.55 53.056 Microcrystalline Cellulose 50 70 Sodium Starch Glycolate 6 9 Polyvinyl Pyrrolidione K 30 3 5 Colloidal silicon dioxide 2 3 Magnesium stearate 2 3 Isopropyl Alcohol QS QS Tablet weight 100 150 (67) The above formulation 11 and 12 granules were compressed using 6.3 mm circular FFBE and 8mm triangular FFBE punch tooling respectively. (68) It was observed that the tablet formulation 11 and 12 has, excellent disintegration properties, with very low friability and good hardness and good dissolution rate done in USP type 2 dissolution apparatus, to the limit of not less than (NLT) 75% (Q) in 30 min. (69) The compression of the above formulation 11 and 12 was run at different speeds from 16 to 25 rpm & the formulation parameters did not change by standard deviation of NMT 1.00 %. (70) The tablets were place on accelerated stability studies according to the ICH guidelines on 40° C ± 2° C / 75% ± 5% RH, 30° C ± 2° C / 60% ± 5% RH'and CRT. Six months studies have been done for the assay, dissolution and impurity conversions to R (+) isomers. (071) The formulations 11 and 12 have shown degradation all the stability conditions, the 3rd and 6th month, the assay of the tablet was found lower then the limit and disintegration time was increased. The change in colour from white to pigmented brown colour of tablet seen at 40° C ± 2° C / 75% ± 5% RH and 30° C ± 2° C / 60% ± 5% RH. This shows possibility of some incompatibility of S (-) amlodipine with the lactose. Example 6 (072) Formulations of Tablets Containing Besilate Salt of S (-) Amlodipine and Atenolol,, Besilate Salt of S (-) Amlodipine and Nebivilol Combination in single unit dosage form. The combination of S(-) Amlodipine besilate with Atenolol and with Nebivilol is formulated with either directly mixing and compressing using suitable tools on tablet compression machine or by granulating together or by adding both to dummy granules as described in above process examples (except example 5 where Lactose is used) as a single tablet Example 7 (073) Formulations of Tablets Containing Besilate Salt of S (-) Amlodipine and Atenolol, Besilate Salt of S (-) Amlodipine and Nebivilol Combination as bilayer tablets. The combination of S (-) Amlodipine besilate with Atenolol and with Nebivilol can also be done by formulating to granules individually and then compressed on a bilayer tableting machine using suitable tooling. The S (-) Amlodipine layer can be prepared by either of the formulation described in above examples (except example 5 where Lactose is used) and separately granulating (aqueous or non-aqueous) or blending (direct compression) Atenolol part and Nebivilol part to produce S (-) Amlodipine besilate with Atenolol bilayer tablets and S (-) Amlodipine besilate with Nebivilol bilayer tablets. Table 6. TABLET COMPOSITIONS one layer is of Besilate Salt of S (-) Amlodipine Average weight 95mg-160mg and another layer of Nebivilol by either of following formulae Ingredients Non Aqueous bilayer (mg / tab) Aqueous bilayer (mg / tab) Nebivilol HC1 2.725-5.45 2.725-5.45 Polysorbate-80 0.5-1.0 0.5-1.0 Microcrystalline cellulose 58.525-117.05 58.525-117.05 Starch 27.5-35.0 27.5-35.0 HPMC E 5 2.5-5.0 2.5-5.0 Croscarmellose sodium 3.0-6.0 3.0-6.0 Polyvinyl Pyrrolidone K30 1.25-2.5 1.25-2.5 Isopropyl alcohol qs - Water - qs Croscarmellose sodium 2.0-4.0 2.0-4.0 Microcrystalline cellulose 10.0-20.0 10.0-20.0 Sodium starch glycollate 1.0-2.0 1.0-2.0 Colloidal silicon dioxide 0.5-1.0 0.5-1.0 Magnesium stearate 0.5-1.0 0.5-1.0 Average weight of Nebivilol layer 110-200 110-200 Tools 10.5 mm circular 10.5 mm circular Continue Table 6. TABLET COMPOSITIONS: one layer is of Besilate Salt of S (-) Amlodipine Average weight 95mg-160mg and another layer of Atenolol by either of following formulae Example 8 (074) Formulations of Tablets Containing Besilate Salt of S (-) Amlodipine and Quinapril HCl, Losartan Potassium Combination as bilayer tablets. The combination of S (-) Amlodipine besilate with Quinapril HCl and with Losartan Potassium can also be done by formulating to granules individually and then compressed on a bilayer tableting machine using suitable tooling. The S (-) Amlodipine layer can be prepared by either of the formulation described in above examples and separately granulating (aqueous or non-aqueous) or blending (direct compression) Quinapril HCl part and Losartan Potassium part to produce S (-) Amlodipine besilate with Quinapril HCl bilayer tablets and S (-) Amlodipine besilate with Losartan Potassium bilayer tablets. Table 7. TABLET COMPOSITIONS one layer is of Besilate Salt of S (-) Amlodipine Average weight 95mg-160mg and another layer of Quinapril HCl by either of following formulae Ingredients Aqueous Bilayer( mg/tablet) Non Aqueous Bilayer( mg/tablet) Quinapril HCl 10.8-21.6 10.8-21.6 Microcrystalline Cellulose 77.7-155.4 77.7-155.4 Light Magnesium carbonate 65.0-130.0 65.0-130.0 Crospovidone 6.0-12.0 6.0-12.0 Polyvinyl Pyrrolidone K 30 - 7.5-15.0 Gelatin 2.5-5.0 - Purified Water QS - Isopropyl Alcohol - QS Crospovidone 6.0-12.0 6.0-12.0 Magnesium Stearate 2-4 2-4 Avg. Weight of Quinapril layer 170-340 175-350 Tools for bilayer 10.5 mm circular to 8.5x12.0 mm capsule shaped 10.5 mm circular to 8.5x12.0 mm capsule shaped Total weight of tablet including two layers 265mg to 500mg Continue Table 7. TABLET COMPOSITIONS one layer is of Besilate Salt of S (-) Amlodipine Average weight 95mg-160mg and another layer of Losartan Potassium by either of following formulae PtfMUsre 21 fcC0jTlCAL8iTD. Example 9 (075) Formulations of Tablets Containing Besilate Salt of S (-) Amlodipine and Candesartan cilexitil Combination as bilayer tablets. The combination of S(-) Amlodipine besilate with Candesartan cilexitil can also be done by formulating to granules individually and then compressed on a bilayer tableting machine using suitable tooling. The S(-) Amlodipine layer can be prepared by either of the formulation described in above examples and separately granulating (aqueous or non-aqueous) or blending (direct compression) Atenolol part and Nebivilol part to produce S(-) Amlodipine besilate with Candesartan cilexitil bilayer tablets. Table 8. TABLET COMPOSITIONS one layer is of Besilate Salt of S (-) Amlodipine Average weight 95mg-160mg and another layer of Candesartan cilexitil by either of following formulae Ingredients Non aqueous Bilayer (mg/tablet) Aqueous Bilayer (mg/tablet) Candesartan cilexitil 8-80 8-80 Microcrystalline Cellulose 50-500 50-500 Sodium starch Glycollate 4-40 4-40 Dibasic Calcium Phosphate Dihydrate 15-150 15-150 Polysorbate 80 0.2-2 0.2-2 Pregelatinized starch (Starch 1500) 0.8-8 0.8-8 Colloidal Silicon Dioxide 2.5-5 2.5-5 Microcrystalline Cellulose 5-50 5-50 Sodium starch Glycollate 3.5-20 3.5-20 Magnesium Stearate 1.0-15 1.0-15 Isopropyl Alcohol Qs - Purified Water - Qs Avg. Weight of Candesartan layer 90-870 90-870 Punch 8mm to 19.5X9.0mm 8mm to 19.5X9.0mm Total weight of tablet including two layers 180mg to 1020mg Conclusion (076) Amlodipine Besilate is a raecemic mixture and a potent molecule that inhibits the transmembrane influx of calcium ions into smooth muscle and cardiac muscle in the dose between 2.5 mg to 10 mg. The conversion of the S (-) isomer to R (+) isomer even at low levels as 1% will contribute to the adverse effect The present invention specially describes the development of a process for controlling the level of R (+) isomer of amlodipine below 0.15%, during the storage and shelf life, to eliminate the adverse effects associated with R (+) isomer. The formulations according to the process of example 5 has failed in stability studies of chemical & physical observations and formulation according to the example 1, 2 and 3 has more process steps, the best suitable formulation for the S (-) amlodipine besilate has been observed is formulations according to the process of example 4, which has the excipient as microcrystalline cellulose, anhydrous dibasic calcium phosphate, lake of quinoline yellow, colloidal Silicon dioxide, sodium starch glycolate and magnesium stearate, however formulations in example 1,2 and 3 are physically and chemically stable as per the stability studies done by ICH conditions. With lower dose tablets the need for good compressibility and uniform distribution of active drug is crucial and critical factor and selection of proper and suitable excipients and process is very essential microcrystalline cellulose is a commonly used compression aid and wacking agent. The dibasic calcium phosphate gives stability to the S (-) amlodipine and controlling the R (+) isomer within the limit. Disintegrants helps in breakup of tablet after the administration, as the active material must be released from the tablet matrix as efficiently as possible to allow rapid dissolution and availability of the drug through formulation to the body system, sodium starch glycolate is used here as disintegrant. Colloidal silicon dioxide helps in increasing the flow property of the granules and has excellent glidant properties. The adhesion of the drug to the punches of the tablet machine must be avoided. When drug accumulates on the punch surfaces this causes the tablet surface to become pitted and therefore unacceptable. Also sticking of the drug in this way results in high ejection forces when removing the tablet from the machine. In practice it is possible to reduce sticking by wet-massing, careful selection of excipients and the use of high levels of anti-adherents, e.g. magnesium stearate. (077) The invention also offers convenience of co-administration of suitable bilayer combination comprising of S (-) Amlodipine besilate with beta-adrenergic receptor blockers, Atenolol, Nebivilol angiotensin-converting-enzyme inhibitor Ramipril, Quinapril Hydrochloride the angiotensin II inhibitor as losartan potassium, and Candesartan celexitil, in tablet formulation as mentioned in examples 6-9 and bilayer tablet and tablet in tablet formulation having the excipient as mentioned in examples 6 to 9 to minimize the contact between active molecules and to avoid chemical incompatibility. We Claim: 1. A process of making stable pharmaceutical formulation of tablet, comprising an effective amount of S (-) Amlodipine besilate together with a pharmaceutically acceptable and chemically compatible diluents or carrier admixture with excipients which on & during shelf life minimizes the inter conversion of S (-) isomer to R (+) isomer less than 0.01% & not more than 0.15% of the total dose thereby reducing or nullifying the side effects caused by the R (+) isomer and shows the best in vitro dissolution profile studies even up to 6 months studied at 40°C ± 2 °C / 75%+ 5% RH accelerated conditions as per ICH guidelines & showing excellent tableting and machinability in production scale, wherein Dicalcium Phosphate anhydrous is used as a chemically compatible, stabilizing, inert tableting aid. 2. A process for making isomerically stable pharmaceutical formulation of tablet as in claim 1/along with one additional cardioactive agent and or with angiotensin converting enzyme inhibitor, an angiotensin II inhibitor, a calcium inhibitor, or a beta adrenergic antagonists, a calcium channel inhibitors in simultaneous or sequential combination with S (-) Amlodipine besilate compressed in mixture as single or separated biphasically as bilayer tablet and or tablet in tablet using suitable tools on a tablet compression machine. 3. A process as claimed in claim 1, where in Dicalcium phosphate anhydrous is used as a chemically compatible, stabilizing, inert tableting aid excipjent along with the other excipients like microcrystalline cellulose, Sodium starch glycollate, Polyvinyl Pyrrolidone (K10 to K120), lake of quinoline yellow, colloidal silicon dioxide and magnesium Stearate either alone or with the combinations as described in claim 2. Showing best in-vitro dissolution & controlling & maintaining R (+) isomer impurity within the limit. 4. A process as claimed in claim 3, wherein the excipient anhydrous dibasic calcium phosphate comprises an amount from 10 to 95% of the total tablet weight. 5. A process as clamed in claim 3, wherein the excipient is microcrystalline cellulose comprise an amount of from 10 - 80% either alone or in combination, where in the binder is Polyvinyl Pyrrolidone comprises an amount from 0.5 to 30% either alone or in combination, where in the disintegrant is sodium starch glycolate comprises an amount from 1 to 10% either alone or in combination, wherein glidant is Colloidal silicon dioxide comprises an amount from to 0.1 to 8% either alone or in combination, wherein the antiadherent is magnesium stearate comprises an amount of from 0.1 to 5% either alone or in combination, wherein the coloring agent is lake of quinoline yellow comprises an amount from 0.01 % to 5% either alone or in combination, of the total tablet weight. 6. A process as claimed in claim 2, wherein beta adrenergic receptor blocker is Atenolol in the dose of 25-100mg and Nebivilol in the dose of 2mg to 10 mg, angiotensin-converting-enzyme inhibitor is Ramipril in the dose of from 0.5 to 40 mg and Quinapril hydrochloride in the dose of from 0.5 to 150 mg, wherein said angiotensin II receptor antagonist is Losartan potassium in the dose of from 20 to 200 mg and Candesartan cilexitil in the dose of from 6 to 80 mg, with the pharmaceutically acceptable excipients which includes diluents as microcystalline cellulose, Dicalcium phosphate, light Magnesium carbonate ranging from 10% to 90%, binder as Polyvinyl Pyrrolidone, gelatin, hydroxypropylmethyl cellulose (6cps to 15 cps), starch (as paste) ranging from 0.1% to 10%, disintegrant sodium starch glycollate, crospovidone ranging from 1% to 10%, lubricant and glidant as magnesium stearate, talc, colloidal silicon dioxide ranging from 0.1% to 5%, disintegrant binder as pregelatinized starch (starch 1500) ranging from 1% to 20%of the total tablet weight. 7. A process as claimed in claimed in claim 1 wherein the stable formulations of tablets containing besilate salt of S (-) Amlodipine were prepared by direct compression method. In this process S (-) Amlodipine besilate (60 mesh pass) in the dose of from 0.5-20mg was geometrically mixed with the lake of quinoline yellow (0.01% to 5 % of total tablet weight), sodium starch glycollate (1 to 10%) and anhydrous dibasic calcium phosphate (10 to 95% of total tablet weight) and blended for 5 min (all ingredients were previously sieved through 60 mesh). This mixture was then sieved through 60 mesh, geometrically mixed and reblended with microcrystalline cellulose. The resultant was then sieved again through 40 mesh and blended for a further 10 min. Finally Colloidal silicon dioxide (0.1 to 0.8% of tablet weight) and magnesium stearate (0.1 to 5 % of tablet) were passed from 60 mesh was added and the whole mixture blended for 5 minutes. The blend was then compressed into tablets using 16 and 27-station rotatory tablet compression machine. The whole procedure was carried out in control condition of temperature (25° c ± 2° C) and relative humidity (40% ± 5% RH) and dark condition protected from direct exposure to light. REFERENCES U.S. Patent Documents 3,663,607 May, 1972 Barret et al., 562/467 4,344,949 Aug., 1982 Hoefle et al., 514/307 4,572,909 Feb., 1986 Campbell et al., 514/356 4,587,258 May., 1986 Gold et al., 514/412 4,879,303 Nov., 1989 Davison et al., 514/356 5,098,910 Mar., 1992 Becker et al., 514/249 5,138,069 Aug., 1992 Carini et al., 548/253 5,196,444 Mar., 1993 Naka et al., 514/381 5,750,707 May, 1998 Spargo et al., 546/321 6,057,344 May, 2000 Young et al., 514/356 6,291,490 Sep., 2001 Young et al., 514/356 6,476,058 Nov., 2002 Foster et al., 514/356 6,331,289 Oct., 1997 Klaveness, et al., 424/9.52 6,576,636 Dec, 2000 Webb, et al., 514/263.3 6,602,902 May, 2001 Shashoua, et al., 6,333,342 Nov., 1999 Foster et al., 514/356 6,451,826 Jul., 2001 Young 514/356 6,524,615 Feb., 2001 Gutierrez-Rocca, et al. 424/451 20030050328 Jul., 2002 Young 514/355 Other Patent Documents 0 089 167 Sep., 1983 EP. 0 331315 Sep., 1989 EP. WO03043989 May 2003 ZHANG XITIAN (CN) CA 02215234 Feb., 1996 Other References Goldmann, S. et al., "Determination of the Absolute Configuration of the Active Amlodipine Enantiomer as (-)-S: A Correction", Journal of Medicinal Chemistry 35(18):3341-3344 (1992). Alker, D. et al., "Long-acting dihydropyridine calcium antagonists. 9. Structure Activity Relationships Around Amlodipine", Eur. J. Med. Chem. 26: 907-913 (1991). The Merck Index, thirteenth Edition, Monograph 491 (1989). Arrowsmith, J. E. et al., "Long-Acting Dihydropyridine Calcium Antagonists. 1. 2-Alkoxymethyl Derivatives Incorporating Basic Substituents", J. Med. Chem. 29: 1696-1702 (1986). Gennaro, A.R., "Remington: The Science and Practice of Pharmacy, 20th Ed." published by Lippincott Williams & Wikins. (Phildelphia, PA), pp. 860-863 (1990). Ariens, E.J., "Stereoselectivity in Pharmacodynamics and Pharmacokinetics", Schweiz. Med. Wochenschr. 120: 131-134(1990). Ariens, E.J., "Racemic Therapeutics-Ethical and Regulatory Aspects", Eur. J. Clin. Pharmacol. 41: 89-93 (1991). Luksa, J. et al., "Pharmacokinetic Behaviour of R-(+)-and S-(-)-Amlodipine After Single Enantiomer Administration," Journal of Chromatography B, 703:185-193 (1997). Kart, E. et al., "Handbook of HPLC," published by Marcel Dekker, Inc. New York, 669 -687(1998). Laufen, H. et al., "Enantioselective Disposition of Oral Amlodipine in Healthy Volunteers," Chirality, 6:531-536 (1994). Dunselman, P. H. et al., "Value of the addition of amlodipine to Atenolol in patients with angina pectoris despite adequate beta blockade". Am. J. Cardiol., 81(2):128-132 (1998) Dated this 28th day of September 2004. Name of the inventor: Mr. Manutosh Manohar Acharya Assignee: Aristo Pharmaceuticals Ltd -( Mercantile Chamber's 3rd Floor, " 12, J.N.Heredia Marg, Graham Road, Ballard Estate, Mumbai - 400053 (INDIA)

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