ES2230369T3 - AMLODIPINE FUMARATE. - Google Patents

Abstract

Amlodipine fumarate salt compounds are useful as calcium channel blockers and in treating or preventing angina or hypertension. The fumarate salts avoid the formation of certain potential impurities that have been found to be associated with amlodipine maleate.

Description

Amlodipine fumarate.

The present invention relates to a new compound, to procedures to prepare it, and to its use for Treatment of medical disorders. In particular, this invention relates to new acid addition salts of amlodipine

Calcium channel blockers (calcium antagonists) are useful in the treatment of heart disease that includes angina pectoris and / or hypertension. It is generally known that derivatives of dicarboxylate dihydropyridine possess activity calcium channel blocker. For example, the document of EP 089167 and the corresponding US patent document 4,572,909 describe a class of derivatives of 2- (group amino) -3,5-dicarboxylate dihydropyridine as useful blockers of calcium channels. These patents identify that one of the most preferred compounds is 2 - [(2-aminoethoxy) -methyl] -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine. This compound, which is now commonly known as amlodipine, It has the following formula:

one

Amlodipine shows good bioavailability and has a long half-life in the body. Although a variety of acid addition salts are mentioned in these patents as potentially suitable, including smokers, the maleate salt is identified as the most preferred acid addition salt. However, the commercial product of amlodipine (NORVASC from Pfizer) uses amlodipine besylate (benzenesulfonate) and not amlodipine maleate. Indeed, subsequent patents EP 244944 and the corresponding US 4,879,303 indicate that the besylate salt provides certain advantages over known salts, which include good formulation properties. Apparently, amlodipine maleate experienced problems in tablet formation and stability, to cause a change during development towards the besylate salt. (See " Review of Original NDA " for NDA # 19-787 of 10/10/1990, obtainable from the FDA under the Freedom of Information Act). The problems / causes of stability and tablet formation are not publicly described in the information available from the
FDA

The present invention relates to salts of Amlodipine fumarate. In particular, one aspect of the invention is refers to an addition salt of amlodipine acid with acid fumaric Another aspect of the invention relates to fumarate of crystalline amlodipine. A preferred form of fumarate of amlodipine is amlodipine hemifumarate.

The invention also relates to a procedure, which comprises contacting the free base of amlodipine or its salt with fumaric acid or its ammonium salt, in presence of a solvent, to form amlodipine fumarate.

Additional aspects of the invention include the use of amlodipine fumarate for the preparation of a medicine for the treatment or prevention of angina pectoris or hypertension, as well as a pharmaceutical composition for use in the treatment and / or prevention of angina pectoris or hypertension, which comprises an effective amount of amlodipine fumarate together with a pharmaceutically acceptable excipient.

This invention relates to a new salt of amlodipine, which does not include problems associated with the salt of maleate and its appropriate equivalent to besylate salt. According to the present invention, an acid addition salt is provided of amlodipine with fumaric acid, that is, fumarate of amlodipine

Fumaric acid, unlike maleic acid, exists in a trans configuration. It has now been discovered that a problem with the formation and / or stability of amlodipine maleate is the potential of amlodipine amine nitrogen to react with the double bond of maleic acid, to form amlodipine aspartate of the following formula:

2

This reaction is an addition of type Michael. The present invention prevents the formation of amlodipine aspartate by selecting a different anion from the salt. In particular, although both maleic acid and fumaric acid contain a double carbon bond, it is prevented, with fumaric acid, that Michael-type addition occurs due to the trans configuration of this acid. Consequently, an aspartate derivative with fumaric acid cannot be formed, and this particular impurity / stability problem that is now known to be associated with amlodipine is avoided.

Amlodipine fumarate, as used in the present invention means any acid addition salt formed by reacting / combining fumaric acid with amlodipine; for example, any salt that is composed of cations of amlodipine and fumaric acid anions. For example, they are including both solid and dissolved forms, such as crystalline and amorphous forms. In addition, the Amlodipine to fumaric acid ratio is 1: 1, although such ratio is included, to be a fumarate compound of amlodipine For example, a preferred amlodipine fumarate has a 2: 1 ratio, which corresponds to a hemifumarate. These and Other specific relationships of amlodipine to fumaric acid are included in the single generic expression "fumarate of amlodipine. "The crystalline forms can be anhydrous, hydrated, solvated, etc. In addition, it should be understood that the compound may exist as one of two enantiomers, due to the presence of a chiral center in the ring of 1,4-dihydropyridine. The shapes can be separated by example, by crystallization or free base chromatography of amlodipine or its salt with an optically active acid, and Become the corresponding fumarate salt. The enantiomers individual, as well as their mixtures, are also included by the singular expression "amlodipine fumarate".

Amlodipine fumarate can be prepared contacting amlodipine (as a free base) or its salt addition of acid other than fumarate, with fumaric acid or its salt of ammonium, in a suitable solvent, preferably being both fumaric acid such as amlodipine completely dissolved. Generally, amlodipine fumarate precipitates in the solution or reaction mixture. Precipitation can be spontaneous depending on the solvent used and the conditions. Alternatively, precipitation can be induced by reducing the solvent temperature, especially if the initial temperature in contact is high. Precipitation can be facilitated also reducing the volume of the solution, or adding a counter solvent, that is, a liquid miscible with the solvent, in which amlodipine fumarate is less soluble.

The amlodipine or its salt to be used in achieving the present invention can be obtained by methods well known in the art, including those described in the aforementioned patents, as well as in US Patent 4,572,909. Another synthetic scheme useful for the preparation of amlodipine or its salts with good yields and purity, through an intermediate product of phthalimidoamlodipine, is also described in the provisional common property application of Serial No. 60 / 258,613, filed on December 29 of 2000, and in the US patent application co-pending common property of Serial No. 09 / 809,351, filed on March 16, 2001, and entitled " Process for Making Amlopidine, Derivatives Thereof, and Precursors Therefor ".

Fumaric acid and its ammonium salts are good known by themselves, and are readily available to the skilled worker in the art.

The solvents useful for carrying out the Salt reaction include water, an alcohol such as methanol or ethanol, a ketone such as acetone or methyl isobutyl ketone, an ester such as ethyl acetate, an ether such as diethyl ether or tetrahydrofuran, a nitrile such as acetonitrile, solvents dipolar aprotic such as dimethylsulfoxide or dimethylformamide, hydrocarbons such as hexane or toluene, and mixtures thereof. The Preferred solvents are those in which the reactants they are more soluble than the amlodipine fumarate product. Of this mode, the salt formation reaction is accompanied by a spontaneous precipitation in the dissolution of the fumarate salt produced. Examples are alcohols such as ethanol and isopropanol, esters such as ethyl acetate, and hydrocarbons such as Toluene.

The precipitated fumarate salt can be isolated in solid state by conventional methods such as filtration or centrifugation, optionally followed by washing and / or drying, and may purified by crystallization, for example at a temperature raised in an appropriate solvent, for example water, such an alcohol  such as methanol, or a ketone such as acetone. The methods described previously allow the preparation of a fumarate compound of crystalline amlodipine.

Amlodipine fumarate is formed preferably as a salt having a 2: 1 molar ratio between amlodipine and fumaric acid (= amlodipine fumarate (1: 2) or amlodipine hemifumarate), as such salt is insoluble or only little soluble in water and in the most used organic solvents Commonly. Amlodipine hemifumarate can even form when an excess of amlodipine or an excess of fumaric acid is used in salt formation. Due to its limited solubility in water, amlodipine hemifumarate is a preferred compound for certain embodiments of the present invention, especially for slow or prolonged release pharmaceutical compositions. Having a lower water solubility, the release profile of amlodipine in the body can be moderated and prolonged longer easily. Using this salt as an active ingredient in tablets or capsules, other means to improve can be avoided or reduced slow or prolonged release (for example, a coating special, special excipients such as insoluble polymers, etc.).

Amlodipine fumarate can also be obtained in amorphous form, for example, lyophilizing a solution of amlodipine and fumaric acid in an appropriate solvent, for example in water Such amorphous forms can be advantageous in comparison. with crystalline forms, since they can be obtained in a form finely powdered with good solubility properties.

Amlodipine smokers, and particularly the amlodipine hemifumarate, may exist as a form without solvent or can be isolated as a hydrate or a solvate. The hydrates and solvates of amlodipine fumarate, especially hydrates or solvates of amlodipine hemifumarate form another aspect of the invention.

Amlodipine fumarate can be characterized by a variety of ordinary methods, such as spectrum of IR, m.p., differential scanning calorimetry curve (DSC), etc. The structure and ratio of amlodipine / fumaric acid can be demonstrated by measuring the 1 H NMR spectrum and / or by methods of assessment.

Amlodipine fumarate is converted in vivo into the amlodipine free base, and thus basically shares the pharmaceutical activity of amlodipine. Consequently, the compound can be used as a suitable form of amlodipine for the administration of amlodipine in a patient in need. Particularly, due to its limited solubility in body fluids, amlodipine hemifumarate is the advantageous salt form of amlodipine, especially for manufacturing final forms of slow or modified release, but its use is not limited to these.

Amlodipine fumarate is a useful blocker of calcium channels, and can be used in this way to treat any heart disease that benefits from administration of a calcium channel blocker. In In particular, amlodipine fumarate can be used to treat or prevent hypertension or angina, by administering a effective amount to a patient who needs it. The specific form Angina pectoris is not particularly limited, and includes specifically stable chronic angina pectoris and angina vasospastic (Prinzmetal angina). The compound can be administered by any appropriate route, which includes orally or parenteral. The "patients" under treatment include human beings and nonhuman animals, especially human beings and non-human mammals

The compound is usually administered as part of a pharmaceutical composition. Consequently, one aspect Additional of the present invention is a pharmaceutical composition to treat or prevent hypertension or angina pectoris, which it comprises an effective amount of amlodipine fumarate and a pharmaceutically acceptable excipient. Excipients include any inert or inactive material used in the manufacture of a pharmaceutical form. For example, the excipients of a tablet include, but are not limited to, calcium phosphate, cellulose, starch or lactose Capsules such as those made of jelly, may contain or carry amlodipine fumarate alone or mixed with other excipients. Liquid dosage forms They are also included, such as oral fluids in the form of solutions or suspensions, as well as injectable solutions. The pharmaceutical composition can be formulated for administration transdermal, in the form of a patch. All the compositions Pharmaceuticals described above may optionally contain one or more of each of the following excipients: vehicles, diluents, dyes, flavoring agents, lubricants, agents solubilizers, disintegrants, binders and preservatives.

The pharmaceutical composition is provided. usually in a unit dose. A unit dose is administered typically once or twice daily, more typically once daily In the case of a transdermal patch, the unit dose (a patch) is usually applied at least once a month, plus commonly at least once every two weeks, and typically once a week. An effective amount of the acid addition salt fumaric amlodipine in a unit dose, for treatment or prevention of hypertension or angina pectoris, is usually within the range of 1 to 100 mg, typically 1 to 50 mg, more typically 1 to 20 mg. In solid oral pharmaceutical forms (tablets, capsules, etc.), the pharmaceutical composition contains typically about 1, 2.5, 5.0, or 10 mg of the fumarate of amlodipine For simplicity, all quantities refer to the corresponding amount of amlodipine free base proportionate to the composition. The specific examples of Pharmaceutical compositions include those described in the document EP 244944, in which amlodipine hemifumarate is used As active ingredient.

All pharmaceutical compositions described previously they can be prepared by known methods and techniques. For example, tablets can be prepared by granulation by dry route / direct compression or by a classic method of wet granulation. Typically, the tablets are they prepare by mixing, filling and compressing tablets. The mixing stage may comprise granulation via wet or dry granulation. Similarly, the capsules they can be made by mixing the ingredients and filling the capsule.

The following examples illustrate the invention.

Example 1 Amlodipine Hemifumarate

10 g of amlodipine are dissolved in 100 ml of ethanol. To this solution are added, at room temperature, 2.83 g of fumaric acid dissolved in 100 ml of hot ethanol. Solid which is formed is filtered and washed with 2x10 ml of ethanol. After drying in a vacuum oven at 35 ° C, 11 g of a solid are obtained White.

Mp .: 170.5 ° C-172.5 ° C

1 H NMR spectrum

3

The 1 H NMR spectrum was measured at 303.2 ° K in a Bruker Advance-400, in deuterated acetic acid at 400 MHz

\delta (ppm) assignment 1.14 (t, 3H, J 11.12 = 7.0 Hz, H-12); 2.32 (s, 3H, H-15); 3.36 (dda, 2H, H-9); 3.59 (s, 3H, H-14); 3.90 (ta, 2H, H-8); 4.04 (c, 2H, J 11.12 = 7.0 Hz, H-11); 4.77 (AB_ {c}, 2H, H-7); 5.41 (s, 1H, H-4); 6.86 (s, 1H, H-2 ''); 7.05 (td, 1H, J_ {3 ', 4'} = J_ {4 ', 5'} = 7.8 Hz, J_ {4 ', 6'} = 1.5 Hz, H-4 '); 7.15 (td, 1H, J_ {4 ', 5'} = J_ {5 ', 6'} = 7.8 Hz, J_ {3 ', 5'} = 1.0 Hz, H-5 '); 7.23 (dd, 1H, J 3 ', 4'} = 7.8 Hz, J 3 ', 5'} = 1.0 Hz, H-3 '); 7.41 (dd, 1H, J5 ', 6'} = 7.8 Hz, J4 ', 6'} = 1.5 Hz, H-6 ');

13 C NMR spectrum

The 13 C NMR spectrum was measured at 303.2 ° K in a Bruker Advance-400, in deuterated acetic acid at 100.6 MHz

\delta (ppm) assignment 14.53 (C-12); 19.15 (C-15); 38.29 (C-4); 40.63 (C-9); 51.54 (C-14); 61.70 (C-11 67.72 (C-8); 68.81 (C-7););

(Continuation)

\delta (ppm) assignment 102.93 (C-3); 104.37 (C-5); 128.04 (C-5 '); 128.66 (C-4 '); 130.24 (C-3 '); 132.48 (C-6 '); 133.26 (C-2 '); 135.35 (2xC-2``); 146.36, 146.45 (C-2, C-6); 146.85 (C-1 '); 168.78 (C-10 '); 169.70, 169.75 (2xC-1``, C-13).

Example 2 Amlodipine Hemifumarate

10 g of amlodipine free base are dissolved in 75 ml dimethylsulfoxide. To this solution are added, to room temperature, 2.84 g of fumaric acid. It is obtained during a few moments, at room temperature, a transparent solution, before a solid forms. The solid is filtered and washed with 2x10 ml of water After drying in a vacuum oven at 50 ° C, it is they obtain 10.5 g of a white solid.

Mp .: 170.8 ° C-172.6 ° C

Example 3 Amlodipine Hemifumarate

5 g of fumaric acid are dissolved in a mixture 100 ml of ethanol and 10 ml of water, at 50 ° C. This solution is add, in portions, 5 g of amlodipine free base for 10 minutes A solid forms approximately 5 minutes later of completing the addition. The suspension is heated until it a solution is obtained, and the reaction mixture is cooled slowly at room temperature. A solid is obtained, which is filtered and wash with 2x10 ml of an ethanol / water mixture (9/1 v: v). After Dry in a vacuum oven at 40 ° C for 18 hours, they are obtained 3.21 g of a white solid.

Mp .: 170.3 ° C-172.6 ° C

Example 4 Pharmaceutical tablet comprising hemifumarate of amlodipine

Composition:

Salt of ADP eq. based on ADP: 5.00 mg 10.00 mg Amlodipine Hemifumarate 5.71 mg 11.42 mg Hydrogen phosphate anhydrous calcium 63.00 mg 126.00 mg Microcrystalline cellulose 124.10 mg 248.10 mg Sodium starch glycolate 4.00 mg 8.00 mg Stearate magnesium 2.00 mg 4.00 mg Total 198.81 mg 397.52 mg

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Manufacturing Procedure:

-

He amlodipine hemifumarate is screened through a 500 sieve \ mum.

-

He anhydrous calcium hydrogen phosphate, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate are sift through a 850 µm sieve.

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He amlodipine hemifumarate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, and sodium starch glycolate they are transferred to a free fall mixer, and mixed during 15 minutes at approximately 25 rpm.

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Be add magnesium stearate, and the powder mixture is mixed during another 5 minutes at about 25 rpm.

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The tablets are compressed using an eccentric Korsch press EK0.

Claims (18)

1. An amlodipine acid addition salt with fumaric acid 2. An acid addition salt according to the claim 1, wherein said salt is in a state crystalline. 3. An acid addition salt according to the claims 1 or 2, wherein said salt is hemifumarate of amlodipine 4. A procedure, which includes putting in base contact free of amlodipine or its salt with fumaric acid or its ammonium salt, in the presence of a solvent, to form a salt of addition of amlodipine acid with fumaric acid. 5. The method according to claim 4, wherein said acid addition salt being formed is amlodipine hemifumarate. 6. The procedure according to claims 4 or 5, wherein the solvent is selected from the group consisting of water, alcohol, ketone, ester, ether, nitrile, dipolar aprotic solvent, hydrocarbon, and mixtures thereof. 7. The method according to claim 6, wherein said solvent is selected from the group consisting in water, methanol, ethanol, acetone, methyl isobutyl ketone, ethyl acetate, ether diethyl, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, hexane, toluene, and mixtures thereof. 8. The procedure according to claims 5, 6 or 7, wherein said solvent is selected from the group consisting of water, ethanol, dimethyl sulfoxide, and their mixtures 9. The procedure according to any of the claims 4-8, further comprising precipitating said acid addition salt in said solvent. 10. The method according to claim 9, in which said precipitation is spontaneous or induced decreasing the temperature, decreasing the volume, or adding a counter solvent. 11. The procedure according to claims 9 or 10, wherein said acid addition salt precipitate is amlodipine hemifumarate. 12. The use of a compound according to any of claims 1 to 3, for the preparation of a medicine to treat or prevent angina or hypertension. 13. The use according to claim 12, in the that said compound is amlodipine hemifumarate. 14. A pharmaceutical composition for use in the treatment and / or prevention of angina pectoris or hypertension, which comprises an effective amount of a compound according to any of claims 1-3, and an excipient pharmaceutically acceptable. 15. The pharmaceutical composition according to the claim 14, wherein said composition is a form pharmaceutical unit for oral administration, and said amount effective is within the range of 1-20 mg, based in the weight of the amlodipine free base. 16. The pharmaceutical composition according to the claims 14 or 15, wherein said pharmaceutical form Unitary is in the form of a tablet or capsule. 17. The pharmaceutical composition according to any of claims 14-16, wherein said effective amount is 2.5, 5 or 10 mg, based on the weight of the amlodipine free base. 18. The pharmaceutical composition according to any of claims 14-17, wherein said compound is amlodipine hemifumarate.