SI21066A2 - 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

The present invention relates to a new compound, to methods for its preparation and to its use in the treatment of medical disorders. In particular, the present invention relates to novel acid addition salts of amlodipine.

Calcium channel blockers (calcium antagonists) are useful in the treatment of heart conditions, including angina and / or hypertension. Dicarboxylate-dihydropyridine derivatives are commonly known to have calcium channel blocking activity. E.g. EP 089 167 and corresponding US 4,572,909 describe the class 2-amino group-3,5-dicarboxylate dihydropyridine derivatives as useful calcium channel blockers. These two patents identify that one of the most preferred compounds is 2 - [(2aminoethoxy) methyl] -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine. This compound, now commonly known as amlodipine, has the following formula:

Amlodipine exhibits good bioavailability and has a long half-life in the body. Many of the acid addition salts, including fumarates, are described in these patents, but the maleate salt is identified as the most preferred acid addition salt. However, the marketed product of amlodipine (NORVASC from Pfizer) uses amlodipine besylate (benzene sulfonate) rather than amlodipine maleate. Indeed, the later patents of EP 244 944 and the corresponding US 4,879,303 state that the besylate salt has certain advantages over the known salts, including good formulation properties. Apparently, deficiencies of amlodipine maleate were problems with tableting and stability, which led to a leap to lead-free salt during development (see Review of Original DNA for DNA # 19-787 10/10/1990, available from the FDA under the Freedom of Information Act (Freedom of Information Act)). The following questions a / reasons for stability and tableting have not been made publicly available in FDA information.

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

The invention also relates to a process comprising contacting fumic acid or its ammonium salt in the presence of a solvent to form amlodipine fumarate.

Further aspects of the invention include a method for treating or preventing angina or hypertension, comprising administering an effective amount of amlodipine fumarate to a patient in need thereof, as well as a pharmaceutical composition for use in treating and / or preventing angina or hypertension comprising an effective amount of amlodipine fumarate together with a pharmaceutically acceptable excipient.

The present invention relates to a new amlodipine salt having no problems associated with the maleate salt, and is a corresponding equivalent to the besylate salt. According to the present invention, the acid addition salt of amlodipine with fumic acid is provided, i.e. amlodipine fumarate.

Unlike maleic acid, there is fumama acid in a trans configuration. We have now discovered that a problem with the formation and / or stability of amlodipine maleate is the possibility for amlodipine amine nitrogen to react with a double bond of maleic acid, forming amlodipine aspartate with the following formula:

This reaction is Michael's type of addition. The present invention avoids the formation of amlodipine aspartate by selecting a different salt anion. Although both maleic acid and fumamic acid contain a carbon double bond, the transconfiguration of fumic acid makes it especially impossible for Michael's type of addition to occur with fumic acid. Therefore, the aspartate derivative cannot be formed with fumic acid and this particular issue of impurity / stability, now known to be linked to amlodipine, is avoided.

Amlodipine fumarate as used herein means any acid addition salt formed by the metabolism / association of fumaric acid with amlodipine; e.g. any salt comprising amlodipine cations and fumic acid anions. E.g. both solid and dissolved forms such as crystalline and amorphous forms are included. Furthermore, the ratio of amlodipine to fumaric acid is not required to be 1: 1, although such is included to have the compound amlodipine fumarate. E.g. the preferred amlodipine fumarate has a 2: 1 ratio, which corresponds to hemifumarate. These and other specific ratios of amlodipine to fumaric acid are all covered in one generic term, amlodipine fumarate. The crystalline forms can be anhydrous, hydrates, solvates, etc. It is further understood that due to the presence of a chiral center on the 1,4 dihydropyridine ring, the compound may exist as one of two enantiomers. Forms can be separated, e.g. by crystallization or chromatography of an amlodipine free base or a salt thereof with an optically active acid and can be converted to the corresponding fumarate salt. Individual enantiomers, as well as mixtures thereof, are also covered by the individual term amlodipine fumarate.

Amlodipine fumarate can be prepared by contacting fumic acid or its ammonium salt in an appropriate solvent, preferably with both fumic acid and amlodipine, which are both completely dissolved in the corresponding solvent by establishing amlodipine (as the free base) or its acid addition salt other than fumarate solvent. In general, amlodipine fumarate is precipitated from solution or reaction mixture. The precipitation may be spontaneous depending on the solvent used and the conditions. Alternatively, precipitation can be induced by lowering the solvent temperature, especially if the initial contact temperature is elevated. The precipitation can also be facilitated by lowering the volume of the solution or by adding a counter-solvent, i.e. a solvent miscible fluid in which amlodipine fumarate is less soluble. Amlodipine or a salt thereof for use in the manufacture of 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 4,572,909. Another useful synthesis scheme for the preparation of amlodipine or its salts in good yields and purity via the phthalimidoamlodipine intermediate is also described in provisional application serial no. No. 60 / 258,613, filed December 29, 2000, jointly owned, the entire contents of which are incorporated herein by reference, and U.S. Pat. No. 09 / 809,351, filed March 16, 2001, jointly owned and titled The Process for the Preparation of Amlodipine, its Derivatives and its Precursors, the entire contents of which are incorporated herein by reference. Fumama acid and its ammonium salts are well known as such and are readily available to one of skill in the art.

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, nitrile such as acetonitrile, dipolam aprotic solvents such as dimethylsulfoxide or dimethylformamide, hydrocarbons such as hexane or toluene and mixtures thereof. Preferred solvents are those in which the reactants are more soluble than the product amlodipine fumarate. In this way, the salt formation reaction is accompanied by the spontaneous precipitation of the produced fumarate salt from the solution. 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 the solid state by conventional methods such as filtration or centrifugation, followed by washing and / or drying, and can be purified by crystallization, e.g. at elevated temperature in a suitable solvent, e.g.

water, an alcohol such as methanol or a ketone such as acetone. The methods described above allow the production of the amlodipine fumarate compound in the crystalline state.

Amlodipine fumarate is preferably formed as a salt with a molar ratio of 2: 1 between amlodipine and fumaric acid (= amlodipine (2: 1) fumarate or amlodipine hemifumarate) as such salt is insoluble or only slightly soluble in water and in most commonly used organic solvents. Amlodipine hemifumarate can be formed even when excess amlodipine or excess fumaric acid is used in salt formation. Due to its limited solubility in water, amlodipine fumarate is preferably a compound for certain embodiments of the present invention, especially for slow- or prolonged-release pharmaceutical compositions. Because it has low water solubility, the release profile of amlodipine in the body is easier to regulate and prolong. By using this salt as the active ingredient in tablets or capsules, other agents for increasing slow or prolonged release (eg, special coatings, special excipients such as insoluble polymers, etc.) can be avoided or reduced.

Amlodipine fumarate can also be obtained in an amorphous form e.g. by lyophilizing a solution of amlodipine and fumic acid in a suitable solvent, e.g. in water. Such amorphous forms can be advantageous over crystalline forms as they can be obtained in a finely powdered form with good solubility properties.

Amlodipine fumarates, and in particular amlodipine hemifumarate, may exist in solvent free form or may be isolated as a hydrate or solvate. The hydrates and solvates of amlodipine fumarate, in particular the hydrates or solvates of amlodipine hemifumarate, form another aspect of the invention.

Amlodipine fumarate can be characterized by a variety of conventional methods such as IR spectrum, melting point, DSC curve, etc. The structure and ratio of amlodipine / fumam acid can be demonstrated by measurement of the < 1 > H-NMR spectrum and / or by titration methods.

Amlodipine fumarate is converted to the amlodipine free base in vivo to participate in the pharmaceutical activity of amlodipine. Thus, the compound can be used as an appropriate form of amlodipine for administration of amlodipine to a patient in need thereof. Due to its limited solubility in body fluids, amlodipine hemifumarate is a particularly useful form of amlodipine salt, especially for the production of slow or modified-release end forms, but its use is not limited thereto.

Amlodipine fumarate is a useful calcium channel blocker and can thus be used to treat any cardiac condition that would benefit from the administration of a calcium channel blocker. In particular, amlodipine fumarate can be used to treat or prevent hypertension or angina by administering an effective amount to a patient in need. The specific form of angina is not particularly limited and specifically includes chronic stable angina pectoris and vasospastic angina (Prinzmetal angina). The compound may be administered by any suitable route, including oral or parenteral. The patients we intend to treat include humans and animals, especially humans and mammals.

The compound is typically administered as part of a pharmaceutical composition. Therefore, a further aspect of the invention is a pharmaceutical composition for treating or preventing hypertension or angina, comprising an effective amount of amlodipine fumarate and a pharmaceutically acceptable excipient. Excipients include any inert or inactive material used in the manufacture of the pharmaceutical dosage form. E.g. tablet excipients include, but are not limited to, calcium phosphate, cellulose, starch or lactose. Capsules such as those made from gelatin may contain or carry amlodipine fumarate alone or in admixture with other excipients. Liquid dosage forms such as oral fluids in the form of solutions or suspensions as well as injectable solutions are also included. The pharmaceutical composition may be formulated for transdermal administration in the form of a patch. All of the pharmaceutical compositions described above may optionally contain one or more of the following excipients: carriers, diluents, colorants, flavoring agents, lubricants, solubilizing agents, disintegrants, binders and preservatives.

The pharmaceutical composition is usually prepared in a unit dose. A single dose is typically given once or twice a day, more typically once a day. In the case of a transdermal patch, a single dose (one patch) is generally given at least once a month, more generally at least once every two weeks, and typically once a week. The effective amount of fumamic acid addition salt of amlodipine in a single dose to treat or prevent hypertension or angina is generally within the range of 1 to 100 mg, typically 1 to 50 mg, more typically 1 to 20 mg. In solid oral dosage forms (tablets, capsules, etc.), the pharmaceutical composition typically contains about 1, 2.5, 5.0, or 10 mg of amlodipine fumarate. For the sake of simplicity, all amounts refer to the corresponding amount of amlodipine free base supplied to the composition. Specific examples of pharmaceutical compositions include those described in EP 244944, wherein amlodipine hemifumarate is used as the active ingredient.

All of the pharmaceutical compositions described above can be prepared by known methods and techniques. For example, the tablets may be made by dry granulation / direct compression or the conventional wet granulation method. Typically, tablets are made by mixing, filling and compressing them into tablets. The mixing step may include wet granulation or dry granulation. Similarly, capsules can be made by mixing the ingredients and filling them into capsules.

The following examples illustrate the invention.

Example 1

Dissolve amlodipine hemifumarate g amlodipine in 100 ml ethanol. 2.83 g of fumic acid dissolved in 100 ml of hot ethanol are added to this solution at room temperature. The solid formed is filtered and washed with 2x10 ml of ethanol. After drying in a vacuum oven at 35 ° C, a white solid was obtained.

M.p .: 170.5 ° C-172.5 ° C.

¹ H-NMR spectrum

¹ H-NMR. spectrum was measured at 303.2 K on Bruker Avance-400 in deuterated acetic acid at 400 MHz.

δ (ppm) determination

1.14 (t, 3H, J _ZU2 = 7.0Hz, H-12);

2.32 (s, 3H, H-15);

3.36 (bdd, 2H, H-9);

3.59 (s, 3H, H-14);

3.90 (bt, 2H, H-8);

4.04 (q, 2H, // 7 72 = 7.0Hz, H-11);

4.77 (Abq, 2H, H-7);

5.41 (s, 1H, H-4);

6.86 (s, 1H, H-2);

7.05 (dt, 1H, J ₃ ' ₄ ^ Λτ = 7.8Ηζ, Λ', 6 '= 1.5Ηζ, H-4');

7.15 (dt, 1H, Λ-, 5 '= Λ', 6 '= 7.8Ηζ, J ₃ ^ = 1.0Hz, H-5');

7.23 (dd, 1H, Λ ^ 7.8Ηζ, Λ, ₅ <= 1.0Ηζ, H-3 ′);

7.41 (dd, 1H, Λ-, _6. = 7.8Ηζ, Λ ', 6' = 1.5Ηζ, H-6 ');

¹³ C-NMR spectrum:

...

The C-NMR spectrum was measured at 303.3 K on Bruker Avance-400 in de-tensed acetic acid at 100.6 MHz.

δ [ppm]

14.53 19.15 38.29 40.63

51.54 61.70 67.72 68.81 102.93 104.37 128.04 128.66 130.24 132.48 133.26 135.35

146,36,146,45

146.85

168.78

169.70,169.75 determination (C-12);

(C-15);

(C-4);

(C-9);

(C-14);

(C-11);

(C-8);

(C-7);

(C-3);

(C-5);

(C-5 ¹ );

(C-4 ');

(C-3 ¹ );

(C-6 ');

(C-2 ¹ ); (2xC-2); (C-2, C-6); (C-1 ');

(C-10);

(2xC-1, C13).

-1010

Example 2

Dissolve amlodipine hemifumarate g amlodipine free base in 75 ml of dimethyl sulfoxide. 2.84 g of fumaric acid were added to this solution at room temperature. At room temperature, a clear solution is obtained for a few moments before a solid forms. The solid was filtered off and washed with 2x10 ml water. After drying in a vacuum oven at 50 ° C, 10.5 g of a white solid are obtained.

M.p .: 170.8 ° C-172.6 ° C

Example 3

Dissolve amlodipine hemifumarate g fumamic acid in a mixture of 100 ml ethanol and 10 ml water at 50 ° C. To this solution was added 5 g of amlodipine free base in portions over a period of 10 minutes. The solid forms about 5 minutes after the addition is complete. The suspension is heated until a solution is obtained and the mixture is slowly cooled to room temperature. A solid was obtained which was filtered off and washed with 2x20 ml of ethanol / water (9/1 v: v). After drying in a vacuum oven at 40 ° C for 18 hours, 3.21 g of a white solid are obtained.

M.p .: 170.3 ° C-172.6 ° C.

-1111

Example 4

A pharmaceutical tablet comprising amlodipine hemifumarate

Composition:

ADP salt of Eq. ADP database: 5.0 mg 10.0 mg amlodipine hemifumarate 5.71 mg 11,42 mg anhydrous calcium hydrogen phosphate 63,0 mg 126.0 mg microcrystalline cellulose 124.1 mg 248,1 mg sodium starch glycolate 4.0 mg 8.0 mg magnesium stearate 2.0 mg 4.0 mg In total 198,81 mg 397.52 mg

Manufacturing process:

- Amlodipine hemifumarate is sieved through a 500 gm sieve.

- Anhydrous calcium hydrogen phosphate, microcrystalline cellulose, sodium starch glycolate and magnesium stearate are sieved through a 850 gm sieve.

- Transfer amlodipine hemifumarate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose and sodium starch glycolate to a free-fall mixer and stir for 15 minutes at about 25 rpm.

- Magnesium stearate is added and the powder mixture is stirred for a further 5 minutes at about 25 rpm.

- The tablets are compressed using a Korsch EKO eccentric press.

Claims (8)

Patent claims 1. Acid addition salt of amlodipine with fumic acid. 2. Amlodipine fumarate in crystalline state. Amlodipine salt according to claims 1 or 2, characterized in that the salt is amlodipine hemifumarate. A pharmaceutical composition for use in the treatment and / or prevention of angina or hypertension, characterized in that it comprises an effective amount of a compound according to any one of claims 1-3 and a pharmaceutically acceptable excipient. Pharmaceutical composition according to claim 4, characterized in that said composition is in unit dosage form for oral administration and an effective amount within the range of 1-20 mg based on the weight of amlodipine free base is indicated. Pharmaceutical composition according to claims 4 or 5, characterized in that said unit dosage form is a tablet or capsule form. Pharmaceutical composition according to any one of claims 4-6, characterized in that said effective amount is 2.5, 5 or 10 mg based on the weight of the amlodipine free base. Pharmaceutical composition according to any one of claims 4-7, characterized in that said compound is amlodipine hemifumarate.