SI21067A2 - Amlodipine hemimaleate - Google Patents

Abstract

Amlodipine hemimaleate is useful as a calcium channel blocker and can be used to treat or prevent angina or hypertension.

Description

BioOrganics B.V.

Amlodipine hemimaleate

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

Pharmaceuticals with antianginal and antihypertensive properties are described in US 4,572,909 and US 4,879,303. A particularly important compound among these is amlodipine, 3-ethyl 5-methyl ester ± 2 - [(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro6-methyl-3,5-pyridinecarboxylic acid . Amlodipine has the following structural formula:

This compound is used for drug preparation and has calcium channel blocking activity, useful in regulating hypertension and angina. Particularly useful forms of amlodipine for human use are its maleate and benzenesulfonate salts. Examples 9, 11, 12 and 22 of US 4,572,909 as well as J. Med. Chem. 29,1698 (1986) describe the preparation of amlodipine maleate (in a 1: 1 molar ratio) by dissolving a reaction mixture containing in situ crude amlodipine base in ethyl acetate or ethanol and adding a solid maleic acid while precipitating the maleate salt of amlodipine. The salt was then isolated by filtration and recrystallized from ethyl acetate or acetone / ethyl acetate 1: 1. Amlodipine maleate described in the prior art is therefore a compound with a 1: 1 molar ratio between amlodipine and maleic acid. This compound is more precisely called amlodipine hydrogenmaleate.

The present invention relates to the discovery of a novel amlodipine salt useful for the preparation of amlodipine-containing drugs and is a suitable equivalent for the marketed amlodipine benzene sulfonate. More specifically, the present invention relates to amlodipine hemimaleate of formula (D:

.COOH

COOH

Another aspect of the present invention relates to a process comprising contacting amlodipine free base or a salt thereof with maleic acid or its ammonium salt in the presence of a solvent to form amlodipine hemimaleate.

In a further aspect, the present invention relates to a method for treating or preventing angina or hypertension, comprising administering to a patient in need thereof an effective amount of amlodipine hemimaleate, as well as a pharmaceutical composition for use in treating and / or preventing angina or hypertension, comprising an effective amount of amlodipine hemimaleate together with a pharmaceutically acceptable carrier.

FIG. 1 is the IR spectrum of the material of Example 1.

FIG. 2 is the IR spectrum of the material of Example 2.

The present invention is based on the discovery of a new form of the maleate salt of amlodipine, namely amlodipine hemimaleate. Hemimaleate is essentially characterized by a 2: 1 molar ratio of amlodipine to maleic acid. The compound of formula (1) is useful for treating various cardiovascular disorders, e.g. hypertension and angina.

The compound of formula (1) has a chiral center on the 1,4-dihydropyridine ring of the amlodipine moiety, so it can exist in two optically active forms. The forms can be separated by crystallization or free base chromatography, optionally as a salt with optically active acid, and converted to the corresponding hemimaleate salt. The individual isomers and their mixtures of the compounds of formula (1) are all covered by one term amlodipine hemimaleate.

The present invention also provides a process for the preparation of a compound of formula (1) comprising contacting amlodipine or a salt thereof with maleic acid to form amlodipine hemimaleate. Preferably, amlodipine hemimaleate is precipitated from the solvent by the degree of contact. The precipitation may be spontaneous at the stirring temperature, but it may also be accelerated by cooling the solution obtained, reducing the volume of the solution, or by adding a solute, i. a solvent miscible fluid in which amlodipine hemimaleate is less soluble. In one embodiment, two mole equivalents of amlodipine or a salt thereof are mixed with one equivalent of maleic acid or its ammonium salt in a suitable solvent, and then the amlodipine hemimaleate compound is precipitated from the solvent. The temperature may vary from the melting point of the solvent, more typically from room temperature to the boiling point of the solvent.

However, amlodipine hemimaleate may also be formed when one equivalent of amlodipine or a salt thereof is in contact with one equivalent of maleic acid; e.g. by dissolving mole amounts of 1: 1 amlodipine base and maleic acid in a very dilute aqueous environment (at least 200 ml water per 1 g amlodipine) at room temperature, with amlodipine hemimaleate crystallizing spontaneously after a fixed latency period.

The amlodipine free base can be prepared according to the procedures generally disclosed in US 4,572,909. Another useful synthetic scheme for the production of amlodipine or its salts in good yields and purity via the phthalimido amlodipine intermediate is described in provisional application Serial No. 60 / 258,613, jointly owned, filed December 29, 2000, the entire contents of which are incorporated herein by reference, and U.S. Pat. No. 09 / 809,351, which is in the process and is jointly owned, filed March 16, 2001, entitled The Process for the Preparation of Amlodipine, its Derivatives and Precursors, the entire contents of which are incorporated herein by reference. Maleic acid is commercially available.

Suitable solvents include water, alcohol, e.g. methanol or ethanol, ketone, such as e.g. acetone or methyl isobutyl ketone, an ester such as e.g. ethyl acetate, ether, such as e.g. diethyl ether or tetrahydrofuran, nitrile, such as e.g. acetonitrile, a dipole aprotic solvent such as e.g. dimethylsulfoxide or dimethylformamide, a hydrocarbon such as e.g. hexane or toluene and mixtures thereof.

In order to avoid the formation of certain impurities during the salt formation reaction, it may be desirable to combine amlodipine and maleic acid under acidic conditions, as described in more detail in provisional application serial no. No. 60 / 258,612, jointly owned, filed December 29, 2000, the entire contents of which are incorporated herein by reference, and U.S. Pat. No. 09 / 809,343, which is in the joint ownership process, filed March 16, 2001, entitled Process for the manufacture of amlodipine maleate, the entire contents of which are incorporated herein by reference.

The precipitated amlodipine hemimaleate can be isolated in solid state by conventional methods such as e.g. filtration or centrifugation, optionally then washing and / or drying being carried out and can be purified by crystallization, e.g. at elevated temperature in a suitable solvent, e.g. water, alcohol, such as methanol, or ketone, such as e.g. acetone. Such processes permit the production of the compound in the crystalline state.

Amlodipine hemimaleate can also be obtained in an amorphous form, e.g. by lyophilizing its solution formed with a suitable solvent, e.g. in water. Such amorphous forms may be preferred over the crystalline form because they can be obtained in a fine powder form with good solubility properties.

Amlodipine hemimaleate may be in solvent free form or may be isolated as a hydrate or solvate. Conventional isolation of the product obtained by crystallization or precipitation of amlodipine hemimaleate from an aqueous solution, i.e., after filtration, washing and drying in vacuo at room temperature, usually yields amlodipine hemimaleate hydrate. The product contains varying amounts of water (up to 7%), and after prolonged vacuum drying at slightly elevated temperature, the amount of water is reduced to a content of about 1.92.0% corresponding to the monohydrate. On the other hand, after exposing the anhydrous amlodipine hemimaleate to the extended state under increased moisture, hydrates comprising 2.5, 4 and 5 molar equivalents of water can be isolated. Amlodipine hemimaleate hydrates, in particular monohydrate, form a particular aspect of the present invention and are covered by the above formula (1) as well as the single term amlodipine hemimaleate.

By drying at elevated temperatures, the bound water can be removed from the hydrate after anhydrate formation. The anhydrous form of amlodipine hemimaleate is essentially metastable (hygroscopic) and slowly absorbs water at room humidity, especially in elevated humidity and changes back to a hydrated form. The dehydration and rehydration step can advantageously be used to improve / regulate the crystalline size of amlodipine hemimaleate hydrate. This is useful for practical applications of hemimaleate in pharmaceutical dosage forms such as e.g. tablets or capsules where the particle size of the active compound may be significant.

The methanolic solvate of amlodipine hemimaleate can be prepared by precipitation of amlodipine hemimaleate from a methanol solution, filtration and drying of the resulting solid in vacuo at room temperature. The methanol solvate contains about 6% methanol, although the amount of bound methanol may vary. Prolonged vacuum drying at elevated temperature gives unsolvated amlodipine hemimaleate identical to the anhydrate described above.

It is not excluded that amlodipine hemimaleate also forms solvates with other solvents useful in its preparation or purification; such solvates are also within the scope of the present invention.

Amlodipine hemimaleate can be characterized by a variety of physical properties. It has an IR spectrum that is clearly different from that of amlodipine maleate. When obtained in hydrated or solvated form, it has no defined melting point; DSC and TGA analyzes show that it melts together with the release of the bound solvent in the range of about 85 to 100 ° C.

The structure and ratio of amlodipine / maleic acid in the product can be demonstrated by measuring the NMR spectrum compared to amlodipine maleate prepared by the prior art.

Amlodipine hemimaleate can be converted to amlodipine in vivo to essentially share pharmaceutical activity with amlodipine. Thus, amlodipine hemimaleate is a useful calcium channel blocker and can therefore be used to treat any cardiac condition that may benefit from the administration of calcium channel blockers. In particular, amlodipine hemimaleate may be used to treat or prevent hypertension or angina by administering an effective amount to a patient in need thereof. The specific form of angina is not particularly limited and includes in detail chronic stable angina and vasospastic angina (Prinzmetal angina). The compound can be administered by any suitable route, including oral or parenteral. The patients we intend to treat include humane and non-human beings, especially humane and non-human mammals.

The compound is typically administered as part of a pharmaceutical composition. Thus, a further aspect of the present invention is a pharmaceutical composition for treating or preventing hypertension or angina, comprising an effective amount of amlodipine hemimaleate and a pharmaceutically acceptable excipient. Excipients include any inert or inactive material used in the manufacture of the pharmaceutical dosage form. Tablet excipients include, but are not limited to, e.g. calcium phosphate, cellulose, starch or lactose. Capsules, such as e.g. those made from gelatin may contain or carry amlodipine hemimaleate alone or in admixture with other excipients. Liquid dosage forms are also included, such as e.g. oral liquids in the form of liquors or suspensions as well as injectable solutions. The pharmaceutical composition can 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, flavors, lubricants, solubilizers, disintegrants, binders and safeners.

The pharmaceutical composition is usually provided in a single 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 (1 patch) is generally administered at least once a month, more generally at least once every two weeks and typically once a week. The effective amount of amlodipine hemimaleate in a single dose to treat or prevent hypertension and angina is generally in 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 hemimaleate. For the sake of simplification, all quantities refer to the corresponding amount of amlodipine free base provided for the composition. The usual starting human oral dose of amlodipine for both hypertension and angina is 5 mg once daily with a maximum dose of 10 mg once daily. In small, small or elderly individuals or patients with hepatic insufficiency, 2.5 mg once daily can be started and this dose can be used when amlodipine is added to other antihypertensive therapy. Specific examples for pharmaceutical compositions include those described in EP 244944, wherein amlodipine hemimaleate is used as the active ingredient.

Preferred pharmaceutical compositions will have a pH in the range of about 5.5 to 7.0 when measured as 20 wt. % water slurry as described in more detail in US Patent Application Serial no. No. 09 / 809,346, which is in the process and is jointly owned, filed March 16, 2001, under the heading Pharmaceutical compositions comprising amlodipine maleate, its entire contents being incorporated herein by reference. These compositions generally provide good or improved stability.

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

The examples below illustrate the present invention.

Example 1 - Amlodipine hemimaleate g amlodipine free base and 7.1 g maleic acid were placed in 1250 ml water at 50 ° C. The mixture was heated to 80 ° C and stirred for 10 minutes. The resulting suspension was allowed to cool to room temperature and then stirred at room temperature for 10 hours. A solid was formed which was filtered off, washed with 2 x 50 ml of water and dried in a vacuum oven at 30 ° C.

Yield: 55.7 g (98% yield, calculated on maleic acid) mp: 89.7 ° C - 94.7 ° C (5 ° C / min) Uncorrected mass spectrum: FAB +: 933.2

NMR spectrum:

4 '

OH

The OH 1 H-NMR spectrum was measured at 303.2 K on Bruker Avance-400 in deuterated dimethyl sulfoxide at 400 MHz.

δ allocation

1.13 (t, 3H, Hz, H-12)

2.33 (s, 3H, H-15)

2.95 (bdd, 2H, H-9)

3.53 (s, 3H, H-14)

3.59 (bt, 2H, H-8)

4.00 (m, 2H, H-11)

4.65 (Abq, 2H, H-7)

5.34 (s, 1H, H-4)

6.07 (s, 1H, H-2)

7.15 (dt, 1H, J ₃ >, 4 '= J4'5' = 7.8 Hz, J ₄ ' ₆ - 1.5 Hz, H-4')

7.25 (bt, 1H, H-5 ')

7.28 (dd, 1H, J ₃ , ₄ = 7.8 Hz, J ₃ , ₅ ~ 1.0 Hz, H-3 ')

7.37 (dd, IH, J _{5th 6th} = 7.6 Hz, J _O '= 1.5 Hz, H-6') ¹³ C-NMR spectrum:

^{The 13} C-NMR spectrum was measured at 303.2 K on Bruker Avance-400 in deuterated dimethyl sulfoxide at 100.6 MHz.

-1010

δ assignment 13,97 (C-12) 18.07 (C-15) 36.76 (C-4) 39.58 (C-9) 50.37 (C-14) 59.23 (C-ll) 66.59 (C-7) 69.52 (C-8) 101.85, 101.88 (C-3, C-5) 127.27 (C-5 ') 127.65 (C-4 ') 128.90 (C-3 ¹ ) 130.92 (C-6 ¹ ) 131.10 (C-2 ¹ ) 136.01 (2xC-2) 145.16, 145.22 (C-2, C-6) 145.72 (C-l *) 166.25 (C-10) 167.10, 167.21 (2xC-l, C13)

IR spectrum (KBr): FIG. 1.

Example 2 - Amlodipine hemimaleate monohydrate g amlodipine was added to a solution of 284 mg of maleic acid in 50 ml of water. The suspension was heated to 80 ° C for 10 minutes to dissolve almost completely. The mixture was allowed to cool to room temperature. After stirring overnight at room temperature, the solid was filtered off and dried in a vacuum oven at 30 ° C for 2 hours.

-1111

Water content (TGA): 2.9% water;

After prolonged drying for 2 days at 30 ° C, the water content drops to

2.0%.

DSC: melting endotherm 83.1-92.1 ° C.

IR spectrum: FIG. 2.

Example 3 - Amlodipine Hemimaleate Hydrate

Dissolve 285 mg of maleic acid in 500 ml of water. The mixture was heated to 80 ° C in a water bath and 2 g of amlodipine were added. The mixture was stirred for 15 minutes and the resulting suspension filtered. Allow the filtrate to cool to room temperature. A solid is formed which is filtered off. The solid has the appearance of small shiny tiles (crystals). This is dried in a vacuum oven at 25 ° C overnight.

DSC: melting endotherm 93.9-100.0 ° C.

TGA: water content 3.1%

Purity (HPLC) 98.9%.

Example 4 - Amlodipine hemimaleate - preparation from 1: 1 molar mixture

0.57 mg of maleic acid is dissolved in 1000 ml of water. 2 g of amlodipine (molar equivalent) are added while stirring. After standing in the dark at room temperature for two days, the solid was filtered off and dried in a vacuum oven at 30 ° C.

DSC: melting endotherm 76.4-88.8 ° C.

Purity (HPLC) 99%.

Example 5 - Amlodipine hemimaleate hydrate - preparation from 1: 1 molar mixture

-1212

A solution of 0.57 g of maleic acid in 500 ml of water was added 2 g of amlodipine. Amlodipine dissolves to form a new solid. After standing in the dark at room temperature for two days, decant the suspension. The wet solid was dried in vacuo at 30 ° C for 2 hours.

TGA: melting endotherm 92.0-100.9 ° C, water 6.5%.

Purity (HPLC) 99+%.

Example 6 - Amlodipine hemimaleate A methanolic solvate of amlodipine base was dissolved in 10 ml of methanol. Dissolve 285 mg of maleic acid in 10 ml of methanol. This solution was added to a methanolic solution of amlodipine and stored at -20 ° C. After 5 days, the resulting solid was filtered off and dried in vacuo at room temperature.

Methanol content: 6.5%

DSC: melting endotherm 92.5-96.5 ° C.

It will be readily apparent to those skilled in the art of the invention described that we can make further changes and modifications to the actual implementation of the concepts and embodiments described herein or be easily learned in practicing the invention without departing from the spirit and scope of the invention as defined by the following claims .

Claims (7)

1. Amlodipine hemimaleate of formula (1) _Z COOH 'COOH (1) · 2. Amlodipine hemimaleate in crystalline state. 3. Amlodipine hemimaleate monohydrate. 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 to 3 and a pharmaceutically acceptable carrier. Pharmaceutical composition according to claim 4, characterized in that said composition is a unit dosage form for oral administration, and said effective amount is in the range of 1 to 20 mg by weight of the amlodipine free base. Pharmaceutical composition according to claim 4 or 5, characterized in that said unit dosage form is a tablet or capsule form. -1414 Pharmaceutical composition according to claim 4, 5 or 6, characterized in that said effective amount is 2.5, 5 or 10 mg by weight of amlodipine free base.