AU2001100432A4 - Process for making amlodipine maleate - Google Patents

Description

Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION INNOVATION PATENT APPLICANT: BioOrganics B.V.

Invention Title: PROCESS FOR MAKING AMLODIPINE MALEATE The following statement is a full description of this invention, including the best method of performing it known to me: M:\CommonWord97\9001-9500\9452bio\20011003.doc PROCESS FOR MAKING AMLODIPINE MALEATE The present invention relates to a process for making amlodipine maleate with good purity.

Calcium channel blockers (calcium antagonists) are useful in treating cardiac conditions including angina and/or hypertension. Dicarboxylate-dihydropyridine derivatives are generally known to possess calcium channel blocking activity. For example, EP 089 167 and corresponding US 4,572,909 disclose a class of 2-amino dihydropyridine derivatives as being useful calcium channel blockers. These patents identify that one of the most preferred compounds is 2-[(2-aminoethoxy)methyl]-4-(2chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine. This compound, which is now commonly known as amlodipine, has the following formula:

H

CH

3 N -o N H2

H

3 CO O1OCH3 0 0 Amlodipine exhibits good bioavailability and has a long half-life in the body. While a variety of acid addition salts are taught in these patents to be suitable, the maleate salt is identified as the most preferred acid addition salt. Examples 9,11,12 and 22 of EP 89167 as well as J. Med. Chem. 29, 1698 (1986) disclose the preparation of amlodipine maleate (with 1:1 molar ratio of both components) by dissolving a reaction mixture containing an in situ prepared raw amlodipine base into ethyl acetate or into ethanol and adding thereto solid maleic acid whereby the maleate salt of amlodipine precipitates. The salt is then isolated by filtration and recrystallized from ethyl acetate or from acetone/ethyl acetate 1:1 mixture.

2 However, the commercial product of amlodipine (NORVASC by Pfizer) uses amlodipine besylate (benzene sulfonate) and not amlodipine maleate. Indeed, subsequent patents EP 244 944 and corresponding US 4,879,303 indicate that the besylate salt provides certain advantages over the known salts including good formulating properties. Apparently, amlodipine maleate suffered from tabletting and stability problems so as to cause a switch during development to the besylate salt. (See "Review of Original NDA" for NDA# 19-787 of 10.10.1990, obtainable from FDA under Freedom of Information Act). The stability and tabletting issues/causes are not publicly disclosed in the information available from the

FDA.

The present invention relates to the discovery of a heretofore undisclosed impurity associated with amlodipine maleate and to a process for preventing its formation during production. Specifically, the present invention relates to a process that comprises reacting amlodipine-or a pharmaceutically acceptable salt thereof with maleic acid under an acidic environment to form an amlodipine maleate product. Typically the process relates to the manufacture of an amlodipine maleate salt substantially free of amlodipine aspartate, which comprises the steps of either adding, continuously or portionwise, a source of amlodipine into a solution or suspension of maleic acid to form a solution, wherein the relative molar amount of maleic acid to amlodipine being added is at least 1.01:1 or (2) contacting, continuously or portionwise, a source of amlodipine with a solution or suspension of maleic acid under pH control to form a solution whereby the pH of the solution does not exceed 6.5; and separating amlodipine maleate in a solid form from the solution. Further the present invention relates to a process of purification of amlodipine maleate, which comprises crystallizing or precipitating amlodipine maleate from a solution thereof wherein said solution comprises an excess of maleic acid.

Fig. 1 shows the IR plot for the material of Example 1.

Fig. 2 shows the DSC curve for the material of Example 1.

Fig. 3 shows the x-ray diffractogram for the material of Example 1.

Though the process of converting amlodipine free base or salt into an amlodipine maleate salt is essentially simple, it has now been discovered that the known procedures for manufacturing amlodipine maleate may give rise to substantial amounts of a side product represented by the formula

H

CH

3 N o NH COOH

H

3 CO 0 .O CH 3

COOH

ICOOH

0 0

CI

(1) The. compound of formula which is hereinafter referred to as "amlodipine aspartate," is a side product associated only with maleate salts of amlodipine as it is formed by a Michael addition reaction of the amino group of amlodipine to the double bond of the maleic acid.

It has now been discovered that the production procedure described in the abovecited patents and literature may produce negligible amounts of amlodipine aspartate as a byproduct in a laboratory scale, but that substantial increases in amlodipine aspartate byproduct are likely on a production scale, namely at enhanced temperatures which are needed for complete conversion and for obtaining amlodipine maleate in a good crystalline form.

The presence of a side product in any substance intended to be administered to a human patient as a therapeutic agent is generally undesirable. Removing side products and impurities can result in higher production costs and lower yields due to the loss of material in the purification step. It is thus advantageous to form the desired product in the first instance with as few side products and impurities as possible.

The present invention is based on the finding that amlodipine maleate may be prepared substantially free from amlodipine aspartate by careful selection of reaction conditions. Namely, it was found that the pH of the reaction mixture during the formation of amlodipine maleate should be essentially acidic. A process for manufacture of an amlodipine maleate salt substantially free of amlodipine aspartate comprising a reaction of amlodipine with maleic acid, whereby the reaction environment is essentially acidic, thus forms a basic aspect of the invention.

Accordingly, a first embodiment of the present invention comprises adding the starting material containing amlodipine (herein under: "source of amlodipine") to a solution of maleic acid in such a way that maleic acid can be in excess to amlodipine in the reaction mixture; by adding amlodipine base to a molar equivalent or excessive amount maleic acid and preferably to an excess thereof. The unreacted maleic acid present during the addition of the amlodipine source provides an acidic pH for the reaction mixture during salt formation. Preferably, a free base of amlodipine or another acid addition salt of amlodipine is added into a solution or suspension of maleic acid in a suitable solvent to form a solution wherein the amount of maleic acid is at least 1.01 times the molar amount of amlodipine, preferably at least 1.05 times the molar amount of amlodipine. After addition, amlodipine maleate separates out in a solid state. In this process, the amlodipine reagent is employed in a solid state or in a solution or in a suspension and may be charged continuously or portionwise. A suitable minimum excess of maleic acid is about 1 molar percent or more, i.e. of about 1.01 molar equivalents, an advantageous extent is of about 5 molar percent, and may be even substantially higher, e.g. up to 50 or 100 molar percent, i.e. 2 molar equivalents. The use of an excess amount of maleic acid is advantageous for industrial scale production, where the actual amount of the charged amlodipine may be in some cases be difficult to determine.

The amlodipine source may be contacted with maleic acid in a solvent under pH control, whereby the pH value is maintained below the value of 7, preferably below 6.5, and typically in the range between 4.5 to 6.5, optionally by portionwise or continuous addition of maleic acid. At pH lower than 4.5, the formation of amlodipine aspartate is sufficiently suppressed as well but other side products may sometimes be formed. Generally it is most convenient, even under pH control, to add the amlodipine source to the maleic acid as in the first embodiment, but this is strictly speaking not required. After addition, amlodipine maleate separates out in a solid state.

This process of monitoring the pH is also useful in the case where the source of amlodipine is an unpurified material, as the actual content of amlodipine therein is normally only approximated and/or the amlodipine source may also contain impurities or side products of a basic nature, which may also react with maleic acid. For instance, a raw amlodipine obtained from deprotection of phthalimido-amlodipine by an excess of methylamine may contain traces of methylamine, the amount of which is determinable only with difficulties. Thus, the pH of the reaction mixture is monitored during the addition or treatment of the maleic acid solution, or suspension, with the source of amlodipine and adjusted such as by addition of acid, preferably maleic acid, as needed to maintain pH control under the value of less than 7 as described above.

Alternatively, the pH can be maintained in the acidic region by using an acid addition salt of amlodipine other than the maleate. The necessary acidic pH is adjusted by liberation of the corresponding acid from such salt during the formation of the maleate, as illustrated by the equation: Amlodipine .HX maleic acid amlodipine maleate HX, Wherein X is an anion of the corresponding acid.

As this reaction proceeds essentially in an equilibrium state, amlodipine salts should be employed which are more soluble in the reaction medium than amlodipine maleate. As the amlodipine maleate separates out from the solution, the equilibrium is continuously shifted towards the formation of the next amlodipine maleate. Suitable salts are e.g.

amlodipine hydrochloride, methane sulfonate or benzenesulfonate. In general, any suitable salt which is more soluble in the reaction solvent then amlodipine maleate may be used.

In processes of the invention, various sources of amlodipine may be used for reaction with maleic acid. For instance, there may be used a reaction mixture obtained after the final step of amlodipine synthesis. Such processes are known from prior art and the final steps thereof usually comprise deprotection of an amino-protecting group in an amlodipine precursor as outlined in the following scheme: H

H

CH3 N O NPrt CH 3 N NH 2 In the scheme, N-Prot represents a substituent or group protecting or masking the amino-group; it may comprise a benzylamino or phthalimido group (EP 89 167), azido group (EP 89 167 tritylaminogroup (EP 599220), hexamethylenetetramino group (EP 902016) etc. Another useful synthesis scheme for making amlodipine or salts thereof in good yields and purity via a phthalimidoamlodipine intermediate is described in commonlyowned provisional application serial No. 60/258,613, filed December 29, 2000, the entire contents of which are incorporated herein by reference, and in commonly-owned co-pending U.S. patent application serial No. 09/809,351, filed on March 16, 2001, and entitled "Process for Making Amlodipine, Derivatives Thereof, and Precursors Therefor," the entire contents of which are incorporated herein by reference.

After the deprotection reaction, the reaction mixture may be treated by known methods to provide advantageously a solution of raw amlodipine in a suitable solvent. Such a solution-may be used as the amlodipine source for the formation of the amlodipine maleate essentially free from amlodipine aspartate by the process of the present invention. As an alternative, amlodipine free base obtained by the amlodipine synthesis may be isolated in a solid state, e.g. by a process outlined in Int. J. Pharm. 133, 72 (1996) and the free base may be charged in a crude or purified state. In another alternative, amlodipine free base (with or without isolation thereof) may also be converted to a salt other than the maleate prior to the contact with maleic acid. The amlodipine source can be in dissolved form in a solvent, a solid state material or a suspension.

As pointed above, the common key aspect of any of the process of our invention is that the source of amlodipine is contacted with maleic acid in an acidic environment. In general, the pH of reaction mixture should not exceed the value of approximately 6.5 during the salt formation reaction.

Various solvents or solvent systems may be applicable in the process of our invention. The preferred solvents are those in which the starting materials are sufficiently soluble and in which the produced amlodipine maleate is only sparingly soluble. Such solvents comprise water, an alcohol such as methanol, ethanol or isopropanol, an ester such as ethyl acetate, a ketone such as acetone, a nitrile such as acetonitrile, an ether such as dioxan or tetrahydrofuran, a carbohydrate such as toluene or mixtures thereof. It is an advantage of the present invention that certain solvents which are inconvenient to be used in the prior art procedures, such as water, may be used without difficulty in the present process.

The temperature during the contacting of the amlodipine source with maleic acid may vary from ambient temperature to the boiling point of the solvent or solvent system and may vary also during the course of reaction. Preferred are temperatures are higher than 40 0

C

as amlodipine maleate crystallizes from a hot solution as good and/or large crystals. If working at ambient temperature, amlodipine maleate precipitates in small crystals that are frequently difficult to filter and dry. However, the formation of amlodipine aspartate is temperature dependent. It has been observed that when maleic acid is added to amlodipine base as in the process of prior art, undesirable amounts of the amlodipine aspartate are formed at temperatures higher than about 40 0 C. For instance, the addition of maleic acid to amlodipine base in isopropanol at 80 0 C may produce amlodipine maleate impurified with approx. 0.7% of the aspartate. However, as in accordance with the preferred aspects of the invention, wherein the amlodipine is added to the maleic acid, higher temperatures can be used without difficulty. This is especially advantageous when the reaction temperature is higher than 40 0 C, e.g. if a solvent is used which requires higher temperatures to convert amlodipine or maleic acid into a solution or if the reaction mixture should be concentrated by evaporation. For instance, addition of amlodipine base to 5% molar excess of maleic acid in hot isopropanol yielded amlodipine maleate with only 0.03% of aspartate.

The importance of the essentially acidic environment, especially the presence of an excess of maleic acid, in respect to minimization of the rate of formation of amlodipine aspartate may be manifested also in processes of purification of amlodipine maleate from other impurities by crystallization or precipitation. Elevated temperatures which are necessary for dissolving amlodipine maleate in a crystallization or precipitation solvent may contribute to the formation of amlodipine aspartate as well. As the solubility of amlodipine aspartate is similar in most crystallization solvents, common crystallization techniques do not allow to separate amlodipine maleate therefrom and thus, ironically, the crystallization rather "impurifies" the product. If, however, an excess of maleic acid is present in the crystallization system, the formation of amlodipine aspartate is minimised. Thus a further aspect of the present invention relates to a process of separating amlodipine maleate in a solid state from a solution by precipitation or crystallization, characterised in that free maleic acid in amount from 1% to 100% molar excess, preferably in amount of about 5% molar excess, is present during the separation.

The precipitation or crystallization of amlodipine maleate from a solution having an excess of maleic acid can thus be used as a purification step. Another aspect of the present invention comprises forming purified amlodipine free base or salts thereof by conversion of the precipitated or crystallized amlodipine maleate. Specifically, once the amlodipine maleate is precipitated or crystallized from a solution containing an excess of maleic acid, it can be converted to another salt of amlodipine with good purity. Conversion can be carried out directly by treating the amlodipine maleate in solution with a suitable acid.

Alternatively, conversion can also include treating the amlodipine maleate in solution with a base, either organic or inorganic base, to form amlodipine free base followed by treatment of the free base, with or without isolation thereof, with the desired acid to form the intended amlodipine salt. The new salt can be precipitated or otherwise removed from the solvent.

Because of the purity of the precipitated or crystallized amlodipine maleate, it along with the converted salt forms and optional free base, may be produced in pharmaceutically acceptable quality, essentially without any subsequent purification. Examples of salts preparable by this process include amlodipine benzene sulfonate (besylate) and amlodipine hydrochloride.

In common solvents suitable for crystallization of amlodipine maleate such as water, methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, toluene and mixtures thereof, the necessary excess of maleic acid should be at least 1 molar percent and up to 100 molar percent, advantageously between 5 to 25 molar percent. Proper extent of maleic acid useful in an industrial process may be determined in each particular case by ordinary set of experiments, taking the solvent, concentration and temperature regimen into consideration and having the yield and purity as the criteria of evaluation.

The amlodipine maleate that is "substantially free" from amlodipine aspartate means that the amlodipine maleate contains less than 1 wt%, preferably less than 0.5 wt%, more preferably less than 0.2 wt%, and most preferably less than 0.1 wt% of amlodipine aspartate.

The amlodipine maleate substantially free from amlodipine aspartate may be used in therapy as a pharmaceutically acceptable salt of amlodipine. Accordingly, amlodipine maleate substantially free from amlodipine aspartate forms another aspect of the present invention.

The molecule of amlodipine has a chiral centre on the 1,4-dihydropyridine ring and exists in two optically active forms. The forms may be separated by crystallisation or chromatography, optionally in the form of a salt, for example a salt with an optically active base or acid, and may be accordingly converted into individual isomers of amlodipine maleate of our invention by processes described above. The individual isomers of amlodipine or their mixtures can be used in the present invention. Correspondingly, the individual or mixed isomers of amlodipine maleate substantially free from amlodipine aspartate are also within the scope of this invention.

Amlodipine maleate substantially free from amlodipine aspartate may be used as a calcium channel blocker and thus can be used to treat any cardiac condition that would be benefited by administration of a calcium channel blocker. In particular, the amlodipine maleate free from amlodipine aspartate can 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 specifically includes chronic stable angina pectoris and vasospastic angina (Prinzmetal's angina). The compound can be administered by any suitable route including orally or parenterally. The "patients" intended to be treated include human and non-human animals especially humans and non-human mammals.

The compound is usually administered as part of a pharmaceutical composition.

Accordingly, a further aspect of the invention is a pharmaceutical composition for treating or preventing hypertension or angina that comprises an effective amount of amlodipine maleate substantially free from amlodipine aspartate and a pharmaceutically acceptable excipient.

Excipients include any inert or non-active material used in making a pharmaceutical dosage form. For example, tablet excipients include, but are not limited to, calcium phosphate, cellulose, starch or lactose. Capsules such as those made of gelatin, may contain or carry amlodipine maleate alone or in admixture with other excipients. Liquid dosage forms are also included such as oral liquids in the form of liquors or suspensions, as well as injectable solutions. The pharmaceutical composition may be formulated for transdermal administration in the form of a patch. All of the above described pharmaceutical compositions may optionally contain one or more of each of the following excipients: carriers, diluents, colorants, flavoring agents, lubricants, solubilizing agents, disintegrants, binders and preservatives.

The pharmaceutical composition is normally provided in a unit dose. A unit dose is typically administered once or twice daily, more typically once daily. In the case of a transdermal patch, the unit dose (one patch) is generally applied at least once a month, more commonly at least once a bi-week, and typically once a week. An effective amount of amlodipine maleate free from amlodipine aspartate in a unit dose for treating or preventing 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 the amlodipine maleate. For simplicity, all amounts refer to the corresponding amount of amlodipine free base provided to the composition. The usual initial human oral dose of amlodipine for both hypertension and angina is 5 mg once daily with a maximum dose of 10 mg once daily.

Small, fragile, or elderly individuals, or patient with hepatic insufficiency may be started at mg once daily and this dose may be used when adding amlodipine to other antihypertensive therapy. Specific examples of pharmaceutical compositions include those described in EP 244944 wherein amlodipine maleate according to the present invention is used as the active ingredient.

Preferred pharmaceutical compositions will have a pH within the range of from about to 7.0, when measured as a 20 wt% aqueous slurry as is described in more detail in commonly-owned co-pending U.S. patent application serial No. 09/809,346, filed on March 16, 2001, and entitled "Pharmaceutical Compositions Comprising Amlodipine Maleate," the entire contents of which are 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. For example, the tablets can be made by dry granulation/direct compression or by a classical wet granulation method. Typically, tablets are made by blending, filling and compressing into tablets. The blending step may comprise a wet granulation or dry granulation. Similarly, capsules can be made by blending the ingredients and filling the capsule.

The above compositions are also useful in reducing heart failure symptoms, improving systolic left ventricular function and increasing exercise capacity in patients with ischaemic LVD and heart failure without current angina.

Amlodipine maleate compositions of the invention, may be also used in medical applications in combination with other antihypertensive and/or antianginal agents, for instance with ACE- inhibitors such as benazepril. The combination may be realized in a form of single combination preparation, e.g. a capsule containing amlodipine maleate and benazepril hydrochloride, or by separate administration of drugs containing the above agents. Similarly, amlodipine maleate may also be combined with HMG-CoA reductase inhibitors, particularly statins such as lovastin, simvastatin, atorvastatin, etc.

Accordingly, the present invention further provides a method for treating and/or preventing any one or more of angina, hypertension and heart failure by administering a pharmaceutical composition of the invention comprising an effective and/or prophylactic amount of amlodipine maleate to a sufferer in need thereof.

In preparing amlodipine maleate as an active ingredient or in a pharmaceutical composition, it may be beneficial to assay for the presence and/or amount of amlodipine aspartate in order to insure that the active or compositional forms are sufficiently free from the aspartate impurity. This is useful in checking, for example, the effectiveness of the crystallization conditions chosen for making amlodipine maleate substantially free from amlodipine aspartate in accordance with the present invention. Assaying for amlodipine aspartate as well as how to make amlodipine aspartate as a reference standard or reference marker composition is described more fully in co-pending commonly owned U.S. patent application serial No. 09/809,347, filed on March 16, 2001, and entitled "Reference Standards For Determining The Purity Or Stability Of Amlodipine Maleate And Processes Therefor," the entire contents of which are incorporated herein by reference.

Examples Example 1 Amlodipine maleate from crude amlodipine Step 1 Decomposition ofphthalimidoamlodipine The reactor Al is charged with 64 1 of 40% aqueous methylamine and 8.0 kg of phthalimidoamlodipine under stirring. The suspension is stirred at 40 45 °C for 8 hours.

Then 120 1 of toluene is added and the mixture is stirred for 30 minutes. Then the mixture is allowed to stand for separation of layers, the aqueous layer is separated and discarded. The toluene layer is washed with 40 1 of water. The toluene solution is concentrated on a rotary evaporator at 60 0 C until the first precipitate occurs (the volume approx. 12 litres). The residue is poured into a container and the evaporator is washed with 4 1 of ethanol which is combined with the toluene solution. The content of amlodipine in the solution is determined by titration. Result: 6.13 kg.

Step 2 Formation of amlodipine maleate 1.83 kg of maleic acid is dissolved in 70 1 of ethanol at 50 55 0 C in reactor A2. The solution is filtered through pressure filter into the clean reactor Al. The reactor A2 and the filter are washed with 7 1 of ethanol. The temperature of the combined solution is adjusted to 50 55 °C.

The solution of 6.13 kg of amlodipine free base from the preceding step is placed into the reactor A2 and 66 1 of ethanol is added. The solution is charged from the reactor A2 through the pressure filter (pressed with nitrogen) to the stirred solution in the reactor Al.

The reactor and the filter are washed with 7 1 of ethanol. The temperature in Al increases spontaneously to 65 0 C (cooling not necessary). The mixture is then stirred and slowly cooled to 15-20 0 C. The precipitated solid product is filtered off on a nutche filter, washed on the filter with 2x4 1 of ethanol and dried in at temperature, of max Yield: 5,85 kg of Amlodipine maleate Purity(HPLC) <0.05% of aspartate Particle size 80 -100 pim in average Comparative process 5 kg of wet amlodipine free base is suspended in 17.5 1 of isopropanol. The suspension is heated to 65 °C and a clear solution is obtained. 1.17kg of maleic acid is added portionwise. Temperature increases to 70 °C and again a clear solution is obtained. Seeding crystals are added and crystallization started, whereby the temperature increases to 72.5 °C.

The mixture is cooled to 30 oC in 1.5 hours and further cooled to 2 °C in 1 hour. The crystals were filtered off and washed with 3 x 5.8 1 of isopropanol and dried in a vacuum oven at 40 °C for 2 days.

Yield: 4960 g Purity: 0.63% of Amlodipine aspartate Example 2 0.58 g of maleic acid is dissolved in 25 ml of water and heated to approximately To this solution, 2.0 g of amlodipine is added portionwise. The solution turns slightly yellow during addition and when addition is complete a solid starts to precipitate from the mixture. The mixture is slowly cooled to room temperature and the solid is filtered off.

After washing the solid with 5 ml of water, the solid is dried in a vacuum oven at 50 0 C for 24 hours leaving 2.4 g of a white solid.

HPLC: aspartate content 0.01% NMR: correspond to amlodipine maleate.

Comparative process: 2 g of amlodipine is suspended in 25 ml of water and heated to approximately 60 0

C.

To this suspension, 0.58 g of maleic acid is added portion wise. The suspension became clear (slightly yellow) and a solid started to precipitate. The mixture was slowly cooled to room temperature and the solid is filtered off. The solid is washed with 5 ml of water and dried in a vacuum oven at 50 0 C for 24 hours leaving 2.4 g of a white solid.

HPLC: aspartate content 0.2 NMR: amlodipine maleate approx. 10% of amlodipine free base.

Example 3 Amlodipine maleate from amlodipine hydrochloride 1 g of amlodipine hydrochloride is dissolved in 20 ml of water. To this solution 0.26 g of maleic acid is added and the mixture is stirred until everything is dissolved. After a few minutes a solid precipitates and the mixture is stirred at room temperature for one hour. The solid is filtered off over a paper filter and washed with 2x5 ml of water. After drying in a vacuum oven, 0.72g of the product as a solid is obtained.

Aspartate content (HPLC): 0.01% Example 4 Amlodipine maleate from amlodipine mesylate 1 g of amlodipine mesylate is dissolved in 42 ml of water. 0.23 g of maleic acid is added to this solution and the mixture is stirred until a clear solution is obtained. After a few minutes a solid appears and the mixture is stirred at room temperature for one hour. The solid is filtered off over a paper filter and washed with 2x5 ml of water. After drying in a vacuum oven, 0.73g of the product is obtained as an off white solid.

Aspartate content (HPLC): 0.01% Example Crystallization of amlodipine maleate g of amlodipine maleate is dissolved in a mixture of 60 ml of EtOH and 0.055 g of maleic acid at reflux. The solution is cooled in a refrigerator to 5 10 0 C and the precipitate is filtered and dried.

Yield: 4.5 g HPLC 0.046% of aspartate Comparative Process g of amlodipine maleate is dissolved in 240 ml ofEtOH at reflux. The solution is cooled to 20 OC and the precipitate formed is filtered and dried.

Yield: 16,3 g HPLC(IN): 0.67% of aspartate Reference Example Preparation of the amlodipine aspartate as a reference standard 16 g of amlodipine and 12 g of amlodipine maleate are melted in a 300 ml flask. The melted substance is cooled to room temperature and dissolved in 300 ml of dichloromethane.

The mixture is extracted with 300 ml of a 1M NaOH solution. The organic layer is discarded and the aqueous layer acidified with 55 ml of a 6 M HCI solution. The mixture is extracted with 300 ml of dichloromethane. The layers are separated and the organic layer dried over Na 2

SO

4 The mixture is evaporated to dryness and the resulting waxy solid recrystallized from ethanol. The obtained sticky solid is dried in a vacuum oven at 40 °C leaving 4.7 g of an off white product.

Yield: 4.7 g (39 Mp: 178 °C 183 °C (decomposed) The invention having been described, it will be readily apparent to those skilled in the art that further changes and modifications in actual implementation of the concepts and embodiments described herein can easily be made or may be learned by practice of the invention, without departing from the spirit and scope of the invention as defined by the following claims.

Claims (8)

1. Process, which comprises reacting amlodipine or an acid addition salt thereof with maleic acid under an acidic environment to form an amlodipine maleate product.

2. Process according to claim 1 wherein said amlodipine maleate product contains less than 1 wt amlodipine aspartate, based on the amount of amlodipine maleate.

3. Process for the manufacture of an amlodipine maleate salt substantially free of amlodipine aspartate wherein the amlodipine is contacted, continuously or portionwise, with a solution or suspension of the maleic acid under pH control to form a solution whereby the pH of the solution does not exceed 6.5; and the amlodipine maleate is separated in a solid form from the solution.

4. Process of purification, which comprises crystallizing or precipitating amlodipine maleate from a solution thereof wherein said solution comprises an excess of maleic acid, optionally followed by converting the amlodipine maleate to another acid addition salt, preferably being amlodipine benzene sulphonate or amlodipine hydrochloride.

Amlodipine maleate substantially free from amlodipine aspartate.

6. A pharmaceutical composition for treating or preventing hypertension or angina that comprises an effective amount of amlodipine maleate substantially free from amlodipine aspartate and a pharmaceutically acceptable excipient wherein said composition is preferably in a unit dose form containing 1 to 20 mg of said amlodipine maleate and the amount of amlodipine aspartate is less than 0.2 wt

7. Amlodipine benzene sulfonate or amlodipine hydrochloride obtainable according to the process of claim 4.

8. The use of amlodipine maleate substantially free from amlodipine aspartate for the manufacture of a medicament for the treatment of hypertension, angina or heart failure.