OA13133A - Process for making amlodipine maleate. - Google Patents

Abstract

A process for making amlodipine maleate comprises reacting amlodipine or an acid addition salt thereof with maleic acid under an acidic environment to form an amlodipine maleate product. The process allows for the formation of amlodipine maleate substantially free from amlodipine aspartate.

Description

PROCESS FOR MAKING AMLODIPINE MALEATE ‘ WO 02/053542 13133· PCT/NLO1/00607 1 5

The présent invention relates to a process for making amlodipine maleate with good purity.

Calcium channel blockers (calcium antagonists) are useful in treating cardiacconditions including angina and/or hypertension. Dicarboxylate-dihydropyridine dérivativesf 10 are generally known to possess calcium channel blocking activity. For example, EP 089 167and corresponding US 4,572,909 disclose a class of 2-amino group-3,5-dicarboxylatedihydropyridine dérivatives as being useful calcium channel blockers. These patentsidentify that one of the most preferred compounds is 2-[(2-aminœthoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine. This 15 compound, which is now commonly known as amlodipine, has the following formula:

Amlodipine exhibits good bioavailability and has a long half-life in the body. Whilea variety of acid addition salts are taught in these patents to be suitable, the maleate sait is 20 identified as the most preferred acid addition sait. Examples 9,11,12 and 22 of EP 89167 aswell as J. Med. Chem. 29, 1698 (1986) disclose the préparation of amlodipine maleate (with1:1 molar ratio of both components) by dissolving a reaction mixture containing an in situprepared raw amlodipine base into ethyl acetate or into éthanol and adding thèreto solidmaleic acid whereby the maleate sait of amlodipine précipitâtes. The sait is then isolated by 25 filtration and recrystallized from ethyl acetate or from acetone/ethyl acetate 1:1 mixture. * WO 02/053542 PCT/NL01/00607 13133’ 2

However, the commercial product of amlodipine (NORVASC by Pfizer) usesamlodipine besylate (benzene sulfonate) and not amlodipine maleate. Indeed, subséquentpatents EP 244 944 and corresponding US 4,879,303 indicate that the besylate sait providescertain advantages over the known salts including good formulating properties. Apparently, 5 amlodipine maleate suffered front tabletting and stabilîty problems so as to cause a switchduring development to the besylate sait. (See “Review of Original NDA” for NDA# 19-787of 10.10.1990, obtainable from FDA under Freedom of Information Act). The stabilîty andtabletting issues/causes are not publicly disclosed in the information available from theFDA. 10 The présent invention relates to the discovery of a heretofore undisclosed impurity associated with amlodipine maleate and to a process for preventing its formation duringproduction. Specifically, the présent invention relates to a process that comprises reactingamlodipine or a pharmaceutiçally acceptable sait thereof with maleic acid under an acidicenvironment to form an amlodipine maleate product. Typically the process relates to the 15 manufacture of an amlodipine maleate sait substantially free of amlodipine aspartate, whichcomprises the steps of (a) either (1) adding, continuously or portionwise, a source ofamlodipine into a solution or suspension of maleic acid to form a solution, wherein therelative 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 20 suspension of maleic acid under pH control to form a solution whereby the pH of thesolution does not exceed 6.5; and (b) separating amlodipine maleate in a solid form from thesolution. Further the présent invention relates to a process of purification of amlodipinemaleate, which comprises crystallizing or precipitating amlodipine maleate from a solutionthereof wherein said solution comprises an excess of maleic acid. 25 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 sait into an amlodipine 30 maleate sait is essentially simple, it has now been discovered that the known procedures for WO 02/053542 13133· PCT/NL01/00607 3 manufacturing amlodipine maleate may give rise to substantial amounts of a side productrepresented by the formula (1):

The compound of foimula (1), which is hereinafter referred to as “amlodipineaspartate,” is a side product associated only with maleate salts of amlodipine as it is formed 10 by a Michael addition reaction of the amino group of amlodipine to the double bond of themaleic acid.

It has now been discovered that the production procedure described in the above-cited patents and Iiterature may produce negligible amounts of amlodipine aspartate as a by-product in a laboratory scale, but that substantial increases in amlodipine aspartate by- 15 product are likely on a production scale, namely at enhanced températures which are neededfor complété 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 ahuman patient as a therapeutic agent is generally undesirable. Removing side products andimpurities can resuit in higher production costs and lower yields due to the loss of matériel 20 in the purification step. It is thus advantageous to form the desired product in the firstinstance with as few side products and impurities as possible.

The présent invention is based on the finding that amlodipine maleate may beprepared substantially free from amlodipine aspartate by carefùl sélection of reactionconditions. Namely, it was found that the pH of the reaction mixture during the formation of 25 amlodipine maleate should be essentially acidic. A process for manufacture of anamlodipine maleate sait substantially free of amlodipine aspartate comprising a reaction of WO 02/053542 PCT/NL01/00607 13133· 4 amlodipine with maleic acid, whereby the reaction environment is essentially acidic, thusforms a basic aspect of the invention.

Accordingly, a first embodiment of the présent invention comprises adding thestarting material containing amlodipine (herein under: “source of amlodipine”) to a solution 5 of maleic acid in such a way that maleic acid can be in excess to amlodipine in the reactionmixture; i.e., by adding amlodipine base to a molar équivalent or excessive amount maleicacid and preferably to an excess thereof. The unreacted maleic acid présent during theaddition of the amlodipine source provides an acidic pH for the reaction mixture during saitformation. Preferably, a free base of amlodipine or another acid addition sait of amlodipine 10 is added into a solution or suspension of maleic acid in a suitable solvent to form a solutionwherein 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, amlodipinemaleate séparâtes out in a solid state. In this process, the amlodipine reagent is employed ina solid state or in a solution or in a suspension and may be charged continuously or 15 portionwise. A suitable minimum excess of maleic acid is about 1 molar percent or more, i.e. of about 1.01 molar équivalents, an advantageous extent is of about 5 molar percent, andmay be even substantially higher, e.g. up to 50 or 100 molar percent, i.e. 2 molaréquivalents. The use of an excess amount of maleic acid is advantageous for industrial scaleproduction, where the actual amount of the charged amlodipine may be in some cases be 20 difficult to détermine.

The amlodipine source may be contacted with maleic acid in a solvent under pHcontrol, whereby the pH value is maintained below the value of7, preferably below 6.5, andtypically in the range between 4.5 to 6.5, optionally by portionwise or continuous addition ofmaleic acid. At pH lower than 4.5, the formation of amlodipine aspartate is sufficiently 25 suppressed as well but other side products may sometimes be formed. Generally it is mostconvenient, even under pH control, to add the amlodipine source to the maleic acid as in thefirst embodiment, but this is strictly speaking not required. After addition, amlodipinemaleate séparâtes out in a solid state.

This process of mOnitoring the pH is also useful in the case where the source of 30 amlodipine is an unpurified material, as the actual content of amlodipine therein is normallyonly approximated and/or the amlodipine source may also contain impurities or side WO 02/053542 13133· PCT/NLO 1/00607 products of a basic nature, which may also react with maleic acid. For instance, a rawamlodipine obtained from deprotection of phthalimido-amlodipine by an excess ofmethylamine may contain traces of methylamine, the amount of which is determinable onlywith difficulties. Thus, the pH of the reaction mixture is monitored during the addition or 5 treatment of the maleic acid solution, or suspension, with the source of amlodipine andadjusted such as by addition of acid, preferably maleic acid, as needed to maintain pHcontrol under the value of less than 7 as described above.

Altematively, the pH can be maintained in the acidic région by using an acid additionsait of amlodipine other than the maleate. The necessary acidic pH is adjusted by libération 10 of the corresponding acid from such sait during the formation of the maleate, as illustratedby the équation:

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 15 be employed which are more soluble in the reaction medium than amlodipine maleate. Asthe amlodipine maleate séparâtes out from the solution, the equilibrium is continuouslyshifted towards the formation of the next amlodipine maleate. Suitable salts are e.g.amlodipine hydrochloride, methane sulfonate or benzenesulfonate. In general, any suitablesait which is more soluble in the reaction solvent then amlodipine maleate may be used. 20 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 finalstep of amlodipine synthesis. Such processes are known from prior art and the final stepsthereof usually comprise deprotection of an amino-protecting group in an amlodipineprecursor as outlined in the following scheme:

25 WO 02/053542 13133· PCT/NLO1/00607 6

In the scheme, N-Prot représente a substituent or group protecting or masking theamino-group; it may comprise a benzylamino or phthalimido group (EP 89 167), azidogroup (EP 89 167 ), tritylaminogroup (EP 599220), hexamethylenetetramino group (EP902016) etc. Another useful· synthesis scheme for making amlodipine or salts thereof in 5 good yields and purity via a phthalimidoamlodipine intermediate is described in commonly-owned provisional application serial No. 60/258,613, filed December 29, 2000, the entirecontents of which are incoiporated herein by référencé, and in commonly-owned co-pendingU.S. patent application serial No. 09/809,351, filed on March 16,2001, and entitled “Processfor Making Amlodipine, Dérivatives Thereof, and Precursors Therefor,” the entire contents 10 of which are incorporated herein by référencé.

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. Sucha solution may be used as the amlodipine source for the formation of the amlodipine maleateessentially free firom amlodipine aspartate by the process of the présent invention. As an 15 alternative, amlodipine free base obtained by the amlodipine synthesis may be isolated in asolid State, e.g. by a process outlined in Int. J. Pharm. 133, 72 (1996) and the free base maybe charged in a crude or purified State. In another alternative, amlodipine free base (with orwithout isolation thereof) may also be converted to a sait other than the maleate prior to thecontact with maleic acid. The amlodipine source can be in dissolved form in a solvent, a 20 solid State material or a suspension.

As pointed above, the common key aspect of any of the process of our invention isthat the source of amlodipine is contacted with maleic acid in an acidic environment. Ingeneral, the pH of reaction mixture should not exceed the value of approximately 6.5 duringthe sait formation reaction. 25 Various solvents or solvent Systems may be applicable in the process of our invention. The preferred solvents are those in which the starting matériels are sufficientlysoluble and in which the produced amlodipine maleate is only sparingly soluble. Suchsolvents comprise water, an alcohol such as methanol, éthanol or isopropanol, an ester suchas ethyl acetate, a ketone such as acetone, a nitrile such as acetonitrile, an ether such as 30 dioxan or tetrahydrofuran, a carbohydrate such as toluene or mixtures thereof. It is an WO 02/053542 PCT/NL01/00607 13133 7 advantage of the présent invention that certain solvents which are inconvénient to be used inthe prior art procedures, such as water, may be used without difficulty in the présent process.

The température during the contacting of the amlodipine source with maleic acidmay vary from ambient température to the boiling point of the solvent or solvent System and 5 may vary also during the course of reaction. Preferred are températures are higher than 40°Cas amlodipine maleate crystallizes from a hot solution as good and/or large crystals. Ifworking at ambient température, amlodipine maleate précipitâtes in small crystals that arefrequently difficult to filter and dry. However, the formation of amlodipine aspartate istempérature dépendent. It has been observed that when maleic acid is added to amlodipine 10 base as in the process of prior art, undesirable amounts of the amlodipine aspartate areformed at températures higher than about 40°C. For instance, the addition of maleic acid toamlodipine base in isopropanol at 80°C may produce amlodipine maleate impurifîed withapprox. 0.7% of the aspartate. However, as in accordance with the preferred aspects of theinvention, wherein the amlodipine is added to the maleic acid, higher températures can be 15 used without difficulty. This is especially advantageous when the reaction température ishigher than 40°C, e.g. if a solvent is used which requires higher températures to convertamlodipine or maleic acid into a solution or if the reaction mixture should be concentratedby évaporation. For instance, addition of amlodipine base to 5% molar excess of maleic acidin hot isopropanol yielded amlodipine maleate with only 0.03% of aspartate. 20 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 amlodipineaspartate may be manifested also in processes of purification of amlodipine maleate fromother impurities by crystallization or précipitation. Elevated températures which arenecessary for dissolving amlodipine maleate in a crystallization or précipitation solvent may 25 contribute to the formation of amlodipine aspartate as well. As the solubility of amlodipineaspartate is similar in most crystallization solvents, common crystallization techniques donot allow to separate amlodipine maleate therefrom and thus, ironically, the crystallizationrather “impurifies” the product. If, however, an excess of maleic acid is présent in thecrystallization System, the formation of amlodipine aspartate is minimised. Thus a further 30 aspect of the présent invention relates to a process of separating amlodipine maleate in asolid State from a solution by précipitation or crystallization, characterised in that free maleic PCT/NL01/00607 WO 02/053542

c 8 acid in amount from 1% to 100% molar excess, preferably in amount of about 5% molarexcess, is présent during the séparation.

The précipitation or crystallization of amlodipine maleate ffom a solution having anexcess of maleic acid can thus be used as a purification step. Another aspect of the présent 5 invention comprises forming purified amlodipine free base or salts thereof by conversion ofthe precipitated or crystallized amlodipine maleate. Specifically, once the amlodipinemaleate is precipitated or crystallized ffom a solution containing an excess of maleic acid, itcan be converted to another sait of amlodipine with good purity. Conversion can be carriedout directly by treating the amlodipine maleate in solution with a suitable acid. 10 Altematively, conversion can also include treating the amlodipine maleate in solution with abase, either organic or inorganic base, to form amlodipine free base followed by treatment ofthe free base, with or without isolation thereof, with the desired acid to form the intendedamlodipine sait. The new sait can be precipitated or otherwise removed ffom the solvent.Because of the purity of the precipitated or crystallized amlodipine maleate, it along with the 15 converted sait forms and optional free base, may be produced in pharmaceutically acceptablequality, essentially without any subséquent purification. Examples of salts preparable bythis process include amlodipine benzene sulfonate (besylate) and amlodipine hydrochloride.

In common solvents suitable for crystallization of amlodipine maleate such as water,methanol, éthanol, isopropanol, acetone, acetonitrile, ethyl acetate, toluene and mixtures 20 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 aciduseful in an industrial process may be determined in each particular case by ordinary set ofexpérimente, taking the solvent, concentration and température regimen into considérationand having the yield and purity as the criteria of évaluation. 25 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%, morepreferably less than 0.2 wt%, and most preferably less than 0.1 wt% of amlodipine aspartate.The amlodipine maleate substantially free ffom amlodipine aspartate may be used in therapyas a pharmaceutically acceptable sait of amlodipine. Accordingly, amlodipine maleate 30 substantially free ffom amlodipine aspartate forms another aspect of the présent invention. WO 02/053542 PCT/NL01/00607 13133- 9

The molécule of amlodipine has a chiral centre on the 1,4-dihydropyridine ring andexiste in two optically active forms. The forms may be separated by crystallisation orchromatography, optionally in the form of a sait, for example a sait with an optically activebase or acid, and may be accordingly converted into individual isomers of amlodipine 5 maleate of our invention by processes described above. The individual isomers ofamlodipine or their mixtures can be used in the présent invention. Correspondingly, theindividual or mixed isomers of amlodipine maleate substantially free from amlodipineaspartate are also within the scope of this invention.

Amlodipine maleate substantially free from amlodipine aspartate may be used as a 10 calcium channel blocker and thus can be used to treat any cardiac condition that would bebenefited by administration of a calcium channel blocker. In particular, the amlodipinemaleate free from amlodipine aspartate can be used to treat or prevent hypertension orangina by administering an effective amount to a patient in need thereof. The spécifie formof angina is not particularly limited and specifically includes chronic stable angina pectoris 15 and vasospastic angina (Prinzmetal's angina). The compound can be administered by anysuitable route including orally or parenterally. The “patients” intended to be treated includehuman and non-human animais especially humans and non-human mammals.

The compound is usualîy administered as part of a pharmaceutical composition.Accordingly, a further aspect of the invention is a pharmaceutical composition for treating or 20 preventing hypertension or angina that comprises an effective amount of amlodipine maleatesubstantially free from amlodipine aspartate and a pharmaceutically acceptable excipient.Excipients include any inert or non-active material used in making a pharmaceutical dosageform. 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 25 amlodipine maleate alone or in admixture with other excipients. Liquid dosage forms arealso included such as oral Iiquids in the form of liquors or suspensions, as well as injectablesolutions. The pharmaceutical composition may be formulated for transdermaladministration in the form of a patch. Ail of the above described pharmaceuticalcompositions may optionally contain one or more of each of the following excipients: 30 carriers, diluents, colorants, flavoring agents, fabricants, solubilizing agents, désintégrants,binders and preservatives. WO 02/053542 PCT/NL01/00607 13133· 10

The pharmaceutical composition is normally provided in a unit dose. A unit dose istypically administered once or twice daily, more typically once daily. In the case of atransdermal patch, the unit dose (one patch) is generally applied at least once a month, morecommonly at least once a bi-week, and typically once a week. An effective amount of 5 amlodipine maleate ftee fiom amlodipine aspartate in a unit dose for treating or preventinghypertension 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.), thepharmaceutical composition typically contains about 1, 2.5, 5.0, or 10 mg of the amlodipinemaleate. For simplicity, ali amounts refer to the corresponding amount of amlodipine free 10 base provided to the composition. The usual initial human oral dose of amlodipine for bothhypertension 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 2.5 mg once daily and this dose may be used when adding amlodipine to otherantihypertensive therapy. Spécifie examples of pharmaceutical compositions include those 15 described in EP 244944 wherein amlodipine maleate according to the présent invention isused as the active ingrédient.

Preferred pharmaceutical compositions will hâve a pH within the range of fiom about 5.5 to 7.0, when measured as a 20 wt% aqueous slurry as is described in more detail incommonly-owned co-pending U.S. patent application serial No. 09/809,346, filed on March 20 16,2001, and entitled “Pharmaceutical Compositions Comprising Amlodipine Maleate,” the entire contents of which are incorporated herein by référencé. These compositions generallyprovide good or improved stability.

Ail of the pharmaceutical compositions described above can be made by knownmethods and techniques. For example, the tablets can be made by diy granulation/direct 25 compression or by a classical wet granulation method. Typically, tablets are made byblending, fïlling and compressing into tablets. The blending step may comprise a wetgranulation or dry granulation. Similarly, capsules can be made by blending the ingrédientsand fïlling the capsule.

The above compositions are also usefol in reducing heart failure symptoms, 30 improving systolic left ventricular fonction and increasing exercise câpacity in patients withischaemic LVD and heart failure without current angina. WO 02/053542 PCT/NL01/00607 13133- 11

Amlodipine maleate compositions of the invention, may be also used in medicalapplications in combination with other antihypertensive and/or antianginal agents, forinstance with ACE- inhibitors such as benazepril. The combination may be realized in aform of single combination préparation, e.g. a capsule containing amlodipine maleate and 5 benazepril hydrochloride, or by separate administration of drugs containing the aboveagents. Similarly, amlodipine maleate may also be combined with HMG-CoA reductaseinhibitors, particularly statins such as lovastin, simvastatin, atorvastatin, etc.

Accordingly, the présent invention further provides a method for treating and/orpreventing any one or more of angina, hypertension and heart failure by administering a 10 pharmaceutical composition of the invention comprising an effective and/or prophylacticamount of amlodipine maleate to a sufferer in need thereof.

In preparing amlodipine maleate as an active ingrédient or in a pharmaceuticalcomposition, it may be bénéficiai to assay for the presence and/or amount of amlodipineaspartate in order to insure that the active or compositional forms are suffîciently ffee from 15 the aspartate impurity. This is useful in checking, for example, the effectiveness of thecrystallization conditions chosen for making amlodipine maleate substantially ffee fromamlodipine aspartate in accordance with the présent invention. Assaying for amlodipineaspartate as well as how to make amlodipine aspartate as a référencé standard or referencemarker composition is described more fully in co-pending commonly owned U.S. patent 20 application serial No. 09/809,347, fîled on March 16, 2001, and entitled “ReferenceStandards For Determining The Purity Or Stability Of Amlodipine Maleate And ProcessesTherefor,” the entire contents of which are incorporated herein by reference.

Examples 25

Example 1 Amlodipine maleate from crude amlodipine

Step 1 Décomposition of phthalimidoamlodipine

The reactor Al is charged with 64 1 of 40% aqueous methylamine and 8.0 kg of 30 phthalimidoamlodipine under stining. The suspension is stirred at 40 - 45 °C for 8 hours.Then 1201 of toluene is added and the mixture is stirred for 30 minutes. Then the mixture is WO 02/053542 PCT/NLO1/00607 13133 · 12 allowed to stand for séparation of layers, the aqueous layer is separated and discarded. Thetoluene layer is washed with 40 1 of water. The toluene solution is concentrated on a rotaryevaporator at 60°C until the first precipitate occurs (the volume approx. 12 litres). Theresidue is poured into a container and the evaporator is washed with 4 1 of éthanol which is 5 combined with the toluene solution. The content of amlodipine in the solution is determinedby titration. Resuit: 6.13 kg.

Step 2 Formation of amlodipine maleate 1.83 kg of maleic acid is dissolved in 70 1 of éthanol at 50 - 55°C in reactor A2. The 10 solution is filtered through pressure fil ter into the clean reactor Al. The reactor A2 and thefilter are washed with 7 1 of éthanol. The température of the combined solution is adjustedto 50 - 55 °C.

The solution of 6.13 kg of amlodipine ffee base from the preceding step is placedinto the reactor A2 and 661 of éthanol is added. The solution is charged from the reactor A2 15 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 éthanol. The température in Al increasesspontaneously to 65°C (cooling not necessary). The mixture is then stirred and slowly cooledto 15-20°C. The precipitated solid product is filtered off on a nutche filter, washed on thefilter with 2x41 of éthanol and dried in at température, of max 40°C. 20 Yield: 5,85 kg of Amlodipine maleate

Purity(HPLC) : <0.05% of aspartateParticle size - 80 -100 pm in averageComparative process 25 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 addedportionwise. Température increases to 70 °C and again a clear solution is obtained. Seedingcrystals are added and crystallization started, whereby the température increases to 72.5 °C.The mixture is cooled to 30 °C in 1.5 hours and further cooled to 2 °C in 1 hour. The 30 crystals were filtered off and washed with 3 x 5.8 1 of isopropanol and dried in a vacuumoven at 40 °C for 2 days. WO 02/053542 13133· 13 PCT/NL01/00607

Yield: 4960 g

Purity: 0.63% of Amlodipine aspartate

Example 2 5 0.58 g of maleic açid is dissolved in 25 ml of water and heated to approximately 60°C. To this solution, 2.0 g of amlodipine is added portionwise. The solution tums slightlyyellow during addition and when addition is complété a solid starts to precipitate ffom themixture. The mixture is slowly cooled to room température 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°C for 10 24 hours leaving 2.4 g (93%) of a white solid. HPLC: aspartate content 0.01% NMR: correspond to amlodipine maleate.

Comparative process: 15 2 g of amlodipine is suspended in 25 ml of water and heated to approximately 60°C.

To this suspension, 0.58 g of maleic acid is added portion wise. The suspension becameclear (slightly yellow) and a solid started to precipitate. The mixture was slowly cooled toroom température and the solid is filtered off. The solid is washed with 5 ml of water anddried in a vacuum oven at 50°C for 24 hours leaving 2.4 g (93%) of a white solid. 20 HPLC: aspartate content 0.2 % NMR: amlodipine maleate + approx. 10% of amlodipine free base.

Example 3

Amlodipine maleate ffom amlodipine hydrochloride 25 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 fewminutes a solid précipitâtes and the mixture is stirred at room température for one hour. Thesolid is filtered off over a paper filter and washed with 2x5 ml of water. After drying in avacuum oven, 0.72g (61%) of the product as a solid is obtained. 30 Aspartate content (HPLC): 0.01% WO 02/053542 13133· 14 PCT/NL01/00607

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 isadded to this solution and the mixture is stirred until a clear solution is obtained. After a few 5 minutes a solid appears and the mixture is stirred at room température for one hour. Thesolid is filtered off over a paper filter and washed with 2x5 mi of water. After drying in avacuum oven, 0.73g (70%) of the product is obtained as an off white solid.

Aspartate content (HPLC): 0.01 % 10 Example 5

Crystallization of amlodipine maleate 5 g of amlodipine maleate is dissolved in a mixture of 60 ml of EtOH and 0.055 g ofmaleic acid at reflux. The solution is cooled in a refrigerator to 5 - 10°C and the precipitateis filtered and dried. 15 Yield: 4.5 g HPLC (IN): 0.046% of aspartate

Comparative Process 20 g of amlodipine maleate is dissolved in 240 ml of EtOH at reflux. The solution is20 cooled to 20 °C and the precipitate formed is filtered and dried.

Yield: 16,3 g HPLC(IN): 0.67% of aspartate

Reference Example 25 Préparation 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. Themelted substance is cooled to room température and dissolved in 300 ml of dichloromethane.The mixture is extracted with 300 ml of a IM NaOH solution. The organic layer isdiscarded and the aqueous layer acidified with 55 ml of a 6 M HCl solution. The mixture is 30 extracted with 300 ml of dichloromethane. The layers are separated and the organic layerdried over Na2SO4. The mixture is evaporated to dryness and the resulting waxy solid WO 02/053542 13133 · PCT/NL01/00607 15 recrystallized from éthanol. The obtained sticky solid is dried in a vacuum oven at 40 °Cleaving 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 inthe art that further changes and modifications in actual implémentation of the concepts andembodiments described herein can easily be made or may be leamed by practice of the 10 invention, without departing from the spirit and scope of the invention as defined by thefollowing daims.

Claims (26)

1. WO 02/053542 13133· PCT/NLO 1/00607 16 CLAIMS

   1. Process, which comprises reacting amlodipine or an acid addition sait thereof with maleic acid under an acidic environment to form an amlodipine maleate product.
2. 2. Process according to daim 1, wherein said amlodipine or sait thereof is added toan équivalent or molar excessive amount of maleic acid. 10
3. 3. Process according to daims 1 or 2, wherein said amlodipine maleate productcontains less than 1 wt % amlodipine aspartate, based on the amount of amlodipinemaleate.
4. 4. Process according to claim 3, wherein said amlodipine maleate product contains less than 0.2 wt % amlodipine aspartate, based on the amount of amlodipine maleate.
5. 5. Process for the manufacture of an amlodipine maleate sait substantially free ofamlodipine aspartate wherein the amlodipine is added continuously or portionwise into a 20 solution or suspension of the maleic acid to form a solution, wherein the relative molaramount of maleic acid to amlodipine being added is at least 1.01:1; and amlodipinemaleate in a solid form is separated from the solution.
6. 6. Process according to claim 5, wherein the relative molar 25 amount of maleic acid to amlodipine being added is at least about 1.05:1.
7. 7. The process according to daims 5 or 6, wherein the source of amlodipine isselected from the group consisting of raw amlodipine obtained after the synthesis ofamlodipine, purifîed amlodipine free base; and an acid addition sait of amlodipine other 30 than the maleate. WO 02/053542 13133· PCT/NLO1/00607 17
8. 8. The process according to claim 7, wherein said source of amlodipine is in a solidState form or dissolved in a solvent.
9. 9. Process for the manufacture of an amlodipine maleate sait substantially free of 5 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 solutionwhereby the pH of the solution does not exceed 6.5; and the amlodipine maleate isseparated in a solid form from the solution.
10. 10. Process according to claim 9, wherein the source of amlodipine is selected from the group consisting of raw amlodipine obtained after the synthesis of amlodipine;purified amlodipine free base; and an acid addition sait of amlodipine other than themaleate.
11. 11. Process according to any of the preceding daims 9 or 10, wherein said source of amlodipine is in a solid State form or dissolved in a solvent.
12. 12. Process according to any of the preceding daims, wherein said source ofamlodipine is an acid addition sait of amlodipine other than the maleate sait, in a solid 20 State or dissolved or suspended in a suitable solvent.
13. 13. Process according to any of the preceding daims, wherein said amlodipine sourceis added to said maleic acid solution or suspension.
14. 14. Process of purification, which comprises crystallizing or precipitating amlodipine maleate from a solution thereof wherein said solution comprises an excess of maleic acid.
15. 15. Process according to daim 14, which further comprises converting saidamlodipine maleate to another acid addition sait. 30 WO 02/053542 13133· PCT/NL01/00607 18
16. 16. The process according to daim 14, wherein said amlodipine maleate is convertedto amlodipine benzene sulfonate, amlodipine hydrochloride or amlodipine methanesulfonate.
17. 17. The process according to claim 16, wherein said conversion comprises treating said amlodipine maleate with base to form amlodipine free base and treating saidamlodipine free base with benzene sulfonic acid, methane sulfonic acid or hydrochloricacid.
18. 18. Amlodipine maleate obtainable according to the process of any of the preceding daims 1-14.
19. 19. Amlodipine maleate substantially free from amlodipine aspartate.
20. 20. Amlodipine maleate according to claim 19, wherein the amount of amlodipine aspartate is less than 0.2 wt%.
21. 21. A pharmaceutical composition for treating or preventing hypertension or anginathat comprises an effective amount of amlodipine maleate substantially free from. 20 amlodipine aspartate and a pharmaceutically acceptable excipient.
22. 22. The pharmaceutical composition according to claim 21, wherein said compositionis in a unit dose form containing 1 to 20 mg of said amlodipine maleate and the amountof amlodipine aspartate is less than 0.2 wt %. 25
23. 23. A method for treating hypertension, angina or heart failure, which comprisesadministering an effective amount of amlodipine maleate substantially free fromamlodipine aspartate.
24. 24. Amlodipine benzene sulfonate, obtainable according to the process of claim 15 or 16. WO 02/053542 13133· 19 PCT/NL01/00607
25. 25. Amlodipine hydrochloride, obtainable according to the process of claim 15 or 16.
26. 26. The use of amlodipine maleate substantially free from amlodipine aspartate for 5 the manufacture of a médicament for the treatment of hypertension, angina or heart failure. 10 15 20 C 25 30