SI21068A2 - Amlodipine maleate or its acid addition salt - Google Patents

Abstract

The submitted invention refers to amlodipine maleate or its acid addition salt of high purity. It can be obtained by reaction of amlodipine or its acid addition salt with maleic acid in acid environment to yield the product amlodipine maleate. The latter contains essentially no amlodipine aspartate.

Description

BioOrganics B.V.

Amlodipine maleate or its acid addition salt

The present invention relates to amlodipine maleate or an acid addition salt thereof in good purity.

Calcium channel blockers (calcium antagonists) are useful in the treatment of heart conditions, including angina and / or hypertension. Dicarboxylate-dihydropyridine derivatives are generally known to have calcium channel blocking activity. E.g. EP 089 167 and the corresponding US 4,572,909 describe a class of 2-amino group-3,5-dicarboxylate dihydropyridine derivatives as useful calcium channel blockers. These 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 has good bioavailability and a long half-life in the body. Many of the acid addition salts are described in these patents, but the most preferred acid addition salt is the maleate salt. In Cases 9, 11, 12 and 22 of EP 89167 as well as in J. Med. Chem. 29, 1698 (1986) describes the preparation of amlodipine maleate (with a 1: 1 molar ratio of both components) by dissolving a reaction mixture containing in situ crude amlodipine base, in ethyl acetate or ethanol, and adding solid maleic acid, wherein the maleate salt of amlodipine is precipitated.

The salt was then isolated by filtration and recrystallized from ethyl acetate or from a 1: 1 acetone / ethyl acetate mixture.

However, the marketed product of amlodipine (NORVASC from Pfizer) uses amlodipine besylate (benzene sulfonate) rather than amlodipine maleate. Indeed, the following patent EP 244 944 and the corresponding US 4,879,303 states that the besylate salt has certain advantages over the known salts, including good formulation properties. Apparently, the disadvantages of amlodipine maleate were problems with tableting and stability, so this caused a leap during development into the besylate salt. (See Original NDA Review for NDA # 19-787 dated 10/10/1990, obtainable from the FDA under the Freedom of Information Act). The issues / causes of stability and tableting are not publicly disclosed in information available to the FDA.

The present invention relates to the discovery of an unprecedented impurity combined with amlodipine maleate and to a process for preventing its formation during preparation. Specifically, the present invention relates to a process comprising the reaction of amlodipine or a pharmaceutically acceptable salt thereof with maleic acid in an acidic environment to obtain the product amlodipine maleate. Typically, the process involves the preparation of an amlodipine maleate salt substantially free of amlodipine aspartate, comprising the steps of (a) either (1) adding, continuously or in portions, the source of amlodipine to a solution or suspension of maleic acid to obtain a solution, wherein is the relative molar amount of maleic acid against amlodipine added at least 1.01: 1, or (2) contacted continuously or in fractions, the source of amlodipine with a solution or suspension of maleic acid while controlling pH to obtain a solution, at pH the solution does not exceed 6.5; and (b) making amlodipine maleate in solid form from solution. The present invention further relates to a process for purifying amlodipine maleate comprising crystallized or precipitating amlodipine maleate from a solution thereof, wherein the solution comprises an excess of maleic acid.

FIG. 1 shows an IR diagram for the material of Example 1. FIG. 2 shows the DSC curve for the material of case 1.

FIG. 3 shows an X-ray diffractogram for the material of Example 1.

Although the process for converting amlodipine free base or salt to amlodipine maleate salt is substantially simple, we have now discovered that significant known by-products of formula (1) can be produced by known processes for the preparation of amlodipine maleate:

.COOH 'COOH (2)

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

We have now discovered that the preparation process described in the above-mentioned patents and in the literature can produce negligible amounts of amlodipine aspartate as a by-product on a laboratory scale, but significant increases in the by-product of amlodipine aspartate are possible on an industrial scale, namely at elevated temperatures required for complete conversion and for obtaining amlodipine maleate in good crystalline form.

The presence of a by-product in any substance intended to be administered to a human patient as a therapeutic agent is generally undesirable. Removal of by-products and impurities can lead to higher preparation costs and lower yields due to material loss in the purification step. It is thus advantageous to obtain the desired product as soon as possible with as few by-products and impurities.

The basis of the present invention is the finding that amlodipine maleate can be prepared substantially free of amlodipine aspartate by carefully selecting the reaction conditions. Namely, it was found that the pH of the reaction mixture during the formation of amlodipine maleate must be substantially acidic. A process for the preparation of an amlodipine maleate salt, substantially free of amlodipine aspartate, comprising the reaction of amlodipine with maleic acid, wherein the reaction environment is substantially acidic, thus forming the basic aspect of the invention.

Thus, the first embodiment of the present invention involves the addition of starting material containing amlodipine (hereinafter: source of amlodipine) to a solution of maleic acid in such a way that maleic acid can be in excess of amlodipine in the reaction mixture; i.e. by adding an amlodipine base to the mole equivalent or excess amount of maleic acid and preferably to its excess. The unprocessed 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 to a solution or suspension of maleic acid in a suitable solvent to obtain 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 is eliminated in the solid state. In this process, amlodipine reagent is used in the solid state or in solution or in suspension and can be batched continuously or in portions. A suitable minimum excess of maleic acid is about 1 mol% or more, i.e. about 1.01 mole equivalents, the preferred range is about 5 mole percent and may even be substantially higher, e.g. up to 50 or 100 mol% i.e. 2 mole equivalents. The use of an excess amount of maleic acid is useful for preparation on an industrial scale, where the actual amount of batch amlodipine can in some cases be difficult to determine.

The amlodipine source can be contacted with the maleic acid in the solvent at pH control, keeping the pH below 7, preferably below 6.5, typically in the range of 4.5 to 6.5, optionally by adding maleic acid in proportions or continuously. . The formation of amlodipine aspartate is also satisfactorily prevented at pH below 4.5, but sometimes other by-products may be formed. Generally, it is most advantageous, even with pH control, to add an amlodipine source to maleic acid as in the first embodiment, but this is not strictly required. After addition, amlodipine maleate is eliminated in the solid state.

This pH control process is also useful in the case where the source of amlodipine is an unpurified material, since the actual content of amlodipine in it is normally only known approximately, and / or the amlodipine source may also contain impurities or by-products of a basic nature, which may also react with maleic acid. E.g. crude amlodipine obtained from the deprotection of phthalimido-amlodipine with excess methylamine may contain traces of methylamine, the amount of which can only be determined with difficulty. Thus, the pH of the reaction mixture is controlled while adding or treating the solution of maleic acid or suspension with an amlodipine source and adjusting, as with the addition of acid, preferably maleic acid, as necessary to maintain the pH control below 7 as described above.

On the other hand, the pH can be maintained in the acidic range using the acid addition salt of amlodipine, which is different from maleate. The required acidic pH is adjusted by releasing the corresponding acid from such a salt during the formation of maleate, as shown by the equation:

amlodipine.HX + maleic acid -----> amlodipine maleate + HX where X is the anion of the corresponding acid.

As this reaction takes place essentially at equilibrium, amlodipine salts that are more soluble in the reaction medium than amlodipine maleate should be used. As amlodipine maleate is eliminated from the solution, the equilibrium shifts continuously towards the formation of the next amlodipine maleate. Suitable salts are e.g. amlodipine hydrochloride, methanesulfonate or benzenesulfonate. In general, any suitable salt that is more soluble in the reaction solvent than amlodipine maleate can be used.

In the processes of the invention, various sources of amlodipine can be used to react with maleic acid. E.g. the reaction mixture obtained after the final step of amlodipine synthesis can be used. Such methods are known in the art, and their final steps typically comprise deprotection of the amino protecting group in the amlodipine precursor, as shown in the following scheme:

In the scheme, the N-Prot is a substituent or group protecting or masking the amino group; may include benzylamino or phthalimido group (EP 89 167), azido group (EP 89 167), tritylamine group (EP 599220), hexamethylenetetramine group (EP 902016), etc. Another useful synthesis scheme for the preparation of amlodipine or its salts in good yields and purity via the phthalimidoamlodipine intermediate is described in provisional application no. No. 60 / 258,613, filed December 29, 2000, which is jointly owned and all of the contents herein are incorporated by reference, and in U.S. Pat. No. 09 / 809,351, filed March 16, 2001, entitled: The process for the preparation of amlodipine, its derivatives and precursors for it, which is simultaneously in the process and is jointly owned, the entire contents of which are incorporated herein by reference.

After the deprotection reaction, the reaction mixture can be treated by known methods to obtain a solution of crude amlodipine in a suitable solvent. Such a solution can be used as a source of amlodipine to form amlodipine maleate, substantially free of amlodipine aspartate by the process of the present invention. Alternatively, the amlodipine free base obtained by amlodipine synthesis can be isolated in the solid state, e.g. by the procedure described in Int. J. Pharm. 133, 72 (1996), and the free base can be batch raw or purified. In another alternative, amlodipine free base (with or without its isolation) may also be converted to a salt other than maleate prior to contact with maleic acid. The amlodipine source may be in dissolved solvent form, solid material or suspension.

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

Various solvents or solvent systems may be employed in the process of the present invention. Preferred solvents are those in which the starting materials are sufficiently soluble and in which the produced amlodipine maleate is only poorly soluble. Such solvents include water, alcohol, such as methanol, ethanol or isopropanol, ester, such as ethyl acetate, ketone, such as acetone, nitrile, such as acetonitrile, ether, such as dioxane or tetrahydrofuran, hydrocarbon, such as toluene, or mixtures thereof. The advantage of the present invention is that certain solvents which are unfavorable for use in known processes, such as water, can be used without difficulty in the present process.

The temperature when contacting an amlodipine source with maleic acid may vary from room temperature to the boiling point of the solvent or solvent system and may also vary during the course of the reaction. Preferred temperatures are higher than 40 ° C when amlodipine maleate crystallizes from hot solution as good and / or large crystals. When operated at room temperature, amlodipine maleate precipitates in small crystals that are often 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 the amlodipine base as in the known process, undesirable amounts of amlodipine aspartate are formed at temperatures above about 40 ° C. E.g. by adding maleic acid to amlodipine base in isopropanol at 80 ° C, amlodipine maleate can be obtained contaminated with about 0.7% aspartate. However, as in accordance with the preferred aspects of the invention, when amlodipine is added to maleic acid, higher temperatures can be used without difficulty. This is particularly advantageous when the reaction temperature is higher than 40 ° C, e.g. using a solvent that requires higher temperatures to convert amlodipine or maleic acid into solution, or if the reaction mixture is concentrated by evaporation. E.g. by adding amlodipine base to a 5% molar excess of maleic acid in hot isopropanol, amlodipine maleate was obtained with only 0.03% aspartate.

The importance of a substantially acidic environment, in particular the presence of an excess of maleic acid, with respect to minimizing the rate of formation of amlodipine aspartate may also be demonstrated in processes for the purification of amlodipine maleate from other impurities by crystallization or precipitation. The elevated temperatures required to dissolve amlodipine maleate in crystallization or precipitating solvent may also contribute to the formation of amlodipine aspartate. As the solubility of amlodipine aspartate is similar in most crystallization solvents, conventional crystallization techniques do not allow the extraction of amlodipine maleate from them, and thus ironically crystallization is actually a contaminant product. However, if excess maleic acid is present in the crystallization system, the formation of amlodipine aspartate is minimized. Thus, a further aspect of the present invention relates to a process for deciding solid-state amlodipine maleate from a precipitate or crystallization solution, characterized in that free maleic acid is present in the amount of from 1% to 100% molar excess, preferably in the amount of about 5 % molar excess.

The precipitation or crystallization of amlodipine maleate from the solution with excess maleic acid can therefore be used as a purification step. Another aspect of the present invention comprises the formation of a purified amlodipine free base or its salts by conversion of precipitated or crystallized amlodipine maleate. Specifically, when amlodipine maleate is precipitated or crystallized from a solution containing excess maleic acid, it can be converted to another amlodipine salt of good purity. The conversion can be carried out directly by treating amlodipine maleate in acid solution. On the other hand, the conversion may also include treating amlodipine maleate in solution with a base, either organic or inorganic base, to give an amlodipine free base, followed by treatment of the free base, with or without its isolation with the desired acid to obtain the intended amlodipine salt. The new salt can be precipitated or otherwise removed from the solvent. Due to the purity of precipitated or crystallized amlodipine maleate, this, together with the converted salt forms and the optional free base, can be prepared in a pharmaceutically acceptable quality substantially without any further purification. Examples of salts that can be prepared by this process are amlodipine benzenesulfonate (besylate) and amlodipine hydrochloride.

In conventional warms suitable for crystallization of amlodipine maleate, such as water, methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, toluene and mixtures thereof, a maleic excess of at least 1 mole percent and up to 100 mole percent, with a yield of between 5 to 25 mol%. The appropriate amount of maleic acid useful in the industrial process can be determined on a case-by-case basis by a standard series of experiments, taking into account the solvent, concentration and temperature regime and using yield and purity as the evaluation criteria.

Amlodipine maleate, which is substantially free of amlodipine aspartate, means that amlodipine maleate contains less than 1 wt. %, preferably below 0.5% by weight, more preferably below 0.2% by weight, and most preferably below 0.1% by weight of amlodipine aspartate. Amlodipine maleate, substantially free of amlodipine aspartate, can be used in therapy as a pharmaceutically acceptable salt of amlodipine. Therefore, amlodipine maleate, substantially free of amlodipine aspartate, forms another aspect of the present invention.

The amlodipine molecule has a chiral center on the 1,4-dihydropyridine ring and exists in two optically active forms. The forms can be separated by crystallization or chromatography, optionally in the form of salts, e.g. salts with an optically active base or acid, and can therefore be converted to the individual isomers of amlodipine maleate according to the invention by the methods described above. The individual isomers of amlodipine or mixtures thereof may be used in the present invention. Accordingly, the individual or mixed isomers of amlodipine maleate, substantially free of amlodipine aspartate, are also within the scope of the present invention.

Amlodipine maleate, essentially free of amlodipine aspartate, can be used as a calcium channel blocker and can thus be used to treat any cardiac condition that would benefit it from administering a calcium channel blocker. In particular, amlodipine maleate without amlodipine aspartate can be used to treat or prevent hypertension or angina by administering an effective amount to a patient undergoing treatment

-101 needed. The specific form of angina is not particularly limited and specifically includes chronic stable angina and vasospastic angina (Prinzmetal angina). The compound can be administered by any suitable route, including oral or parenteral. The patients they are intended to treat are humans and non-human animals, especially humans and non-human mammals.

The compound is typically administered as part of a pharmaceutical composition. Thus, a further aspect of the invention is a pharmaceutical composition for treating or preventing hypertension or angina, comprising an effective amount of amlodipine maleate, substantially free of amlodipine aspartate, and a pharmaceutically acceptable excipient. Excipients are any inert or inactive material used in the preparation of the pharmaceutical dosage form. E.g. Excipients for tablets include, but are not limited to, calcium phosphate, cellulose, starch or lactose. Capsules, such as those made from gelatin, may contain or carry amlodipine maleate alone or in admixture with other excipients. Liquid dosage forms are also included, such as oral slurries 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 each of the following excipients, such as carriers, diluents, colorants, flavors, lubricants, solubilizers, disintegrants, binders and preservatives.

The pharmaceutical composition is usually in unit dose. A single dose is typically given once or twice daily, more typically once daily. In the case of a transdermal patch, a single dose (one patch) is generally administered at least once a month, more generally at least twice a week and typically once a week. The effective amount of amlodipine maleate without amlodipine aspartate in a single dose to treat or prevent hypertension or angina is generally in the range of 1 to 100 mg, typically 1 to 50, 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 maleate. For the sake of simplicity, all amounts 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.

-1111

Small, fragile, or elderly individuals or patients with hepatic insufficiency may start at 2.5 mg once daily and this dose can be used when amlodipine is added to other antihypertensive therapy. Specific examples of pharmaceutical compositions include those described in EP 244944, wherein the amlodipine maleate of the present invention is used as the active ingredient.

Preferred pharmaceutical compositions will have a pH in the range of 5.5 to 7.0 when measured as a 20 wt.% Aqueous suspension, as described in more detail in U.S. Pat. No. 09 / 809,346, filed March 16, 2001, entitled: Pharmaceutical compositions comprising amlodipine maleate, which is jointly owned and simultaneously in process, and its entire contents are incorporated herein by reference. These compositions generally provide good or improved stability.

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

The above compositions are also useful in reducing the symptoms of heart failure, improving systolic left ventricular function, and increasing physical fitness in patients with ischemic LVD and heart failure without angina.

The amlodipine maleate compositions of the invention may also be used in medical applications in combination with other antihypertensives and / or antianginal agents, e.g. with ACE inhibitors such as benazepril. The combination can be carried out in the form of a single combination preparation, e.g. capsules containing amlodipine maleate and benazepril hydrochloride, or by separately administering medicines containing the above agents. Similarly, amlodipine maleate can also be combined with HMG-CoA reductase inhibitors, in particular statins such as lovastatin, simvastatin, atorvastatin, etc.

-1212

Thus, the present invention is further a method of treating and / or preventing any 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 patient in need of such treatment .

In preparing amlodipine maleate as an active ingredient or in a pharmaceutical composition, it may be useful to test for the presence and / or amount of amlodipine aspartate to ensure that the active forms or forms of the compositions are sufficiently free of aspartate impurity. This is useful in controlling e.g. efficiency of crystallization conditions selected for the preparation of substantially free amlodipine maleate in accordance with the present invention. Testing for amlodipine aspartate as well as how to make amlodipine aspartate as a reference standard or reference marker composition is described more fully in U.S. Pat. No. 09 / 809,347, filed March 16, 2001, entitled Reference standards for the determination of the purity or stability of amlodipine maleate and the processes that are jointly owned and contemplated and its entire contents are incorporated herein by reference.

EXAMPLES

Example 1

Amlodipine maleate from crude amlodipine

Tier 1 Decomposition of phthalimidoamlodipine

64 1 40% aqueous methylamine and 8.0 kg of phthalimidoamlodipine are added to Al reactor with stirring. The suspension was stirred for 8 hours at 40-45 ° C. Then 120 l of toluene was added and the mixture was stirred for 30 minutes. The mixture is then allowed to stand for the separation of layers, the aqueous layer is separated and discarded. The toluene layer was washed with 40 l of water. Concentrate the toluene solution on a rotary evaporator at 60 ° C until the first precipitate appears (volume about 12 l). The residue was poured into a vessel and the evaporator was washed with 4 l of ethanol, which was combined with

-1313 toluene solution. The content of amlodipine in the solution is determined by titration. Result: 6.13 kg.

Tier 2 Amlodipine maleate formation

1.83 kg of maleine solution was dissolved in 70 l of ethanol at 50-55 ° C in reactor A2. The solution was filtered through a pressure filter into a pure Al reactor. The reactor A2 and the filter were washed with 7 L of ethanol. Adjust the temperature of the pooled solution to 50-55 ° C.

A solution of 6.13 kg of amlodipine free base from the previous step was added to reactor A2 and 66 l of ethanol was added. Batch the solution from reactor A2 through a pressure filter (nitrogen pressure) into the mixed solution into reactor Al. The reactor and filter were washed with 7 L of ethanol. The temperature in Al rises spontaneously to 65 ° C (no cooling required). The mixture was then stirred and slowly cooled to 15-20 ° C. The precipitated solid product was filtered off with suction, washed on a filter with 2x4 l of ethanol and dried at a temperature of not more than 40 ° C.

Yield: 5.85 kg of amlodipine maleate.

Purity (HPLC): <0.05% aspartate

Particle size - average 80-100 pm

Comparative procedure kg of wet amlodipine free base was suspended in 17.5 l of isopropanol. The suspension was heated to 65 [deg.] C. to give a clear solution. 1.17 kg of maleic acid were added in portions. The temperature rises to 70 ° C and again a clear solution is obtained. The crystalline pellets are added and crystallization begins, with the temperature rising to 72.5 ° C. The mixture was cooled to 30 ° C for 1.5 hours and further cooled to 2 ° C for 1 hour. The crystals were filtered off and washed with 3x5.8 l of isopropanol and dried in a vacuum oven at 40 ° C for 2 days.

-1414

Yield: 4960 g

Purity: 0.63% amlodipine aspartate

Example 2

0.58 g of maleic acid are dissolved in 25 ml of water and heated to about 60 ° C. 2.0 g of amlodipine are added portionwise to this solution. The solution turns slightly yellow as it is added and after the addition is complete, a solid begins to precipitate from the mixture. The mixture was slowly cooled to room temperature and the solid filtered off. After washing the solid with 5 ml of water, the solid was dried in a vacuum oven at 50 ° C for 24 hours to give 2.4 g (93%) of a white solid.

HPLC: 0.01% aspartate content

NMR: Corresponds to amlodipine maleate.

Comparative procedure:

g of amlodipine is suspended in 25 ml of water and heated to about 60 ° C. To this suspension, 0.58 g of maleic acid was added in portions. The suspension becomes clear (slightly yellow) and the solid begins to precipitate. The mixture was slowly cooled to room temperature and the solid filtered off. The solid was washed with 5 ml of water and dried in a vacuum oven at 50 ° C for 24 hours to give 2.4 g (93%) of a white solid.

HPLC: aspartate content of 0.2%

NMR: amlodipine maleate + approx. 10% amlodipine free base.

Example 3

Amlodipine maleate from amlodipine hydrochloride g amlodipine hydrochloride is dissolved in 20 ml of water. 0.26 g of maleic acid is added to this solution and the mixture is stirred until all is dissolved. After a few minutes

-1515 precipitated solid, and the mixture was stirred at room temperature for 1 hour. The solid was filtered off through a paper filter and washed with 2x5 ml of water. After drying in a vacuum oven, 0.72 g (61%) of the product are obtained as a solid.

Aspartate content (HPLC): 0.01%

Example 4

Amlodipine maleate from amlodipine mesylate g 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 formed and the mixture was stirred at room temperature for 1 hour. The solid was filtered off through a paper filter and washed with 2x5 ml of water. After drying in a vacuum oven, 0.73 g (70%) of the product is obtained as a dirty white solid.

Aspartate content (HPLC): 0.01%

Example 5

Crystallization of amlodipine maleate g Amlodipine maleate is dissolved in a mixture of 60 ml EtOH and 0.055 g maleic acid at reflux. The solution was cooled in a refrigerator at 5-10 ° C, the precipitate was filtered and dried.

Yield: 4.5 g

HPLC (ΙΝ): 0.046% aspartate

Comparative procedure Dissolve amlodipine maleate in 240 ml of EtOH at reflux. The solution was cooled to 20 ° C and the precipitate formed was filtered off and dried.

-1616

Yield: 16.3 g

HPLC (ΙΝ): 0.67% aspartate

Reference case

Preparation of amlodipine aspartate as reference standard g of amlodipine and 12 g of amlodipine maleate were melted in a 300 ml flask. The molten substance was cooled to room temperature and dissolved in 300 ml of dichloromethane. The mixture was extracted with 300 ml of IM NaOH solution. The organic layer was discarded and the aqueous layer was acidified with 55 ml of 6 M HCl solution. The mixture was extracted with 300 ml of dichloromethane. The layers were separated and the organic layer was dried over Na ₂ SO ₄ . The mixture was evaporated to dryness and the resulting waxy solid recrystallized from ethanol. The resulting sticky solid was dried in a vacuum oven at 40 ° C to give 4.7 g of a dirty white product.

Yield: 4.7 g (39%)

Melting point: 178 ° C-183 ° C (dec.)

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

Claims (22)

PATENT APPLICATIONS Claims 1. Amlodipine maleate or an acid addition salt thereof, obtainable by a process comprising the metabolism of amlodipine or its acid addition salt with maleic acid in an acidic environment to obtain the product amlodipine maleate. Amlodipine maleate or its acid addition salt according to claim 1, characterized in that in the process amlodipine or its salt is added to an equivalent or molar excess of maleic acid. Amlodipine maleate or an acid addition salt thereof according to claim 1 or 2, characterized in that in the process the product amlodipine maleate contains less than 1 wt. % of amlodipine aspartate based on the amount of amlodipine maleate. Amlodipine maleate or an acid addition salt thereof according to claim 3, characterized in that in the process the product amlodipine maleate contains less than 0.2% by weight of amlodipine aspartate based on the amount of amlodipine maleate. 5. Amlodipine maleate or an acid addition salt thereof according to claims 1 to 4, substantially free of amlodipine aspartate, characterized in that in the process of amlodipine is added continuously or in proportions to a solution or suspension of maleic acid to obtain a solution having a relative molar amount maleic acids against amlodipine added at least 1.01: 1, and amlodipine maleate in solid form are separated from the solution. Amlodipine maleate or its acid addition salt according to claim 5, characterized in that the process has a relative molar amount of maleic acid against the added amlodipine at least about 1.05: 1. Amlodipine maleate or an acid addition salt thereof according to claim 5 or 6, characterized in that the source of amlodipine is selected from the group consisting of crude -1818 amlodipine obtained after synthesis of amlodipine, purified amlodipine free base and acid addition salt of amlodipine other than maleate. Amlodipine maleate or its acid addition salt according to claim 7, characterized in that the process is a solid source of amlodipine or dissolved in a solvent. Amlodipine maleate or its acid addition salt according to claims 1 to 4, characterized in that in the process amlodipine is contacted continuously or in portions with a solution or suspension of maleic acid at pH control to obtain a solution, wherein the pH of the solution does not exceed 6,5; and amlodipine maleate is separated in solid form from the solution. Amlodipine maleate or an acid addition salt thereof according to claim 9, characterized in that in the process the source of amlodipine is selected from the group consisting of crude amlodipine obtained after the synthesis of amlodipine; purified amlodipine free bases; and the acid addition salts of non-maleate amlodipine. Amlodipine maleate or an acid addition salt thereof according to claim 9 or 10, characterized in that the process is a solid source of amlodipine or dissolved in a solvent. Amlodipine maleate or its acid addition salt according to claims 9 to 11, characterized in that in the process the source of amlodipine is the acid addition salt of amlodipine other than the maleate salt in solid state or dissolved or suspended in a suitable solvent. Amlodipine maleate or an acid addition salt thereof according to claims 9 to 12, characterized in that the source of amlodipine is added to the solution or suspension of maleic acid in the psotop solution. Amlodipine maleate or an acid addition salt thereof according to claims 1 to 13, characterized in that the process comprises crystallizing or precipitating amlodipine maleate from its solution, wherein the solution comprises an excess of maleic acid. -1919 Amlodipine maleate or its acid addition salt according to claim 14, characterized in that the process further comprises converting amlodipine maleate to another acid addition salt. Amlodipine maleate or an acid addition salt thereof according to claim 14, characterized in that in the process amlodipine maleate is converted to amlodipine benzene sulfonate, amlodipine hydrochloride or amlodipine methane sulfonate. Amlodipine maleate or an acid addition salt thereof according to claim 16, characterized in that the conversion process comprises treating amlodipine maleate with a base to obtain an amlodipine free base and treating the amlodipine free base with benzene sulfonic acid, methane sulfonic acid or hydrochloric acid . Amlodipine maleate according to claims 1 to 17, characterized in that the amount of amlodipine aspartate is less than 0.2% by weight. A pharmaceutical composition for treating or preventing hypertension or angina, characterized in that it comprises an effective amount of amlodipine maleate, substantially free of amlodipine aspartate, and a pharmaceutically acceptable excipient. Pharmaceutical composition according to claim 19, characterized in that the composition is in unit dose form containing 1 to 20 mg of amlodipine maeate and the amount of amlodipine aspartate is less than 0.2% by weight. 21. Amlodipine benzene sulfonate obtainable by the process of claim 15 or 16. Amlodipine hydrochloride obtainable by the process of claim 15 or 16.