WO2003101965A1

WO2003101965A1 - Two crystalline hydrate forms of amlodipine benzenesulfonate of high purity, processes for their preparation and use

Info

Publication number: WO2003101965A1
Application number: PCT/EP2003/005632
Authority: WO
Inventors: Zoran Ham; Borut Furlan; Anton Copar; Uros Urleb
Original assignee: Lek Pharmaceuticals D.D.
Priority date: 2002-05-31
Filing date: 2003-05-28
Publication date: 2003-12-11
Also published as: AU2003242590A1; SI21233A

Abstract

The novel crystalline amlodipine benzenesulfonate dihydrate of high purity is disclosed, as well as the process for preparation of the novel crystalline amlodipine benzenesulfonate dihydrate of high purity and the crystalline amlodipine benzenesulfonate monohydrate of high purity, suitable for the preparation of pharmaceutical formulations for the treatment of cardiac diseases or hypertension, and their use as intermediate compounds in the improved process of purification of the nonhydrate benzenesulfonate (besylate) salt of amlodipine.The process for preparation of the crystalline amlodipine benzenesulfonate dihydrate is carried in the way that from the C1-C5 alcoholic solution of amlodipine benzenesulfonate with water while stirring at a temperature of 20°C or lower the crystals of pure amlodipine benzenesulfonate dihydrate are separated, and isolated.The process for preparation of the crystalline amlodipine benzenesulfonate monohydrate is carried in the way that from the C1-C5 alcoholic solution of amlodipine benzenesulfonate with water while stirring at a temperature of 30°C or higher the crystals of pure amlodipine benzenesulfonate monohydrate are separated, and isolated.

Description

TWO CRYSTALLINE HYDRATE FORMS OF AMLODIPINE BENZENESULFONATE OF HIGH PURITY, PROCESSES FOR THEIR PREPARATION AND USE

Field of the invention

The present invention belongs to the field of active substances and the group of heterocyclic compounds, and the pharmaceutical industry and relates to a novel crystalline dihydrate form of amlodipine benzenesulfonate of high purity, to the process for preparing the novel crystalline dihydrate form of amlodipine benzenesulfonate, to the process for preparing the crystalline monohydrate form of amlodipine benzenesulfonate, both in the pure forms suitable for pharmaceutical use and the preparation of pharmaceutical formulations and to their use as intermediate compounds in an improved purification process of known and in prior art described nonhydrate benzenesulfonate (besylate) salt of amlodipine .

Amlodipine benzenesulfonate is a selective calcium channel blocker acting an the cardiovascular system and represents a valuable anti-ischemic and antihypertensive agent.

amlodipine benzenesulfonate

Technical problem

There is a need for amlodipine benzenesulfonate of a high purity and for a new process for its preparation in a simple and feasible way which would afford the desired substance in a high yield and of high purity.

Prior art

Amlodipine is INN name for 3-ethyl 5-methyl (+/-)-2-[(2- aminoethoxy) methyl] -4- (2-chlorophenyl) -1, 4-dihydro-6-methyl- 3, 5-pyridinedicarboxylate, which was disclosed in European patent EP 89167 as the new substance and a useful anti- ischemic and hypertensive agent. Pharmaceutically acceptable acid addition salts of amlodipine were also disclosed, of which the maleate salt is disclosed as being particularly preferred.

Amlodipine in its free base form may be prepared in different ways as explained in the above mentioned European patent EP 89167. According to these processes amlodipine base can be prepared by removal of the amino-protecting group from the precursor of amlodipine, i.e., the 1, 4-dihydropyridine derivative, wherein the 2-standing amino group is protected by selected protective groups. In case the amino group is protected by a benzyl group, the protective group is removed by catalytic hydrogenation over a palladium catalyst in solvent such as methanol at room temperature. In a particularly preferred process when the amino protective group of 1, 4-dihydropyridine derivative is a phthalimido group, this amino-protecting group is removed by reaction of the amino-protecting group from the 1, 4-dihydropyridine derivative in alkaline medium with a) a primary amine such as methylamine, b) a hydrazine hydrate or c) an alkaline metal hydroxide, followed by the reaction with hydrochloric or sulfuric acid. If desired, the obtained amlodipine base is converted to its pharmaceutically acceptable acid addition salt. In European patent EP 89167, there is also described a process for the preparation of amlodipine base from its precursor having a 2-standing azido group, which is reduced to amlodipine base and then, if desired, converted to its pharmaceutically acceptable acid addition salt.

A disadvantage of these processes are relatively poor yields of said precursor of amlodipine which is prepared by already known in the art Hantzsch's synthesis of asymmetrical 1,4- dihydropyridine diesters. A process for preparing amlodipine base, where for protection of the amino group in the 1,4- dihydropyridine derivative a phthaloyl group is used which is then removed in an alkaline medium, requires the use of toxic substances which must not be present in the desired pharmaceutically acceptable acid addition salt of amlodipine. Methylamine and especially hydrazine hydrate are the toxic and cancerogenic compounds.

Amlodipine base may be also obtained by reduction of the azido 1, 4-dihydropyridine derivative, however, the handling of azido compounds is not convenient due to the well known explosiveness of azidic structures, especially starting azidoethanol .

European patent EP 244944 discloses the new benzenesulfonate (besylate) salt of amlodipine and the pharmaceutical forms containing the same. Because of its good solubility, good stability, non-hygroscopicity and good processability, this salt is outstandingly suitable for the preparation of pharmaceutical forms of amlodipine. As disclosed in that patent, the benzenesulfonate salt of amlodipine is prepared by conversion of amlodipine base with benzenesulfonic acid or ammonium benzenesulfonate in an inert solvent such as industrial methylated ethanol. Only the maleate, tosylate and besylate salts do not pick up any moisture when exposed to

75% relative humidity at 37 °C for 24 hours. Even when exposed to 95% relative humidity at 30 °C for 3 days both the besylate and maleate salts of amlodipine remain anhydrous whilst the tosylate salt of amlodipine formed the dihydrate salt. Therefore, the besylate salt of amlodipine may be considered to be non-hygroscopic and thus provides the preparation of stable pharmaceutical formulations while minimizing the risk of intrinsic chemical breakdown.

European patent EP 599220 discloses a novel process for preparing amlodipine benzenesulfonate according to which a new, not yet described in the literature, precurzor of amlodipine known under the chemical name 3-ethyl 5-methyl (+/-) 2- [2- (N-tritylamino) -ethoxymethyl] -4- (2-chlorophenyl) - 1, 4-dihydro-6-methyl-3, 5-pyridindecarboxylate, prepared by Hantzsch's synthesis, in reaction with benzenesulfonic acid in a methanolic medium or an aqueous methanolic medium at a temperature from 20 °C to the reflux temperature is converted into the benzenesulfonate salt of amlodipine which is then isolated and purified. The process is characterized by good overall yields of the desired compound, avoidance of the handling with certain toxic and cancerogenic chemicals, and avoidance of the preparation and isolation of amlodipine base which is needed in the processes disclosed in European patents EP 89167 and EP 244944. According to the object of the invention, as disclosed in EP 599220, no amlodipine base is formed at conversion.

From the dissertation of J. Rollinger, Doctoral Thesis "Polymorphism in Binary Systems - with special regard to antihypertensive drug substances" (1999) , University of

Innsbruck, a crystalline form of amlodipine benzenesulfonate (besylate) monohydrate is known and isolated, however, a process for its preparation and use are not described. Summary of the invention

The problem underlying the present invention is to overcome the disadvantages in the prior art and provide new and useful amlodipine benzenesulfonate compounds, process for their preparation and uses thereof. This problem can surprisingly be solved by preferably providing the compounds and processes as defined in the claims.

The invention relates to the preparation of a novel crystalline dihydrate form of amlodipine benzenesulfonate of high purity and a crystalline monohydrate form of amlodipine benzenesulfonate of high purity which are suitable for the preparation of the pharmaceutical forms as such instead of known and in the literature described commercial nonhydrate form of amlodipine benzenesulfonate, as well as for the use of both crystalline hydrates of amlodipine benzenesulfonate as intermediate compounds in purification of a nonhydrate form of amlodipine benzenesulfonate.

The invention further relates to the pharmaceutical formulations such as tablets, capsules and sterile aqueous solutions which comprise the crystalline amlodipine benzenesulfonate monohydrate or the crystalline amlodipine benzenesulfonate dihydrate together with a pharmaceutically acceptable diluent or carrier. Tablets may comprise the crystalline amlodipine benzenesulfonate monohydrate or crystalline amlodipine benzenesulfonate dihydrate in admixture with excipients. The preferred formulation includes the crystalline monohydrate or crystalline dihydrate amlodipine benzenesulfonate, a compression aid such as microcrystalline cellulose, an additive to provide sheen to the tablet such as anhydrous dibasic calcium phosphate, a disintegrant such as sodium starch glycollate and a lubricant such as magnesium stearate. The invention also refers to the use of both crystalline hydrate forms of amlodipine benzenesulfonate in the treatment of cardiac diseases, especially angina pectoris, or hypertension .

Description of the preferred embodiments

Amlodipine benzenesulfonate in a crude (impure) nonhydrate form is prepared as disclosed in European patent EP-B-0599220 by first using Hantzsch's synthesis of unsymmetrical 1,4- dihydropyridine diesters by condensing ethyl 4-[2-(N- tritylamino) ethoxy] acetoacetate, methyl (E)-3-amino crotonate and 2-chlorobenzaldehyde in a methanolic medium at the reflux temperature of the reaction mixture to prepare 3- ethyl 5-methyl (+/-) 2- [N-tritylamino) -ethoxymethyl] -4- (2- chlorophenyl) -1, 4-dihydro-6-methyl-3, 5-pyridinedicarboxylate which, without isolation from the methanolic mixture, is converted with benzenesulfonic acid (in 5 to 15% excess) in a methanolic medium at a temperature between 20°C and reflux temperature of the reaction mixture.

According to the process disclosed in patent EP-B-0599220, upon conversion the obtained crude (impure) amlodipine benzenesulfonate is isolated and purified including stirring after the completion of conversion at a temperature below 0°C, preferably at a temperature about -10°C.

Despite carefully conducted Hantzsch's synthesis of the unsymmetrical dihydropyridine nucleus according to the process disclosed in patent EP-B-0599220, accompanying impurities are formed. One among the impurities formed in said synthesis by alternative condensation of the present intermediates is diethyl 2, 6-bis [ (2-aminoethoxy) methyl] -4- (2- chlorophenyl) -1, 4-dihydro-6-methyl-3, 5-pyridinedicarboxylate (hereinafter referred to as sim-AML) which may be also present in crude amlodipine benzenesulfonate up to 5%. By recrystallization from a suitable lower alcohol such as methanol, the percent of said impurity is decreased but the yield of the desired compounds is also considerably lowered by multiple recrystallization of crude amlodipine benzenesulfonate.

Another impurity which is present in amlodipine benzenesulfonate, prepared according to the process disclosed in patent EP-B-0599220, is dimethyl-2- [ (2- aminoethoxy) methyl] -4- (2-chlorophenyl) -1, 4-dihydro-6-methyl- 3, 5-pyridinedicarboxylate (hereinafter referred to as DMA).

We have surprisingly and unexpectedly found that crude amlodipine benzenesulfonate, prepared according to the process disclosed in patent EP-B-0599220, can be preferably better purified in the way to prepare an intermediate crystalline amlodipine benzenesulfonate monohydrate or a new intermediate crystalline benzenesulfonate dihydrate which may be then converted into a nonhydrate form of amlodipine benzenesulfonate of high purity without the necessity for additional purification by recrystallization. Two crystalline hydrate forms, that is, amlodipine benzenesulfonate monohydrate and amlodipine benzenesulfonate dihydrate, are the stable compounds of high purity and therefore suitable for preparation of the pharmaceutical forms as such or as chemical intermediates for the preparation and/or purification of a known commercial nonhydrate form of amlodipine benzenesulfonate of high purity. Optionally, the desired nonhydrate form of amlodipine benzenesulfonate may be additionally purified in the way to repeated twice the described conversion. "High purity" or "pure" includes in the whole content of the present invention an interpretation of "containing substantially no impurities".

According to the process disclosed in the invention, the aforementioned impurities diethyl 2,6-bis[(2- aminoethoxy) methyl] -4- (2-chlorophenyl) -1, 4-dihydro-6-methyl- 3, 5-pyridinedicarboxylate (abbreviated sim-AM ) and dimethyl 2- [ (2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1, 4-dihydro-6- methyl-3, 5-pyridinedicarboxylate (abbreviated DMA) which are present as accompanying compounds in amlodipine benzenesulfonate, prepared according to the process disclosed in EP-B-0599220, are efficiently removed from the nonhydrate form of amlodipine benzenesulfonate.

In contrast to the process disclosed in patent EP-B-0244944, we have surprisingly and unexpectedly found that amlodipine benzenesulfonate may be preferably prepared in the form of the novel crystalline dihydrate of high purity.

Further, it has been unexpectedly found that amlodipine benzenesulfonate, prepared according to the process disclosed in patent EP-B-0599220, can be purified in an improved manner by preferably using the crystalline amlodipine benzenesulfonate monohydrate or the novel crystalline amlodipine benzenesulfonate dihydrate as intermediate compounds which can be then converted into amlodipine benzenesulfonate of high purity according to the process in the present invention. Amlodipine benzenesulfonate which is prepared and purified according to the present invention contains less total impurities than amlodipine benzenesulfonate which is prepared and purified by recrystallization from ethanol according to the process disclosed in patent EP-B-0599220.

The process of purification of a nonhydrate form of amlodipine benzenesulfonate with the aid of intermediate crystalline hydrate forms of amlodipine benzenesulfonate (monohydrate and dihydrate forms of amlodipine benzenesulfonate) may be advantageously carried out in the way to convert the hydrate forms of amlodipine benzenesulfonate into the nonhydrate form of amlodipine benzenesulfonate without heating the reaction mixture of the hydrate forms of amlodipine benzenesulfonate in an alcoholic medium such as methanol or ethanol, at a temperature about room temperature or below, preferably between 0 and 30 °C. When using amlodipine benzenesulfonate dihydrate, the conversion is preferably carried out at a temperature from -20°C to +30°C.

The process for preparation of the crystalline monohydrate form of amlodipine benzenesulfonate is based on separation of amlodipine benzenesulfonate from an aqueous medium or an aqueous-alcoholic medium at a temperature exceeding room temperature, preferably at a temperature exceeding 30 °C, most preferred between 30 and 50°C.

In this process, thermal crystallization from water or a mixture of alcohol-water may be used wherein a hot, preferably clear aqueous or aqueous-alcoholic solution of amlodipine benzenesulfonate is then slowly cooled, preferably to a temperature below 40 °C where the crystals of the pure crystalline amlodipine benzenesulfonate are separated and isolated.

Another preferred variant is carried out by precipitation of the monohydrate form of amlodipine benzenesulfonate in the way to mix an alcoholic solution of amlodipine benzenesulfonate with water at a temperature exceeding 30 °C, preferably by pouring or adding dropwise of an alcoholic solution of amlodipine benzenesulfonate to water or vice versa by pouring or adding dropwise water to an alcoholic solution of amlodipine benzenesulfonate, preferably by adding dropwise an alcoholic solution of amlodipine benzenesulfonate to water while stirring.

The process for preparation of the novel crystalline dihydrate form of amlodipine benzenesulfonate is based on separation of amlodipine benzenesulfonate from aqueous- alcoholic media at a temperature below room temperature, preferably at a temperature below 20 °C, preferably between -50 to 20°C, more preferred between 0 and 20°C.

The process is carried out by precipitation of a stirring alcoholic solution of amlodipine benzenesulfonate with water at a temperature below 20 °C, preferably by pouring or adding dropwise alcoholic solution of amlodipine benzenesulfonate to water or pouring or adding dropwise water to an alcoholic solution of amlodipine benzenesulfonate, preferably by adding dropwise of an alcoholic solution of amlodipine benzenesulfonate to water while stirring.

Another preferred variant of preparation of the novel dihydrate form of amlodipine benzenesulfonate is carried out from aqueous-alcoholic media by evaporation solvents, used in the process, at a temperature preferably below 20°C.

In the present invention lower Ci-₅ alkanol of branched or straight chain, preferably methanol and ethanol, more preferably methanol, may be used as alcohol.

For preparation of both crystalline hydrate forms of amlodipine benzenesulfonate, crude amlodipine benzenesulfonate or already purified prepared according to process disclosed in patent EP-B-0599220 may be used.

The process for the preparation of both crystalline hydrate forms of amlodipine benzenesulfonate (monohydrate and dihydrate forms of amlodipine benzenesulfonate) and the process for purification of the nonhydrate form of amlodipine benzenesulfonate with the aid of said crystalline hydrate forms of amlodipine benzenesulfonate as intermediate compounds are preferably carried out under careful monitoring of the precipitation temperatures whereat, regarding to the choice of convenient temperature range of conversion, crystals of the desired form of amlodipine benzenesulfonate are produced wherein the process according to the invention is reproducible.

In carrying out the processes according to the invention at a temperature between 20 and 30 °C, the processes are not reproducible or mixtures of amlodipine benzenesulfonate monohydrate and dihydrate are produced. Therefore, the precipitation temperatures should be carefully monitored to prevent the conversion be carried out in the temperature range between 20 and 30 °C.

According to the aim of the invention, purification of crude amlodipine benzenesulfonate with the aid of crystalline amlodipine benzenesulfonate dihydrate as an intermediate compound is preferred with respect to use of crystalline amlodipine benzenesulfonate monohydrate as an intermediate compoun .

It has surprisingly and unexpectedly been found that a crystalline amlodipine benzenesulfonate monohydrate and more a crystalline amlodipine benzenesulfonate dihydrate are more soluble in lower Cι_₅ alcohols than a nonhydrate form of amlodipine benzenesulfonate. Because at dissolving crystalline hydrates of amlodipine benzenesulfonate in lower Ci-₅ alcohols at a temperature about room temperature, water becomes a minor component in the mixture, there occurs exceeding solubility of a nonhydrate form of amlodipine benzenesulfonate which for this reason is spontaneously separated. On account of this phenomenon, purification of amlodipine benzenesulfonate is feasible in lower Cι_₅ alcohols, preferably in methanol, without heating of the reaction mixture thus preventing formation of the impurity DMA. According to the process disclosed in the present invention, more pure amlodipine benzenesulfonate may be prepared than that prepared according to the process disclosed in patent EP-B-0599220.

Preferred crystalline hydrate forms of amlodipine benzenesulfonate (monohydrate and dihydrate forms of amlodipine benzenesulfonate) are characterized by the following physico-chemical and spectroscopic parameters, presented comparatively with the analog data for the nonhydrate form of amlodipine benzenesulfonate:

1. Melting point

The microscope with a microhot stage »VEB Wagetechnik Rapido PHMK 79/2307« was used. Nonhydrate form of amlodipine benzenesulfonate: 201-202 °C Monohydrate form of amlodipine benzenesulfonate: 89-97 °C, preferably 92-95°C

Dihydrate form of amlodipine benzenesulfonate: 80-85°C, preferably 82-83°C

Water content

Karl-Fischer titration was carried out on an apparatus "METROHM 678 EP/KF Processor" and "METHROHM DOSIMAT 665", used balance »METTLER AE 200«

Monohydrate form of amlodipine benzenesulfonate: 2.9-3.3% (theoretically 3.08%)

Dihydrate form of amlodipine benzenesulfonate: 5.9-6.1% (theoretically 5.97%)

3. Dynamic scanning calorimetry (DSC)

A dynamic scanning calorimeter »PERKIN ELMER, DSC Pyris 1, USA« was used. The instrument was calibrated with the indium standard, using a reference pot as the reference. The mass (weight) of the measured sample was between 4 and 5 mg, and for between sample comparison the instrument recorded the results per mass unit among between the samples. The heating rate was 10°C/min, temperature interval from 0 to 250°C.

Dynamic scanning calorimetric graph of the crystalline monohydrate form of amlodipine benzenesulfonate, shown in Figure 2, and dynamic scanning calorimetric graph of the crystalline dihydrate form of amlodipine benzenesulfonate, shown in Figure 3, indicate a strong endothermic peak about the temperatures of melting points measures an a Kofler microscope. However, at the same time there occurs elimination of water and conversion into a nonhydrate form which is manifested in repeated crystallization and an exothermic negative peak in the baseline with a resumed strong exothermic peak at a melting point temperature of the nonhydrate form of amlodipine benzenesulfonate, as shown in comparative Figure 1 of the dynamic scanning calorimetric graphs of the nonhydrate, monohydrate and dihydrate forms of amlodipine benzenesulfonate. Because of that simultaneous occurrence of water loss the melting point temperature according to Kofler and the temperature of the endothermic peak may also essentially differ.

4. IR (infrared) spectroscopy

An infrared spectrometer »BIO-RAD FTS-60, Digilab-Division« was used. The spectra were recorded as the tablets, prepared with KBr (concentration 1 mg/100 to 150 mg)

IR (infrared) spectra of to date known nonhydrate form of amlodipine benzenesulfonate, shown in Figures 4 and 5, amlodipine benzenesulfonate monohydrate, shown in Figures 6 and 7 and amlodipine benzenesulfonate dihydrate, shown in 8 and 9, more or less mutually differ over the entire wave number scale, the most characteristic differences are within the following range (in cm^-1) :

Reflection infrared (ATR-IR) spectroscopy:

IR spectra were measured an a NICOLET NEXUS FTIR spectrometer and ATR module.

ATR-IR spectra of the nonhydrate form, monohydrate form and dihydrate form of amlodipine benzenesulfonate are within the range 1200-650 c -1 defined in Figure 10:

5. Raman spectroscopy

A Raman spectrometer »PE 2000 Raman spectrometer« was used.

Raman spectra were recorded within the range 150-4000 cm^"1 for the selected samples.

Raman spectra of the nonhydrate form of amlodipine benzenesulfonate, monohydrate form and dihydrate form of amlodipine benzenesulfonate are defined in Figure 11 (nonhydrate form) , Figure 12 (monohydrate form) and Figure 13 (dihydrate form) .

6. X-ray powder analysis

The samples were measured an a Siemens D-5000 diffractometer .

The selected samples were ground in an agate mortar. Diffractograms of the samples were measured using the reflection technique (CuKα radiation) within the range of 2 to 37° 2θ, step 0.036° 2θ, integration time 1 second, divergence slit V20, entrance slit 0.6 mm).

X-ray powder diffractograms of a nonhydrate form, monohydrate form and dihydrate form of amlodipine benzenesulfonate are shown in Figure 14 (dihydrate form) , Figure 15 (monohydrate form) and Figure 16 (nonhydrate form) .

The following column lists the characteristic diffraction angles of the crystalline amlodipine benzenesulfonate dihydrate as 2-theta with the accuracy of ± 0.06° 2θ. Only the medium (m) , strong (s) and very strong (vs) characteristic diffraction angles are presented.

2-theta intensities

4 . 83 vs

10 . 38 s

12 . 44 m

13 . 33 vs

14 . 49 m

15 . 52 vs

18 . 06 s

18 . 43 s

19 . 10 m 19.39 vs

20.75 vs

21.43 vs

22.29 s 22.73 s

23.25

23.62 m

24.20 s

24.66 vs 24.99 vs

25.39 m

26.33 m

26.89 vs

28.16 m 29.30 m

29.62 vs

30.69 m

31.08 s

31.43 32.57 m

32.81 s

33.74 s

34.27 m

34.80 m 35.57 s

The following column lists the characteristic diffraction angles of the crystalline amlodipine benzenesulfonate monohydrate as 2-theta with the accuracy of ± 0.06° 2θ. Only the medium (m) , strong (s) and very strong (vs) characteristic diffraction angles are presented. 2-theta intensities

4. 69 vs

9. 51 vs

11. 02 m

13. 77 vs

14. 08 vs

14. 90 m

16. 48 m

17. 09 m

17. 36 m

18. 52 s

19. 16 s

20. ,03 s

20. ,58 s

21. ,36 vs

21. .66 vs

22, .19 s

22. .96 vs

23. .55 s

23. .88 s

24. .44 m

24, .68 m

25, .52 s

26, .07 vs

26 .73 vs

28 .00 vs

28 .49 m

28 .95- m

29 .48 s

29 .71 s

30 .13 m

31 .03 s

32 .10 m

32 .37 s

33 .93 s

35 .46 m The invention is illustrated but in no way limited by the following examples:

PREPARATION OF THE STARTING SUBSTANCE

EXAMPLE 1

Amlodipine benzenesulfonate crude (impure)

To a suspension of 100 g (2.3 mole) 55 to 60% of sodium hydride in paraffin oil and 500 ml of anhydrous tetrahydrofuran was added a solution of 312 g (1.0 mole) of N-tritylaminoethanol in 850 ml of anhydrous tetrahydrofuran at a temperature of 20 - 30 °C. The reaction mixture was stirred at this temperature for 2 hours and then cooled to -5°C. To the cold mixture a solution of 171 g (1.0 mole) of ethyl 4-chloroacetoacetate in 180 ml of anhydrous tetrahydrofuran was added dropwise maintaining a temperature of the mixture between 0°C and 5°C. The mixture was stirred further for 5 hours at this temperature and 15 hours at a temperature at 15 - 20 °C. The reaction was interrupted by the addition of 100 ml of absolute ethanol and 200 ml of water, the mixture was then diluted by addition of 2800 ml of water and neutralized with HC1 to a pH value of 7. The organic phase was separated, diluted with 1000 ml of ethylacetate and washed twice with 750 ml of a brine (60 g of sodium chloride/liter of water) . The solvent was evaporated to a viscous oil.

The oil was diluted with 1250 ml of methanol, 100 g (0.85 mole) of methyl 3-aminocrotonate, 120 g (0.85 mole) of o- chlorobenzaldehyde were added and the reaction mixture was heated under reflux temperature for 15 hours, whereupon 160 g (1.0 mole) of benzenesulfonic acid in 200 ml of methanol was added to the mixture and the resulting mixture was heated at reflux temperature further for 2 hours. The mixture was cooled to a temperature below 0°C and the precipitate was filtered off. The filtrate was evaporated to a viscous oil. To the oil was added 500 ml of water and the mixture was continually washed with a toluene/heptane mixture. Water and the organic phase were removed and the residue was recrystallized twice from hot ethyl acetate (350 ml) .

This yielded 126 g of the crude amlodipine benzenesulfonate, melting point 192-198°C

The assay (determined by the HPLC "High Performance Liquid Chromatography" method ) :

The following abbreviations were used:

diethyl-2, 6-bis [2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1, 4- dihydro-6-methyl-3, 5-pyridinedicarboxylate (sim-AML) = 3.67%

dimethyl-2- [ (2-aminoethoxy) ethyl] -4- (2-chlorophenyl) -1, 4- dihydro-6-methyl-3, 5-pyridinedicarboxylate ( DMA) = 4.12%

PROCESS FOR PREPARATION OF HYDRATE FORMS OF AMLODIPINE BENEZENSULPHONATE ACCORDING TO THE INVENTION

EXAMPLE 2

Amlodipine benzenesulfonate dihydrate

Method A: Precipitation from water

1.0 g (1.76 mmole) of amlodipine benzenesulfonate was dissolved in 8 ml of methanol at room temperature. While stirring this solution was added dropwise to 50 ml of demineralized water. After the completion of the addition dropwise, stirring of the mixture was continued. A white precipitate was produced after several minutes. After further 15-minute stirring, the suspension was filtered by suction and the crystals were dried in a vacuum drier at 40 °C to the constant weight. This yielded 0.92 g of slightly oily product as amlodipine benzenesulfonate dihydrate, melting point 82 - 83°C and water content 5.97% (determined by Karl-Fischer method) .

EXAMPLE 3

Amlodipine benzenesulfonate dihydrate

Method B : Preparation of large crystals by solvent evaporation

1.0 g (1.76 irimole) of amlodipine benzenesulfonate was dissolved in 15 ml of methanol and an equivalent volume (15 ml) of demineralized water was added. The solution was placed in the ventilated fume hood at room temperature. On solvent evaporation colourless crystals of amlodipine benzenesulfonate dihydrate grew. After two days the crystals were separated from mother liquor by suction. The crystals were dried in a vacuum drier at 40 °C. for 3 hours. This yielded pure crystals of the amlodipine benzenesulfonate dihydrate as larger prismatic plates.

EXAMPLE 4

Amlodipine benzenesulfonate dihydrate

Variant of method A

1.0 g (1.76 mmole) of amlodipine benzenesulfonate was dissolved in 16 ml of methanol at room temperature and the mixture was cooled to -45°C. To the stirring solution 48 ml of demineralized water was added dropwise. After the completion of the addition dropwise, the mixture was stirred further for 15 minutes at -40 to -50°C, then the suspension was filtered by suction and the crystals were dried on the filter. This yielded 0.88 g of the slightly sticky product as amlodipine benzenesulfonate dihydrate, melting point 80 - 83°C and water content 6.28% (determined by Karl-Fischer method) .

EXAMPLE 5

Amlodipine benzenesulfonate monohydrate

Method A: Thermal recrystallization

1 g (1.76 mmole) of amlodipine benzenesulfonate was suspended in 10 ml of demineralized water at room temperature. The suspension was heated to the temperature just below a melting boiling. Amlodipine benzenesulfonate dissolved completely. The solution was cooled slowly to room temperature. On cooling a white precipitate was produced which was filtered by suction and dried in a vacuum drier at 40 °C to the constant weight. This yielded 0.85 g of fine crystals of the amlodipine benzenesulfonate monohydrate, melting point 90 - 96°C and water content 3.16% (determined by Karl-Fischer method) .

EXAMPLE 6

Amlodipine benzenesulfonate monohydrate

Method B: Precipitation from water

1.0 g (1.76 mmole) of amlodipine benzenesulfonate was dissolved in 5 ml of methanol by gentle heating (30 - 35 °C) , This gently heated solution was right away added dropwise to 50 ml of demineralized water. After the completion of the addition dropwise, stirring of the mixture was continued. After several minutes a white precipitate was produced. After further 15 minutes, the precipitate was separated from mother liquor by filtration. The crystals were dried in a vacuum drier at 40 °C to the constant weight. This yielded 0.52 g of fine crystals of the amlodipine benzenesulfonate monohydrate, melting point 92 - 95 °C and water content 3.15% (determined by Karl-Fischer method) .

EXAMPLE 7

Amlodipine benzenesulfonate monohydrate

Variant of method A

1 g (1.76 mmole) of amlodipine benzenesulfonate was suspended in a mixture of 16 ml of water and 6 ml of methanol at room temperature. The suspension was heated to 70 °C to dissolve amlodipine benzenesulfonate and cooled to 30 °C to produce the crystals, then the mixture was cooled to -10°C. The precipitate was filtered by suction and dried in a vacuum drier at 40 °C to the constant weight. This yielded 0.87 g of fine crystals of the amlodipine benzenesulfonate monohydrate, melting point 91 - 93 °C and water content 3.10% (determined by Karl-Fischer method) .

EXAMPLE 8

Nonhydrate form of amlodipine benzenesulfonate

4.1 g (6.80 mmole) of dihydrate form of amlodipine benzenesulfonate was dissolved in 20 ml of methanol at room temperature and the resulting solution was stirred for 15 minutes. The precipitate produced was filtered and dried in a vacuum drier at 40 °C. This yielded 1.52 g of amlodipine benzenesulfonate, melting point 200 - 201°C and water content 0.09 % (determined by Karl-Fischer method). EXAMPLE 9

Nonhydrate form of amlodipine benzenesulfonate

2.21 g (3.66 mmole) of amlodipine benzenesulfonate dihydrate was dissolved in 40 ml of ethanol at room temperature and stirred for 15 minutes. The precipitate produced was filtered and dried in a vacuum drier at 45°C. This yielded 1.03 g of amlodipine benzenesulfonate, melting point 198 - 200°C and water content 0.06% (determined by Karl-Fischer method).

EXAMPLE 10

Nonhydrate form of amlodipine benzenesulfonate

2.4 g (4.10 mmole) of amlodipine benzenesulfonate monohydrate was dissolved in 40 ml of ethanol and stirred for 10 minutes. The formed precipitate was filtered and dried in a vacuum drier at a temperature 40°C. This yielded 0.69 g of amlodipine benzenesulfonate, melting point 200-202 °C and water content 0.13% (determined by Karl-Fischer method).

PURIFICATION OF AMLODIPINE BENZENESULFONATE ACCORDING TO THE INVENTION

EXAMPLE 11

50 g (88 mmole) of the crude amlodipine benzenesulfonate, prepared as described in Example 1, was dissolved in 400 ml of methanol at room temperature to obtain a clear yellow solution which while stirring at 18 °C was added dropwise to

2.5 L of water. After the completion of the addition dropwise, the resulting mixture was stirred further for 30 minutes. Thereupon the precipitate was produced, filtered off and dried at 40°C. This yielded 34.88 g of the crystalline dihydrate form of amlodipine benzenesulfonate, the melting point 80 - 84 °C.

Assay (determined by HPLC method) :

Abbreviation "AmIBS" referred herein in the subsequent examples is meaning amlodipine benzenesulfonate

AmIBS: 98.18% sim AML: 0.18% DMA: 0.72%

EXAMPLE 12

7 g (12.3 mmole) of the crude amlodipine benzenesulfonate, prepared as described in Example 1, was suspended in 70 ml of water at room temperature. The suspension was heated to reflux temperature of the reaction mixture whereat the compound was dissolved and the resulting solution was cooled slowly to room temperature. A thick white precipitate was produced. The precipitate was filtered off and dried in a vacuum drier at 35 to 40 °C.

This yielded 5.8 g of the monohydrate form of amlodipine benzenesulfonate, melting point 88 - 94°C.

Assay (determined by HPLC method) :

AmIBS: 94.86% sim AML: 0.84% DMA: 0.81 %

EXAMPLE 13

Amlodipine benzenesulfonate 10 g (17.6 mmole) of the crude amlodipine benzenesulfonate, prepared as described in Example 1, was dissolved in 80 ml of methanol to obtain a clear yellow solution which while stirring at 18 °C was added dropwise to 500 ml of water. After the completion of the addition dropwise, the resulting mixture was stirred further for 30 minutes. The produced precipitate of amlodipine benzenesulfonate dihydrate was filtered off and dried at 40°C.

The resulting precipitate was added to 20 ml of methanol. The crystals were first dissolved, the yellow solution became turbid and the crystals were produced. The precipitate was filtered off and dried under vacuum at 35 °C.

This yielded 2.08 g of the white crystals of amlodipine benzenesulfonate of high purity, melting point 199 - 201°C.

Assay (determined by HPLC method) :

AmIBS: 99.22% sim AML: 0.0% DMA: 0.45%

EXAMPLE 14

Amlodipine benzenesulfonate

4.5 g (7.9 mmole) of the crude amlodipine benzenesulfonate, prepared according to Example 1, was dissolved in 36 ml of methanol to obtain a clear yellow solution which while stirring at 18 °C was added dropwise to 225 ml of water. After the completion of the addition dropwise, the mixture was stirred further for 30 minutes. Thereupon the produced precipitate of amlodipine benzenesulfonate dihydrate was filtered off and dried at 40°C. The produced precipitate of amlodipine benzenesulfonate dihydrate was suspended in 27 ml of methanol and heated to reflux temperature of the reaction mixture and then cooled. Thereupon the precipitate was produced which was filtered off and dried under vacuum at 50 °C.

This yielded 2.08 g of white crystals of the nonhydrate form of amlodipine benzenesulfonate of high purity, melting point 199 - 201°C.

Assay (determined by HPLC method) :

AmIBS: 99.34% sim AML: 0.04% DMA: 0.51 %

EXAMPLE 15

Amlodipine benzenesulfonate dihydrate of high purity (suitable for pharmaceutical forms)

2.0 g (33 mmole) of the intermediate amlodipine benzenesulfonate dihydrate, prepared according to Example 14, was dissolved in 16 ml of methanol to obtain a clear yellow solution which while stirring at 15°C was added dropwise to 100 ml of water. After the completion of the dropwise addition, the mixture was stirred further for 60 minutes. The precipitate was filtered off and dried under vacuum at 40 °C.

This yielded 1.45 g of the dihydrate form of amlodipine benzenesulfonate with the following assay (determined by HPLC method) :

AmIBS: 99.39% (calculated to nonhydrate form of amlodipine benzenesulfonate) sim AML: 0.0% DMA : 0 . 31%

The obtained compound was dissolved in 13 ml of methanol and added dropwise to 80 ml of cold water (5°C) . Thereupon the precipitate was produced which was filtered off and dried under vacuum at 40 °C.

This yielded 1.13 g of the dihydrate form of amlodipine benzenesulfonate of high purity, melting point 82 - 84 °C.

Assay (determined by HPLC method) :

AmIBS: 99.75% (calculated to nonhydrate form of amlodipine benzenesulfonate) sim AML: 0.0% DMA: 0.25%

EXAMPLE 16

Amlodipine benzenesulfonate monohydrate of high purity (suitable for pharmaceutical forms)

8.28 g (14.6 mmole) of amlodipine benzenesulfonate, prepared according to process described in Example 14 (assay 99.34% AmIBS, 0.04% sim AML, 0.51 DMA), was dissolved in 15 ml of hot methanol and cooled to 10 °C to afford precipitate formation which was then filtered off and dried under vacuum at 40°C.

This yielded 6.2 g of the nonhydrate form of (purified) amlodipine benzenesulfonate with the assay 99.59% AmIBS, 0.0% sim AML, 0.41 % DMA (determined by HPLC method).

The obtained amlodipine benzenesulfonate (nonhydrate form) was suspended in 62 ml of water and heated to reflux temperature of the reaction mixture and then cooled slowly to room temperature. Thereupon the precipitate was produced which was filtered off and dried under vacuum at 40 °C.

This yielded 5.63 g of the monohydrate form of amlodipine benzenesulfonate of high purity, with the following assay (determined by HPLC method) :

AmIBS: 99.73% sim AML: 0.0% DMA: 0.34%.

Claims

1. The crystalline amlodipine benzenesulfonate dihydrate.

2. The crystalline amlodipine benzenesulfonate dihydrate containing substantially no impurities.

3. The crystalline amlodipine benzenesulfonate dihydrate according to claim 1 or 2 which has a melting point between 80 and 85°C.

4. The crystalline amlodipine benzenesulfonate dihydrate according to claim 3, which has a melting point between 82 and 83°C.

5. The crystalline amlodipine benzenesulfonate dihydrate according to any of claims 1 to 4 which has a water content between 5.9% and 6.1%.

6. The crystalline amlodipine benzenesulfonate dihydrate according to any of claims 1 to 5 having the following characteristic diffraction angles:

2 theta intensities

4.83 vs

10.38 s 12.44 m 13.33 vs 14.49 m 15.52 vs 18.06 s 18.43 s 19.10

19.39 vs 20.75 vs

21 . 43 vs

22 . 29 s 22 . 73 s 23 . 25 m 23.62 m 24.20 s 24.66 vs 24.99 vs 25.39 m 26.33 m 26.89 vs 28.16 m

29.30 29.62 vs 30.69 m

31.08 s

31.43

32.57 m

32.81 s 33.74 s

34.27 m

34.80 m

35.57 s

7. The crystalline amlodipine benzenesulfonate dihydrate according to any of claims 1 to 6 having the following characteristic group of peaks in the IR spectrum: 1695, 1682, 1643 cm^-1.

8. A process for preparation of the crystalline amlodipine benzenesulfonate dihydrate, comprising the steps of stirring at a temperature of 20 °C or below the alcoholic solution of amlodipine benzenesulfonate with water and separating and isolating the crystals of amlodipine benzenesulfonate dihydrate.

9. The process for preparation of the crystalline amlodipine benzenesulfonate dihydrate according to claim 8, wherein lower alkanol of 1 to 5 carbon atoms is used as alcohol.

10. The process for preparation of the crystalline amlodipine benzenesulfonate dihydrate according to claim 8 or 9, wherein ethanol and methanol are used as alcohol.

11. The process for preparation of the crystalline amlodipine benzenesulfonate dihydrate according to any of claims 8 to

10, wherein methanol is used as alcohol.

12. The process for preparation of the crystalline amlodipine benzenesulfonate dihydrate according to any of claims 8 to 11 characterized by adding dropwise the alcoholic solution of amlodipine benzenesulfonate to water at a temperature between -50°C and +20°C.

13. The process for preparation of the crystalline amlodipine benzenesulfonate dihydrate according to any of claims 8 to 11 characterized by adding dropwise the alcoholic solution of amlodipine benzenesulfonate to water at a temperature between 0°C and +20°C.

14. The process for preparation of the crystalline amlodipine benzenesulfonate dihydrate according to any of claims 8 to 13, wherein from the solution of amlodipine benzenesulfonate in a mixture of alcohol and water as the solvent the crystals of pure amlodipine benzenesulfonate are produced by gradual evaporation of the solvent.

15. The process for preparation of the crystalline amlodipine benzenesulfonate dihydrate according to claim 14, wherein the solvent is a mixture of methanol and water in a ratio of from 20:80 to 80:20 vol/vol %.

16. A process for preparation of the crystalline amlodipine benzenesulfonate monohydrate comprising the steps of stirring at a temperature of 30 °C or above the alcoholic solution of amlodipine benzenesulfonate with water and separating and isolating the crystals of pure amlodipine benzenesulfonate monohydrate.

17. The process for preparation of t crystalline amlodipine benzenesulfonate monohydrate according to claim 16, wherein lower alkanol of 1 to 5 carbon atoms is used as alcohol.

18. The process for preparation of the pure crystalline amlodipine benzenesulfonate monohydrate according to claim 16 or 17, wherein ethanol or methanol is used as alcohol.

19. The process for preparation of the crystalline amlodipine benzenesulfonate monohydrate according to any of claims 16 to 18, wherein methanol is used as alcohol.

20. The process for preparation of the crystalline amlodipine benzenesulfonate monohydrate according to claims 16 to 19 characterized by adding dropwise the alcoholic solution of amlodipine benzenesulfonate to water at a temperature between +30°C and +50 °C.

21. The process for preparation of the crystalline amlodipine benzenesulfonate monohydrate according to any of claims 16 to

20. characterized in that the hot aqueous solution of amlodipine benzenesulfonate having a temperature between 70 and 100°C is cooled to a temperature below 40°C whereat the crystals of the pure crystalline amlodipine benzenesulfonate monohydrate are separated and isolated.

22. The process for purification of the nonhydrate form of amlodipine benzenesulfonate, wherein the crystalline amlodipine benzenesulfonate dihydrate is converted to the pure nonhydrate form of amlodipine benzenesulfonate.

23. The process for purification of the nonhydrate form of amlodipine benzenesulfonate, wherein the crystalline amlodipine benzenesulfonate monohydrate is converted to the pure nonhydrate form of amlodipine benzenesulfonate.

24. The process for purification of the nonhydrate form of amlodipine benzenesulfonate according to claim 22, wherein the crystalline amlodipine benzenesulfonate dihydrate is prepared according to any of claims 8 to 15 and then converted into the pure nonhydrate form of amlodipine benzenesulfonate .

25. The process for purification of the nonhydrate form of amlodipine benzenesulfonate according to claim 23, wherein the crystalline amlodipine benzenesulfonate monohydrate is prepared according to any of claims 16 to 21 and then converted into the pure nonhydrate form of amlodipine benzenesulfonate .

26. The process for purification of the nonhydrate form of amlodipine benzenesulfonate according to claim 24, wherein from the solution of the amlodipine benzenesulfonate dihydrate in lower alcohol of 1 to 5 carbon atoms while stirring the reaction mixture at a temperature between -20 and 30 °C the pure amlodipine benzenesulfonate is spontaneously separated, and then isolated.

27. The process according to claim 26 wherein methanol or ethanol is used as a lower alcohol.

28. The process according to claim 26 or 27 wherein methanol is used as a lower alcohol.

29. A pharmaceutical formulation comprising the crystalline amlodipine benzenesulfonate dihydrate admixed with a pharmaceutically acceptable diluent or carrier.

30. A tablet comprising the crystalline amlodipine benzenesulfonate dihydrate admixed with excipients.

31. A pharmaceutical formulation comprising the crystalline amlodipine benzenesulfonate monohydrate admixed with a pharmaceutically acceptable diluent or carrier.

32. The tablet comprising the crystalline amlodipine benzenesulfonate monohydrate admixed with excipients.

33. Use of the crystalline amlodipine benzenesulfonate dihydrate for the preparation of medicinal products for the treatment of cardiac diseases or hypertension.

34. Use of the crystalline amlodipine benzenesulfonate monohydrate for the preparation of medicinal products for the treatment of cardiac diseases or hypertension.