SI21233A - High purity crystalline hydrate forms of amlodipine benzensulphonate, methods of their preparation and usage - Google Patents

Abstract

Described are a new, high-purity crystalline amplodipine benzensulphonate dihydrate and a method of its preparation as well as of its monohydrate form, both suitable for preparation of pharmaceutical forms used in the therapy of heart diseases or hypertension and applicable as intermediary compounds in the improved method, set up in accordance with the EP 0599220 B patent, of purifying the non-hydrate benzensulphonate salt of amplodipine. The crystalline amplodipine benzensulphonate dehydrate is obtained through a process of mixing a C1-C5 alcoholic solution of amplodipine benzensulphonate with water at the temperature of 20 degrees Centigrade or lower, whereby crystals of pure amplodipine benzensulphonate dihydrate are extracted and can thereupon be isolated. Similarly, the crystalline amplodipine benzensulphonate monohydrate is obtained through a process of mixing a C1-C5 alcoholic solution of amplodipine benzensulphonate with water at the temperature of 30 Degrees Centigrade or higher, whereby crystals of pure amplodipine benzensulphonate monohydrate are extracted and can in turn be isolated.

Description

High-purity crystalline hydrate form of amlodipine benzenesulfonate, processes for their preparation and use

Field of the Invention (MPC C 07 D 211/90)

The present invention relates to the active substances and groups of heterocyclic compounds and the pharmaceutical industry and relates to a new crystalline dihydrate form of high-purity amlodipine benzenesulfonate, to a process for the preparation of a new crystalline dihydrate form to amlodipine benzenesulfonate, to a process for the preparation of crystalline monohydrate benzenesulfonate amlodipenate form amlodipenate form pure forms suitable for pharmaceutical use and the preparation of pharmaceutical forms, and for their use as intermediates in the improved purification process of the known and non-hydrated benzenesulfonate (besylate) salt of amlodipine.

Amlodipine benzenesulfonate is a selective vascular channel blocker of calcium and is a valuable anti-ischemic and antihypertensive agent.

-ci o

o amlodipine benzenesulfonate

A technical problem

There is a need for high-purity amlodipine benzenesulfonate and a new process for its preparation in order to obtain the desired substance in a readily practicable manner and in high yield and high purity.

The state of the art

Amlodipine is the INN name for 3-ethyl 5-methyl (+/-) - 2 - [(2-aminoethoxy) methyl] -4- (2-chlorophenyl) 1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, which has been described as a new substance in European patent EP 89167 as a valuable anti-ischemic and antihypertensive agent. The pharmaceutically acceptable acid addition salts of amlodipine, of which the maleate salt is particularly suitable, have also been described.

Amlodipine in free base form can be prepared by the methods described in said European patent EP 89167. According to these methods, amlodipine base is prepared in such a way that from the precursor of amlodipine, that is, the 1,4-dihydropyridine derivative having the amino group in position 2 protected with the selected protecting groups, these amino protecting groups are removed from the amino protected 1,4-dihydropyridine derivative. If the amino group is protected by a benzyl group, the protecting group is removed by catalytic hydrogenation with a palladium catalyst in a solvent such as methanol and at room temperature. In a particularly suitable process wherein the amino protecting group is a derivative

The 1,4-dihydropyridine phthaloyl protecting group removes this amino protecting group by metabolizing the amino protected 1,4-dihydropyridine derivative in an alkaline medium with a) a primary amine such as methylamine b) hydrazine hydrate or c) alkali metal hydroxide and the subsequent action of hydrochloric or sulfuric acid. The amlodipine base obtained is optionally metabolised to its pharmaceutically acceptable acid addition salt.

European Patent EP 89167 also discloses a process for the preparation of an amlodipine base from an amlodipine precursor with an azide group in position 2, which is reduced to an amlodipine base and then optionally converted to its pharmaceutically acceptable acid addition salt.

The disadvantage of these processes is that the yields of said amlodipine precursor, which are prepared by the well-known Hantzsch method of preparing asymmetric 1,4-dihydropyridine asymmetric diesters, are known in the literature. A process for the preparation of an amlodipine base in which a phthaloyl group is used to protect the amino group in the 1,4-dihydropyridine derivative, which is subsequently removed in an alkaline medium, requires the use of toxic substances which may not be present in the desired pharmaceutically acceptable acid addition salt of amlodipine. Methylamine and in particular hydrazine hydrate are toxic and carcinogenic compounds.

Amlodipine base may also be obtained by reduction of the 1,4-dihydropyridine azide derivative, but working with the azide compounds is disadvantageous due to the known explosiveness of the azide structures, especially the starting azidoethanol.

European Patent EP 244944 describes a new benzenesulfone (besylate) salt of amlodipine and the pharmaceutical forms containing it. Due to its good water solubility, high stability, non-hygroscopicity and good processing properties, this salt is extremely advantageous for the preparation of amlodipine pharmaceutical forms. According to the description of the patent, the benzenesulfonate salt of amlodipine is prepared by metabolizing the amlodipine base with benzenesulfonic acid or with ammonium benzenesulfonate in an inert solvent, such as industrial methylated ethanol. They state that only the maleate, tosylate and besylate salts of amlodipine do not bind any moisture upon exposure at 75% relative humidity at 37 ° C for 24 hours. Even at 95% relative humidity at 30 ° C, the amylodipine and malate salts of amlodipine remain in the non-hydrated form for 3 days, while the tosylate amlodipine salt forms the dihydrate salt. Therefore, the besylate salt of amlodipine is considered to be non-hygroscopic and allows the preparation of stable pharmaceutical formulations with reduced potential for internal chemical degradation.

European Patent EP 599220 describes a new process for the preparation of amlodipine benzenesulfonate, according to which a novel and not yet described precursor of amlodipine, which is chemically 3-ethyl 5-methyl (+/-) 2- [2- (N-tritylamino), is metabolised -ethoxymethyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate prepared by the Hantzsch method, with benzenesulfonic acid in methanolic or aqueous methanolic medium at a temperature of 20 ° C to reflux temperature, and then the benzenesulfonate salt of amlodipine is isolated and purified. The process is characterized by good overall yields of the desired compound, avoidance of treatment with certain toxic and carcinogenic chemicals, and avoidance of the preparation and isolation of the amlodipine base required in the processes described by European Patents EP 89167 and EP 244944. describes European patent EP 599220, amlodipine base is not produced at all in metabolism.

The crystalline form of amlodipine benzenesulfonate (bezilate) monohydrate is known and characterized from the dissertation of J. Rollinger, Doctoral Thesis Polymorphism and Binary Systems - with special regard to antihypertensive drug substances (1999), but the process of its preparation and use is not described.

Description of solution to a technical problem with implementation examples

The invention is based on the task of preparing a novel crystalline dihydrate form of high-purity amlodipine benzenesulfonate and a crystalline monohydrate form of high-purity amlodipine benzenesulfonate, which can be used to prepare the pharmaceutical forms as such instead of the known and non-commercially available commercial non-hydrate forms of amlodipine benzenesulfonate and amlodipine benzenesulfonate hydrates as intermediates in the purification of the non-hydrated form of amlodipine benzenesulfonate.

The invention further relates to pharmaceutical preparations, namely tablets, capsules and sterile aqueous solutions containing crystalline amlodipine benzenesulfonate monohydrate or crystalline amlodipine benzenesulfonate dihydrate, together with a pharmaceutically acceptable diluent or carrier. The tablets may contain crystalline amlodipine benzenesulfonate monohydrate or crystalline amlodipine benzenesulfonate dihydrate in combination with excipients. The preferred composition comprises crystalline monohydrate or crystalline dihydrate of amlodipine benzenesulfonate, in a composition with a compressing agent such as microcrystalline cellulose, an additive for achieving tablet gloss as anhydrous dibasic calcium phosphate, disintegrant as sodium starch glycolate and lubricant as magatars.

The invention also relates to the use of both crystalline hydrate forms of amlodipine benzenesulfonate in the treatment of heart disease, in particular angina, or hypertension.

Amlodipine benzenesulfonate in crude (impure) non-hydrated form is prepared according to the description in European patent EP-B-0599220 by first synthesizing 1,4-dihydropyridine asymmetric diesters by condensation of ethyl 4- [2- (Ntrylamino) ethoxy] with the Hantzsch method of acetoacetate, methyl (E) -3-amino crotonate and 2-chlorobenzaldehyde in methanol medium at reflux temperature of the reaction mixture was prepared 3-ethyl 5-methyl (+/-) 2- [N -tritylamino) -ethoxymethyl] -4- (2 -chlorophenyl) -1,4-dihydro-6-methyl-3,5pyridindicarboxylate, which, without isolation from the methanol reaction mixture, is reacted with benzenesulfonic acid (in 5 to 15% excess) in methanolic medium at a temperature between 20 ° C and temperature of the reaction mixture reflux.

According to the description of patent EP-B-0599220, the metabolically obtained crude (impure) amlodipine benzenesulfonate is isolated and purified, including stirring after completion of the metabolism, at a temperature lower than 0 ° C, preferably at a temperature of about -10 ° C.

Despite the carefully performed synthesis of the asymmetric dihydropyridine nucleus by Hantzsch in accordance with the procedure of patent EP-B-0599220, accompanying impurities are generated. One of the impurities resulting from the alternative condensation of the constituents present in said synthesis is diethyl 2,6-bis [(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl3,5 -pyridindicarboxylate (hereinafter referred to as sim-AML), which may be up to 5% in crude amlodipine benzenesulfonate. Recrystallization from a suitable lower alcohol, such as methanol, decreases the proportion of said impurity, but the recrystallization of crude amlodipine benzenesulfonate also significantly reduces the yield of the desired compound.

Another impurity present in amlodipine benzenesulfonate prepared according to the procedure of 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).

Surprisingly and unexpectedly, we have found that crude amlodipine benzenesulfonate prepared in accordance with the process of patent EP-B-0599220 can be significantly better purified by preparing an intermediate crystalline amlodipine benzenesulfonate monohydrate or a new intermediate crystalline amlodipine benzenesulfonate dihydrate, which can be is converted to the non-hydrated form of high-purity amlodipine benzenesulfonate without the need for further purification by recrystallization. Crystalline hydrate forms, i.e. amlodipine benzenesulfonate monohydrate and amlodipine benzenesulfonate dihydrate, are stable compounds of high purity and are therefore suitable for the preparation of pharmaceutical forms as such or as chemical intermediates for the preparation and / or purification of the known commercial non-hydrate form of amlodipine benzenesulfonate. In the present case, the desired non-hydrated form of amlodipine benzenesulfonate can be further purified by repeating the described metabolism twice.

In accordance with the process of the invention of the non-hydrated form of amlodipine benzenesulfonate, the above impurities of diethyl 2,6-bis [(2-aminoethoxy) methyl] -4 (2-chlorophenyl) -1,4-dihydro-6-methyl-3 are effectively removed , 5-pyridinedicarboxylate (approx. Sim-AML) and dimethyl 2 [(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridindicarboxylate (approx. DMA ) which are present as companion compounds in amlodipine benzenesulfonate prepared according to the procedure described in patent EP-B-0599220.

Contrary to the description of EP-B-0244944, it was surprisingly and unexpectedly found that amlodipine benzenesulfonate can be prepared in the form of a novel high purity crystalline dihydrate.

It was also an unexpected finding that the purification of amlodipine benzenesulfonate prepared according to the description of patent EP-B-0599220 could be significantly better by using crystalline amlodipine benzenesulfonate monohydrate or new crystalline amlodipine benzenesulfonate dihydrate as intermediates, which can then be converted into intermediates according to the process of the invention to high purity amlodipine benzenesulfonate. The amlodipine benzenesulfonate prepared and purified according to the invention contains less total impurities than the amlodipine benzenesulfonate prepared and purified by recrystallization from methanol according to the procedure described in EP-B-0599220.

The process of purifying the non-hydrate form of amlodipine benzenesulfonate using the intermediate crystalline hydrate forms of amlodipine benzenesulfonate (monohydrate and dihydrate form of amlodipine benzenesulfonate) may be carried out in such a way as to convert the hydrate form of amlodipine benzenesulfonate to non-hydratipenesulfonate such as methanol or ethanol, at a temperature of about room temperature or below, preferably between 0 and 30 ° C.

The process for preparing the crystalline monohydrate form of amlodipine benzenesulfonate is based on the excretion of amlodipine benzenesulfonate from aqueous or water-alcoholic media at temperatures above room temperature, preferably at temperatures higher than 30 ° C, more preferably between 30 and 50 ° C.

In this process, thermal crystallization from water or a mixture of alcoholide can be used, whereby the hot clear aqueous or aqueous-alcoholic solution of amlodipine benzenesulfonate is then slowly cooled.

Alternatively, precipitation of the monohydrate form of amlodipine benzenesulfonate is obtained by mixing an alcoholic solution of amlodipine benzenesulfonate with water at a temperature higher than 30 ° C, preferably by pouring or dripping an alcoholic solution of amlodipine benzenesulfonate into water or vice versa, by pouring alcohol or water amlodipine benzenesulfonate solution, preferably by dropwise adding an alcoholic solution of amlodipine benzenesulfonate to water while stirring.

The process of preparing a novel crystalline dihydrate form of amlodipine benzenesulfonate is based on the excretion of amlodipine benzenesulfonate from water-alcoholic media at temperatures below room temperature, preferably at temperatures below 20 ° C, preferably between - 50 and 20 ° C, more preferably between 0 and 20 ° C. .

The process is carried out by precipitation with the mixing of an alcoholic solution of amlodipine benzenesulfonate with water at temperatures below 20 ° C, preferably by pouring or dripping an alcoholic solution of amlodipine benzenesulfonate into water or by pouring or dripping water into an alcoholic solution of amlodipine benzenesulfonate, preferably by an alcohol solution with benzenesulfonate water while stirring.

Another embodiment of the preparation of a novel dihydrate form of amlodipine benzenesulfonate is derived from aqueous-alcoholic media by evaporation of the solvents used at a temperature lower than 20 ° C.

In the present invention, lower C1.5 straight or branched chain alcohol, preferably methanol and ethanol, more preferably methanol, can be used as alcohol.

For the preparation of both crystalline hydrate forms of amlodipine benzenesulfonate, either crude amlodipine benzenesulfonate or already purified as prepared according to the process description of EP-B-0599220 can be used.

The process of preparing both crystalline hydrate forms of amlodipine benzenesulfonate (monohydrate and dihydrate form of amlodipine benzenesulfonate) and the process of purifying the non-hydrate form of amlodipine benzenesulfonate with the aid of said crystalline hydrate forms of amlodipine benzenesulfonate as an intermediate with careful control of the precipitate crystals of the desired form of amlodipine benzenesulfonate are obtained, the processes of the invention being reproducible.

When the processes of the invention are carried out at temperatures between 20 and 30 ° C, the processes are unrepeatable or mixtures of the monohydrate and dihydrate of amlodipine benzenesulfonate are formed. Therefore, precipitating temperatures must be carefully controlled to avoid metabolism occurring in the temperature range between 20 and 30 ° C.

According to an object of the invention, the purification of crude amlodipine benzenesulfonate using crystalline amlodipine benzenesulfonate dihydrate as an intermediate is preferred over the use of crystalline amlodipine benzenesulfonate monohydrate as an intermediate.

Surprisingly and unexpectedly, we have found that crystalline amlodipine benzenesulfonate monohydrate and more crystalline amlodipine benzenesulfonate dihydrate are more soluble in lower Ci_5 alcohols than the non-hydrated form of amlodipine benzenesulfonate. Since the dissolution of crystalline hydrates of amlodipine benzenesulfonate in lower C _1-5 alcohols at room temperature, water becomes a minority component in the mixture, the excess solubility of the non-hydrated form of amlodipine benzenesulfonate is thereby eliminated and spontaneously eliminated. This phenomenon makes it possible to purify amlodipine benzenesulfonate in lower C _1-5 alcohols, preferably in methanol, without heating the reaction mixture, thereby preventing the formation of DMA impurities. In accordance with the process described in the invention, pure amlodipine benzenesulfonate can be prepared than can be prepared according to the method of patent EP-B-0599220.

Both crystalline hydrate forms of amlodipine benzenesulfonate (the monohydrate and dihydrate forms of amlodipine benzenesulfonate) are determined by the following physicochemical and spectroscopic parameters, given comparatively with analogous data for the non-hydrate form of amlodipine benzenesulfonate:

-1010

1. Melting point

We used a microscope with a "VEB VVagetechnik Rapido PHMK 79/2307" heating table non-hydrate 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: 85 ° C, preferably 82-83 ° C

2. Water content

Karl-Fischer titration was performed on a METROHM 678 EP / KF Processor and METHROHM DOSIMAT 665 weighing instrument "METTLER AE 200" monohydrate form of amlodipine benzenesulfonate used: 2.9-3.3% (theoretical 3.08%) dihydrate form of amlodipine benzenesulfonate : 5.9-6.1% (theoretical 5.97%)

3. Dynamic differential calorimetry (DSC)

We used a differential dynamic calorimeter "PERKIN ELMER, DSC Pyris 1, USA"

The instrument was calibrated with the indium standard and an empty crucible was taken as a reference. The weight of the sample measured was between 4 and 5 mg, and the instrument reported the results per unit mass for comparability between samples. The heating rate was 10 ° C / min and the temperature interval was 0 to 250 ° C.

The differential calorimetric graph of the crystalline monohydrate form of amlodipine benzenesulfonate, as illustrated in Figure 2, and the differential calorimetric graph of the crystalline dihydrate form of amlodipine benzenesulfonate, as illustrated in Figure 3,

-1111 strong endothermic peak around the melting point temperatures measured on a Kofler microscope. However, at the same time, water is released and converted to the non-hydrate form, which is reflected in the recrystallization and the exothermic pit at the base line and with a re-strong endothermic peak at the melting point of the non-hydrate form of amlodipine benzenesulfonate, as illustrated in comparative Figure 1 of differential calorimetric graphs, monohydrate and dihydrate forms of amlodipine benzenesulfonate. Due to this parallel phenomenon of water loss, the Kofler melting point and the endothermic peak temperature can also differ significantly.

4. IR (infra-red) spectroscopy:

We used an infrared spectrometer "BIO-RAD FTS-60, Digilab-Division"

The spectra were recorded as KBr prepared tablets (concentration 1 mg / 100-150 mg)

IR (infra-red) spectra of the hitherto known non-hydrated form of amlodipine benzenesulfonate, as illustrated in Figures 4 and 5, amlodipine benzenesulfonate monohydrate, as illustrated in Figures 6 and 7, and amlodipine benzenesulfonate dihydrate, when illustrated in Figures 8 and 9, differ more or less on the whole scale of the wavenumber, the most characteristic differences being in the following ranges (in cm ' ¹ ):

Area (cm ' ¹ ) non-hydrated form monohydrate form dihydrate form 1600-1700 1698 1688 1695 1675 1648 1682 1616 1606 1643 1604 1400-1340 1384 1390 1385 1366 1367 1347 1368 1320-1250 1303 1308 1314 1265 1288 1261 1287

-1212

Infrared (ATR-IR) spectroscopy:

The IR spectra were recorded with a NICOLET NEXUS FTIR spectrometer and a mount for recording ATR spectra.

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

5. Raman spectroscopy

We used Raman spectrometer "PE 2000 Raman spectrometer"

The Raman spectra in the range 150-4000 cm ' ¹ were recorded with the selected samples.

The Raman spectra of the nonhydrate form of amlodipine benzenesulfonate, the monohydrate form and the 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

Samples were taken on a Siemens D-5000 diffractometer

The selected samples were ground in an agate plate. The diffractograms of the samples were recorded using a reflection technique (CuKa radiation) in the range of 2 to 37 ° 2Θ, step 0.036 ° 2Θ, integration time 1 second, divergence gap V20, receiver slot 0.6 mm).

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

-1313

The following column gives the characteristic angles of crystalline amlodipine benzenesulfonate dihydrate as 2-theta with an accuracy of ± 0.06 ° 20. Only the medium strength (s) and the strong (m) and the very strong (grain) characteristic deviations are given.

theta intensities

4.83 grain 10.38 m 12.44 s 13.33 grain 14.49 s 15.52 grain 18.06 m 18.43 m 19.10 s 19.39 grain 20.75 grain 21.43 grain 22.29 m 22.73 m 23.25 s 23.62 s 24.20 m 24.66 grain 24.99 grain 25.39 s 26.33 s 26.89 grain 28.16 s 29.30 s 29.62 grain 30.69 s 31.08 m 31.43 s 32.57 s 32.81 m 33.74 m 34.27 s 34.80 s 35.57 m

The following column gives the characteristic displacement angles of crystalline amlodipine benzenesulfonate monohydrate as 2-theta with an accuracy of ± 0.06 ° 2Θ. Only medium strength (s) and strong (m) and very strong (grain) characteristic yields are given.

-1414

2 theta int 4.69 grain 9.51 grain 11.02 s 13.77 grain 14.08 grain 14.90 s 16.48 s 17.09 m 17.36 s 18.52 m 19.16 m 20.03 m 20.58 m 21.36 grain 21.66 grain 22.19 m 22.96 grain 23.55 m 23.88 m 24.44 s 24.68 s 25.52 m 26.07 grain 26.73 grain 28.00 grain 28.49 s 28.95 s 29.48 m 29.71 m 30.13 s 31.03 m 32.10 s 32.37 m 33.93 m 35.46 s

The invention is explained but is not limited by the following examples:

-1515

PREPARATION OF OUTPUT COMPOUND

EXAMPLE 1

Amlodipine benzenesulfonate crude (impure)

To a suspension of 100 g (2.3 mol) of 55 to 60% sodium hydride in paraffin oil in 500 ml of anhydrous tetrahydrofuran was added a solution of 312 g (1.0 mol) of Ntritylaminoethanol in 850 ml of anhydrous tetrahydrofuran at a temperature of 20-30 ° C. The reaction mixture was stirred at this temperature for 2 hours, then cooled to -5 ° C. A solution of 171 g (1.0 mol) of ethyl 4-chloroacetoacetate in 180 ml of anhydrous tetrahydrofuran was added dropwise to the cooled mixture, keeping the temperature of the mixture between 0 ° C and 5 ° C. The mixture was then stirred for 5 hours at this temperature and for another 15 hours at 15 to 20 ° C. The reaction was quenched by the addition of 100 ml of absolute ethanol and 200 ml of water, then the mixture was diluted with additional 2800 ml of water and neutralized with HCl to a pH of 7. The organic layer was separated, diluted with 1000 ml of ethyl acetate and washed twice with 750 ml of brine (60 g of sodium chloride per liter of water). The solvents were evaporated to a viscous oil.

Dilute the oil with 1250 ml of methanol, add 100 g (0.85 mol) of methyl 3aminocrotonate, 120 g (0.85 mol) of o-chlorobenzaldehyde, and heat the reaction mixture at reflux for 15 hours, then add 160 g (1.0) to the mixture. mol) of benzenesulfonic acid in 200 ml of methanol and the mixture was heated at reflux for 2 hours. The mixture was then cooled to below 0 ° C and the precipitate filtered off. Evaporate the filtrate to a viscous oil. 500 ml of water was added to the oil and the mixture was continuously washed with toluene / heptane. The residue was taken up in water and the organic phase and recrystallized twice from hot ethyl acetate (350 ml).

126 g of crude amlodipine benzenesulfonate are obtained with a melting point of 192-198 ° C

Content (determined by HPLC »High Performance Liquid Chromatography):

The following abbreviations are used:

-1616 diethyl-2,6-bis [2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate (approx. Sim-AML) = 3.67% dimethyl-2 - [(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate (approx. DMA) = 4.12%

PROCEDURE FOR PREPARING HYDRAULIC FORMS OF AMLODIPINE BENZENSULPHONATE IN THE DESCRIPTION OF THE INVENTION

EXAMPLE 2:

Amlodipine benzenesulfonate dihydrate

Method A: Conversion from water

1.0 g (1.76 mmol) of amlodipine benzenesulfonate were dissolved in 8 ml of methanol at room temperature. Then, with stirring, this solution was added to 50 ml of demineralized water. After the addition was complete, the mixture was further stirred. After a few minutes, a white precipitate began to fall out. After stirring for a further 15 minutes, the suspension was filtered off with suction and the crystals were dried with a vacuum oven to a constant mass at 40 ° C. 0.92 g of a slightly lubricated product were obtained as amlodipine benzenesulfonate dihydrate with a melting point of 82-83 ° C and a water content of 5.97% (determined by the Karl-Fischer method).

EXAMPLE 3:

Amlodipine benzenesulfonate dihydrate

Method B: Preparation of large crystals by solvent evaporation

1.0 g (1.76 mmol) of amlodipine benzenesulfonate were dissolved in 15 ml of methanol and the same amount (15 ml) of demineralized water was added. The solution was left in

-1717 digestion at room temperature. As solvent evaporated, colorless crystals of amlodipine benzenesulfonate dihydrate grew. The crystals were separated by suction from the mother liquor after two days. The crystals were dried in a vacuum oven at 40 ° C for 3 hours. Pure crystals of amlodipine benzenesulfonate dihydrate were obtained in the form of larger prismatic wafers.

EXAMPLE 4:

Amlodipine benzenesulfonate dihydrate

Variation of method A

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

EXAMPLE 5:

Amlodipine benzenesulfonate monohydrate

Method A: The thermal recrystallization of g (1.76 mmol) of amlodipine benzenesulfonate was suspended in 10 ml of demineralized water at room temperature. The suspension was heated to a temperature just below boiling point. Amlodipine benzenesulfonate dissolved completely. The solution was slowly cooled to room temperature. During cooling, a white precipitate precipitated, which was filtered off by suction and dried to constant weight in a vacuum oven at 40 ° C. 0.85 g of fine crystals of amlodipine monohydrate were obtained

-1818 benzenesulfonate with a melting point of 90-96 ° C and a water content of 3.16% (determined by Karl-Fischer method).

EXAMPLE 6:

Amlodipine benzenesulfonate monohydrate

Method B: A conversion from water of g (1.76 mmol) of amlodipine benzenesulfonate was dissolved in 5 ml of methanol by gentle heating (30-35 ° C). Immediately afterwards, this slightly warmed solution was added dropwise while stirring in 50 ml of demineralized water. After the addition was complete, the mixture was continued stirring. After a few minutes, a white precipitate began to secrete. After a further 15 minutes, the precipitate was separated from the mother liquor by filtration. The crystals were dried in a vacuum oven at 40 ° C to constant weight. 0.52 g of fine crystals of amlodipine benzenesulfonate monohydrate were obtained with a melting point of 92-95 ° C and a water content of 3.15% (determined by Karl-Fischer method).

EXAMPLE 7:

Amlodipine benzenesulfonate monohydrate

A variation of method A g (1.76 mmol) 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 allow amlodipine benzenesulfonate to dissolve, then cooled to 30 ° C to remove crystals, and then cooled to -10 ° C. The precipitate was filtered off by suction and dried to constant weight in a vacuum oven at 40 ° C. 0.87 g of fine crystals of amlodipine benzenesulfonate monohydrate with a melting point of 91-93 ° C and a water content of 3.10% (Karl-Fischer method) were obtained.

-1919

EXAMPLE 8

Non-hydrated form of amlodipine benzenesulfonate

4.1 g (6.80 mmol) of the dihydrate form of amlodipine benzenesulfonate were dissolved in 20 ml of methanol at room temperature and the solution was stirred for 15 min. The precipitate is filtered off and dried in a vacuum oven at 40 ° C. 1.52 g of amlodipine benzenesulfonate are obtained with a melting point of 200-201 ° C and a water content of 0.09% (determined by Karl-Fischer method).

EXAMPLE 9:

Non-hydrated form of amlodipine benzenesulfonate

2.21 g (3.66 mmol) of amlodipine benzenesulfonate dihydrate were dissolved in 40 ml of ethanol at room temperature and stirred for 15 min. The precipitated precipitate was filtered off and dried in a vacuum oven at 45 ° C. 1.03 g of amlodipine benzenesulfonate are obtained with a melting point of 198-200 ° C and a water content of 0.06% (determined by Karl-Fischer method).

EXAMPLE 10:

Non-hydrated form of amlodipine benzenesulfonate

2.4 g (4.10 mmol) of amlodipine benzenesulfonate monohydrate were dissolved in 40 ml of ethanol and stirred for 10 min. The precipitated precipitate was filtered off and dried in a vacuum oven at 40 ° C. 0.69 g of amlodipine benzenesulfonate is obtained with a melting point of 200 - 202 ° C and a water content of 0.13% (determined by the Karl-Fischer method).

-2020

CLEANING OF AMLODIPINE BENZENSULPHONATES WITHIN THE INVENTION

EXAMPLE 11:

g (88 mmol) of crude amlodipine benzenesulfonate prepared according to Example 1 was dissolved in 400 ml of methanol at room temperature to give a clear yellow solution which was added dropwise to 2.5 L of water while stirring at 18 ° C. After the addition was complete, the mixture was stirred for 30 minutes. This removes the precipitate, which is filtered off and dried at 40 ° C.

34.88 g of the crystalline dihydrate form of amlodipine benzenesulfonate are obtained with a melting point of 80-84 ° C.

Content (determined by HPLC method):

the abbreviation AmIBS as referred to in the following examples means amlodipine benzenesulfonate

AmIBS: 98.18% simAML: 0.18%

DMA: 0.72%

EXAMPLE 12:

g (12.3 mmol) of crude amlodipine benzenesulfonate prepared according to Example 1 was suspended in 70 ml of water at room temperature. The suspension is heated to the reflux temperature of the reaction mixture, whereby the compound is dissolved and then the solution is slowly cooled to room temperature. A thick white precipitate is eliminated. The precipitate was filtered off and dried in a vacuum oven at 35 to 40 ° C.

5.8 g of the monohydrate form of amlodipine benzenesulfonate are obtained with a melting point of 88-94 ° C.

-2121

Content (determined by HPLC method):

AmIBS: 94.86% sim AML: 0.84%

DMA: 0.81%

EXAMPLE 13:

Amlodipine benzenesulfonate g (17.6 mmol) of crude amlodipine benzenesulfonate prepared according to Example 1 was dissolved in 80 ml of methanol to give a clear yellow solution which was added dropwise to 500 ml of water while stirring at 18 ° C. After the addition was complete, the mixture was stirred for 30 minutes. The precipitated precipitate of amlodipine benzenesulfonate dihydrate was filtered off and dried at 40 ° C.

The precipitate was added to 20 ml of methanol. The crystals are first dissolved, the yellow solution is turbid and the crystals fall out. The precipitate was filtered off and dried in vacuo at 35 ° C.

2.08 g of white crystals of high-purity amlodipine benzenesulfonate are obtained, with a melting point of 199-201 ° C.

Content (determined by HPLC method):

AmIBS: 99.22% sim AML: 0.0%

DMA: 0.45%

-2222

EXAMPLE 14:

Amlodipine benzenesulfonate

4.5 g (7.9 mmol) of crude amlodipine benzenesulfonate prepared according to Example 1 were dissolved in 36 ml of methanol to give a clear yellow solution which was added dropwise to 225 ml of water while stirring at 18 ° C. After the addition was complete, the mixture was stirred for 30 minutes. The precipitated amlodipine benzenesulfonate dihydrate precipitate is filtered off and dried at 40 ° C.

The resulting precipitate of amlodipine benzenesulfonate dihydrate was suspended in 27 ml of methanol and heated to reflux temperature of the reaction mixture, which was then cooled. This removes the precipitate, which is filtered off and dried in vacuo at 50 ° C.

2.08 g of white crystals of the non-hydrate form of high-purity amlodipine benzenesulfonate are obtained, at a position of 199-201 ° C.

Content (determined by HPLC method):

AmIBS: 99.34% sim AML: 0.04%

DMA: 0.51%

EXAMPLE 15:

High-purity amlodipine benzenesulfonate dihydrate (suitable for pharmaceutical forms)

2.0 g (3.3 mmol) of intermediate amlodipine benzenesulfonate dihydrate prepared according to Example 14 were dissolved in 16 ml of methanol to give a clear yellow solution which was added dropwise to 100 ml of water while stirring at 15 ° C. When done

-2323 The mixture was stirred for an additional 60 minutes. The precipitate was filtered off and dried in vacuo at 40 ° C.

1.45 g of the dihydrate form of amlodipine benzenesulfonate are obtained with the following content (determined by the HPLC method):

AmIBS: 99.39% (converted to the non-hydrated form of amlodipine benzenesulfonate) sim AML: 0.0%

DMA: 0.31%

The resulting compound was dissolved in 13 ml of methanol and added dropwise to 80 ml of cold water (5 ° C). This removes the precipitate, which is filtered off and dried in vacuo at 40 ° C.

1.13 g of the high purity amlodipine benzenesulfonate dihydrate is obtained at a melting point of 82-84 ° C.

Content (determined by HPLC method):

AmIBS: 99.75% (converted to the non-hydrated form of amlodipine benzenesulfonate) sim AML: 0.0%

DMA: 0.25%

EXAMPLE 16:

High Purity Amlodipine Benzenesulfonate Monohydrate (Pharmaceutical Form Suitable)

8.28 g (14.6 mmol) of amlodipine benzenesulfonate prepared according to the procedure of Example 14 (99.34 AmIBS content, 0.04% sim AML, 0.51% DMA) was dissolved in 15 ml of boiling methanol and cool to 10 ° C to remove the precipitate, which is then filtered and dried in vacuo at 40 ° C.

-2424

6.2 g of the non-hydrated form (purified) of amlodipine benzenesulfonate are obtained with a content of 99.59% AmIBS, 0.0% sim AML, 0.41% DMA (determined by HPLC method).

The resulting amlodipine benzenesulfonate (non-hydrated form) was suspended in 62 ml of water and heated to reflux temperature of the reaction mixture, then slowly cooled to room temperature. This removes the precipitate, which is filtered off and dried in vacuo at 40 ° C.

5.63 g of the high purity amlodipine benzenesulfonate monohydrate form are obtained, having the following content (determined by the HPLC method):

AmIBS: 99.73% sim AML: 0.0%

DMA: 0.34%.

LEK, a pharmaceutical and chemical factory, d.d.

Claims (37)

PATENT APPLICATIONS 1. Crystalline amlodipine benzenesulfonate dihydrate. 2. Crystalline amlodipine benzenesulfonate dihydrate in pure form. 3. Crystalline amlodipine benzenesulfonate dihydrate having a melting point between 80 and 85 ° C. 4. Crystalline amlodipine benzenesulfonate dihydrate having a melting point between 82 and 83 ° C. 5. Crystalline amlodipine benzenesulfonate dihydrate having a water content between 5,9% and 5% 6.1%. 6. Crystalline amlodipine benzenesulfonate dihydrate, determined inter alia by the following characteristic angles: : theta intensity 4.83 grain 10.38 m 12.44 s 13.33 grain 14.49 s 15.52 grain 18.06 m 18.43 m 19.10 s 19.39 grain 20.75 grain 21.43 grain 22.29 m 22.73 m 23.25 s 23.62 s 24.20 m 24.66 grain 24.99 grain 25.39 s 26.33 s 26.89 grain -2626 28.16 s 29.30 s 29.62 grain 30.69 s 31.08 m 31.43 s 32.57 s 32.81 m 33.74 m 34.27 s 34.80 s 35.57 m. 7. Crystalline amlodipine benzenesulfonate dihydrate having inter alia the following characteristic group of peaks in the IR spectrum: 1695, 1682, 1643 cm ' ¹ A process for the preparation of crystalline amlodipine benzenesulfonate dihydrate, characterized in that crystals of amlodipine benzenesulfonate dihydrate are isolated from the alcoholic solution of amlodipine benzenesulfonate dihydrate by stirring at 20 ° C or lower. A process for the preparation of crystalline amlodipine benzenesulfonate dihydrate according to claim 8, wherein the lower alkanol of C 1 to C 5 carbon atoms is used as the alcohol. A process for the preparation of crystalline amlodipine benzenesulfonate dihydrate according to claims 8 and 9, using ethanol and methanol as alcohol. A process for the preparation of crystalline amlodipine benzenesulfonate dihydrate according to claims 8 to 10, using methanol as the alcohol. A process for the preparation of crystalline amlodipine benzenesulfonate dihydrate according to any one of claims 8 to 11, characterized in that an alcoholic solution of amlodipine benzenesulfonate is added to water at a temperature between -50 ° C and +20 ° C. -2727 A process for the preparation of crystalline amlodipine benzenesulfonate dihydrate according to any one of claims 8 to 11, characterized in that an alcoholic solution of amlodipine benzenesulfonate is added to water at a temperature between 0 ° C and +20 ° C. 14. A process for the preparation of crystalline amlodipine benzenesulfonate dihydrate, characterized in that crystals of pure amlodipine benzenesulfonate dihydrate are recovered from the solution of amlodipine benzenesulfonate dihydrate by a gradual evaporation of the solvent at a temperature below 20 ° C, followed by isolation of the crystalline solvent. . Process according to claim 14, characterized in that the lower alkanol having C-ι to C ₅ carbon atoms is used as the alcohol. Process for the preparation of crystalline amlodipine benzenesulfonate dihydrate according to claims 14 and 15, characterized in that the solvent is a mixture of methanol and water in a ratio of 20:80 to 80:20 vol / vol%. Process for the preparation of crystalline amlodipine benzenesulfonate monohydrate, characterized in that crystals of pure amlodipine benzenesulfonate monohydrate are recovered from the alcoholic solution of amlodipine benzenesulfonate with water, while stirring at a temperature of 30 ° C or more. 18. A process for the preparation of the crystalline amlodipine benzenesulfonate monohydrate according to claim 17, characterized in that it is used as alcohol lower alkanol with a C, to C, ₅ carbon atoms. Process for the preparation of pure crystalline amlodipine benzenesulfonate monohydrate according to claims 17 and 18, characterized in that ethanol or methanol is used as alcohol. -2828 A process for the preparation of crystalline amlodipine benzenesulfonate monohydrate according to claims 17 to 19, characterized in that methanol is used as the alcohol. Process for the preparation of pure crystalline amlodipine benzenesulfonate monohydrate according to claims 17 to 20, characterized in that an alcoholic solution of amlodipine benzenesulfonate is added to water at a temperature between 30 ° C and +50 ° C. 22. A process for the preparation of crystalline amlodipine benzenesulfonate monohydrate, characterized in that the hot aqueous solution of amlodipine benzenesulfonate is cooled to a temperature lower than 40 ° C at a temperature of less than 40 ° C, whereby crystals of pure crystalline amlodipine benzenesulfonate are recovered, we isolate them. Process for the preparation of amlodipine benzenesulfonate dihydrate, characterized in that it is prepared according to any one of claims 8 to 16. Process for the preparation of amlodipine benzenesulfonate monohydrate, characterized in that it is prepared according to any one of claims 17 to 22. 25. A process for the purification of the non-hydrated form of amlodipine benzenesulfonate, characterized in that the crystalline amlodipine benzenesulfonate dihydrate is converted to the pure non-hydrated form of amlodipine benzenesulfonate. 26. A process for the purification of the non-hydrated form of amlodipine benzenesulfonate, characterized in that the crystalline amlodipine benzenesulfonate monohydrate is converted to the pure non-hydrated form of amlodipine benzenesulfonate. 27. A process for the purification of the non-hydrated form of amlodipine benzenesulfonate, characterized in that the crystalline amlodipine benzenesulfonate dihydrate is prepared according to any one of claims 8 to 16 and subsequently converted to the pure non-hydrated form of amlodipine benzenesulfonate. -2929 28. A process for the purification of the non-hydrated form of amlodipine benzenesulfonate, characterized in that the crystalline amlodipine benzenesulfonate monohydrate is prepared according to any one of claims 17 to 22 and subsequently converted to the pure non-hydrated form of amlodipine benzenesulfonate. 29. The process for the purification of the nonhydrate form of amlodipine benzenesulfonate, characterized in that from the solution of amlodipine benzenesulfonate dihydrate in a lower alcohol with a C, to C ₅ carbon atoms at a temperature of between -20 and +30 ° C spontaneously while stirring the reaction mixture is stripped pure amlodipine benzenesulfonate, which we isolate. Process according to claim 29, characterized in that methanol or ethanol is used as the lower alcohol. A process according to claims 29 and 30, characterized in that methanol is used as the lower alcohol. 32. A pharmaceutical composition comprising crystalline amlodipine benzenesulfonate dihydrate in composition with a pharmaceutically acceptable diluent or carrier. 33. Tablet containing crystalline amlodipine benzenesulfonate dihydrate in combination with excipients. 34. A pharmaceutical composition comprising crystalline amlodipine benzenesulfonate monohydrate in composition with a pharmaceutically acceptable diluent or carrier. 35. Tablet containing crystalline amlodipine benzenesulfonate monohydrate in combination with excipients. 36. Use of crystalline amlodipine benzenesulfonate dihydrate for the preparation of a medicament for the treatment of heart disease or hypertension. -3030 37. Use of crystalline amlodipine benzenesulfonate monohydrate for the preparation of a medicament for the treatment of heart disease or hypertension.