LERCANIDIPINE HYDROBROMIDE, A PROCESS FOR ITS PREPARATION, CRYSTALLINE FORMS AND COMPOSITIONS THEREOF

DESCRIPTION

Field of the invention

This invention relates to a new salt of a calcium channel blocker. In particular, it relates to a new salt of lercanidipine, the hydrobromide, a process for its preparation, two crystalline forms and compositions thereof.

Background of the invention

Lercanidipine is an antagonist of L-type calcium channels, and has been found to be very active as an antihypertensive and as an agent for the treatment of angina and coronary disease. It is currently marketed as antihypertensive in the form of its hydrochloride salt, under different trademarks, including Zanidip ^™ .

The chemical name of lercanidipine is methyl 1 ,1 ,N-trimethyl-N-(3,3-diphenylpropyl)- 2-aminoethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) pyridine-3,5-dicarboxylate. It has the following formula I:

(D

Lercanidipine was disclosed in U. S. Patent No. 4705797. This patent discloses several asymmetric diesters of 1 ,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid and different processes for its preparation. In particular, example 16 discloses the preparation of lercanidipine by Hantzsch cyclisation and its isolation in the form of its hydrochloride hemihydrate with a melting point of 119-123 ⁰ C. In more recent publications it is said that the product obtained in U.S. Patent No. 4705797 was lercanidipine hydrochloride hemihydrate amorphous form. This product is described as hygroscopic, which can lead to an inconstant composition and difficulties in handling during the preparation of pharmaceutical formulations. Moreover, the stability of the lercanidipine hydrochloride hemihydrate is not entirely satisfactory.

European patent application EP 825862 discloses the preparation of (S)- enantiomers of 1 ,4-dihydropyridines, in particular lercanidipine, their use in the treatment of heart failure and their use in the manufacture of medicines for such treatment.

In Drugs of the Future, Vol. 12, No. 12, pages 1113-1116, 1987, the same process as U.S. Patent No. 4705797 was used, but the product was obtained in a different method to obtain crystalline lercanidipine hydrochloride, melting at 186 to 188 ⁰ C.

European patent application EP 824517 discloses a process for the preparation of lercanidipine in the anhydrous hydrochloride form. According to the Example 1 the melting point of the anhydrous form is 186-188 ⁰ C.

European patent application EP 1432683 describes that lercanidipine hydrochloride in an anhydrous non-hygroscopic crystalline form displayed batch-to-batch variability despite careful process control and even observation of the melting point believed to be characteristic of the solid product obtained by the process of Example 1 of EP 824517 of 186-188 ⁰ C. This variability was manifest in seemingly unpredictable appearing (and disappearing) differences in one or more of product appearance (e.g., colour), melting point and solubility, and also differences in bioavailability in animals, and differences in crystal size. This raised issues as to whether assurances of purity and/or reproducibility can be made (e.g., to regulatory authorities) whereby

the product is always the same. The inventors discovered novel lercanidipine hydrochloride polymorphs and the patent discloses two crude lercanidipine hydrochloride solids, Form A and Form B, comprising different ethyl acetate percentages, and a new lercanidipine hydrochloride crystalline Form (II) with a melting point of about 207-211 ⁰ C (determined as DSC peak).

European patent application EP 1423367 discloses two new crystalline lercanidipine hydrochlorides, Form (III) and Form (IV), with melting points of 137-15O ⁰ C and 116- 135 ⁰ C (thermomicroscopic analysis), respectively.

More recently, Recordati Ireland Ltd. has applied for a new international patent, WO 2006/021397, with the title "Lercanidipine salts". The patent states that there is a need for lercanidipine salts that have solubility and/or alternative physical properties other than and preferably more desirable than, the previously isolated forms of lercanidipine hydrochloride, including, but not limited to, reduced inter-patient variability, reduced food effect, and little or no polymorphism. In the first and independent claim, a lercanidipine salt is claimed and an acid counterion selected from the group consisting of: (i) inorganic acids, (ii) sulphonic acids, (iii) monocarboxylic acids, (iv) dicarboxylic acids, (v) tricarboxylic acids, and (vi) aromatic sulphonimides, provided that the acid counterion is not hydrochloric acid. In particular, amorphous L-lactate, cinnamate, salicylate, maleate, saccharinate, besylate and napadisylate, and crystalline besylate and napadisylate are claimed. The Examples describe the preparation of amorphous lercanidipine besylate (Example 1), crystalline lercanidipine besylate (Example 2), and crystalline (and amorphous) lercanidipine napadisylate (Example 3). Example 4 describes that a salt screening was performed using a number of counterions and a lercanidipine free base in order to determine which, if any, counterions were capable of producing lercanidipine salts. None of the counterions (acetate, cinnamate, fumarate, L-lactate, DL-lactate, L-malate, maleate, DL-mandelate, mesylate, sulphate and tosylate) was capable of producing crystalline lercanidipine, even after several attempts. The same applies for Example 5 where twelve additional counterions were assayed: citrate, mucate, gentisate, gluconate, 2-oxo-glutarate, phosphate, saccharinate, salicylate, L-tartrate, terephtalate, malonate and oxalate. None of the twelve

counterions was capable of producing crystalline lercanidipine salts, and few of them produced characterized amorphous salts. The choice of crystallization techniques was influenced by the known difficulty in obtaining crystalline lercanidipine salts. As a conclusion it is established that: "The present example, as well as experiments described in Example 4, demonstrates the difficulty and unpredictability of forming crystalline salts of lercanidipine". No indication was made to use bromide as a counterion.

Summary of the invention

The problem to be solved by the present invention is to provide lercanidipine in an advantageous crystalline form. The present inventors have studied the stability and the like of lercanidipine hydrochlorides, anhydrous and hemihydrate, and surprisingly they have succeeded in obtaining a new crystalline salt, the hydrobromide, that overcomes some disadvantages of other amorphous and crystalline lercanidipine salts of the state of the art.

Thus, a first aspect of the invention relates to a hydrobromide salt of lercanidipine.

In one embodiment of the invention, the hydrobromide salt of lercanidipine is a crystalline polymorph referred to herein as Form B, which is characterised by an X- ray powder diffraction pattern having significant peaks at about 9.5, 9.8, 10.8, 12.5, 16.0, 17.2, 19.9, 21.7, 23.6, 23.7, and 24.8 ± 0.2 degrees two-theta, substantially in accordance with Figure 9. It is further characterised by having an onset of melt at approximately 131 ⁰ C as measured by differential scanning calorimetry at 20°C/minute (see Figure 8). It is further characterised by an infra- red spectrum containing peaks at 3205, 3085, 2945, 2650, 1705, 1675, 1525, 1490, 1345, 1320, 1225, 1190, 1120, 1095, 1015, 700, 695 crrT ¹ (see Figure 7).

In another embodiment of the invention, the hydrobromide salt of lercanidipine is a crystalline polymorph referred to herein as Form A, which is characterised by an X- ray powder diffraction pattern having significant peaks at about 9.6, 11.1, 15.9, 16.1, 16.4, 19.3, 19.8, 21.1, 23.3, 25.2, 26.0, and 26.2 ± 0.2 degrees two-theta,

substantially in accordance with Figure 12. It is further characterised by having an onset of melt at approximately 207 ⁰ C as measured by differential scanning calorimetry at 20°C/minute (see Figure 11 ). It is further characterised by an infra red spectrum containing peaks at 3205, 3080, 2945, 2775, 1705, 1675, 1525, 1485, 1350, 1315, 1215, 1175, 1120, 1095, 1010, 705, 695 cm ¹ (see Figure 10).

A second aspect of the invention relates to a process for preparing lercanidipine hydrobromide salt which comprises contacting lercanidipine free base with hydrogen bromide in a suitable solvent, and isolating lercanidipine hydrobromide.

A third aspect of the invention relates to a process for preparing lercanidipine hydrobromide Form B, which comprises: a) dissolving lercanidipine base in an organic solvent and treating the solution with HBr; b) isolating a residue from the organic phase c) treating the residue obtained in b) with ethyl acetate, d) allowing to cool at room temperature and stirring for 3-4 hours.

A fourth aspect of the invention relates to a process for preparing lercanidipine hydrobromide Form A, which comprises: a) heating lercanidipine hydrobromide with ethyl acetate to reflux, and b) cooling the suspension at room temperature and stirring for 8 to 12 hours.

A fifth aspect of the invention relates to a pharmaceutical composition comprising lercanidipine hydrobromide salt, as an active ingredient.

A further aspect of the invention relates to the use of a hydrobromide salt of lercanidipine for the treatment of hypertension and for the treatment of angina and coronary disease.

Advantageously, the salt according to the first aspect of the invention has proved to be more stable in a stability assay in light conditions at high temperature (100 ⁰ C).

More advantageously, the salt according to the first aspect of the invention has proved to be more stable in an assay in the presence of humidity and at elevated temperature (i.e. 75 % humidity and 40 ⁰ C, 30 % humidity and 40 ⁰ C).

Brief description of the Figures

Figure 1 : IR spectrum of the lercanidipine hydrochloride hemihydrate Figure 2: DSC of the lercanidipine hydrochloride hemihydrate Figure 3: X-ray powder diffraction pattern for the lercanidipine hydrochloride hemihydrate

Figure 4: IR spectrum of the anhydrous lercanidipine hydrochloride

Figure 5: DSC of the anhydrous lercanidipine hydrochloride

Figure 6: X-ray powder diffraction pattern for the anhydrous lercanidipine hydrochloride Figure 7: IR spectrum of the lercanidipine hydrobromide Form B Figure 8: DSC of the lercanidipine hydrobromide Form B Figure 9: X-ray powder diffraction pattern for the lercanidipine hydrobromide

Form B

Figure 10: IR spectrum of the lercanidipine hydrobromide Form A Figure 11 : DSC of the lercanidipine hydrobromide Form A

Figure 12: X-ray powder diffraction pattern for the lercanidipine hydrobromide

Form A

Detailed description of the invention

The inventors have studied the stability and the like of lercanidipine hydrochloride, anhydrous and hemihydrate forms, and have succeeded in obtaining a new salt, lercanidipine hydrobromide that has remarkably better storage stability and ease of handling than the hydrochloride forms of the state of the art.

The lercanidipine hydrobromide can be obtained in two different crystalline forms, referred to herein as Form A and Form B. Form A is the name for the one that has the higher melting point (capillary tube), at 200-202 ⁰ C. The melting point of Form B is 138-140 ⁰ C.

These two different crystalline Forms A and B of the lercanidipine hydrobromide can be produced depending upon the crystallization conditions used. These different crystalline forms have different three-dimensional structures and have different physicochemical properties.

The present invention encompasses individual crystalline forms of the lercanidipine hydrobromide and mixtures thereof, and the process to obtain it.

When the crystalline forms A and B of the lercanidipine hydrobromide are allowed to stand so that they are open to the atmosphere or are mixed with water or a solvent, they may absorb water or a solvent to form a hydrate or a solvate. The present invention also encompasses these hydrates and solvates.

The lercanidipine hydrobromide can be prepared from the lercanidipine base. The lercanidipine base can be prepared according to a similar procedure to those described in the U.S. Patent No. 4705797.

The lercanidipine hydrobromide salt may be prepared in a variety of different conditions. According to the invention it may be obtained by contacting lercanidipine free base with hydrogen bromide in a suitable solvent, and isolating lercanidipine hydrobromide. Hydrogen bromide used in the salt-formation process may be an aqueous solution or in gaseous form. Aqueous solution of hydrogen bromide is commercially available. Gaseous hydrogen bromide may be obtained commercially, or prepared by methods known in the art. Preferably, the suitable solvent is one in which lercanidipine may be completely dissolved. Thus, preferably the solvent used is an organic solvent and it is preferably selected from the group consisting of chlorinated hydrocarbons, carboxylic acid esters, alcohols or mixtures thereof that additionally may contain water. More preferably the solvent used is methylene chloride. Hydrogen bromide is preferably used in aqueous solution and it is preferably added to the solution when lercanidipine has already been dissolved. The contacting time may vary depending on the solvent and the temperature used; it may range from 10 minutes to 24 hours. In a preferred embodiment the contacting

process is carried out at a temperature ranging from room temperature to the reflux temperature of the solvent used. More preferably, it is carried out at room temperature.

The hydrobromide salt of lercanidipine may be obtained directly from the process described in the preceding paragraph. However, in a preferred embodiment, particularly when aqueous hydrogen bromide is used, the step of contacting the free base and the hydrogen bromide is followed by isolation of a residue from the organic phase and treatment with a second inert solvent. Thus, preferably, the organic phase is separated, optionally washed, and the solvent is eliminated (e.g. by evaporation). The resulting residue is treated with a second inert organic solvent to render the desired hydrobromide salt. Generally, the treatment comprises heating and stirring. The crystals may be obtained by different precipitation methods. Said second inert organic solvent may be selected from the group consisting of aliphatic alcohols and aliphatic carboxylic acid esters. Preferably, it is selected from C ₃ -C ₆ aliphatic carboxylic acid esters. Yet more preferably, said second organic solvent is ethyl acetate.

When the residue is treated with the second solvent in ethyl acetate, Form B or Form A is obtained depending on the stirring time and temperature. Form A needs a higher temperature and more time, and its melting point is higher, which is an indication that it is the more thermodynamically stable form.

The Form B hydrobromide salt may be obtained by different processes. A preferred process for preparing Form B is by treating the aforementioned residue with ethyl acetate. The treatment preferably involves dissolving the residue and heating it at a temperature selected from the range of room temperature to reflux, preferably at 50 ⁰ C. The aim of this heating is also to eliminate traces of other volatile solvents other than ethyl acetate. The solution is preferably maintained at this temperature a little longer, until a suspension is formed, preferably one hour. Afterwards, the suspension is allowed to cool at room temperature for some hours, preferably from 3 to 4 hours. Then it is stirred for 2 to 3 hours at room temperature, to render the crystalline Form B.

The Form A hydrobromide salt may be obtained from the aforementioned residue or from a different solid form of hydrobromide salt of lercanidipine, e.g. from Form B. A preferred process for preparing Form A is from Form B. A hydrobromide salt of lercanidipine is treated with ethyl acetate. Preferably, the treatment comprises heating at the reflux temperature for 6 to 10 hours, more preferably from 7 to 8 hours. The suspension is then allowed to cool to room temperature (i.e. 20 ⁰ C to 25 ⁰ C) and then it is stirred for 8 to 12 hours to yield crystalline Form A.

Precipitated crystals can be collected by filtration, centrifugation or decantation methods. Isolated crystals may be washed with an appropriate solvent. The washing solvent can include, for example, an alcohol such as ethanol or isopropanol; a ketone such as acetone; an ester such as methyl acetate or ethyl acetate; an aromatic hydrocarbon such as toluene, xylene; a nitrile such as acetonitrile; an ether such as tetrahydrofuran, or a mixture thereof, with or without water. Preferably ethyl acetate which may contain water is used.

Isolated crystals can be dried between 10 and 100 ⁰ C, preferably between 30 and 50 ⁰ C until the weight of said crystals becomes constant, if necessary, in the presence of a drying agent such as silica gel or calcium chloride and under reduced pressure.

Crystals thus obtained can be further purified by recrystallization or slurry- purification.

These crystalline forms exhibit an excellent pharmacokinetic profile such as oral absorption and the like and are, therefore, practically useful medicines

When the crystalline forms of lercanidipine hydrobromide of the present invention are used as a solid medicine , preferably as an antihypertensive and as an agent for the treatment of angina and coronary disease, said crystalline forms can be administered alone or as a mixture of said crystalline form with an appropriate pharmacologically acceptable carrier. Compositions according to the present

invention can be in unit dosage form such as tablets, capsules, granules, powders, suspensions, troches or the like for oral or parenteral administration.

In one embodiment, the pharmaceutical compositions comprise at least one of the crystalline forms Form A or Form B.

The pharmaceutical compositions can be prepared in a known manner by using additives such as excipients, binding agents, disintegrating agents, lubricating agents, stabilizing agents, corrigents, suspending agents and diluents.

The selection of the most suitable carrier will depend on the administration route. Carriers can be solid, semisolid or liquid diluents as well as capsules and may optionally provide modified release of the active drug. For example, a preparation to be administered orally in the form of tablets can include, in addition to the active ingredient, solubilizers (e.g. a polyethoxylated fatty acid), components which modify the drug release (e.g. hydroxypropylmethyl cellulose), fillers (e.g. lactose), binders (e.g. hydroxypropylmethyl cellulose) and/or lubricants (e.g. sodium stearylfumarate).The tablets can be coated with suspensions of colouring pigments (e.g. iron oxide) and film forming agents (e.g. cellulose derivatives). A preparation to be administered parenterally may be an aqueous solution of the active ingredient, possibly including a co-solvent such as polyethylene glycol.

The daily dose of the active ingredient depends on individual needs (e.g. the patient's condition, body weight, age, gender etc.) as well as on the administration route. Generally, the oral dosage may range from 0.1 to 100 mg.

The hydrobromide salts of lercanidipine are useful as an antihypertensive and as an agent for the treatment of angina and coronary disease.

Best mode for carrying out the invention

The present invention is further described by the following Examples and Test Examples.

EXAMPLES

Example 1 : Lercanidipine hydrobromide Form B

Lercanidipine base (141.3 g, 0.231 mol) is dissolved in methylene chloride (425 ml). The solution is treated with 22% aqueous HBr (193 g, 0.255 mol), and stirred for 15 minutes. It is ascertained that the pH is acid and the lower organic phase is decanted, which is then washed with 3 % aqueous HBr (150 g). The organic phase is evaporated to dryness to give the oily pure compound. Ethyl acetate (600 ml) is added to the residue. The solution obtained is heated to 50 ⁰ C in order to evaporate the remaining methylene ^{^} chloride. It is kept at 50 ⁰ C for 1 hour to induce precipitation and the suspension is allowed to cool for 3-4 hours at room temperature. It is stirred for 2-3 hours at 20 - 25 ⁰ C and filtered and well drained. The solid is washed with ethyl acetate (3 x 50 ml) and dried by heating under vacuum at 40 ⁰ C to obtain title product , quantitatively, 160.0 g.

Example 2: Lercanidipine hydrobromide Form A

Lercanidipine hydrobromide Form B (55 g) is suspended in ethyl acetate (220 ml). It is heated at gentle reflux and kept at reflux for 7-8 hours. The suspension is cooled to 20-25 ⁰ C and stirred overnight. It is filtered and well drained and washed with ethyl acetate (2 x 25 ml). It is dried in an oven at 50 ⁰ C with air flow to render the title product , nearly quantitatively, 54.6 g.

Phvsicochemical characterization

Below, a comparison of the physicochemical properties of the crystalline hydrobromide salts of lercanidipine Form A and Form B of the invention, and two of the known hydrochloride salts of lercanidipine is provided.

a) Melting points

Melting points were measured with an SMP3 Stuart Scientific (Bibby) equipment.

b) IR spectra

Infrared spectra were recorded on a Perkin Elmer, FT Paragon 1000 IR instrument and the sample preparation was done on a potassium bromide disk. Results are reported in Table 1 , expressed in cm-1 values.

Table 1

C) DSC

All DSC thermograms mentioned in this invention were recorded on a Mettler Toledo DSC 822e instrument, at a uniform heating rate of 20°C/min. The temperatures indicated correspond to the onset of the endotherma associated with the melt (see table 2).

An expert in the art will however note that in DSC measurements there is a certain degree of variability in actual measured onset and peak temperatures which is dependant on the rate of heating, crystal shape and purity, and a number of measurement parameters.

Table 2

d) X-ray powder diffraction pattern

All X-ray diffraction patterns mentioned in this application were recorded on an automatic Philips X ^' Pert instrument equipped with a Cu tube and a secondary monochromator made of graphite.

Table 3. X-ray data of Form B

Table 4. X-ray data of Form A

Test Example 1

Objective

Compare the thermal stability of the different crystalline forms of lercanidipine hydrochloride and hydrobromide in light conditions, at 100 ⁰ C.

Methodology

Samples, of 1 ,00 g in all cases, were placed in encapsulated head space vials, 75,5 x 23 mm , submerged in a thermostatized silicon bath at 100±1°C.

The assay was carried out with simultaneous irradiation using two lamps ,

- Lamp A: Vilber Lourmat, model VL-4.L (4 w - 365 nm Tube)

- Lamp B: Ledu 271-2, cool light lamp and the samples were checked after 24 h and 48 h of treatment by HPLC analysis. The results are reported in Table 5, expressed in % area HPLC.

Table 5

Conclusions

The results show the different stabilities in light and high temperature conditions. The hydrochloride salts of lercanidipine are more unstable than the hydrobromide salts. The hydrochloride hemihydrate is significantly more unstable than the anhydrous hydrochloride. The hydrobromide Form A remains unaltered after 48 hours of treatment.

Test Example 2: Stability assay in humidity and high temperature conditions Objective

Compare the stabilities in humidity and high temperature conditions for the different crystalline forms of lercanidipine hydrochloride and hydrobromide salts.

Methodology

The different crystalline forms of lercanidipine hydrochloride and hydrobromide salts were subjected to controlled conditions of humidity and temperature. Samples of 1 ,0 g of each of the products were placed in flasks and suitably protected to avoid contamination of the samples. The samples so prepared were subjected to controlled conditions of humidity and temperature (i.e. 75 % humidity and 40 ⁰ C, 30 % humidity and 40 ⁰ C), for two weeks. The samples were checked for hygroscopicity, determining water content by the Karl Fisher (KF) method after one week and after two weeks of treatment. The equipment used was as follows:

Climatic chamber at 75% controlled humidity and a temperature of 40 ⁰ C. Reference: THI-SE.1. Model Binder.

Flow air oven P-Selecta at a temperature of 40 ⁰ C, using CaCI ₂ .6H ₂ O to control humidity and a closed glass vessel. This salt in high saturation conditions provides a humidity of approximately 30 %.

The results are reported in Table 6 below.

Table 6

Conclusions

The results obtained show that the lercanidipine hydrobromide salts are more stable than the hydrochloride salts. Furthermore, the hydrochloride hemihydrate is significantly more hygroscopic than the anhydrous form, while hydrobromide Form A remains significantly unaltered, even after two weeks under 75 % humidity.