ES2332168B1 - PSEUDOPOLIMORFICA FORM OF NICARDIPINE HYDROCLORIDE, PROCEDURE FOR PREPARATION AND FORMULATION CONTAINING IT. - Google Patents

Abstract

Pseudopollmorphic form of hydrochloride nicardipine, procedure for its preparation and formulation that the contains

The present invention relates to a new pseudopolymorphic form of nicardipine hydrochloride, which in later it will be called Dh Form, characterized by the diffractogram X-ray powder shown in Table 1 and Figure 1, at a procedure for its preparation, to the procedure for Obtaining a nicardipine hydrochloride solvate, useful for the preparation of the new pseudopolymorphic form, and to the use of this Form Dh as a medicine and in the preparation of rapid-release pharmaceutical formulations of emergency.

Description

Pseudopolymorphic form of hydrochloride of nicardipine, procedure for its preparation and formulation that the  contains

Field of the Invention

The present invention relates to a new pseudopolymorphic form of nicardipine hydrochloride. In In particular, the invention relates to the hydrochloride form of hydrated nicardipine, referred to hereinafter Form Dh.

The present invention also relates to a procedure for the preparation of said new Form Dh, at procedure for obtaining a hydrochloride solvate of nicardipine, useful for the preparation of said new form pseudopolymorphic, and to the use of this Dh Form as medicine.

The new pseudopolymorphic form Dh of Nicardipine hydrochloride is useful for the preparation of Emergency rapid release pharmaceutical formulations for the treatment of vascular diseases, such as crises hypertensive

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Background of the invention

Nicardipine hydrochloride is an organic salt derived from a 1,4-dihydropyridine whose chemical nomenclature according to IUPAC is: (±) -2- (Benzylmethylamino) ethyl methyl 1,4-dihydro-2,6-dimethyl- hydrochloride 4- (m-nitrophenyl) pyridino-3,5-dicarboxylate [ Merk Index, Ed.12, page 6580 ]. It is a molecule with two chiral centers, marked 1 and 2 in the chemical formula of nicardipine hydrochloride, which is included below.

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Nicardipine hydrochloride was first synthesized in Japanese laboratories Yamanouchi Pharma Co. Ltd. [ M. Murakami et al. Belg. Patent 811324 ; 1974 ; idem US pat. 3985758 ; 1976 ; Iwanami et al., Chem. Pharm. Bull . 1979 , 27, 1426 ] in the form of a racemic mixture where therapeutic properties were identified as vasodilator agent. From then until now, applications have been found for the treatment of various disorders and diseases such as those referred to below:

- Treatment of hypertension, hypertensive crisis, stable angina pectoris, ischemia (cell death) due to cerebral infarction [ US2007249689-A1; WO2007121483-A2; LE Muñoz Almeda et al. Rev. Esp. Anesthesiol. Reanim ; 2001 , 48, 71; J. Varon et al. Chest , 2000 , 118, 221 ].

- Delays the onset of cognitive impairment in vascular dementia and Alzheimer's [S. López, Randomized , double-blind, placebo-controlled experimental clinical trial of the effect of nicardipine on cognitive function in patients with vascular dementia , II National Alzheimer's Conference, November 1999, Bilbao; Spain].

- The oral formulation of hydrochloride joint nicardipine with anticancer drugs and anti-neoplastic increases bioavailability (amount in blood) of these [WO9715269-A; ES2109899-T3].

During the synthesis stages of nicardipine hydrochloride it was possible to isolate said drug in two crystalline forms, which were called alpha (?) And beta (?) Phases, whose melting points are 189-190 and 169-170 ° C, respectively . Subsequently, the phases were characterized by infrared techniques, X-ray powder, and the solubilization kinetics at PH = 7 in distilled water of each phase were studied. The solubilization kinetics studies showed that the β phase is solubilized slightly faster than the α phase. However, after 30 min. the saturation concentration in water is 0.96 mg / L for the α phase and 0.98 mg / L
for the β phase, these two concentrations being practically identical [J. Yan, P. Giundechi; Boll Chim. Pharm 1990, 129, 276 ]. The β phase, due to its lower melting point (169 ° C) and its slightly higher dissolution rate, is metastable with respect to the α phase. Its higher dissolution rate makes this β-phase the most commercially available as solid racemate powder.

On the other hand, both crystalline forms are sensitive to light, the β phase presenting a degradation kinetics due to the incidence of light faster than the a phase and the grinding of both causes their amorphization [R. Teraoka, M. Otsuka, Y. Matsuda, Int. J. Pharm . 2004, 286, 1].

There are to date formulations containing nicardipine hydrochloride suitable for oral, transdermal and intravenous administration. Nicardipine hydrochloride, administered orally, in the β crystalline form, and in the racemic form (nicardipine hydrochloride is marketed and administered as a racemic mixture), has a bioavailability of between 10-40%, being only active the enantiomer (S), in doses of 20 or 30 mg of the drug. The rest is degraded by the liver before it can exert its therapeutic action by the so-called first-pass metabolism [the drug is metabolized (chemical degradation reactions) with great efficiency by the liver from the portal circulation (portal vein), what which implies the need to administer much higher doses when administered orally with respect to any other route]. In addition, by presenting very high permeability to body tissues, rapid increases in drug concentration occur in short periods of time in the bloodstream, which produces side effects.

For emergency quick releases, the Nicardipine hydrochloride is formulated to be administered from immediately dissolved intravenously. They describe stable formulations for one year, already prepared in containers protected from light that do not require dilution to be administered in case of medical emergency [WO2007123984].

However, these oral emergency quick-release formulations have low bioavailability due to the so-called first-pass metabolism , which implies the need to administer much higher doses when administered orally with respect to any other route.

Description of the invention

The present invention provides a new pseudopolymorphic form of the hydrochloride of (±) -2- (benzylmethyl-
mino) ethyl methyl 1,4-dihydro-2,6-dimethyl-4- (m-nitrophenyl) pyridino-3,5-dicarboxylate (nicardipine hydrochloride), which has improved solubility and kinetics of solubilization with respect to polymorphic forms α and β known in the state of the art, with a modified pharmacokinetics with respect to both α and β polymorphic forms, and with a higher bioavailability with respect to the known α and β polymorphic forms.

Therefore, the first aspect of the present invention is to provide the pseudopolymorphic form of hydrated nicardipine di D hydrochloride, referred to herein as Forward Form (pseudopolymorphic) Dh.

A second aspect of the invention is provide a procedure for the preparation of said Form pseudopolymorphic Dh from a hydrochloride solvate of Nicardipine

A third aspect of the invention is provide a procedure for obtaining said solvate from Nicardipine hydrochloride, useful for the preparation of the Form pseudopolymorphic Dh.

A fourth aspect of the invention is provide an alternative procedure for obtaining said nicardipine hydrochloride solvate, useful for Preparation of the pseudopolymorphic form Dh.

A fifth aspect of the invention is the Form pseudopolymorphic Dh as medicine.

A sixth aspect of the invention is the use of said pseudopolymorphic form Dh for the preparation of a medicine for the treatment of diseases vascular

A seventh aspect of the invention is a pharmaceutical formulation comprising said Form pseudopolymorphic Dh together with pharmaceutically excipients acceptable.

Advantageously, said pharmaceutical formulation it has bioavailability superior to that of polymorphic forms α and β and, therefore, lower doses are necessary of the drug.

Description of the figures

Figure 1.1 shows the ray diffractogram X of the Dh Form of nicardipine hydrochloride (vertical axis: height (beads); horizontal axis: angle º2 \ theta).

Comparative Figure 1.2 shows the X-ray diffractogram of Form Dh compared to that of Forms α and β.

Figure 2.1 shows the infrared spectrum (IR) of Form Dh of nicardipine hydrochloride and of Forms α and β in the range of wave numbers 400-4,000 cm -1.

Figure 2.2 shows the infrared spectrum (IR) of the Form Dh and of the Forms α and β extended in the range of wave numbers 1,400-1,750 cm -1.

Figure 3 shows the calorimetry analysis Scan Differential (DSC) of Nicardipine Di Hydrochloride hydrated, Form Dh, and of the α and β forms.

Figure 4.1 shows the profile of the thermogram (TGA) corresponding to the new phase when heated to 1ºC / min.

Figure 4.2 shows the mass spectrometry analysis by electronic impact of the gases released during the heating process of the new phase (Form Dh) in the characterization by thermogravimetric analysis.
trico.

Figure 5 shows the crystalline structure of hydrated nicardipine hydrochloride, Form Dh. Figure 5 shows the perspective of a unit cell consisting of 4 molecules of nicardipinium hydrochloride and 8 molecules of water from the crystallographic axis b .

Figure 6 shows the molecular structure that Introduces Hydrated Nicardipine Hydrochloride in the Form Dh.

Figure 7 schematically shows a equipment to carry out obtaining a solvate of nicardipine hydrochloride, useful as a starting material for Preparation of the new Form Dh.

Detailed description of the invention

According to the first aspect of the invention, a pseudopolymorphic form of nicardipine hydrochloride (Form Dh) characterized by having spikes on the powder X-ray diffractogram shown in the Table 1 below. Figure 1 shows said diffractogram.

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TABLE 1

2

3

To register X-ray diffractograms in powder a Bruker AXS D8 diffractrometer has been used | : | equipped with a position sensitive Lynxeye detector.

The powders were crushed in an agate mortar and subsequently carefully deposited in the hollow of a sample holder equipped with a quartz monocrystal (supplied by The Gem Dugout , Swarthmore, PA). Generator regulation: 40 kV, 40 mA.

On the other hand, the Dh Form of the hydrochloride of Nicardipine is also characterized by a spectrum of infrared (IR) with the peaks, in units of cm -1, which are shown in Figures 2.1 and 2.2.

And finally, the Dh Form of the hydrochloride of Nicardipine is also characterized by having a point of melting of 135-150 ° C, as shown in the Fig 3.

It is also object of the present invention provide a procedure for the preparation of Form Dh of nicardipine hydrochloride.

The process for preparing the pseudopolymorphic form Dh is characterized in that it comprises suspending nicardipine hydrochloride or a solvate thereof in a non-solvent and water, at a temperature between
-20 ° C and 60 ° C, or suspend the nicardipine hydrochloride or a solvate thereof in pure water, at a temperature
lit between 1-99 ° C, in both cases at atmospheric pressure, in order to provide the pseudopolymorphic form Dh.

The non-solvent can saturate, supersaturate or mix with water at a ratio organic solvent: water from 100: 1 to 1: 100 (v / v), preferably of 1: 1 (v / v).

In the present invention for the term "non-solvent", also called "bad solvent "or" poor solvent "means a solvent in which nicardipine hydrochloride or a solvate thereof is insoluble or partially soluble.

Preferably said non-solvent is selected from ethyl ether, methyl ether, propyl ether, butyl ether, tetrahydrofuran, water, ethylene glycol, acetonitrile, isopropanol, 2-octanol, acetone, methyl ketone, or mixtures of the same, with ethyl ether being preferable.

From a poly crystalline sample of Hydrated nicardipine hydrochloride, Form Dh, obtained from In this way, a study of the crystalline structure has been carried out of nicardipine di hydrochloride hydrated from the profile of X-ray powder diffraction. The new phase dihydrate (Dh) crystallizes in the monoclinic system and the group spatial P2_ {1} / c. The corresponding cell parameters are: a = 11.3214; b = 10.69677; c = 24,01993; α = 90; ? = 99,11943; γ = 90; V_ {cell} = 2872,1Ä3. See Figure 5 Crystal structure and Figure 6 molecular structure.

Next, Table 2 is included where show the atomic coordinates of the crystalline structure of the hydrated nicardipine hydrochloride.

TABLE 2

4

5

In a third aspect of the invention, provides a procedure for obtaining a solvate of Nicardipine hydrochloride, useful for the preparation of the Form pseudopolymorphic Dh, comprising:

- the solution of nicardipine hydrochloride (NiH) (form α, form β, any mixture of these or a solvate) in an organic solvent at a concentration between 10-4 and 1 g NiH / ml;

- slow addition of a anti-solvent at a temperature between -20ºC and 40ºC, which causes the solvate precipitation of nicardipine hydrochloride.

In the present invention for the term "organic solvent" means an ionic solvent; Neutral polar or neutral apolar. The solvent may contain C, H, O, F, CI, I, Br, N, S, Se, P, B in its chemical structure.

Preferably, said organic solvent is select from chloroform, acetone, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butylacetate, tert-butyl methyl ether, chlorine benzene, cumene, ethyl acetate, di-methyl sulfoxide, ethanol, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, nitromethane, nitrobenzene, benzonitrile, N-methylpyrrolidone, toluene, xylene, acetonitrile, dimethylformamide, 2-octanol, 1-octanol, formamide, pyridine, diethylformamide, 2-methoxyethanol, 1,1,2-trichloroethene, dichloromethane, 1,4-dioxane, water, sulfolane, methanol, ethylene glycol, polyethylene glycol, or mixtures of these in any proportion, preferably (1: 1) (v / v).

In the present invention for the term "anti-solvent" means a solvent that induces the precipitation of a solute found in dissolution.

Preferably said anti-solvent is selected from hexane, ether ethyl, pentane, methyl ether, water, acetone, methyl ethyl ketone, ethyl acetate, 2-propanol, 1-propanol, acetonitrile, 1,4-dioxane, toluene, cyclohexane, benzene, or mixtures of these in any proportion, preferably (1: 1) (v / v).

Even more preferably, said solvent organic is chloroform and said anti-solvent is Select between hexane and ethyl ether. In one embodiment preferred is obtained nicardipine hydrochloride chloroformate (1: 1).

In a fourth aspect of the invention, provides an alternative procedure for obtaining a nicardipine hydrochloride solvate comprising:

- nicardipine hydrochloride solution (form a, form R, any mixture thereof, any solvate or Dh form) in an organic solvent at a concentration between 10 4 and 1 g NiH / ml,

- thermostatization of said solution at a temperature between -50ºC and 50ºC,

- addition of a compressed fluid, which is soluble with the organic solvent and acting as anti-solvent on nicardipine hydrochloride, until reaching a working pressure between 1 and 200 bars, which causes solvate precipitation in solid form; Y

- separation of the resulting precipitated solid a working pressure

Said compressed fluid is selected from carbon dioxide (CO2), Freons like Freon R-124 (F 2 HC-CHF 2), ethane (CH 3 -CH 3), carbon monoxide (CO), hydrogen (H2). Said organic solvent and said solvate is as defined above.

Advantageously, a stage of stirring in the reactor to favor contact between the fluid tablet, the solution comprising the hydrochloride of Nicardipine and organic solvent.

Next, an embodiment is included of the invention for obtaining a solvate of nicardipine hydrochloride, in particular chloroformate of nicardipine hydrochloride, referring to Figure 7, without limiting the scope of protection of the present invention and understanding that a person skilled in the art can make modifications without changing the essence of the present invention

In a preferred embodiment, the process for obtaining nicardipine hydrochloride chloroformate, it is carried out in a team schematically represented in the Figure 7

In particular, the Team presents a container (12) containing a solution of nicardipine hydrochloride (α phase, β phase, amorphous phase, hydrochloride solvate of nicardipine, phase Dh) in chloroform at a concentration between 10-4 and 1 g NiH / mL (solution A). This vessel (12) is connected, via a pipe, to a pump (10), thanks to which the solution can be supplied to the precipitation vessel (6), provided that the valve (11) is open Also, the container containing the compressed fluid which acts as an anti-solvent (1) is also connected to a pump (3), through which said fluid is introduced compressed to said vessel (6), provided that the valves (2) and (4) are open The reactor (6) is thermostatized between -50 and 50 ° C, and a known volume of Solution A is introduced into the reactor (6) through the nozzle (5). The compressed fluid is introduced into the reactor (6) once the valve (4) is opened, until reaching the desired final pressure (1 to 200 bars), and a desired concentration of the compressed fluid in the expanded chloroform (X_ {FC} = 0.01-0.99). The precipitate formed as a consequence of the anti-solvent effect of the compressed fluid on Solution A it is deposited on the filter (7), which separates the material particulate depending on the light of the same filter. In a preferred embodiment, a stirring system can be used (14) to favor the reach of the system equilibrium during this stage. Particulate material must be separated at the same work pressure, in which the precipitation has occurred. Therefore, when opening the valve (8) to start the filtration, It is necessary to supply nitrogen gas (13) to the reactor (6), the which acts as a plunger and maintains constant pressure within the reactor (6). Alternatively, the filter may be external with respect to to the reactor (6), as long as it is at the same conditions of pressure (P) than the reactor (6). Once the separation is finished of the solid, depressurization of the unit of filtration, to collect the precipitated solid. Preferably, before depressurization and after filtered, a drying stage of the material can be performed particulate Drying can be done by, for example, a compressed fluid stream.

Characterization of the new pseudopolymorphic form Dh X-ray powder diffraction analysis (XRPD)

In Figure 1.1 and Comparative Figure 1.2, the diffraction profiles of the phase are represented dihydrate (Dh), the β phase and the α phase. Just like the diffraction profile of the dihydrated phase can be observed (Dh) has peaks in different positions 2 \ theta and intensities relative different than the α and β phases.

Infrared Spectroscopy (IR) Analysis

The infrared spectra of the phase crystalline dihydrate, and of the? and? phases, between 400-4000 cm -1 are represented in the Figure 2.1. In the figure it can be seen that the profile of the bands located between 2,250-2,700 cm -1 is Different for all three phases. This broadband, multiple and medium intensity can probably be assigned to the vibration of tension of the NH + group of the quaternary amine. If the spectrum in the range of wave numbers between 1,400-1,750 cm -1, (Figure 2.2) are observed differences in the relative positions of the centered bands around 1,700, 1,650 and 1,605 cm -1 for all three phases. These bands can be assigned to voltage vibrations uC = O of the esters groups, uC = C of the conjugate system of the 1,4-dihydropyridine and at voltage vibration uC = C from the benzene group linked to the dihydropyridine ring, respectively.

Differential scanning calorimetry analysis (DSC)

The DSC analyzes (Figure 3) performed using a heating ramp of 5ºC / min, they reveal that this crystalline phase (Dh phase) produced from the melt chloroformate between 135-150 ° C, melting point that is different of the? and beta? phases, whose melting points are 189-190 and 169-170 ° C, respectively.

Characterization by thermogravimetric analysis (TGA)

The new phase was characterized by a thermogravimetric analyzer coupled to a mass spectrometer, by electronic impact, which detects the gases emitted by the Sample during the heating process. TGA's profile, obtained by submitting a sample of phase Dh to a ramp of Slow heating of 1 ° C / min, is shown in Figure 4.1. In Figure 4.2 shows the variation of the intensity of the peaks of the mass spectrum of gases released during the thermogravimetric analysis experiment, where the molecular peaks m / z = 17 and m / z = 18 that are characteristic of Water.

As can be seen from the profile obtained by thermogravimetric analysis (TGA) and of the evolution of the mass spectrum, there is a loss of weight of the 6.5%, between 110-150ºC, which corresponds to a Sample water loss. This result indicates that the molar ratio between nicardipine hydrochloride and water is of 1: 2 On the other hand, this water loss coincides with the point of sample fusion observed by DSC (see Figure 3).

The solubility analyzes performed show that the new pseudopolymorphic form Dh has a value of higher solubility than known polymorphic phases, probably because intermolecular interactions in the solid are of less intensity, as reflected in their lower melting temperature In addition, the presence of water in the new Dh Form favors it being more hydrophilic and presenting less surface tension between solid and water. Unexpectedly, the presence of water in the chemical structure of nicardipine has demonstrated to modify the pharmacokinetics of the same as linked to a lower melting point means that it is a crystalline phase thermodynamically less stable than known phases and it solubilizes faster than the anhydrous phases known.

These results make the new Form pseudopolymorphic Dh a good candidate as a medicine. Further, Said Dh Form is especially useful for the treatments of emergence of vascular diseases, such as crises hypertensive

Therefore, the invention also relates to a pharmaceutical formulation comprising said Form pseudopolymorphic Dh together with pharmaceutically excipients acceptable. And a formulation is especially advantageous Nicardipine Di Hydrochloride Pharmaceutical Hydrate in suspension, solution and in fast-release solid solutions of emergency.

Examples Example 1 Preparation of the pseudopolymorphic form Dh of hydrochloride nicardipine (water-saturated non-solvent)

100 mg of a chloroformate of nicardipine hydrochloride (1: 1) in 20 mL of saturated ethyl ether of water (approx. 10 mg of water / 20 mL ether). Leave a few hours at T = 8 ° C and the new Dh Form is obtained, with a 100% yield.

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Example 2 Preparation of the pseudopolymorphic form Dh of hydrochloride nicardipine (sabresaturated non-solvent of Water)

100 mg of chloroformate are suspended nicardipine hydrochloride (1: 1) in 20 mL of ethyl ether supersaturated in water (100 mg of water / 20 mL ether). It leaves some hours at T = 8 ° C and the new Form Dh is obtained. With 100% of performance.

Example 3 Preparation of the pseudopolymorphic form Dh of hydrochloride nicardipine (mixture of non-solvent and water)

300 mg of chloroformate are suspended nicardipine hydrochloride (1: 1) in a 1: 1 (v / v) mixture of water and ethyl ether (total volume, V = 40 mL) at T = 8 ° C. A portion of Unsolubilized solid is suspended in water. After a while time the new Dh Form is formed, with a performance quantitative.

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Example 4 Preparation of the pseudopolymorphic form Dh of hydrochloride nicardipine (pure water)

300 mg of chloroformate are suspended Nicardipine hydrochloride (1: 1) in 20 mL of water at T = 8 ° C. A portion of unsolubilized solid is suspended in water. After in a short time the new Dh Form is formed, with a performance quantitative.

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Example 5 Obtaining a hydrochloride solvate from nicar-dipina from a liquid solvent a atmospheric pressure

A solution of nicardipine hydrochloride, β phase in chloroform with a concentration C = 0.08 g NiH / mL of chloroform is prepared. 7 mL of this solution is added in a test tube. About 20 mL of n-hexane are added . After 72 hours, the appearance of crystals of nicardipine hydrochloride chloroformate (mp = 115 ° C) is observed.

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Example 6 Obtaining a hydrochloride solvate from nicar-dipina from a liquid solvent a atmospheric pressure

A solution of nicardipine hydrochloride, β phase in chloroform with a concentration C = 0.08 g NiH / mL of chloroform is prepared. 7 mL of this solution is added in a test tube. About 20 mL of ethyl ether are added . After 72 hours, the appearance of crystals of a nicardipine hydrochloride chloroformate (mp = 115 ° C) is observed.

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Example 7 Obtaining a nicardipine hydrochloride solvate from of a compressed fluid (see Fig 7)

A hydrochloride solution of nicardipine, β phase in chloroform with a concentration C = 0.12 g NiH / mL chloroform (Solution A). 115 mL of this solution in a 275 mL high pressure reactor. Is added slowly at a flow rate of 5 ml / min liquid CO2 and stir the system at an approximate speed of 500 rpm (revolutions per minute). The pressurization of the system by the addition of CO2 is carried out until the final system pressure is P = 10 MPa, and the molar fraction of CO2 in the expanded chloroform of X_ {CO2} = 0.7. As a consequence of the effect CO2 solvent on solution A, se obtains a precipitate, which is filtered at a pressure of 10 MPa, by using N2 gas. Once the filtration, the system depressurizes up to 4 MPa. In all the process the system temperature is maintained at 35 ° C. It takes make a short drying with pure CO2 working continuously at P = 4 MPa. Once the drying stage is finished, the depressurization of the system to atmospheric pressure, and access to the filter unit to collect the solid. The solid obtained in This experiment corresponds to the hydrochloride chloroformate of Nicardipine (p.f = 115 ° C), and the yield is quantitative 99%.

Claims (14)

1. Pseudopolymorphic form of (±) -2- (Benzylmethylamino) ethyl methyl 1,4-dihydro-2,6-dimethyl-4- (m-nitrophenyl) pyridine-3,5-dicarboxylate di hydrochloride, designated as Hereinafter hydrated nicardipine hydrochloride (Dh), characterized by at least the following X-ray diffractogram: 6 7 2. Pseudopolymorphic form Dh according to claim 1, characterized in that it has a melting point between 135 and 150 ° C. 3. Pseudopolymorphic form Dh according to any of the preceding claims as medicament. 4. Use of the pseudopolymorphic form Dh according to any of claims 1 to 3 for the preparation of a medicine for the treatment of diseases vascular, such as hypertensive crises. 5. Formulation comprising the form pseudopolymorphic Dh according to any one of claims 1 to 3 in conjunction with pharmaceutically acceptable excipients. Method of preparation of the pseudopolymorphic form Dh according to any one of claims 1 to 3, characterized in that it comprises suspending nicardipine hydrochloride or a solvate thereof in a non-solvent and water at a temperature between -20 ° C and 60 ° C, or in pure water at a temperature between 1 ° C and 99 ° C, to provide the pseudopolymorphic form Dh. 7. The method according to claim 6, characterized in that said non-solvent is saturated with water, is supersaturated with water or mixed with water in an organic solvent: water ratio between 100: 1 and 1: 100 (v / v). Method according to claim 6 or 7, characterized in that said non-solvent is selected from ethyl ether, methyl ether, propyl ether, butyl ether, tetrahydrofuran, water, ethylene glycol, acetonitrile, isopropanol, 2-octanol, acetone Methyl ketone 9. Method for obtaining a nicardipine hydrochloride solvate useful as a starting product for the preparation of the pseudopolymorphic Form Dh according to any one of claims 1 to 8, characterized in that it comprises the dissolution of nicardipine hydrochloride in a organic solvent at a concentration between 10-4 and 1 g NiH / ml, followed by the slow addition of an anti-solvent at a temperature between -20 ° C and 40 ° C, which causes solvate precipitation. 10. Method according to claim 9, characterized in that said anti-solvent is selected from chloroform, acetone, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butylacetate, tert-butyl methyl ether, chlorine benzene , hexane, cumene, ethyl acetate, methyl sulfoxide, ethanol, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, nitromethane, nitrobenzene, benzonitrile, N-methylpyrrolidone, toluene, xylene, acetonitrile, dimethylformamide, 2-octanol, 1-octanol, formamide, pyridine, diethylformamide, 2-methoxyethanol, 1,1,2-trichloroethene, dichloromethane, 1,4-dioxane, water, sulfolane, methanol, ethylene glycol, polyethylene glycol, or mixtures of these in any proportion. 11. Method for obtaining a nicardipine hydrochloride solvate useful as a starting product for the preparation of the pseudopolymorphic form Dh according to any of claims 1 to 8, characterized in that it comprises the dissolution of nicardipine hydrochloride in a organic solvent at a concentration between 10-4 and 1 g NiH / ml; thermostatization of said solution at a temperature between -50 ° C and 50 ° C, followed by the addition of a compressed fluid, which is soluble with the organic solvent and acts as an anti-solvent on nicardipine hydrochloride, until reaching a pressure between 1 and 200 bars, which causes solvate precipitation in solid form and, finally, separation of the precipitated solid while maintaining the working pressure. 12. Method according to claim 9 or 11, characterized in that said organic solvent is selected from chloroform, acetone, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butylacetate, tert-butyl methyl ether, chlorine benzene, cumene, ethyl acetate, methyl sulfoxide, ethanol, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2 -methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, nitromethane, nitrobenzene, benzonitrile, N-methylpyrrolidone, toluene, xylene, acetonitrile, dimethylformamide, 2-octanol, 1-octanol, formamide, pyridine , diethylformamide, 2-methoxyethanol, 1,1,2-trichloroethene, dichloromethane, 1,4-dioxane, water, sulfolane, methanol, ethylene glycol, polyethylene glycol, or mixtures of these in any proportion. 13. Method according to claim 11, characterized in that said compressed fluid is carbon dioxide (CO2), Freons such as Freon R-124 (F2 HC-CHF2), ethane ( CH 3 -CH 3), carbon monoxide (CO), hydrogen (H 2). 14. Method according to claim 11, characterized in that a stirring step is carried out in the reactor to favor contact between the compressed fluid and the solution comprising nicardipine hydrochloride in the organic solvent.