HRP980321A2 - Antiviral compound - Google Patents

Description

State of the art

The described invention relates to the antiviral compound [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-( phenylmethyl)propyl]-tetrahydro-3-furanyl ester (also known as 4-amino-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)- butyl)-N-isobutyl-benzenesulfonamide; VX-478; 141W94; amprenavir; compound of formula (I)), to its pharmaceutical formulations, and to its use in therapy.

Virally encoded proteases, which are essential for viral replication, are required to process viral protein precursors. Interference with the processing of protein precursors inhibits the formation of infectious virions. Therefore, viral protease inhibitors can be used to prevent or treat chronic and acute viral infections. [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl] (2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro - 3-furanyl ester has HIV aspartyl protease inhibitory activity and is very suitable for inhibiting HIV-1 and HIV-2 viruses.

Structure of [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro -3-furanyl ester, compound of formula (I) is shown below:

[image] .

We have now found that the compound of formula (I) can be obtained in a new crystalline form, form V, which exhibits particularly good pharmaceutical properties. The V shape is particularly stable and generally not hygroscopic. Bioreservoirs of this crystalline form can be made in crystalline form of high purity, that is, so that the ratio of amorphous and other crystalline forms of the compound of formula I is limited. Furthermore, Form V can be easily formulated into pharmaceutical preparations, such as tablets, capsules and liquid systems. The shape of the V can be determined using X-ray powder diffraction.

Detailed description of the invention

According to the first aspect of the invention, a new crystalline form of the compound of formula (I), form V, is provided.

The invention relates to the crystalline form, both in pure form and in the form of a mixture of other crystalline forms of the compound of formula (I) and in a mixture with other forms of the compound of formula (I), such as solvated crystalline forms. For example, in a bioreservoir containing Form V of a compound of formula (I), there may also be other solvated or unsolvated forms of a compound of formula (I). Unless otherwise indicated, a compound of formula (I) refers to an amorphous compound of formula (I).

In the first aspect of the described invention, Form V of the compound of formula (I) is provided. The V shape can be determined using the powder X-ray diffractograms shown in Figures 1 and 2. The intense diffraction peaks characteristic of the V shape can occur at the following approximate 2θ angles (using Kα X-radiation): 10.48; 16.81; 21:19; 19.77; 20.93; 9.68; 17.98; 19.38 and 12.77. Further details are shown in Table 3. The shape of the V can be determined by the X-ray powder diffractogram that includes at least five peaks shown in Table 3. The shape of the V can be determined by the d-value of the peaks at 13.53; 9,13; 8.44; 6.92; 6.08; 5.70; 5.27; 4.93; 4.58; 4.49; 4.42; 4.24; 4.19; 4.08; 3.91; 3.80; 3.74; 3.48 and 3.11 angstroms (rounded to about 0.01 angstroms). A suitable diagnostic peak for form V in the presence of other crystalline forms of the compound of formula (I) is the d-value peak of 13.53 or the 2θ angle at about 6.53. The shape of the V can be determined from the powder X-ray diffractogram, which contains a d-value peak at about 13.53. The shape of the V can be determined from the powder X-ray diffractogram which contains a peak at a 2θ angle of 6.53.

Table 1 shows a list of 2θ peak angles for the theoretical powder X-ray diffractogram, which were calculated using atomic coordinates and primitive cell parameters from single crystal X-ray diffraction analysis. The shape of the V can be determined using an X-ray powder diffractogram containing at least the five peaks shown in Table 1.

The theoretical X-ray powder diffractogram obtained using the atomic coordinates from the single crystal diffraction analysis and the primitive cell parameters from the indexing of the experimental diffractogram is shown in Table 2 and Figure 3. The shape of V can be determined using the X-ray powder diffractogram containing at least five peaks shown in Table 2.

Form V has a melting point of about 130 °C. The V shape is particularly suitable since it is thermodynamically stable. Suspended mixtures of other forms of the compound of formula I are shown to be completely converted to form V over several hours or days.

Therefore, in a further aspect, the described invention provides a process for the production of a compound of formula (I) in form V comprising treating a compound of formula (I) with a solubilizing solution which serves to facilitate the conversion of a given amount of a compound of formula (I) into said form V and then isolating said crystalline form or multiple crystalline forms.

Therefore, a further aspect of the invention is a process for the production of a compound of formula (I) in crystalline form, and said process comprises the steps:

a) formation of the compound of formula (I) in solution in the form of a free base;

b) isolating the compound of formula (I) from solution and optionally removing the unbound (unsolvated) solvent, in order to obtain the compound of formula (I) in a mostly pure form;

c) optionally treating the compound of formula (I) with a solubilizing solvent which serves to convert a given amount of optionally dried compound of formula (I) from step b) into the mentioned crystalline form; and

d) isolation of the mentioned crystalline form.

The compound of formula (I) can be obtained by any method known in the art, but is preferably obtained by the methods described in WO 94/05639 and US patent no. 5,585,397, which are incorporated herein by reference.

The synthesis of a compound of formula (I) usually leads to the formation of the compound in solution, in the reaction mixture, which can be separated and purified to form a solid product. Numerous factors influence the crystalline form of the mentioned product, and in accordance with the described invention the conditions of separation and/or successive processing can be adapted to obtain the compound of formula (I) in form V. Suitably, purified (for example by means of double recrystallization) form I of the compound of formula ( I) can be used as a starting material or as a seed material for forming the V shape.

The described invention also provides Form V of the compound of formula (I) for use in medical therapy, for example for the treatment of viral diseases in animals, for example in humans. The compound is particularly applicable for treating diseases caused by retroviruses, such as HIV infections, for example acquired immune deficiency syndrome (AIDS) and AIDS-like complex (ARC), as well as diseases caused by hepatitis B and hepatitis C.

In addition to its use in human medical therapy, Form V of the compound of formula (I) can also be used in other animals for the treatment of viral diseases, for example in other mammals.

The described invention also provides a method for treating a viral infection, especially an HIV infection, in animals, for example in mammals, such as humans, which comprises administering to said animal an antivirally effective amount of Form V of the compound of formula (I).

The described invention also provides the use of form V of the compound of formula (I) in the preparation of a medicament for the treatment of a viral infection.

Form V of the compound of formula (I), also designated herein as the active ingredient, may be administered in a manner appropriate to the condition being treated, but the preferred route of administration is oral. However, it is obvious that the preferred mode may vary with, for example, the condition of the recipient.

For each of the applications and indications listed above, the required amount of active ingredient (as defined above) will depend on numerous factors including the severity of the condition being treated and the identity of the recipient, which is solely at the discretion of the physician or veterinarian who determines them. However, for each of these uses and indications, a generally suitable effective dose will be from 5 to 100 mg per kilogram of recipient's body weight per day, and a preferred amount will be from 8 to 70 mg per kilogram of recipient's body weight per day (if not otherwise indicated, all masses of the active ingredient are calculated with respect to the free base of the compound of formula (I)). The desired dose is preferably present in the form of one, two, three or four or more sub-doses which are applied at appropriate time intervals during the day. These subdoses may be administered in unit dosage forms, for example containing about 25 to 2000 mg, preferably about 25, 50, 150, 200 or 250 mg of active ingredient per unit dosage form.

Although it is possible for the active ingredient to be administered alone, it is preferred that it be present in the form of a pharmaceutical formulation. The formulation comprises the active ingredient as defined above, together with one or more pharmaceutically acceptable excipients and optionally with other therapeutic ingredients. The excipient must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and that it is not harmful to its recipient.

Formulations include those suitable for oral administration, and may typically be present in unit dosage form prepared by a process well known in the pharmaceutical art. Such procedures include the step of bringing the active ingredient into association with a carrier consisting of one or more auxiliary ingredients. It is usual to obtain formulations by bringing the active ingredient into uniform and intimate association with liquid carriers or finely divided solid carriers, or with both, and then if necessary by additional shaping of the product.

Formulations of the described invention suitable for oral administration may be present in the form of discrete units, such as capsules, cachets or tablets (such as a tablet for swallowing, dispersing or chewing) each of which contains a predetermined amount of active ingredient; in the form of powder or granules; in the form of a solution or liquid emulsion of the water-in-oil type. The active ingredient may also be present in the form of a large tablet, slurry or paste.

The tablet can be obtained by pressing or casting, optionally with one or more auxiliary ingredients. Pressed tablets can be obtained by pressing in a suitable machine the active ingredient in free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert emollient, preservative, and surface-active or dispersing agent. Molded tablets may be made by casting the powdered compound in a suitable machine, or the compound wetted with an inert liquid emollient. Tablets can optionally be coated or scored, and they can be formulated to allow slow or controlled release of the active ingredient.

The active ingredient can also be present in a formulation that includes particles of the active ingredient of micrometer or nanometer dimensions, where the formulation can also contain other pharmaceutical agents, and can optionally be translated into a solid form.

A soft gelatin capsule formulation may be obtained, for example, by heating four (4) kilograms (kg) of Vitamin E TPGS (obtained from Eastman Chemical Co.) at 50°C until liquid. 2.005 g of polyethylene glycol 400 (PEG 400) (a small amount of aldehyde, <10 ppm, obtained from Union Carbide or Dow Chemical Co.) heated to 50 °C can be added to liquid vitamin E TPGS, which is mixed until homogeneous solution. The resulting solution can be heated up to 65 °C. 1.5 kg of the compound of formula (I) form V may be dissolved in a solution of vitamin E TPGS which has been liquefied and PEG 400. 0.395 kg of propylene glycol at room temperature may be added and mixed until a homogeneous solution is formed. The solution can be cooled to 28-35 °C. The solution can then be depleted. The mixture is conveniently encapsulated at 28-35 °C at a fill weight equivalent to 150 mg of compound without volatile components, into size 12 oval white, opaque, soft gelatin oval capsules using a capsule filling machine. The capsule liners can be dried to a constant moisture content of 3-6% water by mass and a capsule hardness of 7-10 Newtons, and placed in a suitable container.

Preferred unit dosage formulations are those containing a daily dose of the active ingredient or a unit daily subdose (as hereinbefore discussed) or an appropriate fraction thereof.

It should be understood that in addition to the foregoing ingredients, the formulation of this invention may include other agents common in the art depending on the type of formulation in question, for example a formulation suitable for oral administration may include flavoring agents or taste masking agents.

The following examples are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

Example 1

Preparation of [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro -3-furanyl ester form I

The compound of formula (I) is dissolved in a solution consisting of polyethylene glycol 400 (PEG-400), vitamin E TPGS, and propylene glycol in a ratio of 2:1:0.2, so that a concentration of 19% by mass of the compound of formula (I) is obtained. . A 1:1 solution of water and PEG-400 is added to this solution, in order to obtain a final concentration of the compound of formula (I) of 5-75% by mass. After standing for 4-24 hours at room temperature, fine needle crystals of the compound of formula (I) begin to settle. These were isolated and identified as form I polymorphs of the compound of formula (I).

Example 2

Preparation of [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro -3-furanyl ester of form I, by introducing a seed of crystallization

Isopropanol/water: A solution of the compound of formula (I) (41.0 kg) in isopropanol (406 L) is concentrated to about 1 g/2.5 ml. The solution is cooled to 15-20 °C and sprinkled with crystals of Form I polymorph of the compound of formula (I) as crystallization seeds. The mixture is stirred overnight to complete crystallization. Add water (151 l) slowly, while cooling the bioreservoir to 5-10 °C. The suspension is kept at 5-10 °C for approximately 1 hour. The mixture is then filtered and the solid components are washed with 76 L of water and then with 57 L of methyl tert-butyl ether. The product is dried in a vacuum oven at 50-60 °C for approximately 18 hours, so that 34.8 kg of Form I polymorph of the compound of formula (I) is obtained.

Example 3

Preparation of [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro -3-furanyl ester form V

A compound of formula (I) (0.970 kg) is suspended in 3.88 L (4.0 volumes) of industrial methanol in a 10 L jacketed laboratory reactor. The heating starts with the alignment of the lining at 50 °C. The suspension dissolves when the internal temperature reaches 35 °C. The clear solution is heated at 40 °C for 30 minutes to ensure dissolution. Demineralized water (1.94 L, 2 volumes) is added over 15 to 20 minutes. The coating is then placed at 20 °C. When the internal temperature drops below 25 °C, the solution is sprinkled with the compound of formula (I) of form I (10 g, 1 mass %). The mixture is then stirred at 20°C to 23°C for 1 to 10 hours. Water (2.91 L, 3 volumes) was then added over 2 hours at room temperature. The suspension is then allowed to stand at 10°C to 12°C for 1 hour, and the resulting Form V is collected by vacuum filtration (flash filtration). Form V was vacuum dried at 50 °C for 24 hours. The characteristic powder X-ray diffractogram is shown in Figure 1.

Example 4

Preparation of [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro -3-furanyl ester of acetone solvate

About 10 g of the compound of formula (I) (form I) is added to about 8 ml of acetone and stirred for several minutes at room temperature. The acetone solvate of the compound of formula (I) precipitates over several minutes to several hours. The mixture is left to stand in a sealed container at room temperature for 2-7 days to allow crystal formation. Crystals of the acetone solvate of the compound of formula (I) are isolated by vacuum filtration. After air-drying for several hours, the acetone solvate is placed in a heated glass ampoule. The acetone solvate was satisfactorily stable at room temperature for several days to several weeks.

Example 5

Preparation of [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl] (2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro -3-furanyl ester form V from acetone solvate

100 mg-200 mg of an acetone solvate of a compound of formula (I) is introduced into 2 ml glass ampoules (eg Hewlett Packard HPLC ampoules P/N 5181-3375 with caps P/N 5181-1210) which are then heated. The ampoules are stored at 50-60 °C for 1 month, during which time the acetone solvate of the compound of formula (I) is transformed into the compound of formula (I) form V.

Example 6

Suspension test for [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl] -tetrahydro-3-furanyl ester form V

A water/ethanol solution of 50 mass % is prepared. One gram of the compound of formula (I) is added to 10 ml of a 50% ethanol/water solution and stirred for 4 hours in a closed container, using a magnetic stirrer and a stirring rod. An additional 300 mg of the compound of formula (I) is added to the solution and the solution is stirred in a closed vessel for 2-4 days. The excess solid component is isolated and then tested using differential scanning calorimetry (DSC) or X-ray powder diffraction. Form V has a melting point of about 130 °C.

Example 7

X-ray diffraction pattern of powder [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl) propyl]-tetrahydro-3-furanyl ester form V using single crystal X-ray diffractogram data

The crystal structure of the single crystal of formula (I) form V was determined using single crystal X-ray diffraction. Single crystal X-ray diffraction data were collected on a Siemens P3 diffractometer with monochromatized Cu-Kα X-radiation. The unit cell parameters were determined from 12 reflections of the monoclinic crystal system, P2(1), with a=9.289; b=10,529; c=13.754 (a, b and c units are in angstroms) and β=102.09 °. Using atomic coordinates and unit cell parameters, the X-ray diffractogram for the powder was calculated. The nine most intense peaks are given in Table 1.

Table 1

X-ray diffraction pattern of powder [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl) propyl]-tetrahydro-3-furanyl ester form V using single crystal X-ray diffraction patterns

List of 9 highest peaks

[image]

Example 7

Powder X-ray diffractogram (calculated) for [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]-tetrahydro-3-furanyl ester of Form V using atomic coordinates from single crystal X-ray diffraction analysis and unit cell parameters from indexing of experimental powder data

The 2θ values derived from the single crystal data shown in Table 1 differ from the observed experimental powder diffraction values due to the lack of refinement in the unit cell parameters. Using the 2 θ values determined from experimental X-ray powder diffraction, the experimental powder diffractogram was indexed to obtain a more accurate set of unit cell parameters. With the use of unit cell parameters from powder diffractogram indexing and atomic (fractional) coordinates from X-ray diffraction on a single crystal, a more accurately calculated powder diffractogram was obtained.

Table 2

Powder X-ray diffractogram (calculated) using atomic coordinates from single crystal X-ray diffractogram data analysis and unit cell parameters from indexing of the experimental powder diffractogram

Calculate the diffractogram

[image]

Table 2 gives a list of 19 intense peaks from the calculated diffractogram, based on the following unit cell parameters: a=9.3305; b=10.5818; c=13.8040; (a, b and c units are in angstroms), and β=102.13 °. The relative intensities of the peaks in the calculated diffractogram are given not only by inserting data for the single crystal, but also by using the peak profiles (shape and spread) used in the calculation of the simulated powder diffractogram.

Example 8

Obtained powder X-ray diffractogram for [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-( phenylmethyl)propyl]-tetrahydro-3-furanyl ester form V

Table 3 lists the 19 most intense peaks from the experimental diffractogram on V-shaped 141W94 powder. The data were obtained on a Scintag XDS2000 diffractometer with fixed incident and receiving slits using frontally packed sample preparations. To determine the error in the 2θ determinations, the V-form 141W94 sample was standardized with 1-tetradecanol and NIST SRM 675 mica as internal standards. The contribution from Kα II diffraction was mathematically removed before determining the peak position using the three leading point alignment technique.

The values of relative intensities were determined from the 141W94 V-shaped sample, which was not standardized with internal standards.

Comparing the acceptable 2θ values with the observed 2θ values for the internal standards shows that the error in the observed 2θ values was less than +0.02 °. The error in determining the observed 2θ values was caused by errors in alignment on the diffractometer and in sample preparation. The error in the 2θ and d-values shown in Table 3 is the difference between the observed and calculated values (see Table 2). It should be noted that the observed relative intensities depend on the geometry of the diffractometer, as well as on the sample preparation technique. Additionally, close diffraction lines that are not fully resolved by the diffractometer can affect the observed relative intensity values.

Table 3

Obtained powder X-ray diffractogram for [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl]-(2-methylpropyl)amino]-2-hydroxy -1- (phenylmethyl)propyl]-tetrahydro-3-furanyl ester form V

Experimental (standardized sample)

[image]

The observed 2θ values and d-values are mostly in the vicinity of 0.01° and 0.01 angstroms, respectively. The largest errors in d-values occur at the lowest 2θ angles. In addition to the experimental error in the determination of the 2θ and d-values for the V-form 141W94 sample, the observed V-form 2θ and d-values also vary from sample to sample due to variations in crystallinity and lattice type, a region in the 2θ values of + 0.09 ° was observed .

Rounded to the nearest 0.01 angstrom, the diffraction peaks shown in Table 3 should be 13.53; 9,13; 8.44; 6.92; 6.08; 5.70; 5.27; 4.93; 4.58; 4.49; 4.42; 4.24; 4.19; 4.08; 3.91; 3.80; 3.74; 3.48 and 3.11. The error in determining the d-value is the largest for the highest d-value, and decreases with decreasing d-value. For the 13.53 d-value of the peak, the observed difference between the observed and calculated values is 0.03 angstroms. A more conservative estimate of the error should be 0.05 angstroms at the highest d-values (for example 13.53 angstroms) to 0.02 angstroms at the lowest d-values (for example 3.80 angstroms).

If the 141W94 form V is a minor component in the presence of other crystal form(s), not all diffraction peaks of form V may be observed due to overlap with peaks from other crystal forms and variations in sample crystallinity.

Experimental (both raw data and data observed with standardized Kα II diffraction) and calculated diffractograms for form V are shown in Figures 1, 2 and 3, respectively. The calculated diffractogram for Form I is shown in Figure 4. It should be understood that the relative intensities of observed peaks in experimental powder diffractograms may vary due to sample particle size, shape, crystallinity effects, variations in powder sample preparation for diffraction, and instrumental scanning conditions.

Claims (14)

1. Form V, characterized in that [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]-tetrahydro-3-furanyl ester. 2. Form V, characterized by the fact that it is a compound of formula (I): [image] . 3. Crystal form [3S-[3R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro -3-furanyl ester, characterized by the fact that in its powder X-ray diffractogram it contains a peak at at least five of the following angles 2θ: 10.48; 16.81; 21.19; 19.77; 20.93; 9.68; 17.98; 19.38 and 12.77. 4. Crystal form [3S-[3R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro -3-furanyl ester, indicated by the d-value peak present at 13.53 angstroms. 5. Pharmaceutical preparation, characterized in that it comprises a compound according to one of claims 1-4 and at least one of its pharmaceutically acceptable carriers. 6. A compound according to one of claims 1 to 4, characterized in that it is used in medical therapy. 7. A compound according to one of claims 1 to 4, characterized in that it is used in the preparation of a medication for the treatment of a retroviral infection. 8. A method for treating a retroviral infection in humans, indicated by the fact that it includes the use in humans as a host of an effective anti-retroviral treatment amount of the compound according to one of claims 1 to 4. 9. A process for obtaining a compound according to one of claims 1 to 4, characterized in that it comprises crystallization of form V [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl]( 2-Methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro-3-furanyl ester from aqueous solution. 10. Pharmaceutical preparation according to claim 5, characterized in that it is in powder form. 11. Pharmaceutical preparation according to claim 5, characterized in that it is in the form of a suspension. 12. Pharmaceutical preparation according to claim 5, characterized in that it is in the form of a soft gelatin capsule. 13. Pharmaceutical preparation according to claim 5, characterized in that it comprises nanometer-sized particles [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino] -2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro-3-furanyl ester optionally converted to solid form. 14. The compound of formula (I) according to one of claims 1 to 4, characterized in that it is of pure polymorphic form V with an X-ray powder diffractogram as shown in Figure 1.