CZ20003709A3 - New crystalline forms of the antiviral benzimidazole compound - Google Patents

Abstract

New crystalline forms and solvates of 5,6-dichloro-2-(isopropylamino)-1-P-L-ribofuranosyl-1H-benzimidazole of formula (I), which is used in medical practice. New crystalline forms and solvates are defined by X-ray diffraction patterns. Their production and their use as substances with antiviral activity are described.

Description

Novel crystalline forms of antiviral benzimidazole compound

Technical field

The invention relates to anhydrous crystalline forms and solvates of compound 5,6-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H benzimidazole (known as 1263W94; a compound of formula (I)) with antiviral activity, pharmaceutical compositions containing anhydrous crystalline forms and solvates thereof and their therapeutic use.

BACKGROUND OF THE INVENTION

5,6-Dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H benzimidazole (1263W94) is a benzimidazole derivative used in medical practice. Patent application WO 96/01833 discloses 5,6-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H-benzimidazole and its use in the prophylaxis and treatment of viral diseases, in particular those which are caused by herpes viruses. The compound described in patent application WO 96/01833 is an amorphous, non-crystalline, hygroscopic substance.

5,6-Dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H benzimidazole, a compound of formula (I), has the following structure:

The compound of formula (I) may be prepared in novel crystalline forms or in the form of solvates. These novel crystalline forms and solvates of the invention are thermodynamically more stable than the amorphous form described in WO96 / 01833. Another advantage of the novel crystalline forms and solvates of the invention is that they are not hygroscopic. These crystalline forms and solvates are easy to store and readily prepare pharmaceuticals such as tablets, capsules, and liquid systems. These crystalline forms and solvates are characterized by typical X-ray powders.

Description of the picture

Figure 1. X-ray (powder) of Form I of the compound of formula (I). This radiograph was obtained according to the procedures described in Example 18.

Figure 2. X-ray X-ray of Form II of the compound of formula (I). This radiograph was obtained according to the procedures described in Example 18.

Figure 3. X-raygram of ethanolate of the compound of formula (I). This radiograph was obtained according to the procedures described in Example 18.

Figure 4. X-ray xenogram of Form IV of the compound of formula (I). This radiograph was obtained according to the procedures described in Example 18.

Figure 5. X-ray X-ray of Form V of Compound of Formula (I). This radiograph was obtained according to the procedures described in Example 18.

Figure 6. X-ray x-ray of Form VI of the compound of formula (I). This radiograph was obtained according to the procedures described in Example 18.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula (I) in a novel crystalline form, Form I. Form I is defined by the X-ray graph in Figure 1 obtained by a properly focused diffractometer equipped with a graphite bent-beam curvature monochromator using copper X-ray radiation.

Form I is prepared from a mixture of an amorphous compound of formula (I) and a novel crystalline Form II of a compound of formula (I) by dissolving and heating in water or toluene at temperatures above 50 ° C. Upon heating, the suspension becomes a sticky gum which, upon further heating, becomes a solid.

The invention further relates to a compound of formula (I) in a novel crystalline form

II. Form II is defined by the X-ray pattern in Figure 2, which is obtained by a properly focused diffractometer equipped with a graphite monochromator for curving the bent beam using X-rays from a copper cathode.

Form II is prepared by crystallizing or recrystallizing an amorphous compound of formula (1) from a mixture of methanol and water or methanol and toluene. Recrystallization yielded a methanol solvate which, on drying, lost methanol to give Form II.

The invention further provides a compound of formula (I) in the form of a white free-flowing powder (referred to herein as an "ethanolate or ethanol solvate of a compound of formula (I)). Ethanolate is defined by the X-ray diffractometer in Figure 3, obtained by a properly aimed diffractometer equipped with a graphite monochromator for curving the bent beam using X-rays from a copper cathode

Ethanolate is prepared from a solution of the compound in a mixture of ethanol and water or ethanol and toluene.

The invention further relates to a compound of formula (I) in a novel crystalline form

IV. Form IV is defined by the X-ray graph in Figure 4, which is obtained by a properly focused diffractometer equipped with a graphite monochromator for curving the bent beam using X-rays from a copper cathode.

Form IV is prepared by dissolving and heating the amorphous compound of formula (I) in water or toluene at temperatures above 50 ° C. Form IV is also produced by dissolving Form II in water for several months.

The invention further relates to a compound of formula (I) in a novel crystalline form

V. Form V is defined by the X-ray diffractometer in Figure 4, which is obtained by a properly oriented diffractometer equipped with a graphite monochromator of the curvature of the bent beam using X-rays from a copper cathode cc. Form V is prepared by the sequential addition of water to an amorphous compound of formula (I) with rapid stirring at 70 ° C for two hours. After a further 7 hours while the compound is stirred and heated to 65-70 ° C, heating and stirring is discontinued. The compound was allowed to stand at room temperature for 2.5 days and then filtered. The resulting white granular solid was allowed to air dry overnight. Form V is also prepared by dissolving a mixture of Form II and Form I in water at 90 ° C for 20 minutes. Another method for preparing Form V is by dissolving other crystalline forms or solvates of the compound of formula (I), preferably Form IV or ethanolate, in acetonitrile and allowing the solution to stand at room temperature until Form V precipitates therefrom.

The invention further provides a compound of formula (I) in the form of a mixture of any two or more anhydrous crystalline forms and or solvates of the invention or a mixture of an amorphous substance and one or more anhydrous crystalline forms and or solvates of the invention. The compound of formula (I) is also isolated by acid / base precipitation.

As used herein, the term "solvate" means a complex of various stoichiometers formed from a solute (a compound of formula (I)) and a solvent. The solvent is, for example, water, methanol, ethanol or acetic acid. As used herein, a compound of formula (I) means an amorphous form of that compound, unless another form or solvate is indicated.

X-rays of the various crystalline forms and solvates of the invention are prepared by conventional techniques on devices known in the art. The X-rays in Figures 1-6 are taken with a Phillips X-Pert MPD diffractometer system equipped with a graphite bent-beam curvature monochromator using a copper cathode x-ray and an automatic divergent slit. The detector is a xenon proportional computer. The powder sample used to make the X-ray is prepared by conventional methods of preparing the settled sample using a 16 mm diameter and 2 mm thick holder.

Figures 1, 2, 4, 5, 6 and 3 show X-ray patterns of powder samples of Forms I, II, IV, V, VI and ethanolate. Each form and solvate is assigned an X-ray pattern that is unique to the form. Each crystalline form or solvate has an X-ray pattern with a unique arrangement of diffraction peaks, which are expressed at 2 theta (°) angles, d-distances ()), or relative peak intensities.

The values of the 2 theta diffraction angles and the corresponding d - distances determine the location of the different vertices on the X - ray. The values of d - distances are calculated by the Bragg equation from the measured angles of 2 theta and the wavelength of radiation from the copper cathode cd. Depending on the type of diffractometer used and the sample preparation method, slight deviations at the measured angles of 2 theta and d distances are expected. Larger deviations are expected for relative peak intensities. The identification of a particular crystalline form of the compound is mainly based on the measured 2 theta angles or d-distances, less on the relative peak intensities. In a mixture of crystalline forms, the strongest diffraction peak of each form may overlap the diffraction peak of another form. In a mixture of crystalline forms, identification is based on the presence of a peak of lower intensity that does not overlap the peak of another crystalline form. When identifying Form I

5,6-Dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H benzimidazole, the only most characteristic peak of the 2 theta angle appears at 2.57 degrees or E at a distance of 34.35 A. Identifying ethanolate 5 , 6 dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H benzimidazole, the only most characteristic peak of the 2 theta angle appears at 6.63 degrees or E - a distance of 13.33 A. When identifying Form IV 5, 6 Dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H benzimidazole, the only most characteristic peak of the 2 theta angle appears at 11.78 degrees or E - distance 7.51 A.

It is preferred that the identification of the various anhydrous crystalline forms and or solvates of the invention depends on multiple 2 theta angles or multiple d distances. Each of the various anhydrous crystalline forms and / or solvates.

5,6-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H benzimidazole is identified by the presence of multiple 2 theta peaks, including two, three, four, five, six, seven, eight, nine or ten 2 theta angles that are characteristic of a particular crystalline form. Form I is identified by the presence of X-ray diffraction peaks that appear at at least the following five locations, expressed at 2 theta angles: 7.90; 10.39; 14.63; 15.79; 20.75; 21.99; 22.77; 24.14; 24.71 and 25.71 degrees. Form II is identified by the presence of X-ray diffraction peaks that appear at at least the following five locations, expressed at 2 theta angles: 7.91; 17.33; 18.23; 19.60; 21.88; 23.24; 23.92; 25.27; 27.70 and 29.21 degrees. Ethanolate is identified by the presence of X-ray diffraction peaks that appear at at least five following locations, expressed at 2 theta angles: 9.07; 10.38; 15.95; 17.72; 20.75; 21.37; 22.96; 23.93; 25.40 and 29.05 degrees. Form IV is identified by the presence of X-ray diffraction peaks that appear at at least five of the following locations, expressed at 2 theta angles: 9.29; 16.04; 18.67; 22.06; 22.68; 23.34; 24.40; 29.64; 30.92 and 31.62 degrees. Form V is identified by the presence of X-ray diffraction peaks that appear at at least the following five locations, expressed at 2 theta angles: 13.30; 18.13; 18.78; 20.41; 21.75; 23.02; 26.87; 28.34; 28.55 and 30.22 degrees.

The determination of the aforementioned angles of 2 theta and distances has certain limits of reliability. Reliability in d - distance determination increases with increasing diffraction angle sensing or d - distance reduction. The confidence limits for the above-mentioned 2 theta angles for forms I, IV, V and ethanolate are ± 0.05 degrees for each peak determination. The confidence limits of the above-mentioned 2 theta angles for Form II are ± 0.09 degrees for each peak. The confidence limits for d - spacings for forms I, IV, V and ethanolate are ± 0.05 Angstroms. The confidence limits for d - distances for Form II are ±

0.09 Angstroms.

· · · · · · · ·

A suitable way of comparing X-rays to identify a particular crystalline form is to place X-rays of an unknown form on the X-rays of a known form, despite the confidence limits in determining the angles of 2 theta and d distances. An X-ray xenogram of the unknown form 5,6-dichloro-2 (isopropylamino) -1- (β-L-ribofuranosyl) -1H-benzimidazole obtained as described in this application is placed in Figure 1 to immediately determine if it is the X-ray of an unknown form is the same as the X-ray of Form I. If the X-ray is identical to Figure 1, then the unknown crystalline form is unambiguously identified as Form I. In the same way

by placing X-rays in Figures 2, 4, 5 or 3, it is ascertained whether the unknown crystalline form is Form II, IV, V or ethanolate.

Although the main criteria for identifying a particular crystalline form is the determination of angles of 2 theta and distances, it is also appropriate to compare the relative peak intensities. As mentioned above, the relative peak intensities vary with the diffractometer used and the sample preparation method. Peak intensities are recorded as the intensities relative to the peak intensity of the strongest peak. Intensity units on the X-ray diffraction curve are counts / sec. Absolute counts = counts / time x counting time = counts / sec x 10 sec Form I 5.6

- Dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H benzimidazole has X-ray angles of 2 theta, d distances (A) and relative peak intensities (I) of the fifteen most intense peaks obtained by described in Example 18 below:

Form I angle 2 theta (°) A ¹ AND 7.90 11.19 58.8 10.39 8.51 49.7 14.63 6.05 33.3 15.79 5.61 46.1 16.95 5.23 16.4 19.24 4.61 14.4 20.75 4.28 29.4 21.99 4.04 21.0 22.77 3.90 100.0 24.14 3.68 35.2 24.71 3.60 20.5 25.72 3.46 13.9 25.97 3.43 43.2 29.44 3.03 13.9 31.09 2.87 14.7

¹ confidence limits = approximately ± 0.05

Form II 5,6-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H benzimidazole has these angular values of 2 theta, d-distances and relative peak intensities of the 15 most intense peaks obtained as described in Example 18 below. :

• ·

Form II angle 2 theta (°) A ¹ AND 7.91 11.17 100.0 10.86 8.14 10.1 12.69 6.97 <5.2 13.65 6.48 4.7 14.94 5.93 8.4 16.11 5.50 12.8 17.33 5.11 17.5 18.23 4.86 18.2 19.60 4.53 19.6 21.88 4.06 18.8 23.24 3.82 19.0 23.92 3.72 26.7 25.27 3.52 24.5 27.70 3.22 34.9 29.21 3.06 14.2

¹ confidence limits = approximately ± 0.09

Form II also has peaks at the following 2 theta angles: 7.9; 10.9; 16.1; 17.3; 18.2; 19.6; 21.9; 23.9 degrees.

5,6-Dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H-benzimidazole Ethanolate has these 2 theta angles, d-distances and relative peak intensities of the 15 most intense peaks obtained as described in Example 18 below. :

• · ····

ethanolate angle 2 theta (°) A ¹ AND 9.07 9.74 45.2 10.38 8.52 22.7 15.95 5.55 40.4 17.72 5.00 100.0 18.96 4.68 17.2 19.79 4.48 18.4 20.75 4.28 30.4 21.37 4.16 27.7 21.89 4.06 19.0 22.08 4.02 17.5 22.96 3.87 40.6 23.93 3.72 41.3 25.40 3.50 26.7 27.65 3.22 19.8 29.05 3.07 25.4

¹ confidence limits = approximately ± 0.05

Ethanolate also peaks at these 2 theta angles: 6.6; 9.1; 9.4; 10.4; 11.0; 14.7; 16.0; 17.2; 17.7; 18.3; 20.8; 21.4; 23.0; 23.9; 25.4; 27.7; 29.1 degrees.

Form IV of 5,6-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H-benzimidazole has these angular values of 2 theta, d-distances and relative peak intensities of the 15 most intense peaks obtained as described below in the Example 18:

• · ♦ ···

Form IV angle 2 theta (°) A ¹ AND 9.29 9.51 15.6 11.78 7.51 12.5 16.04 5,52 20.1 18.67 4.75 25.1 19.54 4.54 11.5 22.06 4.03 100.0 22.39 3.97 11.6 22.68 3.92 17.9 23.34 3.81 15.5 23.68 3.75 10.0 24.40 3.65 28.7 28.72 3.11 11.1 29.64 3.01 13.0 30.92 2.89 26.5 31.62 2.83 13.9

¹ confidence limits = approximately ± 0.05

Form IV also peaks at the following 2 theta values: 7.5; 9.3; 11.8; 16.0; 18.7; 19.4; 19.5; 22.1; 22.7; 24.4; 29.6; 30.9 degrees.

Form V 5,6-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H-benzimidazole has these angular values of 2 theta, d-distances and relative peak intensities of the 15 most intense peaks obtained as described in the Example below 18:

♦ ··· ·· ·

9

Form V angle 2 theta (°) A ¹ AND 9.07 9.75 19.1 9.35 9.46 14.3 10.74 8.23 14.0 13.30 6.65 26.1 17.04 5.20 18.5 18.13 4.89 39.2 18.78 4.72 57.0 20.41 4.35 39.5 21.75 4.08 100.0 22.71 3.91 15.8 23.02 3.86 20.3 26.87 3.32 23.4 28.34 3.15 24.7 28.55 3.12 51.1 30.22 2.95 39.0

¹ confidence limits = approximately ± 0.05

Form V has peaks at the following 2 theta values: 9.1; 9.3; 10.7; 13.3; 17.0; 18.1; 18.8; 20.4; 21.8; 26.9; 28.6; 30.2 degrees.

Based on the above characteristics of X-rays of forms I, II, IV, V and ethanolate, and knowledge of how to make these X-rays, it is easy for each of these anhydrous crystalline forms or solvates 5,6 dichloro-2- (isopropylamino) -1- (β - L - ribofuranosyl) - 1H benzimidazole identified. X-rays of all anhydrous crystalline forms or solvates prepared by the methods described in this application contain additional peaks. In each of the above tables, the fifteen most intense peaks characteristic of a particular crystalline form or solvate are shown. Tables should not be construed as an exhaustive list of peaks formed by individual forms or solvates.

· 4 4 ·· * 4 <4 4 4 4 • 4,444

Other physical methods are used to identify anhydrous crystalline forms or solvates. Techniques known in the art that are used to physically characterize crystalline forms or solvates include melting point determination, differential calorimetry for in-line examination of samples, infrared radiation and water sorption. These methods are used either alone or in combination to characterize a given crystalline form or solvate.

The invention relates to anhydrous crystalline forms and solvates both in pure form and in admixture with other forms or solvates of the compound of formula (I). An example is a mixture of Form I with one or more forms II, IV, V or ethanolate. An alternative is a mixture of Form I with an amorphous form of a compound of Formula (I). Another option is to mix Form I with both the amorphous form of the compound of formula (I) and one or more other crystalline forms or solvates, including Forms II, IV, V, and ethanolate. Any of forms II, IV, V or ethanolate form in a similar manner mixtures with other forms or with an amorphous form. One aspect of the invention is a mixture of forms I and V. Another aspect of the invention is a mixture of form II and amorphous form. Another aspect is a mixture of forms I, IV and V. Another aspect is a mixture of forms I, IV, V and amorphous forms. Other mixtures of two or more anhydrous crystalline forms and solvates of the invention will certainly be determined by those skilled in the art.

The invention includes the aforementioned mixtures of any anhydrous crystalline form or solvate with an amorphous compound of formula (I) or with one or more other anhydrous crystalline form or solvate. Mixtures of a form or solvate with an amorphous compound of formula (I) and / or another crystalline form or solvate may result in masking or the absence of one or more of the X-ray diffraction peaks described above for that particular form. Methods for analyzing mixtures of crystalline forms are known in the art to determine precisely whether or not a particular crystalline form is present in the mixture.

• ·

9 · ···· · · · ···· · ·

Any anhydrous crystalline form or solvate of the invention is admixed with the hydrated crystalline form. For example, hydrated crystalline forms of the compound of formula (I) are present in each batch containing the anhydrous crystalline form of the compound of formula (I).

The invention relates to a process for preparing a compound of formula (I) in anhydrous crystalline form, which comprises dissolving an amorphous compound of formula (I) in a solvent to obtain one or more anhydrous crystalline forms and or solvates.

The invention relates to a process for the preparation of a compound of formula (I) in anhydrous crystalline form, comprising the steps of:

a) forming a solution of the compound of formula (I) in the form of the free base or a salt thereof;

b) isolating the compound of formula (I) from solution and optionally removing the free (wet, undissolved) solvent, leaving the compound of formula (I) in dry form;

c) converting the optionally dried compound of formula (I) from step b) to the anhydrous crystalline form by treating the compound of formula (I) with a solvent; and

d) isolating the anhydrous crystalline form.

The compound of formula (I) is produced by any method known in the art, preferably as described in patent application WO 96/01833, to which reference is made.

Synthesis of a compound of formula (I) results in a compound in solution in the reaction mixture from which it is recovered as a solid by separation and purification. The compound of formula (I) is further optionally dried. Many different factors influence the crystalline form of the compound as a solid. According to the invention, the modification of the conditions results in

999

9

9999

Separation and / or subsequent manufacture to produce a compound of formula (I) in the form of one particular anhydrous crystalline form or solvate or in the form of a mixture of two or more anhydrous crystalline forms or solvates.

A suitable solvent is a water-soluble organic solvent that dissolves sufficiently. The solvent is used in an amount allowing partial dissolution of the compound to convert and precipitate the desired anhydrous crystalline form of the compound of formula (I), for example, from the hydrated crystalline form. The solvent is preferably removed by drying under vacuum.

The wet compound of formula (I) after the first isolation (point b) above) is dried, for example at a temperature between 30 and 70 ° C, to obtain a dry compound of formula (I).

The invention encompasses the use of crystalline forms and solvates of a compound of formula (I) in medical practice, for example in the treatment or prophylaxis, including suppression of recurrence of symptoms, viral diseases of animals, for example mammals, including humans. Anhydrous crystalline forms and solvates of the compound of formula (I) are particularly suitable for the treatment or prophylaxis of viral diseases, for example herpes infections, CMV infections, diseases caused by hepatitis B virus and hepatitis C virus. for the treatment and prophylaxis of viral diseases in other animals, such as mammals.

The invention relates to a method for the treatment or prophylaxis of viral infections, in particular herpes infections, CMV infections, diseases caused by hepatitis B virus and hepatitis C virus in animals, e.g. mammals, including humans, comprising administering an effective amount of an antiviral compound of formula form or solvate.

The invention relates to the use of anhydrous crystalline forms or solvates of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of a viral infection.

• «• ·

As used herein, the term prophylaxis means preventing infection, preventing the occurrence of symptoms, and preventing recurrence of symptoms.

The anhydrous crystalline forms and solvates of the compound of formula (I) are administered by any suitable route, preferably orally. The most suitable route of administration varies, for example, according to the condition of the recipient.

The amount of active compound administered (as defined above) in the above indications and uses is influenced by a variety of factors, including the severity of the disease and the condition of the patient, and is ultimately determined by the attending physician or veterinarian. In general, an effective dose in these indications and uses is in the range of 0.01 to 250 mg per kilogram of body weight of the recipient per day, preferably in the range of 0.1 to 100 mg per kilogram of body weight per day, more preferably at between 0.5 and 30 mg per kilogram of body weight per day, preferably between 1.0 and 30 mg per kilogram of body weight per day (all doses of active ingredient are calculated for the free base of the compound of formula (I) unless otherwise stated). The required amount of active compound is administered during the day in one, two, three or four or more doses at appropriate intervals. These doses are administered in unit dosage forms containing 10 to 1200 mg, or 50 to 500 mg, preferably 20 to 500 mg, most preferably 100 to 400 mg of active ingredient per unit dosage form.

The active ingredient is administered alone or in a pharmaceutical formulation. The pharmaceutical composition comprises the active ingredient as defined above, one or more pharmaceutically acceptable vehicles and optionally other therapeutic agents. The vehicle is "acceptable" in the sense of being compatible with the other ingredients of the formulation and in terms of harmlessness to the recipient.

Formulations suitable for oral administration in unit dosage form are prepared by any method known in the pharmaceutical art. In manufacture, the active ingredient is combined with a carrier which constitutes one or more accessory ingredients. In general, all products are produced uniformly by joining • · ·· ··

Active substances with liquid carriers or solid carriers divided at the end of the process or both, if necessary with subsequent division of the preparation.

Formulations of the invention for oral administration are presented in unit dose form such as capsules, capsules, sachets with granules or tablets (swallowable, soluble or chewable tablets) with a given amount of active ingredient in a single dosage form; or in the form of a powder or granules; in the form of a solution or suspension in an aqueous or non-aqueous liquid; or in the form of an oil-in-water or water-in-oil emulsion. The active ingredient is also in the form of a bolus, electuary or paste.

Tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are prepared in a suitable machine by compressing the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, glidant, inert solvent, preservative, surfactant or dispersant. Molded tablets are made by casting a mixture of the compound in the form of a powder and an inert liquid solvent in a suitable machine. The tablets may optionally be coated, scored or formulated such that the release of the active ingredient is slow or controlled.

The anhydrous crystalline forms and solvates of the invention are also administered topically, parenterally, and by other suitable methods using the carriers and methods described in patent application WO 96/01833. In the manufacture of dosage forms in which the anhydrous crystalline forms or solvates are completely dissolved in a solvent such as solutions, for example for parenteral use, it is not possible to identify the particular crystalline form used in the solution. All anhydrous crystalline forms and solvates are suitable for the manufacture of solutions in which the crystalline forms or solvates are completely dissolved in a suitable solvent.

Preferably, the individual dosage forms comprise a daily dose of the active ingredient or a daily sub-dose of the active ingredient (as described above) or a portion thereof.

- 18 ·· ··

The compositions according to the invention also contain other substances commonly used in the manufacture of pharmaceutical preparations, for example oral preparations contain flavorings or taste-masking agents.

The following examples are given by way of illustration. However, the invention is not limited to these examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Form I 5, 6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole

200 mg of the compound of formula (I) was placed in a thermal activity monitor (TAM) and a few drops of water were dripped onto the powder to wet it. The tube was sealed and stored in a TAM chamber at 50 ° C. The mixture was cooled to room temperature and filtered. The wet residue was dried under vacuum at 60 ° C overnight to give the compound of formula (I) in Form I.

Figure 1 shows an X-ray x-ray of the product of Example 1.

Example 2

Form 15,6-Dichloro-2- (isopropylamino) -1-beta-L-ribofuranosyl-1H-benzimidazole

1.5 g of the compound of formula (I) was dissolved in 30 ml of water and heated to 65 ° C with stirring. After 0.5 hours, mixing became difficult as rubber began to form. Further heating, the gum turned into a solid, which was broken with a spatula. The mixture was heated at 65-70 ° C for 9 hours. Then

The mixture was cooled to 20 ° C, the solid was collected by filtration and dried under vacuum at 40 ° C for 24 hours. ° C to give the compound of formula (I) in Form I.

The X-ray xenogram of the product of Example 2 is shown in Figure 1.

Example 3

Form I 5, 6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H benzimidazole g of the compound of formula (I) and 1.5 ml of water was stirred in an oil bath and heated to 80 ° C. Stirring was complete after the powder turned into a gum. Heating was continued for another 8 hours. The solid was pulverized with a spatula and mixed occasionally. After cooling to 20 ° C, the solid was collected and dried under vacuum at 40 ° C for 4 hours.

An X-ray xenogram of the product of Example 3 is shown in Figure 1.

Example 4

Form I 5, 6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole g of the compound of formula (I) in 15 ml of toluene was refluxed for 19 hours. During heating, the suspension turned into a gum and this became a solid by further heating. The solid was collected by filtration and dried at 40 ° C under vacuum to give the compound of formula (I).

An X-ray xenogram of the product of Example 4 is shown in Figure 1.

• ·

- 20 Example 5

Preparation of 5,6-dichloro-2- (isopropylamino) -1-beta-L-ribofuranosyl-1H benzimidazole form I from Form II g of the compound of formula (I) Form II in toluene (10 mL, 5 volumes) was heated to 60 ° C. At this temperature the solid began to settle on the walls of the tube. Further heating to 95 ° C gave an oil. Heating was continued at 105 ° C, toluene (2.5 volumes) was added and heating continued. While stirring rapidly, reflux was continued for 3 hours. After cooling the oil bath to 80 ° C (internal temperature 73 ° C), heating was continued with rapid stirring for a further 3 hours. The mixture was heated under reflux for 16 hours and then allowed to cool to room temperature. The milled solid was collected by filtration, rinsed with toluene (2 x 5 mL) and dried under vacuum at 20 ° C and 40 ° C to give a white solid. The solid residue was removed from the tube, collected by filtration and dried under vacuum at 20 ° C. The filtrate was concentrated under reduced pressure to give a yellow solid.

An X-ray xenogram of the product of Example 5 is shown in Figure 1.

Example 6

Preparation of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole form I from Form II g of the compound of formula (I) was stirred with 1.5 ml of water in an oil bath at 80 ° C . Once the oil bath temperature reached 60 ° C, mixing of the mixture became difficult. After heating with occasional stirring for 8 hours, the mixture was cooled to room temperature. Finally, the mixture was dried under vacuum at 40 ° C for 4 hours.

An X-ray X-ray of the product of Example 6 is shown in Figure 1.

• ·

Example 7

Form 115,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole

100 g of the compound of formula (I) was added to toluene stirred in methanol (4: 1,440 mL) and heated to 65 ° C to form a clear solution. The solution was purified by rinsing (toluene in methanol (4: 1, 110 mL, warm) on the filter. After heating the solution again to 65 ° C, toluene (4.5 volumes) was slowly added while maintaining the internal temperature at 65 ° C. After the addition of toluene was complete, the solution was cooled to 40 ° C for 1 hour and allowed to stand at 40 ° C. After 0.5 hour, the mixture was treated with compound of formula (I) Form II and then allowed to stand for 4.5 hours. After 1 hour at 20 ° C, the suspension was allowed to stand for 12 hours at 20 ° C, then cooled to 5 ° C for 1 hour and allowed to stand for 3 hours .The solid was collected by filtration rinsing with toluene (2 x 100 mL). The wet cake was transferred to a dryer and dried at 20 ° C under vacuum.

An X-ray X-ray of the product of Example 7 is shown in Figure 2.

Example 8

Form II 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole

The compound of formula (I) (1.0 pbw) was dissolved in ethyl acetate (6.0 volumes) and filtered. The filtrates were concentrated to 3 volumes.

The solvent was completely changed, the solution was refilled to 3.5 volumes with methanol. After adding 0.5 volumes of water, the solution was cooled to 0-5 ° C. A small amount of pure compound of formula (I) was added to the solution during crystallization and the solution was left at 0-5 ° C for 2 hours. The product was filtered (without rinsing) and dried under vacuum at room temperature for 24-48 hours. A second portion of the yield was obtained by evaporating the filtrate to half volume followed by

Cooling, addition of the compound of formula (I) and crystallization similar to those described above.

An X-ray X-ray of the product of Example 8 is shown in Figure 2.

Example 9

Form II 5, 6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H benzimidazole g of the compound of formula (I) was dissolved in 20 ml of methanol and heated to 50 ° C. After addition of 5 ml of water, the mixture was slowly cooled to 5 ° C and stirred at 5 ° C for 1 hour. The solid was collected by filtration and dried under vacuum for 15 hours at 20 ° C and then for 4 hours at 40 ° C to give the compound of formula (I).

An X-ray xenogram of the product of Example 9 is shown in Figure 2.

Example 10

Production of mixtures of forms 5,6-dichloro - 2- (isopropylamino) - 1-beta-L ribofuranosyl-1H-benzimidazole

The compound of formula (I) was dissolved in 60 ml of 2N hydrochloric acid, stirred for 0.5 hours and filtered. After the filtrate was heated to 60 ° C, 55 ml of 2N sodium hydroxide was slowly added to the mixture while maintaining the internal temperature at 60-70 ° C. The mixture was stirred at 65-70 ° C for 2 hours and then cooled to 20 ° C in 2 hours. The solid was collected by filtration, rinsed with water (2 x 30 mL) and dried under vacuum at 40 ° C for 16 hours to give the compound of formula (I) (8.8 g; 88 g / l).

• »

- 23 Example 11

5,6-Dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole Ethanolate

··

The compound of formula (I) (1.0 part by weight) was dissolved in ethanol in water (10.0 volumes) at 70 ° C for 2 hours. The ethanol: water (v: v) ratios were as follows: 10: 90, 15: 85, 20: 80, 25: 75 and 30: 70. The resulting white free-flowing powder was filtered and air dried. The ethanol solvate was similarly obtained from ethanol in toluene (5: 95, 10: 90, 15: 85, 20: 80, 25: 75 and 30: 70).

An X-ray xenogram of the product of Example 11 is shown in Figure 3.

Example 12

5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole ethanolate g of the compound of formula (I) was added to toluene slurried in ethanol (7: 1, 200 mL) and heated at 81 ° C under reflux to form a clear solution. Crystallization occurred at 50 ° C while cooling the solution to 20 ° C. The suspension was cooled to 0-5 ° C and allowed to stand for 2 hours. The solid was collected by filtration and rinsed with toluene (2 x 20 mL). The wet cake was dried under vacuum at 40 ° C.

Recrystallization of the compound of formula (I) from ethanol in water or ethanol in toluene afforded an ethanol solvate containing 0.5 moles of ethanol per mole of compound of formula (I).

An X-ray X-ray of the product of Example 12 is shown in Figure 3.

- 24 • »····

Example 13

Form IV 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole g form I prepared as described in Example 1 above was mixed with 300 mL of water. The mixture was heated at 50 ° C for 6 days and then cooled to room temperature. The solid granular crystalline material was filtered and dried at 60 ° C under vacuum.

The X-ray xenogram of the product of Example 13 is shown in Figure 3.

Example 14

Form V 5,6-Dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole

2.0 g of the compound of formula (I) were gradually added to 40 ml of water at 70 ° C for 2 hours with rapid stirring. The mixture was heated to 65-70 ° C and stirred for an additional 7 hours, then stirring and heating was complete. After standing at room temperature for 2.5 days, the mixture was filtered. The white granular solid residue was air dried overnight to give the compound of formula (I) as Form V.

An X-ray X-ray of the product of Example 14 is shown in Figure 5.

Example 15

Form V 5,6-Dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole

72.86 mg of the compound of formula (I) in form VI was completely dissolved in 1 ml of acetonitrile. After standing at room temperature for 30 days, large crystals of the compound of formula (I) in Form V precipitated from solution.

An X-ray of the product of Example 15 is shown in Figure 5.

Example 16

Form VI 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole

200 mg of the ethanolate of the compound of formula (I) was weighed into small tubes. Hydrostats with saturated NaCl solutions and excess solid NaCl were placed in the tubes. The tubes were sealed and stored at 80 ° C. After removal from the tubes, samples were heated to 170 ° C in a DSC differential calorimeter and then cooled to room temperature. The powder was collected from DSC dishes and analyzed by X-ray.

Characteristics: An X-ray xenogram of the product of Example 16 (Form VI) is shown in Figure 6. The measurements yielded the following values of 2 theta angles, d-distances, relative intensities, and Miller indices:

- 26 • 9 9 * 9 9 9 9 9999 999999 9 9 9 9 9 99 9999

9

9 99

Table 1: X-ray X-ray Form VI of 1263W94

2 Theta (°) ¹ A ² AND H ³ K ³ I ³ 8.53 10.36 14.5 0 0 4 10.47 8.45 25.6 1 0 2 12.80 6.91 16.8 0 0 6 14.16 6.25 16.4 1 1 2 13.51 6.55 21.4 1 1 0 14.95 5.92 60.4 1 1 3 15.98 5.54 26.2 1 1 4 17.23 5.14 100.0 1 1 5 19.25 4.61 19.3 2 0 1 21.41 4.15 26.5 2 1 0 21.83 4.07 60.4 2 1 2 22.35 3.97 38.3 2 1 3 23.07 3.85 48.7 2 1 4 27.49 3.24 30.9 2 1 8 30.11 2.97 18.5 2 2 6

¹ confidence limits are ± 0.05 degree ² confidence limits are ± 0.05 degree ³ Miller indices, h, k, and I above are used to describe a set of parallel faces on a crystal

Example 17

Production of Form VI of 5,6-dichloro-2- (isopropylamino) -1-beta-L-ribofuranosyl 1H-benzimidazole by crystallization from ethyl acetate in toluene

To a suspension of 5,6-dichloro-2- (isopropylamino) -1- (1,3,5-tri-O-acetyl-beta-L-ribofuranosyl) -1H-benzimidazole (385 g) in TMBE (1790 mL) • ·

27 containing methanol (179 mL) was added sodium hydroxide (2M, 1790 mL). The mixture was stirred at 25-30 ° C until completion of the reaction. After separation of the layers, the aqueous layer was further extracted with TBME (716 mL). The combined organic solutions were washed with 10 g / L sodium chloride solution (2 x 1790 mL). The organic solution was concentrated to 2.5 volumes (895 mL) at atmospheric pressure. After addition of ethyl acetate (2864 mL), the solution was again concentrated to 2.5 volumes. The solution was cooled to 40-50 ° C and purified by rinsing with ethyl acetate (716 mL). The purified solution was concentrated under atmospheric pressure to 3.3 volumes (1180 mL).

The solution was heated to 60 ° C. Toluene (3000 mL) at 60 ° C was added to the ethyl acetate solution for 1 hour. The resulting mixture was allowed to stand overnight at 60 ° C, then cooled to 0-5 ° C in 1 hour and allowed to stand at 0.5 ° C for 2 hours. The suspension was filtered, rinsed with ethyl acetate and toluene 1: 4 (2 x 716 mL) and dried under vacuum at 40 ° C for 18 hours to give 5,6-dichloro-2- (isopropylamino) -1- (beta-L - ribofuranosyl) -1H benzimidazole in form VI.

Characteristic: as in Example 16.

Example 18

Experimental methods of crystalline forms and solvates characteristics

X-ray powder

X-rays were generated on a Phillips X Pert MPD diffractometer equipped with a graphite monochromator of the curvature of the bent beam using X-rays from a copper cathode and an automatic divergence slit. The diffractometer was used in a scan step mode of 0.04 ° per step and 1 second for the duration of the step. The detector was a xenon proportional computer with a graphite monochromator. Samples were filled by settling until • 4

- 28 brackets with a diameter of 16 mm and a thickness of 2 mm. X-rays of forms I, II, IV, V, VI and ethanolate are shown in Figures 1, 2, 4, 5, 6 and 3.

Example 19

Tablet Preparation A

Tablets with ethanolate 1263W94 direct compressed tablet

content of active substance 100 mg 400 mg basic components ethanolate 1263W94 105.9 ² 423,6 ³ microcrystalline cellulose, NF 200.0 800.0 crospovidone, NF 20.0 80.0 magnesium stearate, NF 0.8 3.2 total (base) 326.7 mg 1306.8 mg coating components Opadry White YS - 1 - 18034 9.0 36.0 distilled water USP ¹ q.s. q.s. total (base) 335.7 mg 1342.8 mg theoretical dose size (basics) kg 0.8168 tablet 2500

¹ removed during production ² equivalent of 100 mg 1263W94 per tablet ³ equivalent of 400 mg 1263W94 per tablet • ·

- 29 Tablets with a combination of Form II and Amorphous Form 1263W94 Direct Compressed Tablet

content of active substance 100 mg 400 mg basic components 1263W94 103.3 ² 413,2 ³ anhydrous lactose, NF 65.0 260.0 microcrystalline cellulose, NF 20.0 80.0 crospovidone, NF 12.0 48.0 magnesium stearate, NF 1.0 4.0 total (base) 201.3 mg 805.2 mg coating components Opadry White YS-1 -18034 6.0 24.0 distilled water USP ¹ q.s. q.s. total (base) 207.3 mg 892.2 mg theoretical dose size (basics) kg 0.785 tablet 3900

¹ removed during manufacture ² equivalent of 100 mg of 1263W94 per tablet ³ equivalent of 400 mg of 1263W94 per tablet

Direct compression tablet manufacturing process

All ingredients, except magnesium stearate, were sieved on a 20-30 mesh screen. All components, except magnesium stearate, were ground until combined. The magnesium stearate was screened as described above, added to the other ingredients and ground. Tablets were compressed on a rotary press. By mixing Opadry White with water a coating suspension was formed

- 30 concentration of 10 g / l. The tablets were coated with an amount not exceeding 3% by weight.

Preparation B

Tablets with ethanolate 1263W94 tablet prepared by wet granulation

content of active substance 100 mg 400 mg basic components ethanolate 1263W94 105.9 ² 423,6 ³ microcrystalline cellulose, NF 75.0 300.0 crospovidone, NF 15.0 60.0 povidone, USP, K30 7.5 30.0 magnesium stearate, NF 0.6 2.4 distilled water USP ¹ q.s. q.s. total (base) 204.0 mg 816.0 mg coating components Opadry White YS - 1 - 18034 6.0 24.0 distilled water USP ¹ q.s. q.s. total (base) 210.0 mg 840.0 mg theoretical dose size (basics) kg 0,714 tablet 3500

¹ removed during manufacture ² equivalent of 100 mg of 1263W94 per tablet ³ equivalent of 400 mg of 1263W94 per tablet

Tablets with a combination of Form II and Amorphous Form 1263W94 tablet prepared by wet granulation

content of active substance 100 mg 400 mg basic components 1263W94 103.3 ² 413,2 ³ anhydrous lactose, NF 60.0 240.0 microcrystalline cellulose, NF 20.0 80.0 crospovidone, NF 12.0 48.0 povidone, USP, K30 6.0 24.0 sodium lauryl sulfate, NF 2,0 8.0 colloidal silica, NF 0.6 2.4 magnesium stearate, NF 1.0 4.0 distilled water USP ¹ q.s. q.s. total (base) 204.9 mg 819.6 mg coating components Opadry White YS - 1 - 18034 6.0 24.0 distilled water USP ¹ q.s. q.s. total (base) 210.9 mg 843.6 mg theoretical dose size (basics) kg 0.799 tablet 3900

¹ removed during manufacture ² equivalent of 100 mg of 1263W94 per tablet ³ equivalent of 400 mg of 1263W94 per tablet

Process for making tablets by wet granulation

The ingredients were sieved on a 20-30 mesh screen. The ingredients were dry blended in a high shear granulator until they were combined and then were

- 32

in a high shear granulator, granulated using distilled water. The granules were dried to lose less than 2% by weight on drying. The granules were sieved as described above. The remaining ingredients were screened in the same manner and mixed with the granules. Tablets were compressed on a rotary press. By mixing Opadry White with water a coating suspension was prepared at a concentration of 10 g / l. The tablets were coated with an amount not exceeding 3% by weight.

Example 20

Capsule

The following preparation was made using the compound of formula (I) in Form II in the manner described below.

Capsule with 1263W94 in form II

content of active substance 100 mg Capsule filling ingredients 1263W94 (active substance) 101.0 ¹ anhydrous lactose, NF 232.0 crospovidone, NF 17.0 magnesium stearate, NF 1.0 total fill weight 351.0 mg capsule packaging ingredients gelatin on the opaque tip and body 81.1 total weight 432.5 mg

¹ equivalent of 100 mg 1263W94 per tablet

Capsule manufacturing process

The ingredients of the capsule filling were mixed in the mortar with a pestle using geometric dilution. The combined fill ingredients were manually filled into gelatin capsules and the capsules were then manually sealed.

Example 21

Oral suspension

This preparation was made using a compound of formula (I) in form I, II, V or a mixture of forms I and V as described below.

Oral suspension with 1263W94

content of active substance 30 mg / ml folders in 100 ml 1263W94 (active substance) 3,0 g sucrose 50,0 g propylene glycol 5.0 g sodium chloride 0.5 g citric acid q.s. sodium citrate q.s. microcrystalline cellulose; and sodium carboxymethylcellulose 2.5 g sodium carboxymethylcellulose 0.25 g polysorbate 80 0.2 g sodium benzoate 0.1 g methylparaben 0.1 g flavor 0.2 ml dye 0,005 g distilled water USP q.s. total volume 100.0 ml

99 * • » • 9 9 9 • * * * • • · • « • • 9 9 • 9 9 ♦  * • 9 9 9 * ··· • · • · ·

Procedure for the manufacture of an oral solution

Sucrose was dissolved in distilled water to 70% of the total batch volume. Sodium chloride, citric acid, sodium citrate and sodium benzoate were dissolved in the solution with stirring. Citric acid or sodium citrate was used to adjust the pH, which should be between 5.0 and 6.0.

Microcrystalline cellulose and sodium carboxymethylcellulose (Avicel RC 591) were added to the solution with stirring, and stirring was continued until a uniform, smooth suspension was formed. Polysorbate was then added with stirring. In a separate vessel, methyl paraben was dissolved in propylene glycol and sodium carboxymethylcellulose (0.25 g) was dispersed in the solution. This liquid was added to the bulk dispersion with stirring. The active ingredient was gradually dispersed in this bulky liquid with stirring. The dispersion was stirred until it became uniform. After adding flavor and color, the volume was made up to 100 ml with distilled water. The suspension was then homogenized by passing through a pump and a colloid mill.

The invention is illustrated by the preceding examples, but is not limited to these examples. The invention is defined in the following claims, including equivalents thereof.

Claims (15)

PATENT CLAIMS 1. 5,6-Dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole Form II characterized by the X-ray diffraction pattern in Figure 2, characterized in that the X-ray diffractometer is obtained by a diffractometer equipped with a graphite monochromator. Copper cathode radiation; and. 2. A crystalline form of 5,6-dichloro-2- (isopropylamino) -1-β-L ribofuranosyl-1H-benzimidazole characterized by an X-ray expressed in 2 theta angles and obtained by a diffractometer equipped with a graphite bent-beam curvature monochromator using copper X-ray radiation and characterized in that the x-ray pattern comprises 2 theta angles at five or more locations selected from the group of five or more of the following locations: 7.91 ± 0.09; 17.33 ± 0.09; 18.23 ± 0.95; 18.23 ± 0.95; 19.60 ± 0.09; 21.88 ± 0.09; 23.24 ± 0.09; 23.92 ± 0.09; 25.27 ± 0.09; 27.70 ± 0.09 and 29.21 ± 0.09 degrees. 3. Ethanol solvate of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole characterized by the X-ray pattern in Figure 3, characterized in that the X-ray pattern is obtained by a diffractometer equipped with a graphite monochromator. of copper cathode; and. • «• 9 * * - 36 4. 5,6-Dichloro-2- (isopropylamino) -1-β-L ribofuranosyl-1H-benzimidazole ethanol solvate characterized by an X-ray expressed in 2 theta angles and obtained by a diffractometer equipped with a graphite bent-beam curvature monochromator using copper x-ray X-rays and characterized in that the x-ray pattern comprises 2 theta angles at five or more locations selected from the group of five or more of the following locations: 9.07 ± 0.05; 10.38 ± 0.05; 15.95 ± 0.05; 17.72 ± 0.05; 20.75 ± 0.05; 21.37 ± 0.05; 22.96 ± 0.05; 23.93 ± 0.05; 25.40 ± 0.05 and 29.05 ± 0.05 degrees. 5. 5,6-Dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole in form V characterized by the X-ray diffraction pattern in Figure 5, characterized in that the X-ray diffractometer is obtained by a diffractometer equipped with a graphite monochromator. Copper cathode radiation; and. 6. Crystalline form 5,6-dichloro-2- (isopropylamino) -1-β-L ribofuranosyl-1H-benzimidazole characterized by an X-ray expressed in 2 theta angles and obtained by a diffractometer equipped with a graphite bent-ray curvature monochromator using copper X-ray radiation and characterized in that the x-ray pattern comprises 2 theta angles at five or more locations selected from the group of five or more of the following locations: 13.30 ± 0.05; 18.13 ± 0.05; 18.78 ± 0.05; 20.41 ± 0.05; 21.75 ± 0.05; 23.02 ± 0.05; 26.87 ± 0.05; 28.34 ± 0.05; 28.55 ± 0.05 and 30.22 ± 0.05 degrees. • * ···· - 37 7; A composition comprising a mixture of two or more forms or solvates of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole according to any one of claims 1 to 6. A preparation comprising 5,6-dichloro-2- (isopropylamino) -1-β-L ribofuranosyl-1H-benzimidazole in form II according to claims 1 and 5, 6 dichloro-2- (isopropylamino) -1-β-L- ribofuranosyl -1H benzimidazole in amorphous form. 9. A preparation containing 5,6-dichloro-2- (isopropylamino) -1-β-L ribofuranosyl-1H-benzimidazole in form I characterized by the X-ray pattern in Figures 1 and 5, 6-dichloro-2- (isopropylamino) -1 β - L - ribofuranosyl - 1H - benzimidazole in form V characterized by the X-ray diffraction pattern in Figure 5, characterized in that the X-ray diffractometers are obtained with a diffractometer equipped with a graphite bent-beam curvature monochromator using copper X-ray X-ray radiation. The formulation according to claim 9 further comprising 5,6-dichloro-2 (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole in form VI characterized by an X-ray expressed in 2 theta values obtained by a diffractometer equipped with a graphite monochromator the use of X-rays from a copper cathode and wherein said X-ray X-ray comprises 2 theta angles at five or more locations selected from the group of five or more of the following locations: 9.29 ± 0.05; 16.04 ± 0.05; 18.67 ± 0.05; 22.06 ± 0.05; 22.68 ± 0.05; 23.34 + 0.05; 24.40 ± 0.05; 29.64 ± 0.05; 30.92 ± 0.05 and 31.62 ± 0.05 degrees. 9 4 ♦ 9 - 38 • · 9 9 9 • 99 • 4 9 9 9 99 9 9 A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and at least one pharmaceutically acceptable carrier. 12.5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole according to any one of claims 1 to 6 for use in medical practice. Use of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of viral infections. A method of treating viral infections in humans, comprising administering to the human host an effective amount of a solvate or crystalline form of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H benzimidazole according to any one of the claims 1 to 6. 15. A process for the preparation of 5,6-dichloro-2- (isopropylamino) -1-β-L ribofuranosyl-1H-benzimidazole in anhydrous crystalline form, characterized in that it comprises the following steps: (a) preparation of 5,6-dichloro-2- (isopropylamino) -1-β-L ribofuranosyl-1H-benzimidazole in solution as the free base or a salt thereof; (b) isolating 5,6-dichloro-2- (isopropylamino) -1-β-L ribofuranosyl-1H-benzimidazole from solution and optionally removing the free solvent so as to remain dry 5,6-dichloro-2- (isopropylamino) -1- β-L-ribofuranosyl-1H-benzimidazole; c) dissolving 5,6-dichloro-2- (isopropylamino) -1-β-L ribofuranosyl-1H-benzimidazole in a solvent, thereby yielding a certain amount of said optionally dried 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole is converted to 5,6-dichloro-2- (isopropylamino) 1-β-L-ribofuranosyl-1H-benzimidazole in said anhydrous crystalline form; and d) isolating said anhydrous crystalline form.