MXPA00009703A - Form vi 5,6-dichloro-2-(isopropylamino)- 1-(&bgr;-l-ribofuranosyl)-1h-benzimidazole - Google Patents

Abstract

The invention relates to Form VI 5, 6-dichloro-2- (isopropylamino)-1-&bgr;-L-ribofuranosyl-1H-benzimidazole, pharmaceutical compositions, and their use in medical therapy.

Description

FORM VI OF 5.6 -DICLORO- 2 - (ISOPROPILAMINO) - 1 - (BETA-L-RIBOFURANOSIL) - 1H- BENCIMIDAZOLE BACKGROUND OF THE INVENTION The present invention relates to a crystalline form of the antiviral compound 5,6-dichloro-2- (isopropylamino) -1- (β-ribofuranosyl) -lH-benzimidazole (also known as 1263W94; the formula (I)), to pharmaceutical formulations comprising this crystalline form of the antiviral compound and to its use in therapy. I / 5,6-Dichloro-2- (isopropylamino) -1- (β-L-I ribofuranosyl) -lH-benzimidazole is a benzimidazole derivative useful in medical therapy. O96 / 01833 describes the compound of the formula (I) and its use for the treatment or prophylaxis of viral infections such as those caused by the herpes viruses. The compounds as described in WO96 / 01833 are in the form of a non-crystalline, amorphous material. The structure of 5,6-dichloro-2- (isopropylamino) -l- (β-L-ribofuranosyl) -1H-benzimidazole, the compound of the formula (I), is shown below: It has now been found that the compound of the formula (I) can exist in various crystalline forms and solvates. In addition, a particular crystalline form of the compound of the formula (I), form VI, which is anhydrous and crystalline and surprisingly has particularly good pharmaceutical properties, has been discovered. Form VI is the thermodynamically most stable form of the compound of formula (I). It can be prepared easily and can be manufactured on a commercial scale. It is particularly stable and essentially non-hygroscopic. Batches of this crystalline form can be processed in a consistent manner at a high purity of crystal form, ie, where the proportion of other amorphous and crystalline forms of the compound of the formula (I) is limited. In addition, this crystalline, anhydrous form has good storage properties and can be formulated easily in pharmaceutical compositions such as tablets and capsules. The crystalline forms and solvates of the compound of the formula (I) can be characterized by their powder diffraction patterns in X-rays.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1.- X-ray powder diffraction pattern of the form I of the compound of the formula (I). This pattern was obtained according to. the procedures set forth in Example 22. Figure 2.- X-ray powder diffraction pattern of the form II of the compound of the formula (I). This pattern was obtained according to the procedures set forth in Example 22. Figure 3. X-ray powder diffraction pattern of the ethanol solvate of the compound of the formula (I) (subsequently "ethanolate"). This pattern was obtained according to the procedures set forth in Example 22. Figure 4. X-ray powder diffraction pattern of the form IV of the compound of the formula (I). This pattern was obtained according to the procedures set forth in Example 22.

Figure 5. X-ray powder diffraction pattern of the V form of the compound of the formula (I) This pattern was obtained according to the procedures set forth in Example 22. Figure €. X-ray powder diffraction pattern of the VI form of the compound of the formula (I) This pattern was obtained according to the procedures set forth in Example 22. Figure 7.- TGA thermogram for the VI form of the compound of the formula (I). This thermogram of TGA was obtained according to the procedures set forth in Example 22. Figure 8.- Moisture absorption isotherm for the VI form of the compound of the formula (I). Figure 9.- DSC thermogram for the form VI of the compound of the formula (I). This TGA thermogram was obtained according to the procedures set forth in Example 22. Figure 10.- X-ray diffraction pattern of the individual crystal for an individual crystal of the VI form of the compound of the formula (I).

This pattern was obtained according to the procedures set forth in Example 22.

DETAILED DESCRIPTION OF THE INVENTION According to a first aspect of the invention, the compound of the formula (I) is provided in a thermodynamically stable crystalline form (referred to later as form VI). Form VI is defined by the X-ray powder diffraction pattern illustrated in Figure 6, which is obtained by an appropriately aligned diffractometer, equipped with a diffracted beam graphite monochromator using copper Ka X radiation. Form VI can be prepared from the ethanol solvate of the compound of formula (I) at certain relative humidities. Form VI can also be prepared from thick seeded suspensions of Form II or ethanol solvate in water with Form VI. Other solvent systems that can produce the VI form in the seed include ethyl acetate / toluene, isopropanol / toluene, 2-butanone / toluene. In a further aspect of the invention, the compound of the formula (I) is provided as a mixture of the form VI with any one or more of the forms I, II; IV, V or solvates or as a mixture of the VI form and amorphous material, or as a mixture of the VI form, amorphous material and one or more different crystalline forms or solvates. As used herein, the term "solvate" is a complex of variable stoichiometry formed by a solute (a compound of the formula (I)) and a solvent. Solvents, by way of example, include water, methanol, ethanol, or acetic acid. Hereinafter, the reference to a compound of the formula (I) is to the amorphous form of this compound, unless another form or solvate thereof is specified. Subsequently herein by "anhydrous crystalline form" according to the invention, it is meant a crystalline form having substantially the same X-ray powder diffraction pattern as shown in Figure 6 when measured with an appropriately aligned diffractometer equipped with a graphite monochromator with diffracted beam using a KX copper ratio. The X-ray powder diffraction pattern of the crystalline, anhydrous form VI of the present invention is determined using conventional techniques and equipment known to those skilled in the art of physical characterization.

The diffraction patterns in Figures 1-6 were obtained with a Philips X-Pert MPD diffractometer system equipped with a diffracted beam graphite monochromator using copper Ka X radiation and an automated divergent slot. A proportional xenon counter was used as the detector. The powder sample used to generate the X-ray powder diffraction data was prepared by conventional filling sample preparation techniques using a carrier 16 mm in diameter and approximately 2.0 mm thick. A powder sample of each of the forms I, II, IV, V, VI and ethanolate were used to produce the X-ray powder diffraction patterns of Figures 1, 2, 4, 5, 6 and 3, respectively. The X-ray diffraction patterns for each of the various shapes and solvates are unique to the particular shape. Each anhydrous, crystalline or solvate form exhibits a diffraction pattern with a unique set of diffraction peaks that can be expressed at 2 theta (°), d-spaced (Á) and / or relative peak intensities. The diffraction angles 2 theta and the corresponding d-spaced values account for the positions of the various peaks in the X-ray diffraction pattern. The d-spacing values were calculated with the observed 2 theta angles and the length of Copper Kal wave using the Bragg equation. Light variations in the 2 theta angles observed and the d-spaced angles are expected based on the specific diffractometer used and the sample preparation technique of the analyzer. More variation is expected for peak, relative intensities. Identification of the exact crystal shape of a compound should be based preliminarily on 2 theta angles observed or d-spaced with a less important place at the peak, relative intensities.

To identify the VI form of 5,6-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H-benzimidazole, the peak of the most characteristic, individual 2 theta angle occurs at 8.53 degrees, or 10.36 Á d-spaced. Although one skilled in the art can identify the VI shape of the characteristic 2-theta angle peak at 8.53 degrees, in some circumstances it may be desirable to rely on multiple 2 theta angles or multiple d-spaced angles for the identification of the VI form. Form VI of 5,6-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -IH-benzimidazole can also be identified by the presence of multiple characteristic 2-theta angle peaks including two, three, four , five, six, seven, eight, nine, ten or eleven of the angles of 2 theta that are reasonably characteristic of this particular crystalline form. These peaks present in the following positions, expressed in 2 theta angles: 8.53, 10.47, 13.51, 14.95, 15.98, 17.23, 21.41, 21.83, 22.35, 23.07, and 27.49 degrees. In one embodiment, at least five of the previous 2 theta angles are used to identify the VI form. The anhydrous, crystalline VI form typically exhibits peaks of 2 theta angles in addition to the above peaks. For example, the VI form may exhibit peaks of 2 theta angle in essentially the following positions: 8.5, 10.5, 12.8, 13.5, 14.2, 15.0, 16.0, 17.2, 17.8, 19.2, 21.4, 21.8, 22.4, 23.1, 25.0, 25.4, 27.5, 29.2, 30.1, 31.1, and 32.6 degrees. There is some margin of error in each of the 2-theta d-spaced angles previously reported. The error in determining the d-spacings decreases with the increase in the diffraction scan angle or decreasing in d-spacing. The margin of error at the angles of 2 theta above is about ± 0.05 degrees for each of the previous, peak assignments. The margin of error in the values of the d-spaced is approximately ± 0.05 Ángstrom. Since some margin of error is possible in the allocation of the 2 theta and d-spaced angles, the preferred method for comparing powder scattering patterns in X-rays in order to identify a particular crystalline form is to superpose the pattern of X-ray powder diffraction of the unknown form with respect to the diffraction pattern in the X-ray powder in a known manner. For example, one skilled in the art can superpose an X-ray powder diffraction pattern of an unidentified, crystalline form of 5, β-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -lH -benzimidazole, obtained using the methods described herein, with respect to Figure 6 and easily determine whether the X-ray diffraction pattern of the unidentified form is substantially the same as the X-ray powder diffraction pattern of the Form VI. If X-ray powder diffraction pattern is substantially the same as Figure 6, the previously unknown crystalline form can easily and accurately be identified as the VI form. The same technique can be used to determine whether the unidentified crystal form is any of the forms I, II, IV, V, or ethanolate by superimposing the X-ray powder diffraction pattern on Figures 1, 2, 4, 5 or 3 respectively. Although angles of 2 theta or d-spaced are the preliminary method for identifying a particular crystalline form, it may also be desirable to compare relative peak intensities. As noted above, the relative peak intensities may vary depending on the specific diffractometer used and the technique of sample preparation of the analyzer. Peak intensities are reported as intensities relative to the peak intensity of the strongest peak. The intensity units in the X-ray diffraction graph are counts / second. Absolute accounts = how many / time / account time = accounts / second x 10 seconds. Considering angles of 2 theta, d-spacing (Á) and peak intensity, relative (I), the form 5,6-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -lH-benzimidazole exhibits The following characteristics of the X-ray diffraction pattern: 1 Error margin = approximately ± 0.05 degrees. margin of error = approximately ± 0.05 Angles, Based on the above characteristic features of the X-ray powder diffraction pattern of the VI form, one skilled in the art can easily identify the VI form of 5,6-dichloro-2- (isopropylamino) -1- (β-L -ribofuranosyl) -lH-benzimidazole. It will be appreciated by those skilled in the art that the X-ray powder diffraction pattern of a sample of form VI, obtained using the methods described above, may exhibit additional peaks. The table above and the following provide the fifteen most intense peaks that are characteristic of that particular crystalline form or solvate. Tables should not be construed as an exhaustive list of the peaks exhibited by the particular form or solvate. In contrast to the above, the X-ray powder diffraction characteristics of the VI form, forms I, II, IV, V and ethanolate each exhibit different angles of 2 theta, d-spaced and relative intensities, which are you can use to differentiate each of these forms from the VI form and from each other. The forms I, II; IV, V and ethanolate are defined by their X-ray powder diffraction pattern, obtained with an appropriately-lined diffractometer equipped with a diffracted beam graphite monochromator using copper Ka X radiation; the patterns are provided in Figures 1, 2, 4, 5, and 3, respectively.

Form I of 5,6-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H-benzimidazole is further characterized by the following angles of 2 theta, d-spaced, and relative peak intensities, obtained by the method of Example 22 below 1 Error margin = approximately ± 0.05.

Form II of 5,6-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H-benzimidazole is further characterized by the following angles of 2 theta, d-spaced, and relative peak intensities, obtained by the method of Example 22 below Error margin = approximately + 0.09.

Form II can also exhibit peaks at essentially the following 2 theta angles: 7.9, 10.9, 16.1, 17.3, 18.2, 19.6, 21.9, 23.9 degrees. The 5,6-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H-benzimidazole ethanolate is further characterized by the following angles of 2 theta, d-spaced, and relative peak intensities, obtained by the method of Example 22 below.

Error margin = approximately ± 0.05 Ethanolate can also exhibit peaks at essentially the following 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 . The IV form of 5,6-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H-benzimidazole is further characterized by the following angles of 2 theta, d-spaced, and the relative peak intensities, obtained by the method of Example 22 below.

Error margin = approximately ± 0.05 Form IV can also exhibit peaks at essentially the following 2 theta angles: 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 of 5,6-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H-benzimidazole is further characterized by the following angles of 2 theta, d-spaced, and relative peak intensities, obtained by the method of Example 22 below.

Error margin = approximately + 0.05 Form V can also exhibit peaks at essentially the following 2 theta angles: 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. Other methods of physical characterization can also be employed to identify the anhydrous crystalline form VI of the present invention. Examples of suitable techniques that are known to those skilled in the art to be useful for the physical characterization or identification of a crystalline or solvate form include but are not limited to melting point, differential scanning calorimetry, and absorption spectra. infrared These techniques can be employed alone or in combination to characterize a crystalline, anhydrous, or solvate form. The invention relates to the crystalline, anhydrous form VI in both the pure form and in admixture with other forms of the compound of the formula (I) For example, the VI form may be in admixture with one or more of the forms I, II, IV, V or ethanolate. Alternatively, the VI form may be in admixture with the amorphous compound of the formula (I). In another embodiment, the VI form is in mixture with both the amorphous compound of the formula (I) as with one or more different crystalline forms or solvates including forms I, II, IV, V and ethanolate.

The present invention expressly contemplates the above mixtures of the VI form with one or more of the amorphous compound of the formula (I), and / or other anhydrous, crystalline and solvate forms. It should be understood that mixtures of the VI form with the amorphous compound of the formula (I) and / or other crystalline forms or solvates can result in the masking or absence of one or more of the X-ray powder diffraction peaks. above, described above for the VI form. Methods are known in the art to analyze these mixtures of crystalline forms in order to provide accurate identification of the presence or absence of particular crystalline forms in the mixture. In addition to the above forms, the VI form can also be mixed with the crystalline, hydrated forms. For example, in any batch containing the crystalline, anhydrous form VI of the compound of the formula (I), the crystalline, hydrated form VI may also exist. Since the VI form of the crystalline, anhydrous form of the compound of the formula (I) is essentially free of water of hydration, the proportion of the hydrate forms of the VI form of the compound of the formula (I) in any batch of the compound can be measured by the total water of the hydration content of each batch. Accordingly, in a second aspect of the present invention, the VI form of the compound of the formula (I) is provided, which has a total volatile content of not more than 0.3% by weight (w / w) as determined by a TA Instruments HI-Res TGA 2950 thermogravimetric analyzer (Figure 7). The absorption of gravimetric water vapor showed that the VI form only absorbed 0.3% of water when it was brought into equilibrium with a relative humidity of 95% at room temperature (Figure 8). According to a further aspect, the present invention provides a process for the production of the compound of the formula (I) in the crystalline, anhydrous form VI which comprises treating the compound of the formula (I) with a solubilizing solvent which serves to converting an amount of the compound of the formula (I) to the crystalline, anhydrous VI form. The invention also provides a process for the production of the VI form of the compound of the formula (I). The process comprises the steps of: a) forming or providing the compound of the formula (I) in solution either in free base or salt form; b) isolating the compound of the formula (I) from the solution and optionally removing the unbound solvent (wet, unsolvated) leaving the compound of the formula (I) in a substantially dry form; c) treating the compound of the formula (I) with a solubilizing solvent which serves to convert an amount of the optionally dry compound of the formula (I) of step b) into the crystalline, anhydrous form VI; and d) isolate form VI, crystalline, anhydrous. In one embodiment of the present invention, the VI form of the compound of the formula (I) is prepared by recrystallization from ethyl acetate / toluene. According to this process, the compound of the formula (I) is treated with a solubilization solvent comprising ethyl acetate and toluene to convert the compound of the formula (I) to the crystalline, anhydrous VI form and the crystalline VI form , anhydrous is isolated from the solution, such as by removal of the solubilizing agent, for example, evaporation or drying.

The compound of the formula (I) (may be in either the free base or salt form.) The compound of the formula (I) may be prepared by any method known in the art., but preferably by the methods described in WO 96/01833, incorporated herein by reference in its entirety. The synthesis of the compound of the formula (I) generally leads to the formation of the compound in solution in the reaction mixture from which it can be separated and purified as a solid product. The compound of the formula (I) can then be dried optionally. Several factors have an influence on the crystalline form of the solid product and in accordance with the present invention the separation and / or subsequent processing conditions are adjusted to produce the compound of the formula (I) as the crystalline, anhydrous VI form or as a mixture of the VI form with one or more crystalline, anhydrous or solvate forms and / or amorphous material. For example, a hydrated form of the compound of the formula (I) can be converted to the crystalline, anhydrous form, using a suitable solvent under appropriate conditions. This suitable solvent, which is preferably a water-soluble organic solvent, must be sufficiently soluble and is used in an amount to allow the partial solubilization to effect the conversion and precipitation for example from a crystalline form, anhydrous to the crystalline, anhydrous form , desired of the compound of the formula (I). Advantageously, the solvent is optionally removed by drying under vacuum. The wet compound of the formula (I) after the first isolation (as in step b, above) is preferably dried for example at about 30 ° C to about 70 ° C to provide the substantially dry compound of the formula (I) ). The present invention also provides the VI form of the compound of the formula (I) for use in medical therapy, for example, in the treatment or prophylaxis of a viral disease in an animal, for example, a mammal, such as a human . The compound is especially useful for the treatment or prophylaxis, including suppression of the recurrence of viral diseases, such as herpes virus infections for example, CMV infections, as well as the disease caused by the hepatitis B and hepatitis C viruses. In addition to its use in human medical therapy, the VI form of the compound of the formula (I) can be administered to other animals for the treatment or prophylaxis of viral diseases, for example, other mammals. The present invention also provides a method for the treatment or prophylaxis, including suppression of recurrence, of a viral infection, particularly a herpes infection, CMV infection, or disease caused by hepatitis B virus or hepatitis C in an animal, for example, a mammal such as a human comprising administering to the animal an effective antiviral amount of the VI form of the compound of the formula (I). The present invention also provides the use of the VI form of the compound of the formula (I) in the preparation of a medicament for the treatment or prophylaxis of a viral infection. Form VI of the compound of formula (I) can be administered by any route appropriate to the condition being treated, but in general the preferred route of administration is oral. However, it will be appreciated that the preferred route may vary, for example, with the condition of the receiver. For each of the utilities and indications indicated above, the required amounts of the active ingredient (as defined above) will depend on several factors including the severity of the condition being treated and the identity of the recipient and will ultimately be at the discretion of the practitioner or veterinarian who attends. In general, however, for each of these utilities, and indications, an adequate effective dose will be in the range of 0.01 to 250 mg per kilogram of receptor body weight per day, advantageously in the range of 0.1 to 100 mg per kilogram. of body weight per day, preferably in the range of 0.5 to 30 mg per kilogram of body weight per day, particularly from 1.0 to 30 mg per kilogram of body weight per day (unless otherwise indicated, all weights of the active ingredient are calculated with respect to the free base of the compound of the formula (I)). The desired dose is preferably presented as one, two, three or four or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing about 10 to 1200 mg, or 50 to 500 mg, preferably about 20 to 500 mg, and more preferably 100 to 400 mg. mg of active ingredient per unit dose form. While it is possible for the active ingredient to be administered alone, it is preferred to present it as a pharmaceutical formulation. The formulation comprises the active ingredient as defined above, together with one or more pharmaceutically acceptable excipients therefor. and optionally other therapeutic ingredients. The excipient (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The formulations include those suitable for oral administration and may conveniently be presented in the unit dosage form prepared by any of the methods well known in the pharmacy art. These methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more auxiliary ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, forming the product. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, granule vials or tablets (such as ingestible, dispersible or chewable tablets) each containing a predetermined amount of the active ingredient.; or as powder or granules; or as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as a liquid emulsion of oil in water or liquid emulsion of water in oil. The active ingredient can also be presented as a bolus, electuary or paste. A tablet can be made by compression or molding optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a fluid form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, dispersing agent or surfactant. The molded tablets can be made by molding in a suitable machine a mixture of the wetted powder compound with an inert liquid diluent. The tablets can optionally be coated or labeled, either can be formulated to provide slow or controlled release of the active ingredient therein. In addition to the oral dosage forms described above, the crystalline, anhydrous VI form in the present invention can also be formulated for administration by the routes of topical, parenteral and other administration, using the carriers and techniques described in WO96 / 01833. It will be appreciated by those skilled in the art that the preparation of the dosage forms as solutions in crystalline, anhydrous form VI substantially completely dissolved in a solvent, for example, for parenteral administration, will impede the identification of the pure crystalline form used in the preparation of the solution. However, crystalline, anhydrous VI form can be conveniently used for the preparation and solutions by substantially completely solubilizing the crystalline form or solvate in a suitable solvent.

Preferred unit dose formulations are those containing a daily dose or sub-daily unit dose (as cited above) or an appropriate fraction thereof, in the active ingredient. It should be understood that in addition to the ingredients mentioned in particular above, the formulation of this invention may include other agents conventional in the art having considered the type of formulation in question, for example those suitable for oral administration may include flavoring agents or agents of taste masking. The following examples are proposed for illustration only and are not intended to limit the scope of the invention in any way.

EXAMPLE 1 Form I of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole The compound of the formula (I) (200 mg) was placed in a Thermal Activity Monitor ( TAM) and a few drops of water were added to wet the powder. The vial was sealed and placed in a TAM chamber at 50 ° C. The mixture was cooled to room temperature and filtered. The wet residue was dried in vacuo at 60 ° C overnight to give the form I of the compound of the formula (I). The X-ray powder diffraction pattern of the product of Example 1 is shown in Figure 1.

Example 2 Form I of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole The compound of the formula (I) (1.5 g) was dispersed in water (30 ml) and heated at 65 ° C with shaking. After about 0.5 h, agitation became difficult since a gum formed. After further heating, the gum became solid and broke with a spatula. The mixture was heated at 65-70 ° C for 9 hours. The mixture was cooled to 20 ° C and the solid was collected by filtration and dried in vacuo at 40 ° C for 24 hours to give the form I of the compound of the formula (I). The X-ray powder diffraction pattern of the product of Example 2 is shown in Figure 1.

EXAMPLE 3 Form I of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole The compound of the formula (I) (5 g) and water (1.5 ml) was stirred and heated in a bath of oil to 80 ° C. The powder became a gum and ceased stirring. Heating was continued for 8 hours. The solid was loosened with a spatula and stirred occasionally. After cooling to 20 ° C, the solid was collected and dried in vacuo at 40 ° C for 4 h. The X-ray powder diffraction pattern of the product of Example 3 is shown in the Figure 1.

Example 4 Form I of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole The compound of the formula (I) (2 g) in toluene (15 ml) was heated to reflux for 19 h.

In heating, the suspension was turned into a gum that solidified on further heating.

The solid was collected by filtration and dried in vacuo at 40 ° C to yield the compound of the formula (I).

The X-ray powder diffraction pattern of the product of Example 4 is shown in Figure 1.

Example 5 Preparation of Form I of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole from Form II Form II of the compound of formula (I) (2) g) in toluene (10 ml, 5 vol) was heated to 60 ° C, at which point the solid began to stick to the sides of the flask. In continuous heating at 95 ° C, an oil was formed. The heating is continued at 105 ° C, then it is added to toluene (2.5 vol) and heating is continued. Reflux was continued for 3 h with rapid stirring. The bath temperature of the oil was reduced to 80 ° C (internal temperature 73 ° C) and the heating was continued for 3 hours again with rapid stirring. The mixture was refluxed again for 16 h and then allowed to cool to room temperature. The loose solid was collected by filtration washing with toluene (2 x 5 ml) and dried in vacuo at 20 ° C and at 40 ° C in vacuo to yield a white solid. The residual solid was removed from the flask, collected by filtration, and dried in vacuo at 20 ° C. The filtrate was concentrated under reduced pressure to produce a solid. The X-ray powder diffraction pattern of the product of Example 5 is shown in Figure 1.

Example 6 Preparation of Form I of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole from Form II Form II of the compound of formula (I) (5 g) was stirred with water (1.5 ml) in an oil bath at 80 ° C. When the temperature of the oil bath reached about 60 ° C, the mixture became difficult to stir. Heating was continued for 8 h with occasional stirring and then cooled to room temperature. The material was dried in vacuo at 40 ° C for 4 h. The X-ray powder diffraction pattern of the product of Example 6 is shown in the Figure 1.

Example 7 Form II 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole The compound of the form (I) (100 g) was added to toluene / stirred methanol (4: 1.440 ml) and heated to 65 ° C to give a clear solution. The solution was clarified through a filter with an in-line bath (toluene / methanol [4: 1, 110 ml, hot]). The solution was heated back to 65 ° C and toluene (4.5 vol) was slowly added maintaining the internal temperature above 65 ° C. When the addition was completed, the solution was cooled to 40 ° C for 1 hour and aged at 40 ° C. After 0.5 h, the mixture was seeded with the form II of the compound of the formula (I) and then aged for an additional 4.5 h. The suspension was cooled to 20 ° C for 1 h and aged at 20 ° C for 12 h and then cooled to 5 ° C for 1 h and aged for 3 h. The solid was collected by filtration, washed with toluene (2 x 100 ml). The wet cake was transferred to a drier and was run in vacuo at 20 ° C. The X-ray powder diffraction pattern of the product of Example 7 is shown in Figure 2.

EXAMPLE 8 Form II of 5,6-dichloro-2- (i sopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole The compound of the formula (I) (1.0 weight) was dissolved in ethyl acetate (6.0 vol) and subjected to a finished filtration. The filtrates were concentrated to approximately 3 volumes. Assuming a complete exchange of solvent, the solution was reconstituted to 3.5 volumes with methanol. Water (0.5 vol) was added and the solution was cooled to 0-5 ° C. The crystallization was seeded with a small amount of the pure compound of the formula (I) and the solution was stored at 0-5 ° C for 2 hours. The product was filtered (not washed) and dried in vacuo for 24-48 h at room temperature. A second crop was obtained by evaporation of the filtrate at half volume followed by cooling, plating, and crystallization in a similar manner as before. The X-ray powder diffraction pattern of the product of Example 8 is shown in Figure 2.

EXAMPLE 9 Form II of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole The compound of the formula (I) (10 g) was dissolved in methanol (20 ml) with heating at 50 ° C. Water (5 ml) was added and the mixture was cooled to 5 ° C slowly and stirred at 5 ° C for 1 h. The solid was collected by filtration and dried in vacuo at 20 ° C for 15 h and at 40 ° C for 4 h to yield the compound of the formula (I). The X-ray powder diffraction pattern of the product of Example 9 is shown in Figure 2.

EXAMPLE 10 Preparation of mixtures of the Forms of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole The compound of the formula (I) can be dissolved in 2N hydrochloric acid (60%). ml) and stirred for 0.5 h and filtered. The filtrate is heated to 60 ° C and 2 N sodium hydroxide (55 ml) is slowly added, maintaining the internal temperature between 60-70 ° C during the addition. The mixture is stirred at 65-70 ° C for 2 hours and then cooled to 20 ° C for 2 hours. The solid is collected by filtration by washing with water (2 x 30 ml) and dried in vacuo at 40 ° C for 16 h to yield the compound of the formula (I) (8.8 g, 88%).

Example 11 5,6-Dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole ethanolate The compound of the formula (I) (1.0 weight) was dispersed in ethanol / water (10.0 vol) at 70 ° C for 2 hours. The ethanol / water ratios (v / V) were as follows: 10/90, 15/85, 20/80, 25/75 and 30/70. The resultant white solid powder was filtered and dried with air. The ethanol solvate was obtained in a similar manner from ethanol / toluene solutions (ratios 5/95, 10/90, 15/85, 20/80, 25/75 and 30/70). The recrystallization of the compound of the formula (I) from ethanol / water and an ethanol solvate containing 0.5 mole of ethanol per mole of the compound of the formula (I). The X-ray powder diffraction pattern 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 The compound of the formula (I) (20 g) was added to toluene / ethanol agithane (7). : 1, 200 ml) and heated to reflux (81 ° C) to give a clear solution. The solution was cooled to 20 ° C and crystallization occurred at about 50 ° C. The suspension was cooled to 0-5 ° C and aged for 2 h. The solid was collected by filtration, and washed with toluene (2 x 20 ml). The filter cake was dried in vacuo at 40 ° C. Recrystallization of the compound of the formula (I) from the anol / toluene gave an ethanol solvate containing 0.5 moles of ethanol per mole of the compound of the formula (I). The X-ray powder diffraction pattern of the product of Example 12 is shown in Figure 3.

EXAMPLE 13 Form IV of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole Water (300 ml) was added to the form I (4 g) as prepared in Example 1 above and stir for 20 minutes. The mixture is then heated at 50 ° C for 6 days, and then cooled to room temperature. The crystalline, coarse, solid material was dried and filtered at 60 ° C. The X-ray powder diffraction pattern of the product of Example 13 is shown in Figure 4.

Example 1 Form V of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-lH-benzimidazole The compound of the formula (I) (2.0 g) was added gradually to water (40 ml) at 70 ° C with rapid stirring for 2 hours. After heating to 65-70 ° C with stirring for an additional 7 h, heating and stirring were discontinued. After settling for 2.5 days at room temperature, the mixture was filtered. The white, coarse solid residue was allowed to air dry overnight giving the V form of the compound of the formula (I). The X-ray powder diffraction pattern of the product of Example 14 is shown in Figure 5.

EXAMPLE 15 Form VI of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzyl idazole The ethanolate of the compound of the formula (I) (200 mg) is weighed into small bottles. Hydrostats with saturated NaCl solutions and excess NaCl solid were inserted into the flasks. The bottles were then sealed very well and stored at 80 ° C. Samples were removed from the flask and heated to 170 ° C in a differential scanning calorimeter and subsequently cooled to room temperature. The powder was collected from DSC trays and analyzed by X-ray diffraction. Characterization: The X-ray powder diffraction pattern of the product of Example 15 (form IV) is shown in figure 6. The DSC thermogram for the VI form is illustrated in Figure 9. The TGA thermogram for the VI form is illustrated in Figure 7. The moisture absorption isotherm for the VI form is shown in Figure 8.

Example 16 Conversion of Form II of 5,6-dichloro-2- (isopropylamino) -1- (beta-L-ribofuranosyl) -1H-benzimidazole to Form VI Approximately 200 mg of Form II seeded with 5 mg was dispersed d form VI in 1 ml of distilled water and stirred in a water bath at 45 ° C. After 28 hours of stirring, the solid was examined with X-ray diffraction. The results on X-ray diffraction suggested that form II has been converted to form VI completely. Characterization: as for Example 15.

Example 17 Conversion of the ethanol solvate of 5,6-dichloro-2- (isopropylamino) -1- (beta-L-ribofuranosyl) -1H-benzimidazole to Form VI Approximately 200 mg of ethanolate seeded with 5 mg of Form VI they were dispersed in 1 ml of distilled water and shaken in a water bath at 45 ° C. After 28 hours of stirring, the solid was examined with X-ray diffraction. The results of the X-ray diffraction suggested that the ethanol solvate of the compound of the formula (I) has been completely converted to the VI form. Characterization: as for Example 15.

Example 18 Conversion of the ethanol solvate of 5, 6-dichloro-2 - (isopropylamino) -1- (beta-L-ribofuranosyl) -1H-benzimidazole to Form VI Ten grams of ethanolate seeded with 100 mg of Form VI made from the previous conversion study were dispersed in 50 ml of distilled water at 45 ° C. After 5 hours, all of the ethanolate was converted to the VI form, as determined by X-ray diffraction examination. The solid was collected by filtration, washing with water (3 x 5 ml) and dried in an oven. emptied at 100 ° C for 3 hours. Characterization: as for Example 15.

Example 19 Conversion of the ethanol solvate of 5,6-dichloro-2- (isopropylamino) -1- (beta-L-ribofuranosyl) -1H-benzimidazole to Form VI The ethanolate stability samples stored at 80 ° C / 50 % relative humidity (RH), 60 ° C / 75% RH, 60 ° C / 50% RH, and 40 ° C / 75% RH under sealed conditions for 2 months were also partially or completely converted into the form SAW . Characterization: as for Example 15.

Example 20 Preparation of Form VI of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole by seeding A solution of 5,6-dichloro-2- (isopropylamino) -1- (ß-L-ribofuranosyl) -1H-benzimidazole (10 g) in ethyl acetate (25 ml) and toluene (30 ml) was seeded with the VI form of 5,6-dichloro-2- (isopropylamino) -1- (beta-L-ribofuranosyl) -IH-benzimidazole (100 mg). The mixture was heated at 50 ° C for 3 hours to form a suspension. Additional toluene (70 ml) was added over 30 minutes. The suspension was cooled to 25 ° C and aged at 25 ° C for 2 hours. The solid was collected by filtration, washing with ethyl acetate / toluene (1: 4, 20 ml). The solid was dried in vacuo at 40 ° C to yield the form VI 5,6-dichloro-2- (isopropylamino) -1- (beta-L-ribofuranosyl) -1H-benzimidazole.

Characterization: as for Example 15.

Example 21 Preparation of Form VI of 5,6-dichloro-2- (isopropylamino) -1- (beta-L-ribofuranosyl-1H 9 -benzimidazole by recrystallization from ethyl acetate / toluene Sodium hydroxide (2 M) was added , 1790 ml) to a slurry of 5,6-dichloro-2- (isopropylamino) -1- (2, 3, 5-tri-O-Acetyl-beta-L-ribofuranosyl) -lH-benzimidazole (358 g) in .TBME (1790 mL) containing methanol (179 mL) The mixture was stirred at 25-30 ° C until the reaction was finished The layers were separated and the aqueous layer was further extracted with TBME (716 mL). The combined organic solutions were washed with 10% brine (2 x 1790 mL) The organic solution was concentrated at atmospheric pressure to about 2.5 vol (825 mL) Ethyl acetate (2864 mL) was added and the solution was concentrated again at about 2.5 vol. The solution was cooled to 40-50 ° C, and the resulting solution was clarified, rinsed with ethyl acetate (716 ml) in the cell line. The clarified solution was concentrated at atmospheric pressure to approximately 3.3 vol (1180 ml). The solution was heated to 60 ° C. The toluene (3000 ml) was heated to 60 ° C and added to the ethyl acetate solution for 1 hour. The resulting mixture was aged at 60 ° C overnight before cooling to 0-5 ° C for 1 hour, then aging at 0.5 ° C for 2 hours. The slurry was filtered, washed with ethyl acetate: toluene 1: 4 (2 x 716 ml) and dried in vacuo at 40 ° C for 18 hours to give the VI form of 5,6-dichloro-2- ( isopropylamino) -1- (beta-L-ribofuranosyl) -lH-benzimidazole. Characterization: as for Example 15.

EXAMPLE 22 Experimental Methods for the Characterization of Form VI Differential Scanning Calorimetry and Thermogravimetric Analyzer Differential Scanning Calorimetry (DCS) was performed on a TA Instruments DSC 2920 differential scanning calorimeter with a DSC autosampler. Samples of 1 to 3 mg were curled in normal aluminum pans with holes and heated from 25 ° C to 250 ° C at a rate of 10 ° C / minute under argon purge. The percentage of the total weight loss of the drug substance was determined on a TA Instruments Hi-Res TGA 2950 (TGA) thermogravimetric analyzer with an argon purge.

X-ray powder diffraction X-ray powder diffraction patterns were determined on a Philips X 'Pert MPD diffractometer equipped with a diffracted beam graphite monochromator using copper Ka X radiation and an automated divergent slot. The diffractometer was run in the gradual scan mode at 0.04 degrees per step and a cut of one second per step. A proportional xenon counter with a graphite monochromator was used as the detector. The samples were filled back into a 16 mm diameter carrier having a thickness of approximately 2.0 mm. X-ray powder diffraction patterns of forms I, II, IV, V, VI and ethanolate are given in Figures 1, 2, 4, 5, 6, and 3, respectively. The following data, measured at angles of 2 theta, d-spacing, relative intensities, and Miller indices were obtained: Table 1: X-ray Powder Diffraction of Form VI of 1263W94 Error margin is approximately ± 0.05 degrees. 2 Error margin is approximately ± 0.05 A. 3 The Miller, h, k, and 1 indexes above are used to define only a set of parallel planes in the crystal.

Moisture Absorption The moisture absorption / desorption studies were carried out in an VTI vacuum microbalance at 25 ° C after drying the sample at 60 ° C under vacuum. Moisture absorption was monitored under vacuum from 0 to 95% relative humidity and desorption was monitored from 95 to 5% relative humidity. The criteria for equilibrium at a given relative humidity were less than 3 μg of weight change in 18 minutes.

X-ray Diffraction of the Individual Crystal The structure of an individual crystal of the VI form of 5,6-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -lH-benzimidazole was determined using light diffraction X of the individual crystal. The X-ray diffraction data of the individual crystal was determined on a Bruker AXS SMART diffractometer equipped with a diffracted beam graphite monochromator using molybdenum Ka X radiation (lambda = 0.71071A) at 160 K. The unit cell parameters and the group of space were determined to be, the tetragonal crystal system, P4 (3) 2 (l) 2, with a = b = 9.1542, c = 41.687 (units a, b, c in Angstrom), and alpha = beta = gamma = 90 degrees. Unitary cell parameters at ambient conditions, a = b = 9.2794, c = 41.593 (units a, b, c in Angstrom), and alpha = beta = gamma = 90,000 degrees, were calculated by graduating the X-ray powder pattern experimental Using the atomic coordinates of the individual crystal data and the unit cell parameters of the graduation of the experimental powder pattern, an X-ray powder diffraction pattern was calculated. The X-ray diffraction pattern for an individual crystal of the VI form of 1263W94 is given in Figure 10. The 15 most intense peaks from 2 to 35 two theta are presented below in terms of 2 theta angles, d-spacing, relative intensity and Miller indices.

Table 2: X-ray Diffraction Pattern in Dust Calculated Based on X-ray Diffraction of Individual Crystal of Form VI of 1263W94 1 Error margin is ± 0.05 degrees. 2 Error margin is ± 0.05 Á. 3 The Miller, h, k, and 1 indexes above are used to define only a set of parallel planes in the crystal.

The 2 theta values derived from the individual crystal data shown in the graph differ from the powder diffraction, experimental, observed, previously reported values, mainly due to sample preparation errors such as sample displacement error , minor errors in the diffractometer alignment, and variation in the peak determination method by the computer. The relative intensity of the peaks in the calculated pattern is affected not only by the individual crystal input data but also by the peak profile (shape and spreading) used in the calculation of the simulated powder pattern.

Example 23: Tablet Formulation The following formulations were prepared as follows using the VI form of the compound of the formula (I).

Formulation A Tablets of 1263W94 (form VI Direct Compression Potency 100.0 mg 400 mg Ingredients of core 1263W94 (active) 100.0¿ 400.0J Microcrystalline cellulose, NF 93.5 374.0 Cros-povidone, NF 4.0 16.0 Colloidal silicon dioxide, NF-0.4 Magnesium stearate, NF 2.5 10.0 Total (core) 00.0 mg 800.4 mg Ingredients of Opadry White coating YS-1-18034 6.0 24.0 Purified Water USP1 CS CS Total (core) 206.0 mg 824.4 mg Theoretical Lot Size (cores) Kg 15.0 33.0 Tablets 75000 41254 1 Removed during processing Equivalent to 100 mg of 1263W94 per tablet Equivalent to 400 mg of 1263W94 per tablet Manufacturing procedure by direct compression All the ingredients are sifted, except magnesium stearate, using a 20 or 30 mesh. All ingredients are mixed, excluding magnesium stearate, until they are uniform. The magnesium stearate is screened as before. The magnesium stearate is added to the other ingredients and mixed. The tablets are compressed using a rotary press. A 10% coating suspension is prepared by mixing Opadri with water. The tablets are coated a. a gain in weight of approximately 3%.

Formulation B Tablets of 1263W94 (Form VI Wet granulation Power 100.0 mg 400 mg Core ingredients 1263W94 (active) 102. O2 408. O3 Lactose, anhydrous, NF 60.0 240.0 Microcrystalline cellulose, NF 20.0 80.0 Cros-povidone, NF 15.0 60.0 Povidone, USP, K30 7.5. 30.0 Magnesium Stearate, NF 0.6 2.4 Purified Water USP1 'CS CS Total (core) 205.1 mg 816.0 mg Ingredients of Opadri White coating YS-1-18034 6.0 24.0 Purified Water USP1 CS CS Total (core) 211.1 mg 840.0 mg Theoretical Lot Size (cores) Kg 0.718 Tablets 3500 1 Removed during processing 2 Equivalent to 100 mg of 1263W94 per tablet Equivalent to 400 mg of 1263W94 per tablet Formulation B-1 Tablets of 1263W94 (Form VI) Wet granulation Potency - 400 mg Core ingredients 1263W94 (active) 4002 Microcrystalline cellulose, NF 298.0 Lactose, anhydrous, NF 60.0 Cros-povidone, NF 24.0 Povidona, USP 12.0 Magnesium stearate, NF 2.0 Purified Water USP1 CS Total (core) 816.0 mg Coating ingredients Opadri White YS-1-18034 24.0 Purified Water USP1 CS Total (core) 820.0 mg 1 Removed during processing 2 Equivalent to 100 mg of 1263W94 per tablet Manufacturing procedure for wet granulation The granulation ingredients are screened using a 20 or 30 mesh. The ingredients of the granulate are mixed dry in a high cut granulator until which are uniform and then granulated in a high cut granulator using purified water. The granule is dried at a loss in drying of less than 2%. The granule is sifted as before. The remaining ingredients are sifted as before. The granule is mixed with the remaining ingredients. The tablets are compressed using a rotary press. A 10% coating suspension is prepared by mixing Opadri with water. The tablets are coated at a weight gain of about 3%.

Example 24: Capsule Formulation The following formulation can be prepared as follows using the VI form of the compound of formula (I).

Capsule of 1263W94 (Form VI) Potency 100 mg Capsule filling ingredients 1263W94 (active) 101. . O1 Lactose, anhydrous, NF 232. 0 Cros-povidone, NF 17. 0 Magnesium stearate, NF 1. 0 Total Fill Weight 351. 0 Gelatin capsule cover, white opaque cap and 81.1 body Total Weight 432.5 1 Equivalent to 100 mg of 1263W94 per Tablet Capsule manufacturing process The capsule filling ingredients are mixed using a mortar and pestle by geometric dilution. The combined capsule filling ingredients are filled into the gelatin capsules by hand. The capsules are closed by hand.

Example 25: Formulation of Oral Solution The following formulation was prepared as follows using the VI form of the compound of formula (I) - 1263W94 Oral Solution (Prepared using Form VI) Potency 30 mg / ml Ingredients per 100 ml 1263W94 3.0 g Citric acid, anhydrous 0.3 g Hydrochloric acid IN 6.9 ml Propylene glycol USP 20.0 ml Purified water USP 20.0 ml Hydrochloric acid ÍN CS Sorbitol solution (60% w / v) 50.0 ml Purified Water USP CS Total Volume 100.0 ml Manufacturing process for the oral solution Propylene glycol, water and hydrochloric acid (6.9 ml) were combined to uniformity. Citric acid was added and the mixture was stirred until the citric acid dissolved. The ingredient was added and dissolved when mixed. If necessary, the pH can be adjusted to subtract between 2.0 and 2.5 by adding IN hydrochloric acid solution or IN sodium hydroxide solution.

Subsequently, the sorbitol solution was added and mixed uniformly. The general volume was adjusted to 100 ml by the addition of purified water.

Example 26: Formulation of Oral Suspension The following formulation can be prepared as follows using the VI form of the compound of formula (I).

Oral Suspension of 1263W94 (Form VI) Power 30 mg / ml Ingredients per 100 ml 1263W94 (active) 3.0 g Sucrose 50.0 g Propylene glycol USP 5.0 g Sodium Chloride 0.5 g Citric Acid CS Sodium Citrate CS Cellulose Microcid stalin and 2.5 g Sodium Carboxymethylcellulose Sodium Carboxymethylcellulose 0.25 g Polysorbate 80 0.2 g Sodium Benzoate 0.1 g Methylparaben 0.1 g Flavoring 0.2 ml Dye 0.005 g Purified Water USP CS Total Volume 100.0 ml Procedure for manufacturing the oral solution Sucrose is dissolved in purified water at approximately 70% of the total batch volume. As long as it is continuously mixed, chlorine of sodium, citric acid, sodium citrate and sodium benzoate are added and dissolved. If necessary, the pH is adjusted to be between 5.0 and 6.0, by adding enough citric acid or sodium citrate as necessary. Microcrystalline cellulose and sodium carboxymethylcellulose are added (Avicel RC 591) as long as it is mixed and mixing is continued until a smooth, uniform dispersion is formed. Polysorbate 80 is added while mixing. In a separate vessel, methylparaben is dissolved in propylene glycol and sodium carboxymethylcellulose (0.25 g) is dispersed, and this liquid is added to the bulk dispersion while mixing. The active ingredient is gradually dispersed in the bulk liquid as long as it is mixed continuously, to produce a uniform dispersion. Flavoring and coloring are added and the volume is adjusted to 100 ml by the addition of purified water. The suspension is then homogenized by passing through a pump and a colloid mill. The above examples are illustrative of the present invention and are not considered as limiting the same. The invention is defined by the following claims including equivalents thereof. It is noted that in relation to this date, the best method known by the applicant to carry out the present invention is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property:

Claims (16)

1. Form VI of 5,6-dichloro-2- (isopropylamino) -l-β-L-ribofuranosyl-1H-benzimidazole characterized by a powder diffraction pattern in X-rays expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a diffracted beam graphite monochromator that uses copper Ka X radiation, this X-ray powder diffraction pattern that comprises 2 theta angles at 8.53 ± 0.05 degrees.

2. Form VI of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole having substantially the same X-ray powder diffraction pattern as Figure 6, characterized in that the diffraction pattern X-ray powder is obtained with a diffractometer equipped with a diffracted beam graphite monochromator using copper Ka X radiation.

3. A crystalline form of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole, characterized by a X-ray powder diffraction pattern expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a diffracted beam graphite monochromator using copper Ka X radiation, where the X-ray powder diffraction pattern comprises angles of 2 theta in 5 or more positions selected from the group consisting of 8.53 + 0.05, 10.47 ± 0.05, 13.51 ± 0.05, 14.95 ± 0.05, 15.98 ± 0.05, 17.23 ± 0.05, 21.41 + 0.05, 21.83 ± 0.05, 22.35 ± 0.05, 23.07 ± 0.05, and 27.49 ± 0.05 degrees.

4. A crystalline form of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole, characterized by a powder diffraction pattern of X-rays expressed in terms of 2 theta angle and peak intensities relative (I) and obtained with a diffractometer equipped with a diffracted beam graphite monochromator using copper Ka X radiation.

5. A composition, characterized in that it comprises the VI-form of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole according to any of claims 1-4 and 5,6-dichloro- Amorphous 2- (isopropylamino) -1-β-L-ribofuranosyl-lH-benzimidazole.

6. A pharmaceutical composition, characterized in that it comprises a crystalline form of a compound as claimed in any of claims 1 to 4 and at least one pharmaceutically acceptable carrier therefor.

7. The 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole as claimed in any of claims 1-4 for use in medical therapy.

8. The use of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole as claimed in any of claims 1-4 in the preparation of a medicament for the treatment or prophylaxis of a Viral infection.

9. A method for the treatment or prophylaxis of a viral infection in a human, characterized in that it comprises administering to the human, an effective antiviral amount of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H- • crystalline benzimide z ol as claimed in any one of claims 1 to 4.

10. A process for the production of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-lH-benzimidazole as claimed in any of claims 1 to 4, characterized in that it comprises the addition of the VI form of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole for an aqueous suspension of Form II or to an aqueous suspension of the ethanol solvate of 5,6-dichloro-2- ( isopropylamino) -1-ß-L-ribofuranosyl-lH-benzimidazole.

11. A process for the production of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole in the crystalline, anhydrous form VI, the process is characterized in that it comprises the steps of: a) providing 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole in solution either in free base or salt form; b) isolate 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole from the solution and optionally remove the unbound solvent leaving 5,6-dichloro-2- (isopropylamino) -1-ß-L-ribofuranosyl-lH-benzimidazole in the substantially dry form; c) treating 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole with a solubilizing solvent which is used to convert an amount of 5,6-dichloro-2- (isopropylamino) -1-ß-L-ribofuranosyl-lH-benzimidazole optionally dry in crystalline, dry form of .5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole; and d) isolating the crystalline, anhydrous VI form.

12. A process for the production of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole as claimed in any of claims 1 to 4, characterized in that it comprises the crystallization of 5,6. - dichloro-2- (isopropylamino) -1-ß-L-ribofuranosyl-lH-benzimidazole from a solution of ethyl acetate and toluene.

13 A pharmaceutical composition according to claim 6, characterized in that it is in the form of a powder.

14. A pharmaceutical composition according to claim 6, characterized in that it is in the form of a tablet.

15. A pharmaceutical composition according to claim 6, characterized in that it is in the form of a capsule.

16. A pharmaceutical composition according to claim 6, characterized in that it is in the form of a suspension.