CZ20003716A3 - Form VI of 5,6-dichloro-2-(isopropylamino)-1-beta-L-ribofuranosyl-1H-benzimidazole - Google Patents

Abstract

Crystalline Form VI of 5,6-dichloro-2- (isopropylamino) -1- (β-Lribofuranosyl) -1H-benzimidazole, pharmaceutical compositions a their use in medicine.

Description

Technical field

The present invention relates to a crystalline form of the antiviral compound 5,6-dichloro-2 (isopropylamino) -1- (3-L-ribofuranosyl) -1H-benzimidazole (also known as 1263W94; a compound of formula I)), pharmaceutical compositions comprising the crystalline form of an antiviral compound and its use for treatment.

BACKGROUND OF THE INVENTION

5,6-Dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H-benzimidazole is a benzimidazole derivative that is used for medical treatment. WO96 / 01833 discloses a compound of formula I and its use for the treatment or prophylaxis of viral infections, such as infections caused by herpes viruses. The compound as described in WO96 / 01833 is in the form of an amorphous, non-crystalline material.

The structure of the 5,6-dichloro-2- (isopropylamino) -1- (p-L-ribofuranosyl) -1H-benzimidazole compound of formula I is as follows:

SUMMARY OF THE INVENTION

We have now found that the compound of formula I can exist in various crystalline forms and solvates. We also found a special crystalline form of the compound of formula

I, Form VI, which is anhydrous and crystalline and which surprisingly exhibits good pharmaceutical properties. Form VI is the thermodynamically most stable form of the compound of formula I. It is easy to prepare and can be produced on a commercial scale. It is particularly stable and substantially non-hygroscopic. Dosages of this crystalline form can be consistently prepared in a high crystalline form of purity, i.e. where the ratios of other and crystalline forms of the compound of Formula I are limited. In addition, this anhydrous crystalline form has good storage properties and can be readily formulated into pharmaceutical compositions such as tablets and capsules, these crystalline forms and solvates of the compound of Formula I can be characterized by their X-ray powder diffraction patterns.

Figure 1. X-ray powder diffraction pattern of Form I of the compound of Formula I.

This diagram was obtained according to the procedures described in Example 22.

Figure 2. X-ray powder diffraction pattern of Form II of the compound of Formula I. This diagram was obtained according to the procedures described in Example 22.

Figure 3. X-ray powder diffraction pattern of the ethanol solvate of the compound of formula I (hereinafter "ethanolate"). This diagram is obtained according to the procedures described in Example 22. Figure 4. X-ray powder diffraction pattern of Form IV of the compound of Formula I. This diagram is obtained according to the procedures described in Example 22.

Figure 5. X-ray powder diffraction pattern of Form V of the compound of Formula I. This pattern was obtained according to the procedures described in Example 22.

Figure 6. X-ray powder diffraction pattern of Form VI of the compound of Formula I. This pattern was obtained according to the procedures described in Example 22.

Figure 7. TGA thermogram of Form VI of the compound of Formula I. This TGA thermogram is obtained according to the procedures described in Example 22.

Figure 8. Moisture sorption isotherm of Form VI of the compound of Formula I.

Figure 9. DSC thermogram of Form VI of the compound of Formula I. This TGA thermogram was obtained according to the procedures described in Example 22.

Figure 10. Single crystal X-ray diffraction pattern of Form VI of the compound of Formula I. This diagram is obtained according to the procedures described in Example 22.

According to a first aspect, the invention provides a compound of formula I in a thermodynamically stable crystalline form (referred to herein as Form VI). Form VI is defined by the X-ray powder diffraction pattern illustrated in Figure VI, which is obtained by a suitably oriented diffractometer equipped with a graphite monochromator with diffraction of the beam using X-rays of Kα medium. Form VI may be prepared at certain relative humidities from the ethanol solvate of Compound I. Form VI may also be prepared from a grafted slurry of Form II or ethanol in water with the form

VI. Other solvent systems that can lead to Form VI by seeding include ethyl acetate / toluene, isopropanol / toluene, 2-butanone / toluene.

In another aspect, the present invention provides a compound of formula I as a mixture of Form VI with any one or more forms I, II, IV, V or solvates, or as a mixture of Form VI and amorphous material or as a mixture of Form VI, amorphous material and one or more crystalline forms or solvates.

The term "solvate" as used herein is a complex of variable stoichiometry composed of a solute (a compound of formula I) and a solvent. Water, methanol, ethanol or acetic acid can be used as solvents. The following reference to a compound of formula I, unless otherwise specified, is an amorphous form of the compound.

As used herein, the term "anhydrous crystalline form" means a crystalline form having substantially the same X-ray powder diffraction pattern as shown in Figure 6, which is obtained by a suitably oriented diffractometer equipped with a graphite monochromator with a diffraction pattern using copper X-ray radiation.

The X-ray powder diffraction pattern of the anhydrous crystalline Form VI of the invention is determined using conventional techniques and equipment known to those skilled in the art. Diffraction diagrams of Figures 1 to 6 were obtained using a Philips X-Pert MPD diffractometer equipped with a diffractometer equipped with a graphite monochromator with diffraction of the beam using a copper copper X-ray and an automatic divergent slit. A xenon proportional counter was used as a detector. A powder sample used to generate X-ray powder diffraction data is prepared by conventional sample filling techniques using a 16 mm diameter and 2.0 mm thick holder.

A powder sample of each of Form I, II, IV, V and VI and ethanolate was used to obtain the X-ray powder diffraction diagrams shown in Figures 1, 2, 4, 5, 6 and 3. X-ray diffraction patterns are specific to each of the various forms and solvates. Each crystalline anhydrous form or solvate exhibits a diffraction pattern with a specific set of diffraction peaks that can be expressed in 2 theta angles (°), d-inter-plane distances (Angstrom), and / or relative peak intensities.

The 2 theta diffraction angles and the corresponding d-spacing values explain the positions of the different vertices in the X-ray diffraction diagram. The d-spacing values are calculated from the observed 2 theta angles and the wavelength Ka 1 using the Bragg equation. The slight deviations at the 2 theta angles and d-spacing found are due to the different diffractometers used and the sample preparation technique for analysis.

Larger deviations are expected in relative peak intensity. The identification of the exact crystalline form of the compound will be based primarily on the found 2 theta angles or d-inter-plane distances, less on the relative peak intensity.

To identify 5,6-dichloro-2- (isopropylamino) -1- (β-L-ribofuranosyl) -1H-benzimidazole form VI, the most characteristic peak is the 2 theta angle at 8.53 degrees or d-interplanar distance of 10.36 A.

Although one skilled in the art can identify Form VI from the characteristics of the 2 theta angle peaks of 8.53 degrees, in some cases it may be desirable to rely on multiples of the 2 theta angle or multiples of the d-interplanar distance to identify Form VI. 5,6-Dichloro-2- (isopropylamino) -1- (3-L-ribofuranosyl) -1H-benzimidazole Form VI can also be identified by the presence of multiples of 2 theta peak angles including two, three, four, five, six, seven , eight, nine, ten or all eleven 2 theta angles that are the reliable characteristics of this particular crystalline form. These peaks occur at the following positions, expressed at 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 above 2 theta angles are used to identify Form VI. Crystalline anhydrous Form VI typically exhibits other 2 theta peaks in addition to the aforementioned peaks. For example, Form VI may have 2 theta peaks at substantially 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.

When determining the angle 2 of the theta and the d-inter-plane space, a certain error tolerance is allowed. The error in determining distances d decreases with increasing diffraction scanning angle or decreasing distance d. The error at the above 2 theta angle is approximately ± 0.05 degrees for each peak determined above. The error in the distance d values is approximately ± 0.5 A.

Since some tolerance is allowed in determining the 2 theta angles and the distance d, a preferred method of comparing the X-ray powder diffraction pattern to identify a particular crystalline form is to overlap the X-ray powder diffraction pattern of an unknown form over the X-ray powder diffraction pattern of a known form. For example, one of ordinary skill in the art can obscure the X-ray powder diffraction pattern of an undefined crystalline form of 5,6-dichloro-2- (isopropylamino) -1- (β-Libro-furosyl) -1H-benzimidazole obtained using the methods described herein through Figure 6 and easily determine whether the X-ray the diffraction pattern of the undefined form is substantially identical to the X-ray powder diffraction pattern of Form 6. If the X-ray powder diffraction pattern is substantially the same as Figure 6, then the previously mentioned unknown crystalline form can be readily and accurately determined as Form VI. The same technique can be used to determine undefined crystalline forms I, II, IV, V or ethanolate by overlaying the X-ray powder diffraction pattern through Figures 1, 2, 4, 5 or 3.

Although 2 theta angles or distances d are the primary method of identifying a particular crystalline form, it may also be desirable to compare relative peak intensities. As mentioned above, the relative intensity may vary depending on the particular diffractometer used and the sample preparation technique. Peak intensities are reported as peak intensities. Intensity units on the X-ray diffraction axis are pulses / sec. Absolute number of pulses = pulses / time x counting time = pulses / sec. X 10 s. Due to 2 theta angles, distance d (A) and relative peak intensity I, form VI 5,6-dichloro-2- (isopropylamino) - 1- (4-L-ribofuranosyl) -1H 6 • benzimidazole, exhibits the following characteristics of the X-ray diffraction pattern:

Form VI angle 2 theta (°) ¹ A ² AND 8.53 10.36 14.5 10.47 8.45 25.6 12.80 6.91 16.8 14.16 6.25 16.4 13.51 6.55 21.4 14.95 5.92 60.4 15.98 5.54 26.2 17.23 5.14 100.0 19.25 4.61 19.3 21.41 4.15 26.5 21.83 4.07 60.4 22.35 3.97 38.3 23.07 3.85 48.7 27.49 3.24 30.9 30.11 2.97 18.5

¹ Error Tolerance = about ± 0.05 degrees ² Error Tolerance = about + 0.05 Angstrom In view of the above features of the X-ray powder diffraction pattern of Form VI, one of ordinary skill in the art can easily identify Form VI of 5,6-dichloro-2- (isopropylamino) - 1- (3-L-ribofuranosyl) -1H-benzimidazole. One skilled in the art is aware that the X-ray powder diffraction pattern of a sample of Form VI obtained according to the methods described in this application may exhibit further peaks. The above table and the following tables provide the fifteen most intense peaks that are characteristic of a particular crystalline form or solvate. These tables should not be construed as an exhaustive list of peaks exhibited by a particular form or solvate.

In contrast to the aforementioned X-ray powder diffraction characteristics of Form VI, Forms I, II, IV, V and the enolate each exhibit different 2 theta angles, distances d, and relative intensities that can be used to distinguish each of these forms from Form VI and each other. Forms I, II, IV, V and enolate are defined by an X-ray powder diffraction pattern obtained by a suitably oriented diffractometer equipped with a graphite monochromator with diffraction of the beam using copper X-ray radiation; the diagrams are shown in Figures 1, 2, 4, 5 and 3.

• ·

Form 1 of 5,6-dichloro-2- (isopropylamino) -1- (3-L-ribofuranosyl) -1H-benzimidazole is further characterized by the following 2 theta angles, d-spacing distances and relative peak intensities, obtained according to the procedure of Example 22 further.

Form I angle 2 theta (°) ¹ 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

Error tolerance = approximately ± 0.05

Form II of 5,6-dichloro-2- (isopropylamino) -1- (3-L-ribofuranosyl) -1H-benzimidazole is further characterized by the following 2 theta angles, d-spacing distances and relative peak intensities, obtained according to the procedure of Example 22 further

Form II angle 2 theta (°) ¹ 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

• 9 9 9 9 9 9 9 9 99 99 99 9 9 99 99 9

999 99 999 999 999 99 9 ^{1 1} Error tolerance = approximately ± 0.09

Form II may also exhibit peaks at substantially 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- (3-L-ribofuranosyl) -1H-benzimidazole ethanolate is further characterized by the following 2 theta angles, d-spacing distances and relative peak intensities, obtained according to the procedure of Example 22 below. .

Ethanolate angle 2 theta (°) ¹ 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 Error tolerance = approximately ± 0.05

The ethanolate may also have peaks at substantially 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,

29.1 degrees.

Form IV of 5,6-dichloro-2- (isopropylamino) -1- (3-L-ribofuranosyl) -1H-benzimidazole is further characterized by the following 2 theta angles, d-spacing distances and relative peak intensities, obtained according to the procedure of Example 22 further.

· * «

Form IV angle 2 theta (°) 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 Error tolerance = approximately ± 0.05

Form IV may also exhibit peaks at substantially 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- (p-L-ribofuranosyl) -1H-benzimidazole is further characterized by the following 2 theta angles, d-spacing distances and relative peak intensities, obtained according to the procedure of Example 22 below.

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 Error tolerance = approximately ± 0.05

9 99

9999

99

Form V may also exhibit peaks at substantially the following 2 theta angles: 9.1,

9.3, 10.7, 13.3, 17.0, 18.1, 20.4, 21.8, 26.9, 28.6, 30.2 degrees.

Other methods of physical characterization may also be used to identify the anhydrous crystalline Form VI of the invention. Examples of suitable techniques known to those skilled in the art to be used to physically characterize or identify a crystalline form or solvate include, but are not limited to, melting point, differential scanning calorimetry, and infrared absorption spectrum. These techniques can be used alone or in combination to characterize a given anhydrous crystalline form or solvate.

The invention relates to anhydrous crystalline form VI, both in pure form and in admixture with other forms of the compound of formula I. For example, form VI may be admixed with any one or more of forms I, II, IV, V or ethanolate. Alternatively, Form VI may be admixed with an amorphous compound of Formula I. In another embodiment, Form VI may be admixed with both an amorphous compound of Formula I and one or more other crystalline forms or solvates including Forms I, II, IV, V and ethanolate.

Specifically, the present invention contemplates the aforementioned mixtures of Form VI with one or more amorphous compounds of Formula I and / or other crystalline anhydrous forms and solvates. It should be appreciated that mixtures of Form VI with an amorphous compound of Formula I and / or other crystalline forms may result in masking or absence of one or more of the above-mentioned X-ray powder diffraction peaks described above for Form VI. Methods for analyzing such mixtures of crystalline forms to accurately identify the presence or absence of particular crystalline forms are known.

Further, in addition to the above forms, Form VI can also be mixed with hydrated crystalline forms. For example, at any dosage containing the anhydrous crystalline compound of Formula I of Form VI, the hydrated crystalline Form VI may also be. Since the anhydrous crystalline form of the compound of Formula I of Form VI is substantially free of hydration water, the proportion of the hydrated forms of the compound of Formula I of Form VI at any dose of the compound can be measured by determining the total hydration water content of each dose.

According to a second aspect, the present invention provides a compound of formula I of Form VI which has a total volatile content of no more than 0.3% by weight. (w / w) as determined by the TA Instruments Hi-Res TGA 2950 Thermogravimetric Analyzer (Figure 7). Gravimetric measurement of the water vapor sorption showed that Form VI absorbed only 0.3% water at equilibrium to 95% relative humidity at room temperature (Figure 8).

In another aspect, the present invention provides a process for preparing a compound of Formula I in anhydrous crystalline Form VI, which comprises treating a compound of Formula I with a solubilizing agent that serves to convert an amount of a compound of Formula I into an anhydrous crystalline Form VI.

The invention also provides a process for preparing a compound of Formula I of Form VI. The procedure includes the following steps:

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

b) isolating the compound of formula I from solution and optionally removing unbound (wet, unsolvated) solvent to give the compound of formula I in substantially dry form;

c) treating the compound of formula I with a solubilizing agent to convert the optionally dry compound of formula I from step b) to the anhydrous crystalline form VI; and

d) isolating the anhydrous crystalline form VI.

In one embodiment of the invention, Compound I of Form VI is prepared by recrystallization from ethyl acetate / toluene. According to this procedure, the compound of formula I is treated with a solubilizing agent comprising ethyl acetate and toluene to convert the compound of formula I to the anhydrous crystalline form VI and the anhydrous crystalline form VI is isolated.

4444 • 4 4

4 4 4 4 • 4 4

44 from the solution by removing the solubilizing solvent, for example by evaporation or drying. The compound of formula I may be either in the free base form or in the form of a salt.

The compound of formula I can be prepared by any method known in the art, but preferably by the methods described in WO96 / 01833, incorporated herein by reference.

Synthesis of a compound of formula I generally results in the formation of a compound in solution in the reaction mixture from which the compound can be separated and purified as a solid product. The compound of formula VI may optionally be dried. A number of factors affect the crystalline form of the solid product, and separation and / or post-treatment conditions are selected according to the present invention to form a compound of formula I as the anhydrous crystalline form VI or as a mixture of form VI with one or more other anhydrous crystalline forms or solvates and / or amorphous material. For example, the hydrate form of a compound of formula I can be converted to the anhydrous crystalline form using a suitable solvent and under suitable conditions.

Such a suitable solvent, which is preferably a water-soluble organic solvent, should have sufficient solubility and be used in sufficient quantity to achieve partial dissolution to effect conversion and precipitation, for example, from the anhydrous crystalline form to the desired anhydrous crystalline form. Preferably, the solvent may optionally be removed by vacuum drying.

The wet compound of formula I is preferably dried, for example, at a temperature of from about 30 ° C to about 70 ° C after the first isolation (as mentioned in step b) above to give a substantially dry compound of formula I.

The present invention also provides a compound of Formula I of Form VI for use in medicine, for example in the treatment and prophylaxis of a viral disease in an animal, such as a mammal, such as a human. The compound is particularly useful for the treatment or prophylaxis, including suppression of the recurrence of viral diseases, such as infections caused by herpes virus, for example CMV infections, as well as diseases caused by hepatitis B virus and hepatitis C.

Further, for use in human medicine, the compound of Formula I of Form VI may be administered to other animals, for example, other mammals, for the treatment or prophylaxis of viral diseases.

The present invention also provides a method of treatment or prophylaxis, including suppressing the recurrence of viral infections, particularly infections caused by herpes virus, CMV infection or diseases caused by hepatitis B virus and hepatitis C in animals, e.g. mammals, comprising administering to the animal an antiviral effective amount of .

The present invention also provides the use of a compound of Formula I of Form VI for the preparation of a pharmaceutical composition for the treatment or prophylaxis of a viral infection.

The compound of Formula I of Form VI may be administered by any route suitable for the treatment of the disease, but the preferred route of administration is oral. However, it will be appreciated that the preferred mode of administration may vary, for example, according to the condition of the patient.

For each of the above uses and indications, the required amounts of active ingredient (as defined above) will depend on a number of factors, including the severity of the disease and the condition of the patient, and the final decision will always depend on the attending physician or veterinarian. In general, however, an effective dosage in the range of 0.01 to 250 mg per kg body weight of patient per day, preferably 0.1 to 100 mg per kg body weight per day, more preferably in the range of 0, 5 to 30 mg per kg of body weight per day, in particular 1.0 to 30 mg per kg of body weight per day (unless otherwise indicated all weights of the active ingredient are based on the free base of the compound of formula I). The desired dose is preferably composed of one, two, three or four multiple divided doses administered at appropriate intervals throughout the day. These divided doses may be administered in individual dosage forms comprising about 10 to 1200 mg or 50 to 500 mg, preferably 20 to 500 mg, and most preferably 100 to 400 mg of active ingredient per dosage form.

• 4

4 ·· 4 <44 44 4 • ····

4 ··

4 4 4 4

4 4 4 4

4 4 4

4 44

While it is possible for the active ingredient to be administered alone, it is preferably administered in the form of a pharmaceutical composition. The composition comprises the active ingredient as defined above together with one or more pharmaceutically acceptable excipients and optionally other active ingredients. The excipient (s) must be 'acceptable' in the sense of being compatible with the other ingredients in the formulation and not harmful to the recipient.

The pharmaceutical compositions include forms suitable for oral administration and may preferably be in unit dosage form prepared by any of the methods well known in the art of pharmacy, such methods comprising the step of admixing the active ingredient with a carrier comprising one or more additional ingredients. In general, the compositions are prepared by uniformly and intimately mixing the active ingredient with liquid carriers or finely divided solid carriers, or both, and then shaping the product if necessary.

The pharmaceutical compositions of the present invention suitable for oral administration may be in the form of discrete units such as capsules, lozenges, granule bags or tablets (for swallowing, dispersing or chewing), each unit containing a specified amount of the active ingredient; as powders or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be in the form of a bite, electuary or paste.

Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine a free-flowing active ingredient, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Molded tablets may be molded in a suitable machine using a powder mixture moistened with an inert liquid diluent, optionally the tablets may be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient present.

99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99

In addition to the oral dosage forms described above, crystalline Form VI of the invention may also be formulated for topical, parenteral and other routes of administration using the carriers and techniques described in WO96 / 01833. One skilled in the art will appreciate that the preparation of dosage forms such as solutions of anhydrous crystalline Form VI substantially completely dissolved in a solvent for parenteral administration will make it impossible to identify the particular crystalline form used to prepare the solution. However, anhydrous crystalline Form VI may conveniently be used to prepare solutions by substantially dissolving the crystalline form or solvates in a suitable solvent.

Preferred single dosage forms are those containing a daily dose or a divided daily dose (as noted above) or a portion thereof of the active ingredient.

It goes without saying that in addition to the aforementioned components of the compositions according to the invention, these compositions may contain other substances known in the art according to the type of composition contemplated, for example oral compositions may contain flavoring or taste-masking agents.

The following examples are given by way of illustration only and are not intended to limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

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

The compound of formula I (200 g) is placed in a thermal activity monitor (TAM) and a few drops of water are added to make the powder wet. The vial was sealed and placed in a TAM chamber at 50 ° C. The mixture was cooled to ambient temperature and filtered. The wet residue was dried under vacuum at 60 ° C overnight to give Form I of Compound I.

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

Example 2

Form I 5,6-dichloro-2- (isopropylamino) -1-3-L-ribofuranosyl-1H-benzimidazole 9 9 9 9 9 9

99

The compound of formula I (1.5 g) was suspended in water (30 mL) and heated to 65 ° C with stirring. After about 0.5 hours, stirring becomes difficult as a gum is formed. After further heating, the gum is converted to a solid which is crushed with a spatula. Heat the mixture at 65-70 ° C for 9 hours. The mixture was cooled to 20 ° C and the solid was collected by filtration and dried under vacuum at 40 ° C for 24 hours to give Form I of the compound of Formula I.

The X-ray powder diffraction diagram 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

The compound of formula I (5 g) and water (1.5 mL) were stirred and heated in an oil bath at 80 ° C. The powder turned into a gum and the mixing was stopped. Heating is continued for 8 hours. The solid is released 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.

The X-ray powder diffraction diagram 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

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

Form II of Compound I (2 g) in toluene (10 mL, 5 vol) was heated to 60 ° C when the solid became sticky to the vessel walls. Continued heating to 95 ° C gave an oil. Continue heating to 105 ° C, then add toluene (2.5 vol.) And add toluene (2.5 vol.). The heating continues. The reflux was continued for 3 hours with rapid stirring. The oil bath temperature was lowered to 80 ° C (internal temperature 73 ° C) and heating was continued for 3 hours with rapid stirring. The mixture was heated again at reflux for 16 hours and then allowed to cool to room temperature. The free solid was collected by filtration and washed with toluene (2 x 5 mL) and dried under vacuum at 20 ° C to give a white solid under vacuum at 40 ° C. The residual solid was removed from the flask, collected by filtration and dried under vacuum at 20 ° C. The filtrate was concentrated under reduced pressure to give a solid.

The X-ray powder diffraction diagram of the product of Example 5 is shown in Figure 1.

Example 6

Preparation of Form I from Form II 5,6-dichloro-2- (isopropylamino) -1-p-L-ribofuranosyl-1H-benzimidazole

Form II of compound I (5 g) was stirred with water (1.5 mL) in an oil bath at 80 ° C.

Once the bath temperature reaches about 60 ° C, the mixture is difficult to stir. Heating was continued for 8 hours with occasional stirring, and then the mixture was cooled to room temperature. This material was dried under vacuum at 40 ° C for 4 hours.

The X-ray powder diffraction diagram of the product of Example 6 is shown in Figure 1.

Example 7

Form II 5,6-dichloro-2- (isopropylamino) -1-3-L-ribofuranosyl-1H-benzimidazole

The compound of formula I (100 g) was added to a stirred mixture of toluene / methanol (4: 1.440 mL) and heated to 65 ° C to give a clear solution. The solution was clarified by washing on a filter (toluene / methanol [4: 1, 110 mL, warm solution]). The solution was heated back to 65 ° C and toluene (4.5 vol.) Was added slowly while maintaining the internal temperature above 65 ° C.

After the addition was complete, the solution was cooled to 40 ° C over 1 hour and aged at 40 ° C. After 0.5 h, the mixture was seeded with Form II of Compound I and aged for an additional 4.5 h. The suspension is cooled to 20 ° C over 1 hour and aged at 20 ° C for 12 hours and then cooled to 5 ° C over 1 hour and aged for 3 hours. The solid was collected by filtration, washed with water

• ·· ·· ········

9 9 with toluene (2 x 100 mL). The wet cake was transferred to an oven and dried under vacuum at 20 ° C.

The X-ray powder diffraction diagram 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 wt) was dissolved in ethyl acetate (6 vol) and subjected to final filtration. The filtrates are concentrated to approximately 3 volumes. Assuming complete solvent exchange, the solution was diluted with 3.5 volumes of methanol. Water (0.5 vol.) Was added and the solution was cooled to 0-5 ° C. Crystallization is seeded with a small amount of pure compound of formula I and the solution is stored at 0-5 ° C for 2 hours. The product is filtered (without washing) and dried under vacuum for 24 to 48 hours at ambient temperature. The second part is obtained by evaporating the filtrate to half volume and then cooling, seeding and crystallizing in a similar manner as described above.

The X-ray powder diffraction diagram 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

The compound of formula I (10 g) was dissolved in methanol (20 mL) with heating to 50 ° C. Water (5 mL) was added and the mixture was cooled slowly to 5 ° C and stirred at 5 ° C for 1 hour. The solid was collected by filtration and dried under vacuum at 20 ° C for 15 hours and at 40 ° C for 4 hours to give the compound of formula I.

The X-ray powder diffraction diagram of the product of Example 9 is shown in Figure 2.

Example 10

Preparation of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole mixtures

The compound of formula I can be dissolved in 2N hydrochloric acid (60 mL) and stirred for 0.5 h and filtered. The filtrate was heated to 60 ° C and 2N sodium hydroxide (55 ml) was added slowly while maintaining the internal temperature between 60 and 70 ° C during the addition.

* 9 • 9

9 ·· 9 • 99 «99 ····

99

9 9 9

9 9 9

9 9 9

9 · ·

99

The mixture was stirred at 65-70 ° C for 2 hours and then cooled to 20 ° C over 2 hours. The solid was collected by filtration, washed 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%).

Example 11

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

The compound of formula I (1.0 wt.) Is suspended in ethanol / water (10.0 vol.) 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 powder was filtered and air dried. Ethanol solvate is similarly obtained from ethanol / toluene solutions (ratios 5/95, 10/90, 15/85, 20/80, 25/75 and 30/70).

Recrystallization of the compound of formula I from ethanol / water yields ethanol solvate containing 0.5 moles of ethanol per mole of compound of formula I.

The X-ray powder diffraction diagram of the product of Example 11 is shown in the figure

3.

Example 12

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

The compound of formula I (20 g) was added to a stirred mixture of toluene / ethanol (7: 1, 200 ml) and heated to reflux (81 ° C) until a clear solution was obtained. The solution was cooled to 20 ° C and crystallized at about 50 ° C. The suspension is cooled to 0-5 ° C and aged for 2 hours. The solid was collected by filtration and washed with toluene (2 x 20 mL). The wet cake is dried under vacuum at 40 ° C.

Recrystallization of the compound of Formula I from ethanol / toluene yields ethanol solvate containing 0.5 moles of ethanol per mole of compound of Formula I.

The X-ray powder diffraction diagram of the product of Example 12 is shown in the figure

3.

Example 13

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

Water (300 mL) was added to Form I (4 g) as prepared in Example 1 and the mixture was stirred for 20 minutes. The mixture was then heated at 50 ° C for 6 days and then cooled to room temperature. The solid, granular crystalline material was filtered and dried under vacuum at 60 ° C.

The X-ray powder diffraction diagram of the product of Example 13 is shown in the figure

4.

Example 14

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

The compound of formula I (2.0 g) was added sequentially over 2 hours to water (40 mL) at 70 ° C with vigorous stirring. The mixture was heated at 65-70 ° C for an additional 7 hours and then stirring and heating were discontinued. The mixture was allowed to stand for 2.5 days at ambient temperature and then filtered. The granular white solid is allowed to air dry overnight to give Form V of the compound of Formula I.

The X-ray powder diffraction diagram of the product of Example 14 is shown in the figure

5.

Example 15

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

Ethanolate of the compound of formula I (200 mg) was weighed into small vials. Hydrostats with saturated NaCl solutions and excess solid NaCl were charged to the vials. The vials are then sealed very well and stored at 80 ° C. The samples were removed from the vials and heated to 170 ° C in a differential scanning calorimeter (DSC) and then cooled to room temperature. The powder is collected from DSC dishes and analyzed by X-ray diffraction.

Characterization: The X-ray powder diffraction diagram of the product of Example 15 (Form VI) is shown in Figure 6. The DSC thermogram for Form VI is shown in Figure 9. The TGA thermogram for Compound VI is shown in Figure 7. 8.

Example 16 9 9 9 9 9 9 9 9

Conversion of 5,6-dichloro-2- (isopropylamino) -1- (beta-L-ribofuranosyl) -1H-benzimidazole Form II to Form VI

About 200 mg of Form II inoculated 5 mg of Form VI is suspended in 1 ml of distilled water and the mixture is stirred in a water bath at 45 ° C. After stirring for 28 hours, the solid was examined by X-ray diffraction. X-ray diffraction results show that Form II was completely converted to Form VI.

Characterization: as in Example 15.

Example 17

Conversion of 5,6-dichloro-2- (isopropylamino) -1- (beta-L-ribofuranosyl) -1-benzimidazole ethanol solvate to form VI

About 200 mg of the ethanolate grafted with 5 mg of Form VI is suspended in 1 ml of distilled water and the mixture is stirred in a water bath at 45 ° C. After stirring for 28 hours, the solid was examined by X-ray diffraction. X-ray diffraction results show that the ethanol solvate of formula I has been completely converted to form VI:

Characterization: as in Example 15.

Example 18

Conversion of 5,6-dichloro-2- (isopropylamino) -1- (beta-L-ribofuranosyl) -1H-benzimidazole ethanol solvate to form VI g of the inoculated 100 mg of form VI prepared in the above conversion are suspended in 50 ml of distilled water at 45 ° C. Deň: 32 ° C. After 5 hours, all the ethanolate was converted to Form VI as determined by X-ray diffraction. The solid was collected by filtration, washed with water (3 x 5 mL) and dried in a vacuum oven at 100 ° C for 3 hours.

Characterization: as in Example 15.

Example 19

Conversion of 5,6-dichloro-2- (isopropylamino) -1- (beta-L-ribofuranosyl) -1H-benzimidazole ethanol solvate to form VI «·· ♦ • ·

Ethanolate samples stored at 80 ° C / 50% relative humidity (RH), 60 ° C / 75% RH, 60 ° C / 50% RH and 40 ° C / 75% RH under closed conditions for 2 months are also partially or completely converted to Form VI.

Characterization: as in Example 15.

Example 20

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

A solution of 5,6-dichloro-2- (isopropylamino) -1- (beta-L-ribofuranosyl) -1H-benzimidazole (10 g) in ethyl acetate (25 mL) and toluene (30 mL) was seeded with Form VI 5.6 -dichloro-2 (isopropylamino) -1- (beta-L-ribofuranosyl) -1H-benzimidazole (100 mg). The mixture was heated at 50 ° C for 3 hours to form a suspension. Toluene (70 ml) was then added over 30 minutes. The suspension is cooled to 25 ° C and aged at 25 ° C for 2 hours. The solid was collected by filtration, washed with ethyl acetate / toluene (1: 4, 20 mL). The solid was dried under vacuum at 40 ° C to give 5,6-dichloro-2 (isopropylamino) -1- (beta-L-ribofuranosyl) -1H-benzimidazole Form VI

Characterization: as in Example 15.

Example 21

Preparation of 5,6-dichloro-2- (1-propylamino) -1- (beta-L-ribofuranosyl) -1H-benzimidazole form by recrystallization from ethyl acetate / toluene

Sodium hydroxide (2M, 1790 mL) was added to a slurry of 5,6-dichloro-2- (isopropylamino) -1 (2,3,5-tri-O-acetyl-beta-L-ribofuranosyl) -1H-benzimidazole ( 358 g) in TMBE (1790 mL) containing methanol (179 mL). The mixture was stirred at 25-30 ° C until the reaction was complete. 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 under reduced pressure to about 2.5 volumes (895 mL). Ethyl acetate (2864 mL) was added and the solution was again concentrated to 2.5 volumes. The solution was cooled to 40-50 ° C and the resulting solution was clarified, washed with ethyl acetate (716 mL). The clear solution was concentrated under reduced pressure to 3.3 volumes (1180 mL).

• 9

9 · 9 9 9

9 · · · 99

9

9999999 99 99

The solution was heated to 60 ° C. Toluene (3000 mL) was heated to 60 ° C and added to the ethyl acetate solution over 1 hour. The resulting mixture was aged at 60 ° C overnight and then cooled to 0-5 ° C over 1 hour and aged at 0.5 ° C for 2 hours. The slurry was filtered, washed with 1: 4 ethyl acetate: toluene (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.

Characterization: as in Example 15.

Example 22

Experimental Methods for Characterization of Form VI

Differential scanning calorimetry and thermogravimetric analyzer

Differential scanning calorimetry (DSC) is performed on a TA Instruments DSC 2920 differential scanning calorimeter equipped with an automated sampler. Samples of 1 to 3 mg are placed in standard aluminum pans with holes and heated to 25 ° C to 250 ° C at a rate of 10 ° C / minute with nitrogen purge. The percentage of total drug weight loss is determined on a TA Instruments Hi-Res TGA 2950 Thermogravimetric Analyzer (TGA) under nitrogen purge.

X-ray powder diffraction

The X-ray powder diffraction pattern is determined on a Philips X'Pert MPD diffractometer equipped with a graphite monochromator with a diffraction pattern using copper X-ray radiation and an automatic divergence slit. The diffractometer operates using a scan of 0.04 ⁰ per step and a time of 1 second per step. A proportional counter with a graphite monochromator is used as a detector. The samples are filled into a 16 mm diameter holder having a thickness of about 2.0 mm. X-ray powder diffraction diagrams of Forms I, II, IV, V, VI and ethanolate are shown in Figures 1,2, 4, 5, 6 and

3. The following values of 2 theta angles, d-inter-plane distances, relative intensities, and Miller indices were obtained:

• · «9 9 9 9 9 9 9 9 • 9 9 9 9 9 9 9

9999 9 9 99 99

9 9 9 9 9

9 9 9 9 9 9 9 9 9 99

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

2 Theta (°) ¹ A ² AND h ^J k ³ l ^J 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 Tolerance c it is approximately ± 0.5 degrees.

² The error tolerance is approximately ± 0.5 A.

^The Miller indices h, k and I from above are used to unambiguously define sets of parallel planes in a crystal.

Moisture sorption

Moisture sorption / desorption studies were performed on a VTI vacuum balance at 25 ° C after drying the sample at 60 ^° under vacuum. Moisture absorption is observed in a vacuum of from 0 to 95% relative humidity and desorption is observed at a relative humidity of from 95% to 5%. The criteria for equilibrium at a given relative humidity were less than 3 pg of weight change over 18 minutes.

Single crystal X-ray diffraction

The crystalline structure of the single crystal of 5,6-dichloro-2- (isopropylamino) -1- (beta-L-ribofuranosyl) -1H-benzimidazole is determined using single crystal X-ray diffraction. Single crystal X-ray diffraction data is determined on a Brucker AXS SMART diffractometer equipped with a graphite monochromator with a diffraction pattern using λ α molybdenum x-ray (lambda = 0.71071 Å) at 160K. Unit cell parameters and spatial group were determined to be tetragonal crystal system, P4 (3) 2 (1) 2, s = b = 9.1542, c = 41.687 (units a, b, c in angstroms) and alpha = beta = gamma = 90 degrees. Basic cell parameters under normal conditions, a = b = 9.2794, c = 41.593 (units of a, b, c in angstroms) and alpha = beta = gamma = 90,000 degrees are calculated by recording X-ray powder sample.

X-ray powder diffraction of the sample is calculated using the single crystal atom coordinate data and the cell parameters from the recording of the experimental powder sample. The X-ray diffraction pattern for the single crystal form VI of 1263W94 is shown in Figure 10. The 15 most intense peaks from 2 to 35 two theta are shown below in the 2 theta angles, d-interplanar space, relative intensity, and Miller indices.

Table 2: Calculated X-ray powder diffraction pattern based on single crystal X-ray diffraction of Form VI 1263W94

2 Theta (°) ¹ A ² AND h ^J k ^J P 17.21 5.15 100.0 1 1 5 21.82 4.07 57.4 2 1 2 23.06 3.85 53.2 2 1 4 14.93 5.93 51.4 1 1 3 22.34 3.98 39.9 2 1 3 10.43 8.47 29.2 1 0 2 12.78 6.92 22.2 1 0 4 8.50 10.40 21.3 0 0 4 15.96 5.55 19.2 1 1 4 30.11 2.97 17.8 2 2 6 32.61 2.74 17.7 3 0 7 19.23 4.61 17.6 2 0 1 21.39 4.15 17.1 2 1 0 17.71 5.0 15.5 1 0 7 13.48 6.56 15.5 1 1 0 ¹ Tolerance c the error is approximately ± 0.5 degrees.

² The error tolerance is approximately ± 0.5 A.

• · ··· · · ···· · · · · · · · · · ·

9A ·· · · · · · * é-kj C ··· ·· · · ······· 9 ^three Miller indices h, k I above are used to uniquely define sets of parallel planes in the crystal.

The 2 theta values derived from the single crystal data shown in the graph differ from the experimental powder diffraction values reported above, mainly due to sample preparation errors, such as sample displacement error, small diffractometer alignment errors, and variation in the peak determination method. The relative intensity of the peaks in the calculated sample is due not only to the single crystal data but also to the peak profile (shape and extension) used in the calculation of the artificial powder sample.

Example 23: Tablet formulation

The following formulations were prepared using Form VI of the compound of Formula I

Formulation A

Tablets 1263W94 (Form VI)

Direct compression

Efficiency 100 mo 400 mq Core components 1263W94 (active) 100,0 ² 400.0 ³ Microcrystalline cellulose, NF 93.5 374.0 Crospovidone, NF 4.0 16.0 Colloidal silica, NF - 0.4 Magnesium stearate, NF 2.5 10.0 Total (core) 200.0 mg 800.4 mg Coating components Opadry White YS-1 -18034 6.0 24.0 Purified Water USP ¹ QS QS Total (core) 206.0 mg 824.4 mg

Theoretical charge size (core) • ·

27 Mar: • ·· · ·· · «« V · ♦ · · · · · · · · • · · · · · · * · «· · · 1 ··· · · · · ··· * ··· kg 15.0 33.0 tablets 75000 41254

¹ Removed during processing ² Equivalent 100 mg 1263W94 per tablet ³ Equivalent 400 mg 1263W94 per tablet

Production process for direct compression

All ingredients are sieved except for magnesium stearate using a 20-30 mesh screen. All components are mixed, except for magnesium sulfate, until the mixture is uniform. The magnesium stearate is sieved as above and added to the other ingredients and mixed. The tablets are compressed using a rotary press. A 10% coating suspension is prepared by mixing Opadry with water. The tablets were coated so that the coating content was 3% by weight.

Formulation B

Tablets 1263W94 (Form VI)

Wet granulation

Efficiency 100 mq 400 mq Core components 1263W94 (active) 102,0 ² 408,0 ³ Anhydrous lactose 60.0 240.0 Microcrystalline cellulose, NF 20.0 80.0 Crospovidone, NF 15.0 60.0 Povidone, USP, K30 7.5 30.0 Magnesium stearate, NF 0.6 2.4 Purified Water USP ¹ QS QS Total (core) 205.1 mg 816.0 mg Coating components Opadry White YS-1 -18034 6.0 24.0 Purified Water USP ¹ QS QS

444 4 · · · · 4 4 * 4 4 4 4 · • <444 4 4 4 4 4 4 • 4 44 4444 44 44 44 4444444 · 4 44

Total (core) 211.1 mg 840.0 mg

Theoretical charge size (core) kg 0.718 tablets 3500 ¹ Removed during processing ² Equivalent 100 mg 1263W94 per tablet ³ Equivalent 400 mg 1263W94 per tablet

Formulation B-1

Tablets 1263W94 (Form VI)

Wet granulation

Efficiency_400 mg

Core components

1263W94 (active) 400.0 ² Microcrystalline cellulose 298.0 Lactose, aqueous 60.0 Crospovidone, NF 24.0 Povidone, USP 12.0 Magnesium stearate, NF 2,0 Purified Water USP ¹ QS Total (core) 816.0 mg Coating components Opadry White YS-1-18034 24.0 Purified Water USP ¹ QS Total (core) 820.0 mg

¹ Removed during processing ² Equivalent 400 mg 1263W94 per tablet * · · · · · · · · · · · · · · · · · · · · · · · ·

Production process for wet granulation

The granular ingredients are sieved using a 20 to 30 mesh screen. All ingredients are mixed in a high shear granulator and then granulated in a high shear granulator using purified water. The granules are dried to loss by drying less than 2%. The granules are sieved as above. The granules are mixed with the remaining ingredients. The tablets are compressed using a rotary press. A 10% coating suspension is prepared by mixing Opadry with water. The tablets were coated so that the coating content was 3% by weight.

Example 24: Capsule formulation

The following formulation can be prepared using a compound of Formula I of Form VI.

Capsules 1263W94 (Form VI)

Efficiency _100 mg

Foaming ingredients for the capsule

1263W94 (active) 101.0 ¹

Lactose, anhydrous NF 232.0

Crospovidone, NF 17.0

Magnesium stearate, NF 1.0

Total fill weight 351.0 mg

Capsule case

Gelatin, opaque cap 81.1 and body

Total weight 432.5 mg ¹ Equivalent to 100 mg 1263W94 per tablet

Production process for capsules

999 9

The filling components of the capsule are mixed using a mortar and pestle by geometric dilution. The combined capsule filler ingredients are manually filled into gelatin capsules. The capsules are closed manually.

Example 25: Oral Solution Formulation

The following formulation can be prepared using a compound of Formula I of Form VI.

Oral solution 1263W94 (prepared using compound VI)

Efficiency_30 mg / ml

Ingredients per 100 ml

1263W04 3.0 g

Citric acid, anhydrous 0,3 g

Hydrochloric acid 1N 6.9 ml

Propylene glycol USP 20.0 ml

Purified Water USP 20.0 ml

Hydrochloric acid 1N QS

Sorbitol solution (60% w / v) 50.0 mL Purified Water USP QS

Total volume 100.0 ml

Oral solution production process

Propylene glycol, water and hydrochloric acid (6.9 ml) were mixed thoroughly. Citric acid is added and the mixture is stirred until the citric acid is dissolved. The active ingredient is added and dissolved by stirring. If necessary, adjust the pH to between 2.0 and 2.5 by adding 1N hydrochloric acid or 1N sodium hydroxide. Sorbitol is added and mixed thoroughly. The final volume was adjusted to 100 ml by the addition of water.

Example 26: Oral suspension formulation

The following formulation can be prepared using a compound of Formula I of Form VI.

• 4 ··

Oral suspension 1263W94 (Form VI)

Efficiency

Folders

1263W94 (active)

Sucrose Propylene glycol Sodium chloride Citric acid Sodium citrate

Microcrystalline cellulose and sodium carboxymethylcellulose Polysorbate 80

Sodium benzoate

Methylparaben

Aromat

Dye

Purified water USP Total volume mg / ml per 100 ml 3.0 g 50.0 g 5.0 g 0.5 g QS QS 2.5 g

0.25 g 0.2 g 0.1 g 0.1 g 0.2 ml 0.005 g QS

100.0 ml

Manufacturing procedure for oral solution

Sucrose is dissolved in purified water to approximately 70% of the total batch volume. Sodium chloride, citric acid sodium citrate and sodium benzoate are added under continuous stirring and the components are dissolved. If necessary, adjust the pH to between 5.0 and 6.0 by adding sufficient citric acid or sodium citrate. Microcrystalline cellulose and sodium carboxymethylcellulose (Avicel RC 591) are added with stirring and stirring is continued until the mixture is uniform and a fine dispersion is formed. Polysorbate 80 is added with stirring. 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 suspension with stirring. Under continuous stirring, the active ingredient is gradually dispersed in a bulk liquid to obtain a uniform dispersion. The flavor and color are added and the volume is adjusted to a volume of water

100 ml. The suspension is then homogenized by passing through a pump and a colloid mill.

The above examples are illustrative only and are not intended to limit the scope of the invention in any way. The invention is defined by the following claims, including equivalents thereof.

Claims (15)

PATENT CLAIMS 1. Form VI of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole, characterized by an X-ray powder diffraction pattern expressed at 2 theta angles and obtained by a diffractometer equipped with a graphite monochromator with a diffraction pattern of using copper copper X-ray radiation, wherein said X-ray powder diffraction pattern comprises a 2 theta angle at 8.53 ± 0.05 degrees. 2. Form VI of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole, characterized by substantially the same X-ray powder diffraction pattern as shown in Figure 6, wherein said X-ray powder diffraction pattern the diagram is obtained with a diffractometer equipped with a graphite monochromator with ray diffraction using X-ray Ka. A crystalline form of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole, characterized by an X-ray powder diffraction pattern expressed at 2 theta angles and obtained by a diffractometer equipped with a graphite monochromator with x-ray diffraction. copper radiation, wherein said X-ray powder diffraction pattern comprises 2 theta angles at 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 an X-ray powder diffraction pattern expressed at 2 theta angles and relative peak intensities (I) and obtained by a graphite diffractometer X-ray diffraction monochromator using copper copper X: 9 9 « J * • * 9 9 99 · ·· · * 9 » angle 2 theta (°) ¹ AND 8.53 ± 0.05 14.5 10.47 ± 0.05 25.6 12.80 ± 0.05 16.8 14.16 ± 0.05 16.4 13.51 + 0.05 21.4 14.95 ± 0.05 60.4 15.98 ± 0.05 26.2 17.23 ± 0.05 100.0 19.25 ± 0.05 19.3 21.41 ± 0.05 26.5 21.83 ± 0.05 60.4 22.35 ± 0.05 38.3 23.07 ± 0.05 48.7 27.49 ± 0.05 30.9 30.11 ± 0.05 18.5 A composition comprising Form VI of 5,6-dichloro-2 (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole according to any one of claims 1 to 4 and amorphous 5,6-dichloro- 2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole. A pharmaceutical composition comprising a crystalline form of a compound as claimed in any one of claims 1 to 4 and at least one pharmaceutically acceptable carrier. 5,6-Dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole as claimed in any one of claims 1 to 4 after use in medicine. Use of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole as claimed in any one of claims 1 to 4 for the preparation of a medicament for the treatment or prophylaxis of a viral infection. 9. A method of treatment or prophylaxis of viral disease in humans, comprising administering to a human an effective antiviral amount of crystalline 5,6-dichloro-2 (isopropylamino) -1-beta-L-ribofuranosyl-1H-benzimidazole as claimed in any of claims 1 to 4. · 9 »w 9 w w w w w w w w w 4 4 4 4 4 4 4 A process for the preparation of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole as claimed in any one of claims 1 to 4, comprising the addition of Form VI 5, 6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole to an aqueous suspension of Form II or an aqueous suspension of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-ethanol -benzimidazole. 11. A process for the preparation of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole in anhydrous crystalline Form VI, the process comprising 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) isolating 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole from solution and optionally removing unbound solvent to obtain 5,6-dichloro-2- (isopropylamino) -1-β -L-ribofuranosyl-1H-benzimidazole in substantially dry form; c) treating the 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole with a solubilizing agent to convert the optionally dry 5,6-dichloro-2 (isopropylamino) -1-β -L-ribofuranosyl-1H-benzimidazole to the anhydrous crystalline form VI of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole; and d) isolating said anhydrous crystalline form VI. A process for the preparation of 5,6-dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole as claimed in any one of claims 1 to 4, characterized in that it comprises crystallization of 5,6- dichloro-2- (isopropylamino) -1-β-L-ribofuranosyl-1H-benzimidazole from a solution of ethyl acetate and toluene. 13. A pharmaceutical composition according to claim 6 in powder form. Pharmaceutical composition according to claim 6, characterized in the form of a tablet. is that it is ve Pharmaceutical composition according to claim 6, characterized in the form of a capsule.