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

Abstract

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

Description

Technical area

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; compound of formula I)), pharmaceutical compositions containing this crystalline form of the antiviral compound and its use for treatment.

State of the art

5,6-Dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole is a benzimidazole derivative which is used for treatment in medicine. WO96/01833 describes 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 5,6-dichloro-2-(isopropylamino)-1-(p-L-ribofuranosyl)-1H-benzimidazole, a compound of formula I, is as follows:

The essence of the invention

We have now found that the compound of formula I can exist in various crystalline forms and solvates. We have further 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 manufactured on a commercial scale. It is particularly stable and substantially non-hygroscopic. Batches of this crystalline form can be consistently prepared in a high purity crystalline form, 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 easily 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 is 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 pattern is 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 pattern 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 pattern 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 is 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 is 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 compound of formula I.

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

Figure 10. X-ray powder diffraction pattern of a single crystal of form VI of the compound of formula I. This pattern 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 with a suitably oriented diffractometer equipped with a graphite monochromator with Kα X-ray diffraction using medium. Form VI can be prepared at certain relative humidities from the ethanol solvate of compound I. Form VI can also be prepared from a seed slurry of Form II or the ethanol solvate in water with 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 of 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 other crystalline forms or solvates.

The term "solvate" as used herein is a complex of variable stoichiometry formed by a solute (a compound of Formula I) and a solvent. Water, methanol, ethanol or acetic acid may be used as solvents. Reference hereinafter to a compound of Formula I, unless another form or solvate is specified, refers to the amorphous form of that compound.

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

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. The diffraction patterns of Figures 1 to 6 were obtained using a Philips X-Pert MPD diffractometer equipped with a diffractometer equipped with a graphite monochromator with copper Kα X-ray diffraction and an automatic diverging slit. A xenon proportional counter was used as the detector. The powder sample used to generate X-ray powder diffraction data was prepared using conventional sample loading techniques using a 16 mm diameter and 2.0 mm thick sample holder.

A powder sample of each of Forms I, II, IV, V and VI and ethanolate was used to obtain the X-ray powder diffraction patterns shown in Figures 1, 2, 4, 5, 6 and 3. The X-ray diffraction patterns are specific to each of the different forms and solvates. Each crystalline anhydrous form or solvate exhibits a diffraction pattern with a specific set of diffraction peaks which can be expressed in terms of 2 theta angles (°), d-interplanar spacings (Angstroms) and/or relative peak intensities.

The 2 theta diffraction angles and the corresponding d-interplanar spacing values explain the positions of the various peaks in the X-ray diffraction pattern. The d-interplanar spacing values are calculated from the observed 2 theta angles and the wavelength Ka 1 using the Bragg equation. Slight variations in the observed 2 theta angles and d-interplanar spacings are due to the different diffractometers used and the technique of sample preparation for analysis.

Larger variations are expected in the relative intensity of the peaks. Identification of the exact crystalline form of a compound will be based primarily on the 2 theta angles or d-interplanar spacings found, less on the relative intensity of the peaks.

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

Although one skilled in the art can identify Form VI from the 2 theta angle peak characteristics 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 spacing to identify Form VI. 5,6-dichloro-2-(isopropylamino)-1-(3-L-ribofuranosyl)-1 H-benzimidazole Form VI can also be identified by the presence of multiples of the 2 theta angle peak characteristics, including two, three, four, five, six, seven, eight, nine, ten or all eleven 2 theta angles, which are reliable characteristics of this particular crystalline form. These peaks occur at 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 above 2 theta angles are used to identify Form VI. Crystalline anhydrous Form VI typically exhibits additional 2 theta angle peaks in addition to the above peaks. For example, Form VI may exhibit 2 theta angle 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.

A certain tolerance for error is allowed in the determination of the 2 theta angle and the d-interplanar spacing. The error in the determination of the d-distances decreases with increasing diffraction scan angle or decreasing d-distance. The error in the above 2 theta angle is approximately ± 0.05 degrees for each peak determined above. The error in the d-distance values is approximately ±0.5 A.

Since some tolerance is allowed in the determination of the 2 theta angles and the d distance, a preferred method of comparing X-ray powder diffraction patterns to identify a particular crystalline form is to overlay the X-ray powder diffraction pattern of the unknown form over the X-ray powder diffraction pattern of the known form. For example, one skilled in the art can overlay the X-ray powder diffraction pattern of an undefined crystalline form of 5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole obtained using the methods described herein over Figure 6 and readily determine whether the X-ray powder 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 identical to Figure 6, then the previously unknown crystalline form can be readily and accurately determined to be 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 over Figures 1, 2, 4, 5 or 3.

Although 2 theta angles or d distances are the primary method of identifying a particular crystalline form, it may also be desirable to compare the relative peak intensities. As noted above, the relative intensity may vary depending on the particular diffractometer used and the sample preparation technique. Peak intensities are reported as intensities relative to the peak with the strongest intensity. The units of intensity on the X-ray diffraction axis are counts/s. Absolute count = counts/time x counting time = counts/s. x 10 s. Given the 2 theta angles, d distances (A), and relative peak intensities I, Form VI of 5,6-dichloro-2-(isopropylamino)-1-(-L-ribofuranosyl)-1H6 • · · benzimidazole, exhibits the following X-ray diffraction pattern characteristics:

Form VI angle 2 theta (°) ¹ A ² I 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 = approximately ±0.05 degrees ² Error tolerance = approximately +0.05 Angstroms Given the above-described characteristics of the X-ray powder diffraction pattern of Form VI, one skilled in the art can readily identify Form VI of 5,6-dichloro-2-(isopropylamino)-1-(3-L-ribofuranosyl)-1H-benzimidazole. One skilled in the art will recognize that the X-ray powder diffraction pattern of a sample of Form VI obtained according to the methods described in this application may exhibit additional 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 above-described X-ray powder diffraction characteristics of Form VI, Forms I, II, IV, V and the enolate each exhibit distinct 2 theta angles, d-distances and relative intensities which can be used to distinguish each of these forms from Form VI and from each other. Forms I, II, IV, V and the enolate are defined by X-ray powder diffraction patterns obtained with a suitably oriented diffractometer equipped with a graphite monochromator with beam diffraction using X-rays as copper; the patterns 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-interplanar spacings and relative peak intensities, obtained according to the procedure of Example 22 below.

Form I angle 2 theta (°) ¹ A ¹ I 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-interplanar spacings and relative peak intensities, obtained according to the procedure of Example 22 below.

Form II angle 2 theta (°) ¹ A ¹ I 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

• · • 99 · · 9 9 9 9 • 9 9·« 9 9 99 99 9 • · ·· ·«««

999 99 999 «999 99 9« 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.

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

Ethanolate angle 2 theta (°) ¹ A ¹ I 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

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,

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-interplanar spacings and relative peak intensities, obtained according to the procedure of Example 22 below.

• · • *« • · · · • · · • « · · · • · · · « ·

Form IV angle 2 theta (°) ¹ I 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 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 2 theta angles, d-interplanar spacings and relative peak intensities, obtained according to the procedure of Example 22 below.

Form V angle 2 theta (°) ^! A ¹ I 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 can also exhibit peaks at essentially 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 physical characterization methods 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 for use in the physical characterization or identification of the crystalline form or solvates include, but are not limited to, melting point, differential scanning calorimetry, and infrared absorption spectrum. These techniques may be used alone or in combination to characterize the anhydrous crystalline form or solvates.

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 in admixture with any one or more of Forms I, II, IV, V or ethanolate. Alternatively, Form VI may be in admixture with an amorphous compound of Formula I. In another embodiment, Form VI may be in admixture with both the amorphous compound of Formula I and one or more other crystalline forms or solvates, including Forms I, II, IV, V and ethanolate.

The present invention specifically contemplates mixtures of the above-mentioned Form VI with one or more amorphous compounds of Formula I and/or other crystalline anhydrous forms and solvates. It should be noted that mixtures of Form VI with an amorphous compound of Formula I and/or other crystalline forms may result in the 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.

Furthermore, in addition to the above forms, Form VI may also be in admixture with hydrated crystalline forms. For example, in any batch containing an anhydrous crystalline compound of Formula I Form VI, hydrated crystalline Form VI may also be present. Since the anhydrous crystalline form of a compound of Formula I Form VI is substantially free of water of hydration, the proportion of hydrated forms of a compound of Formula I Form VI in any batch of the compound can be measured by determining the total water of hydration content of each batch.

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

According to another aspect, the present invention provides a process for preparing a compound of formula I in anhydrous crystalline form VI, which process comprises treating a compound of formula I with a solubilizing agent which serves to convert a quantity of a compound of formula I into anhydrous crystalline form VI.

The invention also provides a process for preparing a compound of formula I of form VI. The process comprises the following steps:

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

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

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

d) isolating anhydrous crystalline form VI.

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

4444 • 4 4 4

4 4 4 4 • · 4 4

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

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

The synthesis of a compound of formula I generally results in the formation of the compound in solution in a reaction mixture from which the compound can be separated and purified as a solid product. The compound of formula VI can optionally be dried. The crystalline form of the solid product is influenced by a number of factors and, according to the present invention, the separation and/or subsequent processing conditions are selected to provide the compound of formula I as 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 hydrated 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 dissolving power and should 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 of the compound of formula I. Advantageously, the solvent may optionally be removed by drying under vacuum.

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

The present invention also provides a compound of formula I form VI for use in medicine, for example in the treatment and prophylaxis of viral disease in animals, for example mammals, such as humans. The compound is particularly useful for the treatment or prophylaxis, including suppression of recurrence, of viral diseases, such as infections caused by herpes virus, for example CMV infection, and also diseases caused by hepatitis B virus and hepatitis C virus.

Furthermore, for use in human medicine, the compound of formula I form VI can 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 suppression of recurrence of viral infections, particularly infections caused by herpes virus, CMV infection or disease caused by hepatitis B and hepatitis C virus in animals, e.g. mammals, which comprises administering to the animal an antivirally effective amount of a compound of formula I form VI.

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

The compound of formula I, form VI, may be administered by any route suitable for treating the disease, but the preferred route of administration is oral. It will be appreciated, however, that the preferred route of administration may vary, for example, depending on 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 rest with the attending physician or veterinarian. In general, however, for each of these uses and indications, an effective dose in the range of 0.01 to 250 mg per kg of body weight of the patient per day, preferably in the range of 0.1 to 100 mg per kg of body weight per day, more preferably in the range of 0.5 to 30 mg per kg of body weight per day, especially 1.0 to 30 mg per kg of body weight per day (unless otherwise stated, all weights of active ingredient are based on the free base of the compound of formula I). The required dose is preferably comprised of one, two, three or four more divided doses, administered at appropriate intervals during the day. These divided doses may be administered in individual dosage forms containing 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 4

4 44

Although it is possible for the active ingredient to be administered alone, it is preferably administered in the form of a pharmaceutical composition. The composition contains 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 composition and not deleterious to the recipient.

Pharmaceutical compositions include forms suitable for oral administration and may be conveniently presented in unit dosage form, prepared by any of the methods well known in the art of pharmacy, such methods comprising the step of bringing into association the active ingredient with a carrier which contains one or more other ingredients. In general, compositions are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers or finely powdered solid carriers or both, and then, if necessary, shaping the product.

Pharmaceutical compositions of the present invention suitable for oral administration may be in the form of discrete units such as capsules, lozenges, sachets of granules 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 fluid emulsion. The active ingredient may also be in the form of a chew, elixir or paste.

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

• 99 • · • ·· ·· ·« ··» · · ·«> · • · · · · · · • ······ • · · · · · · • 99 9999 99 99

In addition to the oral dosage forms described above, the crystalline Form VI of the invention can 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 specific crystalline form used to prepare the solution. However, anhydrous crystalline Form VI can be conventionally used to prepare solutions by substantially completely 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 defined above), or a portion thereof, of the active ingredient.

It is understood that in addition to the above-mentioned components of the compositions of the invention, these compositions may contain other substances commonly known in the art according to the type of composition in question, for example, compositions for oral administration may contain flavoring agents or taste-masking agents.

The following examples are provided for illustration only and do not limit the scope of the invention in any way.

Examples of embodiments of the invention

Example 1

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

Compound of formula I (200 g) was placed in a thermal activity monitor (TAM) and a few drops of water were added to make the powder moist. The vial was sealed and placed in the 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 pattern of the product of Example 1 is shown in Figure 1.

Example 2

Form I of 5,6-dichloro-2-(isopropylamino)-1-3-L-ribofuranosyl-1H-benzimidazole • * ♦ · 9 • · · · · • · 9 9 • · · 9 • 9 9 «

99

Compound of formula I (1.5 g) was suspended in water (30 mL) and heated with stirring to 65°C. After approximately 0.5 hour, stirring became difficult as a gum formed. Upon further heating, the gum converted to a solid which was crushed with a spatula. The mixture was heated to 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 compound of formula I.

The X-ray powder diffraction pattern of the product of Example 2 is shown in Figure 1.

Example 3

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

The compound of formula I (5 g) and water (1.5 ml) were stirred and heated in an oil bath to 80 °C. The powder turned into a gum and stirring was stopped. 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 hours.

The X-ray powder diffraction pattern of the product of Example 3 is shown in Figure 1.

Example 4

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

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 upon 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 of 5,6-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1Hbenzimidazole

Form II of compound I (2 g) in toluene (10 mL, 5 vol.) was heated to 60 °C, at which point the solid began to become sticky to the sides of the vessel. Continued heating to 95 °C produced an oil. Heating was continued to 105 °C, then toluene (2.5 vol.) was added and heating was continued. Heating at reflux was continued for 3 h with rapid stirring. The oil bath temperature was reduced to 80 °C (internal temperature 73 °C) and heating was continued for 3 h with rapid stirring. The mixture was heated at reflux again for 16 h and then allowed to cool to room temperature. The free solid was collected by filtration and washed with toluene (2x5 mL) and dried in vacuo at 20°C and in vacuo at 40°C to give a white solid. The remaining solid was removed from the vessel, collected by filtration and dried in vacuo at 20°C. The filtrate was concentrated under reduced pressure to give 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 from Form II of 5,6-dichloro-2-(isopropylamino)-1-p-L-ribofuranosyl-1H-benzimidazole

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

Once the bath temperature reached about 60°C, the mixture became 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 pattern of the product of Example 6 is shown in Figure 1.

Example 7

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

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, 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 hour, the mixture was seeded with Form II of Compound I and aged for a further 4.5 hours. The suspension was 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 * · • · • ·· · w

• ·· ·· ··· ·· ··

9 9 · « · · · • · · « • · · · ·« ·· with toluene (2 x 100 ml). The wet cake is transferred to a drying oven and dried under vacuum at 20 °C.

The X-ray powder diffraction pattern of the product of Example 7 is shown in Figure 2.

Example 8

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

Compound of formula I (1.0 wt.) is dissolved in ethyl acetate (6 vol.) and subjected to a final filtration. The filtrates are concentrated to approximately 3 volumes. Assuming complete solvent exchange, the solution is diluted with 3.5 volumes of methanol. Water (0.5 vol.) is added and the solution is cooled to 0-5 °C. The crystallization is seeded with a small amount of pure compound of formula I and the solution is kept at 0-5 °C for 2 hours. The product is filtered (without washing) and dried under vacuum for 24-48 hours at ambient temperature. A second portion is obtained by evaporating the filtrate to half its volume and then cooling, seeding and crystallization in a similar manner as above.

The X-ray powder diffraction pattern of the product of Example 8 is shown in Figure 2.

Example 9

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

The compound of formula I (10 g) was dissolved in methanol (20 ml) while 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 pattern of the product of Example 9 is shown in Figure 2.

Example 10

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

The compound of formula I can be dissolved in 2N hydrochloric acid (60 mL) and stirred for 0.5 hour and filtered. The filtrate is heated to 60°C and 2N sodium hydroxide (55 mL) is added slowly, 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.) was suspended 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 resulting powder was filtered and air dried. The ethanol solvate was obtained in a similar manner from ethanol/toluene solutions (ratio 5/95, 10/90, 15/85, 20/80, 25/75 and 30/70).

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

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

3.

Example 12

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

The compound of formula I (20 g) was added to a stirred mixture of toluene/ethanol (7:1, 200 ml) and heated at reflux (81 °C) until a clear solution was obtained. The solution was cooled to 20 °C and crystallization occurred at a temperature of approximately 50 °C. The suspension was 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 was dried under vacuum at 40 °C.

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

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

4.

Example 14

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

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

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

5.

Example 15

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

The ethanolate of the compound of formula I (200 mg) is weighed into small vials. Hydrostats with saturated NaCl solutions and excess solid NaCl are placed in the vials. The vials are then tightly sealed and stored at 80°C. Samples are 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 the DSC dishes and analyzed by X-ray diffraction.

Characterization: The X-ray powder diffraction pattern 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. The moisture sorption isotherm for Form VI is shown in Figure 8.

Example 16 • · ···· · · · · 9 9 9 9 9 9 9 9

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

About 200 mg of form II seeded 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 28 hours of stirring, the solid is examined by X-ray diffraction. The X-ray diffraction results show that form II has been completely converted to form VI.

Characterization: as in example 15.

Example 17

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

About 200 mg of the ethanolate seeded 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 28 hours of stirring, the solid is examined by X-ray diffraction. The 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 the ethanol solvate of 5,6-dichloro-2-(isopropylamino)-1-(beta-L-ribofuranosyl)-1H-benzimidazole to Form VI g of the ethanolate seeded with 100 mg of Form VI prepared in the above conversion was suspended in 50 mL of distilled water at 45°C. After 5 hours, all of the ethanolate had been converted to Form VI as determined by X-ray diffraction. The solid was collected by filtration, washed with water (3x5 mL) and dried in a vacuum oven at 100°C for 3 hours.

Characterization: as in example 15.

Example 19

Conversion of ethanol solvate of 5,6-dichloro-2-(isopropylamino)-1-(beta-L-ribofuranosyl)-1Hbenzimidazole 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 will also be partially or completely converted to Form VI.

Characterization: as in example 15.

Example 20

Preparation of Form VI of 5,6-dichloro-2-(isopropylamino)-1-(beta-L-ribofuranosyl)-1Hbenzimidazole by grafting

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 was 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 is dried under vacuum at 40 °C to give Form VI of 5,6-dichloro-2(isopropylamino)-1-(beta-L-ribofuranosyl)-1H-benzimidazole.

Characterization: as in example 15.

Example 21

Preparation of Form VI of 5,6-dichloro-2-(isopropylamino)-1-(beta-L-ribofuranosyl)-1H-benzimidazole 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 is concentrated under reduced pressure to 3.3 volumes (1180 mL).

• 9

9 · 9 9 9

9·«·99

9 9 9 9 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 Form VI of 5,6-dichloro-2(isopropylamino)-1-(beta-L-ribofuranosyl)-1H-benzimidazole.

Characterization: as in example 15.

Example 22

Experimental methods for the 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 perforated aluminum dishes and heated from 25°C to 250°C at a rate of 10°C/minute while purging with nitrogen. The percentage of total weight loss of the drug substance is determined on a TA Instruments Hi-Res TGA 2950 thermogravimetric analyzer (TGA) while purging with nitrogen.

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 copper Ka X-ray diffraction and an automatic divergence slit. The diffractometer is operated using a scan rate of ^0.040 per step and a time of 1 second per step. A proportional counter with a graphite monochromator is used as the detector. The samples are loaded into a holder with a diameter of 16 mm and a thickness of about 2.0 mm. The X-ray powder diffraction patterns of Forms I, II, IV, V, VI and the ethanolate are shown in Figures 1, 2, 4, 5, 6 and

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

• · «9 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 9 9 9 99

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

2 theta (°) ¹ A ² I ^hJ to ^{3 lJ} 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 nyby is approximately ±0.5 degrees.

² The error tolerance is approximately ±0.5 A.

³ The Miller indices h, k, and I above are used to uniquely 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 ^°C under vacuum. Moisture absorption is observed in vacuum from 0 to 95% RH and desorption is observed from 95% to 5% RH. The criteria for equilibrium at a given RH was less than 3 pg weight change over 18 minutes.

Single crystal X-ray diffraction

The crystal structure of a single crystal of the form 5,6-dichloro-2-(isopropylamino)-1-(beta-Lribofuranosyl)-1 H-benzimidazole is determined by single crystal X-ray diffraction. The single crystal X-ray diffraction data is determined on a Brucker AXS SMART diffractometer equipped with a graphite monochromator with beam diffraction using • · • ·* · molybdenum Κα X-rays (lambda = 0.71071 A) at 160 K. The determination of the unit cell parameters and space group revealed that it is a tetragonal crystal system, P4(3)2(1)2, with a = b = 9.1542, c = 41.687 (units a, b, c in angstroms) and alpha = beta = gamma = 90 degrees. The unit cell parameters under normal conditions, a = b = 9.2794, c = 41.593 (units a, b, c in angstroms) and alpha = beta = gamma = 90.000 degrees are calculated by recording the X-ray radiation of the powder sample.

Using the atomic coordinate data of the single crystal and the unit cell parameters from the experimental powder sample recording, the X-ray powder diffraction pattern of the sample is calculated. The X-ray powder diffraction pattern of the sample for the single crystal of Form VI 1263W94 is shown in Figure 10. The 15 most intense peaks from 2 to 35 two theta are listed below in terms of 2 theta angles, d-interplane spacing, relative intensity and Miller indices.

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

2 theta (°) ¹ A ² I ^hJ to ^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 movement is approximately ±0.5 degrees.

² The error tolerance is approximately ±0.5 A.

• · ··· · · ··· « ···· · · · · · · · ·

9A · · ·· · * · · é-kj ··· C· ······· ·· ·9 ³ The Miller indices h, k and I above are used to uniquely define sets of parallel planes in a crystal.

The 2 theta values derived from the single crystal data shown in the graph differ from the experimental powder diffraction values shown above mainly due to errors in sample preparation, such as sample transfer error, small errors in diffractometer adjustment, and variations in the computer peak determination method. The relative peak intensities in the calculated sample are due not only to the input 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 months 400 m2 Core components 1263W94 (active) 100.0 ² 400.0 ³ Microcrystalline cellulose, NF 93.5 374.0 Crospovidone, NF 4.0 16.0 Colloidal silicon dioxide, 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 • ·· · ·· · · · · «« in · ♦ · · · · · · · • · · · · · · · * ··· · · · « Ϊ · · · « · · · 1··· • · · · · ···*··· «· ·· kg 15.0 33.0 tablets 75000 41254

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

Production process for direct compression

All ingredients are sieved, except magnesium stearate, using a 20 to 30 mesh sieve. All ingredients are mixed, except magnesium sulfate, until the mixture is homogeneous. 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 are coated so that the coating content is 3% by weight.

Formulation B

Tablets 1263W94 (form VI)

Wet granulation

Efficiency 100 sq m 400 m2 Core components 1263W94 (active) 102.0 ² 408.0 ³ Lactose Anhydrous 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 · • <444 « 4 4 4 4 4 • 4 44 4444 «44 44 4444444 ·4 44

Total (core) 211.1 mg 840.0 mg

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

Formulation B-1

Tablets 1263W94 (form VI)

Wet granulation

Efficacy_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 to 400 mg of 1263W94 per tablet *· « · • · ··· · · « · · · • · · · · · · · · · · · · · · · · · · · » » · ·

Production process for wet granulation

The ingredients for the granules are screened 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 a loss on drying of less than 2%. The granules are screened 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 are coated so that the coating content is 3% by weight.

Example 24: Capsule formulation

The following formulation can be prepared using a compound of formula I of form VI.

Capsule 1263W94 (Form VI)

Efficacy _100 mg

Filling ingredients for the capsule

1263W94 (active) 101.0 ¹

Lactose, anhydrous NF 232.0

Crospovidone, NF 17.0

Magnesium stearate, NF 1.0

Total filling 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 capsule filling ingredients are mixed using a mortar and pestle by geometric dilution. The combined capsule filling ingredients are filled manually 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)

Efficacy_30 mg/ml

Ingredients per 100 ml

1263W04 3.0g

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 manufacturing process

Propylene glycol, water and hydrochloric acid (6.9 ml) are 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 the mixture is mixed thoroughly. The final volume is adjusted to 100 ml by adding 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

Components

1263W94 (active)

Sucrose Propylene glycol Sodium chloride Citric acid Sodium citrate

Microcrystalline Cellulose and Sodium Carboxymethyl Cellulose Sodium Carboxymethyl Cellulose Polysorbate 80

Sodium benzoate

Methylparaben

Aromatic

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 process 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 with continuous stirring and the ingredients are dissolved. If necessary, adjust the pH by adding sufficient citric acid or sodium citrate to a value between 5.0 and 6.0. Microcrystalline cellulose and sodium carboxymethylcellulose (Avicel RC 591) are added with stirring and stirring is continued until the mixture is homogeneous and a fine dispersion is obtained. 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 with stirring to the bulk suspension. With continuous stirring, the active ingredient is gradually dispersed in the bulk liquid to obtain a homogeneous dispersion. Flavor and color are added and the volume is adjusted by adding water to

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

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

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.