HK1085483B - Anhydrous crystalline azido cytosine hemisulfate derivative - Google Patents

Description

Anhydrous crystalline azidocytosine hemisulfate derivatives

The present invention relates to the hemisulfate salt of 1- [4(S) -azido-2 (S), 3(R) -dihydroxy-4- (hydroxymethyl) -1(R) -cyclopentyl ] -cytosine (Ia) and polymorphic crystalline forms thereof with improved stability and physical properties that facilitate the preparation, handling and formulation of the compound of formula I. The present invention also relates to a process for preparing polymorphic crystalline forms of a compound of formula Ia.

The compound 1- [4(S) -azido-2 (S), 3(R) -dihydroxy-4- (hydroxymethyl) -1(R) cyclopentyl ] -cytosine I is a potent antiviral agent (U.S. patent application 10/167,106, filed 6/11/2002; J.G.Moffatt, In nucleic acids Analogs; R.T.Walker, E.DeClercq and F.Eckstein, eds., Plenum Publishing, New York, 1979, page 144; H.Maag et al, J.Med.chem.199235: 1440-1451). Although biological activity is a prerequisite for effective drugs, the compounds must be capable of large scale preparation and the physical properties of the compounds can significantly affect the efficacy and cost of the formulated active ingredient. Despite its potent antiviral activity, the use of the free base I is limited due to thermal instability, poor crystallinity and hygroscopicity which create challenges, handling and formulation problems.

Salts of acidic and basic compounds may alter or improve the physical properties of the parent compound. However, these salt-forming agents must be identified empirically by the pharmacist, since there is no reliable way to predict the effect of the salt species on the properties of the parent compound present in the dosage form. Unfortunately, there is a lack of effective screening techniques that effectively simplify The screening process (G.W.Radebaugh and L.J.ravin preformulation. in, Remington: The Science and Practice of Pharmacy; A.R.Gennaro eds.; Mack Publishing Co.Easton, PA, 1995; p. 1456-.

Different polymorphic forms of salts are often encountered in pharmaceutical compounds. Polymorphism is the ability of any element or compound to crystallize into more than one distinct crystal species. The physical properties including solubility, melting point, density, hardness, crystal shape and stability can be quite different for different polymorphic forms of the same compound.

By scattering techniques such as x-ray diffraction powder patterns, by spectroscopic methods such as infrared,¹³c nuclear magnetic resonance spectroscopy and characterization of the polymorphic forms by thermal techniques such as differential scanning calorimetry or differential thermal analysis. The compounds of the present invention are best characterized by their X-ray powder diffraction pattern determined according to procedures well known in the art. For a discussion of these techniques, see j.haleblian, j.pharm.sci.1975.64: 1269-: 911-929. Although the intensities of the peaks in the x-ray powder diffraction patterns of different batches of hemisulfate Ia may vary slightly, the peaks and peak positions are characteristic for a particular polymorph.

The problem that must be solved is to identify suitable salts that (i) possess suitable chemical stability during the manufacturing process, (ii) are efficiently prepared, purified and recovered, (ii) provide acceptable solubility in pharmaceutically acceptable solvents, (iii) are suitable for handling (such as flowability and particle size) and formulate or modify the physical and chemical properties of the compound in a manner that negligible decomposition, (iv) exhibit acceptable chemical stability during the formulation process. In addition, salts containing a high molar percentage of active ingredient are highly desirable because they minimize the amount of material that must be formulated and administered to produce a therapeutically effective dose. These often conflict with requirements, making identification of suitable salts a challenging and important issue that must be addressed carefully by skilled pharmaceutical chemists before drug development can be performed.

The present invention relates to crystal hemisulfate salt forms of 1- [4(S) -azido-2 (S), 3(R) -dihydroxy-4- (hydroxymethyl) -1(R) cyclopentyl ] -cytosine (Ia), methods of making the polymorphic forms of (Ia), pharmaceutical compositions containing the hemisulfate salt of (Ia), and methods of using the hemisulfate salt of (Ia) to treat diseases mediated by hepatitis C virus.

Many objects and advantages of this invention can be directly understood by those skilled in the art by reference to the accompanying drawings in which:

FIG. 1 shows the x-ray powder diffraction of the form A polymorph of Ia.

FIG. 2 shows the x-ray powder diffraction of the form B polymorph of Ia.

FIG. 3 shows the x-ray powder diffraction of the form C polymorph of Ia.

Figure 4 shows the differential scanning calorimetry curve for the free base I.

FIG. 5 shows a differential scanning calorimetry curve for the form C polymorph of Ia.

Surprisingly, it has been found that the hemisulfate salt of I is significantly more stable than the free base and, in addition, is an anhydrous, non-hygroscopic crystalline salt with superior properties relative to other salts. Three new anhydrous polymorphic forms of the hemisulfate salt of I have been isolated and identified: form A, form B and form C. Form a and form B are converted to form C in the presence of moisture.

In one embodiment of the present invention, there are provided hemisulfate salts of 1- [4(S) -azido-2 (S), 3(R) -dihydroxy-4- (hydroxymethyl) -1(R) cyclopentyl ] -cytosine (Ia) and solvates thereof.

In another embodiment of the present invention, a polymorphic form (form a) of a compound according to claim 1 having an x-ray scattering pattern as shown in figure 1 is provided.

In another embodiment, a process for preparing the form a polymorph of Ia by crystallizing compound (I) from an aged solution ethanolic sulfuric acid is provided.

In another embodiment of the present invention, a polymorphic form of Ia (form B) is provided having an X-ray scattering pattern as shown in FIG. 2.

In another embodiment, a process is provided for preparing the form B polymorph of Ia by crystallizing (I) from isopropanol/water (85: 15) and sulfuric acid.

In another embodiment of the present invention, there is provided a polymorphic form of Ia (form C) with an X-ray diffraction pattern as shown in FIG. 3.

In another embodiment, a process is provided for preparing the form C polymorph of Ia by crystallizing I from isopropanol/water (60: 40) in the presence of sulfuric acid. In another embodiment of the invention, the pH of the isopropanol/water recrystallization solution is adjusted from about 5 to about 3 with sulfuric acid.

In another embodiment of the present invention, there is provided a method of treating a disease mediated by hepatitis C virus by administering to a patient in need thereof a therapeutically effective amount of the compound of form A polymorph of Ia.

In another embodiment of the present invention, there is provided a method of treating a disease mediated by hepatitis C virus by administering to a patient in need thereof a therapeutically effective amount of the compound of form B polymorph of Ia.

In another embodiment of the present invention, there is provided a method of treating a disease mediated by hepatitis C virus by administering to a patient in need thereof a therapeutically effective amount of the compound of form C polymorph of Ia.

In another embodiment of the present invention, there is provided a method of treating a disease mediated by hepatitis C virus by administering to a patient in need thereof a therapeutically effective amount of compound Ia delivered at a dose of 1-100 mg/kg/body weight of the patient/day.

In another embodiment of the present invention, there is provided a method of treating a disease mediated by hepatitis C virus by administering to a patient in need thereof a therapeutically effective amount of compound Ia in combination with an immune system modulator.

In another embodiment of the present invention, there is provided a method of treating a disease mediated by hepatitis C virus by administering to a patient in need thereof a therapeutically effective amount of compound Ia in combination with interferon or a chemically derivatized interferon.

In another embodiment, a pharmaceutical composition is provided comprising the hemisulfate salt of I in admixture with at least one pharmaceutically acceptable carrier or excipient.

Nucleoside I is an organic azide which is potentially thermally unstable. Differential Scanning Calorimetry (DSC) of I indicates no melting endotherm. A large exothermic decomposition peak was recorded, with an onset temperature of about 150 ℃ and a peak heating rate at 198 ℃ with an enthalpy of-1053J/g.

All polymorphic forms of hemisulfate salt Ia exhibit better thermal stability than the parent compound I and various other salts. Differential scanning calorimetry of form A of Ia exhibited exothermic decomposition that started at about 185 deg.C. Form B of Ia exhibited exothermic decomposition starting at about 189 deg.C. Form C of Ia exhibited an exothermic decomposition that started at about 210 deg.C.

Accelerated Rate Calorimetric (ARC) determination of free base I (adiabatic calorimetric conditions) records a large decomposition exotherm with a corrected onset temperature of 102 ℃, an adiabatic temperature rise of 388 ℃ and an enthalpy of-194 Cal/g. In contrast, form C, hemisulfate salt Ia, exhibited a corrected exothermic decomposition onset temperature of 152 deg.C, an adiabatic temperature rise of 265 deg.C, and an enthalpy of-132 Cal/g, which substantially reduced the risk of decomposition during manufacture and processing.

The hemisulfate salt also provides improved physical properties and handling characteristics, as shown in table 1. No change in chemical purity or polymorphism was observed when accelerated stability testing was performed at high temperature or at high temperature and relatively high humidity. Hemisulfate salts are crystalline materials with high bulk density, which are easier to handle than the free base, as evidenced by increased recovery and improved flowability. It has also been found that hemisulfates are less hygroscopic than the free base. No weight increase was observed when Ia was stored at relatively high humidity. Due to its non-hygroscopic nature, the anhydrous crystalline I hemisulfate salt retains better physical appearance and handling properties over a longer period of time. The improved physical properties of the pharmaceutical dosage form enhance physician and patient acceptance and increase the likelihood of successful treatment.

TABLE 1 physical Properties of hemisulfate form C Ia
						Condition	Time of day	Appearance of the product	Weight gain	Polymorphic forms	Analysis of
93％RH	4 weeks	White powder	0％	C type	99.9
						60℃	1 week	White powder	N/A	C type	99.9
	2 weeks	White powder	N/A	N/A	99.9
							4 weeks	White powder	N/A	C type	99.9
40℃/75％RH	1 week	White powder	N/A	C type	99.9
							2 weeks	White powder	N/A	N/A	99.9
	4 weeks	White powder	N/A	C type	99.9
						RH-relative humidity; N/A ═ unanalyzed

The hemisulfate salt imparts little additional molecular weight to the active ingredient, and therefore, the salt has a high percentage of the parent compound, minimizing the amount of active ingredient that must be delivered to the patient. This provides an additional advantage to the compounds of the present invention, since nucleosides often exhibit low bioavailability.

As used herein, an "entity (" a "or" an ") means one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. For example, the terms "a", "an", "one or more" and "at least one" are used interchangeably herein.

As used herein, the term "hemisulfate salt" means a salt in which there are two molar equivalents of the free base per molar equivalent of sulfuric acid.

As used herein, the term "solvate" means that the compound of the present invention, or a salt thereof, further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.

As used herein, the term "hydrate" means that the compound of the present invention or a salt thereof further comprises a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. Hydrates are formed by combining one or more molecules of water with a substrate, wherein the water retains its molecular state as H₂O, the combination being capable of forming one or more hydrates.

As used herein, the term "clathrate" means that a compound of the present invention or a salt thereof is in a lattice form that includes spaces (e.g., channels) in which guest molecules (e.g., solvents or water) are captured.

As used herein, the term "polymorph" or "crystal form" refers to a crystal structure in which a compound can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms generally have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors may cause a crystal form to dominate.

As used herein, the term "immunomodulator" means a therapeutic agent that is involved in or is capable of modifying or modulating immune function. Agents that result in immunomodulation, modulation or enhancement.

As used herein, the term "interferon" refers to a family of proteins that interfere with viral infection of cells and inhibit proliferation of normal and transformed cells, regulate cell differentiation and manipulate the immune system. The 4 major antigenic forms of interferons (α, β, γ and ω) are defined by the cellular source from which they are produced. Type I interferons (interferons α, β and ω) compete with each other for cellular binding to the type I interferon receptor and thus share at least some components of the multi-subunit cell surface receptor, while the receptor for type II interferon (interferon γ) is a unique entity. Both naturally occurring and recombinant interferons can be administered in combination therapy with the compounds of the present invention. Consensus sequences for interferons have been described in U.S. patent No. 4,897,471 (y.

As used herein, the term "chemically derivatized interferon" means an interferon molecule covalently linked to a polymer that alters the physical and/or pharmacokinetic properties of the interferon. A non-limiting list of such polymers includes polyalkylene oxide homopolymers such as polyethylene glycol (PEG) or polypropylene glycol (PPG), polyoxyethylenated polyols, copolymers thereof and block copolymers thereof, provided that the water solubility of the block copolymers is maintained. One skilled in the art will know many methods for linking polymers to interferons (see, e.g., a. kozlowski and j.m.harris j.control. release 200172 (1-3): 217-24; c.w.gilbert and m.park-Cho, U.S. patent No. 5,951,974). A non-limiting list of chemically derivatized IFN α s contemplated in this patent includes PEG-interferon- α -2a (PEGASYS. RTM.) and PEG-interferon- α -2b (PEGINTRON)^TM)。

Formulations of the compounds of formula I may be prepared by methods known in the formulation art. The following examples (below) are provided to enable those of ordinary skill in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

The hemisulfate salts of the present invention may be administered in a variety of oral and parenteral dosage forms. Oral dosage forms may be tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, syrups or suspensions. Parenteral administration includes intravenous, intramuscular, intradermal, subcutaneous, intraduodenal or intraperitoneal administration. In addition, the salts of the present invention may be administered by transdermal (which may include penetration enhancers), buccal, nasal and suppository routes. Alternatively, the salt may be administered by inhalation.

For preparing pharmaceutical compositions from the compounds of the present invention, the pharmaceutically acceptable carrier may be solid or liquid. Solid form preparations include powders, tablets, pills, hard and soft gelatin capsules, cachets, dragees, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

Suitable excipients for tablets, coated tablets, dragees and hard gelatine capsules are, for example, lactose, maize starch and derivatives thereof, magnesium carbonate, magnesium stearate, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, talc and fatty acids or salts thereof, such as stearic acid. If desired, the tablets or capsules may be enteric-coated or sustained release formulations. Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols.

Liquid form preparations include solutions, suspensions, retention enemas, and emulsions, such as water or water/propylene glycol solutions. For parenteral injection, the liquid formulation can be formulated in the form of a solution in water/polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water, adding suitable colorants, flavors, stabilizers, and thickeners as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents. Suitable excipients for solutions and syrups for enteral use are, for example, water, polyols, sucrose, invert sugar and glucose. Suitable excipients for injectable solutions are, for example, water, saline, alcohols, polyols such as polyglycols, glycerol or vegetable oils.

In addition to the active ingredient, the compositions may contain coloring agents, perfumes, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, stabilizers, preservatives, wetting agents, emulsifiers, salts for adjusting osmotic pressure, masking agents, antioxidants and the like.

Since the compounds of the present invention are water soluble, they can be administered intravenously in physiological saline solution (e.g., buffered to a pH of about 7.2-7.5). Conventional buffering agents such as phosphate, bicarbonate or citrate may be used in the compositions of the present invention.

Also included are solid form preparations which are intended to be converted, immediately prior to use, to liquid form preparations for oral administration. The liquid forms include solutions, suspensions and emulsions.

For preparing suppositories, suitable excipients include natural and hardened oils, waxes, fatty acid glycerol, semi-liquid or liquid polyols. The molten homogeneous mixture is then poured into a convenient, graded mold, cooled, and thereby solidified.

Suitable pharmaceutical carriers, excipients and formulations thereof are described in Remington: the Science and practice of Pharmacy 1995, edited by E.W. Martin, Mack Publishing Company, 19 th edition, Easton, Pennsylvania. Examples 7-9 describe representative pharmaceutical formulations containing the compounds of the present invention.

The dosage can be varied within wide limits and can, of course, be adjusted in each particular case to the individual requirements of the patient and to the severity of the condition to be treated. Typical formulations will contain from about 5% to about 95% active compound (w/w). For oral administration, a daily dose of about 0.01 to about 100mg/kg body weight per day is suitable, in monotherapy and/or in combination therapy. Preferred daily dosages are from about 0.1 to about 300mg/kg body weight/day, more preferably from 1 to about 100mg/kg body weight/day, and most preferably from 1.0 to about 50mg/kg body weight/day. Determining the appropriate dosage for a particular situation is within the skill of one of ordinary skill in the art. Typically, treatment is initiated with a smaller dose than the optimal dose of the compound. Thereafter, the dosage is increased by a small increase until the optimum effect in this case is reached. The daily dose may be administered in a single dose or in divided doses, typically 1-5 doses per day.

Preferably the pharmaceutical formulation is in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Alternatively, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

The nucleoside derivatives or the medicaments thereof may be used in monotherapy or in combination therapy, i.e. the therapy may be combined with the administration of one or more additional therapeutically active substances, for example immune system modifiers such as interferons, interleukins, tumour necrosis factors or colony stimulating factors or anti-inflammatory agents and/or anti-viral agents. When the treatment is a combination treatment, the administration may be simultaneous or sequential relative to the nucleoside derivative. As used herein, simultaneous administration thus includes administration of the agents at the same time or at different times. The pharmaceutical composition may optionally contain other therapeutically active agents known in the art.

References herein to treatment extend to the prevention of hepatitis c mediated diseases and the treatment of existing conditions, and treatment of animals includes treatment of humans as well as other mammals. In addition, as used herein, treatment of Hepatitis C Virus (HCV) infection also includes treatment or prevention of a disease or disorder associated with or mediated by Hepatitis C Virus (HCV) infection, or a clinical symptom thereof.

The nucleoside derivatives or the medicaments thereof may be used in monotherapy or in combination therapy, i.e. the therapy may be combined with the administration of one or more additional therapeutically active substances, for example immune system modulators such as interferons, interleukins, tumor necrosis factors or colony stimulating factors; additional antiviral or anti-inflammatory agents. When the treatment is a combination treatment, the administration may be simultaneous or sequential relative to the 4' -substituted nucleoside derivative. As used herein, simultaneous administration thus includes administration of the agents at the same time or at different times.

It will be appreciated that reference herein to treatment extends to prophylaxis as well as treatment of existing conditions, treatment of animals including treatment of humans and other mammals. Moreover, as used herein, treating a Hepatitis C Virus (HCV) infection also includes treating or preventing a disease or condition associated with or mediated by Hepatitis C Virus (HCV) infection, or a clinical symptom thereof.

Formulations of the compounds of formula I are described in U.S. serial No. 10/167,106, which is incorporated herein by reference in its entirety.

Example 1

Polymorph form A

The free base (2.0g) was dissolved in 50mL of hot (ca. 60 ℃ C.) ethanol and a solution of 0.18g of concentrated sulfuric acid dissolved in 2mL of ethanol was added. The resulting slurry was aged at about 70 ℃ for about 3 hours and then cooled to room temperature. The precipitate was filtered (very slow filtration), washed with ethanol and dried under vacuum at about 70 ℃ to yield 2.1g of form A polymorph of Ia. Differential scanning calorimetry showed an exotherm onset at 185 ℃. The polymorphic form produced an x-ray scattering pattern shown in figure 1.

Example 2

Form B polymorph

The free base (0.5g) was dissolved in 10mL of a warm (about 40 ℃ C.) isopropanol-water (9: 1) solution and 1mL of a solution of 0.875g of concentrated sulfuric acid dissolved in 10mL of an isopropanol-water (9: 1) mixture was added. The resulting thick slurry was diluted with 10mL of isopropanol-water (9: 1) and 1mL of water. The resulting slurry was aged at room temperature for about 2 hours, and the precipitated product was filtered, washed with isopropanol and hexane, and dried to constant weight by slowly applying vacuum, yielding 0.56g of form B polymorph of formula Ia. Differential scanning calorimetry showed an exotherm onset at 189 ℃. The polymorphic form produced an x-ray scattering pattern shown in figure 2.

Example 3

Form C polymorph

The free base (3.0g) was dissolved in a solution of isopropanol (20mL) and water (10mL) and the solution was heated to about 60 ℃. Dilute (about 10%) sulfuric acid solution was slowly added to bring the pH to about 3. The resulting solution was aged at about 65-70 ℃ for about 2 hours, during which time dense crystals precipitated. The slurry was cooled to room temperature, filtered, washed with isopropanol, and dried under vacuum at about 70 ℃ to yield 2.8g of the form C polymorph of formula Ia. Differential scanning calorimetry showed an exotherm onset at 210 ℃. The polymorphic form produced an x-ray scattering pattern shown in figure 3.

For C₁₈H₂₆N₁₂O₁₄Calculated value of S: c, 32.44; h3.93; n, 25.22; s4.81; measured value: c, 32.37; h, 3.90; n, 25.08; and S, 4.80.

Example 4

The X-ray powder diffraction patterns of the polymorphic crystal samples were measured on a Scintag X1 powder X-ray diffractometer fitted with a sealed copper K.alpha.1 radiation source. The sample was scanned from 2 ° to 40 ° 2 θ at a rate of 3 ° per minute with 4 and 2 micron incident beam slit widths and 0.5 and 0.2 micron diffracted beam slit widths.

Example 5

This example describes the thermal properties of form C, Ia, and 1- [4(S) -azido-2 (S), 3(R) -dihydroxy-4- (hydroxymethyl) -1(R) cyclopentyl ] -cytosine (I) determined using Differential Scanning Calorimetry (DSC). The instrument used was a Perkin-Elmer DSC-2 with a heating rate of 10 ℃ per minute and a sensitivity of 5mcal per second; or TA DSC 2910 scan at 5 deg.C/min.

Example 6

Table 1 shows the hygroscopicity of form C Ia at 93% relative humidity. A small amount of the polymorphic form C crystals (about 10mg) was dispensed into weighing bottles, placed in a chamber with controlled relative humidity for 4 weeks and the percentage of water absorbed was calculated from the weight obtained. Samples were also analyzed by HPLC against external standards on a Waters 2690 HPLC at 276nm with a Zorbax SB-phenyl column. The mobile phase is a gradient run at 1mL/min consisting of acetonitrile/water with both 10mM heptane sulfuric acid, 0.1% phosphoric acid. The gradient was run from 10% ACN to 100% in 30 minutes. Data were processed using Waters Millennium software version 3.2. Thermal stability was also determined at 60 ℃ and 40 ℃/75% relative humidity. The purity of the sample was determined by HPLC analysis of weighed aliquots against external standards. The experiments suggest that form C polymorph is not hygroscopic and is thermally stable at 40 and 60 ℃ during analysis.

Example 7

Orally administrable compositions

Composition (I)	% weight/weight
		Active ingredient	20.0％
Lactose	79.5％
		Magnesium stearate	0.5％

Mixing the ingredients and dispersing in capsules, each containing about 100 mg; one capsule approximates the total daily dose.

Example 8

Orally administrable compositions

Composition (I)	% weight/weight
		Active ingredient	20.0％
Magnesium stearate	0.5％
		Croscarmellose sodium (Crosscarmellossodium)	2.0％
Lactose	76.5％
		PVP (polyvinylpyrrolidone)	1.0％

The active ingredients are combined and granulated using a solvent such as methanol. The formulation is then dried and formed into tablets (containing about 20mg of active compound) using a suitable tablet press.

Example 9

Orally administrable compositions

Composition (I)	Measurement of
		Active compound	1.0g
Fumaric acid	0.5g
		Sodium chloride	2.0g
Hydroxybenzoic acid methyl ester	0.15g
		Propyl hydroxybenzoate	0.05g
Granulated sugar	25.5g
		Sorbitol (70% solution)	12.85g
Veegum K (Vanderbilt Co., Ltd.)	1.0g
		Perfume	0.035mL
Coloring agent	0.5mg
		Distilled water	Proper amount to 100mL

The ingredients are mixed to form a suspension for oral administration.

The features disclosed in the foregoing description, or the following claims, or the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for attaining the disclosed result, as appropriate, may, separately, or in any combination of such features, be utilised for realising the invention in diverse forms thereof.

The foregoing invention has been described in some detail by way of illustration and example for purposes of clarity and understanding. It will be apparent to those skilled in the art that changes and modifications may be made within the scope of the appended claims. Accordingly, it is to be understood that the above description is intended to be illustrative, and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but instead should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

All patents, patent applications, and publications cited in this application are herein incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application, or publication were individually indicated to be incorporated by reference.

Claims (13)

1. Hemisulfate salt of 1- [4(S) -azido-2 (S), 3(R) -dihydroxy-4- (hydroxymethyl) -1(R) cyclopentyl ] -cytosine (Ia)
2. 2. The polymorphic form a crystalline form of the hemisulfate salt of claim 1 having an x-ray powder diffraction trace with D-spacing substantially as shown: d-spacing I/Io×100 D-spacing I/Io×100 17.5556 26.35 4.3828 35.14 10.2507 18.39 4.1366 78.45 8.5821 15.58 4.1093 83.40 7.2181 8.75 3.7211 18.57 6.2309 62.70 3.6167 56.83 5.8186 100 2.9787 32.98 5.5808 30.52
3. 3. The polymorphic form B crystalline form of the hemisulfate salt of claim 1 having an x-ray powder diffraction trace with D-spacing substantially as shown: d-spacing I/Io×100 D-spacing I/Io×100 22.8037 21.10 4.3696 100 18.9103 13.09 4.1814 81.04 16.7391 36.12 3.3481 36.97 13.1075 18.80 3.2741 33.51 5.7242 74.54 2.6227 19.75

   4. The polymorphic form C crystalline form of the hemisulfate salt of claim 1, having an x-ray powder diffraction trace with D-spacing substantially as shown: d-spacing I/Io×100 D-spacing I/Io×100 7.7865 9.39 4.7788 100 6.1199 5.71 3.9577 46.41 6.0219 3.97 3.8939 71.89 5.6949 9.68 3.7099 90.29 5.4499 1.90 3.0178 26.81 5.1928 13.72 2.7752 12.02 4.9757 1.90
4. 5. A process for preparing the form A polymorph of Ia with D-spacings substantially as described below,

   d-spacing I/Io×100 D-spacing I/Io×100 17.5556 26.35 4.3828 35.14 10.2507 18.39 4.1366 78.45 8.5821 15.58 4.1093 83.40 7.2181 8.75 3.7211 18.57 6.2309 62.70 3.6167 56.83 5.8186 100 2.9787 32.98 5.5808 30.52

   Which comprises crystallizing the compound (I) from an aged solution of ethanolic sulfuric acid
5. 6. A process for preparing the form B polymorph of Ia with D-spacings substantially as described below,

   d-spacing I/Io×100 D-spacing I/Io×100 22.8037 21.10 4.3696 100 18.9103 13.09 4.1814 81.04 16.7391 36.12 3.3481 36.97 13.1075 18.80 3.2741 33.51 5.7242 74.54 2.6227 19.75

   Which comprises crystallizing (I) from isopropanol/water and sulfuric acid in a ratio of 85: 15
6. 7. A process for preparing the form C polymorph of Ia with D-spacings substantially as described below,

   d-spacing I/Io×100 D-spacing I/Io×100 7.7865 9.39 4.7788 100 6.1199 5.71 3.9577 46.41 6.0219 3.97 3.8939 71.89 5.6949 9.68 3.7099 90.29 5.4499 1.90 3.0178 26.81 5.1928 13.72 2.7752 12.02 4.9757 1.90

   Which comprises crystallizing I from isopropanol/water in a ratio of 60: 40 in the presence of sulfuric acid
7. 8. The process of claim 7 wherein the isopropanol/water is adjusted from pH 5 to pH 3 with sulfuric acid.
8. 9. Use of a compound of formula Ia for the preparation of a medicament for the treatment of a disease mediated by the hepatitis C virus
9. 10. The use of claim 9 wherein the compound is the form a polymorph of Ia.
10. 11. The use of claim 9 wherein the compound is the form B polymorph of Ia.
11. 12. The use of claim 9, wherein the compound is the form C polymorph of Ia.
12. 13. A pharmaceutical composition comprising the hemisulfate salt Ia in admixture with at least one pharmaceutically acceptable carrier or excipient.
13. 14. The pharmaceutical composition of claim 13, wherein the hemisulfate salt is polymorphic form C.