WO2007110559A1

WO2007110559A1 - Pharmaceutically acceptable salts and polymorphic forms of sildenafil

Info

Publication number: WO2007110559A1
Application number: PCT/GB2006/004130
Authority: WO
Inventors: Miroslav Zegarac; Ernest Mestrovic; Maja Devcic; Petar Tudja
Original assignee: Pliva Hrvatska D.O.O.; Mcleish, Nicholas, Alistair, Maxwell
Priority date: 2006-03-29
Filing date: 2006-11-06
Publication date: 2007-10-04
Also published as: GB0606234D0

Abstract

The present invention is concerned with new pharmaceutically acceptable salts of sildenafil and new polymorphic forms thereof, processes for preparing the new pharmaceutically acceptable salts and new polymorphic forms, pharmaceutical compositions containing the same, therapeutic uses thereof and methods of treatment employing the same.

Description

PHARMACEUTICALLY ACCEPTABLE SALTS AND POLYMORPHIC FORMS OF SILDENAFIL

Sildenafil is chemically designated as l-[[3-(4,7-dihydro-l-methyl-7-oxo-3-propyl-lH-pyrazolo[4,3- c(]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4-methylpiperazine and can be represented by the following structural formula:

Sildenafil selectively inhibits cyclic guanosine monophosphate(cGMP)-specific phophodiesterase type 5 (PDE5). Following administration of sildenafil cGMP levels are elevated, which gives rise to beneficial platelet anti-aggregatory, anti-vasospastic and vasodilatory activity and potentiation of the effects of nitric oxide (NO) and other nitrovasodilators. Thus sildenafil has utility hi the treatment of a number of disorders, including stable, unstable and variant (Prinzmetal) angina, hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency e.g. post- percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS). Additionally, sildenafil can be used in the treatment of male erectile dysfunction and female sexual disorders. The basic NCE patent for sildenafil is EP 0463756B. Example 12 relates to the preparation of sildenafil as the free base, with reference to the preparation details of Example 9. Although the preparation of salt forms is generally referred to in the specification of EP 0463756B in the context of formula (I) by listing the following pharmaceutically acceptable salts - hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate and tartrate salts, there is no disclosure in EP 0463756B of a pharmaceutically acceptable salt of sildenafil. The extent of the disclosure for sildenafil in EP 0463756B is as the free base. It will be appreciated that the scope of possible disclosure covered by EP 0463756B for compounds represented by formula (I)

where R¹, R², R³ and Y are as defined in EP 0463756B, taken together with the above range of pharmaceutically acceptable acids, is extremely large. On this basis there cannot be considered to be an enabling disclosure in EP 0463756B for each and every possible salt form for all compounds covered by formula (I), given the necessary level of selection that would be necessary to first select a compound having specific R , R , R and Y substituents from the possible range of substituents allowed for in EP 0463756B and secondly to select a specific pharmaceutically acceptable salt from the above list of possible salts.

Sildenafil citrate has subsequently been commercially developed by Pfizer, Inc. and is available under the trademark VIAGRA. It has been found that sildenafil citrate is moderately soluble in water. It is well recognised in the pharmaceutical field that the provision of a drug in a form that is poorly or moderately soluble in water can result in less than optimal performance and thus the provision of a drug form with enhanced solubility is desirable. Poorly or moderately soluble drugs often exhibit incomplete or erratic absorption and hence low bioavailability and slow onset of action. Effectiveness of poorly or moderately soluble drugs can vary from patient to patient, and there can be a strong effect of food on the absorption of such drugs. For certain poorly soluble drugs it has been necessary to increase the dose thereof to obtain the efficacy required.

Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture a drug substance and a drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety, and efficacy of a drug product.

Polymorphic forms as referred to herein can include crystalline and amorphous forms as well as solvate and hydrate forms, which can be further characterised as follows:

(i) Crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice.

(ii) Amorphous forms consist of disordered arrangements of molecules that do not possess a distinguishable crystal lattice.

(iii) Solvates are crystal forms containing either stoichiometric or non-stoichiometric amounts of a solvent. If the incorporated solvent is water, the solvate is commonly known as a hydrate.

When a drug substance exists in polymorphic forms, it is said to exhibit polymorphism.

There are a number of methods that can be used to characterise polymorphs of a drug substance. Demonstration of a non-equivalent structure by single crystal X-ray diffraction is currently regarded as the definitive evidence of polymorphism. X-ray powder diffraction can also be used to support the existence of polymorphs. Other methods, including microscopy, thermal analysis (e.g., differential scanning calorimetry, thermal gravimetric analysis, and hot-stage microscopy), and spectroscopy (e.g., infrared (IR) and near infrared (NIR), Raman and solid-state nuclear magnetic resonance [ssNMR]) are also helpful to further characterise polymorphic forms.

Drug substance polymorphic forms can exhibit different chemical, physical and mechanical properties as referred to above, including aqueous solubility and dissolution rate, hygroscopicity, particle shape, density, flowability, and compactibility, which in turn may affect processing of the drug substance and/or manufacturing of the drug product. Polymorphs can also exhibit different stabilities. The most stable polymorphic form of a drug substance is often chosen during drug development based on the minimal potential for conversion to another polymorphic form and on its greater chemical stability. However, a meta-stable form can alternatively be chosen for various reasons, including better bioavailability.

There is now provided by the present invention, therefore, pharmaceutically acceptable salts of sildenafil with advantageous properties. More specifically, we have now surprisingly found that certain sildenafil salts exhibit beneficial properties and, in particular, provide advantages over commercially available sildenafil citrate.

There is now provided by the present invention, therefore, a pharmaceutically acceptable salt of sildenafil, wherein said salt is formed between sildenafil free base and a pharmaceutically acceptable acid selected from the group consisting of hydrochloric acid, sulphuric acid, ethane sulphonic acid, tartaric acid and fumaric acid.

In particular there is provided by the present invention sildenafil hydrochloride, sildenafil hydrogensulphate, sildenafil hemisulphate, sildenafil hemitartrate, sildenafil esylate and sildenafil fumarate.

Each of the salts provided by the present invention is characterised herein as one or more novel polymorphic forms and as such there is provided by the present invention new polymorphic forms of sildenafil hydrochloride, sildenafil hydrogensulphate, sildenafil hemisulphate, sildenafil hemitartrate, sildenafil esylate and sildenafil fumarate. More particularly, there is provided by the present invention polymorphs I, II and III of sildenafil hydrochloride; polymorphs I, II and III of sildenafil hydrogensulphate; polymorph I of sildenafil hemisulphate; polymorphs I and II of sildenafil hemitartrate; polymorphs I, II, III and IV of sildenafil esylate; and polymorph I of sildenafil fumarate.

The crystalline structure of polymorph I of sildenafil hydrochloride according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 1.

Polymorph I of sildenafil hydrochloride according to the present invention is further characterised as having characteristic peaks (2Θ): 10.9±0.2°, 13.7+0.2°, 15.0±0.2°, 18.0±0.2° and 19.0±0.2°. Further peaks (2θ) associated with polymorph I of sildenafil hydrochloride according to the present invention are selected from one or more of the following: 3.9^D±0.2°, 11.8+0.2°, 14.0+0.2°, 21.3±0.2° and 23.7±0.2°.

Polymorph I of sildenafil hydrochloride according to the present invention is further characterised by a typical digital scanning calorimetry (DSC) thermogram as shown in Figure 2. Polymorph I of sildenafil hydrochloride has a characteristic DSC endotherm at about 236⁰C.

Polymorph I of sildenafil hydrochloride according to the present invention can also be characterised by a vapour sorption of about 1.82% at about 80% relative humidity (RH). Dynamic vapour sorption (DVS) is a technique that measures water vapour or moisture sorption of a material under varying conditions of humidity and it can be used as a measure of the hygroscopicity of a given material.

The water vapour or moisture sorption properties of pharmaceutical materials such as excipients, drug formulations and packaging films are recognized in the art as critical factors in determining the storage, stability, processing and application performance thereof. Moisture sorption properties are thus routinely determined for pharmaceutical materials and have traditionally been evaluated by storing samples over saturated salt solutions of established relative humidities and then regularly weighing until equilibrium is reached. However, there are a number of disadvantages associated with these methods, including: (i) the prolonged period of time taken for the samples to reach equilibrium using a static method, which can often be many days and in many cases can be several weeks; (ii) inherent inaccuracies as the samples have to be removed from the storage container to be weighed, which can cause weight loss or gain; (iii) static methods necessitate the use of large samples sizes (tyρically>lgm); and (iv) the highly labour intensive nature of static methods.

The DVS data as described herein was obtained using the Dynamic Vapour Sorption (DVS) methodology developed by Surface Measurement Systems (SMS) Ltd. for the rapid quantitative analysis of the water sorption properties of solids including pharmaceutical materials. The Surface Measurement Systems DVS instrument rapidly measures uptake and loss of moisture by flowing a carrier gas at a specified relative humidity (RH) over a sample (lmg - 1.5g) suspended from the weighing mechanism of a Cahn D-200 ultra sensitive recording microbalance. This particular microbalance is used because it is capable of measuring changes in sample mass lower than 1 part in 10 million and provides the long-term stability as required for the accurate measurement of vapour sorption phenomena, which may take from minutes to days to complete depending upon the sample size and material. Indeed, a major factor in determining the water sorption behaviour of materials is the need to establish rapid water sorption equilibrium, therefore the DVS instrument allows sorption behaviour to be accurately determined on very small sample sizes (typically 10 mg), thus minimising the equilibration time required.

One of the most critical factors for any instrumentation used for investigating moisture sorption behaviour is the temperature stability of the measurement system. The main DVS instrument systems as used herein are, therefore, housed in a precisely controlled constant temperature incubator with a temperature stability of ±0.1⁰C. This ensures very good instrument baseline stability as well as accurate control of the relative humidity generation. The required relative humidities are generated by accurately mixing dry and saturated vapour gas flows in the correct proportions using mass flow controllers. Humidity and temperature probes are situated just below the sample and reference holders to give independent verification of system performance. The microbalance mechanism is very sensitive to sorption and desorption of moisture. A constant dry gas purge to the balance head is, therefore, provided to give the best performance in terms of baseline stability. The purge flow is manually controlled such that in the event of a power failure, condensation of moisture in the balance head cannot occur. The DVS instrument is fully automated.

It is well known and recognized in the art that the measurement of intrinsic dissolution rates is a tool in the functionality and characterization of bulk drug substances and excipients. The intrinsic dissolution rate is defined as the dissolution rate of a pure substance under the condition of constant surface area and the dissolution rate, and hence bioavailability, of a drug substance is influenced by its solid state properties, namely crystallinity, amorphism, polymorphism, hydration, solvation, particle size, and particle surface area. The measured intrinsic dissolution rate is thus dependent on these solid state properties. The dissolution rate is also influenced by extrinsic factors, such as hydrodynamics (for example, test apparatus and disk rotation speed or fluid flow) and test conditions (for example, temperature, fluid viscosity, pH and buffer strength in the case of ionizable compounds). An intrinsic dissolution rate can be determined by exposing the surface area of a material to an appropriate dissolution medium while maintaining constant temperature, stirring rate and pH. Typically, the intrinsic dissolution is expressed in terms of mg per minute per cm² and specific apparatus and measurement conditions are hereinafter described in greater detail, with specific reference to the apparatus shown in Figure 20.

Polymorph I of sildenafil hydrochloride as provided by the present invention preferably has an intrinsic dissolution rate of at least about 7mg/mincm², measured using ID apparatus substantially as described herein, at a rotation speed of about 100 rpm, in about 900 ml of an acidic medium having a pH of about 1.2. More preferably, polymorph I of sildenafil hydrochloride as provided by the present invention has an intrinsic dissolution rate of at least about 8mg/mincm², still more preferably at least about 9mg/mincm², still more preferably at least about lOmg/mincm² and still more preferably at least about 1 lmg/mincm².

It is particularly preferred that polymorph I of sildenafil hydrochloride as provided by the present invention has an intrinsic dissolution rate of about 11.10 mg/mincm², measured using ID apparatus substantially as described herein, at a rotation speed of about 100 rpm, in about 900 ml of an acidic medium having a pH of about 1.2. Polymorph I of sildenafil hydrochloride as provided by the present invention preferably has an intrinsic dissolution rate of at least about 7mg/mincm², measured using ED apparatus substantially as described herein, at a rotation speed of about 100 rpm, in about 900 ml of an medium having a pH of about 5.5. More preferably, polymorph I of sildenafil hydrochloride as provided by the present invention has an intrinsic dissolution rate of at least about 8mg/mincm², still more preferably at least about 9mg/mincm², still more preferably at least about lOmg/mincm² and still more preferably at least about 10.5 mg/mincm².

It is particularly preferred that polymorph I of sildenafil hydrochloride as provided by the present invention has an intrinsic dissolution rate of about 10.51 mg/mincm², measured using ID apparatus substantially as described herein, at a rotation speed of 100 rpm, in 900 ml of an medium having a pH of5.5.

The crystalline structure of polymorph II of sildenafil hydrochloride according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 3.

Polymorph II of sildenafil hydrochloride according to the present invention is further characterised as having characteristic peaks (2Θ): 6.7°±0.2°, 10.0°±0.2°, 13.3±0.2° and 14.0°±0.2. Further peaks (2Θ) associated with polymorph II of sildenafil hydrochloride according to the present invention are selected from one or more of the following: 15.0°±0.2°, 15.4°±0.2°, 15.5°±0.2° and 22.0°±0.2°.

The crystalline structure of polymorph III of sildenafil hydrochloride according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 4.

Polymorph III of sildenafil hydrochloride according to the present invention is further characterised as having characteristic peaks (2Θ): 6.3°±0.2°, 7.2°±0.2° and 15.6°±0.2°. Further peaks (2Θ) associated with polymorph III of sildenafil hydrochloride according to the present invention are selected from one or more of the following: 9.4°±0.2°, 12.0°±0.2°₅ 12.6°±0.2°, 14.4°±0.2°, 19.6°+0.2^o, 20.2°±0.2° and 23.3°±0.2°. The crystalline structure of polymorph I of sildenafil hydrogensulphate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 5.

Polymorph I of sildenafil hydrogensulphate according to the present invention is further characterised as having characteristic peaks (2Θ): 6.3°±0.2°, 6,9°+0.2°, 12.5°±0.2°, 16.3°+0.2°, 19.1°±0.2° and 22.1°±0.2°. Further peaks (2Θ) associated with polymorph I of sildenafil hydrogensulphate according to the present invention are selected from one or more of the following: 9.3°±0.2°, 13.1°+0.2°, 17.8°±0.2° and 18.0°±0.2°.

The crystalline structure of polymorph II of sildenafil hydrogensulphate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 6.

Polymorph II of sildenafil hydrogensulphate according to the present invention is further characterised as having characteristic peaks (2Θ): 7.2°±0.2°, 9.0°±0.2°, 13.6°±0.2° and 23.4°+0.2°. Further peaks (2Θ) associated with polymorph II of sildenafil hydrogensulphate according to the present invention are selected from one or more of the following: 5.6°±0.2°, 6.3^ό+α2°, 8.2°±0.2°, 11.3°±0.2^o, 16.3°±0,2° and 17.3°±0.2°.

Polymorph II of sildenafil hydrogensulphate as provided by the present invention preferably has an intrinsic dissolution rate of at least about 7mg/mincm², measured using ID apparatus substantially as described herein, at a rotation speed of about 100 rpm, in about 900 ml of an medium having a pH of about 6.4 More preferably, polymorph II of sildenafil hydrogensulphate as provided by the present invention has an intrinsic dissolution rate of at least about 8mg/mincm², still more preferably at least about 9mg/mincm².

It is particularly preferred that polymorph II of sildenafil hydrogensulphate as provided by the present invention has an intrinsic dissolution rate of about 9.94 mg/mincm², measured using ID apparatus substantially as described herein, at a rotation speed of 100 rpm, in 900 ml of a medium having a pH of about 6.4. The crystalline structure of polymorph III of sildenafil hydrogensulphate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 7.

Polymorph III of sildenafil hydrogensulphate according to the present invention is further characterised as having characteristic peaks 7.1°±0.2° , 16.0°±0.2° , 20.5^D±0.2° and 22.6°±0.2°. Further peaks (2Θ) associated with polymorph III of sildenafil hydrogensulphate according to the present invention are selected from one or more of the following: 8.1 °±0.2°, 11.4°±0.2° , 12.1 °±0.2° , 13.4°±0.2^o ₃ 15.6^o±0.2° and 16.2°±0.2°.

Polymorph III of sildenafil hydrogensulphate according to the present invention is further characterised by a typical DSC thermogram as shown in Figure 8. Polymorph III of sildenafil hydrogensulphate has a characteristic DSC endotherm at about 116°C.

Polymorph III of sildenafil hydrogensulphate according to the present invention can also be characterised by a vapour sorption of about 1.41% at about 90% relative humidity (RH). DVS measures water vapour or moisture sorption of a material under varying conditions of humidify arid it can be used to determine the hygroscopicity of a given material.

Polymorph III of sildenafil hydrogensulphate as provided by the present invention preferably has an intrinsic dissolution rate of at least about 7mg/mincrn², measured using ID apparatus substantially as described herein, at a rotation speed of about 100 rprn, in about 900 ml of an acidic medium having a pH of about 1.2.

It is particularly preferred that polymorph III of sildenafil hydrogensulphate as provided by the present invention has an intrinsic dissolution rate of about 7.3 mg/mincm², measured using ID apparatus substantially as described herein, at a rotation speed of 100 rpm, in 900 ml of an acidic medium having a pH of about 1.2.

Polymorph III of sildenafil hydrogensulphate is a crystalline non-hygroscopic form of sildenafil with a higher IDR at pH 1.2 than sildenafil citrate. The crystalline structure of polymorph I of sildenafil hemisulphate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 9.

Polymorph I of sildenafil hemisulphate according to the present invention is further characterised as having characteristic peaks (2Θ): 8.1°±0.2°₅ 10.3°+0.2°₅ 16.2°+0.2°, 17.1°±0.2°, and 24.9°±0.2°. Further peaks (2Θ) associated with Polymorph I of sildenafil hemisulphate according to the present invention are selected from one or more of the following selected from one or more of the following: 6.8°±0.2°, 12.6°±0.2°, 16.0°±0.2°, 21.9°±0.2° and 23.2°±0.2°.

Polymorph I of sildenafil hemisulphate according to the present invention is further characterised by a typical DSC thermogram as shown in Figure 10. Polymorph I of sildenafil hemisulphate has a characteristic DSC endotherm at about 22O⁰C.

The crystalline structure of polymorph I of sildenafil hemitartrate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 11.

Polymorph I of sildenafil hemitartrate according to the present invention is further characterised as having characteristic peaks (2Θ): 5.5°±0.2°, 12.1°±0.2° and 17.4°±0.2°. Further peaks (2Θ) associated with polymorph I of sildenafil hemitartrate according to the present invention are selected from one or more of the following: 8.0°+0.2°, 9.2°±0.2°, ll.l°±0.2°, 14.2°±0.2°₅ 15.7°±0.2°, 16.0°±0.2° and 19.9°±0.2°.

Polymorph I of sildenafil hemitartrate according to the present invention is further characterised by a typical DSC thermogram as shown in Figure 12. Polymorph I of sildenafil hemitartrate has a characteristic DSC endotherm at about 231°C.

Polymorph I of sildenafil hemitartrate according to the present invention can also be characterised by a vapour sorption of about 0.22% at about 90% relative humidity (RH). DVS measures water vapour or moisture sorption of a material under varying conditions of humidity and it can be used to determine the hygroscopicity of a given material.

Polymorph I of sildenafil hemitartrate as provided by the present invention preferably has an intrinsic dissolution rate of at least about 7mg/mincm², measured using ID apparatus substantially as described herein, at a rotation speed of about 100 rpm, in about 900 ml of an acidic medium having a pH of about 1.2, More preferably, polymorph I of sildenafil hemitartrate as provided by the present invention has an intrinsic dissolution rate of at least about 8mg/mincm², still more preferably at least about 9mg/mincm², still more preferably at least about 10 mg/mincm².

It is particularly preferred that polymorph I of sildenafil hemitartrate as provided by the present invention has an intrinsic dissolution rate of about 10.13 mg/mincm², measured using ID apparatus substantially as described herein, at a rotation speed of 100 rpm, in 900 ml of an acidic medium having a pH of about 1.2.

Polymorph I of sildenafil hemitartrate according to the present invention has an IDR of 0.11 mg/mincm² at pH 5.7.

Polymorph I of sildenafil hemitartrate is a crystalline, non-solvated, non-hygroscopic from with a higher melting point and dissolution rate at pH 1.2 than sildenafil citrate.

The crystalline structure of polymorph II of sildenafil hemitartrate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 13.

Polymorph II of sildenafil hemitartrate according to the present invention is further characterised as having characteristic peaks (2Θ): 5.2°±0.2°, 7.2°±0.2°, 12.3°+0.2° and 21.6°±0.2°. Further peaks (2Θ) associated with polymorph II of sildenafil hemitartrate according to the present invention are: selected from one or more of the following 5.6°±0.2°, 8.1°±0.2°, 9.1°±0.2°, 15.6°±0.2°, 16.0°±0.2° and 19.8°+0.2°. The crystalline structure of polymorph I of sildenafil esylate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 14.

Polymorph I of sildenafil esylate according to the present invention is further characterised as having characteristic peaks (2Θ): 8.2°±0.2°, 13.6°±0.2°, 16.2°+0.2°, and 24.9°±0.2°. Further peaks (2Θ) associated with polymorph I of sildenafil esylate according to the present invention are selected from one or more of the following: 6.8°±0.2°, 9.4°±0.2°₃ 9.8°±0.2°, 11.9°±0.2°. 12.5°±0.2° and 19.0°±0.2°.

The crystalline structure of polymorph I of sildenafil esylate according to the present invention is shown in Figure 15. This is further characterised by triclinic space group Pl displaying unit cell parameters comprising crystal axis lengths of a = 10.06+0.01 A₅ b = 10.90+0.01 A, c = 14.17+O.OlA and angles between the crystal axes of α = 83.09±0.01°, β = 68.79±0.01° and γ - 93.15+0.01°. The crystalline structure of polymorph I of sildenafil esylate is further characterised by the following properties:

Empirical formula C24 H36 N6 07 S2

Formula weight 584.71

Volume 1429.6 A³

Z, calculated density 2, 1.358 g/cm³

Wavelength 1.54184 A

Polymorph I of sildenafil esylate according to the present invention can also be characterised by a vapour sorption of about 0.27% at about 80% relative humidity (RH). DVS measures water vapour or moisture sorption of a material under varying conditions of humidity and it can be used to determine the hygroscopicity of a given material.

Polymorph I of sildenafil esylate as provided by the present invention preferably has an intrinsic dissolution rate of at least about 4mg/mincm², measured using ID apparatus substantially as described herein, at a rotation speed of about 100 rpm, in about 900 ml of an medium having a pH of about 6.4. It is particularly preferred that polymorph I of sildenafil esylate as provided by the present invention has an intrinsic dissolution rate of about 4.82 mg/mincm², measured using ID apparatus substantially as described herein, at a rotation speed of 100 rpm, in 900 ml of an medium having a pH of about 6.4.

The crystalline structure of polymorph II of sildenafil esylate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 16.

Polymorph II of sildenafil esylate according to the present invention is further characterised as having characteristic peaks (29): 4.6°+0.2°, 10.5°±0.2°, 11.4°±0.2^o and 18.4°±0.2°. Further peaks (2Θ) associated with polymorph II of sildenafil esylate according to the present invention are selected from one or more of the following: 6.0°±0.2°₅ 9.1°±0.2°₃ 9.9°±0.2°, 15.3°±0.2°, 20.3°±0.2° and 21.0°±0.2°.

The crystalline structure of polymorph III of sildenafil esylate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 17.

Polymorph III of sildenafil esylate according to the present invention is further characterised as having characteristic peaks (2Θ): 6.0°±0.2°, 9.9°±0.2°, 11.9°±0.2° and 22.2°+0.2°. Further peaks (2Θ) associated with polymorph II of sildenafil esylate according to the present invention are selected from one or more of the following: 8.4°±0.2°, 14.2°±0.2°, 16.2°±0.2°₅ 17.9°±0.2°, 20.3°±0.2° and 23.6°±0.2°.

The crystalline structure of polymorph IV of sildenafil esylate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 18.

Polymorph IV of sildenafil esylate according to the present invention is further characterised as having characteristic peaks (2Θ): ll.l°±0.2°, 13.8°+0.2°, 15.1°±0.2°, and 23.4°±0.2°. Further peaks (2Θ) associated with polymorph IV of sildenafil esylate according to the present invention are selected from one or more of the following: 4.6°±0.2^α, 9.2°±0.2°, 12.3°+0.2°, 16,2°±0.2°, 18.4^o±0.2° and 21.2^o±0.2°.

Polymorph IV of sildenafil esylate according to the present invention can also be characterised by a vapour sorption of about 0,38% at about 70% relative humidity (RH). DVS measures water vapour or moisture sorption of a material under varying conditions of humidity and it can be used to determine the hygroscopicity of a given material.

The crystalline structure of polymorph I of sildenafil fumarate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 19.

Polymorph I of sildenafil fumarate according to the present invention is further characterised as having characteristic peaks (2Θ): 7.6°±0.2°, 9.3°±0.2°, 14.7°±0.2°, 15.7°±0.2° and 24.0°+0.2°. Further peaks (2Θ) associated with polymorph I of sildenafil fumarate according to the present invention are selected from one or more of the following: 8.5°±0.2°, 12.8°+0.2°, 16.9°±0.2°, 18.2^o±0.2^o and 21.0°±b.2^~o. ^{" ' . .. . . . . .}

There is also provided by the present invention processes for preparing pharmaceutically acceptable salts of sildenafil substantially as hereinbefore described and also the polymorphic forms thereof as described herein. For example, when mixing sildenafil salt or free base in a solvent to form a solution, warming of the mixture can be necessary to completely dissolve the starting material. If warming does not clarify the mixture, the mixture can be diluted or filtered.

Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

The conditions can also be changed to induce precipitation. In one embodiment the solubility of the solvent can be reduced, for example, by cooling the solvent. In one embodiment, an anti-solvent is added to a solution to decrease its solubility for a particular compound, thus resulting in precipitation.

Another manner to accelerate crystallization is by seeding with a crystal of the product or scratching the inner surface of the crystallization vessel with a glass rod.

Other times, crystallization can occur spontaneously without any inducement. All that is necessary to be within the scope of the claims is to form a precipitate or crystal.

According to the present invention there is further provided a process of preparing a pharmaceutically acceptable salt of sildenafil substantially as hereinbefore described, which process comprises treating sildenafil free base with a pharmaceutically acceptable acid selected from the group consisting of hydrochloric acid, sulphuric acid, ethane sulphonic acid, tartaric acid and fumaric acid. This process will provide the pharmaceutically acceptable salt in a first polymorphic form.

There is also provided a process of polymorph interconversion, which process comprises converting a first polymorphic form of a pharmaceutically acceptable salt of sildenafil as prepared by the above process to a further polymorphic form of the pharmaceutically acceptable sildenafil salt. Typically the interconversion can comprise dissolving (often under reflux conditions) the first polymorphic form in a suitable solvent, such as for example an acetone / water system, acetonitrile or an acetonitrile / water system, or the like, and allowing crystals of the further polymorphic form to form. Alternatively, the first polymorphic form can be dried at an elevated relative humidity over a prolonged period of time to yield the further polymorphic form, which under such conditions is typically hydrated, and a specific example of this interconversion is preparation of sildenafil hydrogensulphate form III dihydrate from sildenafil hydrogensulphate form II.

Sildenafil salts and polymorphs as provided by the present invention are selective inhibitors of cyclic guanosine monophosphate(cGMP)-specific phophodiesterase type 5 (PDE5) and are thus useful in the treatment of a number of disorders, including stable, unstable and variant (Prinzmetal) angina, hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency e.g. post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS). Additionally, sildenafil salts and polymorphs can be used in the treatment of male erectile dysfunction and female sexual disorders.

The present invention further provides, therefore, pharmaceutical compositions comprising a therapeutically effective dose of a sildenafil salt or polymorph according to the invention, together with a pharmaceutically acceptable carrier, diluent or excipient therefor. Excipients are chosen according to the pharmaceutical form and the desired mode of administration.

As used herein, the term "therapeutically effective amount" means an amount of a sildenafil salt or polymorph according to the invention, which is capable of preventing, ameliorating or eliminating a disease state for which administration of a selective inhibitor of cyclic guanosine monophosphate(cGMP)-specific phophodiesterase type 5 (PDE5) is indicated.

By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient is compatible with a sildenafil salt or polymorph according to the invention, and not deleterious to a recipient thereof.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, a sildenafil salt or polymorph according to the present invention is administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases. The appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration. For topical application, a sildenafil salt form according to the present invention can be used in creams, ointments or lotions. Oral administration is preferred.

To achieve the desired prophylactic or therapeutic effect, the dose of a sildenafil salt or polymorph according to the present invention can vary between 0.01 and 50 mg per kg of body weight per day. Each unit dose can contain from 0.1 to 1000 mg, preferably 1 to 500 mg, of a sildenafil salt or polymorph according to the present invention in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.

When a solid composition in the form of tablets is prepared, a sildenafil salt or polymorph according to the present invention is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative or other appropriate substances, or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.

A preparation in the form of gelatin capsules can be obtained by mixing a sildenafil salt or polymorph according to the present invention with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration in the form of drops can contain a sildenafil salt or polymorph according to the present invention typically in conjunction with a sweetener, which is preferably calorie-free, optionally antiseptics such as meihylparaben and propylparaben, as well as a flavoring and an appropriate color.

Water-dispersible granules or powders can contain a sildenafil salt or polymorph according to the present invention mixed with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.

Rectal administration is effected using suppositories prepared with binders which melt at the rectal temperature, for example polyethylene glycols.

Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol. A sildenafil salt or polymorph according to the present invention can also be formulated as microcapsules, with one or more carriers or additives if appropriate.

There is also provided by the present invention a sildenafil salt or polymorph substantially as hereinbefore described for use in therapy.

The present invention further provides a sildenafil salt or polymorph substantially as hereinbefore described, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of a selective inhibitor of cyclic guanosine monophosρhate(cGMP)-specific phophodiesterase type 5 (PDE5). More specifically, the present invention provides a sildenafil salt or polymorph substantially as hereinbefore described, for use in the manufacture of a medicament for the treatment of a number of disorders, including stable, unstable and variant (Prinzmetal) angina, hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency e.g. post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS), male erectile dysfunction and female sexual disorders.

The present invention also provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of a selective inhibitor of cyclic guanosine monophosphate(cGMP)- specific phophodiesterase type 5 (PDE5) in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of a sildenafil salt or polymorph substantially as hereinbefore described. More specifically, the present invention provides a method of treating a number of disorders, including stable, unstable and variant (Prinzmetal) angina, hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency e.g. post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS), male erectile dysfunction and female sexual disorders in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of a sildenafil salt form or polymorph substantially as hereinbefore described. There is also provided by the present invention a sildenafil salt or polymorph substantially as hereinbefore described, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of a selective inhibitor of cyclic guanosine monophosphate (cGMP) - specific phophodi esterase type 5 (PDE5), wherein said sildenafil salt or polymorph according to the invention, provides an enhanced therapeutic effect compared to the therapeutic effect provided by sildenafil citrate. The present invention also provides a corresponding method of treatment, which comprises administering to a patient a therapeutically effective amount of a sildenafil salt or polymorph substantially as hereinbefore described, so that the administered sildenafil salt or polymorph according to the present invention, provides an enhanced therapeutic effect to the patient, compared to the therapeutic effect provided by corresponding administration of sildenafil citrate.

The present invention can be further illustrated by the following Figures and non-limiting Examples.

With reference to the Figures, these are as follows:

Figure 1 : X-ray powder diffraction pattern of sildenafil hydrochloride polymorph ϊ according to the present invention obtained by using a Philips X' Pert PRO with CnKa radiation in 2Θ = 3-40 ° range.

Figure 2: Differential Scanning Calorimetry (DSC) pattern of sildenafil hydrochloride polymorph I obtained by using using a DSC Pyris 1 manufactured by Perkin- Elmer. The experiment was done under a flow of nitrogen (35 ml/min) and heating rate was 10 °C/min. A standard sample pan was used.

Figure 3 : X-ray powder diffraction pattern of sildenafil hydrochloride polymorph II according to the present miceritiørijαhtainedJhy using a Philips X'Pert PRO with CuZa radiation in 2Θ = 3-40 ° range.

Figure 4: X-ray powder diffraction pattern of sildenafil hydrochloride polymorph III according to the present invention obtained by using a Philips X'Pert PRO with CnKa radiation in 2Θ = 3-40 ° range.

Figure 5: X-ray powder diffraction pattern of sildenafil hydrogensulphate polymorph I according to the present invention obtained by using a Philips X'Pert PRO with CuKa radiation in 2Θ = 3-40 ° range. Figure 6: X-ray powder diffraction pattern of sildenafil hydrogensulphate polymorph II according to the present invention obtained by using a Philips X'Pert PRO with CuKa radiation in 2Θ - 3-40 ° range.

Figure 7: X-ray powder diffraction pattern of sildenafil hydrogensulphate polymorph III according to the present invention obtained by using a Philips X'Pert PRO with CaKa radiation in 2θ = 3-40 ° range.

Figure 8: Differential Scanning Calorimetry (DSC) pattern of sildenafil hydrogensulphate polymorph III obtained by using using a DSC Pyris 1 manufactured by Perkin- Elmer. The experiment was done under a flow of nitrogen (35 ml/min) and heating rate was 10 °C/min. A standard sample pan was used.

Figure 9: X-ray powder diffraction pattern of sildenafil hemisulphate polymorph I according to the present invention obtained by using a Philips X'Pert PRO with CaKa radiation in 2θ = 3-40 ° range.

Figure 10: Differential Scanning Calorimetry (DSC) pattern of sildenafil hemisulphate polymorph I obtained by using using a DSC Pyris 1 manufactured by Perkin- Elmer. The experiment was done under a flow of nitrogen (35 ml/min) and heating rate was 10 °C/min. A standard sample pan was used.

Figure 11 : X-ray powder diffraction pattern of sildenafil hemitartrate polymorph I according to the

^"present invention obtained by ^"using a Philips X'Pert PRO with CuKa radiation va.^'2θ = 3-40 ° range.

Figure 12: Differential Scanning Calorimetry (DSC) pattern of sildenafil hemitartrate polymorph I obtained by using using a DSC Pyris 1 manufactured by Perkin- Elmer. The experiment was done under a flow of nitrogen (35 ml/min) and heating rate was 10 °C/min. A standard sample pan was used.

Figure 13: X-ray powder diffraction pattern of sildenafil hemitartrate polymorph II according to the present invention obtained by using a Philips X'Pert PRO with CuKa radiation in 2Θ = 3-40 ° range.

Figure 14: X-ray powder diffraction pattern of sildenafil esylate polymorph I according to the present invention obtained by using a Philips X'Pert PRO with Cui<-α radiation in 2θ = 3-40 ° range.

Figure 15: The crystalline structure of sildenafil esylate polymorph I which is further characterized by atomic positions and other structural parameters obtained from single crystal X-ray analysis

Figure 16: X-ray powder diffraction pattern of sildenafil esylate polymorph II according to the present invention obtained by using a Philips X'Pert PRO with CuKa radiation in 2Θ = 3-40 ° range.

Figure 17: X-ray powder diffraction pattern of sildenafil esylate polymorph III according to the present invention obtained by using a Philips X'Pert PRO with CaKa radiation in 2Θ = 3-40 ° range. Figure 18: X-ray powder diffraction pattern of sildenafil esylate polymorph IV according to the present invention obtained by using a Philips X'Pert PRO with CnKa radiation in 2θ = 3-40 ° range. Figure 19: X-ray powder diffraction pattern of sildenafil fumarate polymorph I according to the present invention obtained by using a Philips XTert PRO with CuZa radiation in 2θ = 3-40 ° range. Figure 20: Intrinsic dissolution (ID) apparatus.

Typical ID apparatus for measuring intrinsic dissolution rates is shown in Figure 8 and consists of a punch (1) and die (2) fabricated out of hardened steel. The base (3) of die (2) has three threaded holes (4a, 4b and 4c) for the attachment of a surface plate (5) made of polished steel, providing a mirror-smooth base for the compacted pellet. Die (2) has a 0.1cm to 1.0cm diameter cavity into which is placed a measured amount of the material whose intrinsic dissolution rate is to be determined. Punch (1) is then inserted in the cavity of die (2) and the test material is compressed with a benchtop tablet press. A hole through the head of punch (1) allows insertion of the metal rod to facilitate removal from die (2) after the test. A compacted pellet of the material is formed in the cavity with a single face of defined area exposed on the bottom of die (2).

The bottom of the cavity of die (2) is threaded so that at least 50% to -7-5% of the compacted pellet - can dissolve without falling out of die (2). The top of die (2) has a threaded shoulder that allows it to be attached to a holder (6). Holder (6) is mounted on a laboratory stirring device, and the entire die (2), with the compacted pellet still in place, is immersed in the dissolution medium and rotated by the stirring device.

The material to be tested is in powder form and is weighed onto a piece of weighing paper. The surface plate (5) is attached to underside (3) of die (2) and secured. The accurately weighed portion of the material under test is placed into the cavity of die (2). Punch (1 ) is placed into the chamber, and the metal plate (5) secured on top of the assembly. The powder is compressed on a hydraulic press for 1 minute at the minimum compression pressure necessary to form a non-disintegrating compacted pellet. Surface plate (5) is detached and die (2), with punch (1) still in place, is screwed into holder (6). All loose powder is removed from the surface of die (2) by blowing compressed air or nitrogen. The die (2) - holder (6) assembly is slid into the dissolution test chuck and tightened. The shaft is positioned in the spindle so that when the test head is lowered, the exposed surface of the compacted pellet is about 3.8 cm from the bottom of the vessel. To calculate the intrinsic dissolution rate, the cumulative amount of test specimen dissolved per unit area of the compacted pellet is plotted against time until 10% is dissolved. The cumulative amount dissolved per unit area is given by the cumulative amount dissolved at each time point divided by the surface area exposed (0.5 cm²). Linear regression is then performed on data points up to and including the time point beyond which 10% is dissolved. The intrinsic dissolution rate of the test specimen, in mg per minute per cm², is determined from the slope of the regression line.

The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention. It will thus be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention.

EXAMPLES

EXAMPLE 1

Preparation of sildenafil hydrochloride polymorph I

5.0 g of sildenafil base was dissolved in 100 ml of acetone under reflux conditions. 18.5 ml of HCl solution in 1-propanol (about 0.63 mol/1) was added and the solution formed following addition was stirred at the same temperature for about 2 hours. About 50 ml of n-heptane was added, yielding white crystals. This suspension was slowly cooled to room temperature and filtered. The crystals so obtained were washed with n-heptane and dried at 50°C under vacuum to yield sildenafil hydrochloride polymorph I.

EXAMPLE 2

Preparation of sildenafil hydrochloride polymorph I 0.3 g of sildenafil base was dissolved in 4.0 ml of 1-propanol under reflux conditions. About 2.1 ml of HCl solution in 1-propanol (about 0.315 mol/1) was added and the solution formed following addition was stirred at the same temperature for about 1 hour. The solution was then cooled to room temperature, yielding white crystals. This suspension was stirred for another 3.5 hours in an ice bath and then filtered. The crystals so obtained were dried at 60°C under vacuum to yield sildenafil hydrochloride polymorph I.

EXAMPLE 3

Preparation of sildenafil hydrochloride polymorph II

50 mg of sildenafil hydrochloride polymorph I was dissolved in an acetone (4.0 ml)/water (0.2 ml) system and the solution was left to evaporate. After about 24 hours, crystals of sildenafil hydrochloride polymorph II were observed.

EXAMPLE 4

Preparation of sildenafil hydrochloride polymorph HI

120 mg of sildenafil base was dissolved in 2.0 ml of toluene by heating. About 0.43 ml of 0.63 mol/1 solution of HCl in 1-propanol was added. After about 24 hours, crystals of sildenafil hydrochloride polymorph III were observed.

EXAMPLE 5

Preparation of sildenafil hydrogensulphate polymorph I

0.5 g of sildenafil base was dissolved in 15 ml of acetonitrile under reflux conditions. About 13.5 ml of 0.09 mol/1 H₂S O₄ was added and the solution formed after addition was stirred at the same temperature for about 1 hour. The solution was then cooled to room temperature, yielding white crystals. The crystals so obtained were filtered, washed with acetonitrile and dried at 7O⁰C under vacuum to yield sildenafil hydrogensulphate polymorph I (acetonitrile solvate).

EXAMPLE 6

Preparation of sildenafil hydro gensubhate polymorph I 0.5 g of sildenafil hydrogensulphate polymorph I was dissolved in an acetonitrile (100 ml)/water (4 ml) system under reflux conditions. The solution was then slowly cooled to room temperature, yielding white crystals. The crystals so obtained were filtered, washed with acetonitrile and dried at 70⁰C under vacuum to yield sildenafil hydrogensulphate polymorph I (acetonitrile solvate).

EXAMPLE 7

Preparation of sildenafil hydrogensulphate polymorph II

2.0 g of sildenafil base was dissolved in 30 ml of ethanol at reflux conditions. About 6.5 ml of H₂SO₄ solution in ethanol (0.72 mol/1) was added and the solution formed after addition was stirred at the same temperature for about 30 minutes. The solution was then cooled to room temperature and stirred overnight, yielding white crystals. The crystals so obtained were filtered, washed with ethanol and dried in air for about 7 hours to yield sildenafil hydrogensulphate polymorph II (hemiethanol solvate).

EXAMPLE 8

Preparation of sildenafil hydrofiensulphate polymorph IH

1.5 g of sildenafil hydrogensulphate polymorph II was dried at 120 ⁰C under vacuum for about 70 hours. The dry sample was placed in a chamber at about 84% relative humidity for about 4 days to yield sildenafil hydrogensulphate polymorph III (dihydrate) containing about 6% of water.

EXAMPLE 9

Preparation of sildenafil hydrogensulphate polymorph HI

20 mg of sildenafil hydrogensulphate polymorph I was dissolved in an acetone (3.0 ml)/water (0.1 ml) system and the solution was left to evaporate. After about 24 hours crystals of sildenafil hydrogensulphate polymorph III (dihydrate) were observed.

EXAMPLE 10

Preparation of sildenafil hemisulphate polymorph I 1.2 g of sildenafil base was dissolved in 50 ml of toluene at about 50 ⁰C. About 10 ml OfH₂SO₄ solution in toluene (about 0.28 mol/1) was added and the solution formed after addition was stirred at the same temperature for about 30 minutes. The solution was then cooled to room temperature and stirred for about 72 hours, yielding white crystals. The crystals so obtained were filtered and dried at 100°C under vacuum to yield sildenafil hemisulphate polymorph I.

BXAMPLE Il

Preparation of sildenafil hemitartrate polymorph I

0.2 g of sildenafil base was dissolved in 5.0 ml of ethanol under reflux conditions. About 4.15 ml of L-(+)-tartaric acid solution in ethanol (about 0.14 mol/1) was added and solution formed after addition was stirred at the same temperature for about 1 hour. The solution was then cooled to room temperature and stirred for about 12 hours, yielding white crystals. The crystals so obtained were filtered and recrystallised from ethanol to yield sildenafil hemitartrate polymorph I.

EXAMPLE 12

Preparation of sildenafil hemitartrate polymorph II

230 mg of sildenafil hemitartrate polymorph I was dissolved in an acetone (25.0 ml)/ water (1.4 ml) system under reflux conditions. The solution was then cooled to room temperature and stirred in an ice bath for about 1.5 hour, yielding white crystals. The crystals so obtained were filtered and dried at 70 ⁰C under vacuum, yielding sildenafil hemitartrate polymorph II.

EXAMPLE 13

Preparation of sildenafil esylate polymorph I

0.225 g of sildenafil base was dissolved in 5.0 ml of acetonitrile under reflux conditions. About 2.8 ml of ethanesulphonic acid solution in acetonitrile (about 0.2 mol/1) was added and the solution formed after addition was stirred at the same temperature for about 1 hour. The solution was then cooled to room temperature, yielding white crystals. The crystals so obtained were filtered, washed with acetonitrile and dried at 40⁰C under vacuum to yield sildenafil esylate polymorph I. EXAMPLE 14

Preparation of sildenafil esylate polymorph I

20 g of sildenafil base was dissolved in 185 ml of acetonitrile under reflux conditions. About 92 ml of ethanesulfonic acid solution in acetonitrile (about 0.5 mol/1) was added and the solution formed after addition was stirred at the same temperature for about 2 hours. The solution was then cooled to room temperature, yielding white crystals. The crystals so obtained were filtered and dried at 70°C under vacuum to yield sildenafil esylate polymorph I.

EXAMPLE 15

Preparation of sildenafil esylate polymorph I

5 g of sildenafil esylate polymorph IV was dissolved in 100 ml of acetonitrile under reflux conditions. The solution was cooled to about 70 °C and seeded with sildenafil esylate polymorph I crystals. The solution was then cooled to room temperature, yielding white crystals. The crystals so obtained were filtered and dried at 7O⁰C under vacuum to yield sildenafil esylate polymorph I.

EXAMPLE 16 ^{" " " ' "}

Preparation of sildenafil esylate polymorph III

2.0 g of sildenafil esylate polymorph IV were dissolved in 20 ml of acetonitrile and 1.0 ml of water under reflux conditions. The solution was then cooled to room temperature and stirred for about 12 hours, yielding white crystals. The crystals so obtained were filtered, yielding sildenafil esylate polymorph III.

EXAMPLE 17

Preparation of sildenafil esylate polymorph II

Mother liquor from filtration of polymorph III crystals in Example 16 was concentrated, yielding white crystals. This suspension was stirred at room temperature for 5-10 minutes. The crystals so obtained crystals were filtered, yielding sildenafil esylate polymorph II. EXAMPLE 18

Preparation of sildenafil esylate polymorph IV

1.8 g of sildenafil base was dissolved in 30 ml of acetonitrile under reflux conditions. About 23 ml of ethanesulfonic acid solution in acetonitrile (about 0.2 mol/1) was added and the solution formed after addition was stirred at the same temperature for about 1 hour. The solution was cooled to room temperature and stirred for about 12 hours, yielding white crystals. The crystals so obtained were filtered, washed with acetonitrile and dried at 4O⁰C under vacuum to yield sildenafil esylate polymorph IV.

EXAMPLE 19

Preparation of sildenafil fumarate polymorph I

0.25 g of sildenafil base was dissolved in 5.0 ml of acetonitrile under reflux conditions. About 3.2 ml of fumaric acid solution in ethanol (about 0.2 mol/1) was added and the solution formed after addition was stirred at the same temperature for about 2 hours. This solution was then cooled to room temperature and stirred for about 12 hours, yielding white crystals. The crystals^" so obtained were filtered and dried at 70°C under vacuum to yield sildenafil fumarate polymorph I.

Claims

1. A pharmaceutically acceptable salt of sildenafil, wherein said salt is formed between sildenafil free base and a pharmaceutically acceptable acid selected from the group consisting of hydrochloric acid, sulphuric acid, ethanesulphonic acid, tartaric acid and fumaric acid.

2. Sildenafil hydrochloride.

3. Sildenafil hydrogensulphate.

4. Sildenafil hemisulphate.

5. Sildenafil hemitratrate.

6. Sildenafil esylate.

7. Sildenafil fumarate.

8. Polymorph I of sildenafil hydrochloride characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 1.

9. Polymorph I of sildenafil hydrochloride characterised as having characteristic peaks (2Θ): 10.9+0.2°, 13.7+0.2°, 15.0+0.2°, 18.0±0.2° and 19.0+0.2°.

10. A polymorph according to claim 9, further characterised by peaks (2Θ) selected from one-or. more of the following: 3.9°+0.2°, 11.8+0.2°, 14.0+0.2°, 21.3+0.2° and 23.7±0.2°.

11. Polymorph I of sildenafil hydrochloride characterised by a differential scanning calorimetry (DSC) thermogram as shown in Figure 2.

12. A polymorph according to claim 11 having a characteristic differential scanning calorimetry (DSC) endotherm at about 236°C.

13. Polymorph I of sildenafil hydrochloride having a vapour sorption of about 1.82% at about 80% relative humidity (RH).

14. Polymorph I of sildenafil hydrochloride having an intrinsic dissolution rate of about 11.10 mg/mincm , measured using ID apparatus substantially as described herein, at a rotation speed of about 100 rpm, in about 900 ml of an acidic medium having a pH of about 1.2.

15. Polymorph I of sildenafil hydrochloride having an intrinsic dissolution rate of about 10.51 mg/mincm², measured using ID apparatus substantially as described herein, at a rotation speed of about 100 rpm, in about 900 ml of an medium having a pH of about 5.5.

16. Polymorph II of sildenafil hydrochloride characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 3.

17. Polymorph II of sildenafil hydrochloride characterised as having characteristic peaks (2Θ): 6.7°±0.2°, 10.0°±0.2°, 13.3±0.2° and 14.0°±0.2.

18. A polymorph according to claim 17, further characterised by peaks (20) selected from one or more of the following: 15.0°±0.2°, 15.4°±0.2°, 15.5°±0.2° and 22.0°±0.2°.

19. Polymorph III of sildenafil hydrochloride characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 4.

20. Polymorph III of sildenafil hydrochloride characterised as having characteristic peaks (2Θ): 6.3°±0.2°, 7.2°±0.2° and 15.6°±0.2°.

21. A polymorph according to claim 20, further characterised by peaks (2Θ) selected from one or more of the following: 9.4°±0.2°, 12.0°±0.2°, 12.6°±0.2°, 14.4°±0.2°, 19.6°+0.2°, 20.2°±0.2° and 23.3°±0.2°.

22. Polymorph I of sildenafil hydrogensulphate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 5.

23. Polymorph I of sildenafil hydrogensulphate characterised as having characteristic peaks (2Θ): 6.3°±0.2°, 6.9°±0.2°, 12.5°+0.2°, 16.3°±0.2°, 19.1°±0.2° and 22.1°±0.2°.

24. A polymorph according to claim 23, further characterised by peaks (2Θ) selected from one or more of the following: 9.3°±0.2°, 13.1°±0.2°, 17.8°±0.2° and 18.0°±0.2°.

25. Polymorph II of sildenafil hydrogensulphate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 6.

26. Polymorph II of sildenafil hydrogensulphate characterised as having characteristic peaks (2Θ): 7.2°±0.2°, 9.0°±0.2°, 13.6°±0.2° and 23.4°±0.2°.

27. A polymorph according to claim 26, further characterised by peaks (2Θ) selected from one or more of the following: 5.6°±0.2°, 6.3°±0.2°, 8.2°±0.2°, 11.3°±0.2°, 16.3°+0.2° and 17.3°±0.2°.

28. Polymorph II of sildenafil hydrogensulphate having an intrinsic dissolution rate of about 9.94 mg/mincm², measured using ID apparatus substantially as described herein, at a rotation speed of about 100 rpm, in about 900 ml of an medium having a pH of about 6.4.

29. Polymorph III of sildenafil hydrogensulphate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 7.

30. Polymorph III of sildenafil hydrogensulphate characterised as having characteristic peaks (2Θ): 7.1°+0.2°, 16.0°+0.2°, 20.5°±0.2° and 22.6°±0.2°.

31. A polymorph according to claim 30, further characterised by peaks (20) selected from one or more of the following: 8.1°±0.2°₅ 11.4°±0.2° , 12.1°±0.2° , 13.4°±0.2° , 15.6°±0.2° and 16.2°±0.2°.

32. Polymorph III of sildenafil hydrogensulphate characterised by a differential scanning calorimetry (DSC) thermogram as shown in Figure 8.

33. A polymorph according to claim 32 having a characteristic differential scanning calorimetry (DSC) endotherm at about 116°C.

34. Polymorph III of sildenafil hydrogensulphate having a vapour sorption of about 1.41% at about 90% relative humidity (RH).

35. Polymorph III of sildenafil hydrogensulphate having an intrinsic dissolution rate of about 7.3 mg/mincm², measured using ID apparatus substantially as described herein, at a rotation speed of about 100 rpm, in about 900 ml of an acidic medium having a pH of about 1.2.

36. Polymorph I of sildenafil hemisulphate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 9.

37. Polymorph I of sildenafil hemisulphate characterised as having characteristic peaks (20): 8.1°±0.2°, 10.3°±0.2°, 16.2°±0.2°, 17.1°±0.2°, and 24.9°±0.2°.

38. A polymorph according to claim 37, further characterised by peaks (20) selected from one or more of the following: 6.8°+0.2°, 12.6°±0.2°, 16.0°±0.2°, 21.9°±0.2° and 23.2°±0.2°.

39. Polymorph I of sildenafil hemisulphate characterised by a differential scanning calorimetry (DSC) thermogram as shown in Figure 10.

40. A polymorph according to claim 33 having a characteristic differential scanning calorimetry (DSC) endotherm at about 22O⁰C.

41. Polymorph I of sildenafil hemitartrate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 11.

42. Polymorph I of sildenafil hemitartrate characterised as having characteristic peaks (2Θ): 5.5°±0.2°, 12.1°±0.2° and 17.4°±0.2°.

43. A polymorph according to claim 42, further characterised by peaks (2Θ) selected from one or more of the following: 8.0°±0.2°, 9.2°±0.2°, ll.l^o+0.2°, 14.2°±0.2°, 15.7°+0.2°, 16.0°±0.2° and 19.9°±0.2°.

44. Polymorph I of sildenafil hemitartrate characterised by a differential scanning calorimetry (DSC) thermogram as shown in Figure 12.

45. A polymorph according to claim 44 having a characteristic differential scanning calorimetry (DSC) endotherm at about 231°C.

46. Polymorph I of sildenafil hemitartrate having a vapour sorption of about 0.22% at about 90% relative humidity (RH).

47. Polymorph I of sildenafil hemitartrate having an intrinsic dissolution rate of about 10.13 mg/mincm², measured using ID apparatus substantially as described herein, at a rotation speed of about 100 rpm, in about 900 ml of an acidic medium having a pH of about 1.2.

48. Polymorph II of sildenafil hemitartrate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 13.

49. Polymorph II of sildenafil hemitartrate characterised as having characteristic peaks (2Θ): 5.2°±0.2°, 7.2°+0.2°, 12.3°±0.2° and 21.6°±0.2°.

50. A polymorph according to claim 49, further characterised by peaks (2Θ) selected from one or more of the following: 5.6°±0.2°, 8.1°±0.2°₅ 9.1°±0.2°, 15.6°±0.2°₅ 16.0°±0.2° and 19.8°±0.2°.

51. Polymorph I of sildenafil esylate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 14.

52. Polymorph I of sildenafil esylate characterised as having characteristic peaks (2Θ): 8.2°+0.2°, 13.6°±0.2°, 16.2°±0.2°, and 24.9°±0.2°.

53. A polymorph according to claim 52, further characterised by peaks (2Θ) selected from one or more of the following: 6.8°±0.2°, 9.4°±0.2°, 9.8°±0.2°, 11.9°±0.2°, 12.5°±0.2° and 19.0°+0.2°.

54. Polymorph I of sildenafil esylate characterised by a crystalline structure substantially as shown in Figure 15.

55. Polymorph I of sildenafil esylate characterised by triclinic space group Pl displaying unit cell parameters comprising crystal axis lengths of a = 10.06+O.OlA, b = 10.90+O.OlA, c = 14.17±0.0lA and angles between the crystal axes of α = 83.09+0.01°, β = 68.79±0.01° and γ = 93.15+0.01°.

56. Polymorph I of sildenafil esylate having a vapour sorption of about 0.27% at about 80% relative humidity (RH).

57. Polymorph I of sildenafil esylate having an intrinsic dissolution rate of about 4.82 mg/mincm², measured using ID apparatus substantially as described herein, at a rotation speed of about 100 rpm, in about 900 ml of an medium having a pH of about 6.4.

58. Polymorph II of sildenafil esylate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 16.

59. Polymorph II of sildenafil esylate characterised as having characteristic peaks (2Θ): 4.6°±0.2°, 10.5°±0.2°, 11.4°±0.2° and 18.4°±0.2°.

60. A polymorph according to claim 59, further characterised peaks (2Θ) selected from one or more of the following: 6.0°±0.2°, 9.1°±0.2°, 9.9°±0.2°, 15.3°±0.2°₅ 20.3°±0.2° and 21.0°+0.2°.

61. Polymorph III of sildenafil esylate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 17.

62. Polymorph III of sildenafil esylate characterised as having characteristic peaks (2Θ): 6.0°±0.2°, 9.9°±0.2°, 11.9°±0.2° and 22.2°±0.2°.

63. A polymorph according to claim 62, further characterised by peaks (2Θ) selected from one or more of the following: 8.4°±0.2°, 14.2°+0.2°, 16.2°±0.2°, 17.9°±0.2°, 20.3°±0.2° and 23.6°±0.2°.

64. Polymorph IV of sildenafil esylate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 18.

65. Polymorph IV of sildenafil esylate characterised as having characteristic peaks (2Θ): l l.l°±0.2°, 13.8°±0.2°, 15.F±0.2°, and 23.4^o±0.2°.

66. A polymorph according to claim 65, further characterised by peaks (2Θ) selected from one or more of the following: 4.6°+0.2°, 9.2°±0.2°, 12.3°±0.2°, 16.2°±0.2°, 18.4°±0.2° and 21.2°±0.2°.

67. Polymorph IV of sildenafil esylate having a vapour sorption of about 0.38% at about 70% relative humidity (RH).

68. Polymorph I of sildenafil fumarate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 19.

69. Polymorph I of sildenafil fumarate characterised as having characteristic peaks (2Θ): 7.6°±0.2°, 9.3°±0.2°, 14.7°±0.2°, 15.7°±0.2° and 24.0°+0.2°.

70. A polymorph according to claim 69, further characterised by peaks (2Θ) selected from one or more of the following: 8.5°±0.2°, 12.8°±0.2°, 16.9°±0.2°, 18.2°±0.2° and 21.0°±0.2°.

71. A process of preparing a pharmaceutically acceptable salt of sildenafil according to any of claims 1 to 7, which process comprises treating sildenafil free base with a pharmaceutically acceptable acid selected from the group consisting of hydrochloric acid, sulphuric acid, ethanesulphonic acid, tartaric acid and fumaric acid.

72. A process according to claim 71, which provides said pharmaceutically acceptable salt of sildenafil in a first polymorphic form according to any of claims 8-15, 19-21, 22-28, 36-47 and 64-70.

73. A process of polymorph interconversion, which process comprises converting said first polymorphic form of a pharmaceutically acceptable salt of sildenafil according to claim 71 to a further polymorphic form of said pharmaceutically acceptable sildenafil salt according to any of claims 16-18, 29-35 and 48-63.

74. A pharmaceutical composition comprising a therapeutically effective dose of a sildenafil salt according to any of claims 1 to 7, or a polymorphic form thereof according to any of claims 8 to 70, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

75. A sildenafil salt form according to any of claims 1 to 70, for use in therapy.

76. Use of a sildenafil salt form according to any of claims 1 to 70, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of a selective inhibitor of cyclic guanosine monophosphate (cGMP) - specific phophodiesterase type 5 (PDE5).

77. A use according to claim 76, wherein the disease state is selected from the group consisting of stable, unstable and variant (Prinzmetal) angina, hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, diseases characterized by disorders of gut motility, male erectile dysfunction and female sexual disorders.

78. Use according to claim 76 or 77, wherein said disease state is male erectile dysfunction.

79. A method of treating a disease state prevented, ameliorated or eliminated by the administration of a selective inhibitor of cyclic guanosine monophosphate (cGMP) - specific phophodiesterase type 5 (PDE5), in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of a sildenafil salt form according to any of claims 1 to 70.

80. A method according to claim 79, wherein the disease state is selected from the group consisting of stable, unstable and variant (Prinzmetal) angina, hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, diseases characterized by disorders of gut motility, male erectile dysfunction and female sexual disorders.

81. A method according to claim 79 or 80, wherein said disease state is male erectile dysfunction.

82. Use of a sildenafil salt form according to any of claims 1-70 for the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of a selective inhibitor of cyclic guanosine monophosphate (cGMP) - specific phophodiesterase type 5 (PDE5), wherein said sildenafil salt form provides an enhanced therapeutic effect compared to the therapeutic effect provided by sildenafil citrate.

83. A use according to claim 82, wherein the disease state is selected from the group consisting of stable, unstable and variant (Prinzmetal) angina, hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, diseases characterized by disorders of gut motility, male erectile dysfunction and female sexual disorders.

84. Use according to claim 82 or 83, wherein said disease state is male erectile dysfunction.