PHARMACEUTICALLY ACCEPTABLE CO- CRYSTALLINE FORMS OF SILDENAFIL

The present invention is concerned with co-crystalline forms of sildenafil, processes of preparing such co-crystalline forms, pharmaceutical compositions containing the same, therapeutic uses thereof and methods of treatment employing the same.

The majority of drug substances are solid at room temperature and their use in crystalline form is often preferred due to their relative ease of isolation, the removal of impurities inherent in the crystallization process and the physico-chemical stability that the crystalline solid state generally affords. Despite the desirability of employing drug substances in crystalline form as above, this is often counter-balanced by problems associated with the physical properties of known crystalline forms of a drug substance, including, inter alia, poor solubility, stability, hygroscopicity, dissolution rate and other associated performance characteristics. In particular, poor solubility can often impede development of a drug substance and significantly lower the market value thereof and poorly soluble drug substances are often estimated to represent about 60% of APIs (active pharmaceutical ingredients) in development and also many major marketed drugs.

Traditionally, these problems that have been associated with the physical properties of a drug substance have been alleviated to date, for example, by the provision of the drug substance in an advantageous salt form, or by the provision of the drug substance as an alternative polymorph or pseudopolymorph, or by the use of an improved final dosage form. Recently, however, the provision of drug substances in co-crystalline forms has been investigated as an alternative approach to modify or control the physical properties of a drug substance. In particular, co-crystallization has been considered as a possible strategy for poorly soluble drug substances that do not form salts with acceptable physicochemical properties, or for drug substances that cannot be made amorphous to improve their physicochemical properties, or for non-ionizable drug substances. Co-crystallization can also be used to isolate or purify a drug substance during manufacturing and a co-crystal former (as hereinafter described) may be recycled. Co-crystallization may also be used for chiral resolution, or to enable drug substances hitherto only known to be amorphous to be crystallized as co-crystals.

Pharmaceutical co-crystals are crystalline molecular complexes that contain the drug substance along with at least one additional complementary molecule (guest) present in the same crystal structure. The additional molecule or guest has been described in the literature as a co-crystal former. A co-crystal can thus be seen to be a multiple component crystal in which a co-crystal former forms a supramolecular synthon with the drug substance and wherein the co-crystal former can be selected to provide advantageous or improved properties to the drug substance, when present in the co-crystalline structure. The drug substance and co-crystal former interact in the forming of such a supramolecular synthon by way of molecular recognition and self assembly, for example by way of hydrogen bonding, and possibly other non-covalent interactions (such as pi-stacking, guest- host complexation, van der Waals interactions and the like), rather than by ion-pairing. In this way, the molecular components of the co-crystal, and in particular the drug substance present in the co- crystal, are not modified covalently. A drug substance, either present as a free acid or free base, or present as a pharmaceutically acceptable salt, can be co-crystallized in this way with a co-crystal former.

The complex nature of API structures means that they inherently contain exterior functional groups that engage in molecular recognition events. Indeed, it is the very presence of these functional, groups that affords biological activity that also provides an ability to interact with itself or with a co- crystal former to form a co-crystal. It is well known in the art that there are two basic types of molecular recognition involved in the formation of co-crystals and also polymorphs. More specifically, functional groups that are self-complementary are capable of forming supramolecular homosynthons (for example, carboxylic acid moieties and amide moieties can form homodimers) and it is also possible for functional groups to engage with different but complementary functional groups to form supramolecular heterosynthons.

These supramolecular intermolecular interactions present in a co-crystal or co-crystalline form can result in several different intermolecular configurations. For example, the co-crystal intermolecular interactions can result in the formation of dimers, linear chains, or cyclic structures. These configurations can further include extended (two-dimensional) networks and isolated triads. As. explained above, the co-crystal intermolecular interactions do not involve ion-pairing and generally include hydrogen bonds, but other modes of molecular recognition may also be present in co- crystalline forms including, pi-stacking, guest-host complexation and van der Waals interactions.

Co-crystalline forms of a drug substance can have different chemical and physical properties compared to the properties of the drug substance when present in a mono-crystalline form, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapour pressure and density. These properties can have a direct effect on the ability to process and / or manufacture a drug substance and the corresponding finalised dosage form, as well as an effect on drug product stability, dissolution and bioavailability. Thus co-crystallization can affect the quality, safety and efficacy of a drug substance. It should be emphasized, however, that the final properties of a co-crystalline form of a drug substance cannot be predicted on the basis of known properties of the drug substances, or the known properties of a co-crystal former, and as such predictions as to co-crystal formation and the associated properties thereof cannot be made on the basis of what is known for the drug substance or co-crystal former in mono-crystalline form.

Examples of known co-crystals may be found in the Cambridge Structural Database. Examples of co-crystals may also be found in Etter et al.,"The use of cocrystallization as a method of studying hydrogen bond preferences of 2- aminopyridine"J. Chem.Soc.Chem. Commuii. 589-591 (1990); Etter et al.," Graph-set analysis of hydrogen-bond patterns in organic crystals" Acta Crystallogr., Sect. B, Struct. Sci. B46 256-262 (1990); Etter et al.," ^" Hydrogen bond directed cocrystallization and molecular recognition properties of diarylureas" J. Am. Chem.Soc 112 8415-8426 (1990). See also,. Gorbotz et al.,"On the inclusion of solvent molecules in the crystal structures of organic compounds'αcta Cryst. B56 625-534 (2000); and Kumar, et al., "Molecular Complexes of Some Mono- and Dicarboxylic Acids with trans-1, 4,-Dithiane-l, 4-dioxide" American Chemical Society, Crystal Growth & Design, Vol. 2, No. 4 (2002).

There are a number of methods that can be used to characterise co-crystalline forms of a drug substance. Demonstration of a co-crystalline structure by single crystal X-ray diffraction is currently regarded as the definitive method. X-ray powder diffraction can also be used to support the existence of a co-crystal. 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, solid-state nuclear magnetic resonance (ssNMR)), are also helpful to further characterise co-crystalline forms.

Sildenafil is chemically designated as l-[[3-(6,7-dihydro-l-methyl-7-oxo-3-propyl-lH-pyrazolo[4,3- ifjpyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4-niethylpipera zine 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 thus 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 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 characterized 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.

Sildenafil citrate has 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 recognized 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 absorption of such drugs. For certain poorly soluble drugs it has been necessary to increase the dose thereof to obtain the efficacy required.

We have now found that the provision of sildenafil in a co-crystalline form can provide improved solubility of the sildenafil under acidic conditions (as present in the stomach) when compared to commercially available sildenafil citrate. This observed improved solubility of sildenafil when provided in a co-crystalline form according to the present invention under acidic conditions is predictive of both an enhanced absorption, especially from the gastrointestinal tract, and an enhanced bioavailability. Such improved solubility of sildenafil as provided by the present invention can be particularly advantageous for orally-administrable formulations of sildenafil.

There is now provided by the present invention, therefore, sildenafil with improved properties, particularly in terms of its solubility in acidic conditions. More specifically, we have now surprisingly found that sildenafil provided in a co-crystalline form with a co-crystal former, exhibits beneficial properties and in particular provides advantages over commercially available sildenafil citrate.

There is now provided by the present invention, therefore, a co-crystal comprising at least one target drug substance and a co-crystal former, characterized in that the target drug substance comprises sildenafil, or a pharmaceutically acceptable salt thereof.

As used herein, the term "target drug substance" denotes the drug substance component of the co- crystal, which has been identified as a candidate for improvement of the physical properties thereof, by incorporation into a co-crystalline form or structure. This wording is intended to distinguish the target drug substance from a further drug substance which may also be present in the co-crystal former of the co-crystal, substantially as hereinafter described. In the context of the present invention, the target drug substance is sildenafil and it is preferred that sildenafil is present as the free base in a co-crystal according to the present invention. As explained above and also as hereinafter described in further detail, sildenafil as provided in a co-crystalline form or structure according to the present invention exhibits improved solubility under acidic conditions when compared to commercially available sildenafil citrate.

According to the present invention, therefore, there is provided sildenafil, or a pharmaceutically acceptable salt thereof, present in a co-crystalline form or structure. More specifically, there is

provided by the present invention a co-crystal comprising sildenafil, or a pharmaceutically acceptable salt thereof, together with a co-crystal former.

As used herein, the terms "co-crystal", "co-crystalline form" or "co-crystalline structure" are used interchangeably to denote crystalline molecular complexes that contain the drug substance along with at least one additional molecule (co-crystal former) present in the same crystal structure. The drug substance and co-crystal former interact to form a supramolecular synthon by way of molecular recognition and self assembly, for example by way of hydrogen bonding, and possibly other non- covalent interactions (such as pi-stacking, guest-host complexation, van der Waals interactions and the like), rather than by ion-pairing.

As used herein, the terms "API" and "drug substance" are also used interchangeably and denote an active pharmaceutical ingredient.

The terms "intermolecular interactions characteristic of the bonding in a co-crystal", "supramolecular intermolecular interactions" or "co-crystal intermolecular interactions", as used herein denote the above described non-ionic, non-covalent bonding seen to be present in a co-crystal. More specifically, this wording covers the above referred to hydrogen bonding, and possibly other non-covalent interactions, for example, pi-stacking, guest-host complexation, van der Waals interactions and the like.

As used herein, the term "co-crystal former" denotes one or more additional molecules present in the same crystal structure as the target drug substance as described above, which one or more additional molecules are capable of forming a supramolecular synthon with the drug substance by way of the intermolecular interactions characteristic of the bonding in a co-crystal. Furthermore, a co-crystal former can be selected to provide advantageous or improved properties to the target drug substance, when the latter is present in the co-crystal structure compared to the properties thereof when present in mono-crystalline form. Preferably in accordance with the present invention, therefore, the co- crystal former is selected to be a polar component, which can impart improved solubility properties to sildenafil, or a salt thereof, when present in a co-crystal of the present invention.

According to the present invention, therefore, the co-crystal former can comprise one or more complementary molecules capable of forming a co-crystal structure with sildenafil, or a pharmaceutically acceptable salt thereof, which can interact directly or indirectly with sildenafil, or a pharmaceutically acceptable salt thereof, by way of the above described co-crystal intermolecular interactions. In the case of indirect interaction of the co-crystal former with sildenafil, or a pharmaceutically acceptable salt thereof, the co-crystal former may interact with a spacer or linker molecule by way of the above described co-crystal intermolecular interactions, which spacer or linker molecule can similarly interact with sildenafil, or a pharmaceutically acceptable salt thereof, or may be ionically or covalently bonded thereto. In certain preferred embodiments, it may be that the co-crystal former can comprise an additional drug substance selected so as to optimize an identified physical property of the target drug substance and also to provide in combination with the target drug substance a combined, dual or synergistic therapeutic effect for a patient group, which would benefit from such combined therapeutic treatment. Alternatively, it may be that the co-crystal former is selected from a pharmaceutically acceptable excipient, capable of forming a co-crystal with the target drug substance, which in the case of the present invention is sildenafil, or a pharmaceutically acceptable salt thereof.

Typically, a co-crystal former present in a co-crystal in accordance with the present invention can comprise one or more molecules having at least one synthon forming moiety selected from the following group: ether, thioether, alcohol, carbonyl, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulphate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulphonic acid, sulphonamide, amide, primary amine, secondary amine, ammonia, tertiary amine, imine, thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-containing heterocyclic ring (such as thiophene), N-containing heterocyclic ring (such as pyrrole, imidazole or pyridine), O-containing heterocyclic ring (such as furan, epoxide or peroxide) and hydroxamic acid moieties. Suitably, the co-crystal former can include one or more of the following types of molecules: organic acids, organic bases, organic salts, alcohols, aldehydes, amino acids, sugars, ionic inorganic compounds, aliphatic esters and ketones, and aromatic esters and ketones.

Substantially as hereinbefore described, it is preferred that in accordance with the present invention the co-crystal former is selected to be a polar component, which can impart improved solubility

properties to sildenafil, or a salt thereof, when present in a co-crystal of the present invention. In particular, as provided by the present invention sildenafil, or a pharmaceutically acceptable salt thereof, when present in a co-crystalline form or structure, has been found to exhibit a significantly improved intrinsic dissolution rate (IDR) compared to sildenafil citrate and the polar co-crystal former is preferably selected so as to impart this improved dissolution rate to the co-crystalline sildenafil.

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 cm ² and specific apparatus and measurement conditions are hereinafter described in greater detail, with specific reference to the results obtained for intrinsic dissolution as illustrated by Figure 7 and the apparatus shown in Figure 8.

Co-crystalline sildenafil as provided by the present invention preferably has an intrinsic dissolution rate of at least about 7mg/mincm ² , 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, co-crystalline sildenafil as provided by the present invention has an intrinsic dissolution rate of at least about 8mg/mincm ² , still more preferably at least about 9mg/mincm ² , still more preferably at least about lOmg/mincm ² and still more preferably at least about 1 lmg/mincm ² .

According to a particularly preferred embodiment of the present invention the co-crystal former selected to provide sildenafil, or a pharmaceutically acceptable salt thereof, in a co-crystalline form

or structure having the above advantageous dissolution properties comprises acetylsalicylic acid, also known under the international non-proprietary name of aspirin. Specifically, therefore, the present invention provides a co-crystal comprising sildenafil acetylsalicylic acid, where preferably the sildenafil is present as its free base form. Preferably, the co-crystal of the present invention consists essentially of sildenafil acetylsalicylic acid and even more preferably the sildenafil acetylsalicylic acid co-crystal as provided by the present invention is monomorphic.

It is particularly preferred that a co-crystal comprising sildenafil acetylsalicylic acid as provided by the present invention has an intrinsic dissolution rate of about 11.75mg/mincm ² , 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.

A co-crystal comprising sildenafil acetylsalicylic acid according to the present invention also has an intrinsic dissolution rate of about 0.47 mg/mincm in 1.2% NaCl solution.

A comparison of the intrinsic dissolution rate of a sildenafil acetylsalicylic acid co-crystal according to the present invention and sildenafil citrate is given in the following table under different pH conditions:

The present invention also provides a process of improving the solubility and / or intrinsic dissolution rate of sildenafil, or a pharmaceutically acceptable salt thereof, in an acidic medium, which process comprises providing sildenafil, or a pharmaceutically acceptable salt thereof, in a co- crystal together with a co-crystal former substantially as described herein. Preferably, the co-crystal former comprises acetylsalicylic acid.

There is also provided by the present invention use of acetylsalicylic acid to improve the solubility and / or intrinsic dissolution rate of sildenafil, or a pharmaceutically acceptable salt thereof, in an acidic medium, characterized in that said acetylsalicylic acid is employed as a co-crystal former in a co-crystal with sildenafil, or a pharmaceutically acceptable salt thereof.

A co-crystal comprising sildenafil acetylsalicylic acid according to the present invention can be further characterized as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 1.

A co-crystal comprising sildenafil acetylsalicylic acid according to the present invention can be still further characterized as having characteristic peaks (2θ): 7.3°±0.2°, 12.8°+0.2°, 16.2°+0.2° and 22.9°+0.2°. Further peaks (2θ) associated with a co-crystal comprising sildenafil acetylsalicylic acid according to the present invention are: 11.6°±0.2°, 12.6°±0.2°, 16.4°±0.2°, 16.6°±0.2°, 18.3°±0.2° and 24.6°±0.2°.

The crystalline structure of a co-crystal comprising sildenafil acetylsalicylic acid according to the present invention is shown in Figure 2. This is further characterized by a triclinic space group P 1 and by displaying unit cell parameters comprising crystal axis lengths of a = 9.67±0.01 A ₅ b = 12.31±0.0lA, c = 14.54±0.0lA and angles between the crystal axes of α = 85.26±0.01°, β = 74.55±0.01° and γ = 82.83±0.01°. The crystalline structure of the sildenafil acetylsalicylic acid co- crystal is further characterized by the following properties:

Empirical formula C ₃₁ H ₃₈ N ₆ O ₈ S

Formula weight 654.73

Volume 1653.1(2)A ³

Z, Calculated density 21.315 g/cm ³

Wavelength 1.54184 A

A co-crystal comprising sildenafil acetylsalicylic acid according to the present invention is further characterized by a typical DSC thermograph as shown in Figure 3. A co-crystal comprising sildenafil acetylsalicylic acid according to the present invention has a characteristic DSC melting endotherm in the range of 144-151 ⁰ C and a melting point of about 147 ⁰ C.

A co-crystal comprising sildenafil acetylsalicylic acid according to the present invention is further characterized by a typical TGA thermograph as shown in Figure 4. As used herein, the term "TGA" refers to thermogravimetric analysis. TGA is a measure of the thermally induced weight loss of a material as a function of the applied temperature. TGA is restricted in transitions that involve either a gain or a loss of mass and it is most commonly used to study desolvation processes and compound decomposition.

A co-crystal comprising sildenafil acetylsalicylic acid according to the present invention is further characterized by a TGA weight loss of about 0.06 % over the temperature range of about 30-150 ⁰ C, which confirms that the sildenafil acetylsalicylic acid co-crystal as prepared according to the present invention is stable to a temperature of about 150° C.

A co-crystal comprising sildenafil acetylsalicylic acid according to the present invention is ^" still ^" further characterized as having an IR pattern, or substantially the same IR pattern, as shown in Figure 5. More particularly, a co-crystal comprising sildenafil acetylsalicylic acid according to the present invention has characteristic IR absorbance bands at about 1756 cm ^"1 and 1698 cm ^"1 . A co- crystal comprising sildenafil acetylsalicylic acid according to the present invention is further characterized by the following IR absorbance bands at about: 3305 cm ^"1 , 1600 cm ^"1 , 1492 cm ^"1 , 1458 cm ^"1 , 1352 cm ^"1 , 1278 cm ^"1 , 1221 cm ^"1 , 1191 cm ^"1 and 1164 cm ^"1 .

A co-crystal comprising sildenafil acetylsalicylic acid according to the present invention is still further characterized as having an NIR pattern, or substantially the same NIR pattern, as shown in Figure 6. More particularly, a co-crystal comprising sildenafil acetylsalicylic acid according to the present invention has characteristic NIR absorbance at about 8840 cm ^"1 , 8498 cm ^"1 , 7242 cm ^"1 , 6405 cm ^"1 , 6004 cm ^"1 , 5944 cm ^"1 , 5807 cm ^"1 , 5004 cm ^"1 ,4671 cm ^"1 ,4509 cm ^"1 , 4415 cm ^"1 and 4313 cm ^"1 .

A co-crystal comprising sildenafil acetylsalicylic acid according to the present invention can also be characterized by a dynamic vapour sorption (DVS) of about 2.432% at about 90% relative humidity (RH). DVS is a measure of the 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 (typically>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 ±0.1 ⁰ C. 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.

There is also provided by the present invention a process for preparing co-crystalline sildenafil substantially as hereinbefore described, which process comprises providing a first source comprising a target drug substance comprising sildenafil, or a pharmaceutically acceptable salt thereof, and a second source comprising a co-crystal former, contacting the first and second sources and causing co-crystalline sildenafil substantially as hereinbefore described to form.

In certain embodiments of a process as provided by the present invention co-crystalline sildenafil substantially as hereinbefore described is formed by solvent crystallization. A co-crystal former and the sildenafil are dissolved in a solvent and then crystallized by means such as cooling, evaporation, addition of a non-solvent, seeding or a combination of any of these techniques.

In an alternative embodiment of a process as provided by the present invention co-crystalline sildenafil substantially as hereinbefore described is formed by slurry conversion, wherein a co- crystal former and sildenafil are suspended in a non-solvent and stirred.

In an alternative embodiment of a process as provided by the present invention co-crystalline sildenafil substantially as hereinbefore described is formed by grinding of the solid components of the co-crystal structure, wherein a co-crystal former and sildenafil are ground together in a mill in a

process known as dry grinding. Optionally, a few drops of solvent may be added to the mixture in a process known as solvent drop grinding.

In an alternative embodiment of a process as provided by the present invention co-crystalline sildenafil substantially as hereinbefore described is formed by blending of powders, wherein a co- crystal former and sildenafil in powder form are mixed together.

In an alternative embodiment of a process as provided by the present invention co-crystalline sildenafil substantially as hereinbefore described is formed by heating, wherein a co-crystal former and sildenafil are mixed together and then heated.

In an alternative embodiment of a process as provided by the present invention co-crystalline sildenafil substantially as hereinbefore described is formed by melt crystallization, wherein a c- crystal former and sildenafil are mixed together and then heated at a temperature above their respective melting points.

According to a preferred embodiment of the present invention, co-crystalline sildenafil substantially as hereinbefore described is prepared by the following steps:

(i) Dissolving sildenafil, or a salt thereof in an appropriate solvent medium, optionally under reflux conditions;

(ii) Dissolving a co-crystal former in an appropriate solvent medium;

(iii) Mixing the resulting solutions obtained by steps (i) and (ii) followed by heating, typically with stirring, for approximately 2 hours; and

(iv) Causing co-crystalline sildenafil substantially as hereinbefore described to crystallize, by means such as cooling, evaporation, addition of a non-solvent, seeding or a combination of any of these techniques; and optionally

(v) Filtering and / or drying the resulting co-crystals.

Co-crystalline sildenafil as provided by the present invention is a selective inhibitor of cyclic guanosine monophosphate (cGMP) - specific phophodiesterase type 5 (PDE5) and is 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 characterized by disorders of gut motility, e.g. irritable bowel syndrome (IBS). Additionally, co- crystalline sildenafil can be used in the treatment of male erectile dysfunction and female sexual disorders.

The present invention further provides, therefore, a pharmaceutical composition comprising a therapeutically effective dose of co-crystalline sildenafil substantially as hereinbefore described, together with a pharmaceutically acceptable carrier, diluent or excipient therefor. Excipients are chosen according to the pharmaceutical form and the desired mode of administration. An excipient may be a co-crystal former, substantially as hereinbefore described.

As used herein, the term "therapeutically effective amount" means an amount or co-crystaimie sildenafil 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 co-crystalline sildenafil 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, co- crystalline sildenafil 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, co-crystalline sildenafil 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 co-crystalline sildenafil 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 co-crystalline sildenafil 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, co-crystalline sildenafil 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 co-crystalline sildenafil 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 co-crystalline sildenafil according to the present invention typically in conjunction with a sweetener, which is preferably calorie-free, optionally antiseptics such as methylparaben and propylparaben, as well as a flavoring and an appropriate colour.

Water-dispersible granules or powders can contain co-crystalline sildenafil 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.

Co-crystalline sildenafil 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 co-crystalline sildenafil substantially as hereinbefore described for use in therapy.

The present invention further provides co-crystalline sildenafil 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 phophodiesterase type 5 (PDE5). More specifically, the present invention provides co-crystalline sildenafil 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 ot 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 characterized 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), which method comprises administering to a patient in need of such treatment a therapeutically effective amount of co-crystalline sildenafil 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 characterized 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 co-crystalline sildenafil substantially as hereinbefore described.

There is also provided by the present invention co-crystalline sildenafil 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 phophodiesterase type 5 (PDE5), wherein said sildenafil present in the co-crystal of the invention provides an enhanced therapeutic effect compared to the therapeutic effect provided by sildenafil, or a pharmaceutically acceptable salt thereof, when present in mono-crystalline form. The present invention also provides a corresponding method of treatment, which comprises administering to a patient a therapeutically effective amount of co-crystalline sildenafil substantially as hereinbefore described, so that the administered sildenafil, or pharmaceutically acceptable salt thereof, as present in a co-crystal according to the present invention provides an enhanced therapeutic effect to the patient, compared to the therapeutic effect provided by corresponding administration of sildenafil, or a pharmaceutically acceptable salt thereof, when present in mono-crystalline form.

As hereinbefore described, in certain preferred embodiments of the present invention it may be that the co-crystal former can comprise an additional drug substance selected so as to optimize an identified physical property of the target drug substance and also to provide in combination with the target drug substance a combined, dual or synergistic therapeutic effect for a patient group, which would benefit from such combined therapeutic treatment. A preferred sildenafil co-crystal as provided by the present invention comprises sildenafil acetylsalicylic acid and this can be employed in therapeutic uses and methods of treatment as provided by the present invention to provide a combined, dual or synergistic therapeutic effect as described above.

According to the present invention, there is, therefore, provided use of (i) sildenafil, or a pharmaceutically acceptable salt thereof, and (ii) acetylsalicylic acid, in the manufacture of a medicament for providing a combined therapeutic effect of sildenafil, or a pharmaceutically acceptable salt thereof, and acetylsalicylic acid, in a single dosage form, wherein said sildenafil, or a

pharmaceutically acceptable salt thereof, and acetylsalicylic acid, are present in a co-crystalline form. The present invention also provides a corresponding method of treatment, which comprises administering to a patient a therapeutically effective amount of a co-crystal comprising sildenafil acetylsalicylic acid substantially as hereinbefore described, so that the administered sildenafil, or pharmaceutically acceptable salt thereof, and administered acetylsalicylic acid, present in a single dosage form, provide a combined, dual or synergistic therapeutic effect to the patient.

In particular, acetylsalicylic acid is known to provide a protective cardiac effect to particular risk groups susceptible to cardiac disease or cardiovascular events and in this way a co-crystal comprising sildenafil acetylsalicylic acid according to the present invention can provide a combined therapeutic effect, which includes a cardiac protective effect due to the presence of acetylsalicylic acid, in conjunction with selective inhibition of cyclic guanosine monophosphate (cGMP) - specific phophodiesterase type 5 (PDE5) due to the presence of sildenafil, or a pharmaceutically acceptable salt thereof. A particular patient group to be treated by this combined therapy includes elderly male patients requiring treatment for male erectile dysfunction with sildenafil, or a pharmaceutically acceptable salt thereof.

More specifically, the present invention provides use of a co-crystal comprising siiαenaπi acetylsalicylic acid as described herein for use in the manufacture of a medicament for the combined treatment of (i) male erectile dysfunction, and (ii) cardiac disease or cardiovascular events. There is similarly provided a corresponding method of treatment which comprises administering a co-crystal comprising sildenafil acetylsalicylic acid as described herein to a patient, so as to prevent, ameliorate or eliminate (i) male erectile dysfunction, and (ii) cardiac disease or cardiovascular events.

Specifically according to the present invention, there is provided use of a co-crystal comprising sildenafil acetylsalicylic acid as described herein for the manufacture of a medicament for the treatment of male erectile dysfunction, wherein the patient is an elderly male, typically of 50 years of age or older. A corresponding method of treatment comprises administering a co-crystal comprising sildenafil acetylsalicylic acid as described herein to an elderly male, typically of 50 years of age or older, to treat male erectile dysfunction.

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

With reference to the Figures, these are as follows:

Fig 1 : An X-ray powder diffraction pattern of a sildenafil acetylsalicylic acid co-crystal according to the present invention obtained by using a Philips X'Pert PRO with CnKa radiation in 2θ = 3-40 ° range.

Fig 2: The crystalline structure of a sildenafil acetylsalicylic acid co-crystal according to the present invention which is further characterized by atomic positions and other structural parameters obtained from the single crystal X-ray analysis.

Fig 3: A Differential Scanning Calorimetry (DSC) pattern of a sildenafil acetylsalicylic acid co- crystal according to the present invention obtained by 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.

Fig 4: A thermograph of a sildenafil acetylsalicylic acid co-crystal according to the present invention obtained by using TGA 7 manufactured by Perkin- Elmer. Experiment was done under flow of nitrogen (35 ml/min) and heating rate was 10 °C/min.

Fig 5: An IR pattern of a sildenafil acetylsalicylic acid co-crystal according to the present invention obtained by using a KBr pellet and Spectrum GX manufactured by Perkin- Elmer. Resolution was 4 cm ^"1

Fig 6: An NIR pattern of a sildenafil acetylsalicylic acid co-crystal according to the present invention obtained by using an MPA manufactured by Bruker. The spectrum was collected by solid probe and resolution was 8 cm ^'1 .

Fig 7: An Intrinsic Dissolution Rate (IDR) pattern for a sildenafil acetylsalicylic acid co-crystal according to the present invention compared to that for sildenafil citrate obtained by using ID apparatus described below at rotation speed of 100 rpm in 900 ml of an acidic medium, pH 1.2 (diluted hydrochloric acid). After 10 minutes the IDR of a sildenafil acetylsalicylic acid co-crystal

according to the present invention is approximately almost twice that of sildenafil citrate under the same conditions.

Fig 8: 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 75% of the compacted pellet can dissolve withoutialling 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 cm ² ). 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 cm ² , 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

4.0 g of sildenafil base and 1.7 g of acetylsalicylic acid were dissolved in 60 ml of toluene and 10 ml of acetonitrile at about 8O ⁰ C. The resulting solution was stirred at the same temperature for about 2 hours and then cooled to room temperature. After about 40 hours, white crystals were filtrated and dried at 50°C under vacuum to yield sildenafil acetylsalicylic acid co-crystal.

EXAMPLE 2

1.0 g of sildenafil base was dissolved in about 15 ml of 2-propanol under reflux conditions. About 4.3 ml of acetylsalicylic acid solution in acetonitrile (about 100 mg/ml) was added and solution was stirred at the same temperature for about 2 hours. The resulting solution was cooled to about 15°C yielding white crystals of sildenafil base. The obtained crystals were filtered and mother liquor was

left to slowly evaporate at room temperature for about 48 hours, yielding sildenafil acetylsalicylic acid single co-crystals.