This patent application claims the benefits of Indian provisional application 201 /MUM/2015 filed on Jan 20, 2015. FIELD OF INVENTION

The present invention is directed to novel synergistically active pharmaceutical compounds, such as a supramolecular complex or an adduct or a co-crystal comprising Ticagrelor and salts of aspirin. It also relates to processes for their preparation, pharmaceutical compositions comprising above novel compounds and their use as medicament.

BACKGROUND OF THE INVENTION

U.S. Patent Nos. 6,251 ,910 and 6,525,060 disclose a variety of triazolo [4,5-d] pyrimidine derivatives, processes for their preparation, pharmaceutical compositions and their use. Ticagrelor,(l S,2S,3R,5S)-3-[7-[{(l R,2S)-2-(3,4- difluorophenyl)cyclopropyl]amino-5-(propylthio)-3H- l ,2,3-triazolo[4,5-d] pyrimidine-3-yl]-5-(2-hydroxyethoxy)- l ,2-cyclopentanediol I, has the following chemical structure. Ticagrelor is currently marketed by AstraZeneca under the trade name BRILINTA and BRILIQUE. Its CAS Number is 274693-27-5. Ticagrelor is a reversibly binding oral P2Y| ₂ ADP receptor antagonist. Ticagrelor is indicated for the treatment or prevention of thrombotic events e.g. stroke, heart attack, acute coronary syndrome or myocardial infarction with ST elevation, other coronary artery diseases and arterial thrombosis plus other disorders related to platelet aggregation (WO 00/34283).

WO 99/05143 discloses a series of triazolo [4,5-dJpyrimidine compounds, including Ticagrelor 1. WO 01 /92262 and WO 2013/079589 disclose various crystalline and amorphous forms of Ticagrelor I . The co-crystal of Ticagrelor 1., with acetyl salicylic acid are reported in WO 2012/164286, whereas WO 2014/000719 reports co-crystals with 3-hydroxy-2-naphthoic acid and solvate with 1 ,4-dioxane. Recently, WO 2014/006091 has disclosed adducts with divalent metal salts as CaCl ₂ and MgCl ₂ .

Ticagrelor 1

Various crystalline forms of Ticagrelor are reported in WO2014/166337, whereas WO2015/014089 reports preparation and use of Ticagrelor monohydrate. WO2015/037016 reports formation of amorphous Ticagrelor via its ferulate salt.

Various processes for the preparation of Ticagrelor, its enantiomers and related intermediates, compounds, and their pharmaceutically acceptable salts are disclosed in U.S. Patents Nos. 6,251,910; 6,525,060; 6,974,868; 7,067,663 and 7,250,419; U.S. Patent Application Nos. 2007/0265282; 207/0293513; 2008/0214812; European Patent Nos. EP0996621 and EP 1 135391.

Other patents as WO2014/023681 ; WO2012/138981 ; US2012/032497; WO201 1/101740; WO201 1/017108; WO2008/018822; WO2008/18823; WO2012/001531 ; WO2013/144295 and WO2012/085665 describe synthetic aspects of Ticagrelor and its intermediates. The salts of some of the key intermediates are disclosed in U.S. Patent Nos. 2010/030224. Indian patent Application 3779/MUM/2013 discloses a methodology to manufacture and analyze highly pure key intermediate cyclopropylamine, without its urea analogue. Another Indian Patent . Application 1457/MUM/2014 and WO2015/ 162630 describe novel processes for preparing triazolo-[4,5-d]- pyrimidines, including Ticagrelor via several novel intermediates and via a new route of synthesis. Ticagrelor is a low solubility and low permeability active pharmaceutical ingredient (API) and is categorized as a class IV compound under the Biopharmaceutical Classification System (BCS). Such APIs are typically subjected to either salt formation or amorphous polymorph formation to improve their solubility and hence bioavailability. Another option and recently getting increasingly popular option is to form a co-crystal of the API. Recent Patent applications WO 2014/000719; WO 2014/006091 ; WO 2013/079589; WO 2012/164286 and WO201 1/067571 disclose a series of inventions on these lines.

A co-crystal is defined as a distinct solid form of the API that consists of a stoichiometric ratio of the API and a guest molecule (also known as co-former) to give a periodically repeating distinct crystalline form. Co-crystals typically provide desired physico-chemical properties with respect to APIs, without altering the chemical structure of API. Co-crystals are known to dissociate in solution at a rate faster than the time it takes for the API to reach the biologically active site. Thus, the therapeutic effect is delivered by the API alone. Co-crystals also affect manufacturability, stability, processing, solubility, dissolution profile, absorption, bioavailability and/or hygroscopicity in comparison to APIs. Additionally mention must be made that the invention of a co-crystal/adduct is not obvious, as per prior art. Lots of exploratory experimental work is required to get co-crystals. Recently, a guidance has been prepared by the Office of Pharmaceutical Sciences in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA) USA, for regulatory classification of Pharmaceutical co- crystals. Subsequently an international group of pharma-experts have recommended to define co-crystals more broadly and to classify them like salts and/or polymorphs in "Crystal Growth and Design, 2012, 12, 2147-2152", an American Chemical Society (ACS) group of publication. EP2340828, US2014/0024622, US2014/03501 10 have disclosed such novel synergistically active compounds, which fall into broad category of supramolecular complexes, adducts, co-crystals linked pro-drugs, mixed crystals and even simply mixtures, as novel pharmaceutical compounds. The use of aspirin or its salts (acetyl salicylic acid and its organic or inorganic salts) as a treatment for patients with, or at risk of a range of cardiovascular disease, is recognized as a worldwide standard of care. Dual platelet inhibition therapy with a P2Yi ₂ -inhibior such as Ticagrelor and acetyl salicylic acid is recognized as a worldwide standard care for patient with acute coronary syndrome. Although AstraZeneca has reported novel co-crystals of Ticagrelor with aspirin in WO2012/164286, but there are serious concerns regarding the quality of co-crystals disclosed, especially from the perspective of organic volatile impurity (OVFS), methylene chloride. Usually, methylene chloride is not a favoured solvent for bulk drug or novel compounds.

Compared to aspirin, the salts of aspirin may offer additional advantages. It is known that sodium salt of aspirin (sodium acetyl salicylate) improves the dissolution profile of organic compounds dramatically (Pal S. et al, J. Lipid Research 1983, 24(10), 1281-1290). Thus, there is a need in the prior art, for further improvement of dissolution profile of Ticagrelor by combining it with salts of aspirin.

The novel synergistically active pharmaceutical compound, such as a supramolecular complex or an adduct or a co-crystal, comprising Ticagrelor and salts of aspirin is chosen in such a way that if compared to Ticagrelor alone, the desired compound, according to invention, should show at least one, preferably more, of the following features (properties):

(a) should show increased or comparable solubility; and/or

(b) the dose response of compound is increased; and/or

(c) the dissolution of the compound is increased or comparable; and/or

(d) the efficacy of the compound is comparable or increased; and/or

(e) the bioavailability of the compound is increased or comparable or acceptable; and/or

(f) the stability of the compound is increased; and/or

(g) the hygroscopicity of the compound is decreased; and/or

(h) the form diversity of he compound is decreased; and/or (i) the morphology of the compound is improved; and/or

(j) the particle size of the compound is improved.

SUMMARY OF THE INVENTION

In a first aspect, the present invention is directed to a synergistically active pharmaceutical compound, such as a supramolecular complex or an adduct or a co-crystal comprising Ticagrelor and salts of aspirin. The present invention is also directed to preparation of such compounds by dissolving Ticagrelor and salts of aspirin in a suitable solvent and heating to reflux to get a clear solution. Cooling of this solution or cooling of concentrated solution or concentration and addition of anti-solvent and finally, precipitation, filtering and drying provides the desired compound.

In a preferred embodiment, the synergistically acting novel pharmaceutical compound, such as a supramolecular complex or an adduct or a co-crystal comprises Ticagrelor and sodium salt of aspirin (The Compound 1). The present invention is also related to pharmaceutical composition comprising above mentioned synergistically acting novel pharmaceutical compound and suitable additives (excipients) e.g. diluents, binders, disintegrates, lubricants, glidants, colorants, and combinations thereof.

In a second aspect, above novel pharmaceutical compound (The Compound 1) is a novel solid state forms, with distinct physico-chemical characteristics.

In a third aspect, 'The Compound shows superior or comparable in vitro and in vivo platelet inhibitory profile.

In a fourth aspect, a novel compound comprising physical mixtures of Ticagrelor and sodium salts of aspirin, in a molar ratio 1 :0.5 to 1 :5 are disclosed. In a fifth aspect, the invention relates to manufacture of medicament for use in prevention of arterial thrombotic complication in patients with coronary artery, cerebrovascular peripheral vascular disease and to methods of treating such disease in human or warm blooded animal body, by administering a therapeutically effective dose of these novel pharmaceutical compounds. BRIEF DESCRIPTION OF ACCOMPANYING FIGURES

Fig. 1 : XRPD data of 'The Compound 1 '

Fig. 2: XRPD data of physical mixture of Ticagrelor and sodium aspirin

Fig. 3: Ή NMR (400 MHz, DMSO-d ₆ ) of sodium aspirin (sodium acetyl salicylate)

Fig. 4: Ή NMR (400 MHZ, CDC1 ₃ ) data of 'The Compound 1 ' Fig. 5: FTIR spectra of 'The Compound 1 '

Fig. 6: FTIR spectra of sodium aspirin

Fig. 7: FTIR spectra of physical mixture of Ticagrelor and sodium aspirin Fig. 8: DTA and TGA of 'The Compound 1 '

Fig. 9: DSC spectra of 'The Compound Γ

Fig. 10: Solid state ¹³ C NMR of 'The Compound 1 '

Fig. 1 1 : Dissolution studies of 'The Compound in blank Fassif

Fig. 12: Dissolution studies of 'The Compound in SGF Fig. 13: In vitro studies data of 'The Compound and related compounds. This figure depicts the effects of ticagrelor, aspirin, ticagrelor+aspirin (1 : 10) and their samples (S I, S2) on ADP (20μΜ) and AA (0.5mM) induced platelet aggregation in in vitro study. IPA=Inhibition of platelet aggregation

Fig. 14: In vivo studies data of 'The Compound Γ and related compounds. This figure depicts the effects of Ticagrelor, aspirin, Ticagrelor+aspirin (1 : 10) and their samples (SI , S2) on ADP (20μΜ) and AA (0.5mM) induced platelet aggregation in in vitro study. IPA=Inhibition of platelet aggregation

Fig. 15: In vivo studies data of 'The Compound and related compounds. This figure depicts the effects of ticagrelor, aspirin, ticagrelor+aspirin (1 : 10) and their samples (SI, S2) on ADP (20μΜ) and AA (0.5mM) induced platelet aggregation in in vivo study. IPA=Inhibition of platelet aggregation DETAILED DESCRIPTION OF THE INVENTION

The present invention describes a synergistically active novel pharmaceutical compound or combination, in particular a supramolecular complex or an adduct or a co-crystal or a linked pro-drug, comprising Ticagrelor and salts of aspirin. The novel compound is a unique new molecular entity for the treatment of or prevention of arterial thrombotic complications e.g. stroke, heart attack, acute coronary syndrome or myocardial infarctions with ST elevation, other coronary artery disease and arterial thrombosis, plus other disorders related to platelet aggregation. One embodiment of the invention is directed to a physical combination comprising Ticagrelor and pharmaceutically acceptable salts of aspirin. Specifically, the pharmaceutically acceptable salt of aspirin is sodium salt of aspirin. More specifically, it is preferred that the two active agents are combined with each other in such a way that they form a new molecular entity in particular, a supramolecular complex or an adduct or a co-crystal, which has distinct and desirable physico-chemical properties, which are different compared to the above physical combination or to the ingredients individually.

Thus, the present invention is directed to a synergistically active compound (The Compound 1 ), in particular a supramolecular complex or an adduct or a co- crystal, comprising Ticagrelor and sodium salt of aspirin. The sodium salt of aspirin (sodium acetyl salicylate) is known to improve solubility of organic molecule dramatically (Pal S. et al, J. Lipid Research 1983, 24(10), 1281 -1290).

The present invention is further directed to linked pro-drug comprising Ticagrelor and salts of aspirin, more specifically sodium salt of aspirin, wherein both active agents are linked by a linking moiety. Thus, the two active components are linked to a linking moiety thereby creating a novel pharmaceutically active linked prodrug. Preferably, the linked pro-drug is substantially pure, as used herein, "substantially pure" refers at least 90%, more preferable at least 95% and most preferably at least 98% purity. As per one preferred embodiment of the present invention, the linked pro-drug has a structure such that the two components are linked to create a supramolecular complex or a co-crystal or an adduct.

For the purpose of the present invention, the term 'synergistically active compound' is intended to describe where the supramolecular complex or an adduct or a co-crystal has at least one or more, preferably more than one, of the following desirable physico-chemical properties such as:

(a) the solubility of 'active compound' is increased or comparable; and/or

(b) the dissolution of 'active compound' is increased or comparable; and/or (c) the dose response of 'active compound' is increased; and/or

(d) the efficacy of 'active compound' is comparable or increased; and/or

(e) the bioavailability of 'active compound' is increased or comparable or accepable; and/or

(f) the stability of 'active compound' is increased; and/or

(g) the hygroscopicity of 'active compound' is decreased; and/or

(h) the form diversity of active compound' is decreased; and/or

(i) the morphology of active compound' is modulated.

For the purpose of the present invention, the term 'compound' is intended to describe a chemical substance comprising covalent bonds within two pharmaceutically active agents, and non-covalent interactions between these two pharmaceutically active agents. Typically, 'hydrogen bonding', 'ionic bandings', 'van der Waals interactions', 'π-π stacking' etc. are involved in these 'non- covalent interactions' for the preparation of supramolecular complex, adducts or co-crystals, as novel synergistically active pharmaceutical compounds. In one embodiment, the synergistically active compound may be considered to be a linked pro-drug, whereby the linking moiety, such as a cation helps form prodrug, which are released in body once the linked pro-drug is ingested and absorbed. In a preferred embodiment, the synergistically active compound is a complex, in particular, a supramolecular complex.

For the purpose of the present invention, the term 'supramolecular complex' is intended to describe an interaction between the two pharmaceutically active agents or their salts, with cations and any other entity present such as a solvent or even water, by means of non-covalent, intermolecular bonding between them. These non-covalent interactions leads to an association of species, present in supramolecular complex, thereby distinguishing this complex as a novel (new) molecular entity, with unique network of interactions. The non-covalent intermolecular bonding can be any interactions known in the prior art to form such supramolecular complexes such as hydrogen bonding, van der Waals forces, π-π stacking, ionic interactions etc.

In a preferred embodiment, the present invention discloses a novel synergistically active pharmaceutical compound (The Compound 1), such as a supramolecular complex or an adduct or a co-crystal, comprising Ticagrelor with sodium salt of aspirin (sodium acetyl salicylate).

The supramolecular complex exist, preferably, in the solid state, which can be either crystalline, or partially crystalline, or amorphous or polymorphous or as a solvate, or hydrate or partially hydrates, or as mixed crystals or as a co-crystal. Typically, the synergistically active novel pharmaceutical compound shows properties such as melting points, IR, XRD, DSC, TGA, ¹³ C solid state NMR etc. which are different from the physical mixture of species.

In a preferred embodiment, the present invention describes novel solid forms of Ticagrelor, with above-mentioned synergistically active pharmaceutical compounds i.e. Ticagrelor with sodium salt of aspirin (The Compound 1).

The novel supramolecular complex/co-crystals/adducts pharmaceutical solid form is consistently reproducible to make, does not have tendency to convert to other biown solid state forms e.g. polymorph and is found to be more stable. The novel solid forms disclosed herein exhibit properties making it suitable for formulating Ticagrelor. These novel solid forms are essentially free from other crystalline or amorphous and solvates polymorphic forms known in earlier prior art of Ticagrelor.

The present invention also discloses various salts of aspirin, inorganic and/or organic ^' salts, which can be utilized to prepare synergistically active pharmaceutical compound with Ticagrelor. Some of the organic salts, but not limited to, could be morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di-, or tri-lower alkyl amine, e.g. ethyl-, tert-butyl, diethyl-, diisopropyl-, triethyl-, tirbutyl-, or dimethylpropylamine, or a mono-, di- or trihydroxyl lower alkyl amine e.g. mono-, di- or triethanol amine, benzathine, lysine, tromethamine etc. Similarly, the pharmaceutically, acceptable inorganic salts of aspirin could be, but not limited to, calcium, magnesium, strontium, potassium, silver, sodium, zinc and iron etc. All these salts of aspirin can be as solvates or hydrates also. The preferred salts of aspirin are sodium, potassium, calcium and magnesium. The most preferred salt of aspirin is sodium salt (sodium acetyl salicylate).

The present invention relates to a novel synergistically active pharmaceutical compound, such as a supramolecular complex or an adduct or a co-crystal, comprising two active pharmaceutical agent e.g. Ticagrelor and sodium salt of aspirin. The meaning of the terms supramolecular complex, adduct of co-crystal is defined in the preceding section.

The invention also covers the novel compounds (The Compound 1) in various polymorphic forms or as solvates. According to the present invention, the novel synergistically active pharmaceutical compound (The Compound 1 ) is characterized by an X-ray powder diffraction (XRPD) pattern, with peaks at about 2Θ (or d-spacing) as shown in table 1. The error limit for 2Θ is ±0.2.

Table 1: XRPD data of 'The Compound 1' 5.58, 13.56, 15.74, 18.31, 22.74, 15.82, 6.52, 5.62, 4.83, 3.90, 3.65,

24.33, 27.12 3.28

In a further aspect of the invention, the XRPD pattern of the pharmaceutically active compound 'The Compound is shown in Fig. 1 , which substantially illustrates the data mentioned in Table 1. Specifically, such synergistically active novel solid state forms of pharmaceutical compounds are preferably characterized by an X-ray powder diffraction (XRPD) pattern taken with a Philips-PANalytical X-ray powder diffractometer using Cu-K a radiation λ= 1.5406 A with Scintillation detector at 25 °C temperature. Scan range was from 5 degree to 40 degree in 2Θ with a Step width [°2Θ]: 0.02 and Step time [s]: 0.5.

A person skilled in the art knows that an XRPD pattern may be obtained, which has one or more measurements error, depending on measurement conditions (such as equipment, sample preparation, machine used). In particular, it is generally known that intensities in XRPD may fluctuate depending on measurement condition, nature of sample and sample preparation. For example, a person skilled in the art knows that relative intensities of peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used, so that the intensities in the XRPD traces included herein are only illustrative in nature and are not intended to be used for absolute comparison. The skilled person also knows that the position of reflections (2Θ values) can be effected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample also affects these values. Hence a person skilled in the art should realize that the diffraction pattern data presented herein should not be constrained as absolute (for further details dn XRPD, see Jenkins, R and Snyder, R. L. 'Introduction to X-ray Powder Diffractometry' John Wily and Sons, 1996). As stated above regarding measurement error of a diffraction angle in XRPD in about 20 values is about 0.5° or less, more specifically it is 0.2° or less. Such degree of a measurement error should be taken into account when considering the XRPD patterns, and when interpreting the peak positions referred to in the text or examples. Similar measurement errors are possible with d-spacing values. Thus, values above 5A may be rounded to one decimal place (margin of error typically ±0.5A), where 2Θ values are ±0.2°.

In an important embodiment, the novel synergistically active pharmaceutical compound (The Compound 1 ) demonstrates improved stability profile, compared to Ticagrelor.

Microdissolution data in aqueous buffers at physiologically relevant pHs (e.g. blank FASSIF-without micelle forming components) demonstrate that 'The Compound Γ has improved solubility in non-micellar systems compared to Ticagrelor. This indicates that 'The Compound is likely to have improved solubility in the lower regions of the GI tract (where micelle forming components are not significantly present compared to the higher GI tract), which may result in improved absorption of Ticagrelor from this region when dosed with 'The Compound rather than Ticagrelor in the free form. This would increase the feasibility of achieving a modified release formulation for delivery of Ticagrelor over an extended period, for example 12-24 hours that could provide suitable plasma exposures following once-daily dosing. Furthermore, the use of 'The Compound 1 ' in a suitable formulation would permit the simultaneous dosing of both Ticagrelor and sodium salt of acetyl salicylic acid active pharmaceutical ingredients. The product of this invention 'The Compound demonstrates a superior dissolution profile in blank Fassif (Fig. 1 1) and in SGF (Fig. 12), with respect to the dissolution profile data reported for earlier co-crystals in Fig. 12 and Fig.13 of WO2012/164286 by AstraZeneca. The concentration of Ticagrelor in 'The Compound reaches up to 17 μg ml in blank Fassif (Fig. 1 1) whereas Fig. 12 of WO2012/164286 co-crystal reports a maximum concentration of only around 8 μ /ηι1. Similarly, the concentration of Ticagrelor with 'The Compound reached up to 25 μ§/Γη1 in SGF (Fig. 12), whereas WO2012/164286 co-crystals reports a maximum concentration of up to around 20 μ£/η 1 (Fig. 13 in WO2012/164286). A person skilled in the art would realize that such improved dissolution profile data of 'The Compound will have significant consequences on the clinical profile of Ticagrelor, especially dose amount, efficacy and consequently cost of treatment for the diseases discussed in the preceding text of prior art, summary of the invention and abstract sections.

Such improved dissolution profile of 'The Compound may also have improved clinical consequences e.g. reduction in side effects, may decrease the inter- and intra- subject variability in blood levels, may show a good absorption rate (e.g. increase in the plasma levels or AUC (area under the curve)), may show higher maximum plasma concentration (C _max ), rnay show decreased time to peak drug concentration (t _max ) and may show desirable change in half life of compound (ti/ ₂ ). All these parameters are extremely important for efficacy, safety, therapeutic dose and cost for the prevention and/or treatment of above mentioned diseases.

The novel synergistically active pharmaceutical compound, such as supramolecular complex or an adduct or a co-crystal, comprising Ticagrelor with salts of aspirin, more specifically sodium salt of aspirin, was prepared by dissolving both in a suitable solvents, in a concentrated manner, with a molar ratio of 1 :0.5 to 1 :5, more preferably 1 :0.5 to 1 :3. Initially, both can be dissolved individually in a suitable solvent and subsequently both solutions can be mixed together. Occasionally, warming was required to get a clear solution of both. Sodium salt of aspirin, as such was prepared by reported method (US patent no. US3064038) and its Ή NMR is reported in Fig 3. The suitable solvent can be methanol, ethanol, acetonitrile, acetone, methyl acetate, ethyl acetate, n-butyl acetate, dichloromethane, dimethyl formamide, isopropyl alcohol, dimethyl sulfoxide, N-methyl pyrrolidone, formamide, pyridine and mixtures thereof. In an embodiment, both active pharmaceutical ingredients (API's) e.g. Ticagrelor and salts of aspirin are soluble or partially soluble in above mentioned suitable solvents.

The preferred suitable solvents are methanol, ethyl acetate and dichloromethane. The most preferred solvent is methanol.

Occasionally, warming and/or reflux is required to get a clear solution of both API's and then, the reaction mixture is allowed to precipitate slowly for suitable time at suitable temperature. Slow cooling of concentrated solutions gave crystalline or amorphous synergistically active pharmaceutical compound (The Compound 1). The concentration of solution can be accomplished either by slow evaporation or by fast distillation. Occasionally, the stirring under cooling condition and/or seeding helps getting better yield of 'The Compound . Sometimes, one has to add suitable anti-solvents to get fast precipitation of compound. The suitable antisolvent (the solvent in which the compound is less soluble) can be selected from water, hydrocarbons such as toluene, hexane, heptane, cyclohexane, isooctane and the like, alcohols such as t-butanol, octanol, decanol, 2-ethoxy ethanol, ethylene glycol and the like, esters such as isopropyl acetate, n-butyl acetate and the like, ketones such as methyl isobutyl, ethers such as diisopropyl ether, methyl tert-butyl ether, 1 ,4-dioxane and the like. In a preferred embodiment, the desired compound 'The Compound Γ is filtered and dried. The drying is usually done by either vacuum drying and/or by hot air oven.

In preparing novel synergistically active pharmaceutical compound 'The Compound 1 ', a measured range of ingredients such as Ticagrelor and sodium salt of aspirin for 'The Compound Γ will be consistently observed, which may also be a mixture of supramolecular complex, adduct, co-crystal and some excess of its ingredients. Thus, 'The Compound may have some excess of Ticagrelor and sodium salt of aspirin as free components, which may not be a part of supramolecular complex, adduct or co-crystal. Such mixtures comprising the supramolecular complex, adduct or co-crystal as defined herein with free Ticagrelor and/or free sodium salt of aspirin are within, the scope of this invention. For example, 'The Compound Γ may be mixture comprising between 50 wt% and 90 wt% of the supramolecular/adduct/co-crystal of Ticagrelor and sodium salt of aspirin and the remainder may comprise Ticagrelor in free form and/or sodium salt of aspirin in free form.

In novel synergistically active pharmaceutical compound 'The Compound Γ, the %wt of 'supramolecular Complex, adduct, co-crystal' may be greater than about 60%, such as greater than about 80%, particularly greater than about 90%, more particularly greater than about 95%, wherein these % refer to the % by weight of the total sample mass of 'The Compound Γ. All such aspects constitute part of this invention.

The present invention also discloses a compound comprising physical mixtures of Ticagrelor and salts of aspirin in a molar ratio of 1 :0.5 to 1 :5. Preferably the salt of aspirin is sodium salt of aspirin. Standard analytical techniques usually employed for characterization of supramolecular complexes/co-crystal/adducts are melting point, XRPD, FTIR, solid state NMR (Ή and ^,3 C-NMR), solution state NMR, DSC and TGA. Single crystal X-ray crystallography can be utilized to understand the nature of crystal lattice packing, including the role and position of solvents, water molecules in case of hydrates and of course, counter ions.

'The Compound exhibited superior or comparable in vitro (Fig. 13) and in vivo (Fig. 14 and Fig. 15) antiplatelet efficacy profile, with respect to Ticagrelor. For details, see Example 1 1.

In yet another embodiment, the invention provides a method of treatment or prevention of the diseases of thrombotic events e.g. stroke, heart attack, acute coronary syndrome or myocardial infarction with ST elevation, other coronary artery diseases ^' and arterial thrombosis plus other disorders related to platelet aggregation, which comprises administering to a person suffering from or susceptible to such disorders, a therapeutically effective dose of synergistically active pharmaceutical compound (The Compound 1), discussed above. 'The Compound 1 ' can also be used for modified release formulation for the delivery of Ticagrelor over an extended period, for example 12-24 hours, which would provide suitable plasma concentration following once daily dosing. Additionally, 'The Compound Γ in a suitable formulation would permit simultaneous dosing of both Ticagrelor and sodium salt of aspirin as active pharmaceutical ingredients.

In another embodiment, the various supramolecular complexes/co- crystals/adducts of the present invention can be used in medicine. These pharmaceutical solid forms can optionally be in a hydrated or solvated form. These solid state forms can be used either alone or in combination or formulated with one or more excipients or other active pharmaceutical ingredients to provide a formulation suitable for the treatment or prevention of arterial thrombotic complications in patients with coronary artery, cerebrovascular or peripheral vascular disease. The route of administration of medicament can be chosen as a form suitable for oral, parenteral rectal and/or administration by inhalation or topical applications. The dosage form may be solid, liquid or powdery. Therefore, the pharmaceutical composition comprising 'The Compound 1 ' of the present invention may suitably be in the form of tablets, pill, capsules, syrups, powders or granules for oral administration, or as sterile parenteral or subcutaneous solutions, suspensions for parenteral administration, or as suppositories for rectal administration.

Suitable excipients and/or carriers include, without being limited to, diluents, adjuvant, carriers, binders, disintegrates, lubricants etc. For example, 'The Compound 1 ' of the present invention or particles thereof, are mixed with a carrier or binder substance e.g. mono-, di- or polysaccharides such as sugars and starch, a sugar alcohol or another polyol, for examples lactose, saccharide, sorbitol, mannitol, starch, cellulose derivatives, a binder such as poly vinyl pyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin and the like are mixed and then compressed into tablets. The Co-crystals, supramolecular complex or adduct of the present invention or particle containing the same, may be coated by another substance. The powder or amorphous mixture of present invention or particle containing the same may also be dispensed into capsules.

Following examples present the key aspect of invention. These examples are non- optimized processes and are only illustrative in nature and do not limit the scope and spirit of invention. It will be apparent for those skilled in the art that many obvious modifications, both to materials and methods, may be practiced without departing from the scope of the invention. Scientifically, the words such as supramolecular complex, co-crystals and adducts have been used interchangeably. 'The compound Γ comprises Ticagrelor with sodium salt of aspirin. The Ή NMR spectra were recorded on a 'Bruker' 400 MHz instrument using CDC1 ₃ and DMSO-d ₆ as a solvent. The Ή chemical shifts are reported in parts per million relative to tetramethylsilane (TMS) as the internal reference. The TGA and DSC spectra were recorded on a 'Hitachi STA7000' instrument with heating rate of 15°C/min. The Solid state ¹³ C NMR was recorded at l O Hz on Bruker Avance 500 instrument.

Example 1: Preparation of synergistically active pharmaceutical compound (The Compound 1) with Ticagrelor and sodium salt of aspirin

A uniform suspension (by visual inspection) of Ticagrelor (500 mg) and sodium acetyl salicylate (240 mg) in 4 mL of methanol was initially stirred at room temperature for 1 hr. The resulting mixture was warmed to 35-40 °C for 2 hr to get a clear solution. Cooling of the reaction mixture at 0 to 5°C and addition of small amount of n-hexane gave 'The Compound , as free flowing solid. Filtering under vacuum, washing with hexane and drying gave 103 mg of 'The Compound . The resulting free flowing solid was analyzed by XRPD. The XRPD comprised peaks, which were different from the XRPD peaks of either Ticagrelor or of sodium salt of aspirin. Further characterizations with 1H NMR, solid state ¹³ C NMR, DSC, TGA and FTIR please check Figures. Fig 1 reports the XRPD of 'The Compound 1 ' . Example 2: Preparation of synergistically active pharmaceutical compound (The Compound 1) with Ticagrelor and sodium salt of aspirin

A uniform suspension (by visual inspection) of Ticagrelor (500 mg) and sodium acetyl salicylate (240 mg) in 4 mL of methanol was initially stirred at room temperature for 1 hr. The resulting mixture was stirred with quick heating and fast cooling for 1 hour to get a clear solution. Cooling of the reaction mixture at 0 to 5°C and seeding with small amount of 'The Compound 1 ' gave free flowing solid. Filtering under vacuum, washing with hexane and drying gave 159 mg of 'The Compound . Example 3: Preparation of synergistically active pharmaceutical compound (The Compound 1) with Ticagrelor and sodium salt of aspirin

A uniform suspension (by visual inspection) of Ticagrelor (500 mg) and sodium acetyl salicylate (240 mg) in 4 mL of ethyl acetate was initially stirred at room temperature for 1 hr. The resulting mixture was warmed to 40 °C for 2 hr to get a clear solution. Cooling of the reaction mixture at 0 to 5°C and addition of small amount of n-hexane gave 'The Compound , as free flowing solids. Filtering under vacuum, washing with hexane and drying gave 145 mg of 'The Compound 1 '. The product was identical to the product obtained in Example 1.

Example 4: Preparation of synergistically active pharmaceutical compound (The Compound 1) with Ticagrelor and sodium salt of aspirin

A uniform suspension (by visual inspection) of Ticagrelor (500 mg) and sodium acetyl salicylate (240 mg) in 4 mL of ethyl acetate was initially stirred at room temperature for 1 hr. The resulting mixture was warmed to 35-45 °C for 2 hr to get a clear solution. Slow evaporation of ethyl acetate and addition of small amount of n-hexane resulted in a free flowing solid. Filtering under vacuum, washing with hexane and drying gave 380 mg of 'The Compound , which was identical to the ^÷ 'product obtained in Example 1.

Example 5: Preparation of synergistically active pharmaceutical compound (The Compound 1) with Ticagrelor and sodium salt of aspirin Ticagrelor (500 mg, 0.96 mmol) and Sodium acetyl salicylate (240 mg, 1.25 equiv) was added to a flask, containing Methanol (7 mL). The reaction mixture was stirred at room temperature for 2 hr to get a clear solution. Distilled out methanol completely under reduced pressure. Add n-Hexane (14 mL) and stir at room temperature for 72 hr. Filter the solid and wash with n-Hexane (5 mL) to get 560 mg of 'The Compound , which was identical to the product obtained in Example 1.

Example 6: Preparation of synergistically active pharmaceutical compound (The Compound 1) with Ticagrelor and sodium salt of aspirin

Ticagrelor (500 mg, 0.96 mmol) and Sodium acetyl salicylate (240 mg, 1.25 equiv) was added to a flask, containing Ethyl acetate (6 mL). The reaction mixture was stirred at room temperature for 2 hr to get a clear solution. Distilled out Ethyl acetate completely under reduced pressure. Add n-Hexane (14 mL) and stir at room temperature for 72 h. Filter the solid and wash with n-Hexane (5 mL) to get 505 mg of 'The Compound Γ, which was identical to the product obtained in Example 1.

Example 7: Preparation of synergistically active pharmaceutical compound (The Compound 1) with Ticagrelor and sodium salt of aspirin

Ticagrelor (500 mg, 0.96 mmol) and Sodium acetyl salicylate (240 mg, 1.25 equiv) was added to a flask, containing Ethyl acetate (7 mL). The reaction mixture was stirred with quick heating and fast cooling for 2 hr to get a clear solution. Removal of ethyl acetate under reduced pressure and addition of n-heptane (14 mL) resulted in a solid. Filter the solid and wash with n-Heptane (5 mL) to obtained 477 mg (69%) of 'The Compound Γ . Example 8: Preparation of synergistically active compound with Ticagrelor and potassium salt of aspirin

Ethyl acetate (6 mL) was added to a flask containing Ticagrelor (400 mg, 0.77 mmol) and potassium acetyl salicylate (208 mg, 1.25 equiv). The reaction mixture was heated to reflux for 2 h. Cool the reaction mixture and distilled out methanol completely under reduced pressure. Add n-Hexane (12 mL) and stir at room temperature for 72 nr. Filter the solid and wash with n-Hexane (5 mL) to get 351 mg (62%) the title compound , with potassium salt of aspirin.

Example 9: Preparation of a compound with ticagrelor and calcium salt of aspirin

Ethyl acetate (6 mL) was added to a flask containing Ticagrelor (400 mg, 0.77 mmol) and calcium acetyl salicylate (191 mg, 0.063 equiv). The reaction mixture was heated to reflux for 2 h. Cool the reaction mixture and distilled out methanol completely under reduced pressure. Add n-Hexane (12 mL) and stir at room temperature for 80 h. Filter the solid and wash with n-Hexane (5 mL) to get white solid, yield 320 mg (58%) of a supramolecular complex, an adduct or a co-crystal of Ticagrelor with calcium salt of aspirin.

Example 10: Preparation of a compound with ticagrelor and magnesium salt of aspirin Methanol (6 mL) was added to a flask containing Ticagrelor (400 mg, 0.77 mmol) and magnesium acetyl salicylate (183 mg, 0.063 equiv). The reaction mixture was heated to reflux for 2 hr. Cool the reaction mixture and distilled out methanol completely under reduced pressure. Add n-Hexane (12 mL) and stir at room temperature for 80 h. Filter the solid and wash with n-Hexane (5 mL) to obtain white solid, yield 294 mg (54%) of a supramolecular complex, an adduct or a co- crystal of Ticagrelor with magnesium salt of aspirin.

Example 11: Dissolution studies of 'The Compound 1'

Micro-dissolution investigation were performed on 72 mg of a sample of 'The Compound in 200 ml of (i) Fasted intestinal fluid (Fassif) without micelle forming components (blanked Fassif) (Fig. 11) and (ii) of Simulated Gastric Fluid (SGF) (Fig. 12). The samples were magnetically stirred (100 rpm) at 36°C and aliquots were taken at appropriate time intervals, centrifuged, filtered through 0.22 micron filter and the supernatant analyzed by HPLC and the concentration of Ticagrelor 1 measured, at λ = 225 A, as a function of time. The column temperature was 25 °C, eluent system used was acetonitrile/buffer (50:50) having flow rate 1 ml/min. Buffer was prepared by dissolving 0.1 ml acetic acid in 100 ml milli-Q water. The results are shown in tables 2 and 3.

Simulated Gastric Fluid (SGF) media was prepared by adding 131.5 ml 1 M HC1 to 4 g NaCl and the resulting solution made up to 2 Liters with milli-Q water (de- ionised water).

Fasted intestinal fluid without micelle forming components (blank Fassif) media was prepared from 0.348 g NaOH pellets, 3.954 g NaH ₂ P0 ₄ H ₂ 0 and 6.186 g NaCl in 1 Liter mili-Q water. The pH was then adjusted to pH 6.5 with IN NaOH or lN HCl.

Table 2: Dissolution data of 'The Compound 1' in blank Fassif (mean data of two experiments)

Table 3: Dissolution data of 'The Compound Γ in SGF (mean data

experiments)

Example 12: Comparative in-vitro and in-vivo anti-platelet efficacy study of Ticagrelor and 'The Compound 1'

Test material details:

Compound: Different forms of Ticagrelor and aspirin

Vehicle: Saline

Species and Sex: Albino Rats, Male

Doses and route: 3 mg/kg P.O.

Volume of administration: 5 ml/kg

Age at Initiation: 6-8 weeks

Body Weight range: 200-250 g

Abbreviations:

Materials and methods: Animal housing

Rats in groups of 3 were housed in clean polypropylene rat cages covered with stainless steel grill top having provision for keeping rat pellet feed and a water bottle with stainless steel drinking nozzle. Clean rice husk was used as bedding material and changed twice a week. Cages will be placed on appropriate racks.

> Environmental conditions

Animals were kept in an environmentally controlled room with 20-25 °C temperatures with acceptable relative humidity. The photoperiod was maintained by light/dark cycle of 12/12 hours throughout the experimental period.

Drinking water and Diet

Drinking water and standard laboratory animal pellet diet were provided ad libitum.

Criteria for selection of animals

The rats were randomized into six groups before the start of the treatment based on body weight. At the start of the treatment, the body weight variation among the animals were not exceed ± 20% of the mean body weight. All animals selected for the study must be in good health.

> Acclimatization

' All animals were acclimatized for a period of two days in the experimental area before the start of the study.

> Animal Identification

Individual animal was ear punched after receipt from breeding facility and animals of each group was identified by tail marking method or picric acid marking method after randomization and grouping. Each cage was identified with a label, which indicates Study, Animal species, Strain, Sex, Cage No, Animal No, Test item, Dose, Group, Date of experiment initiation, Date of experiment termination and Study Scientist.

Experimental design for in-vitro studies: 1 code

0.0019, 0.019, 0.19,

1 T Ticagrelor (T)

1.9, 19

2 A Aspirin (A) 0.19, 1.9, 19, 199, 1999

3 Physical mixture of Ticagrelor and

TA 0.19, 1.9, 19, 199, 1999

Aspirin (molar ratio of 1 : 10)

4 Physical mixture of Ticagrelor and

S I 0.68, 1.3, 6.8, 13, 68 sodium salt of aspirin (molar ratio 1 : 1)

5 S2 'The Compound Γ 0.7, 1.4, 7, 14, 70

> Methodology for in vitro studies:

The main pharmacodynamic measure was inhibition of ADP/AA-induced platelet aggregation of platelet-rich plasma (PRP), quantitated using optical density filter at 405 nm as a measurement point in kinetic mode. Blood was be collected from animals by orbital bleeding under light ether anesthesia at above given time points in tubes containing 3.8% trisodium citrate (1 :9 citrate to blood). To obtain PRP, a citrated tube of blood was inverted 3 to 5 times for gentle mixing and centrifuged at room temperature for 10 minutes at 200g. After centrifugation, the upper turbid layer of PRP removed, and the residual blood was centrifuged for 5 minutes at 2000 g to obtain platelet-poor plasma (PPP). The PPP was used as the baseline optical density for platelet aggregation. A total of 180 μL of PRP containing about 3 x 10 ⁸ /ml platelets will be incubated at 37°C in the 96 well plate for 3-5 minutes, followed by the addition of T/A/TA/S 1/S2 (10 μί) and ADP (20 μΜ, 10 μ\ _^ )/ΑΑ (0.5mM, 10 μΐ,) with intermittent shaking mode. Optical density readings were measure at every 1 -minute with intermittent shaking up to 5 minutes. Platelet aggregation was expressed as the change in optical density at 5 minutes, compared with PPP as a reference. The inhibition of platelet aggregation (IPA) can be calculated from the observed maximal platelet aggregation (MP A) at each scheduled time point for each treatment using the formula:

IPA ( % inhibition) = [(MPA _baseljne - MPA _poetdose )/

MPA _basciinc ] x 100 Graph could be also plotted for % IAP vs. drug concentration. At here, the IC50 was represented by IPA (50%).

The details of in vitro studies data are plotted in Fig.

> Experiment design for in vivo studies:

> Methodology for in vivo studies:

Animals were divided into seven groups by randomization methods. They were treated with C/T/A/TA/S 1/S2 (10 mg/kg) in their respective groups. Blood (0.5 mL) was collected from animals by orbital bleeding under light ether anesthesia in tubes containing 3.8% trisodium citrate (1 :9 citrate to blood) at 0, 1 , 2, 4, 8, and 24 hr after administration of C/T/A/TA/S1/S2 (10 mg/kg). To obtain PRP, a citrated tube of blood was inverted 3 to 5 times for gentle mixing and centrifuged at room temperature for 10 minutes at 200g. After centrifugation, the upper turbid layer of PRP removed, and the residual blood was centrifuged for 5 minutes at 2000 g to obtain platelet-poor plasma (PPP). The PPP was used as the baseline optical density for platelet aggregation. A total of 180 μΐ, of PRP containing about 3 x 10 ⁸ /ml platelets will be incubated at 37°C in the 96 well plate for 3-5 minutes, followed by the addition of ADP (20 μΜ, 20 μΙ,)/ΑΑ (0.5mM, 20 μΐ,) with intermittent shaking mode. Optical density readings were measure at every 1- minute with intermittent shaking up to 5 minutes. Platelet aggregation was expressed as the change in optical density at 5 minutes, compared with PPP as a reference. The inhibition of platelet aggregation (IPA) can be calculated from the observed maximal platelet aggregation (MPA) at each scheduled time point for each treatment using the formula:

IPA ( % inhibition) = [(MPA _b .^ _eJjne - MPA _posrdose )/

MP _basdjae ] x 100

Graph could be also plotted for % IAP vs. time in control and treated groups. At here, AUC for each curve was calculated.

> Statistical Evaluation

Results were expressed as mean ± SEM. The IC50 of each dose response curve was analyzed using normalized response vs. variable slope method in Graphpad Prism 5 software.

The details of in vivo studies data are plotted in Fig. 14 and Fig.15.

Table 4. IC ₅₀ for dose response curve of Ticagrelor, aspirin, Ticagrelor+asirin (1 : 10) and their samples (S I , S2) on ADP (20μΜ) and AA (0.5mM) induced platelet aggregation.

5 S2 'The Compound Γ 7.978±0.12 3.87+0.1 18

Table 5. AUC for time response curve of Ticagrelor, aspirin, Ticagrelor+asirin (1 : 10) and their samples (S I, S2) on ADP (20μΜ) and AA (0.5mM) induced platelet aggregation.

Conclusion:

Ticagrelor and Aspirin treatment showed the inhibition on ADP and AA induced platelet induced aggregation similar to reported publications. In comparison to TA in the in vitro and in vivo study, S2 is a potent AA induced aggregation inhibitor and S I is an equipotent inhibitor of ADP induced platelet aggregation.

Example 13: TGA and DSC

TGA was carried out using Hitachi STA7000 equipment. The sample was kept under nitrogen gas flow during the analysis. The heating rate was 10 °C/min. The TGA shows that there are two distinct regions i.e. 190 °C and 360 °C, in which the mass loss is observed.

Additionally the DSC was carried out on Hitachi STA7000 equipment. The measurement was done under the nitrogen flow of 20 mL/min. Thermal events were observed _s arourid 152 °C and 296 °C. The first event at around 152 °C is presumably because of the Ticagrelor, whereas, the second events appears due to decomposition of sodium salt of aspirin. There is no hump around 138 °C, which is the melting point of aspirin.