WO2016051393A2

WO2016051393A2 - Crystalline form iv of trisodium supramolecular complex comprising valsartan and ahu-377 and methods thereof

Info

Publication number: WO2016051393A2
Application number: PCT/IB2015/059985
Authority: WO
Inventors: Minhua Chen; Yanfeng Zhang; Chaohui YANG; Xiaoyu Zhang; Jiaoyang LI; Peng Wang; Pixu Li
Original assignee: Crystal Pharmatech Inc.; Crystal Pharmatech Co., Ltd.; Suzhou Pengxu Pharmatech Co., Ltd.
Priority date: 2014-12-26
Filing date: 2015-12-24
Publication date: 2016-04-07
Also published as: WO2016051393A3

Abstract

A novel crystalline Form of trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3- ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-methyl-2'-(pentanoyl{2''-(tetrazol-5- ylate)biphenyl-4'-ylmethyl}amino)butyrate] hydrate, process for its preparation, pharmaceutical composition comprising the new form, and use of it for treating or delaying progression or onset of diseases or disorders related to activity of angiotensin receptor 1 (AT1) blockage and neprilysin (NEP) inhibition is disclosed. The novel form was characterized by X-ray powder diffraction, differential scanning calorimetry, and other techniques.

Description

CRYSTALLINE FORM IV OF TRISODIUM SUPRAMOLECULAR COMPLEX COMPRISING VALSARTAN AND AHU-377 AND METHODS THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to Provisional

Application No. 62/096,953, filed on December 26, 2014, which is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to a novel crystalline form of trisodium supramolecular complex comprising valsartan and AHU-377, and pharmaceutical compositions, methods of preparation, and methods of uses thereof.

BACKGROUND OF THE INVENTION

Heart failure (HF) is a major and increasing clinical problem that is associated with substantial morbidity and mortality. It is the leading cause of admission to hospital in individuals older than 65 years.

As the population lives longer resulting in an increased prevalence of cardiovascular risk factors and diseases, and as survival following acute myocardial infarction (Ml) increases, the number of patients living with congestive heart failure (CHF) is expanding. For example, risk factors such as hypertension are common prognostic comorbidities in chronic HF. In parallel, a concomitant increase in the number of hospitalizations for acute decompensated heart failure (ADHF) has occurred. In the United States alone, heart failure (HF) affects 5.7 million Americans, with over 650,000 new cases diagnosed annually, with increasing hospitalization rates.

Heart failure remains a high unmet medical need with an annual mortality rate of about 20%. Reductions in mortality and cardiovascular morbidity have been achieved by the renin-angiotensin-aldosterone system (RAAS) blockers (Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs)) and beta (3)- blockers in HF. While survival rates have improved for HF with reduced ejection fraction (HF-REF) over recent decades, due to more widespread use of drugs that block RAAS and improved acute care, residual mortality rates remain high. For patients with HF with preserved ejection fraction (HF-PEF) no therapy has proven to be effective at reducing morbidity and mortality. Overall, the therapeutic benefits of RAAS blockade with ACE inhibitors and/or ARBs remain limited, possibly caused by angiotensin II escape due to incomplete ACE inhibition or angiotensin II originating from alternative non-ACE pathways, and by other neuro-hormonal and other mechanisms contributing to cardiac disease and outcomes.

A supramolecular complex comprising valsartan, which is an ARB, and AHU-377 (Sacubitril), which is a neprilysin inhibitor, has been approved by US Food and Drag Administration (FDA) under the brand name Entresto for the treatment of heart failure with reduced ejection fraction.

Valsartan blocks the angiotensin II receptor type 1 (ATI). This receptor is found on both vascular smooth muscle cells and the zona glomerulosa cells of the adrenal gland which are responsible for aldosterone secretion. In the absence of ATI blockade, angiotensin causes both direct vasoconstriction and adrenal aldosterone secretion, the aldosterone then acting on the distal tubular cells of the kidney to promote sodium reabsorption which expands extracellular fluid (ECF) volume. Blockade of (ATI) thus causes vasodilation and reduction of ECF volume.

AHU-377 is a prodrug that is activated to sacubitrilat (LBQ657) by de-ethylation via esterases. AHU-377 inhibits the enzyme neprilysin, a neutral endopeptidase that degrades vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin. Thus, AHU-377 increases the levels of these peptides, causing vasodilation and reduction of ECF volume via sodium excretion.

Entresto is a first-in-class medicine (an Angiotensin Receptor Neprilysin Inhibitor, or ARNI) and has a unique mode of action which is thought to reduce the strain on the failing heart. It harnesses the body's natural defenses against heart failure, simultaneously acting to enhance the levels of natriuretic and other endogenous vasoactive peptides, while also inhibiting the renin-angiotensin-aldosterone system (RAAS).

Furthermore, crystallinity of drugs effects, among other physical and mechanical properties, their solubility, dissolution rate, hardness, compressability and melting point. Because these properties may, in turn, effect a drug's manufacture and their utility, there is an existing need in the chemical and therapeutic arts for identification of crystalline forms of drags and ways of reproducibly making them.

Though one crystalline form of the supramolecular complex comprising valsartan and AHU-377 has been reported to exist as a trisodium hemipentahydrate form in US8877938B2 (the "Patent form"), new crystalline forms of the supramolecular complex comprising valsartan and AHU-377, in particular stable polymorphs with superior pharmacological activities suitable for formulation, and convenient methods to prepare them remain a great need.

SUMMARY OF THE INVENTION

The present invention provides a crystalline form of supramolecular complex comprising valsartan and AHU-377 and has desired physicochemical properties, for example, less hygroscopic and better flowability, which make it more suitable for use in dosage forms to achieve desired bioavailability and therapeutic effects. The crystalline form disclosed herein can also be prepared conveniently at a low cost.

The supramolecular complex of this invention is trisodium [3-((lS,3R)-l-biphenyl-4- ylmethyl-3-ethoxycarbonyl-l-butylcarbamoyl) propionate-(S)-3'-methyl-2'-(pentanoyl{2"- (tetrazol-5-ylate) biphenyl-4'-ylmethyl} amino) butyrate] hydrate, having a structure of general Formula I:

(I)

wherein x is a number in the range of 2.0-4.0.

In one aspect, the present invention provides a crystalline form of trisodium [3-((lS, 3R)-l-biphenyl-4-ylmethyl-3-ethoxycarbonyl-l-butylcarbamoyl)propionate-(S)-3'-methyl- 2'-(pentanoyl{2"-(tetrazol-5-ylate) biphenyl-4'-ylmethyl} amino) butyrate] hydrate designated as Form IV.

In another aspect, the present invention provides processes for preparation of crystalline Form IV. In other aspects, the present invention provides pharmaceutical compositions comprising a supramolecular complex of valsartan and AHU-377 in crystalline Form IV, and a pharmaceutically acceptable carrier.

In another aspect, the present invention is directed to methods for treatment of a patient suffering from a disease or condition selected from hypertension, heart failure, congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction, atherosclerosis, angina, renal insufficiency, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, and renal failure conditions, the method comprising administering to the patient a therapeutically effective amount of a supramolecular complex of valsartan and AHU-377 in crystalline Form IV, or a pharmaceutical composition comprising the crystalline Form IV.

In another aspect, the present invention is directed to the use of valsartan and AHU- 377 supramolecular complex Form IV, or a composition comprising crystalline Form IV, in the manufacture of a medicament for treating or delaying progression or onset of a disease or disorder related to activity of angiotensin receptor 1 (ATI) and neprilysin (NEP).

Other aspects and embodiments of the present invention will be further illustrated in the following description and examples.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form IV obtained from example 1.

FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of crystalline

Form IV obtained from example 1.

FIG. 3 shows a thermogravimetric analysis (TGA) thermogram of crystalline Form IV obtained from example 1.

FIG. 4 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form IV obtained from example 2.

FIG. 5 shows a polarized light microscopy (PLM) picture of crystalline Form IV obtained from example 2.

FIG. 6 shows a polarized light microscopy (PLM) picture of Patent form obtained from US8877938B2. FIG. 7 shows dynamic moisture adsorption (DVS) comparison of Form IV and Patent form in US 8877938B2.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on a surprising discovery that a supramolecular complex comprising valsartan and AHU-377 could exist in one new crystalline form having superior physicochemical properties as compared to the Patent form.

In one aspect, the present invention provides a supramolecular complex comprising valsartan and AHU-377.

In another aspect, the supramolecular complex in this invention is trisodium [3-

((lS,3R)-l-biphenyl-4-ylmethyl-3-ethoxycarbonyl-l-butylcarbamoyl)propionate-(S)-3'- methyl-2'-(pentanoyl{2"-(tetrazol-5-ylate) biphenyl-4'-ylmethyl} amino) butyrate] hydrate.

In another aspect, the said supramolecular complex is a crystalline form, designated as Form IV.

In a preferred embodiment, crystalline Form IV is characterized by an X-ray powder diffraction pattern comprising the following 2Θ values measured using CuKa radiation: 12.5°±0.2°, 4.2°±0.2°, and 4.9°±0.2°.

In another embodiment, crystalline Form IV is characterized by an X-ray powder diffraction pattern further comprising the following 2Θ values measured using CuKa radiation: 19.5°±0.2°, 6.4°±0.2°, and 8.0°±0.2°.

In another embodiment, crystalline Form IV is characterized by an X-ray powder diffraction pattern further comprising the following 2Θ values measured using CuKa radiation: 11.5°±0.2°, 8.3^o±0.2°,14.4^o±0.2°.and 15.4°±0.2°

In another embodiment, crystalline Form IV has an X-ray powder diffraction pattern substantially as shown in FIG. 1.

In another embodiment, crystalline Form IV has a differential scanning calorimetry thermogram as shown in FIG. 2, which exhibits two endothermic peaks with onset temperatures of about 65 °C and about 134°C, respectively.

In another embodiment, crystalline Form IV has a thermal gravimetric analysis thermogram as shown in FIG. 3, which exhibits about 5.7% weight loss when heated up to 150 °C.

While not intended to be limiting, crystalline Form IV may be a hydrate with each molecule containing 2.0 to 4.0 molecules of ¾0 (x equals 2.0 to 4.0 in formula I). More preferred, crystalline Form IV may be a hydrate with each molecule containing 2.0 to 3.0 molecules of H₂0 (x equals 2.0 to 3.0 in formula I).

Crystalline Form IV of the supramolecular complex comprising valsartan and AHU- 377, together with one or more pharmaceutically acceptable excipients, of the present invention may be further formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations; and modified release compositions may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir, or combination of matrix and reservoir systems. The compositions may be prepared using techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugarcoated, powder coated, enteric coated, or modified release coated.

In another aspect, the present invention provides pharmaceutical compositions comprising crystalline Form IV, and a pharmaceutically acceptable carrier.

In another aspect, the present invention is directed to a method of treating a patient suffering from hypertension, heart failure, congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction , atherosclerosis, angina, renal insufficiency, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, and/or renal failure conditions, the method comprising administering to the patient a therapeutically effective amount of a supramolecular complex of valsartan and AHU-377 selected from the group consisting of crystalline Form IV, or a pharmaceutical composition comprising crystalline Form IV.

In another aspect, the present invention is directed to the use of supramolecular complex Form IV in the manufacture of a medicament for treating or delaying progression or onset of a disease or disorder related to activity of angiotensin receptor 1 (ATI) and neprilysin (NEP). Disease or disorder related to activity of angiotensin receptor 1 (ATI) and neprilysin (NEP) include, but are not limited to heart failure, cardiac dysrhythmias; mitral stenosis and regurgitation, cardiomyopathies, hypertension and pulmonary heart diseases. In one embodiment, cardiac dysrhythmias comprise atrial fibrillation, new onset atrial fibrillation and recurrent atrial fibrillation. In one embodiment, heart failure comprises congestive heart failure, left heart failure, right heart failure, chronic heart failure, advanced heart failure, acute heart failure, acute decompensated heart failure, heart failure with reduced ejection fraction (HF-REF), and heart failure with preserved ejection fraction (HF-PEF). In particular, heart failure comprises heart failure with preserved ejection fraction (HF- PEF) and heart failure with reduced ejection fraction (HF-REF).

In one embodiment, the mammal suffers from hypertension or heart failure or is prone to suffering from hypertension and/or heart failure. In one embodiment said patients suffering from heart failure are patients suffering from heart failure with preserved ejection fraction (HF-PEF) or heart failure with reduced ejection fraction (HF-REF). In one embodiment said patients suffering from heart failure are patients suffering from heart failure with preserved ejection fraction (HF-PEF).

In another embodiment, the mammal suffers from hypertension.

In another embodiment, the mammal has an enlarged heart.

In another embodiment, the mammal has atherosclerosis.

In another aspect, the present invention is directed to a pharmaceutical solid formulation comprising a unit dosage of crystalline Form IV of trisodium [3-((l S,3R)-l- biphenyl-4-ylmethyl-3-ethoxycarbonyl-l-butylcarbamoyl) propionate-(S)-3'-methyl-2'- (pentanoyl{2"-(tetrazol-5-ylate) biphenyl-4'-ylmethyl} amino) butyrate] hydrate and one or more excipients selected from the group consisting of fillers, disintegrants, glidants, and lubricants.

In one embodiment, said filler is microcrystalline cellulose and/or hydroxypropyl cellulose; said disintegrant is crospovidone; said glidant is colloidal silicon dioxide; and said lubricant is talc or magnesium stearate.

In another embodiment, the pharmaceutical solid formulation is a tablet or capsule. In another embodiment, the pharmaceutical solid formulation for treatment of a disease or disorder selected from the group consisting of hypertension, heart failure, congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction , atherosclerosis, angina, renal insufficiency, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, and renal failure conditions.

The crystalline Form IV of the present invention may include the improvements/advantages over the existing crystalline Form disclosed in US8877938B2 (the "Patent form"), such as superior physicochemical properties, which can facilitate formulation and manufacture processes and enhance absorption and/or bioavailability.

In particular, Form IV is less hygroscopic when exposed to humidity levels ranging from 50%RH to 60%RH at 25 °C compared to Patent form; and PLM pictures of Form IV and Patent form show that the morphology of Form IV is plate-like while Patent form has no specific shape and shows significant agglomeration, indicating Form IV has better flowability than Patent form. In addition, the particle size of Patent form does not appears to be suitable for filtration.

DEFINITIONS

Throughout this specification and in the claims that follow, the following terms are defined with the following meanings, unless explicitly stated otherwise.

The terms in the present invention, if not specifically defined, take their ordinary meanings as would be understood by those skilled in the art.

The term "supramolecular complex" is intended to describe an interaction between the two pharmaceutically active agents, the cations and any other entity present such as a solvent, in particular water, by means of noncovalent, intermolecular bonding between them. This interaction leads to an association of the species present in the supramolecular complex distinguishing this complex over a physical mixture of the species. The supramolecular complex shows properties such as melting point, IR spectrum, etc. that are different from a physical mixture of the species.

The term "treatment" refers to the management and care of a patient for the purpose of combating the disease, condition or disorder.

The term "therapeutically effective amount" refers to an amount of a drug or a therapeutic agent that will elicit the desired biological and/or medical response of a tissue, system or an animal (including man) that is being sought by a researcher or clinician.

The term "mammal" include, but are not limited to, humans, dogs, cats, horses, pigs, cows, monkeys, rabbits and mice. The preferred mammals are humans.

The term "administering" means applying a compound of the invention, or a pharmaceutically acceptable salt, pro-drug or composition thereof, to a subject in need of treatment. The administration of the composition of the present invention in order to practice the present methods of therapy is carried out by administering a therapeutically effective amount of the compounds in the composition to a subject in need of such treatment or prophylaxis. The need for a prophylactic administration according to the methods of the present invention is determined via the use of well-known risk factors. The effective amount of an individual compound is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration, other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment.

The term "pharmaceutically acceptable", as used herein, refers to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.

When the term "about" is applied to a parameter, such as amount, temperature, time, or the like, it indicates that the parameter can usually vary by ±10%, preferably within ±5%, and more preferably within ±2%. However, in the case of a melting or onset temperature of a crystalline form as measured by in a DSC thermogram, the term "about" may indicate that the melting or onset temperature can usually vary within ±2°C, regardless of the absolute value of the melting or onset temperature, as a person skilled in the art would understand it. As would be understood by a person skilled in the art, when a parameter is not critical, a number is often given only for illustration purpose, instead of being limiting.

The term "a," "an," or "the," as used herein, represents both singular and plural forms. In general, when either a singular or a plural form of a noun is used, it denotes both singular and plural forms of the noun.

The following non-limiting examples further illustrate certain aspects of the present invention.

EXAMPLES

X-ray Powder diffraction (XRPD) XRPD was performed with Panalytical Empyrean XRPD on a Si single crystal holder. The 2Θ position was calibrated against Panalytical 640 Si powder standard. Details of XRPD method used in the experiments are listed below.

Parameters Settings/Values (Reflection Mode)

Cu, ka,

X-Ray wavelength Kal (A): 1.540598, Ka2 (A): 1.544426

Ka2/Kal intensity ratio: 0.50

X-Ray tube setting 45 kV, 40 mA

Divergence slit Automatic

Scan mode Continuous Persons skilled in the art of X-ray powder diffraction will realize that the relative intensity of peaks can be affected by, for example, grains above 30 microns in size and non-unitary aspect ratios that may affect analysis of samples. The skilled person will also realize that the position of reflections can be affected 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 may also have a small effect.

When an XRPD pattern of a crystal form is described as comprising certain "representative" or "characteristic" peaks or 2Θ values, they refer to more prominent peaks, or a subset thereof, in the XRPD pattern. Typically, "characteristic peaks" are defined as a subset of representative (prominent) peaks used to differentiate one crystalline polymorph or form from another crystalline polymorph or form. Characteristic peaks may be determined by evaluating which representative peaks, if any, are present in one crystalline polymorph of a compound but not in all other known crystalline polymorphs of that compound. However, not all crystalline polymorphs of a compound would necessarily have at least one characteristic peak. As a person of ordinary skill in the art would understand, in certain situations, the overall diffraction pattern should be used to determine whether a crystal form exists as described or claimed.

Differential Scanning Calorimetry (DSC)

Analytical Instrument: TA Instruments Q2000 DSC.

Heating rate: 5 °C per minute.

Purge gas: nitrogen

Thermal Gravimetric Analysis (TGA)

Analytical Instrument: TA Instruments Q5000 TGA. Heating rate: 10 °C per minute.

Purge gas: nitrogen.

Dynamic Vapor Sorption (DVS)

Dynamic Vapor Sorption (DVS) was measured via a SMS (Surface Measurement Systems) DVS Intrinsic.

RH step size: 10%RH

RH range: 0 to 60%RH

Temperature: 25 °C Polarized light microscope (PLM)

Polarized light microscopic picture was captured on an Axio Lab.Al upright microscope at room temperature.

Example 1. Preparation of supramolecular complex comprising valsartan and AHU-377 crystalline Form IV

To 1.08 mL mixture of methyl tert-butyl ether and methyl alcohol (v: v=l : 0.08) was suspended 263.6 mg of trisodium [3-((lS,3R)-l-biphenyl-4-ylmethyl-3-ethoxycarbonyl-l- butylcarbamoyl) propionate-(S)-3'-methyl-2'-(pentanoyl{2"-(tetrazol-5-ylate) biphenyl-4'- ylmethyl} amino) butyrate] hemipentahydrate. Placed it stirring at 50 °C overnight. The solid was isolated and Form IV was obtained, which was analyzed by XRPD, DSC and TGA. The XRPD data obtained in this example are listed in Table 1.

The XRPD pattern, DSC thermogram, TGA thermogram of the complex obtained from this example are displayed in FIGs. 1-3, respectively.

Table 1

Pos.[°2Th.] d-spacing [A] Rel. Int. [%]

4.2 21.2 95.3

4.9 18.0 29.4

5.3 16.6 53.4

6.4 13.7 14.4

8.0 11.1 7.6

8.3 10.6 7.1

9.7 9.1 13.3

10.7 8.3 4.5

11.5 7.7 7.5

12.5 7.1 100.0 12.9 6.8 6.6

13.7 6.5 5.0

14.4 6.2 7.1

14.9 5.9 6.3

15.4 5.7 6.6

16.0 5.6 4.6

16.7 5.3 6.5

17.0 5.2 18.0

17.4 5.1 6.4

18.1 4.9 14.8

18.8 4.7 6.2

19.5 4.6 22.9

19.7 4.5 10.7

21.3 4.2 12.7

21.5 4.1 7.1

22.7 3.9 5.4

23.0 3.9 10.9

23.6 3.8 3.1

24.8 3.6 3.6

25.2 3.5 7.3

25.7 3.5 4.8

26.7 3.3 2.2

27.1 3.3 5.2

27.8 3.2 5.7

29.9 3.0 6.3

32.0 2.8 1.4

35.0 2.6 1.2

38.6 2.3 0.9

Example 2. Preparation of supramolecular complex comprising valsartan and AHU-377 crystalline Form IV

1) Charged 5.00 g AHU-377 into acetone to form a 30 mL solution;

2) Added the solution into a 250 mL reactor, charge 5.30 g valsartan into the reactor, and charge 70 mL acetone to dissolve them at RT;

3) Fed 1.56 mL 50 wt% sodium hydroxide aqueous solution;

4) Charged 499.2 mg Form IV seed and aged for 0.5 hour;

5) Fed 1.56 mL 50 wt% sodium hydroxide aqueous solution again;

6) Fed lOOmL acetone for 1 hour and aged for 17 hours;

7) Filtered the batch and dry the cake at RT under vacuum overnight. (Yield: 10.12 g) The XRPD pattern and PLM picture of the complex obtained from this example are displayed in FIGs. 4 and 5, respectively. The XRPD data obtained in this example are listed in Table 2.

Table 2

Pos.[°2Th.] d-spacing [A] Rel. Int. [%]

4.2 21.2 100.0

4.7 18.7 8.0

4.9 18.0 8.0

5.3 16.6 11.3

6.4 13.8 3.7

7.9 11.2 2.6

8.3 10.6 4.6

9.5 9.3 4.9

9.7 9.1 4.8

11.5 7.7 3.0

12.5 7.1 76.8

12.9 6.8 2.2

13.6 6.5 1.6

14.4 6.2 2.8

15.4 5.8 2.6

16.0 5.6 1.9

17.0 5.2 6.4

17.4 5.1 3.1

18.1 4.9 3.9

18.8 4.7 4.1

19.4 4.6 10.3

20.1 4.4 2.0

20.6 4.3 1.6

21.3 4.2 4.3

21.5 4.1 2.8

23.0 3.9 3.7

23.5 3.8 1.5

24.6 3.6 1.8

25.2 3.5 5.7

25.7 3.5 2.4

26.6 3.4 1.2

27.1 3.3 2.3

27.8 3.2 2.8

29.9 3.0 3.5

32.0 2.8 0.9

32.8 2.7 0.7

34.3 2.6 0.7

35.0 2.6 0.9

36.2 2.5 0.4

38.6 2.3 0.4

39.3 2.3 0.5 The PLM pictures of Form IV and Patent form are shown in FIGs. 5 and 6, respectively.

Example 3. DVS comparison of Form IV and Patent form in US 8877938B2

To obtain a water adsorption isotherm, a sample of polymorph Form IV was placed on a microbalance in a sealed environmental chamber, and subsequently exposed to different humidity levels ranging from 0%RH or 20%RH to 60%RH, in 10%RH increments. At each humidity level, the polymorph was allowed to equilibrate until the sample experienced a dm/dt less than 0.02wt%. The equilibrium mass at each humidity level was recorded and, along with the dry sample weight, used to generate a plot of weight change versus relative humidity.

FIG. 7 shows DVS comparison of Form IV and Patent form in US8877938B2. Form IV exhibits less moisture uptake when exposed to humidity levels ranging from 50%RH to 60%RH at 25 °C compared to Patent form reported in US8877938B2.

The foregoing examples and description of the preferred embodiments should be taken as illustrating, rather than as limiting, the present invention as defined by the claims. As will be readily appreciated, numerous variations and combinations of the features set forth above can be utilized without departing from the present invention as set forth in the claims.

Claims

1. A crystalline form of trisodium [3-((l S,3R)-l-biphenyl-4-ylmethyl-3- ethoxycarbonyl-l-butylcarbamoyl)propionate-(S)-3'-methyl-2'-(pentanoyl{2"-(tetrazol-5- ylate)biphenyl-4'-ylmethyl}amino)butyrate] hydrate, designated as Form IV, wherein the X-ray powder diffraction pattern comprising the following 2Θ values measured using CuKa radiation: 12.5°±0.2°, 4.2°±0.2°, and 4.9°±0.2°.

2. The crystalline Form IV according to claim 1, wherein the X-ray powder diffraction pattern further comprises the following 2Θ values measured using CuKa radiation: 19.5°±0.2°, 6.4°±0.2°, and 8.0°±0.2°.

3. The crystalline Form IV according to claim 1 or 2, wherein the X-ray powder diffraction pattern further comprises the following 2Θ values measured using CuKa radiation: 11.5°±0.2°, 8.3 °±0.2°, 14.4°±0.2°, and 15.4+0.2°.

4. The crystalline Form IV according to claim 1 , having an X-ray powder diffraction pattern substantially as depicted in FIG. 1.

5. A pharmaceutical composition comprising a crystalline form of the supramolecular complex according to any one of claims 1 to 4, and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5 for treatment of a patient suffering from hypertension, heart failure, congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction , atherosclerosis, angina, renal insufficiency, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, and/or renal failure conditions.

7. A method of treating a patient suffering a disease or disorder selected from the group consisting of hypertension, heart failure, congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction , atherosclerosis, angina, renal insufficiency, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, and renal failure conditions, comprising administering to the patient a therapeutically effective amount of a crystalline form of the supramolecular complex selected from the group consisting of crystalline Form IV according to any one of claims 1 to 4.

8. Use of a crystalline Form IV of the supramolecular complex according to any one of claims 1 to 4, or a pharmaceutical composition according to claim 5 or 6, in the manufacture of a medicament for treating or delaying progression or onset of a disease or disorder related to activity of angiotensin receptor 1 (ATI) and neprilysin (NEP).

9. The use of claim 8, wherein said disease or disorder is selected from the group consisting of hypertension, heart failure, congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction , atherosclerosis, angina, renal insufficiency, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, and renal failure conditions.

10. A pharmaceutical solid formulation comprising a unit dosage of crystalline Form IV of trisodium [3-((lS,3R)-l-biphenyl-4-ylmethyl-3-ethoxycarbonyl-l- butylcarbamoyl) propionate-(S)-3'-methyl-2'-(pentanoyl{2"-(tetrazol-5-ylate) biphenyl-4'- ylmethyl} amino) butyrate] hydrate and one or more excipients selected from the group consisting of fillers, disintegrants, glidants, and lubricants.

11. The pharmaceutical solid formulation of claim 10, wherein said filler is microcrystalline cellulose and/or hydroxypropyl cellulose; said disintegrant is crospovidone; said glidant is colloidal silicon dioxide; and said lubricant is talc or magnesium stearate.

12. The pharmaceutical solid formulation of claim 10 or 11 , which is a tablet or capsule.

13. The pharmaceutical solid formulation according to any one of claims 10 to

12 for treatment of a disease or disorder selected from the group consisting of hypertension, heart failure, congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction , atherosclerosis, angina, renal insufficiency, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, and renal failure conditions.