DESC:The following specification particularly describes the invention and the manner in which it is to be performed (For Complete):

CRYSTALLINE FORMS OF COMPLEX COMPRISING SACUBITRIL, VALSARTAN, SODIUM AND SACCHARIN

FIELD OF INVENTION
The present application relates to crystalline forms LCZ-SA. LCZ-SB and LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin.

BACKGROUND OF INVENTION
US Patent No. 8877938 discloses a crystalline form of supramolecular complex of valsartan and Sacubitril. It is known in the literature as LCZ-696 (Tetrahedron Letters 53, 2012, 275–276). The US’938 patent characterizes the crystalline form of LCZ-696 by XRD having peaks at 4.5, 5.5, 5.6, 9.9, 12.8, 15.7, 17.0, 17.1, 17.2, 18.3, 18.5, 19.8, 21.5, 21.7, 23.2, 23.3, 24.9, 25.3, 27.4, 27.9, 28.0 and 30.2 °2?. But the US’938 patent does not provide the XRD figure of the compound. Tetrahedron Letters 53, 2012, 275–276 discloses the XRD figure of LCZ-696.

SUMMARY OF INVENTION
First aspect of the present application relates to crystalline form LCZ-SA of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by its PXRD pattern having peaks at about 4.18, 4.96, 5.33, 6.03, 6.46, 11.56 and 12.52 ± 0.2 ° 2?. In embodiments, the present application provides crystalline form LCZ-SA of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by its PXRD pattern having additional peaks located at about 14.42, 14.93, 16.92, 17.75 and 24.82 ± 0.2 ° 2?.

Second aspect of the present application relates to crystalline form LCZ-SA of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by a PXRD pattern having peaks located substantially as illustrated in the pattern of Figure 1.
Third aspect of the present application relates to a process for preparing crystalline form LCZ-SA of a complex comprising sacubitril, valsartan, sodium and saccharin comprising the steps of:
(i) dissolving LCZ-696 and saccharin in a suitable solvent;
(ii) adding a suitable anti-solvent ;
(iii) isolating crystalline form LCZ-SA of a complex comprising sacubitril, valsartan, sodium and saccharin from step (ii).

Fourth aspect of the present application relates to crystalline form LCZ-SB of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by its PXRD pattern having peaks at about 4.17, 4.95, 6.05, 11.53, 12.50, 20.04 and 26.86 ± 0.2 ° 2?. In embodiments, the present application provides crystalline form LCZ-SB of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by its PXRD pattern having additional peaks located at about 14.90, 16.92, 17.72 and 24.81 ± 0.2 ° 2?.

Fifth aspect of the present application relates to crystalline form LCZ-SB of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by a PXRD pattern having peaks located substantially as illustrated in the pattern of Figure 2.

Sixth aspect of the present application relates to a process for preparing crystalline form LCZ-SB of a complex comprising sacubitril, valsartan, sodium and saccharin comprising the steps of:
(i) mixing LCZ-696 and saccharin in a suitable solvent;
(ii) isolating crystalline form LCZ-SB of a complex comprising sacubitril, valsartan, sodium and saccharin from step (ii).

Seventh aspect of the present application relates to crystalline form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by its PXRD pattern having peaks at about 4.17, 5.87 and 12.51 ± 0.2 ° 2?. In embodiments, the present application provides crystalline form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by its PXRD pattern having additional peaks located at about 5.19, 16.92, 17.92 and 19.70 ± 0.2 ° 2?.

Eighth aspect of the present application relates to crystalline form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by a PXRD pattern having peaks located substantially as illustrated in the pattern of Figure 3.

Ninth aspect of the present application relates to a process for preparing crystalline form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin comprising the steps of:
(i) providing a mixture of LCZ-696 and saccharin in a suitable solvent;
(ii) isolating crystalline form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin from step (i).

Tenth aspect of the present application relates to pharmaceutical composition comprising crystalline form LCZ-SA or form LCZ-SB or form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustration of a PXRD pattern of crystalline form LCZ-SA of a complex of sacubitril, valsartan, sodium and saccharin, as obtained from Example 1.
Figure 2 is an illustration of a PXRD pattern of crystalline form LCZ-SB of a complex of sacubitril, valsartan, sodium and saccharin, as obtained from Example 2.
Figure 3 is an illustration of a PXRD pattern of crystalline form LCZ-SC of a complex of sacubitril, valsartan, sodium and saccharin, as obtained from Example 5.

DETAILED DESCRIPTION OF INVENTION
First aspect of the present application relates to crystalline form LCZ-SA of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by its PXRD pattern having peaks at about 4.18, 4.96, 5.33, 6.03, 6.46, 11.56 and 12.52 ± 0.2 ° 2?. In embodiments, the present application provides crystalline form LCZ-SA of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by its PXRD pattern having additional peaks located at about 14.42, 14.93, 16.92, 17.75 and 24.82 ± 0.2 ° 2?.

Second aspect of the present application relates to crystalline form LCZ-SA of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by a PXRD pattern having peaks located substantially as illustrated in the pattern of Figure 1.

The crystalline form LCZ-SA of a complex comprising sacubitril, valsartan, sodium and saccharin of the present application is stable and has excellent physico-chemical properties. The crystalline form LCZ-SA of a complex comprising sacubitril, valsartan, sodium and saccharin of the present application may be easily formulated into a pharmaceutical composition.

Third aspect of the present application relates to a process for preparing crystalline form LCZ-SA of a complex comprising sacubitril, valsartan, sodium and saccharin comprising the steps of:
(i) dissolving LCZ-696 and saccharin in a suitable solvent;
(ii) adding a suitable anti-solvent ;
(iii) isolating crystalline form LCZ-SA of a complex comprising sacubitril, valsartan, sodium and saccharin from step (ii).

The solvent in step (i) includes but not limited to an alcohol solvent such as methanol, ethanol and the like; a ketone solvent such as acetone, ethyl methyl ketone and the like; ester solvent such as ethyl acetate, n-butyl acetate and the like; and mixtures thereof. Specifically, the solvent may be an alcohol solvent. The LCZ-696 used in step (i) may be of any crystalline nature or a crude product. In embodiments of step (i), the mixture of a suitable solvent, LCZ-696 and saccharin may be heated up to the boiling point of the solvent to ensure that both LCZ-696 and saccharin are dissolved in the solvent.

The reaction mixture of step (i) may be stirred for about 5 minutes to about 5 hours at a temperature of about 15 °C to about boiling point of the solvent.

In embodiments of step (ii), the suitable anti-solvent includes but not limited to ether solvent such as diethyl ether, methyl tert-butyl ether and the like; aliphatic hydrocarbon solvent such as n-hexane, n-pentane and the like; and mixtures thereof. Specifically, the solvent may be a mixture of an ether solvent and an aliphatic hydrocarbon solvent.

Isolation of the precipitated material of step (ii) may be performed by techniques known in the art e.g. evaporation, distillation, filtration of isolated solid and the like. The solid may be washed with an ether solvent. Suitable temperatures for isolation may be less than about 25 °C, less than about 10 °C, or any other suitable temperatures. Filtration can be achieved by any means known in the art. The solid may optionally be dried. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C and most specifically at about 40 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.

Fourth aspect of the present application relates to crystalline form LCZ-SB of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by its PXRD pattern having peaks at about 4.17, 4.95, 6.05, 11.53, 12.50, 20.04 and 26.86 ± 0.2 ° 2?. In embodiments, the present application provides crystalline form LCZ-SB of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by its PXRD pattern having additional peaks located at about 14.90, 16.92, 17.72 and 24.81 ± 0.2 ° 2?.

Fifth aspect of the present application relates to crystalline form LCZ-SB of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by a PXRD pattern having peaks located substantially as illustrated in the pattern of Figure 2.

The crystalline form LCZ-SB of a complex comprising sacubitril, valsartan, sodium and saccharin of the present application is stable and has excellent physico-chemical properties. The crystalline form LCZ-SB of a complex comprising sacubitril, valsartan, sodium and saccharin of the present application may be easily formulated into a pharmaceutical composition.

Sixth aspect of the present application relates to a process for preparing crystalline form LCZ-SB of a complex comprising sacubitril, valsartan, sodium and saccharin comprising the steps of:
(i) mixing LCZ-696 and saccharin in a suitable solvent;
(ii) isolating crystalline form LCZ-SB of a complex comprising sacubitril, valsartan, sodium and saccharin from step (ii).

The solvent in step (i) includes but not limited to an alcohol solvent such as methanol, ethanol and the like; a ketone solvent such as acetone, ethyl methyl ketone and the like; ester solvent such as ethyl acetate, n-butyl acetate and the like; ether solvent such as diethyl ether, methyl tert-butyl ether and the like; aliphatic hydrocarbon solvent such as n-hexane, n-pentane and the like and mixtures thereof. In one embodiment, the solvent may be a mixture of an alcohol solvent, an ether solvent and an aliphatic hydrocarbon solvent. More specifically, the solvent may be a mixture of ethanol, methyl tert-butyl ether and n-pentane. In another embodiment, the solvent may be a mixture of a ketone solvent, an ether solvent and an aliphatic hydrocarbon solvent. More specifically, the solvent may be a mixture of acetone, methyl tert-butyl ether and n-pentane. In still another embodiment, the solvent may be an ether solvent. Specifically, the solvent may be methyl tert-butyl ether. The LCZ-696 used in step (i) may be of any crystalline nature or a crude product. In embodiments of step (i), the mixture of a suitable solvent, LCZ-696 and saccharin may be heated up to the boiling point of the solvent to ensure that both LCZ-696 and saccharin are dissolved in the solvent.

The reaction mixture of step (i) may be stirred for about 1 hour to about 25 hours at a temperature of about 15 °C to about boiling point of the solvent. Specifically, the reaction mixture of step (i) may be stirred for about 5 hour to about 15 hours at a temperature of about 20 °C to about 30 °C.

Isolation of the precipitated material of step (ii) may be performed by techniques known in the art e.g. evaporation, distillation, filtration of isolated solid and the like. The solid may be washed with an ether solvent. Suitable temperatures for isolation may be less than about 25 °C, less than about 10 °C, or any other suitable temperatures. Filtration can be achieved by any means known in the art. The solid may optionally be dried. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C and most specifically at about 40 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.

Seventh aspect of the present application relates to crystalline form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by its PXRD pattern having peaks at about 4.17, 5.87 and 12.51 ± 0.2 ° 2?. In embodiments, the present application provides crystalline form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by its PXRD pattern having additional peaks located at about 5.19, 16.92, 17.92 and 19.70 ± 0.2 ° 2?.

Eighth aspect of the present application relates to crystalline form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by a PXRD pattern having peaks located substantially as illustrated in the pattern of Figure 3.
The crystalline form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin of the present application is stable and has excellent physico-chemical properties. The crystalline form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin of the present application may be easily formulated into a pharmaceutical composition.

Ninth aspect of the present application relates to a process for preparing crystalline form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin comprising the steps of:
(i) providing a mixture of LCZ-696 and saccharin in a suitable solvent;
(ii) isolating crystalline form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin from step (i).

The solvent in step (i) includes but not limited to an alcohol solvent such as methanol, ethanol and the like; a ketone solvent such as acetone, ethyl methyl ketone and the like; ester solvent such as ethyl acetate, n-butyl acetate and the like; ether solvent such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether and the like; and mixtures thereof. Specifically, the solvent may be an ether solvent. The LCZ-696 used in step (i) may be of any crystalline nature or a crude product. In embodiments of step (i), the mixture of a suitable solvent, LCZ-696 and saccharin may be heated up to the boiling point of the solvent.

The reaction mixture of step (i) may be stirred for about 5 minutes to about 10 hours at a temperature of about 15 °C to about boiling point of the solvent. Specifically, the reaction mixture of step (i) may be stirred for about 1 hours to about 5 hours at about 20 °C to about 30 °C. More specifically, the reaction mixture of step (i) may be stirred for about 5 hours at about 25 °C.

Isolation of the precipitated material of step (ii) may be performed by techniques known in the art e.g. evaporation, distillation, filtration of isolated solid and the like. The solid may be washed with an ether solvent. Suitable temperatures for isolation may be less than about 25 °C, less than about 10 °C, or any other suitable temperatures. Filtration can be achieved by any means known in the art. The solid may optionally be dried. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C and most specifically at about 40 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.

The obtained crystalline form LCZ-SA or form LCZ-SB or form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.

Tenth aspect of the present application relates to a pharmaceutical composition comprising crystalline form LCZ-SA or form LCZ-SB or form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin. Crystalline form LCZ-SA or form LCZ-SB or form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin, as described in the present application, together with one or more pharmaceutically acceptable excipients of the present application may be 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 that 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 any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.

The PXRD conditions for the measurement of PXRD peaks of the complex comprising sacubitril, valsartan, sodium and saccharin of the present application are as follows:
Range: 3° 2? to 40° 2? in conventional reflection mode
Instrument: PANalytical X-ray Diffractometer
Detector: X’celerator
Source: Copper K-alpha radiation (1.5418 Angstrom).

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, ‘generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
A name used herein to characterize a crystalline form should not be considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that these designations are mere identifiers that should be interpreted according to the characterization information also presented herein.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms “comprising” and “comprises” mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

The term “complex” means a compound which comprises two or more components that form a unique molecular structure having unique properties. The complex comprising sacubitril, valsartan, sodium and saccharin of the present application is a multi-component complex having at least four species like sacubitril, valsartan, sodium and saccharin in the compound. These four species are joined by non-covalent intermolecular bonding between them. The non-covalent intermolecular bonding can be any interactions known in the art to form such complex, such as hydrogen bonding, van der Waals forces and p-p stacking. This interaction leads to an association of these four species present in the complex and distinguishes this complex over a physical mixture of the individual species.

The term “optional” or “optionally” is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.

EXAMPLES
Example 1: Preparation of crystalline form LCZ-SA of complex comprising sacubitril, valsartan and saccharin
To a solution of LCZ-696 (500 mg) and saccharin (95.6 mg) in ethanol (2 mL), methyl tert-butyl ether (20 mL) and n-pentane (20 mL) were added and kept at 20-30 °C for 5 days. The precipitated solid was filtered and dried under nitrogen atmosphere to provide the title compound.
Example 2: Preparation of crystalline form LCZ-SB of complex comprising sacubitril, valsartan and saccharin
To a mixture of methyl tert-butyl ether (25 mL), n-pentane (5 mL) and ethanol (5 mL), LCZ-696 (1 g) and saccharin (192 mg) were added. The reaction mixture was stirred for about 24 hours at 25 °C. The precipitated solid was filtered and dried under nitrogen atmosphere for about 1 hour at 25 °C to afford the title compound.
Example 3: Preparation of crystalline form LCZ-SB of complex comprising sacubitril, valsartan and saccharin
To a mixture of methyl tert-butyl ether (25 mL), n-pentane (5 mL) and acetone (5 mL), LCZ-696 (2 g) and saccharin (384 mg) were added. The reaction mixture was stirred for about 24 hours at 25 °C. The precipitated solid was filtered to afford the title compound.
Example 4: Preparation of crystalline form LCZ-SB of complex comprising sacubitril, valsartan and saccharin
A mixture of LCZ-696 (2 g), saccharin (396 mg), methyl tert-butyl ether (50 mL) was stirred for about 24 hours at 25 °C. The solvent was evaporated completely under reduced pressure in a rotavapor at 25 °C to provide the title compound.
Example 5: Preparation of crystalline form LCZ-SC of complex comprising sacubitril, valsartan and saccharin
A mixture of LCZ-696 (2 g) and saccharin (396 mg) in cyclopetyl methyl ether (50 mL) was stirred for 24 hours 25 °C. The solvent was evaporated completely under reduced pressure in a rotavapor at 25 °C to provide the title compound.
,CLAIMS:WE CLAIM:
1. A crystalline form LCZ-SA of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by its PXRD pattern having peaks at about 4.18, 4.96, 5.33, 6.03, 6.46, 11.56 and 12.52 ± 0.2 ° 2?.
2. A process for preparing crystalline form LCZ-SA of a complex comprising sacubitril, valsartan, sodium and saccharin comprising the steps of:
(i) dissolving LCZ-696 and saccharin in a suitable solvent;
(ii) adding a suitable anti-solvent ;
(iii) isolating crystalline form LCZ-SA of a complex comprising sacubitril, valsartan, sodium and saccharin from step (ii).
3. The process of claim 2, wherein the solvent in step (i) is an alcohol solvent.
4. The process of claim 2, wherein the anti-solvent in step (ii) is a mixture of an ether solvent and an aliphatic hydrocarbon solvent.
5. A crystalline form LCZ-SB of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by its PXRD pattern having peaks at about 4.17, 4.95, 6.05, 11.53, 12.50, 20.04 and 26.86 ± 0.2 ° 2?.
6. A process for preparing crystalline form LCZ-SB of a complex comprising sacubitril, valsartan, sodium and saccharin comprising the steps of:
(i) mixing LCZ-696 and saccharin in a suitable solvent;
(ii) isolating crystalline form LCZ-SB of a complex comprising sacubitril, valsartan, sodium and saccharin from step (ii).
7. The process of claim 6, wherein the solvent is selected from a group of alcohol solvent, ketone solvent, ester solvent, ether solvent, aliphatic hydrocarbon and mixtures thereof.
8. A crystalline form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin characterized by its PXRD pattern having peaks at about 4.17, 5.87 and 12.51 ± 0.2 ° 2?.
9. A process for preparing crystalline form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin comprising the steps of:
(i) providing a mixture of LCZ-696 and saccharin in a suitable solvent;
(ii) isolating crystalline form LCZ-SC of a complex comprising sacubitril, valsartan, sodium and saccharin from step (i).
10. The process of claim 9, wherein the solvent is an ether solvent.