DESC:FIELD OF THE INVENTION

The present invention relates novel polymorph of co-crystals of Ibrutinib, Bruton's tyrosine kinase (Btk) inhibitor, with succinic acid. More particularly relates to solvated form of Ibrutinib; succinic acid co-crystal of formula (I), a pharmaceutical composition comprising the same as well as a method of preparing the same.

Formula (I)

BACKGROUND OF THE INVENTION

Kinases have emerged as one of the most intensively pursued targets in current pharmacological research, especially for cancer, due to their critical roles in cellular signaling. In the past one and half decades witnessed an unparalleled success in the development of therapeutically useful kinase inhibitors, powered by tremendous progress in both academic and industrial settings.

During the last few years, a plethora of drug products has reached the market, among that poorly water-soluble drug candidates are becoming more prevalent in the pharmaceutical industry (J Pharmacol Toxicol Methods 2000;44(1):235–49). Further, approximately 40% of the marketed immediate release oral products are categorized as practically insoluble. It was estimated that 70% and more new chemical entities (NCE) are being identified by combinatorial screening program are poorly water-soluble (Eur J Pharm Sci. 2006;29(3-4):278–87). Physical modification often aims to enlarge the particle surface area, improve solubility and improving the stability of an API. Hence, screening of these molecule for polymorphism including solvates, hydrates, co-crystal become part of routine screening in the developmental of new drug.

Pharmaceutical co-crystals can be employed to improve vital physicochemical characteristics of a drug, including solubility, dissolution, bioavailability and stability of pharmaceutical compounds while maintaining its therapeutic activity. Following are literatures suggest that the co-crystal of kinase inhibitor with conformer.

WO 2013189910 A1 discloses co-crystal of imatinib mesilate comprising as active ingredient 4-[(4-methyl-1- piperazinyl) methyl] –N –[4-methyl-3-[ [4-(3-pyridinyl)-2-pyrimidinyl] amino]-phenyl]- benzamide methanesulfonic acid salt and co-crystal former such as benzoic acid, fumaric acid or succinic acid.

WO2014060449 A1 discloses multicomponent molecular crystals (co-crystals), comprising nilotinib or especially a hydrohalogenide salt of nilotinib, and a carboxylic acid, carboxylic acid ester, carboxylic acid amide, or sulfonic acid as a second component acting as a co-crystal former.

WO 2015170345 A1 discloses co-crystals of gefitinib with co-crystal former selected from aliphatic dicarboxylic acid and aromatic di and tricarboxylic acids which exhibit better solubility, dissolution rate hence enhanced bioavailability compared to the parent drug.

WO2016156127 A1 discloses co-crystals of ibrutinib with carboxylic acids, a pharmaceutical composition comprising the same as well as a method of preparing the same. The amide group of ibrutinib establishes H-bonds with the acid group of succinic acid (both carboxylic groups of succinic acid are connected with H-bonds to ibrutinib: O127 –H271 to O91 and O125-H1251 to O1 of the respective molecules) as shown below:

The existence of more than one crystalline form of a given compound, typically in the form of polymorphs or solvates, represents both a problem and an opportunity. "The number of forms known for a given compound is proportional to the time and money spent in research on that compound" (McCrone, W.C. Polymorphism in Physics and Chemistry of the Organic Solid-State, pp. 726, Fox et al. Eds., Interscience: New York, 1965).

In general it was thought that co-crystals are less prone to polymorphism and could be used to minimize polymorphism. Literatures such as Cryst Eng Comm, 2012, 4, 6362–6365 and Cryst. Growth Des., 2012, 12, 2147–2152 suggests that polymorphs are well known for their distinct pharmaceutical behavior and the same is applicable to the polymorphic co-crystals. Further Cryst Eng Comm, 2013,15, 7456-7461 discusses dissolution behavior of metastable form I vs stable form II sulfacetamide-acetamide (1:1) cocrystals and concluded that Form 1 is assembled via N-H•••O=S and N-H•••O=C H bonds whereas form 2 has a similar hydrogen-bonded ring motif made of N-H•••O=C H-bonds.

FORM I FORM II

Ibrutinib is an organic small molecule having IUPAC name 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3, 4-d] pyrimidin-1-yl] piperidin-1-yl] prop-2-en-1-one.

Ibrutinib is a selective, irreversible inhibitor of BTK first disclosed in WO 2008/039218, which has been shown to be highly clinically efficacious in relapsed/refractory CLL and mantle cell lymphoma (see e.g. Burger et. Leukemia & Lymphoma (2013), 54(11), 2385-91).

WO 2013/184572, discloses six different crystalline forms of ibrutinib base. According this publication Ibrutinib has a very low solubility in water (0.013 mg/ml at about pH 8). This results in problems in the bioavailability of the active ingredient.

The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no "standard" procedures that can be used to prepare polymorphic forms of a substance. This is well-known in the art, as reported, for example, by A. Goho, "Tricky Business," Science News, Vol. 166(8), August 2004.

In the pharmaceutical industry, there is a constant need to identify the critical physicochemical parameters such as novel salts, polymorphic forms, and co-crystals that affect the drug's performance, stability, etc., which may play a key role in determining a drug's market acceptance and success. Considering the importance of the Ibrutinib, the present inventors diligently did research and identified novel polymorphic of solvated form of Ibrutinib succinic acid co-crystal.

In the following description, various aspects and embodiments of the invention will become evident. In its broadest sense, the invention could be practiced without having one or more features of these aspects and embodiments. Further, these aspects and embodiments are exemplary.

OBJECT OF THE INVENTION

An objective of the invention is to provide novel polymorph of Ibrutinib:succinic acid co-crystal.

Another objective of the present invention is to provide a novel solvated form of Ibrutinib:succinic acid co-crystal.

SUMMARY OF THE INVENTION

An aspect of the present invention is to provide a novel solvated form of Ibrutinib:succinic acid co-crystal of formula (I):

wherein X is a solvent.

Another aspect of the present invention is to provide a process for the preparation of novel solvated form of Ibrutinib:succinic acid co-crystal comprising:
a) providing a solution of Ibrutinib in a solvent or mixture of solvents;
b) adding succinic acid to the reaction mixture obtained in step a; and
c) isolating solvated form of Ibrutinib: succinic acid co-crystal.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Hydrogen bond geometry of single crystal structure of Ibrutinib: succinic acid :methyl acetate co-crystal.
Figure 2: Packing diagram of the Ibrutinib:succinic acid:methyl acetate co-crystal.
Figure 3: PXRD of Ibrutinib:succinic acid:methyl acetate co-crystal.
Figure 4: DSC of Ibrutinib:succinic acid:methyl acetate co-crystal.
Figure 5: PXRD of Ibrutinib:succinic acid:methyl ethyl ketone co-crystal.
Figure 6: DSC of Ibrutinib:succinic acid:methyl ethyl ketone co-crystal.

DETAILED DESCRIPTION OF THE INVENTION

The term "co-crystal," as used herein, refers to a stoichiometric multi component system comprising an ibrutinib and a pharmaceutical co- crystal former, preferably succinic acid, wherein the active pharmaceutical ingredient and the pharmaceutical co- crystal former are connected by non-covalent interactions. Non-covalent interaction is being defined as an interaction which is neither ionic nor covalent and includes for example: hydrogen bonds, van der Waals forces, and p-p interactions.

The co-crystals of the present invention may contain one or more solvate molecules in the crystalline lattice. Solvates of Ibrutinib that do not further comprise a co-crystal former, i.e. succinic acid are not co-crystals according to the present invention. The solvent molecule is attached to Ibrutinib:succinic acid co-crystal via non-covalent binding or trapped in the crystal lattices.

An embodiment of the present invention is to provide of novel solvated form of Ibrutinib :succinic acid co-crystal, wherein the molar ratio of succinic acid and ibrutinib in the co-crystal is about 0.3 to about 0.6. The novel solvated form of Ibrutinib:succinic acid co-crystal which have improved physiochemical and/or pharmaceutical properties over Ibrutinib itself.

X-ray single crystal study of Ibrutinib: succinic acid:methyl acetate co-crystal provided in the below Table – 1:
Table - 1
Temperature 100K
Crystal System Orthorhombic
Space group P21212
Unit cell dimensions
a 9.817(2) Å
b 35.686(7) Å
c 7.653(2) Å
a 90?
ß 90?
? 90?
Volume, V 2681.1(10) Å3

In the unit cell of novel solvated Ibrutinib:succinic acid co-crystal the packing is stabilized by complex H-bond network of chains formed by Ibrutinib : succinic acid : ibrutinib unities. The hydrogen bond geometry and packing diagram of Ibrutinib:succinic acid;methyl acetate co-crystal of the present invention has shown in the shown in the Figure 1 and Figure 2 respectively.

The PXRD diffraction peaks of Ibrutinib:succinic acid:methyl acetate co-crystal is given in Table -2 below:
Table -2
Angle (2T) Relative intensity (%)
4.84 1.52
9.27 1.39
9.71 43.02
10.20 12.86
11.69 23.95
12.4 0.69
13.24 5.68
13.57 6.64
14.77 16.3
15.11 8.16
15.36 9.55
16.72 6.38
17.16 8.06
17.53 7.82
18 22.67
18.17 37.2
18.58 13.65
19 14.64
19.29 22.12
19.52 11
20.67 100
21.54 10.6
21.94 13.73
22.5 65.51
23.01 19.87
23.55 16.62
24.43 22.45
24.86 5.27
26.1 11.61
26.63 4.09
27.42 5.92
27.66 2.75
28.45 4.55
28.8 5.9
29.64 7.21
30.34 6.2
30.84 3.63
31.71 5.85
32.67 2.11
33.32 2.36
34.48 2.17
35.11 1.4
35.64 2.78
36.64 3.54
36.91 3.55
37.97 1.05
38.66 1.41

Representative compounds of novel solvated Ibrutinib:succinic acid co-crystal includes, but not limited to:
1. Ibrutinib:succinic acid:methyl acetate co-crystal
2. Ibrutinib:succinic acid:methyl ethyl ketone co-crystal
3. Ibrutinib:succinic acid:methyl isopropyl ketone co-crystal
4. Ibrutinib:succinic acid: cyclopropyl methyl ketone co-crystal
5. Ibrutinib:succinic acid: ethyl acetate co-crystal
An another embodiment of the present invention provides a process for the preparation of novel solvated form of Ibrutinib:succinic acid co-crystal comprising :
a) providing a solution of Ibrutinib in a solvent or mixture of solvents;
b) adding succinic acid to the reaction mixture obtained in step a; and
c) isolating solvated form of Ibrutinib: succinic acid co-crystal.
The term suitable solvate denotes that any solvent that forms solvate with Ibrutinib succinic acid co-crystal. Accordingly the suitable solvents of the present invention is selected form the group consisting of methyl acetate, methyl ethyl ketone, ethyl acetate, methyl isopropyl ketone and cyclopropyl methyl ketone.

Yet another embodiment of the present invention, the solvated form of Ibrutinib:succinic acid co-crystal is isolated from the reaction mass by conventional methods, like cooling, adding anti-solvent, distillation etc. Preferably the compound is isolated by adding anti-solvent such as cyclohexane, heptane, hexane, ether etc. The free succinic acid if present in the co-crystal can be removed by slurry washing the compound with water or basic solution.

Still another embodiment of the present invention, about 0.4 to about 2.0 mole equivalent of succinic acid with respect to Ibrutinib is used in step (b). Preferably 0.5 mole equivalent is used.

Yet another embodiment of the present invention, the novel solvated form of Ibrutinib:succinic acid co-crystal contains 3% to 12% solvent in the unit cell.

A pharmaceutical composition according to various embodiments of the invention may be any pharmaceutical form which contains a novel solvated form of Ibrutinib succinic acid as described herein. Depending on the type of pharmaceutical composition, the pharmaceutically acceptable carrier may be chosen from any one or a combination of carriers known in the art. The choice of the pharmaceutically acceptable carrier depends upon the pharmaceutical form and the desired method of administration to be used. For a pharmaceutical composition according to various embodiments of the invention, that one having a novel solvated form of Ibrutinib:succinic acid as described herein, a carrier may be chosen that maintains the cocrystal form. In other words, the carrier, in some embodiments, will not substantially alter the novel solvated form of Ibrutinib: succinic acid co-crystal as described herein.

In the foregoing section, embodiments are described by way of an example to illustrate the process of the invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.

Examples:
Ex-1: Preparation of Ibrutinib:succinic acid: methyl acetate co-crystal
To methyl acetate (100 ml), Ibrutinib (10.0 g) and succinic acid (1.47 g) was added and stirred for 19 hours at 20-30oC. To reaction mass cyclohexane (200ml) was added and stirred for 4 to 5 hours at 20-30oC. The solid obtained was filtered and washed with cyclohexane (20ml). The solid was dried under vacuum at 35-40oC to obtain Ibrutinib:succinic acid:methyl acetate co-crystal (1:0.5) (11.0g) . The PXRD pattern of the obtained solid is shown in Fig-3.
Purity: 99.72% by HPLC
Content of methyl acetate: 6.05% by GC
Succinic acid content: 10.96 % by HPLC

Ex.-2: Preparation of Ibrutinib:succinic acid:methyl ethyl ketone co-crystal
To methyl ethyl ketone (100 ml), Ibrutinib (10.0 g) and succinic acid (1.47 g) was added and stirred for 19 hours at 20-30oC. To reaction mass cyclohexane (200ml) was added and stirred for 3 to 4 hours at 20-30oC. The solid obtained was filtered and washed with cyclohexane (20ml). The solid was dried under vacuum at 35-40oC to obtain Ibrutinib succinic acid:methyl ethyl ketone co-crystal (1:0.5) (11.0g) . The PXRD pattern of the obtained solid is shown in Fig-5.
Purity: 99.66% by HPLC
Content of methyl ethyl ketone: 5.21% by GC
Succinic acid content: 11.19 % by HPLC

Ex.-3: Preparation of Ibrutinib:succinic acid:methyl acetate co-crystal
To methyl acetate (100 ml), Ibrutinib (10.0 g) and succinic acid (2.68 g) was added and stirred for 18 hours at 20-30oC. The solid obtained was filtered and washed with cyclohexane (20ml). The solid was dried under vacuum at 35-40oC to obtain Ibrutinib:succinic acid:methyl acetate co-crystal (1:0.5) (11.0g) . The PXRD pattern of the obtained solid is shown in Fig-3.
Purity: 99.60% by HPLC
Content of methyl acetate: 7.03% by GC
Succinic acid content: 11. 90 % by HPLC

Ex.-4: Preparation of Ibrutinib:succinic acid:methyl ethyl ketone co-crystal
To methyl ethyl ketone (1000 ml), Ibrutinib (100.0 g) and succinic acid (26.81 g) was added and stirred for 2-3 hours at 20-30°C. To reaction mass cyclohexane (2000 ml) was added and stirred for 3 to 4 hours at 20-30°C. The solid obtained was filtered and washed with cyclohexane (100 ml). The solid was dried under vacuum at 35-40° C to obtain a solid having 1:1 Ibrutinib and succinic acid (115.0g). The solid obtained was stirred with water for 12 hrs followed by filtration and drying to obtain solvated form of Ibrutinib:succinic acid:methyl ethyl ketone co-crystal.
Purity: 99.49% by HPLC

Ex.-5: Preparation of Ibrutinib:succinic acid:ethyl acetate co-crystal
To ethyl acetate (100 ml), Ibrutinib (10.0 g) and succinic acid (1.47 g) was added and stirred for 19 hours at 20-30oC. To reaction mass cyclohexane (200 ml) was added and stirred for 3 to 4 hours at 20-30oC. The solid obtained was filtered and washed with cyclohexane (20 ml). The solid was dried under vacuum at 35-40oC to obtain Ibrutinib:succinic acid:ethyl acetate co-crystal (1:0.5) (11.0g) .
Purity: 99.74% by HPLC
Content of ethyl acetate: 7.06% by GC
Succinic acid content: 11.33 % by HPLC

Ex.-6: Preparation of Ibrutinib:succinic acid:methyl isopropyl ketone co-crystal
To methyl isopropyl ketone (100 ml), Ibrutinib (10.0 g) and succinic acid (1.47 g) was added and stirred for 19 hours at 20-30oC. To reaction mass cyclohexane (200ml) was added and stirred for 3 to 4 hours at 20-30oC. The solid obtained was filtered and washed with cyclohexane (20ml). The solid was dried under vacuum at 35-40oC to obtain Ibrutinib: succinic acid: methyl isopropyl ketone co-crystal (1:0.5) (10.6g) .
Purity: 99.76% by HPLC
Content of methyl isopropyl ketone: 4.2% by GC
Succinic acid content: 12.09 % by HPLC

Ex.-7: Preparation of Ibrutinib:succinic acid: cyclopropyl methyl ketone co-crystal
To cyclopropyl methyl ketone (100 ml), Ibrutinib (10.0 g) and succinic acid (1.47 g) was added and stirred for 19 hours at 20-30oC. To reaction mass cyclohexane (200 ml) was added and stirred for 3 to 4 hours at 20-30oC. The solid obtained was filtered and washed with cyclohexane (20ml). The solid was dried under vacuum at 35-40oC to obtain Ibrutinib:succinic acid: cyclopropyl methyl ketone co-crystal (1:0.5) (10.6g) .
Purity: 99.37% by HPLC
Content of cyclopropyl methyl ketone: 7.26% by GC
Succinic acid content: 12.49 % by HPLC

Ex.-8: Preparation of Form B of Ibrutinib
Ibrutinib (10 g) in n-propanol: water (1:1) (40 ml) was charged in to the round bottomed flask equipped with a mechanical stirrer at 50°C-55°C. The reaction mixture was filtered, reheated at 50-550 C and cooled to 25-350C. Form B (seed crystal) was added and stirred at 20-250C.The reaction mixture was cooled to 0-50C, stirred, filtered and dried at 30-350C to obtain Form B of Ibrutinib.
Purity: 99.59% by HPLC
Yield: 68%

Ex.-9: Preparation of Form B of Ibrutinib
Ibrutinib (10 g) in n-propanol: water (1:1) (40 ml) was charged in to the round bottomed flask equipped with a mechanical stirrer at 50°C-55°C. The reaction mixture was filtered, reheated at 50-550 C and cooled to 25-350C. Form B (seed crystal) was added and stirred at 20-250C. Water (20ml) was added to the reaction mixture and stirred at 20-250C. The reaction mixture was cooled to 0-50C, stirred, filtered and dried at 30-350C to obtain Form B of Ibrutinib.
Purity: 82% by HPLC
Yield: 68%
,CLAIMS:1. A process for the preparation of novel solvated form of Ibrutinib: succinic acid: co-crystal comprising :
a) providing a solution of Ibrutinib in a suitable solvent;
b) adding succinic acid to the reaction mixture obtained in step a); and
c) isolating solvated form of Ibrutinib: succinic acid co-crystal.

2. The process as claimed in claim 1,where in the suitable solvent is selected form the group consisting of methyl acetate, ethyl acetate, methyl ethyl ketone, methyl isopropyl ketone and cyclopropyl methyl ketone.

3. The process as claimed in claim 1, where in the isolation of novel solvated form of Ibrutinib: succinic acid: co-crystal in step (c) is done by adding anti-solvent such as cyclohexane, heptane, hexane and ether.

4. The process as claimed in claim 1, wherein the novel solvated form of Ibrutinib: succinic acid: co-crystal is selected from methyl acetate, ethyl acetate, methyl ethyl ketone, methyl isopropyl ketone and cyclopropyl methyl ketone.

5. The process as claimed in claim 4, wherein the novel solvated form of Ibrutinib: succinic acid: co-crystal is methyl acetate.

6. Ibrutinib: succinic acid: methyl acetate co-crystal as claimed in claim 5 having X-ray single crystal study as provided in the below Table:
Temperature 100K
Crystal System Orthorhombic
Space group P21212
Unit cell dimensions
a 9.817(2) Å
b 35.686(7) Å
c 7.653(2) Å
a 90?
ß 90?
? 90?
Volume, V 2681.1(10) Å3

7. Ibrutinib: succinic acid: methyl acetate co-crystal as claimed in claim 5 having PXRD diffraction peaks at 9.71, 11.69, 22.67, 18.17 and 22.5.

Dr. S. Ganesan
Dated 4th May 2018