DESC:Related Patent Application(s):

This application claims the priority to and benefit of Indian Patent Application No. 202141048120 filed on October 22, 2021; the disclosures of which are incorporated herein by reference.

Field of the Invention

The present invention relates to Adipic acid cocrystals of Voxelotor of Formula I.

I
The present invention also relates process for the preparation of Adipic acid cocrystals of Voxelotor.

Background of the Invention

VOXELOTOR (also known as Oxbryta) is chemically known as 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde. The molecular formula is C19H19N3O3 and the molecular weight is 337.4 grams per mole. The structural Formula I is:

I
Voxelotor is an orally bioavailable modulator and stabilizer of sickle cell hemoglobin (HbS), with potential use in the treatment of sickle cell disease (SCD). Upon administration, Voxelotor targets and covalently binds to the N-terminal valine of the alpha chain of HbS. This stabilizes HbS, thereby improving oxygen binding affinity. The binding of Voxelotor to HbS prevents HbS polymerization, reduces sickling, decreases red blood cell (RBC) damage and increases the half-life of RBCs. This improves blood flow and decreases hemolytic anemia.

Voxelotor was first disclosed in US 9,018,210 B2 (WO 2013102142 A1, Global Blood Therapeutics Inc.,).

Several process for preparation of Voxelotor have been disclosed in US 10077249 B2, WO 2020127945 A1, WO 2020127924 A1.

Cocrystal of Voxelotor is disclosed in WO 2021170977 A1.

The occurrence of different crystal forms i.e., polymorphism, is a property of some solid compounds. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties, such as PXRD patterns, IR absorption spectra, melting points (MP), TGA curves, DSC curves, solubilities, stabilities, hygroscopicities and different mechanical properties such as filterability and flowability. The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties. Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in recent articles, including A. Goho, "Tricky Business," Science News, August 21, 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any
previously unidentified form.

The active pharmaceutical ingredients (APIs) containing an acidic or basic functional group this principle can be exploited by the preparation of various crystalline salts of the active pharmaceutical ingredient to modulate and optimize the physicochemical properties of the obtained crystalline solid for a specific application. The changes in the physicochemical properties resulting from the inclusion of a counter ion in the crystal structure are a consequence of both the molecular structure and properties of the active pharmaceutical molecule and counter ion and the intermolecular interactions between the molecules in the crystal structure. It is therefore possible to change the physicochemical properties of the crystalline solid through the inclusion of different counter ions, giving crystalline salts with different physicochemical properties.

On the other hand, the formation of pharmaceutically acceptable co crystals of active pharmaceutical ingredients provides an alternative approach to the generation of new solid forms of the active substance. In this context a cocrystal, or alternatively co-crystal, is understood to be a binary molecular crystal containing the molecules of the API together with another molecular species in a defined stoichiometric ratio where both components are in their neutral state. In this case the terms "cocrystal" and "co-crystal" are generally understood to be synonymous terms referring to such a system. The second component in the cocrystal (the component other than the active pharmaceutical ingredient) is commonly referred to as a "cocrystal former". Pharmaceutically acceptable cocrystal formers include any molecule considered acceptable as a counter ion for a pharmaceutical salt or known as a pharmaceutical excipient.

A widely accepted definition of a pharmaceutical cocrystal is a crystalline system containing an active pharmaceutical molecule and a cocrystal former that is a solid at ambient temperature and pressure in a defined stoichiometric ratio, although a cocrystal is not limited to containing only two components. The components of the cocrystal are linked by hydrogen bonding and other non-covalent and non-ionic interactions. This definition differentiates co crystals from crystalline solvates, in which case one of the components is a liquid at ambient temperature and pressure.
The processes disclose in the prior art for the preparation of Voxelotor cocrystals suffers from one or more drawbacks as reproducibility, less yield, which does not result an industrially feasible process.

Hence, there is a need to provide a simple, reproducible, and industrially feasible process for the preparation of cocrystals of Voxelotor.

Summary of the Invention

The present invention relates to adipic acid cocrystal of Voxelotor and its process for preparation thereof.

Another aspect, the present invention relates to adipic acid cocrystal of Voxelotor is characterized by a PXRD pattern having peaks at about 6.48, 10.22, 10.48, 11.54, 12.63, 12.94, 14.20, 15.06, 15.48, 15.66, 16.04, 17.29, 18.33, 19.94, 20.95, 21.33, 21.93, 22.15, 22.87, 23.97, 24.86, 25.37, 26.44, 27.59, 28.07, 28.93, 29.77, 30.26, 31.12, 32.06, 32.84, 33.76, 34.91, 37.20, 39.38, 43.40, 46.42 and 47.71 ±0.2° 2?.

In another aspect, the present invention relates to adipic acid cocrystal of Voxelotor is characterized by a single crystal pattern having peaks at about a = 8.7334(2) Å, b = 8.9409(2) Å and c = 14.4090(3) Å.

In another aspect, the invention provides a process for the preparation of Adipic acid cocrystal of Voxelotor ;
comprising the steps of;
a) dissolving Voxelotor in a suitable solvent;
b) adding suitable acid to the solution obtained in step a);
c) heat the reaction mass;
d) stir the reaction mass;
e) cool the reaction mass; and
f) isolating the cocrystals of Voxelotor.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure. 1 depicts a PXRD pattern Aadipic acid cocrystal of Voxelotor, obtained by the procedure of example 1.
Figure. 2 depicts a DSC Adipic acid cocrystal of Voxelotor, obtained by the procedure of example 1.
Figure. 3 depicts ORTEP drawing of Adipic acid cocrystal of Voxelotor, obtained by the procedure of example 1.

Detailed Description of the Invention

Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:

The term "solvent” means hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; “ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dimethoxyethane, diethoxyethane, dibutoxyethane, tetrahydrofuran, 1,4-dioxane and the like; “ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; “polar-aprotic solvents” such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcohol solvents” such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, ethane-1,2-diol, propane-1,2-diol, alkyl ethers of ethylene glycol or propylene glycol selected from but not limited to ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono-n-butyl ether and the like; “polar solvents” such as water; formic acid, acetic acid, 2-Methoxyethanol or mixtures thereof.

In another aspect, the present invention provides adipic acid cocrystal of Voxelotor. The Adipic acid cocrystal of Voxelotor is characterized by a PXRD pattern having peaks at about 6.48, 10.22, 10.48, 11.54, 12.63, 12.94, 14.20, 15.06, 15.48, 15.66, 16.04, 17.29, 18.33, 19.94, 20.95, 21.33, 21.93, 22.15, 22.87, 23.97, 24.86, 25.37, 26.44, 27.59, 28.07, 28.93, 29.77, 30.26, 31.12, 32.06, 32.84, 33.76, 34.91, 37.20, 39.38, 43.40, 46.42 and 47.71 ±0.2° 2?.

In another aspect, the present invention provides process for the preparation of Adipic acid cocrystals of Voxelotor:
comprising the steps of;
a) dissolving Voxelotor in a suitable solvent;
b) adding suitable acid to the solution obtained in step a);
c) heat the reaction mass;
d) stir the reaction mass;
e) cool the reaction mass; and
f) isolating the cocrystals of Voxelotor.

Suitable solvent used in step a) is selected from the group consisting of hydrocarbon solvents; nitrile solvents; ether solvents; ester solvents; polar-aprotic solvents; chloro solvents; ketone solvents; nitrile solvents; alcohol solvents; polar solvents. Preferably methyl tert-butyl ether.

Suitable acid used in step b) is selected from the group consisting of Adipic acid, Oxalic acid, Glutaric acid, Glutamic acid and Aspartic acid. Preferably Adipic acid.

The reaction temperature may range from 45 °C to 60 °C and preferably at a temperature in the range from 50 °C to 55 °C. The duration of the reaction may range from 20 to 45 minutes. Preferably for a period of 30 minutes.

Cool the reaction mass range from 0 °C to 10 °C and preferably at a temperature in the range from 0 °C to 5 °C. The duration of the reaction may range from 2 to 4 hours. Preferably for a period of 3 hours.

Solubility
The aqueous solubility of 2:1 Co-crystal of Voxelotor adipic acid and Voxelotor Form II were determined in water at RT. The results are shown in the following Table 1. The Voxelotor adipic acid Co-crystal shows nearly 2 folds increase in aqueous solubility in comparison with Voxelotor Form II.
Table 1
Solvent Media Solubility at RT (mg/mL)
Voxelotor Form II Adipic acid Co-crystal of Voxelotor
Water 0.03 0.06

Single crystal of Voxelotor adipic acid Co-crystal

The single crystal structure which is represented in FIG. 3, the parameters for which are set forth in Table 2.
Table 2
CRYSTALDATA AND DATA COLLECTION PARAMETERS

Identification code Voxelotor hemiadipic acid (Batch No. NRL-201126/2170/138A)
Empirical formula C22H24N3O5
Formula weight 410.44
Temperature 294(2) K
Wavelength 0.71073 Å
Crystal system Triclinic
Space group P -1 P-1
Unit cell dimensions a = 8.7334(2) Å a= 107.1385(6)°.
b = 8.9409(2) Å ß= 93.7980(7)°.
c = 14.4090(3) Å ?= 95.5820(7)°.
Volume 1064.72(4) Å3
Z 2
Density (calculated) 1.280 Mg/m3
Absorption coefficient 0.092 mm-1
F(000) 434
Crystal size 0.260 x 0.220 x 0.140 mm3
? range for data collection 2.402 to 30.676°.
Index ranges -12<=h<=12, -12<=k<=12, -20<=l<=20
Reflections collected 24912
Independent reflections 6405 [R(int) = 0.0476]
Completeness to ? = 25.242° 97.5 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.7461 and 0.6980
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 6405 / 0 / 281
Goodness-of-fit on F2 1.002
Final R indices [I>2s(I)] R1 = 0.0585, wR2 = 0.1878
R indices (all data) R1 = 0.0760, wR2 = 0.2133
Largest diff. peak and hole 0.316 and -0.315 e.Å-3
Measurement Bruker D8 QUEST PHOTON-III Detector
Software Used SHELXTL-PLUS

EXPERIMENTAL PORTION:

The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.

EXAMPLES:

Example-1: Process for the preparation of Adipic acid Cocrystal of Voxelotor
Arranged a cleaned and dried 100 mL 4 neck RB, then charged Voxelotor (1 gram), Methyl tertbutyl ether (6 mL) and Adipic acid (0.55 eq) into RBF at 25-30 °C. Heated the reaction mass to 50-55 °C and stirred for 30 min at 50-55 °C, then cooled the reaction mass to 25-35 °C and stirred the reaction mass for 30 min at 25-35 °C, then cooled the reaction mass to 0-5°C and stirred for 3 hour at 0-5 °C. Filtered the solid and suck dried for 30 min resulted in Voxelotor: Adipic acid (2:1).

Weight-0.8 gram.
,CLAIMS:
1. A co-crystal comprising Voxelotor and Adipic acid.
2. The Co-crystal as claimed in claim 1, wherein the molar ratio of Voxelotor and Adipic acid is 2:1.
3. The Co-crystal as claimed in claim 1, is characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of 6.48, 10.22, 10.48, 11.54, 12.63, 12.94, 14.20, 15.06, 15.48, 15.66, 16.04, 17.29, 18.33, 19.94, 20.95, 21.33, 21.93, 22.15, 22.87, 23.97, 24.86, 25.37, 26.44, 27.59, 28.07, 28.93, 29.77, 30.26, 31.12, 32.06, 32.84, 33.76, 34.91, 37.20, 39.38, 43.40, 46.42 and 47.71 ±0.2° 2?.
4. The Co-crystal as claimed in claim 3, is substantially shown in Figure-1.
5. The Co-crystal as claimed in claim 1 to 3, is prepared comprising the steps of
a) dissolving Voxelotor in a suitable solvent;
b) adding suitable acid to the solution obtained in step a);
c) heat the reaction mass;
d) stir the reaction mass;
e) cool the reaction mass; and
f) isolating the cocrystals of Voxelotor.
6. The Co-crystal as claimed in claim 1, is characterized by single crystal diffractogram comprising reflections at about a = 8.7334(2) Å, b = 8.9409(2) Å and c = 14.4090(3) Å.
7. The single crystal as claimed in claim 6, is substantially shown in Figure-3 and table-2.