BACKGROUND OF THE INVENTION
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl) pyridine-3-yl) methoxy)
10 benzaldehyde (1) is commonly known as “Voxelotor” and it is a haemoglobin S
polymerization inhibitor, indicated for the treatment of sickle cell disease in adults
and pediatric patients 12 years of age and older. Voxelotor is approved by United
States Federal Drug Administration (USFDA) on Nov 25, 2019, to Global Blood
Therapeutics Inc under the brand name OXBRYTA™. It is available in 500mg &
15 300mg oral tablet. Recommended dosage for sickle cell disease is 1500 mg and for
hepatic impairment patients with severe hepatic impairment (Child Pugh C) is 1000
mg taken orally once daily with or without food.
US patent 9018210 B2 describes purification of Voxelotor by silica gel using ethyl
20 acetate and hexane. But this patent publication silent about crystalline forms of
Voxelotor.
US patent 9447071 B2 describes Form-I, Form-II and Form-N of Voxelotor and
process for its preparation thereof.
25
3
Indian patent 202141048120 describes Adipic acid, Oxalic acid, Glutaric acid,
Glutamic acid, and Aspartic acid. Preferably Adipic acid co-crystal of Voxelotor.
PCT patent application WO2022249200 describes methyl paraben and
5 hydroquinone co-crystal of Voxelotor.
Inventors of the present invention surprisingly found novel crystalline form of
Voxelotor comprising Voxelotor and maleic acid and also process for their
preparation thereof.
10
OBJECTIVE OF THE INVENTION
In one objective, the present invention relates to novel crystalline form of Voxelotor
(1).
15 In another objective, the present invention relates to process for the preparation of
novel crystalline form of Voxelotor (1).
In further objective, the present invention relates to novel crystalline form of
Voxelotor (1) obtained according to the present invention is having purity of greater
20 than 99.5%, preferably greater than about 99.7%, more preferably greater than
about 99.8% by High Performance Liquid Chromatography.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to novel crystalline form of Voxelotor
25 (1).
In another aspect, the present invention relates to novel crystalline form of
Voxelotor (1) is characterized by a PXRD pattern having peaks at about 5.38, 6.71,
7.33, 12.74, 13.1, 14.14, 14.82, 15.44, 15.98, 16.29, 16.52, 17.60, 17.82, 18.66,
30 20.37, 20.64, 22.40, 22.85, 23.39, 24.99, 25.98, and 27.65±0.2° 2θ.
4
In another aspect, the present invention relates to a process for the preparation of
novel crystalline form of Voxelotor (1), comprising the steps of:
a) dissolving Voxelotor (1) in a suitable solvent;
b) adding maleic acid to the solution obtained in step a);
5 c) heating and cooling the reaction mass to a suitable temperature; and
d) isolating novel crystalline form of Voxelotor (1).
In another aspect, the present invention relates to another process for the preparation
of novel crystalline form of Voxelotor (1), comprising the steps of:
10 a) providing a solution of Voxelotor and maleic acid in a solvent,
b) isolating crystalline Form of Voxelotor (1)
In another aspect, the crystalline form obtained according to the present invention
could be either co-crystal or salt of Voxelotor (1).
15
In another aspect of the present invention provides novel crystalline form of
Voxelotor (1) obtained according to the present invention is having purity of greater
than 99.5%, preferably greater than about 99.7%, more preferably greater than
about 99.8% by High Performance Liquid Chromatography.

We Claim:
1. A crystalline form of Voxelotor comprising Voxelotor and Maleic acid.
2. The crystalline form as claimed in claim 1, wherein the molar ratio of
Voxelotor and Maleic acid is 1.5-1.0: 1.0-0.5.
5 3. A crystalline form Voxelotor and maleic acid characterized by powder X-ray
diffractogram that comprises one or more peaks at about 5.38, 6.71, 7.33,
12.74, 13.1, 14.14, 14.82, 15.44, 15.98, 16.29, 16.52, 17.60, 17.82, 18.66,
20.37, 20.64, 22.40, 22.85, 23.39, 24.99, 25.98, and 27.65±0.2 degrees 2θ.
4. The crystalline form as claimed in claim 1, is substantially shown in Figure-1.
10 5. A process for the preparation of crystalline form of Voxelotor comprising
Voxelotor and Maleic acid, comprising the steps of:
a) dissolving Voxelotor (1) in a solvent;
b) adding maleic acid to the solution obtained in step a);
c) heating the reaction mass at 40-45°C;
15 d) cooling the reaction mass at 2-5°C; and
e) isolating novel crystalline form of Voxelotor (1).
6. A process for the preparation of crystalline form of Voxelotor comprising
Voxelotor and Maleic acid, comprising the steps of:
a) providing a solution of Voxelotor and maleic acid in a solvent; and
20 b) isolating crystalline form of Voxelotor.
7. The process as claimed in claim 5 and claim 6, wherein the solvent is methyl
tert-butyl ether.
8. A pharmaceutical composition comprising crystalline form of Voxelotor as
claimed in any of the preceding claims and at least one pharmaceutically
25 acceptable excipient.