DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to the filing date of Indian Provisional Application No.
IN 201941030395, filed on Jul 27, 2019;
FIELD OF THE INVENTION:
The present invention relates to Co-crystal of Roxadustat and its preparation thereof.
BACKGROUND OF THE INVENTION:
Roxadustat is chemically known as [(4-hydroxy-1-methy1-7-phenoxy-isoquinoline-3-
carbony1)-amino]-acetic acid and is represented by Formula 1. Roxadustat is for the
treatment of anemia in patients with chronic kidney disease (CKD). It is in Phase III
clinical development in US.
Formula I
Roxadustat was first disclosed in US7323475 patent.
US patent 8883823 disclosed crystalline Roxadustat Form A, Form B, Form C & Form D
[DMSO: water solvate], crystalline sodium salt, crystalline L-arginine salt, crystalline Llysine
salt, crystalline ethanolamine salt, crystalline diethanolamine salt, crystalline
tromethamine salt and their preparations thereof.
US patent 9206134 disclosed crystalline forms I, II, III, IV, V, VI & VII of Roxadustat
and their preparation thereof.
IN201641016266 patent application disclosed amorphous solid dispersion comprising
Roxadustat and a pharmaceutically acceptable carrier and its preparation thereof.
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IN201741007950 patent application disclosed Co-crystal of Roxadustat comprising
Roxadustat and Co-crystal former selected from caffeine, adenine, thymine, saccharine or
the like.
IN201741028591 patent application disclosed L-proline co-crystal of Roxadustat,
crystalline forms of Roxadustat [Form-d & Form-?], urea co-crystal of Roxadustat and
Nicotinamide co-crystal of Roxadustat.
The inventors of the present invention have developed Benzamide Co-crystal of
Roxadustat which is stable to heat and humidity and shows improved solubility compared
to native API and suitable for formulation development.
SUMMARY OF THE INVENTION:
The main aspect of the present invention provides Co-crystal of Roxadustat with
Benzamide and its preparation thereof.
In one aspect, the Co-crystal of Roxadustat Benzamide is characterized by powder X-ray
diffraction pattern having peaks at 11.04, 14.66, 17.19, 22.21, 23.54, 25.26 ± 0.2° 2?.
Yet in another aspect, the Co-crystal of Roxadustat Benzamide is characterized by
powder X-ray diffraction pattern as shown in Figure 1.
Yet in another aspect, the present invention provides a process for the preparation of Cocrystal
of Roxadustat Benzamide comprising the steps of:
a) contacting Roxadustat with Benzamide in presence of an organic solvent, and
b) isolating Co-crystal of Roxadustat Benzamide.
Yet in another aspect, the Co-crystal formed according to the present invention comprises
Roxadustat and Benzamide in the molar ratio of 1:1.
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Brief description of the figures:
Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of Roxadustat Benzamide
(1:1) Co-crystal.
DETAIL DESCRIPTION OF THE INVENTION:
The present invention relates to Co-crystal of Roxadustat with Benzamide and its
preparation thereof.
In one embodiment, the present invention relates to Co-crystal of Roxadustat Benzamide
characterized by powder X-ray diffraction pattern having peaks at 11.04, 14.66, 17.19,
22.21, 23.54, 25.26 ± 0.2° 2?.
Yet in another embodiment, the Co-crystal of Roxadustat Benzamide is characterized by
powder X-ray diffraction pattern as shown in Figure 1.
Yet in another embodiment, the present invention relates to a process for the preparation
of Co-crystal of Roxadustat Benzamide comprising the steps of
c) contacting Roxadustat with Benzamide in presence of an organic solvent,
d) isolating Co-crystal of Roxadustat Benzamide.
Yet in another embodiment, the present invention relates to a process for the preparation
of Co-crystal of Roxadustat Benzamide comprising the steps of
a) contacting Roxadustat with Benzamide in presence of an organic solvent,
b) heating the reaction mass,
c) cooling the reaction mass, and
d) isolating Co-crystal of Roxadustat Benzamide.
According to the present invention, Roxadustat and Benzamide may be contacted in
presence of an organic solvent selected from esters, ketones, alcohols such as ethyl
acetate, acetone, methanol and ethanol preferably ethyl acetate. The resultant reaction
mass may be heated to about 70-85°C followed by cooling to room temperature and
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maintained. The solid formed may be filtered to obtain Co-crystal of Roxadustat
Benzamide.
According to the present invention, the Co-crystal of Roxadustat Benzamide may be
isolated by employing one or more techniques selected from the group consisting of
filtration, decantation, distillation, precipitation, concentration.
According to the present invention, the Co-crystal of Roxadustat Benzamide formed by
the present process is in the molar ratio of 1:1.
Yet in another embodiment, the physical stability of 1:1 co-crystal of Roxadustat
Benzamide was determined by storing the samples at 40°C and 75% relative humidity
(RH) and at 25°C and 60% relative humidity (RH) conditions for six months and the
samples were analyzed by PXRD. The results are shown in below Table 1. The 1:1 Cocrystal
of Roxadustat Benzamide was found to be physically stable at 40°C and 75%
relative humidity (RH) and at 25°C and 60% relative humidity (RH) conditions up to six
months.
Table 1
Conditions/ Polymorph
1:1 Co-crystal of
Roxadustat Benzamide
PXRD
at 40°C/75% RH
Initial Co-crystal
1 month Stable
2 months Stable
3 months Stable
6 months Stable
at 25°C/60% RH
Initial Co-crystal
1 month Stable
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2 months Stable
3 months Stable
6 months Stable
Solubility
The aqueous solubility of 1:1 Co-crystal of Roxadustat Benzamide and literature Form A
were determined in water at 37°C. The results are shown in Table 2. 1:1 Co-crystal of
Roxadustat Benzamide shows ~ 250 folds increase in aqueous solubility in comparison
with Literature Form A.
Table 2
Buffer pH (USP)
Aqueous Solubility at 37°C (mg/mL)
Roxadustat Form A
1:1 Co-crystal of
Roxadustat Benzamide
Water 0.003 0.75
Photostability
The photostability of Roxadustat Form A and 1:1 Co-crystal of Roxadustat with
Benzamide were tested by exposing the samples to UV/VIS radiation for the period of
24h and analyzed by HPLC. The results are shown in Table 3. The results show that 1:1
Co-crystal of Roxadustat Benzamide was found to be photochemically stable for 24h
when exposed to UV/VIS radiation whereas Roxadustat Form A shows the formation of
photoisomer upto a level of 0.14%.
Table 3
S.
No. Composition
Content of photo isomer by HPLC (%)
Initial 24h
1 Roxadustat Form A 0.08 0.14
2
Co-crystal of Roxadustat
Benzamide (1:1)
ND ND
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PXRD Analysis
The said Co-crystal of the present invention is characterized by their X-ray powder
diffraction pattern. Thus, the X-ray diffraction patterns of said co-crystal of the invention
was measured on PANalytical X’Pert PRO powder diffractometer equipped with
goniometer of ?/? configuration and X'Celerator detector. The Cu-anode X-ray tube was
operated at 40kV and 30mA. The experiments were conducted over the 2? range of 2.0°-
50.0°, 0.030° step size and 50 seconds step time.
A pharmaceutical composition comprising of Co-crystal of Roxadustat Benzamide and a
pharmaceutically acceptable excipient.
The pharmaceutical composition of the present invention may be formulated in
accordance with conventional methods and may be prepared in the form of oral
formulations such as tablets, pills, powders, capsules, syrups, emulsions, micro
emulsions, and others, or formulation for parenteral injection, e.g., intramuscular,
intravenous, or subcutaneous administration.
The following example is provided for illustrative purpose only and is not intended to
limit the scope of the invention in anyway.
EXAMPLES:
Example 1: Process for the preparation of 1:1 Co-crystal of Roxadustat Benzamide
In an RBF, charged Roxadustat (5g), Benzamide (2.6g) and Ethyl acetate (150mL) at
25±5°C. Heated the contents to 75-80°C and stirred the suspension for 30-60min at 75-
80°C. The reaction mass was slowly cooled to 25±5°C and maintained under stirring at
25±5°C for 20h. The product obtained was filtered at 25-30°C, washed with Ethyl acetate
(10mL) and dried under vacuum at 45°C for 3h. The solid obtained was identified as 1:1
co-crystal of Roxadustat Benzamide. ,CLAIMS:1) Co-crystal of Roxadustat with Benzamide.
2) The Co-crystal as claimed in claim 1, wherein the molar ratio of Roxadustat and
Benzamide is 1:1.
3) The Co-crystal as claimed in claim 1, is characterized by powder X-ray
diffraction comprising reflections at 2-theta angles of at 11.04, 14.66, 17.19, 22.21,
23.54, 25.26 ± 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, is prepared comprising the steps of
a) contacting Roxadustat with Benzamide in presence of an organic solvent,
b) heating the reaction mass,
c) cooling the reaction mass, and
d) isolating Co-crystal of Roxadustat Benzamide.
6) The process as claimed in claim 5, wherein the organic solvent is selected from the
group consisting of esters, ketones, alcohols such as ethyl acetate, acetone, methanol
and ethanol.
7) The process as claimed in claim 6, wherein the organic solvent is ethyl acetate.
8) A pharmaceutical composition comprising the co-crystal as defined in any one of
claims 1 to 5 and at least one pharmaceutically acceptable excipient.