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Solid Forms Of Venetoclax And Processes For The Preparation Of Venetoclax

Abstract: Aspects of the present application relate to solid forms of Venetoclax and preparative processes thereof. Specific aspects relate to an amorphous form of Venetoclax, its solid dispersion and crystalline forms of Venetoclax or salts thereof. Further aspects of the present application relate to processes for the preparation of Venetoclax.

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Patent Information

Application #
Filing Date
06 December 2018
Publication Number
08/2019
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
sumamaheshwari@drreddys.com
Parent Application

Applicants

DR. REDDY’S LABORATORIES LIMITED
8-2-337, Road No. 3, Banjara Hills Hyderabad 500034

Inventors

1. PEDDIREDDY, Subba Reddy
Flat No: 204, Sri Raghavendra Bhavani Residency, Maavillas Road No: 3, Kasani Kousalya colony, Bachupally, Telangana. Hyderabad 500090
2. KOTTUR, Mohan Kumar
Flat No.406, Sujatha Residency, Tara Nagar, Serilangampally, Telangana. Hyderabad 500019
3. JURUPULA, Ramprasad
H.no 3-138, Jogugudem, Kameypally Khammam 507122, Hyderabad
4. BAIG, Mohammed Azeezulla
Plot no. 211, Street no. 22, HMT Swarnapuri colony, Miyapur, Telangana Hyderabad 500050
5. CHAKKA, Ramesh
Flat No. 206, Sri Tirumala’s Kasaani Residency, Survey No.: 81 to 85, Petbasheerabad, Jeedimetla Village, Telangana. Hyderabad 500067
6. THIPPARABOINA, Rajesh
H. No. 1-1-8/10, Kannala Basthi, Bellampalli Manchiryal 504251
7. PEDDY, Vishweshwar
Plot No. 341, Vasavi Colony, Green Hills Road No.1, Saroornagar Hyderabad 500035
8. RAO, Pallavi
Flat No. 505, Fortune Kumkum Heights, Masid banda, Kondapur Hyderabad 500081
9. ORUGANTI, Srinivas
Flat No. 205-G, Manjeera Diamond Towers, Gopanapally, Gachibowli, Telangana Hyderabad 500046
10. DAHANUKAR, Vilas Hareshwar
Plot No. 11, Lalitha Bloomfield, Near Oakridge International School, Khajaguda, Telangana. Hyderabad 500008

Specification

WE CLAIM:
1. A process for the preparation of an amorphous form of Venetoclax,
comprising the steps of:
a) providing a solution of Venetoclax in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a); and
c) isolating the amorphous form of Venetoclax;
d) optionally combining amorphous form of step c) with at least one pharmaceutically acceptable excipient.

2. The process according to claim 1, wherein the solvent is selected from methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, dichloromethane, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, water or mixtures thereof.
3. A process for the preparation of amorphous form of Venetoclax, comprising the steps of:

a) providing a solution of Venetoclax in a suitable solvent or a mixture thereof;
b) contacting the solution of step a) with an anti-solvent;
c) isolating amorphous form of Venetoclax.

4. The process according to claim 3, wherein the solvent is selected from dimethyl sulfoxide, dimethyl formamide, tetrahydrofuran or mixtures thereof.
5. The process according to claim 3, wherein the anti-solvent is selected from water, n-hexane, n-heptane, cyclohexane, di isopropyl ether, methyl tert-Butyl ether or mixtures thereof.
6. An acid addition salt of Venetoclax, wherein the acid is selected from the group comprising of trifluoro acetic acid (TFA), oxalic acid, maleic acid, Isethionic acid, ortho-phosphoric acid, citric acid, methanesulfonic acid and acetic acid.
7. A process for the preparation of salt of Venetoclax comprising the step of contacting an acid with Venetoclax, wherein acid is selected from the group comprising of trifluoro acetic acid (TFA), oxalic acid, maleic acid, isethionic acid, ortho-phosphoric acid, citric acid, methanesulfonic acid and acetic acid.
8. A process for the preparation of Venetoclax, comprising the step of converting a salt of Venetoclax into its free form, wherein the salt is selected from the group comprising of trifluoro acetic acid (TFA), oxalic acid, maleic

acid, isethionic acid, ortho-phosphoric acid, citric acid, methanesulfonic acid and acetic acid.
9. A crystalline form of Venetoclax that is a:
(a) crystalline Form RT1, that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.39 and 8.56 ± 0.2° 2θ;
(b) crystalline Form RT3, that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.30, 12.57 and 20.06 ± 0.2° 2θ;
(c) crystalline Form RT4, that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.55 and 5.10 ± 0.2° 2θ;
(d) crystalline Form RT5, that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.51 and 25.00 ± 0.2° 2θ.

10. A process for the preparation of crystalline Form RT1 of Venetoclax, comprising the step of contacting Venetoclax with benzyl alcohol.
11. A process for the preparation of crystalline Form RT2 of Venetoclax, comprising the steps of:

a) dissolving or suspending Venetoclax in methyl isopropyl ketone or methyl-tertiary butyl ether or a mixture thereof;
b) optionally, contacting the solution of step a) with an anti-solvent;
c) isolating crystalline Form RT2 of Venetoclax.

12. The process according to claim 11, wherein the anti-solvent is selected from n-hexane, n-heptane, cyclohexane, water or mixtures thereof.
13. A process for the preparation of crystalline Form RT3 of Venetoclax, comprising the steps of:

a) providing a solution of Venetoclax in methylene chloride or a mixture thereof;
b) optionally washing the solution of step a) with water;
c) removing the solvent of step a) to obtain crystalline Form RT3 of Venetoclax.
14. A process for the preparation of crystalline Form RT4 of Venetoclax,
comprising the steps of:
a) dissolving or suspending Venetoclax in methyl iso-butyl Ketone or a mixture thereof;
b) optionally, contacting the solution of step a) with an anti-solvent;
c) isolating crystalline Form RT4 of Venetoclax.

15. A process for the preparation of crystalline Form RT5 of Venetoclax,
comprising the steps of:
a) dissolving or suspending Venetoclax in 1,4-dioxane or mixture thereof;
b) optionally, contacting the solution of step a) with an anti-solvent;
c) isolating crystalline Form RT5 of Venetoclax.

16. The process according to claim 14 or 15, wherein the anti-solvent is selected from n-hexane, n-heptane, cyclohexane, water or mixtures thereof.
17. An amorphous solid dispersion of Venetoclax together with one or more water soluble polymers without surfactant.
18. The amorphous solid dispersion of Venetoclax according to claim 17, wherein
the water soluble polymer is selected from polyvinyl pyrrolidone, povidone K-30,
povidone K-60, povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF,
polysorbate 80, polyoxyethylene-polyoxypropylene copolymers (Poloxamer 188
or pluronic F-68), polyoxyethylene (40) stearate, polyethyene glycol monomethyl
ether, polyethyene glycol, hydroxypropylmethyl cellulose phthalate,
hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL),
hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L),
hydroxyethyl cellulose, soluplus (polyvinyl caprolactam-polyvinyl acetate-
polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14,
cyclodextrins, gelatins, D-alpha-tocopheryl polyethylene glycol 1000 succinate,
polyvinylacetal diethylaminoacetate (AEA), methylcellulose,
carboxymethylethylcellulose or mixture thereof.
19. An amorphous solid dispersion of Venetoclax together with water insoluble polymer with or without surfactant.
20. The amorphous solid dispersion of Venetoclax according to claim 19, wherein the water insoluble polymer is selected from polyvinyl acetate phthalate, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), ethyl cellulose, cellulose acetate phthalate, hypromellose phthalates, syloid or mixture thereof.
21. An amorphous solid dispersion of Venetoclax together with surfactant and without water soluble polymer.
22. The amorphous solid dispersion of Venetoclax according to claim 19 or 21, wherein the surfactant is selected from polyoxyethylene glycerides, fatty acid monoesters of sorbitan, polysorbates, α-tocopheryl polyethylene glycol succinate

(TPGS) or mixtures thereof.

Documents

Application Documents

# Name Date
1 201847046112.pdf 2018-12-06
2 201847046112-STATEMENT OF UNDERTAKING (FORM 3) [06-12-2018(online)].pdf 2018-12-06
3 201847046112-FORM 1 [06-12-2018(online)].pdf 2018-12-06
4 201847046112-DRAWINGS [06-12-2018(online)].pdf 2018-12-06
5 201847046112-DECLARATION OF INVENTORSHIP (FORM 5) [06-12-2018(online)].pdf 2018-12-06
6 201847046112-COMPLETE SPECIFICATION [06-12-2018(online)].pdf 2018-12-06