Crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)phenyl]-(6-methoxy-pyridazin-3-yl)-methanol

Patent metadata

Field	Value
Publication number	US-2021113572-A1
Application number	US-201816498873-A
Country	US
Kind code	A1
Filing date	Mar 28, 2018
Priority date	Mar 30, 2017
Publication date	Apr 22, 2021
Grant date	—

Abstract

A crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol can be prepared as a pharmaceutical composition.

First claim

1 : A crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol.

2 : A crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol, which is characterized by a powder X-ray diffraction pattern having at least two peaks at degrees two theta selected from the group consisting of 4.1, 5.2, 6.1, 8.3, 8.5, 10.1, 10.9, 12.7, 13.0, 13.8, 14.7, 15.0, 18.6, 19.2, 20.0, 20.5, 20.8, 21.3, 22.0, 22.4, 22.8, 23.4, and 24.4, each ±0.2 degrees two theta.

3 : The crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 2 , which is characterized by a powder X-ray diffraction pattern having at least three peaks at degrees two theta selected from the group consisting of 4.1, 5.2, 6.1, 8.3, 8.5, 10.1, 10.9, 12.7, 13.0, 13.8, 14.7, 15.0, 18.6, 19.2, 20.0, 20.5, 20.8, 21.3, 22.0, 22.4, 22.8, 23.4, and 24.4, each ±0.2 degrees two theta.

4 : The crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 1 , which is an anhydrate.

5 : The crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 1 , which is characterized by a powder X-ray diffraction pattern substantially in accordance with FIG. 4 .

6 : The crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 1 , which has a solubility in a simulated gastric fluid without pepsin at a pH of 1.2 of more than 850 μg/mL.

7 : A process for preparing the crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 1 , comprising:
a) preparing a clear solution of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol in a solvent or solvent mixture, optionally with heating, b) cooling the clear solution, c) separating the crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol from the solvent or solvent mixture, and d) drying the crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol.

8 : The process according to claim 7 , wherein the crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl-methanol is characterized by a powder X-ray diffraction pattern having at least two peaks at degrees two theta selected from the group consisting of 4.1, 5.2, 6.1, 8.3, 8.5, 10.1, 10.9, 12.7, 13.0, 13.8, 14.7, 15.0, 18.6, 19.2, 20.0, 20.5, 20.8, 21.3, 22.0, 22.4, 22.8, 23.4, and 24.4, each ±0.2 degrees two theta.

9 : The process according to claim 7 , wherein the solvent or solvent mixture is selected from the group consisting of methanol, ethanol, 1-propanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, tetrahydrofuran, acetonitrile, and mixtures of these, water/1,4-dioxane, water/pyridine, methanol/tetrahydrofuran, methanol/chloroform, methanol/N,N-dimethylformamide, methanol/pyridine, 2-propanol/tetrahydrofuran, 2-propanol/pyridine, acetone/1,4-dioxane, acetone/chloroform, acetone/N,N-dimethylformamide, and acetone/pyridine.

10 : A pharmaceutical formulation, comprising:
the crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 2 .

11 : A method for the preparation of a pharmaceutical dosage form, comprising:
mixing the crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 2 with one or more pharmaceutically acceptable excipients.

12 : A method for the preparation of a pharmaceutical dosage form of the crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 2 , the method comprising:
dissolving or dispersing the crystalline (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol in a melting polymer or molten polymer.

13 : The method according to claim 12 , further comprising:
hot melt extruding hot melt granulating of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol and a polymer to produce a solid dispersion of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol in the polymer.

14 : A method of preparing a pharmaceutical formulation comprising (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol, comprising:
hot melt extruding or hot melt granulating of the crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 2 in combination with a polymer to produce a solid dispersion of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol in the polymer.

15 : A method of treating cancer, comprising:
administering the crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 2 to a patient in need thereof, optionally in combination with at least one of radiotherapy and chemotherapy.

16 : The crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 2 , wherein the powder X-ray diffraction pattern has at least four peaks at degrees two theta selected from the group consisting of 4.1, 5.2, 6.1, 8.3, 8.5, 10.1, 10.9, 12.7, 13.0, 13.8, 14.7, 15.0, 18.6, 19.2, 20.0, 20.5, 20.8, 21.3, 22.0, 22.4, 22.8, 23.4, and 24.4, each ±0.2 degrees two theta.

17 : The crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 2 , wherein the powder X-ray diffraction pattern has at least one of the at least two peaks at degrees two theta selected from the group consisting of 4.1, 5.2, 8.3, 8.5, 10.1, 10.9, 12.7, 13.0, and 21.3, each ±0.2 degrees two theta.

18 : The crystalline form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 1 , wherein the crystalline form has a water uptake level of less than 1% m/m.

19 : The method according to claim 11 , wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of a filler, a binder, a humectant, a disintegrating agent, a wicking agent, a matrix former, and a lubricant.

Assignees

• Merck Patent Gmbh

Inventors

• Lange Michael
• Kuehn Clemens
• Fuchss Thomas
• Maillard David
• Breuning Marcel
• Poma Marco
• Burini Edoardo

Classifications

• A61N5/10

  X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence) · CPC title

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title