Solid form of a bradykinin B2-receptor antagonist
This invention relates to a solid form of the bradykinin (BK) B2-receptor antagonist (S)—N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, pharmaceutical compositions comprising the solid form, and to methods of use thereof in the preparation of a pharmaceutical formulation and in treatment, prevention or management of diseases or conditions susceptible to treatment with a BK B2-receptor antagonist.
1 . Crystalline Form A of(S)—N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl) quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide) monohydrate having an X-ray powder diffraction (XRPD) pattern comprising at least two of the following 2θ values measured using CuKα radiation: 7.9±0.2°, 8.3±0.2°, 10.7±0.2°, 12.5±0.2°, 16.7±0.2°, 17.2±0.2°, 18.7±0.2°, and 20.4±0.2°.
2 . The crystalline Form A according to claim 1 , wherein the XRPD pattern comprises at least three or at least four of the following 2θ values measured using CuKα radiation: 7.9±0.2°, 8.3±0.2°, 10.7±0.2°, 12.5±0.2°, 16.7±0.2°, 17.2±0.2°, 18.7±0.2° and 20.4±0.2°.
3 . The crystalline Form A according to claim 1 , wherein the XRPD pattern further contains one or more of the following 2θ values measured using CuKα radiation: 13.6±0.2°, 14.2±0.2°, 19.3±0.2°, 20.9±0.2°, 22.1±0.2°, 22.6±0.2°, 23.0±0.2°, 23.5±0.2°, 23.9±0.2°, 24.2±0.2°, 25.0±0.2°, 25.5±0.2°, 26.4±0.2°, 26.8±0.2°, 27.7±0.2°, 28.2±0.2°, 28.5±0.2°, 29.3±0.2°, 30.3±0.2°, 31.0±0.2° and 31.7±0.2°.
4 . The crystalline Form A according to claim 1 , wherein a differential scanning calorimetry (DSC) thermogram of said crystalline form A comprises a characteristic peak at 110±10° C. with an onset of approximately 100±10° C.
5 . The crystalline Form A according to claim 1 having an XRPD pattern as shown in FIG. 1 .
6 . A pharmaceutical composition comprising the crystalline Form A according to claim 1 and at least one pharmaceutically acceptable excipient, diluent or carrier.
7 . The pharmaceutical composition according to claim 6 , wherein the pharmaceutical composition is formulated as an aerosol, a cream, a gel, a pill, a capsule, a syrup, a solution, a transdermal patch, a pharmaceutical delivery device; or provided as a kit.
8 . The pharmaceutical composition according to claim 6 , further comprising a CYP3A4 inhibitor, or a pharmaceutically acceptable salt, or solvate thereof.
9 . The pharmaceutical composition according to claim 8 , wherein the pharmaceutical composition is formulated as an aerosol, a cream, a gel, a pill, a capsule, a syrup, a solution, a transdermal patch, a pharmaceutical delivery device; or provided as a kit.
10 . A combination preparation containing crystalline Form A according to claim 1 and at least one further active pharmaceutical ingredient.
11 . The combination preparation according claim 10 , wherein the combination preparation is formulated as an aerosol, a cream, a gel, a pill, a capsule, a syrup, a solution, a transdermal patch, a pharmaceutical delivery device; or provided as a kit.
12 . The combination preparation according to claim 10 , further comprising a CYP3A4 inhibitor, or a pharmaceutically acceptable salt, or solvate thereof.
13 . A method of treating a subject suffering from a disease, disorder or condition responsive to BK B2-receptor modulation or associated with BK B2-receptor activity, comprising administering to the subject an effective amount of the crystalline Form A according to claim 1 .
14 . The method of claim 13 , wherein the disease, disorder or condition responsive to BK B2-receptor modulation or associated with BK B2-receptor activity is angioedema (AE).
15 . The method of claim 14 , wherein the AE is hereditary angioedema (HAE), acquired angioedema (AAE), non-histaminergic idiopathic angioedema, allergic angioedema, drug-induced angioedema, or angioedema of unidentified cause.
16 . The method of claim 15 , wherein the crystalline Form A is orally administered.
17 . A process of preparing crystalline Form A of(S)—N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide) monohydrate having an X-ray powder diffraction (XRPD) pattern comprising at least two of the following 2θ values measured using CuKα radiation: 7.9±0.2°, 8.3±0.2°, 10.7±0.2°, 12.5±0.2°, 16.7±0.2°, 17.2±0.2°, 18.7±0.2° and 20.4±0.2° comprising the steps of:
(a) forming a mixture by adding a compound of formula (I):
to a solvent mixture of Tert-Butyl methyl ether (TBME), Isopropylacetate and cyclohexane;
(b) agitating the mixture; and
(c) isolating and drying the obtained crystals.
18 . The process according to claim 17 , wherein the XRPD pattern comprises at least three or at least four of the following 2θ values measured using CuKα radiation: 7.9±0.2°, 8.3±0.2°, 10.7±0.2°, 12.5±0.2°, 16.7±0.2°, 17.2±0.2°, 18.7±0.2° and 20.4±0.2°.
19 . A process comprising formulating crystalline Form A of claim 1 for oral administration of a therapeutically effective amount of(S)—N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl) quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, wherein the crystalline Form A is formulated into an oral dosage form.