Crystalline form of baxdrostat, as well as its manufacturing method and use.

Abstract

Novel crystalline forms of baxdrostat, methods for producing the same, pharmaceutical compositions containing the crystalline form, and the production of aldosterone synthase inhibitors, as well as the use of the crystalline form in the production of pharmaceuticals for the treatment of hypertension, primary aldosteronism, and chronic kidney disease.

Description

Technical Field

[0001] The present disclosure relates to the field of chemical crystallography, and more particularly, to the crystal forms of baxdrostat, methods for producing the same, and uses thereof.

Background Art

[0002] Baxdrostat is an aldosterone synthase inhibitor developed by CinCor and is used in the treatment of hypertension, primary aldosteronism, and chronic kidney disease. Good results have been obtained in Phase II clinical trials for resistant hypertension.

[0003] The chemical name of baxdrostat is (+)-(R)-N-(4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl) propionamide (hereinafter referred to as Compound I), and its structural formula is as follows.

Chemical Formula

[0004] A crystal form is a solid material in which its constituent components are arranged in a highly ordered microscopic structure and form a crystal lattice extending in all directions. Polymorphism refers to the phenomenon in which a compound exists in two or more crystal forms. A compound can exist in one or two or more crystal forms, but its existence and properties cannot be predicted with any certainty. Different crystal forms of an active pharmaceutical ingredient (API) have different physicochemical properties, which thereby affect the in vivo dissolution and absorption of the medicine, and further affect the clinical efficacy and safety of the medicine to some extent. In particular, in some oral solid or semi-solid formulations with low solubility, the crystal form can be extremely important for the performance of the pharmaceutical formulation. Furthermore, the physicochemical properties of the crystal form, such as fluidity, compressibility, and milling stability, are very important for the manufacturing process. Therefore, polymorphism is an important part in pharmaceutical research and pharmaceutical quality control.

[0005] Patent document 1 (WO2013041591A1) discloses a method for synthesizing compound I, but does not disclose the crystalline form of compound I.

[0006] The inventors of this disclosure have unexpectedly discovered a crystalline form of compound I that has advantages in hygroscopicity and stability, which is extremely important for the development of pharmaceuticals containing compound I. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Public Gazette No. 2013-041591 [Overview of the project]

[0008] The purpose of this disclosure is to provide the crystalline form of compound I, a method for producing the same, and a pharmaceutical composition containing the crystalline form.

[0009] For the purposes of this disclosure, the crystalline form of compound I is provided.

[0010] A hydrate of compound I is provided in accordance with the purposes of this disclosure.

[0011] For the purposes of this disclosure, a crystalline form CSI of compound I is provided (hereinafter referred to as "form CSI").

[0012] The powder X-ray diffraction pattern of a form CSI includes one, two, or three characteristic peaks at 2θ values ​​of 8.1°±0.2°, 14.3°±0.2°, and 21.7°±0.2°. Preferably, the powder X-ray diffraction pattern of a form CSI using CuKα radiation includes characteristic peaks at 2θ values ​​of 8.1°±0.2°, 14.3°±0.2°, and 21.7°±0.2°.

[0013] The powder X-ray diffraction pattern of a form CSI includes one, two, or three characteristic peaks at 2θ values ​​of 15.9°±0.2°, 18.9°±0.2°, and 24.8°±0.2°. Preferably, the powder X-ray diffraction pattern of a form CSI using CuKα radiation includes characteristic peaks at 2θ values ​​of 15.9°±0.2°, 18.9°±0.2°, and 24.8°±0.2°.

[0014] The powder X-ray diffraction pattern of a form CSI includes one, two, three, or four characteristic peaks at 2θ values ​​of 14.7°±0.2°, 17.4°±0.2°, 18.5°±0.2°, and 22.0°±0.2°. Preferably, the powder X-ray diffraction pattern of a form CSI using CuKα radiation includes characteristic peaks at 2θ values ​​of 14.7°±0.2°, 17.4°±0.2°, 18.5°±0.2°, and 22.0°±0.2°.

[0015] The powder X-ray diffraction patterns of the form CSI showed 2θ values ​​of 8.1°±0.2°, 14.3°±0.2°, 21.7°±0.2°, 15.9°±0.2°, 18.9°±0.2°, 24.8°±0.2°, 14.7°±0.2°, 17.4°±0.2°, 18.5°±0.2°, 22.0°±0.2°, and 12.4°±0. Includes one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen characteristic peaks at 2°, 16.3°±0.2°, 16.8°±0.2°, 20.1°±0.2°, 21.1°±0.2°, and 24.5°±0.2°.

[0016] Without any limitation, the XRPD pattern of form CSI using CuKα lines is substantially identical to that shown in Figure 1.

[0017] Without any limitations, the DSC curve for form CSI is substantially identical to that shown in Figure 2. An endothermic peak is present around 103°C, which is the dehydration signal for form CSI.

[0018] Without any limitation, Form CSI is a hydrate.

[0019] Without any limitation, Form CSI shows a weight loss of about 3% - 6% when heated to 150 °C by TGA.

[0020] Without any limitation, the TGA curve of Form CSI is substantially the same as those shown in Figures 4, 5 and 6, showing weight losses of 3.2%, 5.0% and 5.1% respectively when heated to 150 °C.

[0021] In accordance with the objectives of the present disclosure, a method for manufacturing Form CSI is also provided. The method includes placing Compound I in a mixed solvent of methanol and methyl tert-butyl ether, stirring, and separating to obtain Form CSI.

[0022] In accordance with the objectives of the present disclosure, a pharmaceutical composition is provided, which includes a therapeutically effective amount of the crystalline form of Compound I provided by the present disclosure and a pharmaceutically acceptable excipient.

[0023] In accordance with the objectives of the present disclosure, the crystalline form of Compound I provided by the present disclosure can be used in the manufacture of aldosterone synthase inhibitors.

[0024] In accordance with the objectives of the present disclosure, the crystalline form of Compound I provided by the present disclosure can be used in the manufacture of medicaments for treating hypertension, primary aldosteronism and chronic kidney diseases.

Brief Description of the Drawings

[0025] [Figure 1] Figure 1 shows the XRPD pattern of Form CSI. [Figure 2] Figure 2 shows the DSC curve of Form CSI. [Figure 3] Figure 3 shows the 1H NMR spectrum of Form CSI. [Figure 4]Figure 4 shows the TGA curve for form CSI. [Figure 5] Figure 5 shows the TGA curve for form CSI. [Figure 6] Figure 6 shows the TGA curve for form CSI. [Figure 7] Figure 7 shows the superimposed XRPD patterns of the foam CSI before and after storage in sealed packaging (from top to bottom: initial state, 6 months at 25°C / 60%RH, 6 months at 40°C / 75%RH, and 1 month at 60°C / 75%RH). [Figure 8] Figure 8 shows the superimposed XRPD patterns of the foam CSI before and after storage in open packaging (from top to bottom: initial state, 6 months at 25°C / 60%RH, 6 months at 40°C / 75%RH, and 1 month at 60°C / 75%RH). [Figure 9] Figure 9 shows the superposition of XRPD patterns of foam CSI before and after wet ball milling (from top to bottom: initial state, after wet ball milling in ethanol, and after wet ball milling in water). [Figure 10] Figure 10 shows the DVS plot of form CSI. [Figure 11] Figure 11 shows the superposition of the XRPD patterns of Form CSI before and after the DVS test (from top to bottom: before DVS test, after DVS test). [Figure 12] Figure 12 shows images illustrating the experimental phenomena in Example 5 (the left image shows the phenomenon after n-pentane addition, and the right image shows the phenomenon after standing for a certain period of time). [Modes for carrying out the invention]

[0026] This disclosure is further illustrated by the following examples, which describe in detail the manufacture and use of the crystalline forms of this disclosure. It will be apparent to those skilled in the art that modifications to the materials and methods can be made without departing from the scope of this disclosure.

[0027] The abbreviations used in this disclosure are as follows: XRPD: Powder X-ray diffraction 1 1H NMR: Proton Nuclear Magnetic Resonance HPLC: High-Performance Liquid Chromatography DSC: Differential Scanning Calorimetry TGA: Thermogravimetric analysis DVS: Dynamic Vapor Adsorption RH: Relative humidity

[0028] The equipment and methods used for data acquisition are as follows: The XRPD patterns in this disclosure were obtained using a Bruker D8 DISCOVER powder X-ray diffraction apparatus. The conditions for the powder X-ray diffraction method in this disclosure are as follows: X-ray source: Cu, Kα Kα1(Å):1.54060;Kα2(Å):1.54439 Kα2 / Kα1 intensity ratio: 0.50 Voltage: 40kV Current: 40mA Scanning range (2θ): 4.0 degrees to 40.0 degrees

[0029] The DSC data in this disclosure was obtained using METTLER TOLEDO DSC 3. The conditions of the DSC method used in this disclosure are as follows: Heating rate: 10°C / min Purge gas: N2

[0030] 1 ¹H NMR data were obtained using a Bruker Avance II DMX 400M Hz NMR spectrometer. 1–5 mg of the sample was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to obtain solutions with concentrations of 2–10 mg / mL.

[0031] The TGA data in this disclosure was obtained using TA Q500. The conditions of the TGA method in this disclosure are as follows: Heating rate: 10°C / min

[0032] Purge gas: N2 The DVS data in this disclosure was measured using an Intrinsic DVS instrument manufactured by SMS (Surface Measurement Systems Ltd.). The instrument control software is DVS-Intrinsic control software. Typical conditions for the DVS test are as follows: Temperature: 25℃ Gas and flow rate: N2, 200 mL / min RH range: 0%RH to 95%RH

[0033] The detection conditions for the relevant substances in this disclosure are shown in Table 1.

[0034] [Table 1]

[0035] In this disclosure, "crystalline form" refers to a solid material that exhibits different molecular arrangements and / or conformations within a crystal lattice.

[0036] "Room temperature" does not refer to a specific temperature, but rather to a temperature range of 10 to 30°C.

[0037] A "characteristic peak" refers to a representative diffraction peak used to identify a crystal, and typically has a deviation of ±0.2° when using CuKα lines.

[0038] In this disclosure, “stirring” is performed using conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50 to 1800 r / min. Preferably, the magnetic stirring speed is 300 to 900 r / min, and the mechanical stirring speed is 100 to 300 r / min.

[0039] In this disclosure, “separation” is performed using conventional methods in the art, such as centrifugation or filtration. The “centrifugation” procedure is as follows: The sample to be separated is placed in a centrifuge tube and then centrifuged at a rate of 10,000 r / min until all the solids have settled at the bottom of the tube.

[0040] In this disclosure, “crystal” or “crystal form” can be identified by the X-ray diffraction patterns shown herein. Those skilled in the art will understand that powder X-ray diffraction patterns depend on apparatus conditions, sample preparation, and sample purity. The relative intensities of diffraction peaks in a powder X-ray diffraction pattern can also vary depending on experimental conditions. Therefore, the order of diffraction peak intensities cannot be considered the sole or decisive factor in determining the crystal form. In practice, the relative intensities of diffraction peaks in a powder X-ray diffraction pattern are related to the preferred orientation of the crystal, and the diffraction peak intensities shown herein are illustrative; identical diffraction peak intensities are not required. Therefore, those skilled in the art will understand that it is not necessary to have an X-ray diffraction pattern that is exactly the same as the examples shown herein. Any crystal form exhibiting an X-ray diffraction pattern with the same or similar characteristic peaks should be included within the scope of this disclosure. Those skilled in the art can identify whether two sets of patterns reflect the same or different crystal forms by comparing the patterns shown herein with those of an unknown crystal form.

[0041] In some embodiments, the form CSI of this disclosure is pure and substantially free of other crystalline forms. In this disclosure, the term “substantially free” used to describe a novel crystalline form means that the content of other crystalline forms in the novel crystalline form is less than 20% (w / w), specifically less than 10% (w / w), more specifically less than 5% (w / w), and even more specifically less than 1% (w / w).

[0042] In this disclosure, the term “approximately” used with respect to measurable values ​​such as weight, time, and temperature means that the value may vary by ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% from the given value.

[0043] Unless otherwise specified, the following examples were carried out at room temperature.

[0044] According to this disclosure, compound I used as a raw material includes, but is not limited to, solid (crystalline and amorphous), oily, liquid, or solution forms.

[0045] Unless otherwise specified, the raw materials for compound I used in the following examples can be prepared by the method described in document WO2013041591A1 (Patent Document 1), or can be obtained through commercial channels. [Examples]

[0046] [Example 1] 14.6 mg of compound I was weighed into a glass vial, and 0.2 mL of a mixed solvent of methanol and methyl tert-butyl ether (1:19, v / v) was added. The mixture was then stirred at room temperature for 3 days, followed by centrifugation and separation. The resulting solid was obtained by vacuum drying at room temperature. Measurement confirmed that the obtained solid was the form CSI of this disclosure. The XRPD data are shown in Table 2, and the XRPD pattern is substantially identical to that shown in Figure 1.

[0047] The DSC curve for foam CSI is substantially identical to that shown in Figure 2, exhibiting an endothermic peak at approximately 103°C, which corresponds to the dehydration signal of foam CSI.

[0048] Form CSI 1 The 1H NMR spectrum is substantially identical to that shown in Figure 3. The observed peaks are consistent with the structure of compound I, indicating the absence of organic solvent residue in form CSI.

[0049] [Table 2]

[0050] [Example 2] A certain amount of form CSI prepared according to this disclosure was stored under conditions of 25°C / 60%RH, 40°C / 75%RH, and 60°C / 75%RH. Purity and crystal form were confirmed by HPLC and XRPD. The results are shown in Table 3, and the XRPD superpositions are substantially identical to those shown in Figures 7 and 8. These results demonstrate that form CSI is stable with substantially unchanged purity for at least 6 months under 25°C / 60%RH and 40°C / 75%RH conditions, demonstrating excellent stability under both long-term and accelerated conditions. Under 60°C / 75%RH conditions, it is also stable with substantially unchanged purity for at least 1 month, demonstrating very good stability even under stress conditions.

[0051] [Table 3]

[0052] The API in form CSI exhibits good stability under long-term conditions, which is beneficial for the storage of pharmaceuticals. Environmental factors such as seasonal variations, regional climatic differences, and high temperatures and humidity can affect the storage, transportation, and manufacture of active pharmaceutical ingredients and formulations. Therefore, the stability of the API under accelerated and stressed conditions is extremely important for pharmaceuticals. The API in form CSI exhibits good stability even under stressed conditions, contributing to the prevention of adverse effects on the quality of pharmaceuticals due to polymorphic changes or purity degradation during storage.

[0053] [Example 3] A fixed amount of the form CSI solid from this disclosure was placed in a centrifuge tube, and approximately 10 μL of the corresponding solvent and a 5 mm diameter grinding ball were added. The centrifuge tube containing the sample was placed in a GT300 vibrating ball mill, and wet ball milling was performed at 1800 r / min for 10 minutes. The experimental results are shown in Table 4 and Figure 9. The results show that the form CSI did not change before and after wet ball milling, and no significant decrease in crystallinity was observed, indicating good grinding stability.

[0054] [Table 4]

[0055] During the formulation process, it is often necessary to crush or crush APIs. Good physical stability can reduce the risk of API crystallinity degradation and polymorphic transformation during the formulation process.

[0056] [Example 4] A certain amount of the foam CSI of this disclosure was used to measure the weight increase under various humidity conditions using a DVS apparatus. The weight increase at each relative humidity was recorded in a cycle of 60%RH-95%RH-0%RH-95%RH-0%RH. The DVS curve for the foam CSI is shown in Figure 10, showing a weight increase of 0.34% in the range from 60%RH to 80%RH. The superposition of XRPDs before and after the DVS test is substantially identical to that shown in Figure 11. No morphological changes of the foam CSI were observed before and after the DVS test, indicating that the foam CSI has good moisture resistance stability.

[0057] The API in Form CSI exhibits good moisture resistance, which helps avoid the impact on drug quality due to polymorphic changes or purity degradation during storage.

[0058] [Example 5] Referring to Examples 2 and 3 of WO2013041591A1, approximately 200 mg of compound I was weighed into a 20 mL glass vial, followed by dissolution with 2 mL of dichloromethane. Then, 5 mL of n-pentane was added at room temperature. The system became oily, and phase separation occurred. As shown in Figure 12, no solid precipitation was observed.

[0059] The embodiments described above are provided solely to illustrate the technical ideas and features of the Disclosure and are intended to enable those skilled in the art to understand and implement the Disclosure, and should not be construed as limiting the scope of protection of the Disclosure. Any equivalent variations or modifications based on the spirit of the Disclosure should be included within the scope of protection of the Disclosure.

Claims

1. The crystal form of compound I. 【Chemistry 1】

2. A crystalline form of compound I according to claim 1, wherein the powder X-ray diffraction pattern using Cu-Kα rays includes at least one characteristic peak at 2θ values ​​of 8.1°±0.2°, 14.3°±0.2°, and 21.7°±0.2°.

3. A crystalline form of compound I according to claim 1, wherein the powder X-ray diffraction pattern using Cu-Kα rays includes at least one characteristic peak at 2θ values ​​of 15.9°±0.2°, 18.9°±0.2°, and 24.8°±0.2°.

4. A crystalline form of compound I according to claim 1, wherein the powder X-ray diffraction pattern using Cu-Kα rays includes at least one characteristic peak at 2θ values ​​of 14.7°±0.2°, 17.4°±0.2°, 18.5°±0.2°, and 22.0°±0.2°.

5. A crystalline form of compound I according to claim 1, wherein the powder X-ray diffraction pattern using Cu-Kα rays is substantially the same as that shown in Figure 1.

6. A crystalline form of compound I as described in claim 1, wherein the crystalline form of compound I is a hydrate.

7. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of compound I described in claim 1 and a pharmaceutically acceptable excipient.

8. A method for producing an aldosterone synthase inhibitor, comprising using the crystalline form of compound I described in claim 1.

9. A method for producing a drug for treating hypertension, primary aldosteronism, and chronic kidney disease, comprising using the crystalline form of compound I described in claim 1.

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