Crystal form of baxdrostat, and preparation method therefor and use thereof

Abstract

A new crystal form of Baxdrostat, and a preparation method therefor, a pharmaceutical composition containing the crystal form, and the use of the crystal form in the preparation of an aldosterone synthase inhibitor drug and a drug for treating hypertension, primary aldosteronism and chronic kidney disease.

Description

Baxdrostat crystal form, preparation method and use thereof Technical Field

[0001] The present invention relates to the field of crystal chemistry, and more particularly to a crystal form of Baxdrostat, a preparation method thereof, and uses thereof. Background Art

[0002] Baxdrostat is an aldosterone synthase inhibitor developed by CinCor for the treatment of hypertension, primary aldosteronism and chronic kidney disease. It has achieved positive results in a Phase II clinical trial 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:

[0004] A crystal is a solid formed by the orderly three-dimensional arrangement of compound molecules within a microscopic structure, forming a lattice. Polymorphism refers to the phenomenon of a single compound existing in multiple crystalline forms. A compound may exist in one or more crystalline forms, but their existence and properties cannot be precisely predicted. APIs in different crystalline forms have varying physicochemical properties, which can lead to varying dissolution and absorption of the drug in the body, thereby affecting the drug's clinical efficacy to a certain extent. Crystal form is particularly crucial to product performance for poorly soluble oral solid or semisolid dosage forms. Furthermore, the physicochemical properties of the crystal form, such as flowability, compressibility, and grinding stability, also have a significant impact on the production process. Therefore, polymorphism is a crucial aspect of pharmaceutical research and quality control.

[0005] WO2013041591A1 discloses a synthesis method of Compound I, but does not disclose the crystal form of Compound I.

[0006] The inventors of the present application unexpectedly discovered that the crystalline solid of Compound I provided by the present invention exhibits good properties in terms of hygroscopicity and stability, which is of great significance to the development of drugs containing Compound I.

[0007] Summary of the Invention

[0008] The present invention provides a crystalline solid of Compound I, a method for preparing the same, and a pharmaceutical composition comprising the crystalline solid.

[0009] According to the object of the present invention, the present invention provides a crystalline solid of Compound I.

[0010] According to the purpose of the present invention, the present invention provides a hydrate of compound I.

[0011] According to the purpose of the present invention, the present invention provides a crystalline form CSI of Compound I (hereinafter referred to as "crystalline form CSI").

[0012] Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 8.1°±0.2°, 14.3°±0.2°, and 21.7°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 8.1°±0.2°, 14.3°±0.2°, and 21.7°±0.2°.

[0013] Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 15.9°±0.2°, 18.9°±0.2°, and 24.8°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 15.9°±0.2°, 18.9°±0.2°, and 24.8°±0.2°.

[0014] Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, or two, or three, or four of the diffraction angles 2θ of 14.7°±0.2°, 17.4°±0.2°, 18.5°±0.2°, and 22.0°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 14.7°±0.2°, 17.4°±0.2°, 18.5°±0.2°, and 22.0°±0.2°.

[0015] Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has diffraction angles 2θ 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°. , 12.4°±0.2°, 16.3°±0.2°, 16.8°±0.2°, 20.1°±0.2°, 21.1°±0.2°, and 24.5°±0.2°, or any one, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 of them have characteristic peaks.

[0016] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSI is substantially as shown in FIG1 .

[0017] Without limitation, the DSC of crystalline CSI is shown in FIG2 , which has an endothermic peak at around 103° C., which is a dehydration signal of crystalline CSI.

[0018] Without limitation, the crystalline form CSI is a hydrate.

[0019] In a non-limiting manner, when the crystalline form CSI is heated to 150° C. via TGA, the mass loss is approximately 3% to 6%.

[0020] Without limitation, the TGA graphs of Form CSI are shown in FIG4 , FIG5 or FIG6 , which show mass losses of approximately 3.2%, 5.0% and 5.1% when heated to 150° C., respectively.

[0021] According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSI, which comprises: placing compound I in a mixed solvent of methanol and methyl tert-butyl ether, stirring, and separating to obtain the crystalline form CSI.

[0022] According to the purpose of the present invention, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a crystalline solid of Compound I and a pharmaceutically acceptable excipient.

[0023] According to the purpose of the present invention, the present invention provides the use of the crystalline solid of Compound I in the preparation of aldosterone synthase inhibitor drugs.

[0024] According to the purpose of the present invention, the present invention provides use of a crystalline solid of Compound I in preparing a drug for treating hypertension, primary aldosteronism and chronic kidney disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the XRPD pattern of crystal form CSI

[0026] Figure 2 is the DSC diagram of crystal form CSI

[0027] Figure 3 shows the crystal form of CSI 1 H NMR spectra

[0028] Figure 4 is the TGA graph of crystal form CSI

[0029] Figure 5 is the TGA graph of crystal form CSI

[0030] Figure 6 is the TGA graph of crystal form CSI

[0031] Figure 7 XRPD comparison of Form CSI before and after storage under sealed conditions (from top to bottom: before storage, 6 months at 25°C / 60% RH, 6 months at 40°C / 75% RH, 1 month at 60°C / 75% RH)

[0032] Figure 8 XRPD comparison of Form CSI before and after storage under open conditions (from top to bottom: before storage, storage at 25°C / 60% RH for 6 months, storage at 40°C / 75% RH for 6 months, and storage at 60°C / 75% RH for 1 month)

[0033] Figure 9 is a comparison of XRPD images of the crystal form CSI before and after wet ball milling (from top to bottom: before milling, after wet milling in ethanol, and after wet milling in water)

[0034] Figure 10 DVS diagram of crystal form CSI

[0035] Figure 11 XRPD comparison of crystal form CS1 before and after DVS test (from top to bottom: before DVS test, after DVS test)

[0036] Figure 12 is a diagram of the experimental phenomena of Example 5 (left side: experimental phenomena after adding n-pentane, right side: experimental phenomena after standing for a period of time) DETAILED DESCRIPTION

[0037] The present invention is described in detail with reference to the following examples, which describe in detail the preparation and use of the crystalline forms of the present invention. It will be apparent to those skilled in the art that many variations in both materials and methods may be made without departing from the scope of the present invention.

[0038] The abbreviations used in the present invention are explained as follows:

[0039] XRPD: X-ray powder diffraction

[0040] 1 H NMR: hydrogen nuclear magnetic resonance

[0041] HPLC: High Performance Liquid Chromatography

[0042] DSC: Differential Scanning Calorimetry

[0043] TGA: Thermogravimetric analysis

[0044] DVS: Dynamic Water Sorption

[0045] RH: relative humidity

[0046] Instruments and methods used to collect data:

[0047] The XRPD patterns described in the present invention were collected on a Bruker D8 ADVANCE X-ray powder diffractometer. The X-ray powder diffraction method parameters described in the present invention are as follows:

[0048] X-ray source: Cu, Kα

[0049] Kα1 1.54060; 1.54439

[0050] Kα2 / Kα1 intensity ratio: 0.50

[0051] Voltage: 40kV

[0052] Current: 40mA

[0053] Scanning range: from 4.0 to 40.0 degrees

[0054] The DSC graphs described in the present invention were collected on a METTLER TOLEDO DSC 3. The method parameters for differential scanning calorimetry analysis described in the present invention are as follows:

[0055] Scan rate: 10℃ / min

[0056] Shielding gas: N2

[0057] The present invention 1 H NMR data were collected on a Bruker Avance II DMX 400M HZ NMR spectrometer. 1-5 mg of sample was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a 2-10 mg / mL solution.

[0058] The TGA graphs described in the present invention were collected on a TA Q500. The method parameters for the thermogravimetric analysis described in the present invention are as follows:

[0059] Scan rate: 10℃ / min

[0060] Shielding gas: N2

[0061] The DVS plots described herein were collected using an Intrinsic dynamic moisture sorption instrument manufactured by SMS (Surface Measurement Systems Ltd.). The instrument control software was DVS-Intrinsic control software. The method parameters for the dynamic moisture sorption instrument were as follows:

[0062] Temperature: 25℃

[0063] Carrier gas, flow rate: N2, 200 ml / min

[0064] Relative humidity range: 0%RH-95%RH

[0065] The detection method of related substances involved in the present invention is shown in Table 1.

[0066] Table 1

[0067] In the present invention, the "crystal form" refers to a solid substance with different molecular arrangements and / or conformations in the crystal lattice.

[0068] The "room temperature" is not a specific temperature value, but refers to the temperature range of 10-30°C.

[0069] The “characteristic peak” refers to a representative diffraction peak used to identify crystals. When tested using Cu-Kα radiation, the peak position can usually have an error of ±0.2°.

[0070] In the present invention, the "stirring" refers to the use of conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring speed is preferably 300-900 rpm, and the mechanical stirring speed is preferably 100-300 rpm.

[0071] In the present invention, "separation" refers to separation by conventional methods in the art, such as centrifugation or filtration. The "centrifugation" operation is to place the sample to be separated in a centrifuge tube and centrifuge at a speed of 10,000 rpm until all solids settle to the bottom of the centrifuge tube.

[0072] In the present invention, "crystals" or "crystal forms" can be characterized by X-ray powder diffraction. Those skilled in the art will appreciate that X-ray powder diffraction patterns can vary depending on instrument conditions, sample preparation, and sample purity. The relative intensities of diffraction peaks in an X-ray powder diffraction pattern may also vary with experimental conditions, so the diffraction peak intensities cannot be the sole or decisive factor in determining a crystal form. In fact, the relative intensities of diffraction peaks in an X-ray powder diffraction pattern are related to the preferred orientation of the crystal. The diffraction peak intensities shown herein are illustrative and not intended for absolute comparison. Therefore, those skilled in the art will appreciate that the X-ray powder diffraction patterns of the crystal forms claimed by the present invention do not necessarily have to be identical to those in the Examples described herein; any crystal form having an X-ray powder diffraction pattern with characteristic peaks identical or similar to those in these patterns falls within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction patterns listed herein with those of an unknown crystal form to determine whether the two patterns reflect the same or different crystal forms.

[0073] In some embodiments, the crystalline form CSI of the present invention is pure and substantially free of any other crystalline form. As used herein, "substantially free" when referring to a new crystalline form means that the crystalline form contains less than 20% (by weight) of any other crystalline form, particularly less than 10% (by weight) of any other crystalline form, more particularly less than 5% (by weight) of any other crystalline form, and even more particularly less than 1% (by weight) of any other crystalline form.

[0074] The term "about" in the present invention, when used to refer to a measurable value, such as mass, time, temperature, etc., means that there is a certain floating range around the specific value, which can be ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.

[0075] Unless otherwise specified, the following examples were all performed at room temperature.

[0076] According to the present invention, the compound I as a raw material includes but is not limited to solid form (crystalline or amorphous), oily form, liquid form and solution.

[0077] Unless otherwise specified, Compound I used in the following examples can be prepared according to the method described in WO2013041591A1 or obtained through commercial channels.

[0078] Example 1

[0079] 14.6 mg of Compound I was weighed into a glass vial, and 0.2 mL of a 1:19, v / v, methanol-methyl tert-butyl ether mixture was added. The mixture was then stirred at room temperature for 3 days, centrifuged, separated, and dried under vacuum at room temperature to obtain a solid. Testing confirmed that the resulting solid was Form CSI of the present invention. Its X-ray powder diffraction data are shown in Table 2, and its X-ray powder diffraction pattern is shown in Figure 1.

[0080] The DSC graph of crystalline form CSI is shown in FIG2 , which shows an endothermic peak at around 103° C., which is the dehydration signal of crystalline form CSI.

[0081] Crystal form of CSI 1 The H NMR spectrum is shown in Figure 3 , and its peak results are consistent with the structure of Compound I, indicating that there is no organic solvent residue in the crystalline form CSI.

[0082] Table 2

[0083] Example 2

[0084] An appropriate amount of the crystalline form CSI prepared by the present invention was taken and placed under 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH conditions, respectively. The purity and crystalline form were determined by HPLC and XRPD. The results are shown in Table 3, and the XRPD comparison diagrams are shown in Figures 7 and 8. The results show that the crystalline form CSI is stable for at least 6 months under 25°C / 60% RH and 40°C / 75% RH conditions, and the purity remains essentially unchanged. It can be seen that the crystalline form CSI maintains good stability under both long-term and accelerated conditions; it is stable for at least 1 month under 60°C / 75% RH conditions, and the purity remains essentially unchanged, indicating that the stability is also good under more stringent conditions.

[0085] Table 3

[0086] Crystalline CSI APIs exhibit excellent long-term stability, facilitating drug storage. High temperatures and humidity, caused by seasonal variations, regional climate differences, and environmental factors, can impact the storage, transportation, and production of APIs and formulations. Therefore, API stability under accelerated and even more stringent conditions is crucial. Crystalline CSI APIs exhibit excellent stability under these harsh conditions, helping to prevent drug quality from devitalization or purity loss during storage.

[0087] Example 3

[0088] An appropriate amount of crystalline CSI solid was placed in a centrifuge tube. Approximately 10 μL of the corresponding solvent was added, along with a 5 mm grinding ball. The centrifuge tube containing the sample was then mounted on a GT300 vibrating ball mill and wet-milled at 1800 rpm for 10 minutes. The experimental results, shown in Table 4 and Figure 9, demonstrate that the crystalline form of the CSI remained unchanged before and after wet-milling, and there was no significant decrease in crystallinity, demonstrating excellent milling stability.

[0089] Table 4

[0090] During the preparation process, it is often necessary to grind or crush the API. Good physical stability can reduce the risk of API crystallinity reduction and crystal transformation during the preparation process.

[0091] Example 4

[0092] An appropriate amount of crystalline CSI was tested using a dynamic moisture sorption instrument to determine its weight gain at various humidity levels. The system cycled from 60% RH to 95% RH, then to 0% RH, and the mass at each humidity level was recorded. A dynamic moisture sorption (DVS) plot of crystalline CSI is shown in Figure 10, demonstrating a 0.34% weight gain from 60% RH to 80% RH. A comparison of XRPD patterns before and after the DVS test is shown in Figure 11. The crystalline form of crystalline CSI remained unchanged before and after the DVS test, demonstrating good humidity stability.

[0093] Crystalline CSI APIs have better humidity stability, which helps avoid the impact on drug quality caused by crystal transformation or purity loss during drug storage.

[0094] Example 5

[0095] Referring to Examples 2 and 3 of WO2013041591A1, approximately 200 mg of Compound I was weighed into a 20 mL glass vial, 2 mL of dichloromethane was added to dissolve the mixture, and 5 mL of n-pentane was added at room temperature. The system became an oil and phase separated, as shown in Figure 12, with no solid precipitation observed.

[0096] The above embodiments are intended only to illustrate the technical concepts and features of the present invention. Their purpose is to enable those skilled in the art to understand the contents of the present invention and implement them accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be covered by the scope of protection of the present invention.

Claims

1. A crystalline solid of Compound I, 2. The crystalline solid of compound I according to claim 1, characterized in that Using Cu—Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 8.1°±0.2°, 14.3°±0.2°, and 21.7°±0.2°.

3. The crystalline solid of Compound I according to claim 1, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 15.9°±0.2°, 18.9°±0.2°, and 24.8°±0.2°.

4. The crystalline solid of Compound I according to claim 1, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 14.7°±0.2°, 17.4°±0.2°, 18.5°±0.2°, and 22.0°±0.2°.

5. The crystalline solid of Compound 1 according to claim 1, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern is basically as shown in Figure 1.

6. The crystalline solid of Compound 1 according to claim 1, characterized in that It is a hydrate.

7. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline solid of Compound I according to claim 1 and a pharmaceutically acceptable excipient.

8. Use of the crystalline solid of Compound I as claimed in claim 1 in the preparation of aldosterone synthase inhibitor drugs.

9. Use of the crystalline solid of Compound I as claimed in claim 1 in the preparation of drugs for treating hypertension, primary aldosteronism and chronic kidney disease.

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