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

Abstract

The present invention relates to a new crystal form of Zipalertinib, a preparation method therefor, a pharmaceutical composition containing the crystal form, and the use of the crystal form in the preparation of an EGFR inhibitor drug and a drug for treating non-small cell lung cancer with an EGFR exon 20 insertion mutation.

Description

Zipalertinib 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 crystalline form of Zipalertinib, a preparation method thereof, and uses thereof. Background Art

[0002] Zipalertinib is an EGFR inhibitor being developed by Cullinan Oncology and Taiho Pharmaceutical for advanced non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (EGFR Exon 20ins) mutations. It has demonstrated positive clinical results. The US FDA has granted Zipalertinib Breakthrough Therapy designation for the treatment of patients with locally advanced or metastatic NSCLC who have EGFR Exon 20ins mutations and have received prior platinum-based systemic chemotherapy.

[0003] The chemical name of Zipalertinib is (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (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 crystal forms. A compound may exist in one or more crystal forms, but their existence and properties cannot be precisely predicted. APIs in different crystal forms have varying physicochemical properties, which can lead to varying dissolution and absorption in the body, thereby impacting 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 are crucial to the production process. Therefore, polymorphism is a crucial aspect of pharmaceutical research and quality control.

[0005] Amorphous solids are non-crystalline materials lacking long-range order, typically exhibiting a broad "steamed bun" peak in their XRPD patterns. The disordered molecular arrangement within amorphous solids leads to poor stability, making amorphous drugs susceptible to crystallization transitions during production and storage. This poor stability can lead to changes in drug bioavailability, dissolution, and other parameters, ultimately altering the drug's clinical efficacy.

[0006] Prior art WO2015025936A1 discloses a method for preparing Compound I. The resulting yellow solid was found to be amorphous by the inventors of this application. The later published WO2024248083A1 also discloses that the reference example is amorphous.

[0007] The inventors of the present application unexpectedly discovered that the crystalline form of Compound I provided by the present invention has advantages in at least one aspect of solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, and bioavailability, especially good stability, low hygroscopicity, low residual solvent, and high solubility, which solves the problems existing in the prior art and is of great significance to the development of drugs containing Compound I. 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 an anhydrate of Compound I.

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

[0012] In one aspect, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at one, two, or three of the diffraction angles 2θ of 6.8°±0.2°, 11.5°±0.2°, and 13.4°±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at diffraction angles 2θ of 6.8°±0.2°, 11.5°±0.2°, and 13.4°±0.2°.

[0013] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at one, two, or three of the diffraction angles 2θ of 8.7±0.2°, 13.7°±0.2°, and 14.9°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at diffraction angles 2θ of 8.7±0.2°, 13.7°±0.2°, and 14.9°±0.2°.

[0014] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at 3, or 4, or 5, or 6, or 7, or 8, or 9 of the diffraction angle 2θ values ​​of 6.8°±0.2°, 11.5°±0.2°, 13.4°±0.2°, 8.7±0.2°, 13.7°±0.2°, 14.9°±0.2°, 7.6°±0.2°, 15.8±0.2°, 23.3°±0.2°, and 26.4°±0.2°.

[0015] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSV is substantially as shown in FIG1 .

[0016] Without limitation, a thermogravimetric analysis of Form CSV is substantially as shown in Figure 2. Form CSV is heated to approximately 100°C with substantially no weight loss.

[0017] Without limitation, Form CSV is an anhydrate.

[0018] According to the purpose of the present invention, the present invention provides a method for preparing crystalline CSV, characterized in that: compound I is placed in an ester solvent and stirred, the solid is separated, and the obtained solid is heated to obtain crystalline CSV.

[0019] Furthermore, the ester solvent is preferably ethyl acetate; and the heating end temperature is preferably 120°C-150°C.

[0020] According to the purpose of the present invention, the present invention provides a pharmaceutical composition, which comprises an effective therapeutic amount of crystalline CSV and pharmaceutically acceptable excipients.

[0021] According to the purpose of the present invention, the present invention provides use of crystalline CSV in the preparation of EGFR inhibitor drugs.

[0022] According to the purpose of the present invention, the present invention provides use of crystalline CSV in preparing a drug for treating non-small cell lung cancer with EGFR exon 20 insertion mutation.

[0023] Compared with the prior art solids, the crystalline form CSV of the present invention has the following advantages:

[0024] (1) The crystalline CSV provided by the present invention has good stability.

[0025] The purity of the existing amorphous solid was significantly reduced after being placed at 40°C / 75% RH for 3 months and at 60°C / 75% RH for 2 months. The poor chemical stability of the amorphous solid was not conducive to production.

[0026] Crystalline CSV maintained its crystalline form unchanged for at least six months at 40°C / 75% RH and for at least two months at 60°C / 75% RH. Its chemical purity exceeded 99%, and remained essentially unchanged during storage. This suggests that compared to existing solids, crystalline CSV exhibits superior stability under accelerated and more stringent conditions.

[0027] High temperatures and high humidity conditions caused by seasonal differences, regional climate variations, and environmental factors can affect the storage, transportation, and production of APIs and formulations. Therefore, the stability of APIs under accelerated and more stringent conditions is crucial for pharmaceuticals. Crystalline CSV exhibits improved stability under harsh conditions, helping to prevent drug quality from being affected by crystal transformation or purity loss during storage. Crystalline CSV also exhibits excellent humidity stability. After cycling once from 0% RH to 95% RH to 0% RH, the crystal form of the present invention remained unchanged.

[0028] The excellent physical and chemical stability of the API crystal form ensures that the drug will not undergo crystal transformation and is essentially free of impurities during production and storage. The excellent physical and chemical stability of the CSV crystal form ensures consistent and controllable quality of the API and drug product, minimizing changes in drug quality, bioavailability, and toxic side effects caused by changes in crystal form or impurities.

[0029] (2) The crystalline CSV provided by the present invention contains virtually no residual solvent, whereas existing solid organic solvents in the prior art contain high levels of residual solvents and are highly toxic. Low residual solvent in the crystalline CSV API is of great significance for protecting patient health, complying with regulatory requirements, and improving product quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 is the XRPD pattern of crystalline form CSV

[0031] Figure 2 is the TGA graph of crystal form CSV

[0032] Figure 3 is the XRPD pattern of Form K5

[0033] Figure 4 is the TGA diagram of crystal form K5

[0034] Figure 5 is the XRPD pattern of Form K8

[0035] Figure 6 is the TGA diagram of crystal form K8

[0036] Figure 7 is a comparison of XRPD images of the crystalline form CSV before and after storage stability (from bottom to top: before storage, after 2 months at 60°C / 75% RH, after 3 months at 40°C / 75% RH, and after 6 months at 40°C / 75% RH)

[0037] Figure 8 is a comparison of XRPD images of the CSV crystal before and after DVS testing (from bottom to top: before DVS, after DVS)

[0038] Figure 9 is the XRPD pattern of amorphous

[0039] Figure 10 is the TGA graph of amorphous

[0040] Figure 11 is a comparison of XRPD images of amorphous before and after storage stability (from bottom to top: before storage, after 2 months at 60°C / 75% RH, after 3 months at 40°C / 75% RH) DETAILED DESCRIPTION

[0041] 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.

[0042] The abbreviations used in the present invention are explained as follows: XRPD: X-ray powder diffraction TGA: thermogravimetric analysis DVS: dynamic water sorption HPLC: high performance liquid chromatography 1 H NMR: liquid hydrogen nuclear magnetic spectrum RH: relative humidity

[0043] Instruments and methods used to collect data:

[0044] 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:

[0045] X-ray source: Cu, Kα

[0046] Kα1 1.54060; Kα2 1.54439

[0047] Kα2 / Kα1 intensity ratio: 0.50

[0048] Voltage: 40kV

[0049] Current: 40mA

[0050] Scanning range: from 4.0 to 40.0 degrees

[0051] 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:

[0052] Scan rate: 10℃ / min

[0053] Shielding gas: N2

[0054] 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.

[0055] The test parameters of the dynamic solubility and related substances of the present invention are shown in Table 1 and Table 2 respectively.

[0056] Table 1

[0057] Table 2

[0058] The "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm and the mechanical stirring is preferably 100-300 rpm.

[0059] The "drying" is accomplished using conventional methods in the art, such as vacuum drying, forced air drying, or air drying. The drying temperature can be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C. The drying time can be 0.5-48 hours, or overnight. Drying is performed in a fume hood, forced air oven, or vacuum oven. The "room temperature" is not a specific temperature value, but refers to a temperature range of 10-30°C.

[0060] In the present invention, the "crystalline solid" refers to a solid substance with different molecular arrangements and / or conformations in the crystal lattice.

[0061] The "anhydrous substance" refers to a solid substance that does not contain crystal water or crystallization solvent.

[0062] 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°.

[0063] 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.

[0064] In some embodiments, the crystalline form CSV 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, more 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.

[0065] 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%.

[0066] Unless otherwise specified, the following examples were all performed at room temperature.

[0067] 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. Preferably, the compound I as a raw material is in solid form.

[0068] Compound I used in the following examples can be prepared according to existing technologies, for example, according to the method described in WO2015025936A1.

[0069] Example 1: Preparation method of crystalline CSV

[0070] 159.5 mg of Compound I was weighed into a glass vial, 1.3 mL of ethyl acetate was added, and the mixture was suspended and stirred at -20°C for 5 days. The mixture was filtered and dried under vacuum at 25°C for approximately 1.5 hours to obtain a crystalline solid (designated "Form K5"). The resulting solid was heated to 120°C at a rate of 10°C / min under nitrogen and held there for 7 minutes before returning to room temperature to obtain a crystalline solid.

[0071] The obtained crystalline solid was tested to be Form CSV of the present invention. Its X-ray powder diffraction data are shown in Table 3, and its X-ray powder diffraction pattern is shown in Figure 1. The TGA pattern is shown in Figure 2. When heated to approximately 100°C, there was essentially no weight loss, indicating that Form CSV was anhydrous.

[0072] 1 The H NMR data are: 1H NMR (400MHz, DMSO-d6) δ8.95(s,1H),8.48(d,J=7.1Hz,1H),8.39(s,1H),8.14(s,1H),8.10(d,J =8.5Hz,1H),8.06(d,J=7.7Hz,1H),7.83(ddd,J=8.4,7.0,1.4Hz,1H),7.73–7.64(m,1H),6.25(d d,J=17.1,9.8Hz,1H),6.15(dd,J=17.1,2.5Hz,1H),5.98–5.67(m,3H),5.63(dd,J=9.8,2.5Hz, 1H), 4.86–4.74 (m, 1H), 4.27 (dd, J=13.0, 4.9Hz, 1H), 4.17 (dd, J=13.0, 5.2Hz, 1H), 1.51 (s, 3H).

[0073] Table 3

[0074] Example 2: Properties of Form K5

[0075] The crystalline form K5 in Example 1, i.e., ethyl acetate solvate, was characterized, and its XRPD pattern is shown in Figure 3. The TGA pattern is shown in Figure 4, which shows that when heated to 200°C, it has a mass loss of about 9.6%.

[0076] Example 3: Preparation method of crystal form K8

[0077] 51.3 mg of Compound I was weighed into a glass vial, 0.4 mL of dimethyl carbonate was added, and the mixture was suspended and stirred at -20°C for 5 days. The mixture was then filtered and dried under vacuum at room temperature for approximately 1 hour to obtain Form K8 (dimethyl carbonate solvate). The X-ray powder diffraction pattern of Form K8 is shown in Figure 5 , and the TGA pattern is shown in Figure 6 . Upon heating to 180°C, Form K8 exhibited a mass loss of approximately 9.8%.

[0078] Example 4: Preparation method of crystalline CSV

[0079] The crystal form K8 was heated to 120°C at a rate of 10°C / min under nitrogen protection and kept at this temperature for 40 minutes, and then returned to room temperature to obtain the crystal form CSV.

[0080] Example 5: Stability of Crystalline Form CSV

[0081] Appropriate amounts of the present invention's crystalline form CSV were stored at 40°C / 75% RH and 60°C / 75% RH for a period of time. Purity and crystal form were determined by HPLC and XRPD at each sampling time. The results are shown in Table 4, and a comparative XRPD plot is shown in Figure 7. The results demonstrate that crystalline form CSV is stable for at least six months at 40°C / 75% RH, demonstrating its excellent stability even under accelerated conditions. Crystal form CSV is stable for at least two months at 60°C / 75% RH, demonstrating its excellent stability even under more stringent conditions.

[0082] Table 4

[0083] An appropriate amount of the present invention's crystalline form CSV was subjected to a DVS cycle at 25°C, 0% RH, 95% RH, and 0% RH. The crystal forms before and after DVS were tested, as shown in Figure 8. The results show that the crystalline form CSV remained unchanged after the DVS cycle, demonstrating good humidity stability.

[0084] Comparative Example 1: Preparation of prior art solids

[0085] 102.0 mg of Compound I was weighed into a glass vial, and 5 mL of a methanol / ethyl acetate mixture (1:1 volume ratio) was added to obtain a clear solution. This solution was then rotary evaporated at 40°C to obtain a solid. Testing revealed that the resulting solid was amorphous, as shown in Figure 9 for its X-ray powder diffraction pattern and Figure 10 for its TGA pattern. Upon heating to 220°C, the solid exhibited a mass loss of approximately 9.2%. 1 H NMR results showed that the amorphous phase contained residual solvent, which contained approximately 0.41 molar equivalents of ethyl acetate (δ (ppm) 4.03 (q, J = 7.1 Hz, 0.82 H), 1.99 (s, 1.23 H), 1.17 (t, J = 7.1 Hz, 1.23 H)) and 0.40 molar equivalents of methanol (δ (ppm) 3.17 (d, J = 5.2 Hz, 1.19 H), 4.11 (q, J = 5.3 Hz, 0.40 H)).

[0086] Comparative Example 2: Stability of prior art solids

[0087] Appropriate amounts of amorphous phase were stored at 40°C / 75% RH and 60°C / 75% RH for a period of time. Purity and solid form were determined by HPLC and XRPD at each sampling time. The results are shown in Table 5, and a comparative XRPD plot is shown in Figure 11. These results indicate that the purity of the amorphous phase decreased after storage at 40°C / 75% RH for three months and at 60°C / 75% RH for two months, demonstrating that the amorphous phase is not stable under accelerated and harsh conditions.

[0088] Table 5

[0089] Comparative Example 3: Dynamic Solubility of Form CSV and Form 1

[0090] WO2024248083A1 discloses Form I and solvate b. WO2024121805A1 discloses Form 1, Form 2, Form 4, an amorphous form, and multiple cocrystals. Of these forms, Form 1 is the most stable, and Forms I and 1 are identical. The present Form CSV differs from any of the aforementioned forms.

[0091] Appropriate amounts of the crystalline form CSV of the present invention and the crystalline form 1 of WO2024121805A1 were dispersed in FaSSIF and FeSSIF, respectively, to prepare suspensions. The suspensions were equilibrated at 37°C for 1 hour and 4 hours, and then filtered to obtain corresponding saturated solutions. The concentration of compound I in each saturated solution was tested by HPLC. The results are shown in Table 6.

[0092] Table 6

[0093] Results show that the crystalline CSV has higher solubility in both FaSSIF and FeSSIF. The higher solubility of the crystalline CSV provided by the present invention is beneficial for improving drug absorption and bioavailability in the human body. Furthermore, this higher solubility allows for a lower drug dosage while maintaining drug efficacy, thereby reducing side effects and improving drug safety.

[0094] 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. Compound I The crystalline form CSV is characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 6.8°±0.2°, 11.5°±0.2°, and 13.4°±0.2°.

2. The crystalline form CSV of compound 1 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 8.7±0.2°, 13.7°±0.2°, and 14.9°±0.2°.

3. The crystalline form CSV of compound 1 according to claim 1, characterized in that It is anhydrous.

4. The crystalline form CSV 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.

5. A pharmaceutical composition comprising the crystalline form CSV of Compound 1 according to claim 1 and a pharmaceutically acceptable excipient.

6. Use of the crystalline form CSV of Compound 1 according to claim 1 in the preparation of EGFR inhibitor drugs.

7. Use of the crystalline form CSV of Compound 1 according to claim 1 in the preparation of a medicament for treating non-small cell lung cancer with EGFR exon 20 insertion mutation.

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