Icotinib hydrochloride crystal form and preparation method thereof

Abstract

The invention provides an icotinib hydrochloride crystal form shown in a formula (I) and a preparation method thereof, the icotinib hydrochloride crystal form V provided by the invention is a novel crystal form structure, the XRPD characteristic peak combination of the icotinib hydrochloride crystal form V is different from that of all existing crystal forms, and the icotinib hydrochloride crystal form V has high crystallinity and excellent thermodynamic stability; in addition, an oral solid preparation (such as a tablet) prepared from the crystal form still keeps excellent dissolution stability under an accelerated condition, and the change rate of the dissolution behavior after an accelerated test is obviously lower than that of a crystal form in the prior art, so that a key material basis is provided for producing a solid medicinal preparation with high batch-to-batch consistency and reliable clinical curative effect; and the method has important industrial application value.

Description

Technical Field

[0001] This invention relates to icotinib hydrochloride, specifically to icotinib hydrochloride crystal form V and its preparation method. Background Technology

[0002] Icotinib hydrochloride is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor used to treat non-small cell lung cancer (NSCLC). The chemical name of icotinib hydrochloride is 4-[(3-ethynylphenyl)amino]-quinazolino[6,7-b]-12-crown-4 hydrochloride, and its structure is as follows:

[0003]

[0004] Polymorphism in pharmaceuticals has a decisive impact on their physicochemical properties, stability, solubility, bioavailability, and subsequent formulation processes. Therefore, developing novel polymorphs of icotinib hydrochloride with superior overall performance, especially high stability, is of great significance for ensuring drug quality, efficacy, and safety.

[0005] Currently, existing technologies have disclosed various crystal forms of icotinib hydrochloride. Among them, a series of patents from Zhejiang Beta Pharma Co., Ltd. (CN101878218, CN102911179, CN103254204, CN104530061, CN104592242) disclose four crystal forms: Crystal form I (crystallized in isopropanol, without solvates, melting point 225-228℃, characteristic diffraction angles of X-ray powder diffraction (XRPD) include 5.74°, 10.72°, and 11°). Crystal form I (crystallized in 50% ethanol, melting point 224–227℃, containing 2.11 molecules of water of crystallization, XRPD characteristic diffraction angles include 7.46°, 15.04°, 16.24°, 22.46°, etc.), Crystal form II (crystallized in water, melting point 224–227℃, containing 1.90 molecules of water of crystallization, XRPD characteristic diffraction angles include 9.72°, 10.40°, 24.74°, 25.50°, 21.40°, etc.), Crystal form III (crystallized in water, melting point 224–227℃, containing 1.90 molecules of water of crystallization, XRPD characteristic diffraction angles include 9.72°, 10.40 ... II (crystallized in 50% ethanol, melting point 224–227℃, containing 2.11 molecules of water of crystallization, XRPD characteristic diffraction angles include 9.72°, 10.40°, 25.50°, 21.40°, etc.), Crystal form III (crystallized in water, melting point 224–227℃, containing 1.90 molecules of water of crystallization, XRPD characteristic diffraction angles include 9.72°, 10.40°, 25.50°, 21.40 5.06° etc.) and crystal form IV (crystallized in DMF, melting point 223-226℃, containing 0.158 crystalline DMF, XRPD characteristic diffraction angles include 6.34°, 7.66°, 12.26°, 15.70° etc.); the patent (CN114907362) of Dr. Reddy's Laboratories Ltd., India, further discloses 9 crystal forms, including crystal form R and ICB-1 to ICB-8, among which crystal form R XRPD Characteristic diffraction angles include 6.22°, 10.16°, 14.88°, 16.18°, etc. The characteristic diffraction angles of XRPD for the ICB series crystal forms are different (e.g., ICB-3 includes 7.25°, 9.55°, 11.81°, etc., and ICB-5 includes 4.44°, 8.89°, 13.31°, etc.). The combinations of characteristic diffraction peaks of XRPD for the above-disclosed crystal forms are significantly different from the crystal forms protected by this invention.

[0006] However, those skilled in the art have found in practice that, despite the disclosure of numerous crystal forms, ongoing challenges remain in advancing the industrialization, formulation development, and long-term storage of icotinib hydrochloride. For example, crystal form I, which is widely used in existing technologies, exhibits a significant decrease in dissolution consistency under long-term storage or accelerated formulation conditions; other crystal forms, such as crystal form R, are prone to crystal transformation in competitive suspension systems, resulting in insufficient thermodynamic stability; crystal form IV, as a DMF solvator, carries the potential risk of excessive residual solvent; and crystal forms II and III have high water of crystallization content, making them susceptible to water loss or absorption under varying humidity conditions, leading to crystal transformation and affecting product quality stability. These deficiencies limit the application of existing crystal forms in large-scale commercial production and long-term storage. Therefore, developing a new crystal form of icotinib hydrochloride that specifically addresses the above problems, offers superior thermodynamic stability, long-term storage stability, good formulation dissolution consistency, and is suitable for large-scale industrial production has significant practical application value. Summary of the Invention

[0007] The first aspect of the present invention is to provide a crystal form V of icotinib hydrochloride as shown in formula (I).

[0008] A second aspect of the present invention is to provide a method for preparing icotinib hydrochloride crystal form V.

[0009] A third aspect of the present invention is to provide a pharmaceutical composition.

[0010] A fourth aspect of the present invention aims to provide the use of icotinib hydrochloride crystal form V or a pharmaceutical composition in the preparation of a medicament for treating non-small cell lung cancer.

[0011] To achieve the above objectives, the present invention provides the following technical solution:

[0012] The first aspect of the present invention provides a crystal form V of icotinib hydrochloride of formula (I), with an X-ray powder diffraction pattern expressed in diffraction angle 2θ having characteristic peaks at 6.14±0.2°, 10.07±0.2°, 12.39±0.2°, 20.83±0.2°, 22.98±0.2° and 31.47±0.2°.

[0013]

[0014] In some embodiments of the present invention, the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is as follows: Figure 1 As shown.

[0015] In some embodiments of the present invention, the crystal form is a hemihydrate.

[0016] A second aspect of the present invention aims to provide a method for preparing icotinib hydrochloride crystal form V, comprising the following steps:

[0017] a) Dissolve icotinib hydrochloride in a mixed solution of a polar protic solvent and water to form a clear solution, wherein the volume ratio of the polar protic solvent to water is greater than 90%;

[0018] b) Cool the solution obtained in step a) to precipitate crystals;

[0019] c) Separate and dry the obtained crystals to obtain crystal form V of the icotinib hydrochloride.

[0020] In some embodiments of the present invention, the polar protic solvent described in step a) is selected from one or more of methanol, ethanol, and isopropanol.

[0021] In some embodiments of the present invention, the polar protic solvent in step a) is methanol; in some embodiments of the present invention, the polar protic solvent in step a) is ethanol; in some embodiments of the present invention, the polar protic solvent in step a) is isopropanol.

[0022] In some embodiments of the present invention, the volume ratio of the polar protic solvent to water in step a) is 91-99%; in some embodiments of the present invention, the volume ratio of the polar protic solvent to water in step a) is 91%; in some embodiments of the present invention, the volume ratio of the polar protic solvent to water in step a) is 92%; in some embodiments of the present invention, the volume ratio of the polar protic solvent to water in step a) is 93%; in some embodiments of the present invention, the volume ratio of the polar protic solvent to water in step a) is 94%; in some embodiments of the present invention, the volume ratio of the polar protic solvent to water in step a) is 95%; in some embodiments of the present invention, the volume ratio of the polar protic solvent to water in step a) is 96%; in some embodiments of the present invention, the volume ratio of the polar protic solvent to water in step a) is 97%; in some embodiments of the present invention, the volume ratio of the polar protic solvent to water in step a) is 98%; in some embodiments of the present invention, the volume ratio of the polar protic solvent to water in step a) is 99%.

[0023] In some embodiments of the present invention, the volume-to-mass ratio of the mixed solution to icotinib hydrochloride in step a) is 20:1 to 60:1 mL / g; in some embodiments of the present invention, the volume-to-mass ratio of the mixed solution to icotinib hydrochloride in step a) is 20:1 mL / g; in some embodiments of the present invention, the volume-to-mass ratio of the mixed solution to icotinib hydrochloride in step a) is 30:1 mL / g; in some embodiments of the present invention, the volume-to-mass ratio of the mixed solution to icotinib hydrochloride in step a) is 40:1 mL / g; in some embodiments of the present invention, the volume-to-mass ratio of the mixed solution to icotinib hydrochloride in step a) is 50:1 mL / g; in some embodiments of the present invention, the volume-to-mass ratio of the mixed solution to icotinib hydrochloride in step a) is 60:1 mL / g.

[0024] A third aspect of the present invention aims to provide a pharmaceutical composition comprising a therapeutically effective amount of crystal form V of the icotinib hydrochloride of the present invention and one or more pharmaceutically acceptable carriers or excipients.

[0025] The fourth aspect of this invention aims to provide the use of the crystal form V of the icotinib hydrochloride or the pharmaceutical composition thereof in the preparation of a medicament for the treatment of non-small cell lung cancer.

[0026] Beneficial effects:

[0027] The icotinib hydrochloride crystal form V provided by this invention is a novel crystal structure. Its XRPD characteristic peak combination is different from all existing crystal forms, exhibiting high crystallinity and excellent thermodynamic stability. It can exist stably in competitive suspension systems and can transform into other crystal forms. It does not undergo crystal form transformation during long-term storage (30℃ / 65% RH, 6 months). In addition, oral solid dosage forms (such as tablets) prepared from this crystal form still maintain excellent dissolution stability under accelerated conditions. The rate of change in dissolution behavior after accelerated testing is significantly lower than that of existing crystal forms. This provides a key material basis for the production of solid drug formulations with high batch-to-batch consistency and reliable clinical efficacy, and has significant industrial application value. Attached Figure Description

[0028] Figure 1 XRPD pattern of crystal form V of icotinib hydrochloride as shown in Formula I;

[0029] Figure 2 Thermogravimetric analysis (TGA) spectrum of crystal form V of icotinib hydrochloride shown in Formula I;

[0030] Figure 3 Differential scanning calorimetry (DSC) spectrum of crystal form V of icotinib hydrochloride as shown in Formula I.

[0031] Detailed Implementation Methods (Examples)

[0032] To enable those skilled in the art to better understand the present application, the technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present application, and not all embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative effort should fall within the scope of protection of the present application.

[0033] It should be noted that the terms "comprising" and "having" and any variations thereof in the specification, claims and accompanying drawings of this application are intended to cover non-exclusive inclusion. For example, a process, method, system, product or device that includes a series of steps or units is not necessarily limited to those steps or units that are explicitly listed, but may include other steps or units that are not explicitly listed or that are inherent to such process, method, product or device.

[0034] The following are some definitions used in this invention:

[0035] In this invention, "polar protic solvent" refers to an organic solvent that has hydroxyl (-OH) or amino (-NH2) groups and can donate protons. Specifically, it is selected from one or more of methanol, ethanol, and isopropanol. The "volume ratio" of the solvent to water refers to the volume fraction of the polar protic solvent in the mixed solution (e.g., "95% ethanol aqueous solution" means that the volume ratio of ethanol to water is 95:5).

[0036] In this invention, the "volume-to-mass ratio of the mixed solution to icotinib hydrochloride" is expressed in mL / g. It refers to the ratio of the volume (mL) of the mixed solution of the polar protic solvent and water to the mass (g) of the icotinib hydrochloride raw material, and is used to define the ratio of raw material to solvent during the dissolution process.

[0037] In this invention, "pharmaceuticalally acceptable carrier or excipient" refers to a pharmaceutical excipient that does not react with crystal form V of this invention and has no toxic side effects on the human body.

[0038] In this invention, "crystal form" refers to the different crystal structures formed by the same chemical molecule in the solid state due to different molecular arrangements or conformations.

[0039] In this invention, "semihydrate" refers to the crystalline solid form in which each icotinib hydrochloride molecule binds an average of about 0.5 water molecules.

[0040] In this invention, the "X-ray powder diffraction pattern" is obtained using a copper Kα radiation source. The pattern, with diffraction angle (2θ) as the abscissa and diffraction intensity as the ordinate, serves as fingerprint data for identifying and defining crystal structures. In this invention, "as..." Figure 1 The spectrum shown is the core basis for defining crystal form V.

[0041] In this invention, "relative standard deviation" is the ratio of the standard deviation of a set of data to its arithmetic mean, usually expressed as a percentage, and is used to measure the dispersion and reproducibility of the dataset. In this invention, it is used to quantify the fluctuation of the tablet dissolution curve at different time points; the lower the RSD value, the more stable the dissolution behavior and the better the reproducibility.

[0042] In this invention, "accelerated stability testing" refers to stability studies conducted under more stringent temperature and / or humidity conditions than conventional storage conditions, aiming to predict the long-term stability of pharmaceutical products or active pharmaceutical ingredients under proposed storage conditions in a shorter timeframe. Specifically, this refers to a test conducted at 30°C ± 2°C / 65% ± 5% relative humidity (RH) for 6 months.

[0043] The invention will be further analyzed below with reference to specific examples.

[0044] Example 1: Preparation, characterization, and stability verification of icotinib hydrochloride crystal form V.

[0045] Three 1.00 g aliquots of icotinib hydrochloride were mixed with 50 mL of 95% ethanol aqueous solution (ethanol:water = 95:5, v / v), 95% methanol aqueous solution (methanol:water = 95:5, v / v), and 95% isopropanol aqueous solution (isopropanol:water = 95:5, v / v), respectively. The mixtures were heated until dissolved and clear, then cooled to 20–25 °C, stirred, and allowed to crystallize for 12–15 h. The mixtures were then filtered and dried under vacuum at 40–50 °C to obtain three white crystalline powders. X-ray diffraction patterns of the obtained crystals were analyzed using an X-ray diffraction instrument. The powder X-ray diffraction patterns of the three crystals were completely identical (i.e., crystal form V), all as shown in the image. Figure 1 As shown, the characteristic diffraction peaks are located at 2θ of 6.14°, 10.07°, 12.39°, 20.83°, 22.98°, and 31.47°, and the main peaks are sharp, indicating that crystal form V has high crystallinity. Differential scanning calorimetry (DSC) curves ( Figure 2 ) and thermogravimetric analysis (TGA) curves ( Figure 3 Further characterization of its thermal behavior was conducted. Moisture content (KF method) of crystal form V was 2.1%, and combined with the high initial water loss temperature (>100℃) and stepwise weight loss characteristics shown in the TGA curve, this moisture content indicates that it is water of crystallization. Chemometric calculations show that this moisture content corresponds to approximately 0.5 moles of water, thus confirming that crystal form V is the hemihydrate of icotinib hydrochloride.

[0046] Stability verification experiment

[0047] Competitive suspension stability experiment: At room temperature, crystal form V (obtained in Example 1) and crystal form I (prepared according to patent CN101878218), and crystal form V (obtained in Example 1) and crystal form R (prepared according to patent CN114907362) were mixed at a mass ratio of 1:1. 10 mL of water and 10 mL of 95% ethanol aqueous solution were added to each mixture. After sealing, the mixture was competitively suspended for 7 days and filtered. The mixture was then vacuum dried at 40-50℃. The resulting solids were subjected to powder X-ray diffraction. The results showed that the XRPD patterns of the solid products of both mixed systems were completely transformed into the characteristic patterns of crystal form V, proving that the thermodynamic stability of crystal form V is better than that of crystal form I and crystal form R, and that it can spontaneously transform into other crystal forms.

[0048] Long-term stability test: Crystal form V was placed at 30℃ / 65%RH for 6 months, and PXRD was measured periodically. The PXRD pattern showed no observable difference from the initial pattern, indicating that crystal form V has excellent physical and chemical stability. To verify the performance advantage of crystal form V in the final product, it was compared with crystal form I. Using the same formulation and process, crystal form V and crystal form I were prepared into tablets, respectively. Dissolution tests were performed on the prepared tablets, and the relative standard deviation (RSD) of the dissolution curves at different time points was calculated to assess intra-batch homogeneity. Then, the tablets were placed at 30℃ / 65%RH for 6 months for accelerated stability testing, and dissolution was tested again and RSD was calculated. The results are shown in Table 1. The results show that the RSD values ​​of the initial and accelerated dissolution curves of the tablets prepared from crystal form V were significantly lower than those of the tablets prepared from crystal form I. In particular, after accelerated testing, the dissolution behavior of crystal form I tablets fluctuated significantly (e.g., the 5-minute RSD increased from 8.0% to 20.3%), while the dissolution behavior of crystal form V tablets remained highly stable (e.g., the 5-minute RSD increased slightly from 7.6% to 8.2%). This demonstrates that using crystal form V as the active ingredient can significantly improve the long-term stability and quality reproducibility of drug formulations.

[0049] Table 1. Comparison of Relative Standard Deviation (RSD) of Dissolution Curves

[0050]

[0051] Example 2: Effect of Solvent Ratio on Crystal Form

[0052] 1.00 g of icotinib hydrochloride was mixed with 40 mL of 90% ethanol aqueous solution (ethanol:water = 90:10, v / v), heated until dissolved and clear, cooled to 20–25 °C, stirred and crystallized for 12–15 h, filtered, and dried under vacuum at 40–50 °C to obtain a white crystalline powder. XRPD testing (test conditions same as in Example 1) showed that the XRPD spectrum of the obtained crystals was completely consistent with the characteristic peaks of crystal form ICB-3 disclosed in patent CN114907362, and no characteristic peaks of crystal form V were detected. This indicates that crystal form V cannot be obtained when the volume ratio of the polar protic solvent to water is ≤90%.

[0053] Example 3: Effect of different low solvent ratios on crystal form

[0054] Take three 1.00g portions of icotinib hydrochloride and mix them with 30mL of 80% ethanol aqueous solution (ethanol:water = 80:20, v / v), 25mL of 70% ethanol aqueous solution (ethanol:water = 70:30, v / v), and 20mL of 50% ethanol aqueous solution (ethanol:water = 50:50, v / v), respectively. Heat until dissolved and clear, cool to 20-25℃, stir and crystallize for 12-15h, filter, and vacuum dry at 40-50℃ to obtain a white crystalline powder. The obtained crystals were tested by XRPD (test conditions were the same as in Example 1). The XRPD spectra of the three samples were completely consistent and matched the characteristic peaks of the crystal form ICB-3 disclosed in patent CN114907362. This further proves that the low-proportion ethanol aqueous solution system can only generate the existing crystal form ICB-3 and cannot obtain the crystal form V of this invention.

[0055] Example 4: Effect of Seed Crystals on Crystal Form in Low Solvent Ratio Systems

[0056] Take three 1.00g portions of icotinib hydrochloride and mix them with 30mL of 80% ethanol aqueous solution, 25mL of 70% ethanol aqueous solution, and 20mL of 50% ethanol aqueous solution, respectively. Heat until dissolved and clear, cool to 60-65℃, add crystal seed of crystal form V, continue to cool to 20-25℃, stir and crystallize for 12-15h, filter, and vacuum dry at 40-50℃ to obtain a white crystalline powder. The obtained crystals were tested by XRPD (test conditions were the same as in Example 1). The XRPD pattern of the obtained crystals was still consistent with crystal form ICB-3. The crystal seed did not induce the formation of crystal form V, indicating that the solvent volume ratio is the key controlling factor for the formation of crystal form V. The crystal seed cannot change the crystal formation trend under low solvent ratio system.

[0057] Example 5: Effect of extremely low solvent ratio system on crystal form

[0058] 1.00 g of icotinib hydrochloride was mixed with 40 mL of 20% ethanol aqueous solution, heated until dissolved and clear, cooled to 20–25 °C, stirred and crystallized for 12–15 h, filtered, and dried under vacuum at 40–50 °C to obtain a white crystalline powder. XRPD analysis of the obtained crystals showed characteristic peaks of crystal form I, ICB-3, and unknown impurity peaks, indicating a mixed crystal system with no single crystal form formed.

[0059] Example 6: Effect of Extremely Low Proportion Solvent System on Crystal Form

[0060] 1.00 g of icotinib hydrochloride was mixed with 75 mL of 10% (volume ratio) ethanol aqueous solution, heated until dissolved and clear, cooled to 20-25 °C, stirred and crystallized for 12-15 h, filtered, and dried under vacuum at 40-50 °C to obtain a white crystalline powder. The obtained crystals were tested by XRPD, and the spectrum showed the presence of crystal form II, ICB-3 and unknown impurity peaks, indicating that it was a mixed crystal system and a single crystal form could not be obtained.

Claims

1. A crystalline form V of icotinib hydrochloride represented by formula (I), ###0001### Formula (I). characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ has characteristic peaks at 6.14±0.2°, 10.07±0.2°, 12.39±0.2°, 20.83±0.2°, 22.98±0.2° and 31.47±0.2°.

2. The crystalline Form V of icotinib hydrochloride according to claim 1, characterized in that, The X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ is shown in Figure 1.

3. The crystalline Form V of Icotinib hydrochloride according to claim 1 or 2, characterized in that, The crystalline form is a hemihydrate.

4. A method for preparing the crystalline Form V of Icotinib hydrochloride according to any one of claims 1 to 3, characterized in that, The method comprises the following steps: a) dissolving icotinib hydrochloride in a mixed solution of a polar protic solvent and water, wherein the volume ratio of the polar protic solvent to water is greater than 90%, to form a clear solution; b) cooling the solution obtained in step a) to precipitate crystals; c) separating and drying the crystals to obtain the crystalline form V of icotinib hydrochloride.

5. The method of claim 4, wherein, The polar protic solvent in step a) is selected from one or more of methanol, ethanol, isopropanol.

6. The method according to claim 4 or 5, characterized in that, The volume ratio of the polar protic solvent to water in step a) is 95%.

7. The preparation method according to claim 4, characterized in that, The volume to mass ratio of the mixed solution to icotinib hydrochloride in step a) is 20:1-60:1 mL / g; preferably, the volume to mass ratio of the mixed solution to icotinib hydrochloride is 50:1 mL / g.

8. A pharmaceutical composition, characterized by, A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form V of icotinib hydrochloride as claimed in any one of claims 1-3 and one or more pharmaceutically acceptable carriers or excipients.

9. Use of the crystalline form V of icotinib hydrochloride as claimed in any one of claims 1-3 or the pharmaceutical composition of claim 8 in the preparation of a medicament for the treatment of non-small cell lung cancer.

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