Crystal form of eb-1020 and its preparation method and use
A crystal form and application technology, applied in the field of medicinal chemistry, can solve the problems of poor stability of crystal form C, difficult purification of crystal form B, poor compressibility and fluidity of needle-like crystals, and improve hardness/friability. , reduce costs and improve product quality
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Embodiment 1
[0115] Example 1: Preparation of crystal form CS1
[0116] Weigh about 15 mg of compound (I) raw material, place it in DSC, heat it to 248°C at a speed of 10°C / min to melt, then cool to room temperature to obtain a white solid.
[0117] After testing, the obtained solid is the crystal form CS1 of the present invention, and its X-ray powder diffraction data are as follows: figure 1 , shown in Table 1.
[0118] 1 HNMR such as figure 2 As shown, the NMR data are: 1 HNMR{(400MHz,d 6 -DMSO) δ 9.73 (s, 2H), 7.86 (dd, J=18.0, 12.1Hz, 4H), 7.53-7.43 (m, 2H), 7.38 (dd, J=8.6, 1.2Hz, 1H), 3.77 (d, J=11.1Hz, 1H), 3.64-3.49(m, 2H), 3.42(d, J=11.2Hz, 1H), 2.24(dt, J=8.3, 4.2Hz, 1H), 1.48(t, J=5.3Hz, 1H), 1.28-1.15(m, 1H).}
[0119] The DSC of crystal form CS1 obtained in this embodiment is as follows: image 3 As shown, an endothermic peak begins to appear when heated to around 247°C, which is the melting endothermic peak of crystal form CS1.
[0120] The TGA of crystal form CS...
Embodiment 2
[0127] Example 2: Stability of Form CS1
[0128] Weigh the crystal form CS1 of the present invention, place it in the open for 6 weeks under the conditions of 25°C / 60% relative humidity and 40°C / 75% relative humidity, and place it in the open for 1 week under the condition of 80°C, and measure it by HPLC and XRPD The changes of crystal form and chemical purity are shown in Table 3 and Table 4.
[0129] table 3
[0130]
[0131]
[0132] Table 4
[0133] placement conditions Purity after standing for 1 week Purity after 2 weeks Purity after 6 weeks 25℃ / 60% relative humidity 99.93％ 99.95％ 99.94％ 40℃ / 75% relative humidity 99.95％ 99.95％ 99.97％ 80℃ 99.82％ —— ——
[0134] The results show that the crystal form CS1 can be stable for at least 6 weeks under the conditions of 25°C / 60% relative humidity and 40°C / 75% relative humidity, and it can be stable for at least 1 week under the harsh conditions of 80°C. The chemical purity of CS...
Embodiment 3
[0135] Example 3: Comparison of grinding stability of crystal form CS1, existing crystal form A and crystal form B
[0136] Take the crystal form CS1 of the present invention, the existing crystal form A and the crystal form B respectively and place them in a mortar, and grind them manually for 5 minutes. The XRPD patterns of the crystal form CS1 of the present invention before and after grinding are as follows Figure 8 As shown (the picture above is before grinding, and the picture below is after grinding), the XRPD patterns of the existing crystal form A before and after grinding are as follows Figure 9 As shown (the picture above is before grinding, and the picture below is after grinding), the XRPD pictures of the existing crystal form B before and after grinding are as follows Figure 10 As shown (the picture above is before grinding, and the picture below is after grinding).
[0137] The results show that the crystal form CS1 of the present invention does not change...
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