CN115385931A

CN115385931A - Polymorphic substance of dorzolavir sodium and preparation method thereof

Info

Publication number: CN115385931A
Application number: CN202110565497.1A
Authority: CN
Inventors: 蔡志刚; 彭欢; 钟仁欢; 闵思佳; 张良
Original assignee: Shanghai Acebright Pharmaceuticals Group Co ltd; SHANGHAI XIMAI MEDICAL TECHNOLOGY CO LTD
Current assignee: Jiangxi Desino Pharmaceutical Co ltd
Priority date: 2021-05-24
Filing date: 2021-05-24
Publication date: 2022-11-25

Abstract

The invention provides a polymorphic substance of dortavir sodium and a preparation method thereof, and provides (4R, 12aS) -9- ((2,4-difluorobenzyl) carbamoyl) -4-methyl-6,8-dioxo-3, 4,6,8,12, 12a-hexahydro-2H-pyridyl [1',2':4,5]Pyrazino [2,1-b][1,3]Polymorphs of sodium oxazine-7-ate (I) in a further aspect, the present invention provides processes for the preparation of the above polymorphs. Compared with the prior art, the crystal form prepared by the invention has excellent stability, simple and convenient preparation method and high medicinal feasibility, and is suitable for subsequent preparation research and development and industrial production.

Description

Polymorphic substance of dorzolavir sodium and preparation method thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a novel crystal form of (4R, 12aS) -9- ((2,4-difluorobenzyl) carbamoyl) -4-methyl-6,8-dioxo-3, 4,6,8,12, 12a-hexahydro-2H-pyridyl [1',2':4,5] pyrazino [2,1-b ] [1,3] oxazine-7-acid ester sodium and a preparation method thereof.

Background

Integrase catalyzes 2 key steps in the life cycle of HIV and is responsible for the entry and exit of the viral genome into the deoxyribonucleic acid (DNA) of the host cell. Since genomic integration is a critical step in retroviral replication, it is an important target for HIV therapy. Dorzolamide sodium is an HIV integrase inhibitor, is a novel antiretroviral drug, and achieves the purpose of treating AIDS by preventing HIV viruses from entering cells. The drug is developed by Kulansu Schke pharmaceutical company and Japanese salt Ye pharmaceutical company, is approved by the US FDA for the first time to be sold on the market in 8 months in 2013, and has the trade name of TIVICAY. It can be used in combination with other antiretroviral drugs for the treatment of Human Immunodeficiency Virus (HIV) infected adults and children aged 12 years.

The chemical name of the dorawivir sodium is as follows: (4R, 12aS) -9- { [ (2,4-difluorophenyl) methyl]Carbamoyl } -4-methyl-6,8-dioxo-3, 4,6,8,12, 12a-hexahydro-2H-pyrido [1',2':4,5]Pyrazino [2,1-b][1,3]Oxazin-7-ol sodium salt; the chemical formula is: c ₂₀ H ₁₈ F ₂ N ₃ NaO ₅ (ii) a The molecular weight is: 441.36; the chemical structural formula is as follows:

the chemical structural formula of the acid Wei Youli is as follows:

patent WO2010068253 reports an anhydrate and hydrate of dortavir sodium. Patent WO2015139591 discloses that these 2 crystal forms have poor stability, cannot maintain the original crystalline form in aqueous suspension competition, and have low solubility, and these properties make the pharmaceutical preparations thereof have the problems of unstable active substance content, poor production reproducibility, increased impurity crystal form content during storage, reduced drug effect, low bioavailability, and the like.

Patent WO2013038407 reports amorphous form of doriravir sodium and a method for its preparation. Patent WO2015139591 discloses that amorphous form is converted to the anhydrate of patent WO2010068253 upon stirring in water for 5 minutes at room temperature, with poor stability, and is not suitable for use in solid formulations.

Patent WO2015139591 reports crystal form a, crystal form B, crystal form C, crystal form D and crystal form E, for a total of 5 crystal forms. Wherein the solubility of the crystal form A is lower than that of anhydrate and hydrate reported in the original patent WO2010068253, which may cause the reduction of bioavailability. The moisture uptake of form B is greater than that of the anhydrate reported in the original patent WO2010068253, with a change in RH weight of 20% to 80% to 4.3%, which is detrimental to the packaging and storage of pharmaceuticals. The crystal form C and the crystal form E are respectively n-butyl alcohol solvate and trifluoroethanol solvate, and are not suitable for medicinal use. The crystal form D needs to be obtained by taking the crystal form C as an initial raw material and heating to 130-150 ℃ for desolventizing, mixed crystals of the crystal form D and the crystal form C can be easily obtained by the method in mass production, and the heating temperature is too high, so that the risk of generating impurities is caused.

Form M1 is reported in patent WO2015092752 and is an N-methyl pyrrolidone solvate, and 1,2-propylene glycol solvate is reported in patent WO2016102078 and is not suitable for medicinal use.

WO2015118460 reports 4 crystal forms of Form M2, form M3, and Form M4. As can be seen from the comparison patent, form M2 and Form M4 are respectively consistent with XRPD patterns of crystal Form C and crystal Form D in patent WO 2015139591. Form M3 has no other research information except XRPD, and the medicinal feasibility and the industrial production feasibility of the Form M3 are questioned.

WO2015138933 reports Form II, form III, form IV, form V, form VI, form VII, form VIII, form IX, form X, form XI. Wherein the XRPD patterns of Form II, form V and Form VII are consistent with Form M1 in patent WO2015092752, form M4 in patent WO2015118460 and Form B in patent WO2015139591 respectively.

Form III and Form IV in WO2015138933 are obtained from Form II placed in an atmosphere of ethanol and isopropanol, respectively, for 7 days. Form VIII and Form IX are obtained by dissolving Form VI in benzyl alcohol at 150 ℃ and cooling, the dissolving temperature is too high, the risk of impurity generation is caused, and the boiling point of the benzyl alcohol is too high, so that the solvent residue is difficult to remove. Form XI was obtained from Form VI by stirring in isobutanol, and a mixed crystal of Form VI and Form XI was easily obtained. The crystal forms are not suitable for industrial production. From X is an n-butanol solvate and 1,2-propanediol solvate, and is not suitable for pharmaceutical use.

WO2016016279 reports HxA, hy1B and S _EtOH/H2O . Wherein S _EtOH/H2O Unstable, shifted to Hy1B at 40 ℃/75% RH. Hy1B from S _EtOH/H2O Induced by humidity, readily available S _EtOH/H2O And Hy1B. HxA is obtained by suspending acid of cotila Wei Youli in methanol and then adding NaOH solution for reaction, is heterogeneous salt formation and is not beneficial to control of product granularity and the like.

Patent WO2017029642 reports Form I, form II, form L9, form L10, form L11, form L12, 1-amino-2-propanol solvate, and 7 crystal forms in total, wherein Form I and Form II are morpholine solvates and are not suitable for medicinal use. Form L9 has a lower solubility, in water and buffer solutions at pH4.5, than the anhydrate reported in the original patent WO 2010068253. Other crystal forms do not disclose research information such as crystal form stability and the like, the medicinal feasibility is questioned, and the preparation methods of the crystal forms are heterogeneous salt formation, which is not beneficial to the control of the product granularity and the like.

Form a is reported in patent WO 2017208105. Patent WO2019048808 reports Form 1A and Form 1B. However, other research information such as crystal form stability, solubility and the like is not disclosed, and the medicinal feasibility of the crystal form is questionable.

Patent WO2020161742 reports Form S, form N, 1,3-butanediol solvate, benzyl alcohol solvate and Form L, in total, as 5 crystal forms. Wherein the boiling points of 1,3-butanediol and benzyl alcohol are high, respectively 206 ℃ and 207 ℃, and the method has a large risk of overproof solvent residues and is not beneficial to industrial production. And the patent does not disclose other research information of Form S, form N and Form L except XRPD, and the medicinal feasibility thereof is questioned. The preparation methods of Form S and Form N are heterogeneous salt formation. The solvent volume required for preparing Form L is 120 times, and the solvent volume is too large, so that the Form L is not suitable for industrialization.

Patent CN11222549 reports crystal form α and crystal form β. Wherein the crystal form alpha is n-butanol solvate, which is not suitable for medical use. The crystal form beta is obtained by heating the crystal form alpha to 90-200 ℃, the temperature is too high, the risks of overproof impurities and the like are possible, the patent does not disclose research information such as the stability of the crystal form beta and the like, and the medicinal feasibility is questionable.

In order to overcome the defects of the prior art, a new crystal form of dorzolamide sodium which has excellent stability, mechanical stability, high medicinal feasibility, convenient preparation and industrial production is urgently needed in the field.

Disclosure of Invention

The invention aims to provide a novel crystal form of a compound shown in a formula (I), which is easy to prepare and excellent in stability, so as to meet the requirements of pharmaceutical research and industrial production.

In a first aspect of the invention, there is provided a polymorph of a compound of formula (I):

in another preferred embodiment, the polymorph is form XM-I, wherein the X-ray powder diffraction pattern of form XM-I comprises 3 or more 2 Θ values selected from the group consisting of: 7.0 degrees +/-0.2 degrees, 9.4 degrees +/-0.2 degrees, 12.2 degrees +/-0.2 degrees, 13.8 degrees +/-0.2 degrees and 15.1 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-I is a hydrate.

In another preferred embodiment, the crystalline form XM-I has an X-ray powder diffraction pattern comprising 6 or more 2 Θ values selected from the group consisting of: 7.0 degrees +/-0.2 degrees, 9.4 degrees +/-0.2 degrees, 12.2 degrees +/-0.2 degrees, 12.4 degrees +/-0.2 degrees, 13.8 degrees +/-0.2 degrees, 15.1 degrees +/-0.2 degrees, 20.8 degrees +/-0.2 degrees and 31.6 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-I has an X-ray powder diffraction pattern comprising 6 or more 2 Θ values selected from the group consisting of: 7.0 degree plus or minus 0.2 degree, 7.5 degree plus or minus 0.2 degree, 9.4 degree plus or minus 0.2 degree, 10.8 degree plus or minus 0.2 degree, 12.2 degree plus or minus 0.2 degree, 12.4 degree plus or minus 0.2 degree, 13.0 degree plus or minus 0.2 degree, 13.8 degree plus or minus 0.2 degree, 15.1 degree plus or minus 0.2 degree, 17.5 degree plus or minus 0.2 degree, 19.0 degree plus or minus 0.2 degree, 20.8 degree plus or minus 0.2 degree, 24.2 degree plus or minus 0.2 degree, 29.1 degree plus or minus 0.2 degree, 31.6 degree plus or minus 0.2 degree.

In another preferred embodiment, the crystalline form XM-I has an X-ray powder diffraction pattern substantially as shown in figure 1 a.

In another preferred embodiment, the crystalline form XM-I has an X-ray powder diffraction pattern substantially as shown in figure 1b.

In another preferred embodiment, the crystalline form XM-I has a thermogravimetric analysis (TGA) substantially as shown in figure 2.

In another preferred embodiment, the crystalline form XM-I has a Differential Scanning Calorimetry (DSC) profile substantially as shown in figure 3.

In another preferred embodiment, the crystalline form XM-I has a nmr spectrogram substantially as shown in fig. 4 (b) ¹ H NMR)。

In another preferred embodiment, the polymorph is form XM-I ', wherein the X-ray powder diffraction pattern of form XM-I' comprises 3 or more 2 Θ values selected from the group consisting of: 6.5 degrees +/-0.2 degrees, 7.4 degrees +/-0.2 degrees, 12.5 degrees +/-0.2 degrees and 13.1 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-I' has an X-ray powder diffraction pattern comprising 6 or more 2 Θ values selected from the group consisting of: 6.5 degrees +/-0.2 degrees, 7.4 degrees +/-0.2 degrees, 10.2 degrees +/-0.2 degrees, 12.0 degrees +/-0.2 degrees, 12.5 degrees +/-0.2 degrees, 13.1 degrees +/-0.2 degrees, 18.9 degrees +/-0.2 degrees and 19.7 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-I' has an X-ray powder diffraction pattern substantially as shown in figure 7.

In another preferred embodiment, the polymorph is form XM-I ", wherein the form XM-I" has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 6.9 degrees +/-0.2 degrees, 9.3 degrees +/-0.2 degrees, 11.9 degrees +/-0.2 degrees and 12.6 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-I "has an X-ray powder diffraction pattern comprising 6 or more 2 Θ values selected from the group consisting of: 6.9 degrees +/-0.2 degrees, 9.3 degrees +/-0.2 degrees, 11.0 degrees +/-0.2 degrees, 11.9 degrees +/-0.2 degrees, 12.6 degrees +/-0.2 degrees, 13.1 degrees +/-0.2 degrees, 13.5 degrees +/-0.2 degrees and 19.2 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-I "has an X-ray powder diffraction pattern substantially as shown in figure 8.

In another preferred embodiment, the polymorph is form XM-II, wherein the X-ray powder diffraction pattern of form XM-II comprises 3 or more 2 Θ values selected from the group consisting of: 7.0 degrees +/-0.2 degrees, 11.0 degrees +/-0.2 degrees, 11.4 degrees +/-0.2 degrees and 12.6 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-II has an X-ray powder diffraction pattern comprising 4 or more 2 Θ values selected from the group consisting of: 4.6 degrees +/-0.2 degrees, 7.0 degrees +/-0.2 degrees, 11.0 degrees +/-0.2 degrees, 11.4 degrees +/-0.2 degrees, 12.6 degrees +/-0.2 degrees and 14.1 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-II has an X-ray powder diffraction pattern substantially as shown in figure 9.

In another preferred embodiment, the polymorph is form XM-III, wherein the X-ray powder diffraction pattern of form XM-III comprises 3 or more 2 Θ values selected from the group consisting of: 6.0 degrees +/-0.2 degrees, 10.6 degrees +/-0.2 degrees, 11.5 degrees +/-0.2 degrees and 13.2 degrees +/-0.2 degrees.

In another preferred example, the crystalline form XM-III has an X-ray powder diffraction pattern comprising 6 or more 2 Θ values selected from the group consisting of: 6.0 degrees +/-0.2 degree, 8.2 degrees +/-0.2 degree, 10.6 degrees +/-0.2 degree, 11.5 degrees +/-0.2 degree, 11.9 degrees +/-0.2 degree, 13.2 degrees +/-0.2 degree, 18.4 degrees +/-0.2 degree and 19.2 degrees +/-0.2 degree.

In another preferred embodiment, the crystalline form XM-III has an X-ray powder diffraction pattern comprising 6 or more 2 Θ values selected from the group consisting of: 6.0 degrees +/-0.2 degrees, 8.2 degrees +/-0.2 degrees, 10.6 degrees +/-0.2 degrees, 11.5 degrees +/-0.2 degrees, 11.9 degrees +/-0.2 degrees, 12.5 degrees +/-0.2 degrees, 13.2 degrees +/-0.2 degrees, 15.9 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 18.4 degrees +/-0.2 degrees, 19.2 degrees +/-0.2 degrees, 21.6 degrees +/-0.2 degrees and 29.7 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-III has an X-ray powder diffraction pattern substantially as shown in figure 10.

In another preferred embodiment, the polymorph is form XM-IV.

In another preferred embodiment, the crystalline form XM-IV has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 5.6 degrees +/-0.2 degrees, 11.6 degrees +/-0.2 degrees, 18.2 degrees +/-0.2 degrees and 18.9 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-IV has an X-ray powder diffraction pattern comprising 5 or more 2 Θ values selected from the group consisting of: 5.6 degrees +/-0.2 degrees, 11.6 degrees +/-0.2 degrees, 18.2 degrees +/-0.2 degrees, 18.9 degrees +/-0.2 degrees, 22.1 degrees +/-0.2 degrees, 23.3 degrees +/-0.2 degrees, 23.7 degrees +/-0.2 degrees, 26.7 degrees +/-0.2 degrees and 27.1 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-IV has an X-ray powder diffraction pattern comprising 6 or more 2 Θ values selected from the group consisting of: 5.6 degrees +/-0.2 degree, 7.2 degrees +/-0.2 degree, 8.8 degrees +/-0.2 degree, 9.3 degrees +/-0.2 degree, 11.2 degrees +/-0.2 degree, 11.6 degrees +/-0.2 degree, 14.5 degrees +/-0.2 degree, 15.5 degrees +/-0.2 degree, 16.1 degrees +/-0.2 degree, 16.8 degrees +/-0.2 degree, 17.5 degrees +/-0.2 degree, 18.2 degrees +/-0.2 degree, 18.9 degrees +/-0.2 degree, and the like 19.8 degrees +/-0.2 degrees, 22.1 degrees +/-0.2 degrees, 22.8 degrees +/-0.2 degrees, 23.3 degrees +/-0.2 degrees, 23.7 degrees +/-0.2 degrees, 26.4 degrees +/-0.2 degrees, 26.7 degrees +/-0.2 degrees, 27.1 degrees +/-0.2 degrees, 28.3 degrees +/-0.2 degrees, 29.2 degrees +/-0.2 degrees, 31.2 degrees +/-0.2 degrees, 31.7 degrees +/-0.2 degrees and 32.8 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-IV has an X-ray powder diffraction pattern substantially as shown in figure 11.

In another preferred embodiment, the polymorph is form XM-V.

In another preferred embodiment, the crystalline form XM-V has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 5.5 degrees +/-0.2 degrees, 9.1 degrees +/-0.2 degrees, 11.6 degrees +/-0.2 degrees and 17.6 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-V has an X-ray powder diffraction pattern comprising 6 or more 2 Θ values selected from the group consisting of: 5.5 degrees +/-0.2 degrees, 6.3 degrees +/-0.2 degrees, 7.2 degrees +/-0.2 degrees, 9.1 degrees +/-0.2 degrees, 11.1 degrees +/-0.2 degrees, 11.6 degrees +/-0.2 degrees, 12.8 degrees +/-0.2 degrees, 17.6 degrees +/-0.2 degrees and 19.2 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-V has an X-ray powder diffraction pattern comprising 6 or more 2 Θ values selected from the group consisting of: 5.5 degrees +/-0.2 degrees, 6.3 degrees +/-0.2 degrees, 7.2 degrees +/-0.2 degrees, 9.1 degrees +/-0.2 degrees, 10.3 degrees +/-0.2 degrees, 10.7 degrees +/-0.2 degrees, 11.1 degrees +/-0.2 degrees, 11.6 degrees +/-0.2 degrees, 12.8 degrees +/-0.2 degrees, 13.9 degrees +/-0.2 degrees, 15.1 degrees +/-0.2 degrees, 17.6 degrees +/-0.2 degrees, 19.2 degrees +/-0.2 degrees, 21.7 degrees +/-0.2 degrees, 25.2 degrees +/-0.2 degrees, 25.7 degrees +/-0.2 degrees, 27.0 degrees +/-0.2 degrees and 29.8 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-V has an X-ray powder diffraction pattern substantially as shown in figure 12.

In another preferred embodiment, the polymorph is form XM-VI.

In another preferred embodiment, the crystalline form XM-VI has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 5.1 degrees +/-0.2 degree, 7.6 degrees +/-0.2 degree, 15.4 degrees +/-0.2 degree and 18.1 degrees +/-0.2 degree.

In another preferred embodiment, the crystalline form XM-VI has an X-ray powder diffraction pattern comprising 6 or more 2 Θ values selected from the group consisting of: 5.1 degree plus or minus 0.2 degree, 7.6 degree plus or minus 0.2 degree, 10.2 degree plus or minus 0.2 degree, 12.6 degree plus or minus 0.2 degree, 15.4 degree plus or minus 0.2 degree, 16.6 degree plus or minus 0.2 degree, 18.1 degree plus or minus 0.2 degree, 19.0 degree plus or minus 0.2 degree, 21.2 degree plus or minus 0.2 degree, 23.5 degree plus or minus 0.2 degree.

In another preferred embodiment, the crystalline form XM-VI has an X-ray powder diffraction pattern comprising 6 or more 2 Θ values selected from the group consisting of: 5.1 degree plus or minus 0.2 degree, 7.6 degree plus or minus 0.2 degree, 10.2 degree plus or minus 0.2 degree, 11.8 degree plus or minus 0.2 degree, 12.6 degree plus or minus 0.2 degree, 15.4 degree plus or minus 0.2 degree, 16.6 degree plus or minus 0.2 degree, 18.1 degree plus or minus 0.2 degree, 19.0 degree plus or minus 0.2 degree, 21.2 degree plus or minus 0.2 degree, 23.0 degree plus or minus 0.2 degree, 23.5 degree plus or minus 0.2 degree, 25.5 degree plus or minus 0.2 degree.

In another preferred embodiment, the crystalline form XM-VI has an X-ray powder diffraction pattern substantially as shown in figure 13.

In another preferred embodiment, the polymorph is form XM-VII.

In another preferred embodiment, the X-ray powder diffraction pattern of crystalline form XM-VII comprises 2 Θ values selected from the group consisting of: 5.9 degrees +/-0.2 degrees, 7.1 degrees +/-0.2 degrees and 8.1 degrees +/-0.2 degrees.

In another preferred example, the X-ray powder diffraction pattern of said crystalline form XM-VII comprises 3 or more 2 Θ values selected from the group consisting of: 5.9 degrees +/-0.2 degrees, 7.1 degrees +/-0.2 degrees, 8.1 degrees +/-0.2 degrees and 9.3 degrees +/-0.2 degrees.

In another preferred embodiment, the X-ray powder diffraction pattern of said crystalline form XM-VII comprises 4 or more 2 Θ values selected from the group consisting of: 5.9 degrees +/-0.2 degrees, 7.1 degrees +/-0.2 degrees, 8.1 degrees +/-0.2 degrees, 9.3 degrees +/-0.2 degrees, 11.6 degrees +/-0.2 degrees and 15.8 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-VII has an X-ray powder diffraction pattern substantially as shown in figure 14.

In another preferred embodiment, the polymorph is form XM-VIII.

In another preferred embodiment, the crystalline form XM-VIII has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 5.8 degrees +/-0.2 degree, 6.3 degrees +/-0.2 degree, 7.9 degrees +/-0.2 degree and 9.9 degrees +/-0.2 degree.

In another preferred embodiment, the crystalline form XM-VIII has an X-ray powder diffraction pattern comprising 5 or more 2 Θ values selected from the group consisting of: 5.8 degrees +/-0.2 degrees, 6.3 degrees +/-0.2 degrees, 7.9 degrees +/-0.2 degrees, 9.9 degrees +/-0.2 degrees, 12.7 degrees +/-0.2 degrees, 19.0 degrees +/-0.2 degrees, 19.9 degrees +/-0.2 degrees and 21.4 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-VIII has an X-ray powder diffraction pattern comprising 6 or more 2 Θ values selected from the group consisting of: 5.8 degrees +/-0.2 degrees, 6.3 degrees +/-0.2 degrees, 7.9 degrees +/-0.2 degrees, 9.9 degrees +/-0.2 degrees, 12.7 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 18.7 degrees +/-0.2 degrees, 19.0 degrees +/-0.2 degrees, 19.9 degrees +/-0.2 degrees, 20.5 degrees +/-0.2 degrees, 21.4 degrees +/-0.2 degrees, 24.3 degrees +/-0.2 degrees, 25.3 degrees +/-0.2 degrees, 27.6 degrees +/-0.2 degrees, 27.9 degrees +/-0.2 degrees, 29.4 degrees +/-0.2 degrees, 31.1 degrees +/-0.2 degrees and 32.0 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-VIII has an X-ray powder diffraction pattern substantially as shown in figure 15.

In another preferred embodiment, the polymorph is form XM-IX.

In another preferred embodiment, the crystalline form XM-IX has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 6.4 degrees +/-0.2 degrees, 8.0 degrees +/-0.2 degrees, 12.8 degrees +/-0.2 degrees and 19.8 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-IX has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 6.4 degrees +/-0.2 degrees, 8.0 degrees +/-0.2 degrees, 12.8 degrees +/-0.2 degrees, 19.8 degrees +/-0.2 degrees and 21.2 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-IX has an X-ray powder diffraction pattern comprising 6 or more 2 Θ values selected from the group consisting of: 6.4 degrees +/-0.2 degrees, 8.0 degrees +/-0.2 degrees, 12.5 degrees +/-0.2 degrees, 12.8 degrees +/-0.2 degrees, 18.6 degrees +/-0.2 degrees, 19.0 degrees +/-0.2 degrees, 19.8 degrees +/-0.2 degrees, 20.7 degrees +/-0.2 degrees and 21.2 degrees +/-0.2 degrees.

In another preferred embodiment, the crystalline form XM-IX has an X-ray powder diffraction pattern substantially as shown in figure 16.

In a second aspect of the present invention there is provided a process for the preparation of a polymorph according to the first aspect of the present invention, comprising the steps of:

crystallizing a compound of formula (II) and sodium hydroxide as a salt in an inert solvent, or treating a starting compound of formula (I) to obtain the polymorph, wherein the treating comprises one or more steps of: stirring, heating, and standing under certain temperature and humidity conditions.

In another preferred embodiment, the inert solvent is selected from the group consisting of: methanol, ethanol, isopropanol, n-propanol, cyclopentanol, isopropanol, t-butanol, n-butanol, sec-butanol, dichloromethane, chloroform, n-heptane, cyclohexane, methylcyclohexane, n-hexane, water, or combinations thereof.

In another preferred embodiment, the process for preparing the polymorph according to the first aspect of the present invention comprises the steps of:

(a) Providing a first dispersion comprising a first solvent and a starting compound of formula (II) dispersed in the first solvent, and a second solution comprising a second solvent and sodium hydroxide dissolved in the second solvent;

(b) Mixing the first dispersion liquid and the second solution, stirring, crystallizing, and collecting precipitated solids to obtain the polymorphic substance;

wherein the first solvent is an alcohol solvent or a mixed solvent of the alcohol solvent and an alkane solvent; the second solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, or a combination thereof.

In another preferred embodiment, the preparation method comprises the steps of:

(a1) Providing a solution or suspension of a compound of formula (II) starting material in a first solvent;

(b1) Adding a solution of sodium hydroxide in a second solvent to the solution or suspension for crystallization, and collecting precipitated solids to obtain the polymorph;

or the preparation method comprises the following steps:

(a2) Providing a solution or suspension of a compound of formula (II) starting material in a first solvent;

(b2) Adding the solution or suspension to a solution of sodium hydroxide in a second solvent for crystallization, and collecting the precipitated solid to obtain the polymorph.

In another preferred example, the mass ratio of the compound of formula (II) to sodium hydroxide is 3 to 20, preferably 4 to 10.

In another preferred embodiment, the first dispersion is a first solution or a first suspension.

In another preferred embodiment, the first dispersion is a solution or suspension of the compound of formula (II) in the first solvent.

In another preferred embodiment, the first solvent is selected from the group consisting of: an alcohol solvent, an organic solvent, or a combination thereof.

In another preferred embodiment, the alcohol solvent is a C1-C6 alcohol, preferably a C1-C4 alcohol.

In another preferred embodiment, the alcoholic solvent is selected from the group consisting of: methanol, ethanol, isopropanol, n-propanol, cyclopentanol, isopropanol, t-butanol, n-butanol, sec-butanol, or combinations thereof.

In another preferred embodiment, the alkane solvent is selected from the group consisting of: dichloromethane, chloroform, n-heptane, cyclohexane, methylcyclohexane, n-hexane, or combinations thereof.

In another preferred embodiment, the volume ratio of the alcohol solvent to the alkane solvent is 1:1-5, preferably 1:2-4, such as 1:2, 1:3, 1:4.

In another preferred embodiment, the mass/volume ratio of the compound of formula (II) as a starting material to the first solvent is 5 to 500g/L, preferably 8 to 400g/L, more preferably 10 to 350g/L, such as 10g/L, 20g/L, 40g/L, 100g/L, 200g/L, 300g/L.

In another preferred embodiment, the compound of formula (II) starting material is dispersed in the first solvent at 0 to 30 ℃.

In another preferred embodiment, the second solvent is selected from the group consisting of: water, methanol, ethanol, or a combination thereof.

In another preferred embodiment, the mass/volume ratio of the sodium hydroxide to the second solvent is 1 to 100g/L, preferably 2 to 80g/L, such as 4g/L, 8g/L, 15g/L, 30g/L, 50g/L, 70g/L.

In another preferred embodiment, the sodium hydroxide is dissolved in the second solvent at 0 to 30 ℃.

In another preferred embodiment, the first solution and the second solution are subjected to homogeneous reaction.

In another preferred embodiment, the first suspension is reacted heterogeneously with the second solution.

In another preferred embodiment, the second solution is added to the first dispersion to perform crystallization.

In another preferred embodiment, the first dispersion is added to the second solution to perform crystallization.

In another preferred example, the second solution is slowly dropped into the first dispersion to perform crystallization.

In another preferred embodiment, the first dispersion and the second solution are mixed at-20 to 40 ℃.

In another preferred embodiment, the first dispersion and the second solution are mixed and stirred for 0.5 hours to 2 days, preferably 0.5 hours to 24 hours, for example, 1 hour, 5 hours, 12 hours, 24 hours.

In another preferred embodiment, the method further comprises post-treating the precipitated solid to obtain the polymorph, wherein,

the post-treatment comprises vacuum drying or drying under certain temperature and humidity conditions.

In another preferred embodiment, the precipitated solid is dried under vacuum for 18 to 30 hours, preferably 20 to 26 hours, more preferably 24 hours.

In another preferred embodiment, the drying is performed under certain temperature and humidity conditions.

In another preferred embodiment, the drying is carried out at 20 to 50 ℃.

In another preferred embodiment, the drying is carried out at 50% to 80% RH.

In another preferred embodiment, the drying is performed under conditions selected from the group consisting of: RH at 40 ℃/60%, RH at 40 ℃/75%, RH at 25 ℃/75%.

In another preferred example, the precipitated solid is dried for 1 to 14 days under certain temperature and humidity conditions.

In another preferred embodiment, the polymorph can be obtained directly after precipitation of the solid.

In another preferred embodiment, the preparation method of the crystal form XM-I comprises the following steps: and (3) carrying out salt formation crystallization on the solution of the compound shown in the formula (II) in methanol/dichloromethane in the ethanol solution of sodium hydroxide, and carrying out vacuum drying to obtain the crystal form XM-I.

In another preferred embodiment, the preparation method of the crystal form XM-I comprises the following steps: and (3) carrying out salt formation crystallization on the suspension of the compound shown in the formula (II) in ethanol in an aqueous solution of sodium hydroxide, and carrying out vacuum drying to obtain the crystal form XM-I.

In another preferred example, the mass ratio of the compound of formula (II) to sodium hydroxide is 7 to 12, preferably 10.

In another preferred embodiment, the volume ratio of the methanol to the dichloromethane is 1 to 5:1 to 5, preferably 1 to 3:1 to 3.

In another preferred embodiment, the volume ratio of the methanol to the ethanol is 1-50.

In another preferred embodiment, the volume ratio of ethanol to water is 1 to 50.

In another preferred embodiment, the preparation method of the crystal form XM-I' comprises the following steps: the crystalline form XM-I' according to the invention is obtained by salt-forming crystallization of a suspension of the compound of formula (II) in ethanol in an ethanol solution of sodium hydroxide, after standing for 7 days at 40 ℃/60% rh.

In another preferred embodiment, the volume ratio of the suspension solvent of the compound of formula (II) to the solvent of sodium hydroxide is 1-3:1-3, preferably 1-2:1-2.

In another preferred embodiment, the preparation method of the crystal form XM-I' comprises the following steps: the crystalline form XM-I "according to the invention is obtained after crystallization of a suspension of the compound of formula (II) in ethanol as a salt in methanol solution of sodium hydroxide, after standing for 7 days at 40 ℃/75% rh.

In another preferred embodiment, the volume ratio of ethanol to methanol is 1 to 3:1 to 3, preferably 1 to 2:1 to 2.

In another preferred embodiment, the preparation method of the crystal form XM-II comprises the following steps: the crystalline form XM-II of the present invention is obtained by salt crystallization of a suspension of the compound of formula (II) in ethanol in an aqueous solution of sodium hydroxide, after standing for 1 day at 25 ℃/45% RH.

In another preferred embodiment, the volume ratio of the ethanol to the water is 1-3:1-3, preferably 1-2:1-2.

In another preferred embodiment, the preparation method of the crystal form XM-III comprises the following steps: and (3) carrying out salt-forming crystallization on the suspension of the compound shown in the formula (II) in ethanol solution of sodium hydroxide to obtain the crystal form XM-III.

In another preferred embodiment, the volume ratio of the suspension solvent of the compound of formula (II) to the solvent of sodium hydroxide is 1 to 50, preferably 1 to 10.

In another preferred embodiment, the process for the preparation of the polymorph according to the first aspect of the invention comprises the steps of:

(i) Providing a compound of formula (I);

(ii) Treating said starting compound of formula (I) to obtain said polymorph, wherein said treating comprises one or more steps selected from the group consisting of: stirring, heating, and standing under certain temperature and humidity conditions.

In another preferred embodiment, said compound of formula (I) starting material is in solid form.

In another preferred embodiment, the solid form is a crystalline form or an amorphous form.

In another preferred embodiment, the compound of formula (I) is a solution or a slurry, preferably a solution,

wherein, the first solvent is an alcohol solvent or a mixed solvent of the alcohol solvent and an alkane solvent, and preferably any one or more of methanol, ethanol and dichloromethane.

In another preferred embodiment, the solution or slurry of the compound of formula (I) dispersed in the first solvent is stirred at 25-40 ℃ for 10-24 hours to obtain the polymorph.

In another preferred embodiment, the solid form of the compound of formula (I) is heated to obtain the polymorph.

In another preferred embodiment, the compound of formula (I) is heated at atmospheric pressure, preferably under a protective gas atmosphere, more preferably under nitrogen protection.

In another preferred embodiment, the heating temperature is 60 to 150 ℃, preferably 80 to 110 ℃, preferably 100 ℃.

In another preferred embodiment, the heating time is 10min to 1h.

In another preferred embodiment, the solid form of the compound of formula (I) is allowed to stand under temperature and humidity conditions to give the polymorph.

In another preferred embodiment, the compound of formula (I) is placed open.

In another preferred embodiment, the standing temperature is 20 to 60 ℃, preferably 25 to 40 ℃.

In another preferred embodiment, the leaving humidity is 50 to 80% RH.

In another preferred embodiment, the standing time is 0.5 to 5 days, preferably 1 to 3 days, and more preferably 1 day.

In another preferred embodiment, the compound of formula (I) is placed open at 25 ℃/60% RH.

In another preferred embodiment, the preparation method comprises the following steps:

(i1) Providing a solution or slurry of a compound of formula (I) starting material in a first solvent;

(ii 1) treating said solution or slurry to obtain a solid, and collecting the solid to obtain said polymorph, wherein said treating comprises stirring;

or, the preparation method comprises the following steps:

(i2) Providing a solid form of a compound of formula (I) starting material;

(ii 2) treating said solid form to obtain said polymorph, wherein said solid form is crystalline or amorphous, said treating comprising one or more steps of: heating, and standing under certain temperature and humidity conditions.

In another preferred embodiment, the crystal form XM-VII is heated to 100 ℃ under the protection of nitrogen at normal pressure, and the obtained solid is the compound of the formula (I) in the crystal form XM-VII.

In another preferred example, the anhydride of WO2010068253 is suspended in benzyl alcohol and stirred at 40 ℃ for 1 day to give a solid of the compound of formula (I) as crystalline form XM-VI.

In another preferred example, the mass/volume ratio of the anhydride to the benzyl alcohol is 1 to 50g/L, preferably 10 to 30g/L.

In another preferred embodiment, the anhydrate of form XM-VIII is suspended in benzyl alcohol and stirred at 40 ℃ for 1 day to give the solid as form XM-VI of the compound of formula (I).

In another preferred embodiment, the mass/volume ratio of the crystal form XM-VIII to the benzyl alcohol is 1-50 g/L, preferably 10-30 g/L.

In a third aspect of the present invention, there is provided a pharmaceutical composition comprising:

1) A polymorph according to the first aspect of the invention; 2) A pharmaceutically acceptable carrier.

In a fourth aspect of the invention, there is provided the use of a polymorph according to the first aspect of the invention for the preparation of 1) a salt of a compound of formula (I) or a compound of formula (II); 2) A medicament for the treatment of Human Immunodeficiency Virus (HIV) infected adult and pediatric patients aged 12 years.

In a fifth aspect of the invention, there is provided the use of a pharmaceutical composition according to the third aspect of the invention for the preparation of a medicament for the treatment of Human Immunodeficiency Virus (HIV) infected adult and adult patients aged 12 years.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

Figure 1a shows an XRPD pattern of crystalline form XM-I prepared in example 1.

FIG. 1b shows in example 2 XRPD pattern of crystalline form XM-I prepared.

Figure 2 shows a TGA profile of crystalline form XM-I of the present invention.

FIG. 3 shows a DSC of form XM-I of the present invention.

FIG. 4 shows a crystalline form XM-I of the present invention ¹ H NMR spectrum.

FIG. 5 shows XRPD comparison graphs before and after the crystal form XM-I prepared in example 2 was placed at 25 ℃/60% RH, 40 ℃/75% RH and 60 ℃/75% RH (XRPD graphs after 25 ℃/60% RH for one month, 40 ℃/75% RH for one month, 60 ℃/75% RH for 10 days and before the placement, respectively, from top to bottom in the graphs).

Figure 6 shows XRPD patterns of crystalline form XM-I of the invention before and after milling (upper XRPD pattern after milling and lower XRPD pattern before milling).

Figure 7 shows an XRPD pattern of form XM-I' of the invention.

Figure 8 shows an XRPD pattern of crystalline form XM-I "of the present invention.

Figure 9 shows an XRPD pattern of form XM-II of the invention.

Figure 10 shows an XRPD pattern of form XM-III of the invention.

Figure 11 shows an XRPD pattern of form XM-IV of the invention.

Figure 12 shows an XRPD pattern of form XM-V of the invention.

Figure 13 shows an XRPD pattern of form XM-VI of the invention.

Figure 14 shows an XRPD pattern of crystalline form XM-VII of the invention.

Figure 15 shows an XRPD pattern of form XM-VIII of the invention.

Figure 16 shows an XRPD pattern of form XM-IX of the invention.

FIG. 17 shows XRPD comparison patterns of the crystalline form XM-I' of the present invention before and after 25 ℃/60% RH (upper pattern is an XRPD pattern one day after 25 ℃/60% RH, and lower pattern is an XRPD pattern before placing).

Figure 18 shows a comparison of XRPD of form XM-I "of the invention before and after placement at 25 ℃/60% rh (upper panel is the XRPD pattern one day after 25 ℃/60% rh, lower panel is the XRPD pattern before placement).

FIG. 19 shows a comparison of XRPD patterns before and after the crystalline form XM-IV of the present invention was allowed to stand at 40 ℃/75% RH (upper pattern is an XRPD pattern five days after 40 ℃/75% RH and lower pattern is an XRPD pattern before standing).

Figure 20 shows a comparison of XRPD of form XM-VIII of the invention before and after 25 ℃/60% rh (upper panel is the XRPD pattern five days after 40 ℃/75% rh, lower panel is the XRPD pattern before standing).

FIG. 21 shows XRPD comparison graphs before and after the crystal form XM-I prepared in example 1 was placed at 25 ℃/60% RH, 40 ℃/75% RH and 60 ℃/75% RH (XRPD graphs after 25 ℃/60% RH for one month, 40 ℃/75% RH for one month, 60 ℃/75% RH for 10 days and before the placement, respectively, from top to bottom in the graphs).

Detailed Description

The inventors of the present invention have conducted extensive and intensive studies and have surprisingly found a series of polymorphs of dorzolavir sodium. The polymorph has excellent stability (RH at 40 ℃/75 percent and is stable after being placed under open conditions for 30 days) and excellent mechanical stability, has high purity, simple preparation and low cost, and is very suitable for preparing a pharmaceutical composition for inhibiting HIV integrase so as to treat diseases such as immunodeficiency virus (HIV) infection. In addition, the polymorphic substance is not easy to raise, collect and waste in the process of manufacturing split-charging and other medicines, and is beneficial to protecting the health of operators. On this basis, the inventors have completed the present invention.

Term(s) for

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….

As used herein, the term "compound of formula (I)" refers to the sodium salt of (4R, 12aS) -9- { [ (2,4-difluorophenyl) methyl ] carbamoyl } -4-methyl-6,8-dioxo-3, 4,6,8,12, 12a-hexahydro-2H-pyrido [1',2':4,5] pyrazino [2,1-b ] [1,3] oxazin-7-ol, of formula (I).

As used herein, the term "starting compound of formula (I)" refers to the amorphous form and/or various crystalline forms of the compound of formula (I) (including the various crystalline forms mentioned herein and the crystalline forms or amorphous forms mentioned in various documents or patents which may or may not be amorphous, published or published).

As used herein, the term "room temperature" generally means 4-30 deg.C, preferably 20. + -. 5 deg.C.

As used herein, the term "pharmaceutically acceptable" ingredient refers to a substance that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., at a reasonable benefit/risk ratio.

As used herein, the manner of adding the solvent or solution is by direct pouring or by uniform addition, etc.

As used herein, the manner of "slow addition" includes, but is not limited to: dropwise, slowly along the vessel wall, etc.

Polymorphic substance

The solid is present either in amorphous or crystalline form. In the case of crystalline forms, the molecules are positioned within three-dimensional lattice sites. When a compound crystallizes from solution or slurry, it can crystallize in different spatial lattice arrangements (this property is known as "polymorphism"), forming crystals with different crystalline forms, each of which is known as a "polymorph". Different polymorphs of a given substance may differ from each other in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystal form, packing pattern, flowability, and/or solid state stability.

Crystallization of

Production scale crystallization can be accomplished by manipulating the solution such that the solubility limit of the compound of interest is exceeded. This can be accomplished by a variety of methods, for example, dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Or by boiling, atmospheric evaporation, vacuum drying, drying at temperature and humidity, or by some other method to reduce the liquid volume. The solubility of the compound of interest may also be reduced by the addition of an anti-solvent or a solvent in which the compound has low solubility or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility. For a detailed description of the Crystallization see crystallation, third edition, J W Mullins, butterworth-Heineman Ltd.,1993, ISBN 0750611294.

If salt formation is desired to occur simultaneously with crystallization, addition of an appropriate acid or base may result in direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting material. Also, in media where the final desired form is less soluble than the reactants, completion of the synthesis reaction can result in direct crystallization of the final product.

Optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. One example is to dissolve the compound of interest in a solvent at elevated temperature, followed by the addition of an appropriate volume of anti-solvent in a controlled manner so that the system is just below the saturation level. At this point, seeds of the desired form may be added (and the integrity of the seeds maintained) and the system cooled to complete crystallization.

Polymorphs of the invention

The polymorphic substance of the dorzolavir sodium comprises the following crystal forms: form XM-I, form XM-I', form XM-I ", form XM-II, form XM-III, form XM-IV, form XM-V, form XM-VI, form XM-VII, form XM-VIII and form XM-IX.

(1) Crystal form XM-I

The crystalline form XM-I is a hydrate, which X-ray powder diffraction pattern (XRPD) comprises 3 or more 2 Θ values selected from the group consisting of: 7.0 degrees +/-0.2 degrees, 9.4 degrees +/-0.2 degrees, 12.2 degrees +/-0.2 degrees, 13.8 degrees +/-0.2 degrees and 15.1 degrees +/-0.2 degrees. Preferably, the XRPD pattern of form XM-I comprises 6 or more 2 Θ values selected from the group consisting of: 7.0 degrees +/-0.2 degree, 9.4 degrees +/-0.2 degree, 12.2 degrees +/-0.2 degree, 12.4 degrees +/-0.2 degree, 13.8 degrees +/-0.2 degree, 15.1 degrees +/-0.2 degree, 20.8 degrees +/-0.2 degree and 31.6 degrees +/-0.2 degree. Preferably, the XRPD pattern of crystalline form XM-I comprises 6 or more 2 Θ values selected from the group consisting of: 7.0 degree plus or minus 0.2 degree, 7.5 degree plus or minus 0.2 degree, 9.4 degree plus or minus 0.2 degree, 10.8 degree plus or minus 0.2 degree, 12.2 degree plus or minus 0.2 degree, 12.4 degree plus or minus 0.2 degree, 13.0 degree plus or minus 0.2 degree, 13.8 degree plus or minus 0.2 degree, 15.1 degree plus or minus 0.2 degree, 17.5 degree plus or minus 0.2 degree, 19.0 degree plus or minus 0.2 degree, 20.8 degree plus or minus 0.2 degree, 24.2 degree plus or minus 0.2 degree, 29.1 degree plus or minus 0.2 degree, 31.6 degree plus or minus 0.2 degree.

The crystalline form XM-I having an XRPD pattern substantially as shown in figure 1a and figure 1b.

The crystalline form XM-I, a thermogravimetric analysis (TGA) is substantially as shown in figure 2. As can be seen from FIG. 2, the crystalline form XM-I starts to decompose at 360 + -20 ℃.

The crystal form XM-I has a Differential Scanning Calorimetry (DSC) pattern substantially as shown in figure 3. As can be seen from FIG. 3, the crystal form XM-I has a characteristic endothermic peak in the interval of 65-85 ℃, a characteristic endothermic peak in the interval of 225-265 ℃, a characteristic exothermic peak in the interval of 265-285 ℃, and a characteristic endothermic peak in the interval of 350-370 ℃.

The crystal form XM-I and nuclear magnetic resonance hydrogen spectrogram thereof ( ¹ H NMR) is substantially as shown in figure 4.

(2) Crystal form XM-I'

The XRPD pattern of form XM-I' comprises 3 or more 2 Θ values selected from the group consisting of: 6.5 degrees +/-0.2 degrees, 12.0 degrees +/-0.2 degrees, 12.5 degrees +/-0.2 degrees and 13.1 degrees +/-0.2 degrees. Preferably, the XRPD pattern of the crystalline form XM-I' comprises 6 or more 2 Θ values selected from the group consisting of: 6.5 degrees +/-0.2 degrees, 7.4 degrees +/-0.2 degrees, 10.2 degrees +/-0.2 degrees, 12.0 degrees +/-0.2 degrees, 12.5 degrees +/-0.2 degrees, 13.1 degrees +/-0.2 degrees, 18.9 degrees +/-0.2 degrees and 19.7 degrees +/-0.2 degrees. Preferably, the crystalline form XM-I' has an XRPD pattern substantially as shown in figure 7.

(3) Crystalline form XM-I "

The form XM-I "has an XRPD pattern comprising 3 or more 2 Θ values selected from the group consisting of: 6.9 degrees +/-0.2 degrees, 9.3 degrees +/-0.2 degrees, 11.9 degrees +/-0.2 degrees and 12.6 degrees +/-0.2 degrees. Preferably, the form XM-I "has an XRPD pattern comprising 6 or more 2 Θ values selected from the group consisting of: 6.9 degrees +/-0.2 degrees, 9.3 degrees +/-0.2 degrees, 11.0 degrees +/-0.2 degrees, 11.9 degrees +/-0.2 degrees, 2.6 degrees +/-0.2 degrees, 13.1 degrees +/-0.2 degrees, 13.5 degrees +/-0.2 degrees and 19.2 degrees +/-0.2 degrees. Preferably, the crystalline form XM-I "has an XRPD pattern substantially as shown in figure 8.

(4) Crystal form XM-II

The crystalline form XM-II having an XRPD pattern comprising 3 or more 2 θ values selected from the group consisting of: 7.0 degrees +/-0.2 degrees, 11.0 degrees +/-0.2 degrees, 11.4 degrees +/-0.2 degrees and 12.6 degrees +/-0.2 degrees. Preferably, the XRPD pattern of form XM-II comprises 6 or more 2 Θ values selected from the group consisting of: 4.6 degrees +/-0.2 degrees, 7.0 degrees +/-0.2 degrees, 11.0 degrees +/-0.2 degrees, 11.4 degrees +/-0.2 degrees, 12.6 degrees +/-0.2 degrees and 14.1 degrees +/-0.2 degrees. Preferably, the crystalline form XM-II has an XRPD pattern substantially as shown in figure 9.

(5) Crystal form XM-III

The crystalline form XM-III having an XRPD pattern comprising 3 or more 2 θ values selected from the group consisting of: 6.0 degrees +/-0.2 degrees, 10.6 degrees +/-0.2 degrees, 11.5 degrees +/-0.2 degrees and 13.2 degrees +/-0.2 degrees. Preferably, the crystalline form XM-III has an XRPD pattern comprising 6 or more 2 Θ values selected from the group consisting of: 6.0 degrees +/-0.2 degrees, 8.2 degrees +/-0.2 degrees, 10.6 degrees +/-0.2 degrees, 11.5 degrees +/-0.2 degrees, 11.9 degrees +/-0.2 degrees, 13.2 degrees +/-0.2 degrees, 18.4 degrees +/-0.2 degrees and 19.2 degrees +/-0.2 degrees. Preferably, the crystalline form XM-III has an XRPD pattern comprising 6 or more 2 Θ values selected from the group consisting of: 6.0 degrees +/-0.2 degrees, 8.2 degrees +/-0.2 degrees, 10.6 degrees +/-0.2 degrees, 11.5 degrees +/-0.2 degrees, 11.9 degrees +/-0.2 degrees, 12.5 degrees +/-0.2 degrees, 13.2 degrees +/-0.2 degrees, 15.9 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 18.4 degrees +/-0.2 degrees, 19.2 degrees +/-0.2 degrees, 21.6 degrees +/-0.2 degrees and 29.7 degrees +/-0.2 degrees.

Preferably, the crystalline form XM-III has an XRPD pattern substantially as shown in figure 10.

(6) Crystal form XM-IV

The XRPD pattern of the crystal form XM-IV has characteristic peaks at 2 theta values of 5.6 +/-0.2 degrees, 11.6 +/-0.2 degrees, 18.2 +/-0.2 degrees and 18.9 +/-0.2 degrees. Preferably, the XRPD pattern of the crystal form XM-IV has characteristic peaks at 2 theta values of 5.6 +/-0.2 degrees, 11.6 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.9 +/-0.2 degrees, 22.1 +/-0.2 degrees, 23.3 +/-0.2 degrees, 23.7 +/-0.2 degrees, 26.7 +/-0.2 degrees and 27.1 +/-0.2 degrees. Preferably, the crystalline form XM-IV, the XRPD pattern of the X-ray diffraction pattern has 2 theta values of 5.6 +/-0.2 degrees, 7.2 +/-0.2 degrees, 8.8 +/-0.2 degrees, 9.3 +/-0.2 degrees, 11.2 +/-0.2 degrees, 11.6 +/-0.2 degrees, 14.5 +/-0.2 degrees, 15.5 +/-0.2 degrees, 16.1 +/-0.2 degrees, 16.8 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.9 +/-0.2 degrees the characteristic peaks are found at 19.8 degrees +/-0.2 degrees, 22.1 degrees +/-0.2 degrees, 22.8 degrees +/-0.2 degrees, 23.3 degrees +/-0.2 degrees, 23.7 degrees +/-0.2 degrees, 26.4 degrees +/-0.2 degrees, 26.7 degrees +/-0.2 degrees, 27.1 degrees +/-0.2 degrees, 28.3 degrees +/-0.2 degrees, 29.2 degrees +/-0.2 degrees, 31.2 degrees +/-0.2 degrees, 31.7 degrees +/-0.2 degrees and 32.8 degrees +/-0.2 degrees.

Preferably, the crystalline form XM-IV has an XRPD pattern as substantially depicted in figure 11.

(7) Crystal form XM-V

The XRPD pattern of the crystal form XM-V has characteristic peaks at 2 theta values of 5.5 degrees +/-0.2 degrees, 9.1 degrees +/-0.2 degrees, 11.6 degrees +/-0.2 degrees and 17.6 degrees +/-0.2 degrees. Preferably, the XRPD pattern of the crystal form XM-V has characteristic peaks at 2 theta values of 5.5 +/-0.2 degrees, 6.3 +/-0.2 degrees, 7.2 +/-0.2 degrees, 9.1 +/-0.2 degrees, 11.1 +/-0.2 degrees, 11.6 +/-0.2 degrees, 12.8 +/-0.2 degrees, 17.6 +/-0.2 degrees and 19.2 +/-0.2 degrees. Preferably, the XRPD pattern of the crystal form XM-V has characteristic peaks at 2 theta values of 5.5 +/-0.2 °, 6.3 +/-0.2 °, 7.2 +/-0.2 °, 9.1 +/-0.2 °, 10.3 +/-0.2 °, 10.7 +/-0.2 °, 11.1 +/-0.2 °, 11.6 +/-0.2 °, 12.8 +/-0.2 °, 13.9 +/-0.2 °, 15.1 +/-0.2 °, 17.6 +/-0.2 °, 19.2 +/-0.2 °, 21.7 +/-0.2 °, 25.2 +/-0.2 °, 25.7 +/-0.2 °, 27.0 +/-0.2 °, and 29.8 +/-0.2 °.

Preferably, the crystalline form XM-V has an XRPD pattern substantially as shown in figure 12.

(8) Crystal form XM-VI

Preferably, the crystalline form XM-VI has an XRPD pattern with characteristic peaks at 2 θ values of 5.1 ° ± 0.2 °, 7.6 ° ± 0.2 °, 15.4 ° ± 0.2 °, 18.1 ° ± 0.2 °. Preferably, the XRPD pattern of the crystal form XM-VI has characteristic peaks at 2 theta values of 5.1 +/-0.2 degrees, 7.6 +/-0.2 degrees, 10.2 +/-0.2 degrees, 12.6 +/-0.2 degrees, 15.4 +/-0.2 degrees, 16.6 +/-0.2 degrees, 18.1 +/-0.2 degrees, 19.0 +/-0.2 degrees, 21.2 +/-0.2 degrees and 23.5 +/-0.2 degrees. Preferably, the XRPD pattern of the crystal form XM-VI has characteristic peaks at 2 theta values of 5.1 +/-0.2 degrees, 7.6 +/-0.2 degrees, 10.2 +/-0.2 degrees, 11.8 +/-0.2 degrees, 12.6 +/-0.2 degrees, 15.4 +/-0.2 degrees, 16.6 +/-0.2 degrees, 18.1 +/-0.2 degrees, 19.0 +/-0.2 degrees, 21.2 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.5 +/-0.2 degrees and 25.5 +/-0.2 degrees.

Preferably, the crystalline form XM-VI has an XRPD pattern substantially as shown in figure 13.

(9) Crystal form XM-VII

Preferably, the XRPD pattern of the crystal form XM-VII has characteristic peaks at 2 theta values of 5.9 +/-0.2 degrees, 7.1 +/-0.2 degrees and 8.1 +/-0.2 degrees. Preferably, the XRPD pattern of the crystal form XM-VII has characteristic peaks at 2 theta values of 5.9 +/-0.2 degrees, 7.1 +/-0.2 degrees, 8.1 +/-0.2 degrees and 9.3 +/-0.2 degrees. Preferably, the XRPD pattern of the crystal form XM-VII has characteristic peaks at 2 theta values of 5.9 +/-0.2 degrees, 7.1 +/-0.2 degrees, 8.1 +/-0.2 degrees, 9.3 +/-0.2 degrees, 11.6 +/-0.2 degrees and 15.8 +/-0.2 degrees.

Preferably, the crystalline form XM-VII has an XRPD pattern substantially as shown in figure 14.

(10) Crystal form XM-VIII

Preferably, the crystalline form XM-VIII has an XRPD pattern with characteristic peaks at 2 Θ values of 5.8 ° ± 0.2 °, 6.3 ° ± 0.2 °, 7.9 ° ± 0.2 °, 9.9 ° ± 0.2 °. Preferably, the XRPD pattern of the crystal form XM-VIII has characteristic peaks at 2 theta values of 5.8 +/-0.2 degrees, 6.3 +/-0.2 degrees, 7.9 +/-0.2 degrees, 9.9 +/-0.2 degrees, 12.7 +/-0.2 degrees, 19.0 +/-0.2 degrees, 19.9 +/-0.2 degrees and 21.4 +/-0.2 degrees. Preferably, the XRPD pattern of the crystal form XM-VIII has characteristic peaks at 2 theta values of 5.8 DEG +/-0.2 DEG, 6.3 DEG +/-0.2 DEG, 7.9 DEG +/-0.2 DEG, 9.9 DEG +/-0.2 DEG, 12.7 DEG +/-0.2 DEG, 17.0 DEG +/-0.2 DEG, 18.7 DEG +/-0.2 DEG, 19.0 DEG +/-0.2 DEG, 19.9 DEG +/-0.2 DEG, 20.5 DEG +/-0.2 DEG, 21.4 DEG +/-0.2 DEG, 24.3 DEG +/-0.2 DEG, 25.3 DEG +/-0.2 DEG, 27.6 DEG +/-0.2 DEG, 27.9 DEG +/-0.2 DEG, 29.4 +/-0.2 DEG, 31.1 DEG +/-0.2 DEG and 32.0 DEG +/-0.2 deg.

Preferably, the crystalline form XM-VIII has an XRPD pattern as substantially depicted in figure 15.

(11) Crystal form XM-IX

Preferably, the crystalline form XM-IX has an XRPD pattern with characteristic peaks at 2 theta values of 6.4 ° ± 0.2 °, 8.0 ° ± 0.2 °, 12.8 ° ± 0.2 °, 19.8 ° ± 0.2 °. Preferably, the XRPD pattern of the crystal form XM-IX has characteristic peaks at 2 theta values of 6.4 DEG +/-0.2 DEG, 8.0 DEG +/-0.2 DEG, 12.8 DEG +/-0.2 DEG, 19.8 DEG +/-0.2 DEG and 21.2 DEG +/-0.2 deg. Preferably, the XRPD pattern of the crystal form XM-IX has characteristic peaks at 2 theta values of 6.4 DEG +/-0.2 DEG, 8.0 DEG +/-0.2 DEG, 12.5 DEG +/-0.2 DEG, 12.8 DEG +/-0.2 DEG, 18.6 DEG +/-0.2 DEG, 19.0 DEG +/-0.2 DEG, 19.8 DEG +/-0.2 DEG, 20.7 DEG +/-0.2 DEG and 21.2 DEG +/-0.2 deg.

Preferably, the crystalline form XM-IX has an XRPD pattern substantially as shown in figure 16.

Pharmaceutical composition

The pharmaceutical composition comprises the polymorphic substances of the dorzolavir sodium, namely the crystal form XM-I, the crystal form XM-I', the crystal form XM-II, the crystal form XM-III, the crystal form XM-IV, the crystal form XM-V, the crystal form XM-VI, the crystal form XM-VII, the crystal form XM-VIII and the crystal form XM-IX, and pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers thereof within a safe and effective dose range. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition can be blended with the polymorphs of the present invention and with each other without significantly reducing the potency of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween, etc.)

) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

The polymorph of the invention is typically admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) Disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Preferably, the excipient comprises one or more of a filler, a disintegrant, a binder and a lubricant.

Preferably, the filler is any one or a mixture of more of starch, lactose, microcrystalline cellulose, dextrin, mannitol, oxidase and calcium sulfate.

Preferably, the disintegrating agent comprises one or more of carboxymethyl cellulose and salt thereof, cross-linked povidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.

Preferably, the binder comprises any one or more of povidone, hydroxypropyl methyl cellulose, starch slurry and pregelatinized starch.

Preferably, the lubricant comprises any one or more of sodium stearyl fumarate, magnesium stearate and calcium stearate.

In the present invention, the method for drying is a conventional drying method in the art unless otherwise specified, and for example, in the examples of the present invention, drying means drying in a vacuum or atmospheric pressure in a conventional drying oven. Generally, drying is carried out for 0.1 to 50 hours or 1 to 30 hours.

The main advantages of the invention are:

(1) The polymorphic substance of the invention has excellent stability (can be placed for 30 days in an open way under 25 ℃/60% RH and 40 ℃/75% RH), mechanical stability, can greatly reduce the risk of crystal transformation in the preparation process, reduce the risk of change of dissolution rate and bioavailability of the drug caused by crystal change, and is beneficial to crystallization and crystal control in the preparation process.

(2) The preparation method of the polymorphic substance is safe and simple, has less solvent residue, can have amplification feasibility, is simple and easy to operate, and provides help for development of medicaments containing the dortavir sodium, preparation of a preparation formula and industrial production.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

Experimental methods

The solvents used in the present invention were all analytically pure and had a water content of about 0.1%. The compounds of formula (I) used as starting materials in the examples were all purchased commercially. All test methods of the invention are general methods, and the test parameters are as follows:

1. XRPD pattern determination method:

x-ray powder diffraction (XRPD) instrument: bruker D2 Phaser X-ray powder diffractometer; radiation source Cu

(ii) a Generator (Generator) kv:30kv; generator (Generator) mA:10mA; initial 2 θ:2.000 °, scan range: 2.0000-35.000 degrees, scanning step size 0.02 degrees, and scanning speed 0.1s/step.

2. TGA profile determination method:

thermogravimetric analysis (TGA) instrument: TGA type 55 by TA of USA; heating rate: 10 ℃/min; nitrogen flow rate: 40mL/min.

3. DSC chart measurement method:

differential Scanning Calorimetry (DSC) instrument: TA Q2000 by TA, USA; heating rate: 10 ℃/min, nitrogen flow rate: 50mL/min.

4. Nuclear magnetic resonance hydrogen spectroscopy data ( ¹ H NMR) was taken from Bruker Avance II DMX 400M HZ NMR spectrometer. 2mg of the sample was weighed, dissolved in 0.6mL of deuterated dimethylsulfoxide, filtered, and the filtrate was added to a nuclear magnetic tube for testing.

5. Solvent residue test method (GC):

6. the moisture determination method comprises the following steps:

the instrument comprises: karl Fischer moisture tester, hecaojike, AKF-1plus.

7. Sodium content determination method (ICP-OES):

8. chemical purity determination method (HPLC):

9. content determination method (HPLC):

example 1: preparation of crystalline form XM-I

100g of the compound of formula (II) was weighed out and dissolved in 300mL of methanol/dichloromethane (1, 3,v/v). 10g of sodium hydroxide are weighed out and dissolved in 2.5L of ethanol. Slowly adding the compound solution of the formula (II) into the sodium hydroxide solution at 25 ℃, stirring for 2 hours until a large amount of solid is separated out, continuing stirring for 10 hours, and filtering. The wet cake was dried under vacuum at 30 ℃ for 24h to give a solid which was the compound of formula (I) crystalline form XM-I (102.6 g, water subtracted, 92.3% molar yield, 99.87% purity by HPLC).

The resulting solid was subjected to XRPD testing, the X-ray powder diffraction data of which are shown in table 1, and the XRPD pattern of which is shown in figure 1 a; TGA test was carried out on the obtained solid, and its spectrum is shown in FIG. 2; subjecting the obtained solid to DSC test, wherein the spectrum is shown in figure 3; subjecting the obtained solid to ¹ H NMR measurement, spectrum as shown in fig. 4, nuclear magnetic data: ¹ H NMR(400MHz,DMSO-d ₆ )δ10.71(s,1H),7.90(s,1H),7.36(dd,J＝15.5,8.6Hz,1H),7.26–7.17(m,1H),7.04(t,J＝8.2Hz,1H),5.19(s,1H),4.87–4.74(m,1H),4.51(d,J＝5.7Hz,2H),4.31(s,1H),4.19(s,1H),3.98(t,J＝11.5Hz,1H),3.82(d,J＝8.3Hz,1H),1.88(s,1H),1.40(d,J＝13.5Hz,1H),1.26(d,J＝7.1Hz,3H)。

the resulting solid was subjected to additional characterization, with the following results: moisture (KF): 5.3 percent; sodium content: 5.1 percent; the content is as follows: 100.8 percent; solvent residue: ethanol: 640ppm, dichloromethane: not detected, methanol: it was not detected. The solvent residue is less, especially the dichloromethane solvent with higher toxicity, so the medicinal feasibility is high.

TABLE 1

2θ(°)	Relative Strength (%)
		4.7	3.7
7.0	100.0
		9.3	5.7
11.1	3.9
		12.4	10.5
14.0	10.2
		15.3	1.9
18.9	1.7
		21.1	2.2
21.6	5.0
		22.2	1.3
23.2	1.7
		24.1	1.7

Example 2: preparation of crystalline form XM-I

10g of the compound of formula (II) was weighed out and dissolved in 30mL of methanol/dichloromethane (1, 3,v/v). 0.96g of sodium hydroxide is weighed out and dissolved in 250mL of ethanol. Slowly adding the compound solution of the formula (II) into the sodium hydroxide solution at 0 ℃, stirring for 2 hours until a large amount of solid is separated out, continuously stirring for 10 hours, and filtering. And (3) drying the wet filter cake for 24 hours in vacuum at the temperature of 30 ℃, and obtaining a solid which is the crystal form XM-I of the compound shown in the formula (I).

The resulting solid was subjected to XRPD testing, with X-ray powder diffraction data as shown in table 2 and an XRPD pattern as shown in figure 1b. Comparing fig. 1a and fig. 1b, it can be seen that the XRPD pattern of fig. 1a has a weaker peak at 4.7 °, and the two XRPD patterns of the remaining peaks are consistent, possibly due to different crystallinity of the sample. Therefore, the solid of FIG. 1a and FIG. 1b is judged to be in the same crystal form.

TABLE 2

Example 3: preparation of crystalline form XM-I

10g of the compound of the formula (II) are weighed out and suspended in 250mL of ethanol. 0.95g of sodium hydroxide was weighed out and dissolved in 10mL of water. Sodium hydroxide solution was slowly added to the suspension of compound solution of formula (II) at 10 ℃, stirring was continued for 5h, and filtered. And (3) drying the wet filter cake for 24 hours in vacuum at the temperature of 30 ℃, and obtaining a solid which is the crystal form XM-I of the compound shown in the formula (I). The resulting solid was subjected to XRPD testing, the XRPD pattern of which is shown in figure 1 a.

Example 4: preparation of crystalline form XM-I

10g of the compound of the formula (II) are weighed out and suspended in 250mL of ethanol. 0.94g of sodium hydroxide was weighed out and dissolved in 10mL of water. Slowly adding sodium hydroxide solution into the suspension of the compound solution of the formula (II) at-10 ℃, continuously stirring for 5h, and filtering. And drying the wet filter cake at 30 ℃ in vacuum for 24 hours to obtain a solid, namely the crystal form XM-I of the compound shown in the formula (I). The resulting solid was subjected to XRPD testing, the XRPD pattern of which is shown in figure 1b.

Example 5: preparation of crystalline form XM-I

40mg of the compound of the formula (II) are weighed out and suspended in 2mL of ethanol. Weigh 4mg of sodium hydroxide and dissolve in 1mL of ethanol. Slowly dripping sodium hydroxide solution into the compound solution of the formula (II) at-20 ℃, stirring for 1h to precipitate solid, filtering, putting the wet filter cake at 40 ℃/60% RH for 7 days, and obtaining the solid, namely the crystal form XM-I' of the compound of the formula (I). The resulting solid was subjected to XRPD testing, and the X-ray powder diffraction data is shown in table 3, and the XRPD pattern is shown in fig. 7.

TABLE 3

Example 6: preparation of crystalline form XM-I ″

40mg of the compound of the formula (II) are weighed out and suspended in 2mL of ethanol. 4mg of sodium hydroxide are weighed out and dissolved in 1mL of methanol. Slowly dropping sodium hydroxide solution into the compound solution of formula (II) at 5 deg.C, stirring for 1h to precipitate solid, filtering, and placing the wet cake at 40 deg.C/75% RH for 7 days to obtain solid which is compound crystal form XM-I of formula (I). The resulting solid was subjected to XRPD testing, and the X-ray powder diffraction data is shown in table 4, and the XRPD pattern is shown in fig. 8.

TABLE 4

2θ(°)	Relative Strength (%)
		6.9	100.0
9.3	4.0
		11.0	2.9
11.9	8.4
		12.6	5.4
13.1	5.3
		13.5	8.9
19.2	4.3

Example 7: preparation of crystalline form XM-II

40mg of the compound of the formula (II) are weighed out and suspended in 2mL of ethanol. Weigh 4mg of sodium hydroxide and dissolve in 0.2mL of water. Aqueous sodium hydroxide solution was added to the compound suspension of formula (II) at 17 ℃, stirred for 30min and filtered. The wet cake was left at 25 ℃/45% RH for 1 day to give a solid which was the compound of formula (I) crystalline form XM-II. The resulting solid was subjected to XRPD testing, and the X-ray powder diffraction data is shown in table 5, and the XRPD pattern is shown in fig. 9.

TABLE 5

2θ(°)	Relative Strength (%)
		4.6	1.7
7.0	100.0
		11.0	2.9
11.4	4.0
		12.6	4.6
14.1	5.8

Example 8: preparation of crystalline form XM-III

40mg of the compound of the formula (II) are weighed out and suspended in 2mL of ethanol. Weigh 4mg of sodium hydroxide and dissolve in 0.2mL of ethanol. And (3) adding a sodium hydroxide solution into the compound suspension liquid of the formula (II) at 25 ℃, stirring for 30min, and separating out a solid, wherein the separated solid is the crystal form XM-III of the compound of the formula (I). The resulting solid was subjected to XRPD testing, and the X-ray powder diffraction data is shown in table 6, and the XRPD pattern is shown in fig. 10.

TABLE 6

2θ(°)	Relative Strength (%)
		6.0	100.0
8.2	1.7
		10.6	3.2
11.5	3.6
		11.9	3.8
12.5	0.2
		13.2	3.7
15.9	0.2
		16.6	0.2
18.4	0.5
		19.2	0.4
21.6	0.2
		29.7	0.2

Example 9: preparation of crystalline form XM-IV

23mg of the compound of the formula (II) are weighed out and suspended in 2mL of cyclopentanol. Slowly dripping 50mg of 10% sodium hydroxide methanol solution into the compound suspension liquid of the formula (II) at 40 ℃, stirring for 30min, and separating out a solid, wherein the obtained solid is the crystal form XM-IV of the compound of the formula (I). The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 7. The XRPD pattern is shown in FIG. 11.

TABLE 7

Example 10: preparation of crystalline form XM-V

20mg of the compound of the formula (II) are weighed out and suspended in 1ml of n-propanol. Slowly dripping 50mg of 10wt% sodium hydroxide methanol solution into the compound suspension liquid in the formula (II) at 40 ℃, stirring for 30min, and separating out a solid, wherein the obtained solid is the crystal form XM-V of the compound in the formula (I). The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 8. The XRPD pattern is shown in FIG. 12.

TABLE 8

2θ(°)	Relative Strength (%)
		5.5	100.0
6.3	4.7
		7.2	0.4
9.1	3.4
		10.3	0.1
10.7	0.3
		11.1	2.2
11.6	3.9
		12.8	0.5
13.9	0.3
		15.1	0.3
17.6	2.2
		19.2	0.9
21.7	0.3
		25.2	0.2
25.7	0.3
		27.0	0.3
29.8	0.2

Example 11: preparation of crystalline form XM-VI

150mg of the compound of formula (II) is weighed and suspended in 15mL of benzyl alcohol, 1mL of aqueous sodium hydroxide solution (containing 15mg of sodium hydroxide) is added to the suspension, and the mixture is stirred for 1 day at 40 ℃, so that the obtained solid is the crystal form XM-VI of the compound of formula (I). The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 9. The XRPD pattern is shown in FIG. 13.

TABLE 9

2θ(°)	Relative Strength (%)
		5.1	100.0
7.6	8.9
		10.2	4.4
11.8	1.2
		12.6	3.9
15.4	5.7
		16.6	4.7
18.1	13.5
		19.0	4.7
21.2	4.3
		23.0	1.9
23.5	5.0
		25.5	2.0

Example 12: preparation of crystalline form XM-VII

The crystal form XM-V obtained in example 10 is heated to 100 ℃ under the protection of nitrogen at normal pressure, and the obtained solid is the crystal form XM-VII of the compound shown in the formula (I). The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data is shown in table 10. The XRPD pattern is shown in FIG. 14.

TABLE 10

2θ(°)	Relative Strength (%)
		5.9	100.0
7.1	14.6
		8.1	23.1
9.3	2.3
		11.6	1.7
15.8	1.6

Example 13: preparation of crystalline form XM-VIII

100mg of the compound of formula (II) are weighed out and dissolved in 10mL of n-propanol at 40 ℃. And (3) pouring 210mg of a 10wt% sodium hydroxide methanol solution into the solution of the compound shown in the formula (II) at the temperature of 40 ℃, quickly reacting after the addition to obtain the compound shown in the formula (I), wherein the solution is still clear, no solid is separated out, stirring for 24 hours, and then, a solid is separated out, and the obtained solid is the crystal form XM-VIII of the compound shown in the formula (I). The resulting solid was subjected to XRPD testing, and the X-ray powder diffraction data is shown in table 11, and the XRPD pattern is shown in fig. 15.

TABLE 11

2θ(°)	Relative Strength (%)
		5.8	11.6
6.3	100.0
		7.9	21.7
9.9	9.8
		12.7	9.8
17.0	0.3
		18.7	2.8
19.0	6.6
		19.9	4.3
20.5	0.8
		21.4	8.4
24.3	1.8
		25.3	1.3
27.6	0.8
		27.9	0.5
29.4	0.4
		31.1	0.9
32.0	0.4

Example 14: preparation of crystalline form XM-IX

20mg of the compound of formula (II) was weighed out and suspended in 2mL of 1, 2-propanediol at 50 ℃, 31mg of 10wt% sodium hydroxide in methanol was slowly added to the suspension of the compound of formula (II) and stirred for 4h, and the obtained solid was the compound of formula (I) in crystalline form XM-IX. The resulting solid was subjected to XRPD testing, and the X-ray powder diffraction data is shown in table 12, and the XRPD pattern is shown in fig. 16.

TABLE 12

Example 15: preparation of crystalline form XM-VI

20mg of the anhydrate of WO2010068253 obtained in test example 1 was suspended in 1mL of benzyl alcohol and stirred at 40 ℃ for 1 day to obtain a solid which is the crystalline form XM-VI of the compound of formula (I). The resulting solid was subjected to XRPD testing, the XRPD pattern of which is shown in figure 13.

Example 16: preparation of crystalline form XM-VI

20mg of the crystalline form XM-VIII prepared in example 13 was suspended in 1mL of benzyl alcohol and stirred at 40 ℃ for 1 day to obtain a solid form of the compound of formula (I) as crystalline form XM-VI. The resulting solid was subjected to XRPD testing, the XRPD pattern of which is shown in figure 13.

Comparative example 1

The inventors repeat the example 7 of patent WO2015118460 to prepare FormM3 reported in the patent, and obtained form D of patent WO2015139591, indicating that the reproducibility of the method is poor.

Comparative example 2

The inventor repeats the method for preparing Form VI in the patent WO2015138933, finds that the method has poor repeatability, and easily obtains hydrate in WO 2010068253.

Test example 1 stability of Crystal form

Respectively placing the solid crystal form samples prepared by the method under different conditions in an open manner, carrying out XRPD detection on the crystal forms before and after placement, and comparing XRPD patterns of the crystal forms before and after placement. The results are shown in Table 13.

Watch 13

As can be seen by comparing the XRPD patterns before and after the crystal form XM-I is placed in an open environment for 30 days at 25 ℃/60% RH and 40 ℃/75% RH, and the crystal form is not changed after being placed in an open environment for 10 days at 60 ℃/75% RH at high temperature and high humidity, the crystal form XM-I has excellent stability at different temperatures/humidities, is convenient to crystallize in the process of pharmacy and control in the preparation process, is greatly beneficial to the transportation and storage of products, and can greatly reduce the risk of the change of the dissolution rate and the bioavailability of the prepared pharmaceutical composition caused by the change of the crystal form.

In addition, the crystal form XM-I 'and the crystal form XM-I' are converted into the crystal form XM-I after being placed open for one day at 25 ℃/60% RH, which shows that the crystal form XM-I of the present invention is a stable crystal form of the crystal form XM-I 'and the crystal form XM-I', and once again shows that the crystal form XM-I of the present invention has excellent stability and can be used as a method for preparing the crystal form XM-I from the crystal form XM-I 'and the crystal form XM-I'.

The crystal transformation of the crystal forms XM-IV and XM-VIII occurs after 5 days of open placement at 0 ℃/75% RH, which indicates that the stability of the crystal forms XM-IV and XM-VIII is poor.

Test example 2: mechanical stability

Respectively weighing 50mg of the crystal form XM-I, grinding the crystal form XM-I in a mortar for 10min, respectively carrying out XRPD test on the ground solid, wherein a comparison graph of the XRPD of the crystal form before and after grinding is shown in figure 6, and the grinding results are shown in table 14. Compared with XRPD patterns before and after grinding in the figures, the crystal form XM-I provided by the invention has no change before and after grinding, which shows that the crystal form XM-I provided by the invention has excellent mechanical stability and can reduce the crystal transformation risk brought by crushing of bulk drugs in the preparation processing process.

TABLE 14

Discussion of the related Art

(1) The polymorph of the invention has excellent crystal form stability, the crystal form XM-I can be stabilized for at least 30 days by being placed open at 25 ℃/60% RH and 40 ℃/75% RH and can be stabilized for at least 10 days by being placed open at 60 ℃/75% RH, and the crystal form XM-I' can be crystallized into the crystal form XM-I under certain conditions, which shows that the crystal form XM-I is the dominant crystal form. The excellent crystal form stability can reduce the risk of the change of the dissolution rate and the bioavailability of the medicine caused by the change of the crystal form, is beneficial to the crystal form control in the crystallization and preparation processes, and is also beneficial to the production and the storage of products.

(2) The polymorphic substance of the invention has good mechanical stability. The crystal form XM-I has no change before and after grinding, which shows that the crystal form XM-I has excellent mechanical stability and can reduce the crystal transformation risk caused by crushing of raw material medicines in the preparation processing process.

(3) Compared with the prior art, the preparation method of the polymorphic substance is safer and more reliable, has amplification feasibility, is simple and easy to operate, has low cost, and is suitable for research and development of medicaments and industrial production.

(4) The polymorphic substance can be prepared by using low-toxicity or non-toxicity solvents, such as ethanol, water and the like, and has little solvent residue. Meanwhile, the preparation method is a conventional crystallization method capable of realizing industrial production, and the granularity, crystal habit, crystal form and the like can be controlled by controlling process parameters, so that a stable and high-quality product is obtained.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A polymorph of a compound of formula (I):

2. the polymorph of a compound according to formula (I) according to claim 1, wherein the polymorph is form XM-I, wherein the form XM-I has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 7.0 degrees +/-0.2 degrees, 9.4 degrees +/-0.2 degrees, 12.2 degrees +/-0.2 degrees, 13.8 degrees +/-0.2 degrees and 15.1 degrees +/-0.2 degrees.

3. The polymorph of a compound according to formula (I) according to claim 1, wherein the polymorph is form XM-I ', wherein the X-ray powder diffraction pattern of form XM-I' comprises 3 or more 2 Θ values selected from the group consisting of: 6.5 degrees +/-0.2 degree, 7.4 degrees +/-0.2 degree, 12.5 degrees +/-0.2 degree and 13.1 degrees +/-0.2 degree.

4. The polymorph of a compound according to formula (I) according to claim 1, wherein the polymorph is form XM-I ", wherein the form XM-I" has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 6.9 degrees +/-0.2 degrees, 9.3 degrees +/-0.2 degrees, 11.9 degrees +/-0.2 degrees and 12.6 degrees +/-0.2 degrees.

5. The polymorph of a compound of formula (I) according to claim 1, wherein the polymorph is form XM-II, wherein the form XM-II has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 7.0 degrees +/-0.2 degrees, 11.0 degrees +/-0.2 degrees, 11.4 degrees +/-0.2 degrees and 12.6 degrees +/-0.2 degrees.

6. The polymorph of a compound according to formula (I) according to claim 1, wherein the polymorph is form XM-III, wherein the form XM-III has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 6.0 degrees +/-0.2 degrees, 10.6 degrees +/-0.2 degrees, 11.5 degrees +/-0.2 degrees and 13.2 degrees +/-0.2 degrees.

7. A process for the preparation of the polymorph of claim 1, comprising the steps of:

8. A pharmaceutical composition, comprising:

1) The polymorph of claim 1; 2) A pharmaceutically acceptable carrier.

9. Use of a polymorph according to claim 1 for the preparation of 1) a salt of a compound of formula (I) or formula (II); 2) A medicament for the treatment of Human Immunodeficiency Virus (HIV) infected adult and pediatric patients aged 12 years.

10. Use of a pharmaceutical composition according to claim 8 for the preparation of a medicament for the treatment of Human Immunodeficiency Virus (HIV) infected adults and children aged 12 years.