CN113501846A - Almenopterine tenofovir hemifumarate compound, crystal form, preparation method and application thereof - Google Patents

Almenopterine tenofovir hemifumarate compound, crystal form, preparation method and application thereof Download PDF

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CN113501846A
CN113501846A CN202110648580.5A CN202110648580A CN113501846A CN 113501846 A CN113501846 A CN 113501846A CN 202110648580 A CN202110648580 A CN 202110648580A CN 113501846 A CN113501846 A CN 113501846A
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tenofovir
eimeria
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王小雷
林青
杨宝海
何雷
刘梦瑜
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Changzhou Hengbang Pharmaceutical Co ltd
Jiangsu Hansoh Pharmaceutical Group Co Ltd
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Abstract

The invention discloses an eimidophenol tenofovir hemifumarate compound with a structure shown as a formula I, a crystal form, a preparation method and an application thereof. In particular to an eimeria phenol amine tenofovir hemifumarate compound, a crystal form A, a crystal form B and a crystal form C thereof, and a preparation method and application of the crystal forms. The preparation method is simple and easy to implement, and good in reproducibility, and the prepared crystalline form A of the eimidophenol tenofovir hemifumarate compound has good solubility and moisture absorptionSmall sex, and is favorable for the preparation and storage of medicinal preparations.
Figure DDA0003110876030000011

Description

Almenopterine tenofovir hemifumarate compound, crystal form, preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an eimeria phenol amine tenofovir hemifumarate compound, a crystal form of the compound, and a preparation method and application of the compound.
Background
The 9- [ (R) -2- [ [ (S) - [ [ [1- (isopropoxycarbonyl) -1-methyl ] ethyl ] amino ] phenoxy phosphinyl ] methoxy ] propyl ] adenine hemifumaric acid complex (formula I) is a nucleoside reverse transcriptase inhibitor, which is a prodrug of tenofovir (P MPA). PMPA is structurally similar to natural nucleoside monophosphate, and is quickly converted into an active metabolite PMPA diphosphate (PMApp) in vivo; PMPAPP competes with native 5 'deoxyadenosine triphosphate and is incorporated into the viral DNA strand, but because PMPAPP lacks a 3' OH group, 5 ', 3' phosphodiester linkage coupling can no longer be performed, thus resulting in the hindrance of DNA strand elongation and ultimately blocking viral replication. PMPA has been shown to have activity against Human Immunodeficiency Virus (HIV) and Hepatitis B Virus (HBV).
However, PMPA contains phosphate groups, generally has negative charges under physiological pH conditions, and has too strong polarity to pass through biological membranes easily, so that the drugs have poor oral bioavailability, low tissue distribution coefficient and certain renal toxicity. Therefore, when developing the drugs, the negative charge of the phosphate group needs to be masked by using a prodrug principle, so that the defects of the drugs are eliminated. The di-ester prodrug of PMPA, TDF, developed by gillide corporation was approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV infection in 2001, respectively.
TDF significantly improves the pharmacokinetic profile of PMPA to some extent, but it is rapidly hydrolyzed in vivo by non-specific esterases that are widely present in plasma, and especially by carbonic acid esterases present in the intestinal mucosal epithelium, to release PMPA. PMPA at a high concentration in plasma is rapidly discharged from the body due to its poor membrane permeability, and it is difficult to maintain a sufficient concentration at the site of infection; furthermore, PMPA is a substrate for the organic anion transporter of renal proximal tubule epithelial cells (hOAT), and PMPA is easily accumulated in renal proximal tubule epithelial cells at high concentration in plasma, causing a certain risk of nephrotoxicity.
The new generation of monophosphoryl amide monoester prodrug overcomes the defects of TDF, is stable in blood plasma and is not easy to be hydrolyzed by esterase; but is taken up into the cell; immediately converts into PMPA under the action of serine protease (cathepsin A) and in vivo specific amidase, thereby having better tissue permeability and lymphatic tissue and cell targeting. The mono-phosphoric acid amide monoester prodrug GS7340 developed by Gilidide also has stronger antiviral ability and better safety compared with 30 times dosage of TDF.
The 9- [ (R) -2- [ [ (S) - [ [ [1- (isopropoxycarbonyl) -1-methyl ] ethyl ] amino ] phenoxyphosphinyl ] methoxy ] propyl ] adenine hemifumaric acid complex (formula I) releases PMPA as an active ingredient in cells, as does GS 7340. The 9- [ (R) -2- [ [ (S) - [ [1- (isopropoxycarbonyl) -1-methyl ] ethyl ] amino ] phenoxy phosphinyl ] methoxy ] propyl ] adenine hemifumaric acid complex (formula I) has the advantages of absorption and distribution, can effectively exert the drug effect of PMPA as an active ingredient compared with the prodrug such as TDF and the like, and is beneficial to patients as a new generation of PMPA prodrug with the most potential.
In view of the fact that research on the crystal form of the drug has important significance on clinical research of the compound, the invention also aims to improve the solubility and solid stability of the product, reduce the storage cost, prolong the product period and improve the bioavailability of the product, and the invention comprehensively researches the eimetamide tenofovir monofumarate and the crystal form thereof.
Disclosure of Invention
The inventors found a complex of the eimeria amine tenofovir and fumaric acid in a molar ratio of 2: 1. Through intensive studies, a crystalline form of this complex was found. In the aspect of medicinal development, the compound has more advantages than the salt formed by the eimeria phenol amine tenofovir or fumaric acid.
The invention provides a compound 9- [ (R) -2- [ [ (S) - [ [1- (isopropoxycarbonyl) -1-methyl ] ethyl ] amino ] phenoxyphosphinyl ] methoxy ] propyl ] adenine and fumaric acid which are formed into a compound with a molar ratio of 2:1, wherein the compound is called an eiminamide tenofovir hemifumaric acid compound.
Figure BDA0003110876010000031
On the other hand, the compound of the eimeria phenol amine tenofovir hemifumarate provided by the invention can be verified by means of nuclear magnetism and content titration. Recrystallizing the compound in different solvents or under different conditions to obtain 4 crystal forms, namely a crystal form A, a crystal form B, a crystal form C and a crystal form D. The four crystal forms are proved to have the molar ratio of the eimeria phenol amine tenofovir to the fumaric acid of 2:1 by means of nuclear magnetism and content titration.
The compound of the invention exists in a crystalline or amorphous form.
The crystalline form A of the eimeria phenol amine tenofovir hemifumarate complex has an X-ray powder diffraction pattern with a diffraction peak at 5.1 +/-0.2 degrees of 2 theta, or a diffraction peak at 7.7 +/-0.2 degrees, or a diffraction peak at 13.0 +/-0.2 degrees, or a diffraction peak at 15.4 +/-0.2 degrees, or a diffraction peak at 20.9 +/-0.2 degrees, or a diffraction peak at 22.1 +/-0.2 degrees, or a diffraction peak at 25.0 +/-0.2 degrees, or a diffraction peak at 10.2 +/-0.2 degrees, preferably comprises any 2-5, or 3-6, or 3-7, more preferably comprises any 4, 6 or 8 of the diffraction peaks;
alternatively, the first and second electrodes may be,
form a has an X-ray powder diffraction pattern comprising at least one, preferably two, more preferably three, diffraction peaks, at 2 Θ of 5.1 ± 0.2 °, 7.7 ± 0.2 °, 13.0 ± 0.2 °; optionally, at least one strip located at 2 θ of 15.4 ± 0.2 °, 20.9 ± 0.2 °, 22.1 ± 0.2 °, 25.0 ± 0.2 °, 10.2 ± 0.2 °, preferably 2, 3, 4 or 5 strips, for example,
5.1±0.2°、7.7±0.2°；
7.7±0.2°、13.0±0.2°；
5.1±0.2°、13.0±0.2°；
5.1±0.2°、15.4±0.2°；
7.7±0.2°、20.9±0.2°；
13.0±0.2°、22.1±0.2°；
5.1±0.2°、7.7±0.2°、13.0±0.2°；
5.1±0.2°、15.4±0.2°、20.9±0.2°；
7.7±0.2°、20.9±0.2°、22.1±0.2°；
13.0±0.2°、22.1±0.2°、25.0±0.2°；
5.1±0.2°、7.7±0.2°、15.4±0.2°；
7.7±0.2°、13.0±0.2°、25.0±0.2°；
5.1±0.2°、13.0±0.2°、10.2±0.2°；
5.1±0.2°、7.7±0.2°、13.0±0.2°、15.4±0.2°；
5.1±0.2°、15.4±0.2°、20.9±0.2°、22.1±0.2°；
7.7±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°；
13.0±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°；
5.1±0.2°、7.7±0.2°、15.4±0.2°、20.9±0.2°；
5.1±0.2°、13.0±0.2°、22.1±0.2°、25.0±0.2°；
7.7±0.2°、13.0±0.2°、25.0±0.2°、10.2±0.2°；
alternatively, the first and second electrodes may be,
the X-ray powder diffraction pattern of form a optionally further comprises one or more diffraction peaks at 10.5 ± 0.2 °, 10.8 ± 0.2 °, 16.1 ± 0.2 °, 17.0 ± 0.2 °, 19.6 ± 0.2 °, 20.4 ± 0.2 ° and 29.2 ± 0.2 ° 2 Θ; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, 7 thereof; for example,
10.5±0.2°、10.8±0.2°、16.1±0.2°；
10.8±0.2°、16.1±0.2°、17.0±0.2°；
17.0±0.2°、19.6±0.2°、20.4±0.2°；
10.5±0.2°、10.8±0.2°、16.1±0.2°、17.0±0.2°；
10.8±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°；
16.1±0.2°、17.0±0.2°、19.6±0.2°、20.4±0.2°；
10.5±0.2°、10.8±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°、20.4±0.2°；
10.8±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°、20.4±0.2°、29.2±0.2°；
10.5±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°、20.4±0.2°、29.2±0.2°；
alternatively, the first and second electrodes may be,
form A has an X-ray powder diffraction pattern having diffraction peaks at 5.1 + -0.2 °, 7.7 + -0.2 °, 13.0 + -0.2 °, 15.4 + -0.2 °, 20.9 + -0.2 °, 22.1 + -0.2 °, 25.0 + -0.2 °, 10.2 + -0.2 °, 10.5 + -0.2 °, 10.8 + -0.2 °, 16.1 + -0.2 °, 17.0 + -0.2 °, 19.6 + -0.2 °, 20.4 + -0.2 ° and 29.2 + -0.2 ° 2 θ, preferably including diffraction peaks at optionally 4, 5, 6, 8 or 10 ° therein, e.g.,
5.1±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°；
7.7±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°；
13.0±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°；
15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°；
20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°；
22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°；
5.1±0.2°、15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°；
7.7±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°；
13.0±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°；
15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°；
20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°；
22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°；
5.1±0.2°、15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°；
7.7±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°；
13.0±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°；
15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°；
20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°；
22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°；
5.1±0.2°、15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、 10.5±0.2°、10.8±0.2°；
7.7±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、 16.1±0.2°、17.0±0.2°；
13.0±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°、 17.0±0.2°、19.6±0.2°；
15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、 10.8±0.2°、16.1±0.2°；
20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、 16.1±0.2°、17.0±0.2°；
22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°；
5.1±0.2°、7.7±0.2°、13.0±0.2°、15.4±0.2°、20.9±0.2°、22.1±0.2°、 25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°；
7.7±0.2°、13.0±0.2°、15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、 10.2±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°；
13.0±0.2°、15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、 10.5±0.2°、10.8±0.2°、16.1±0.2°、17.0±0.2°；
15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、 10.8±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°；
20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、 16.1±0.2°、17.0±0.2°、19.6±0.2°、20.4±0.2°；
22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°、 17.0±0.2°、19.6±0.2°、20.4±0.2°、29.2±0.2°。
further preferably, the X-ray powder diffraction pattern of the crystal form A is basically shown as figure 1, the DSC pattern is basically shown as figure 1A, the TGA pattern is shown as figure 1B, and the TGA pattern is1The HNMR map is shown in FIG. 1C.
Still more preferably, the DSC pattern of the crystal form A has an endothermic peak near 92 ℃, the TGA pattern of the crystal form A has no weight loss basically before decomposition, and the DSC pattern of the crystal form A has no weight loss1The HNMR graph results show a semi-maleic-rich complex.
The crystalline form B of the eimeria phenol amine tenofovir hemifumarate complex has an X-ray powder diffraction pattern with a diffraction peak at 4.4 +/-0.2 degrees of 2 theta, or a diffraction peak at 6.6 +/-0.2 degrees, or a diffraction peak at 7.7 +/-0.2 degrees, or a diffraction peak at 13.0 +/-0.2 degrees, or a diffraction peak at 15.4 +/-0.2 degrees, or a diffraction peak at 22.1 +/-0.2 degrees, or a diffraction peak at 23.2 +/-0.2 degrees, or a diffraction peak at 26.7 +/-0.2 degrees, preferably comprises any 2-5, or 3-6, or 3-8 of the diffraction peaks, more preferably comprises any 4, 6 or 8 of the diffraction peaks;
alternatively, the first and second electrodes may be,
form B has an X-ray powder diffraction pattern having one or more, preferably two, more preferably three, diffraction peaks at 2 Θ of 4.4 ± 0.2 °, 6.6 ± 0.2 °, 7.7 ± 0.2 °; optionally, at least one strip located at 2 θ of 26.7 ± 0.2, 4.9 ± 0.2 °, 10.5 ± 0.2 °, 13.3 ± 0.2 °, 17.0 ± 0.2 °, preferably 2, 3, 4 or 5 strips thereof, for example,
4.4±0.2°、6.6±0.2°；
6.6±0.2°、7.7±0.2°；
4.4±0.2°、7.7±0.2°；
4.4±0.2°、26.7±0.2°；
6.6±0.2°、4.9±0.2°；
7.7±0.2°、10.5±0.2°；
4.4±0.2°、6.6±0.2°、7.7±0.2°；
4.4±0.2°、26.7±0.2、4.9±0.2°；
6.6±0.2°、4.9±0.2°、10.5±0.2°；
7.7±0.2°、10.5±0.2°、13.3±0.2°；
4.4±0.2°、6.6±0.2°、13.3±0.2°；
6.6±0.2°、7.7±0.2°、17.0±0.2°；
4.4±0.2°、7.7±0.2°、10.5±0.2°；
4.4±0.2°、26.7±0.2、4.9±0.2°、10.5±0.2°；
6.6±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°；
7.7±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°；
4.4±0.2°、6.6±0.2°、26.7±0.2、4.9±0.2°；
6.6±0.2°、7.7±0.2°、4.9±0.2°、10.5±0.2°；
4.4±0.2°、7.7±0.2°、10.5±0.2°、13.3±0.2°；
4.4±0.2°、6.6±0.2°、7.7±0.2°、17.0±0.2°；
the X-ray powder diffraction pattern of form B optionally further comprises one or more diffraction peaks at 4.9 ± 0.2 °, 10.5 ± 0.2 °, 13.3 ± 0.2 °, 17.0 ± 0.2 °, 20.4 ± 0.2 °, 20.9 ± 0.2 °, and 22.8 ± 0.2 ° 2 Θ; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, 7 thereof; for example,
4.9±0.2°、10.5±0.2°、13.3±0.2°；
10.5±0.2°、13.3±0.2°、17.0±0.2°；
13.3±0.2°、17.0±0.2°、20.4±0.2°；
4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°；
10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°；
13.3±0.2°、17.0±0.2°、20.4±0.2°、20.9±0.2°；
4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°、20.9±0.2°；
4.9±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°、20.9±0.2°、22.8±0.2°；
10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°、20.9±0.2°、22.8±0.2°；
alternatively, the first and second electrodes may be,
form B has an X-ray powder diffraction pattern having diffraction peaks at 4.4 + -0.2 °, 6.6 + -0.2 °, 7.7 + -0.2 °, 13.0 + -0.2 °, 15.4 + -0.2 °, 22.1 + -0.2 °, 23.2 + -0.2 °, 26.7 + -0.2 °, 4.9 + -0.2 °, 10.5 + -0.2 °, 13.3 + -0.2 °, 17.0 + -0.2 °, 20.4 + -0.2 °, 20.9 + -0.2 ° and 22.8 + -0.2 ° 2 θ, preferably including any of 4, 5, 6, 8 or 10 diffraction peaks, e.g.,
4.4±0.2°、13.0±0.2°、15.4±0.2°、22.1±0.2°；
6.6±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°；
7.7±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°；
15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°；
22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°；
23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
4.4±0.2°、13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°；
6.6±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°；
7.7±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°；
13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°；
15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°；
22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
4.4±0.2°、13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°；
6.6±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
7.7±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°；
13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°；
15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°；
4.4±0.2°、13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、 4.9±0.2°、10.5±0.2°；
6.6±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、 13.3±0.2°、17.0±0.2°；
7.7±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°；
13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、 10.5±0.2°、13.3±0.2°；
15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、1 3.3±0.2°、17.0±0.2°；
22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、 17.0±0.2°、20.4±0.2°；
4.4±0.2°、6.6±0.2°、7.7±0.2°、13.0±0.2°、15.4±0.2°、22.1±0.2°、 23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
6.6±0.2°、7.7±0.2°、13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、 26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°；
7.7±0.2°、13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、 4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°；
13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、 10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°；
15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、 13.3±0.2°、17.0±0.2°、20.4±0.2°、20.9±0.2°；
、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、 17.0±0.2°、20.4±0.2°、20.9±0.2°、22.8±0.2°。
further preferably, form B has an X-ray powder diffraction pattern substantially as shown in figure 2, a DSC pattern substantially as shown in figure 2A, and a TGA pattern substantially as shown in figure 2B1The HNMR map is shown in fig. 2C.
Still more preferably, the DSC pattern of the crystal form B has an endothermic peak near 95 ℃, the TGA pattern of the crystal form B has no weight loss basically before decomposition, and the DSC pattern of the crystal form B has no weight loss basically before decomposition1The HNMR graph results show a semi-maleic-rich complex.
An X-ray powder diffraction pattern of the crystalline form C of the eimeria amine tenofovir hemifumarate complex has a diffraction peak at 5.0 +/-0.2 degrees of 2 theta, or has a diffraction peak at 7.8 +/-0.2 degrees, or has a diffraction peak at 13.1 +/-0.2 degrees, or has a diffraction peak at 14.4 +/-0.2 degrees, or has a diffraction peak at 18.1 +/-0.2 degrees, or has a diffraction peak at 20.5 +/-0.2 degrees, or has a diffraction peak at 21.0 +/-0.2 degrees, or has a diffraction peak at 22.2 +/-0.2 degrees, preferably comprises any 2-5, or 3-6, or 3-8 of the diffraction peaks, more preferably comprises any 4, 6 or 8 of the diffraction peaks;
alternatively, the first and second electrodes may be,
form C has an X-ray powder diffraction pattern having one or more, preferably two, more preferably three, diffraction peaks at 2 Θ of 5.0 ± 0.2 °, 7.8 ± 0.2 °, 13.1 ± 0.2 °; optionally, it may further comprise at least one strip located at 2 θ of 14.4 ± 0.2 °, 18.1 ± 0.2 °, 20.5 ± 0.2 °, 21.0 ± 0.2 °, 22.2 ± 0.2 °, preferably 2, 3, 4 or 5 strips thereof, for example,
5.0±0.2°、7.8±0.2°；
7.8±0.2°、13.1±0.2°；
5.0±0.2°、13.1±0.2°；
5.0±0.2°、14.4±0.2°；
7.8±0.2°、18.1±0.2°；
13.1±0.2°、20.5±0.2°；
5.0±0.2°、7.8±0.2°、13.1±0.2°；
5.0±0.2°、20.5±0.2°、21.0±0.2°；
7.8±0.2°、18.1±0.2°、20.5±0.2°；
13.1±0.2°、14.4±0.2°、18.1±0.2°；
5.0±0.2°、7.8±0.2°、14.4±0.2°；
7.8±0.2°、13.1±0.2°、20.5±0.2°；
5.0±0.2°、13.1±0.2°、20.5±0.2°；
5.0±0.2°、7.8±0.2°、13.1±0.2°、14.4±0.2°；
7.8±0.2°、13.1±0.2°、14.4±0.2°、18.1±0.2°；
5.0±0.2°、13.1±0.2°、18.1±0.2°、20.5±0.2°；
5.0±0.2°、7.8±0.2°、13.1±0.2°、21.0±0.2°；
5.0±0.2°、14.4±0.2°、18.1±0.2°、20.5±0.2°；
7.8±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°；
13.1±0.2°、20.5±0.2°、21.0±0.2°、22.2±0.2°；
the X-ray powder diffraction pattern of form C optionally further comprises one or more diffraction peaks at 9.7 ± 0.2 °, 10.6 ± 0.2 °, 11.5 ± 0.2 °, 15.5 ± 0.2 °, 16.3 ± 0.2 °, 17.1 ± 0.2 °, and 19.8 ± 0.2 ° 2 Θ; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, 7 thereof; for example,
9.7±0.2°、10.6±0.2°、11.5±0.2°；
10.6±0.2°、11.5±0.2°、15.5±0.2°；
11.5±0.2°、15.5±0.2°、16.3±0.2°；
9.7±0.2°、10.6±0.2°、11.5±0.2°、15.5±0.2°；
10.6±0.2°、11.5±0.2°、15.5±0.2°、16.3±0.2°；
11.5±0.2°、15.5±0.2°、16.3±0.2°、17.1±0.2°；
9.7±0.2°、10.6±0.2°、11.5±0.2°、15.5±0.2°、16.3±0.2°、17.1±0.2°；
10.6±0.2°、11.5±0.2°、15.5±0.2°、16.3±0.2°、17.1±0.2°、19.8±0.2°；
9.7±0.2°、11.5±0.2°、15.5±0.2°、16.3±0.2°、17.1±0.2°、19.8±0.2°；
alternatively, the first and second electrodes may be,
form C has an X-ray powder diffraction pattern having diffraction peaks at 5.0 + -0.2 °, 7.8 + -0.2 °, 13.1 + -0.2 °, 14.4 + -0.2 °, 18.1 + -0.2 °, 20.5 + -0.2 °, 21.0 + -0.2 °, 26.7 + -0.2 °, 4.9 + -0.2 °, 10.5 + -0.2 °, 13.3 + -0.2 °, 17.0 + -0.2 °, 20.4 + -0.2 °, 20.9 + -0.2 ° and 22.8 + -0.2 ° 2 θ, preferably including diffraction peaks at 4, 5, 6, 8 or 10 optionally therein, e.g.,
5.0±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°；
7.8±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°；
13.1±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°；
18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°；
20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°；
5.0±0.2°、14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°；
7.8±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°；
13.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°；
14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°；
18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°；
20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
5.0±0.2°、14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°；
7.8±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°；
13.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°；
18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°；
5.0±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、 10.5±0.2°、13.3±0.2°；
7.8±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、 13.3±0.2°、17.0±0.2°；
13.1±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、 17.0±0.2°、20.4±0.2°；
14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、 10.5±0.2°、13.3±0.2°；
18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、 13.3±0.2°、17.0±0.2°；
20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、 17.0±0.2°、20.4±0.2°；
5.0±0.2°、7.8±0.2°、13.1±0.2°、14.4±0.2°、18.1±0.2°、20.5±0.2°、 21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
7.8±0.2°、13.1±0.2°、14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、 26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°；
13.1±0.2°、14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4. 9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°；
14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、 10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°；
18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、 13.3±0.2°、17.0±0.2°、20.4±0.2°、20.9±0.2°；
20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、 17.0±0.2°、20.4±0.2°、20.9±0.2°、22.8±0.2°。
further preferably, the X-ray powder diffraction pattern of the crystal form C is basically shown as figure 3, the DSC pattern thereof is basically shown as figure 3A, and the DSC pattern thereof is1HNMR atlas is shown in FIG. 3B。
Still more preferably, said form C has a DSC pattern with an endothermic peak around 83 ℃, and said form C has1The results of the HNMR chart show the hemifumaric acid complex.
The crystalline form D of the eimeria amine tenofovir hemifumarate complex has an X-ray powder diffraction pattern with a diffraction peak at 4.8 +/-0.2 degrees of 2 theta, or a diffraction peak at 6.9 +/-0.2 degrees, or a diffraction peak at 7.8 +/-0.2 degrees, or a diffraction peak at 13.0 +/-0.2 degrees, or a diffraction peak at 14.4 +/-0.2 degrees, or a diffraction peak at 20.4 +/-0.2 degrees, or a diffraction peak at 22.1 +/-0.2 degrees, or a diffraction peak at 25.0 +/-0.2 degrees, preferably comprises any 2-5, or 3-6, or 3-8 of the diffraction peaks, and more preferably comprises any 4, 6 or 8 of the diffraction peaks.
The X-ray powder diffraction pattern of the crystal form D provided by the invention is 4.8 +/-0.2 degrees at 2 theta,
Diffraction peaks at 6.9 + -0.2 deg., 7.8 + -0.2 deg., and 13.0 + -0.2 deg., preferably, further including characteristic peaks at 14.4 + -0.2 deg., 20.4 + -0.2 deg., 22.1 + -0.2 deg., and 25.0 + -0.2 deg., and more preferably, further including diffraction peaks at 9.3 + -0.2 deg., 9.7 + -0.2 deg., 10.6 + -0.2 deg., 15.5 + -0.2 deg., 16.2 + -0.2 deg., 18.0 + -0.2 deg., 19.7 + -0.2 deg., 20.9 + -0.2 deg., 22.9 + -0.2 deg., 24.2 + -0.2 deg., 25.4 + -0.2 deg., 26.1 + -0.2 deg., 26.6 + -0.2 deg., 28.7 + -0.2 deg., and 29.3 + -0.2 deg.
Further preferably, the X-ray powder diffraction pattern is basically as shown in figure 4, the DSC pattern is basically as shown in figure 4A, and the X-ray powder diffraction pattern is basically as shown in figure 41The HNMR map is shown in FIG. 4B.
Still more preferably, said form D has a DSC pattern with an endothermic peak around 84 ℃, and said form D has1The results of the HNMR chart show the hemifumaric acid complex.
In another aspect, the invention provides an innovative process for the preparation of a hemifumaric acid complex: according to the structural characteristics of the monofumarate, introducing free base with the same mole as the monofumarate, and reacting with the naked carboxyl on the monofumarate to prepare the hemifumarate. Based on the crystal form A and the crystal form B, the invention provides a preparation method of the crystal form A and the crystal form B.
The preparation method of the crystalline form A of the eimeria amine tenofovir hemifumarate compound comprises the following steps:
mixing the eiminamide tenofovir monofumarate and the eiminamide tenofovir free alkali with a solvent under a certain temperature condition;
adding an anti-solvent into the solution system to crystallize;
and thirdly, stirring, filtering and collecting solids to obtain the crystalline form A of the eimeria phenol amine tenofovir hemifumarate compound.
The preparation method of the crystal form A of the eimeria phenol amine tenofovir hemifumarate compound comprises the following steps of firstly, controlling the temperature to be 55-70 ℃, preferably 60-65 ℃ and most preferably 65 ℃; the mol ratio of the eimetamol tenofovir monofumarate to the eimetamol tenofovir free alkali is 1: 1-1: 3, preferably 1: 1.1-1: 2, and most preferably 1: 1.2-1: 1.5; the mass volume ratio of the mixture of the eimeria phenol amine tenofovir monofumarate and the eimeria phenol amine tenofovir free base to the solvent is 1g:2 ml-1 g:8ml, preferably 1g:3 ml-1 g:6ml, and most preferably 1g:4 ml; the solvent is selected from cyclic ether, preferably one of tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane, and most preferably tetrahydrofuran; the reaction time is 1-6 h, preferably 2-5 h, and most preferably 2-3 h.
The preparation method of the crystalline form A of the eimeria amine tenofovir hemifumarate compound comprises the following steps of (1) selecting an anti-solvent from fatty ether or alkane, preferably one of methyl tert-butyl ether, isopropyl ether and n-heptane, and most preferably isopropyl ether; the dosage of the anti-solvent is 2-7 times, preferably 3-6 times and most preferably 4-5 times of the dosage of the solvent in the step I.
The preparation method of the crystal form A of the eimeria phenol amine tenofovir hemifumarate compound comprises the step three, wherein the stirring time is 5-24 hours, preferably 8-20 hours, and most preferably 10-18 hours.
On the other hand, the preparation method of the crystalline form B of the eimeria amine tenofovir hemifumarate compound comprises the following steps:
mixing the eiminamide tenofovir monofumarate and the eiminamide tenofovir free alkali with a solvent under a certain temperature condition;
adding an anti-solvent into the solution system to crystallize;
and thirdly, stirring, filtering and collecting solids to obtain the crystal form B of the eimeria phenol amine tenofovir hemifumarate compound.
The preparation method of the crystal form B of the eimeria phenol amine tenofovir hemifumarate compound comprises the following steps of firstly, controlling the temperature to be 0-50 ℃, preferably 10-40 ℃ and most preferably 20-30 ℃; the mol ratio of the eimetamol tenofovir monofumarate to the eimetamol tenofovir free alkali is 1: 1-1: 3, preferably 1: 1.1-1: 2, and most preferably 1: 1.2-1: 1.5; the mass volume ratio of the mixture of the eimeria phenol amine tenofovir monofumarate and the eimeria phenol amine tenofovir free base to the solvent is 1g:2 ml-1 g:8ml, preferably 1g:3 ml-1 g:6ml, and most preferably 1g:4 ml; the solvent is selected from cyclic ether, preferably one of tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane, and most preferably tetrahydrofuran; the reaction time is 1-6 h, preferably 2-5 h, and most preferably 2-3 h.
The preparation method of the crystalline form B of the eimeria amine tenofovir hemifumarate compound comprises the following steps of (1) selecting an anti-solvent from fatty ether or alkane, preferably one of methyl tert-butyl ether, isopropyl ether and n-heptane, and most preferably isopropyl ether; the dosage of the anti-solvent is 2-7 times, preferably 3-6 times and most preferably 4-5 times of the dosage of the solvent in the step I.
The preparation method of the crystal form B of the eimeria phenol amine tenofovir hemifumarate compound comprises the step three, wherein the stirring time is 5-24 hours, preferably 8-20 hours, and most preferably 10-18 hours.
On the other hand, the preparation method of the crystalline form C of the eimeria phenol amine tenofovir hemifumarate compound comprises the following steps:
weighing the free alkali of the eiminamide tenofovir and fumaric acid in a mortar according to the molar ratio of 2: 1;
adding a solvent into the mortar for wetting and grinding;
collecting the solid to obtain the crystalline form C of the eimeria phenol amine tenofovir hemifumarate compound.
The crystalline form of the eimetamol tenofovir hemifumarate compoundC, the mass volume ratio of the mixture of the free alkali of the eimeria phenol amine tenofovir and the fumaric acid to the solvent is 1g:2 ml-1 g:8ml, preferably 1g:3 ml-1 g:6ml, and most preferably 1g:4 ml-1 g:5 ml; step (C) the solvent is selected from fatty alcohols, preferably C1～C3The alcohol solvent of (1) is most preferably ethanol.
On the other hand, the invention also provides a preparation method of the crystalline form D of the eimeria phenol amine tenofovir hemifumarate compound, which comprises the following steps:
weighing the free alkali of the eiminamide tenofovir and fumaric acid in a mortar according to the molar ratio of 2: 1;
adding a solvent into the mortar for wetting and grinding;
collecting the solid to obtain the crystal form D of the eimeria phenol amine tenofovir hemifumarate compound.
According to the above-mentioned steps of the method,
in a preferred embodiment of the invention, the mass volume ratio of the mixture of the step (II) and the solvent is 1g:2 ml-1 g:8ml, preferably 1g:3 ml-1 g:6ml, and most preferably 1g:4 ml-1 g:5 ml; step (C) the solvent is selected from fatty alcohols, preferably C4～C7Most preferably n-hexanol.
In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of the esomeprazole tenofovir hemifumarate complex in combination with one or more pharmaceutically acceptable carriers, diluents or excipients, which are pharmaceutically acceptable. The 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. Wherein compatibility herein means that the components of the composition can be mixed with the active ingredients of the present invention and with each other without significantly diminishing the efficacy of the active ingredients; pharmaceutically acceptable carriers include cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate and the like, solid lubricants such as stearic acid, magnesium stearate and the like, vegetable oils such as soybean oil, castor oil, peanut oil, olive oil and the like, polyols such as propylene glycol, glycerin, mannitol, sorbitol and the like, emulsifiers such as tween series, wetting agents such as sodium dodecyl sulfate, gelatin, talc, colorants, flavoring agents, stabilizers and the like.
The pharmaceutical composition can be a tablet or a capsule.
In another aspect, the invention relates to the use of the crystalline form of the eimeria amine tenofovir hemifumarate complex or a pharmaceutically acceptable composition thereof in a medicament for the treatment of hepatitis, preferably chronic hepatitis b.
The crystalline form of the eimeria phenol amine tenofovir hemifumarate compound has the characteristics of good solubility, small hygroscopicity and high bioavailability, is beneficial to the processing of the medicine and the use in a medicine composition, and has simple and easy preparation method and good reproducibility.
Drawings
Figure 1 is an X-ray diffraction pattern of eimeria phenol amine tenofovir hemifumarate complex form a.
Figure 1A is a DSC profile of eimetamol tenofovir hemifumarate complex form a.
Figure 1B is a TGA profile of eimetamide tenofovir hemifumarate complex form a.
FIG. 1C shows the preparation of crystalline form A of the eimeria phenol amine tenofovir hemifumarate complex1HNMR atlas.
Figure 2 is an X-ray diffraction pattern of eimeria amine tenofovir hemifumarate complex form B.
Figure 2A is a DSC profile of eimetamol tenofovir hemifumarate complex form B.
Figure 2B is a TGA profile of eimetamide tenofovir hemifumarate complex crystalline form B.
Figure 2C shows the preparation of crystalline form B of the eimeria phenol amine tenofovir hemifumarate complex1HNMR atlas.
Figure 3 is an X-ray diffraction pattern of eimeria phenol amine tenofovir hemifumarate complex form C.
Figure 3A is a DSC profile of eimetamol tenofovir hemifumarate complex form C.
FIG. 3B shows EimeiMethod for preparing crystal form C of phenol amine tenofovir hemifumarate complex1HNMR atlas.
Figure 4 is an X-ray diffraction pattern of eimeria amine tenofovir hemifumarate complex form D.
Figure 4A is a DSC profile of eimetamol tenofovir hemifumarate complex form D.
Figure 4B shows the preparation of crystalline form D of the eimeria phenol amine tenofovir hemifumarate complex1HNMR atlas.
Figure 5 is a dynamic moisture adsorption curve for eimetamol tenofovir hemifumarate complex form a.
Figure 6 is a dissolution profile of eimeria amatefuran tenofovir monofumarate and eimeria amatefuran tenofovir hemifumarate complex crystalline form a.
Detailed Description
The following detailed description of embodiments of the present invention is provided in connection with the accompanying drawings and examples. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Example 1: preparation of eimetamide tenofovir hemifumarate compound crystal form A
Weighing 3g of eiminamide tenofovir monofumarate and 3g of eiminamide tenofovir free alkali, mixing with 18mL of tetrahydrofuran, controlling the temperature of the system to be 60 ℃, starting stirring, clarifying the system, keeping the temperature and stirring for 2h, adding 54mL of isopropyl ether into the system under the condition of keeping the temperature, stirring for 12h, filtering, and placing the product at 45 ℃ for forced air drying for 20h to obtain the eiminamide tenofovir hemifumarate compound crystal form A, wherein the molar yield is 92%, and the purity is 98.3%.
Example 2: preparation of eimetamide tenofovir hemifumarate compound crystal form A
Weighing 6g of eiminamide tenofovir monofumarate and 6.5g of eiminamide tenofovir free alkali, mixing with 50 mL of 1, 4-dioxane, controlling the system temperature to 65 ℃, starting stirring, clarifying the system, stirring for 3h under heat preservation, adding 120mL of methyl tert-butyl ether into the system under the heat preservation condition, stirring for 16h, filtering, and placing the product at 40 ℃ for forced air drying for 18h to obtain the eiminamide tenofovir semi-fumarate compound crystal form A, wherein the molar yield is 91%, and the purity is 98.4%.
Example 3: preparation of eimetamide tenofovir hemifumarate compound crystal form A
Weighing 1g of eiminamide tenofovir monofumarate and 1.1g of eiminamide tenofovir free alkali to be mixed with 10 mL of tetrahydrofuran, controlling the temperature of the system to be 60 ℃, starting stirring, clarifying the system, keeping the temperature and stirring for 2.5h, adding 45mL of n-heptane into the system under the condition of keeping the temperature, stirring for 12h, filtering, and placing the product at 45 ℃ for forced air drying for 24h to obtain the eiminamide tenofovir hemifumarate compound crystal form A, wherein the molar yield is 90% and the purity is 98.8%.
Example 4: preparation of eimetamide tenofovir hemifumarate compound crystal form A
Weighing 2g of eiminamide tenofovir monofumarate and 2g of eiminamide tenofovir free alkali, mixing with 12mL of 1, 4-dioxane, controlling the system temperature to be 55 ℃, starting stirring, clarifying the system, stirring for 2h under heat preservation, adding 40mL of methyl tert-butyl ether into the system under the heat preservation condition, stirring for 10h, filtering, and drying the product at 40 ℃ for 20h by blowing to obtain the eiminamide tenofovir hemifumarate compound crystal form A, wherein the molar yield is 91%, and the purity is 98.3%.
Example 5: preparation of eimetamide tenofovir hemifumarate compound crystal form A
Weighing 4g of eiminamide tenofovir monofumarate and 4.5g of eiminamide tenofovir free alkali to be mixed with 40mL of tetrahydrofuran, controlling the temperature of the system to be 62 ℃, starting stirring, clarifying the system, keeping the temperature and stirring for 4h, adding 180mL of isopropyl ether into the system under the condition of keeping the temperature, stirring for 14h, filtering, and placing the product at 45 ℃ for forced air drying for 18h to obtain the eiminamide tenofovir hemifumarate compound crystal form A, wherein the molar yield is 92%, and the purity is 98.6%.
Example 6: preparation of eimetamide tenofovir hemifumarate compound crystal form B
Weighing 3g of eiminamide tenofovir monofumarate and 3.2g of eiminamide tenofovir free alkali, mixing with 20mL of tetrahydrofuran, controlling the system temperature to be 25 ℃, starting stirring, clarifying the system, keeping the temperature and stirring for 2h, adding 70mL of isopropyl ether into the system under the condition of keeping the temperature, stirring for 14h, filtering, and placing the product at 30 ℃ for blast drying for 24h to obtain the eiminamide tenofovir hemifumarate compound crystal form B, wherein the molar yield is 91% and the purity is 98.4%.
Example 7: preparation of eimetamide tenofovir hemifumarate compound crystal form B
Weighing 1.5g of eiminamide tenofovir monofumarate and 1.7g of eiminamide tenofovir free alkali, mixing with 15 mL of 1, 4-dioxane, controlling the system temperature to be 30 ℃, starting stirring, clarifying the system, keeping the temperature and stirring for 2h, adding 45mL of n-heptane into the system under the condition of keeping the temperature, stirring for 12h, filtering, and placing the product at 30 ℃ for forced air drying for 20h to obtain the eiminamide tenofovir hemifumarate compound crystal form B, wherein the molar yield is 90%, and the purity is 98.7%.
Example 8: preparation of eimetamide tenofovir hemifumarate compound crystal form C
Weighing 1g of the eimetaminophen tenofovir free alkali and 0.12g of fumaric acid in a mortar, adding 4mL of ethanol for wetting, and grinding to obtain the compound crystal form C of the eimetaminophen tenofovir hemifumarate.
Example 9: preparation of eimetamide tenofovir hemifumarate compound crystal form C
Weighing 2g of the eimetamol tenofovir free alkali and 0.24g of fumaric acid in a mortar, adding 5.5mL of isopropanol for wetting and grinding to obtain the crystalline form C of the eimetamol tenofovir hemifumarate compound.
Example 10: preparation of eimetamide tenofovir hemifumarate compound crystal form D
Weighing 0.5g of eiminamide tenofovir free alkali and 0.06g of fumaric acid in a mortar, adding 2mL of n-hexanol for wetting and grinding to obtain the crystalline form D of the eiminamide tenofovir hemifumarate compound.
Example 11: preparation of eimetamide tenofovir hemifumarate compound crystal form D
Weighing 2g of eiminamide tenofovir free alkali and 0.24g of fumaric acid in a mortar, adding 4.5mL of n-butanol for wetting, and grinding to obtain the compound crystal form D of the eiminamide tenofovir hemifumarate compound.
Experimental example 12: confirmation of structure of eimeria phenol amine tenofovir hemifumarate compound
The structural formula of the compound of the eimeria amine tenofovir hemifumarate is shown as a formula II:
Figure BDA0003110876010000181
(1) hydrogen nuclear magnetic resonance spectrum (1H-NMR): weighing 10mg of the crystal form A, placing the crystal form A in a 5mm nuclear magnetic tube, dissolving and uniformly mixing with 500 mu L of deuterated dimethyl sulfoxide, detecting a sample by using a Bruker AVANCE400MHz full-digital nuclear magnetic resonance spectrometer, wherein a hydrogen nuclear magnetic resonance spectrogram is shown in a figure 1C, and relevant data are shown in the following table:
chemical shift (ppm) Multiplicity of properties Number of protons Proton assignment Remarks for note
1.08-1.10 d 3 H-22 J＝6.2Hz
1.12-1.14 m 6 H-20，H-20’ /
1.29 s 3 H-29 /
1.32 s 3 H-29’ /
3.83-3.85 m 1 H-13a /
3.86-3.88 m 1 H-13b /
3.97-4.01 m 1 H-11 /
4.16-4.21 m 1 H-10a /
4.26-4.31 m 1 H-10b /
4.81-4.87 m 1 H-19 /
5.28-5.31 d 1 15-NH J＝10.7Hz
6.64 s 1 H-31，H-31’ /
7.07-7.10 d 2 H-26，H-26’ J＝8.0Hz
7.13 t 1 H-28 J＝7.4Hz
7.26 s 2 21-NH2 /
7.30 t 2 H-27，H-27’ J＝7.8Hz
8.13 s 1 H-8 /
8.14 s 1 H-6 /
13.03 br 1 33-OH，33’-OH /
The results showed that a single peak at δ 6.64ppm, corresponding to 1 proton, was assigned to each 1/2 protons of the olefin at position 31/31', confirming that the molar ratio of the eimeria amine tenofovir to fumaric acid in the crystals was 2: 1.
The hydrogen nuclear magnetic resonance spectrograms of the crystal form B, the crystal form C and the crystal form D are respectively shown in a figure 2C, a figure 3B and a figure 4B, and are consistent with the hydrogen nuclear magnetic resonance spectrogram of the crystal form A, and the molar ratio of the eimeria phenol amine tenofovir and the fumaric acid in the crystal is proved to be 2: 1.
(2) Determination of fumaric acid content by acid-base titration: respectively weighing 0.2g of crystal form A, crystal form B, crystal form C and crystal form D, precisely weighing, and adding 40mL of methanol for dissolving. Titration is carried out by using a sodium hydroxide titration solution (0.1mol/L) by adopting a potentiometric titration method (0701 in the four-part general rule of the 2015 version in Chinese pharmacopoeia), and a titration result is corrected by using a blank test. Each 1ml of sodium hydroxide titration solution (0.1mol/L) corresponds to 5.80mg of C4H4O4The results are shown in the following table:
crystal form A Crystal form B Crystal form C Crystal form D
Fumaric acid content 10.6％ 10.6％ 10.7％ 10.6％
The result shows that the theoretical content of fumaric acid in the compound of the eimeria phenol amine tenofovir and hemifumaric acid is 10.6 percent, the actual detection result of the content of 4-crystal type fumaric acid is basically consistent with the theoretical value, and the mol ratio of the eimeria phenol amine tenofovir and the fumaric acid in the crystal is 2: 1.
Experimental example 13: solubility in water
The solubility of the emetamoxifen fumarate and the emetamoxifen hemifumarate complex, form a, were determined separately, with reference to the solubility determination method provided in the ' pharmacopoeia of the people's republic of china ' 2020, with the results shown in the following table:
sample type Amount of water required to dissolve 1g of solute Solubility in water
Almenol tenofovir monofumarate 52mL Slightly soluble
Emamectin benzoate tenofovir hemifumarate compound crystal form A 24mL Dissolution
The result shows that the solubility of the eimeria phenol amine tenofovir hemifumarate compound crystal form A is superior to that of the eimeria phenol amine tenofovir monofumarate, so that the compound has better bioavailability.
Experimental example 14: moisture-wicking property
The moisture absorption weight gain of the crystalline form a of the eimeria phenol amine tenofovir hemifumarate compound under different humidity is examined by using a dynamic moisture adsorption instrument (DVS INTRINSIC), and the result is shown in fig. 5.
The results show that the hygroscopicity of the crystalline form A of the eimeria amine tenofovir hemifumarate compound is small, and the crystalline form A is the excellent characteristic required by the pharmaceutical preparation.
Experimental example 15: interconversion relationship between forms A and B
(1) Solvent mediated phase transition
Research shows that under the condition that no additional seed crystal is added in the same crystallization system, the crystal form B is easy to obtain at low temperature, the crystal form A is easy to obtain at high temperature, the competition condition of the crystal forms A and B mixed by equal mass in a crystallization mother liquor system consisting of tetrahydrofuran/isopropyl ether is considered, and the results are shown in the following table:
type of raw material Crystallization mother liquor system Temperature of Crystal form
Crystal form A/B (250mg/250mg) THF/IPE(5mL/15mL) 25℃ Crystal form B
Crystal form A/B (250mg/250mg) THF/IPE(5mL/15mL) 45℃ Crystal form A/B
Crystal form A/B (250mg/250mg) THF/IPE(5mL/15mL) 55℃ Crystal form A/B
Crystal form A/B (250mg/250mg) THF/IPE(5mL/15mL) 75℃ Crystal form A
The result shows that the crystal form B is the dominant crystal form at low temperature and the crystal form A is the dominant crystal form at high temperature in the crystallization system.
(2) Solid phase transition
The crystal transformation conditions of the crystal forms A and B mixed by equal mass under different temperature blast drying conditions are considered, and the results are shown in the following table:
type of raw material Drying temperature Crystal form
Crystal form A/B (250mg/250mg) 30℃ Crystal form A/B
Crystal form A/B (250mg/250mg) 40℃ Crystal form A/B
Crystal form A/B (250mg/250mg) 50℃ Crystal form A/B
Crystal form A-B(250mg/250mg) 60℃ Crystal form A
The results show that the crystal form B can be transformed into the crystal form A under the high-temperature condition.
Experimental example 16: dissolution rate
Raw and auxiliary materials The weight percentage of the prescription is
Active ingredient 24.1％
Lactose 30.6％
Calcium carboxymethylcellulose 25.4％
Talcum powder 17.4％
Glyceryl behenate 2.5％
Examining the dissolution rate of the eiminamide tenofovir monofumarate and the crystalline form A of the eiminamide tenofovir hemifumarate compound under the prescription process of the powder direct compression preparation, mixing the raw materials and the auxiliary materials in an equal amount increasing mode according to the prescription shown in the table, tabletting by using a DP301 single-punch tablet press, wherein the specification is 25mg, and the dissolution rate of the obtained tablet is examined in a dissolution medium (pH 4.5 acetate buffer solution), and the result is shown in figure 6.
The result shows that the dissolution rate of the preparation product of the eimeria phenol amine tenofovir hemifumarate compound crystal form A as an active ingredient is superior to that of phenol amine tenofovir monofumarate.

Claims (13)

1. An eimetamol tenofovir hemifumarate compound shown as a formula (I),
Figure FDA0003110875000000011
2. the eimeria amantadine tenofovir hemifumarate complex of claim 1, characterized in that it is in crystalline form or amorphous form.
3. A crystalline form of the alminostat tenofovir hemifumarate complex according to claim 2, which is form a, having an X-ray powder diffraction pattern with a diffraction peak at 5.1 ± 0.2 ° at 2 Θ, or a diffraction peak at 7.7 ± 0.2 °, or a diffraction peak at 13.0 ± 0.2 °, or a diffraction peak at 15.4 ± 0.2 °, or a diffraction peak at 20.9 ± 0.2 °, or a diffraction peak at 22.1 ± 0.2 °, or a diffraction peak at 25.0 ± 0.2 °, or a diffraction peak at 10.2 ± 0.2 °, preferably comprising any 2 to 5, or 3 to 6, or 3 to 7, more preferably comprising any 4, 6, or 8 therein;
alternatively, the first and second electrodes may be,
form a has an X-ray powder diffraction pattern comprising at least one, preferably two, more preferably three, diffraction peaks, at 2 Θ of 5.1 ± 0.2 °, 7.7 ± 0.2 °, 13.0 ± 0.2 °; optionally, at least one strip located at 2 θ of 15.4 ± 0.2 °, 20.9 ± 0.2 °, 22.1 ± 0.2 °, 25.0 ± 0.2 °, 10.2 ± 0.2 °, preferably 2, 3, 4 or 5 strips, for example,
5.1±0.2°、7.7±0.2°；
7.7±0.2°、13.0±0.2°；
5.1±0.2°、13.0±0.2°；
5.1±0.2°、15.4±0.2°；
7.7±0.2°、20.9±0.2°；
13.0±0.2°、22.1±0.2°；
5.1±0.2°、7.7±0.2°、13.0±0.2°；
5.1±0.2°、15.4±0.2°、20.9±0.2°；
7.7±0.2°、20.9±0.2°、22.1±0.2°；
13.0±0.2°、22.1±0.2°、25.0±0.2°；
5.1±0.2°、7.7±0.2°、15.4±0.2°；
7.7±0.2°、13.0±0.2°、25.0±0.2°；
5.1±0.2°、13.0±0.2°、10.2±0.2°；
5.1±0.2°、7.7±0.2°、13.0±0.2°、15.4±0.2°；
5.1±0.2°、15.4±0.2°、20.9±0.2°、22.1±0.2°；
7.7±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°；
13.0±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°；
5.1±0.2°、7.7±0.2°、15.4±0.2°、20.9±0.2°；
5.1±0.2°、13.0±0.2°、22.1±0.2°、25.0±0.2°；
7.7±0.2°、13.0±0.2°、25.0±0.2°、10.2±0.2°；
alternatively, the first and second electrodes may be,
the X-ray powder diffraction pattern of form a optionally further comprises one or more diffraction peaks at 10.5 ± 0.2 °, 10.8 ± 0.2 °, 16.1 ± 0.2 °, 17.0 ± 0.2 °, 19.6 ± 0.2 °, 20.4 ± 0.2 ° and 29.2 ± 0.2 ° 2 Θ; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, 7 thereof; for example,
10.5±0.2°、10.8±0.2°、16.1±0.2°；
10.8±0.2°、16.1±0.2°、17.0±0.2°；
17.0±0.2°、19.6±0.2°、20.4±0.2°；
10.5±0.2°、10.8±0.2°、16.1±0.2°、17.0±0.2°；
10.8±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°；
16.1±0.2°、17.0±0.2°、19.6±0.2°、20.4±0.2°；
10.5±0.2°、10.8±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°、20.4±0.2°；
10.8±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°、20.4±0.2°、29.2±0.2°；
10.5±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°、20.4±0.2°、29.2±0.2°；
alternatively, the first and second electrodes may be,
the X-ray powder diffraction pattern of the crystal form A is 5.1 +/-0.2 degrees, 7.7 +/-0.2 degrees, 13.0 +/-0.2 degrees and,
Diffraction peaks at 15.4 + -0.2 °, 20.9 + -0.2 °, 22.1 + -0.2 °, 25.0 + -0.2 °, 10.2 + -0.2 °, 10.5 + -0.2 °, 10.8 + -0.2 °, 16.1 + -0.2 °, 17.0 + -0.2 °, 19.6 + -0.2 °, 20.4 + -0.2 ° and 29.2 + -0.2 °, preferably including diffraction peaks at 4, 5, 6, 8 or 10 positions, optionally, for example,
5.1±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°；
7.7±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°；
13.0±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°；
15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°；
20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°；
22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°；
5.1±0.2°、15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°；
7.7±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°；
13.0±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°；
15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°；
20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°；
22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°；
5.1±0.2°、15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°；
7.7±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°；
13.0±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°；
15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°；
20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°；
22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°；
5.1±0.2°、15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°；
7.7±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°、17.0±0.2°；
13.0±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°；
15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°；
20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°、17.0±0.2°；
22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°；
5.1±0.2°、7.7±0.2°、13.0±0.2°、15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°；
7.7±0.2°、13.0±0.2°、15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°；
13.0±0.2°、15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°、17.0±0.2°；
15.4±0.2°、20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°；
20.9±0.2°、22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°、20.4±0.2°；
22.1±0.2°、25.0±0.2°、10.2±0.2°、10.5±0.2°、10.8±0.2°、16.1±0.2°、17.0±0.2°、19.6±0.2°、20.4±0.2°、29.2±0.2°。
4. the crystalline form of the eimeria amine tenofovir hemifumarate complex of claim 2, wherein the X-ray powder diffraction pattern of form a is substantially as shown in figure 1.
5. A crystalline form of the Almesolamide tenofovir hemifumarate complex of claim 2 which is form B having an X-ray powder diffraction pattern with a diffraction peak at 4.4 ± 0.2 ° 2 θ, or a diffraction peak at 6.6 ± 0.2 °, or a diffraction peak at 7.7 ± 0.2 °, or a diffraction peak at 13.0 ± 0.2 °, or a diffraction peak at 15.4 ± 0.2 °, or a diffraction peak at 22.1 ± 0.2 °, or a diffraction peak at 23.2 ± 0.2 °, or a diffraction peak at 26.7 ± 0.2 °, preferably comprising any 2 to 5, or 3 to 6, or 3 to 8, more preferably comprising any 4, 6 or 8 therein;
alternatively, the first and second electrodes may be,
form B has an X-ray powder diffraction pattern having one or more, preferably two, more preferably three, diffraction peaks at 2 Θ of 4.4 ± 0.2 °, 6.6 ± 0.2 °, 7.7 ± 0.2 °; optionally, at least one strip located at 2 theta of 26.7 + -0.2, 4.9 + -0.2, 10.5 + -0.2, 13.3 + -0.2, 17.0 + -0.2, preferably 2, 3, 4 or 5, for example,
4.4±0.2°、6.6±0.2°；
6.6±0.2°、7.7±0.2°；
4.4±0.2°、7.7±0.2°；
4.4±0.2°、26.7±0.2°；
6.6±0.2°、4.9±0.2°；
7.7±0.2°、10.5±0.2°；
4.4±0.2°、6.6±0.2°、7.7±0.2°；
4.4±0.2°、26.7±0.2、4.9±0.2°；
6.6±0.2°、4.9±0.2°、10.5±0.2°；
7.7±0.2°、10.5±0.2°、13.3±0.2°；
4.4±0.2°、6.6±0.2°、13.3±0.2°；
6.6±0.2°、7.7±0.2°、17.0±0.2°；
4.4±0.2°、7.7±0.2°、10.5±0.2°；
4.4±0.2°、26.7±0.2、4.9±0.2°、10.5±0.2°；
6.6±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°；
7.7±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°；
4.4±0.2°、6.6±0.2°、26.7±0.2、4.9±0.2°；
6.6±0.2°、7.7±0.2°、4.9±0.2°、10.5±0.2°；
4.4±0.2°、7.7±0.2°、10.5±0.2°、13.3±0.2°；
4.4±0.2°、6.6±0.2°、7.7±0.2°、17.0±0.2°；
the X-ray powder diffraction pattern of form B optionally further comprises one or more diffraction peaks at 4.9 ± 0.2 °, 10.5 ± 0.2 °, 13.3 ± 0.2 °, 17.0 ± 0.2 °, 20.4 ± 0.2 °, 20.9 ± 0.2 °, and 22.8 ± 0.2 ° 2 Θ; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, 7 thereof; for example,
4.9±0.2°、10.5±0.2°、13.3±0.2°；
10.5±0.2°、13.3±0.2°、17.0±0.2°；
13.3±0.2°、17.0±0.2°、20.4±0.2°；
4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°；
10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°；
13.3±0.2°、17.0±0.2°、20.4±0.2°、20.9±0.2°；
4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°、20.9±0.2°；
4.9±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°、20.9±0.2°、22.8±0.2°；
10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°、20.9±0.2°、22.8±0.2°；
alternatively, the first and second electrodes may be,
form B has an X-ray powder diffraction pattern having diffraction peaks at 4.4 + -0.2 °, 6.6 + -0.2 °, 7.7 + -0.2 °, 13.0 + -0.2 °, 15.4 + -0.2 °, 22.1 + -0.2 °, 23.2 + -0.2 °, 26.7 + -0.2 °, 4.9 + -0.2 °, 10.5 + -0.2 °, 13.3 + -0.2 °, 17.0 + -0.2 °, 20.4 + -0.2 °, 20.9 + -0.2 ° and 22.8 + -0.2 ° 2 θ, preferably including diffraction peaks at 4, 5, 6, 8 or 10 optionally, e.g.,
4.4±0.2°、13.0±0.2°、15.4±0.2°、22.1±0.2°；
6.6±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°；
7.7±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°；
15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°；
22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°；
23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
4.4±0.2°、13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°；
6.6±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°；
7.7±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°；
13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°；
15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°；
22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
4.4±0.2°、13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°；
6.6±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
7.7±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°；
13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°；
15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°；
4.4±0.2°、13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
6.6±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°；
7.7±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°；
13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°；
15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°；
22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°；
4.4±0.2°、6.6±0.2°、7.7±0.2°、13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
6.6±0.2°、7.7±0.2°、13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°；
7.7±0.2°、13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°；
13.0±0.2°、15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°；
15.4±0.2°、22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°、20.9±0.2°；
22.1±0.2°、23.2±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°、20.9±0.2°、22.8±0.2°。
6. the crystalline form of the eimeria phenol amine tenofovir hemifumarate complex of claim 2, wherein the X-ray powder diffraction pattern of form B is substantially as shown in figure 2.
7. Crystalline form C of the alminostat tenofovir hemifumarate complex according to claim 2, which is form C, having an X-ray powder diffraction pattern with a diffraction peak at 5.0 ± 0.2 ° 2 Θ, or a diffraction peak at 7.8 ± 0.2 °, or a diffraction peak at 13.1 ± 0.2 °, or a diffraction peak at 14.4 ± 0.2 °, or a diffraction peak at 18.1 ± 0.2 °, or a diffraction peak at 20.5 ± 0.2, or a diffraction peak at 21.0 ± 0.2, or a diffraction peak at 22.2 ± 0.2, preferably comprising any 2 to 5, or 3 to 6, or 3 to 8, more preferably comprising any 4, 6, or 8 thereof;
alternatively, the first and second electrodes may be,
form C has an X-ray powder diffraction pattern having one or more, preferably two, more preferably three, diffraction peaks at 2 Θ of 5.0 ± 0.2 °, 7.8 ± 0.2 °, 13.1 ± 0.2 °; optionally, at least one strip located at 2 θ of 14.4 ± 0.2 °, 18.1 ± 0.2 °, 20.5 ± 0.2 °, 21.0 ± 0.2 °, 22.2 ± 0.2 °, preferably 2, 3, 4 or 5 strips, for example,
5.0±0.2°、7.8±0.2°；
7.8±0.2°、13.1±0.2°；
5.0±0.2°、13.1±0.2°；
5.0±0.2°、14.4±0.2°；
7.8±0.2°、18.1±0.2°；
13.1±0.2°、20.5±0.2°；
5.0±0.2°、7.8±0.2°、13.1±0.2°；
5.0±0.2°、20.5±0.2°、21.0±0.2°；
7.8±0.2°、18.1±0.2°、20.5±0.2°；
13.1±0.2°、14.4±0.2°、18.1±0.2°；
5.0±0.2°、7.8±0.2°、14.4±0.2°；
7.8±0.2°、13.1±0.2°、20.5±0.2°；
5.0±0.2°、13.1±0.2°、20.5±0.2°；
5.0±0.2°、7.8±0.2°、13.1±0.2°、14.4±0.2°；
7.8±0.2°、13.1±0.2°、14.4±0.2°、18.1±0.2°；
5.0±0.2°、13.1±0.2°、18.1±0.2°、20.5±0.2°；
5.0±0.2°、7.8±0.2°、13.1±0.2°、21.0±0.2°；
5.0±0.2°、14.4±0.2°、18.1±0.2°、20.5±0.2°；
7.8±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°；
13.1±0.2°、20.5±0.2°、21.0±0.2°、22.2±0.2°；
the X-ray powder diffraction pattern of form C optionally further comprises one or more diffraction peaks at 9.7 ± 0.2 °, 10.6 ± 0.2 °, 11.5 ± 0.2 °, 15.5 ± 0.2 °, 16.3 ± 0.2 °, 17.1 ± 0.2 °, and 19.8 ± 0.2 ° 2 Θ; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, 7 thereof; for example,
9.7±0.2°、10.6±0.2°、11.5±0.2°；
10.6±0.2°、11.5±0.2°、15.5±0.2°；
11.5±0.2°、15.5±0.2°、16.3±0.2°；
9.7±0.2°、10.6±0.2°、11.5±0.2°、15.5±0.2°；
10.6±0.2°、11.5±0.2°、15.5±0.2°、16.3±0.2°；
11.5±0.2°、15.5±0.2°、16.3±0.2°、17.1±0.2°；
9.7±0.2°、10.6±0.2°、11.5±0.2°、15.5±0.2°、16.3±0.2°、17.1±0.2°；
10.6±0.2°、11.5±0.2°、15.5±0.2°、16.3±0.2°、17.1±0.2°、19.8±0.2°；
9.7±0.2°、11.5±0.2°、15.5±0.2°、16.3±0.2°、17.1±0.2°、19.8±0.2°；
alternatively, the first and second electrodes may be,
form C has an X-ray powder diffraction pattern having diffraction peaks at 5.0 + -0.2 °, 7.8 + -0.2 °, 13.1 + -0.2 °, 14.4 + -0.2 °, 18.1 + -0.2 °, 20.5 + -0.2 °, 21.0 + -0.2 °, 26.7 + -0.2 °, 4.9 + -0.2 °, 10.5 + -0.2 °, 13.3 + -0.2 °, 17.0 + -0.2 °, 20.4 + -0.2 °, 20.9 + -0.2 ° and 22.8 + -0.2 ° 2 θ, preferably including diffraction peaks at 4, 5, 6, 8 or 10 optionally therein, e.g.,
5.0±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°；
7.8±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°；
13.1±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°；
18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°；
20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°；
5.0±0.2°、14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°；
7.8±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°；
13.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°；
14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°；
18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°；
20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
5.0±0.2°、14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°；
7.8±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°；
13.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°；
18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°；
5.0±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°；
7.8±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°；
13.1±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°；
14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°；
18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°；
20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°；
5.0±0.2°、7.8±0.2°、13.1±0.2°、14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°；
7.8±0.2°、13.1±0.2°、14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°；
13.1±0.2°、14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°；
14.4±0.2°、18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°；
18.1±0.2°、20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°、20.9±0.2°；
20.5±0.2°、21.0±0.2°、26.7±0.2°、4.9±0.2°、10.5±0.2°、13.3±0.2°、17.0±0.2°、20.4±0.2°、20.9±0.2°、22.8±0.2°。
8. the crystalline form of the eimeria amine tenofovir hemifumarate complex of claim 2, wherein the X-ray powder diffraction pattern of form C is substantially as shown in figure 3.
9. Crystalline form a of the eimeria amine tenofovir hemifumarate complex according to claim 3, prepared by a process comprising the steps of:
mixing the eiminamide tenofovir monofumarate and the eiminamide tenofovir free alkali with a solvent under a certain temperature,
② adding an anti-solvent into the solution system to crystallize,
stirring, filtering and collecting solids to obtain an amebocinol amide tenofovir hemifumarate compound crystal form A;
preferably, the first and second liquid crystal materials are,
the temperature condition of the step (i) is 55-70 ℃, preferably 60-65 ℃, and most preferably 65 ℃;
the mol ratio of the eimetamol tenofovir monofumarate to the eimetamol tenofovir free alkali is 1: 1-1: 3, preferably 1: 1.1-1: 2, and most preferably 1: 1.2-1: 1.5; the mass volume ratio of the mixture of the eimeria phenol amine tenofovir monofumarate and the eimeria phenol amine tenofovir free base to the solvent is 1g:2 ml-1 g:8ml, preferably 1g:3 ml-1 g:6ml, and most preferably 1g:4 ml;
the solvent is selected from cyclic ether, preferably one of tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane, and most preferably tetrahydrofuran; the reaction time is 1-6 h, preferably 2-5 h, and most preferably 2-3 h;
preferably, the first and second liquid crystal materials are,
step (c) the antisolvent is selected from the group consisting of aliphatic ethers or alkanes, preferably one of methyl tert-butyl ether, isopropyl ether and n-heptane, most preferably isopropyl ether; the dosage of the anti-solvent is 2-7 times, preferably 3-6 times and most preferably 4-5 times of the dosage of the solvent in the step I;
preferably, the first and second liquid crystal materials are,
and the stirring time is 5-24 h, preferably 8-20 h, and most preferably 10-18 h.
10. The crystalline form B of the eimeria amine tenofovir hemifumarate complex of claim 5, prepared by a process comprising the steps of:
mixing the eiminamide tenofovir monofumarate and the eiminamide tenofovir free alkali with a solvent under a certain temperature,
② adding an anti-solvent into the solution system to crystallize,
stirring, filtering and collecting solids to obtain an amebocinol amide tenofovir hemifumarate compound crystal form B;
preferably, the first and second liquid crystal materials are,
the temperature condition of the first step is 0-50 ℃, preferably 10-40 ℃, and most preferably 20-30 ℃; the mol ratio of the eimetamol tenofovir monofumarate to the eimetamol tenofovir free alkali is 1: 1-1: 3, preferably 1: 1.1-1: 2, and most preferably 1: 1.2-1: 1.5; the mass volume ratio of the mixture of the eimeria phenol amine tenofovir monofumarate and the eimeria phenol amine tenofovir free base to the solvent is 1g:2 ml-1 g:8ml, preferably 1g:3 ml-1 g:6ml, and most preferably 1g:4 ml; the solvent is selected from cyclic ether, preferably one of tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane, and most preferably tetrahydrofuran; the reaction time is 1-6 h, preferably 2-5 h, and most preferably 2-3 h;
preferably, the first and second liquid crystal materials are,
step (c) the antisolvent is selected from the group consisting of aliphatic ethers or alkanes, preferably one of methyl tert-butyl ether, isopropyl ether and n-heptane, most preferably isopropyl ether; the dosage of the anti-solvent is 2-7 times, preferably 3-6 times and most preferably 4-5 times of the dosage of the solvent in the step I;
preferably, the first and second liquid crystal materials are,
and the stirring time is 5-24 h, preferably 8-20 h, and most preferably 10-18 h.
11. The crystalline eimeria amantadine tenofovir hemifumarate complex form C of claim 7, prepared by a process comprising the steps of:
weighing the free alkali of the eiminamide tenofovir and fumaric acid in a mortar according to the molar ratio of 2:1,
② adding solvent into the mortar for wetting and grinding,
collecting the solid to obtain an amebocide tenofovir hemifumarate compound crystal form C;
preferably, the first and second liquid crystal materials are,
the mass volume ratio of the mixture of the free alkali of the eimeria amine tenofovir and the fumaric acid to the solvent is 1g:2 ml-1 g:8ml, preferably 1g:3 ml-1 g:6ml, and most preferably 1g:4 ml-1 g:5 ml; step (C) the solvent is selected from fatty alcohols, preferably C1～C3The alcohol solvent of (1) is most preferably ethanol.
12. A pharmaceutical composition comprising a therapeutically effective amount of the eimeria amantadine tenofovir hemifumarate complex of claim 1 or a crystalline form of the eimeria amantadine tenofovir hemifumarate complex of any one of claims 2 to 8, and one or more pharmaceutically acceptable carriers, diluents or excipients.
13. Use of the eimeria phenol amine tenofovir hemifumarate complex according to claim 1 or the crystalline form of the eimeria phenol amine tenofovir hemifumarate complex according to any one of claims 2-8, or the pharmaceutical composition according to claim 12 for the preparation of a medicament for the treatment of hepatitis, preferably, the hepatitis is chronic hepatitis b.
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