CN113501846B - Eimerosamine tenofovir hemi-fumaric acid compound, crystal form, preparation method and application thereof - Google Patents

Eimerosamine tenofovir hemi-fumaric acid compound, crystal form, preparation method and application thereof Download PDF

Info

Publication number
CN113501846B
CN113501846B CN202110648580.5A CN202110648580A CN113501846B CN 113501846 B CN113501846 B CN 113501846B CN 202110648580 A CN202110648580 A CN 202110648580A CN 113501846 B CN113501846 B CN 113501846B
Authority
CN
China
Prior art keywords
tenofovir
esomeprazole
eimeric
hemifumarate
crystal form
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202110648580.5A
Other languages
Chinese (zh)
Other versions
CN113501846A (en
Inventor
王小雷
林青
杨宝海
何雷
刘梦瑜
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Changzhou Hengbang Pharmaceutical Co ltd
Jiangsu Hansoh Pharmaceutical Group Co Ltd
Original Assignee
Changzhou Hengbang Pharmaceutical Co ltd
Jiangsu Hansoh Pharmaceutical Group Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Changzhou Hengbang Pharmaceutical Co ltd, Jiangsu Hansoh Pharmaceutical Group Co Ltd filed Critical Changzhou Hengbang Pharmaceutical Co ltd
Priority to CN202110648580.5A priority Critical patent/CN113501846B/en
Publication of CN113501846A publication Critical patent/CN113501846A/en
Application granted granted Critical
Publication of CN113501846B publication Critical patent/CN113501846B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Public Health (AREA)
  • Virology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Secondary Cells (AREA)
  • Fuel Cell (AREA)
  • Analysing Materials By The Use Of Radiation (AREA)

Abstract

The invention discloses an eimeric tenofovir hemi-fumaric acid compound with a structure shown in a formula I, a crystal form, a preparation method and application thereof. In particular to an esomeprazole tenofovir hemi-fumaric acid 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 provided by the invention is simple and easy to implement, has good reproducibility, and the prepared esomeprazole tenofovir hemi-fumaric acid compound crystal form A has the characteristics of good solubility and small hygroscopicity, and is beneficial to preparation and storage of pharmaceutical preparations.

Description

Eimerosamine tenofovir hemi-fumaric acid compound, crystal form, preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an eimeric tenofovir hemi-fumaric acid 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 hemi-fumarate complex (formula I) is a nucleoside reverse transcriptase inhibitor, a prodrug of tenofovir (P MPA). The PMPA structure is similar to natural nucleoside monophosphate, and is rapidly converted into an active metabolite PMPA diphosphate (PMPApp) in vivo; PMPApp competes with natural 5 'deoxyadenosine triphosphate for incorporation into viral DNA strands, but because PMPApp lacks 3' oh groups, 5',3' phosphodiester linkage cannot be performed any more, resulting in a hindered DNA strand extension, ultimately blocking viral replication. The study demonstrates that PMPA has activity against Human Immunodeficiency Virus (HIV) and Hepatitis B Virus (HBV).
However, PMPA contains phosphate groups, and is usually negatively charged under physiological pH conditions, and has too strong polarity to pass through biological membranes easily, so that the medicine has poor oral bioavailability, low tissue distribution coefficient and certain nephrotoxicity. Therefore, when developing the medicines, the prodrug principle is required to mask the negative charge of the phosphate group, so that the defects of the medicines are eliminated. PMPA bipyrate fumarate (tenofovirdisoproxilfumarate, TDF) was approved by the U.S. Food and Drug Administration (FDA) in 2001 for the treatment of HIV infection, respectively.
TDF significantly improves the pharmacokinetic properties of PMPA to some extent, but it is rapidly hydrolyzed in vivo by nonspecific esterases that are widely present in plasma, especially by intestinal mucosal epithelial cell carbonic acid esterases, releasing PMPA. The high concentration of PMPA in plasma is rapidly discharged to the outside of 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 organic anion transporter (joat) of renal proximal tubule epithelial cells, and high concentration of PMPA in plasma is liable to accumulate in renal proximal tubule epithelial cells, causing a certain risk of nephrotoxicity.
The new generation of monophosphoryl monoester prodrugs overcomes the defect of TDF, is stable in blood plasma and is not easy to hydrolyze by esterase; but is absorbed into the cell; the enzyme is immediately converted into PMPA by serine protease (CATHEPSINA) and in vivo specific amidase, so that the enzyme has better tissue permeability and lymphatic tissue and cell targeting. The monophosphoryl monoester prodrug GS7340 developed by gilid corporation also has greater antiviral potency and better safety compared to 30-fold doses of TDF.
The 9- [ (R) -2- [ [ (S) - [ [ [1- (isopropoxycarbonyl) -1-methyl ] ethyl ] amino ] phenoxy phosphinyl ] methoxy ] propyl ] adenine hemi-fumaric acid complex (formula I) releases the active ingredient PMPA in the cells as does GS 7340. The 9- [ (R) -2- [ [ (S) - [ [ [1- (isopropoxycarbonyl) -1-methyl ] ethyl ] amino ] phenoxy phosphinyl ] methoxy ] propyl ] adenine hemi-fumaric acid compound (formula I) can exert the efficacy of the active ingredient PMPA of the compound more effectively than the prodrugs such as TDF and the like due to the advantages of absorption and distribution, and is beneficial to a large number of patients as a most potential new generation PMPA prodrug.
In view of the great significance of the research on the crystal forms of the medicines in clinical research, the invention comprehensively researches the esomeprazole tenofovir monofumarate and the crystal forms thereof in order to improve the solubility and solid stability of the products, reduce the storage cost, prolong the product period and improve the bioavailability of the products.
Disclosure of Invention
The inventors have found a complex of esomeprazole tenofovir and fumaric acid present in a molar ratio of 2:1. Through intensive research, the crystalline form of this complex was found. In terms of pharmaceutical development, this complex is advantageous over the salts formed by esomeprazole tenofovir or fumaric acid.
The invention provides a compound of formula I9- [ (R) -2- [ [ (S) - [ [ [1- (isopropoxycarbonyl) -1-methyl ] ethyl ] amino ] phenoxy phosphinyl ] methoxy ] propyl ] adenine and fumaric acid in a molar ratio of 2:1, which is referred to as an Eimerosamine tenofovir hemi-fumaric acid complex.
On the other hand, the esomeprazole tenofovir hemi-fumaric acid compound provided by the invention can be confirmed by nuclear magnetism and content titration. Recrystallizing the complex 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 verify that the molar ratio of the esomeprazole tenofovir to the fumaric acid in the crystal is 2:1 through a nuclear magnetism and content titration mode.
The esomeprazole tenofovir hemi-fumaric acid compound disclosed by the invention exists in a crystalline state or an amorphous state.
The X-ray powder diffraction pattern of the crystalline form a of the esomeprazole tenofovir hemi-fumaric acid compound has a diffraction peak at 5.1±0.2° or at 7.7±0.2°, or at 13.0±0.2°, or at 15.4±0.2°, or at 20.9±0.2°, or at 22.1±0.2°, or at 25.0±0.2°, or at 10.2±0.2°, preferably comprises any 2 to 5, or 3 to 6, or 3 to 7, more preferably comprises any 4, 6, or 8 of the above diffraction peaks;
Or alternatively
The X-ray powder diffraction pattern of the crystal form A at least comprises one or more diffraction peaks positioned in the angles of 5.1+/-0.2 DEG, 7.7+/-0.2 DEG and 13.0+/-0.2 DEG, preferably comprises two of the diffraction peaks, more preferably comprises three of the diffraction peaks; optionally, it may further comprise at least one 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 thereof, 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°；
Or alternatively
The X-ray powder diffraction pattern of form a optionally further comprises one or more diffraction peaks at 2Θ of 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 at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 are included; for example, the number of the cells to be processed,
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°；
Or alternatively
The X-ray powder diffraction pattern of form a has diffraction peaks at 5.1±0.2°、7.7±0.2°、13.0±0.2°、1 5.4±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 deg. 2 theta, preferably, including those wherein optionally 4, 5, 6, 8 or 10 have diffraction peaks, 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, form a has an X-ray powder diffraction pattern substantially as shown in fig. 1, a DSC profile substantially as shown in fig. 1A, a TGA profile substantially as shown in fig. 1B, and a 1 HNMR profile substantially as shown in fig. 1C.
Still more preferably, the DSC profile of form A has an endothermic peak at about 92 ℃, the TGA profile of form A has substantially no weight loss prior to decomposition, and the 1 HNMR profile of form A shows a semi-fumonic acid complex.
The X-ray powder diffraction pattern of the crystalline form B of the esomeprazole tenofovir hemi-fumarate complex has a diffraction peak at 2θ of 4.4±0.2°, or has a diffraction peak at 6.6±0.2°, or has a diffraction peak at 7.7±0.2°, or has a diffraction peak at 13.0±0.2°, or has a diffraction peak at 15.4±0.2°, or has a diffraction peak at 22.1±0.2°, or has a diffraction peak at 23.2±0.2°, or has a diffraction peak at 26.7±0.2°, preferably comprises any 2 to 5, or 3 to 6, or 3 to 8, more preferably comprises any 4, 6 or 8 of the above diffraction peaks;
Or alternatively
The X-ray powder diffraction pattern of the crystal form B comprises one or more diffraction peaks in the angles of 4.4+/-0.2 DEG, 6.6+/-0.2 DEG and 7.7+/-0.2 DEG, preferably two of the diffraction peaks, more preferably three diffraction peaks; optionally, it may further comprise at least one of the angles of 26.7.+ -. 0.2, 4.9.+ -. 0.2 °, 10.5.+ -. 0.2 °, 13.3.+ -. 0.2 °, 17.0.+ -. 0.2 ℃ and preferably 2, 3, 4 or 5 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 2Θ of 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°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 are included; for example, the number of the cells to be processed,
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°；
Or alternatively
The X-ray powder diffraction pattern of form B has 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°, preferably including those having diffraction peaks at optionally 4,5, 6, 8 or 10, for example,
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 fig. 2, a DSC pattern substantially as shown in fig. 2A, a TGA pattern substantially as shown in fig. 2B, and a 1 HNMR pattern substantially as shown in fig. 2C.
Still more preferably, the DSC profile of form B has an endothermic peak at about 95 ℃, the TGA profile of form B has substantially no weight loss prior to decomposition, and the 1 HNMR profile of form B shows a semi-fumonic acid complex.
The X-ray powder diffraction pattern of the crystalline form C of the esomeprazole tenofovir hemi-fumarate complex has a diffraction peak at 5.0±0.2° or at 7.8±0.2°, or at 13.1±0.2°, or at 14.4±0.2°, or at 18.1±0.2°, or at 20.5±0.2°, or at 21.0±0.2, or at 22.2±0.2°, preferably comprises any of the above diffraction peaks at 2 to 5, or at 3 to 6, or at 3 to 8, more preferably comprises any of 4, 6, or 8;
Or alternatively
An X-ray powder diffraction pattern of form C comprises one or more diffraction peaks at 5.0±0.2°, 7.8±0.2°, 13.1±0.2°, preferably two of the peaks, more preferably three of the peaks; optionally, it may further comprise at least one of the angles 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 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°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 are included; for example, the number of the cells to be processed,
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°；
Or alternatively
The X-ray powder diffraction pattern of form C has diffraction peaks at 5.0±0.2°、7.8±0.2°、13.1±0.2°、1 4.4±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° in 2θ, preferably, including those having diffraction peaks at optionally 4, 5, 6, 8 or 10, for example,
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, form C has an X-ray powder diffraction pattern substantially as shown in fig. 3, a DSC pattern substantially as shown in fig. 3A, and 1 HNMR pattern substantially as shown in fig. 3B.
Still more preferably, the DSC profile of form C has an endothermic peak at about 83℃and the 1 HNMR profile of form C shows a hemi-fumaric complex.
The X-ray powder diffraction pattern of the crystalline form D of the esomeprazole tenofovir hemi-fumaric acid compound has a diffraction peak at 2θ of 4.8±0.2°, or has a diffraction peak at 6.9±0.2°, or has a diffraction peak at 7.8±0.2°, or has a diffraction peak at 13.0±0.2°, or has a diffraction peak at 14.4±0.2, or has a diffraction peak at 20.4±0.2, or has a diffraction peak at 22.1±0.2, or has a diffraction peak at 25.0±0.2, preferably comprises any 2 to 5, or 3 to 6, or 3 to 8, more preferably comprises any 4, 6, or 8 of the above diffraction peaks.
The X-ray powder diffraction pattern of the crystal form D provided by the invention is 4.8+/-0.2 degrees in 2 theta,
Having diffraction peaks at 6.9 + -0.2 deg., 7.8 + -0.2 deg., and 13.0 + -0.2 deg., preferably, further comprising having characteristic peaks at 2θ deg.s of 1.4 + -0.2, 20.4 + -0.2, 22.1 + -0.2, and 25.0 + -0.2 deg., more preferably, further comprising having diffraction peaks at 2θ's of 9. 3±0.2°、9.7±0.2°、10.6±0.2°、15.5±0.2°、16.2±0.2°、18.0±0.2°、19.7±0.2°、 20.9±0.2°、22.9±0.2°、24.2±0.2°、25.4±0.2°、26.1±0.2°、26.6±0.2°、 28.7±0.2° and 29.3 + -0.2 deg..
Further preferably, the X-ray powder diffraction pattern is substantially as shown in FIG. 4, the DSC pattern is substantially as shown in FIG. 4A, and the 1 HNMR pattern is substantially as shown in FIG. 4B.
Still more preferably, the DSC profile of form D has an endothermic peak at about 84℃and the 1 HNMR profile of form D shows a hemi-fumaric complex.
In another aspect, the present invention provides an innovative method of preparing a hemi-fumaric acid complex: according to the structural characteristics of Shan Fuma acid salt, introducing free base with the same mole as that of monofumarate, and reacting with exposed carboxyl groups on the monofumarate to prepare the hemi-fumarate. Based on this, the invention provides methods for the preparation of form a and form B.
The preparation method of the esomeprazole tenofovir hemifumarate compound crystal form A comprises the following steps:
① Mixing the esomeprazole tenofovir monofumarate and the esomeprazole tenofovir free base with a solvent at a certain temperature;
② Adding an antisolvent into the solution system to crystallize the solution system;
③ Stirring, filtering and collecting solids to obtain the crystalline form A of the esomeprazole tenofovir hemifumarate compound.
The temperature condition in the step ① is 55-70 ℃, preferably 60-65 ℃ and most preferably 65 ℃ in the preparation method of the esomeprazole tenofovir half-fumaric acid compound crystal form A; the molar ratio of the eimeric tenofovir monofumarate to the eimeric tenofovir free base is 1:1 to 1:3, preferably 1:1.1 to 1:2, most preferably 1:1.2 to 1:1.5; the mass volume ratio of the mixture of the eimeric tenofovir monofumarate and the eimeric tenofovir free base to the solvent is 1g to 2ml to 1g to 8ml, preferably 1g to 3ml to 1g to 6ml, and most preferably 1g to 4ml; the solvent is selected from one of cyclic ethers, preferably tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, most preferably tetrahydrofuran; the reaction time is 1 to 6 hours, preferably 2 to 5 hours, most preferably 2 to 3 hours.
The preparation method of the esomeprazole tenofovir hemifumarate compound crystal form A comprises the step ②, wherein the antisolvent is selected from fatty ether or alkane, preferably one of methyl tertiary butyl ether, isopropyl ether and n-heptane, and most preferably isopropyl ether; the amount of antisolvent used is 2 to 7 times, preferably 3 to 6 times, most preferably 4 to 5 times the amount of solvent used in step ①.
According to the preparation method of the esomeprazole tenofovir hemifumarate compound crystal form A, the stirring time in the step ③ is 5-24 hours, preferably 8-20 hours and most preferably 10-18 hours.
In another aspect, a method for preparing crystalline form B of an esomeprazole tenofovir hemifumarate complex comprises the steps of:
① Mixing the esomeprazole tenofovir monofumarate and the esomeprazole tenofovir free base with a solvent at a certain temperature;
② Adding an antisolvent into the solution system to crystallize the solution system;
③ Stirring, filtering and collecting solids to obtain the crystalline form B of the esomeprazole tenofovir hemifumarate compound.
The preparation method of the esomeprazole tenofovir hemifumarate compound crystal form B comprises the following steps that ① is carried out at a temperature of 0-50 ℃, preferably 10-40 ℃ and most preferably 20-30 ℃; the molar ratio of the eimeric tenofovir monofumarate to the eimeric tenofovir free base is 1:1 to 1:3, preferably 1:1.1 to 1:2, most preferably 1:1.2 to 1:1.5; the mass volume ratio of the mixture of the esomepiride monofumarate and the esomepiride free base to the solvent is 1g, 2ml to 1g, 8ml, preferably 1g, 3ml to 1g, 6ml, most preferably 1g, 4ml; the solvent is selected from cyclic ether, preferably tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, and most preferably tetrahydrofuran; the reaction time is 1 to 6 hours, preferably 2 to 5 hours, most preferably 2 to 3 hours.
The preparation method of the esomeprazole tenofovir hemifumarate compound crystal form B comprises the step ②, wherein the antisolvent is selected from fatty ether or alkane, preferably one of methyl tertiary butyl ether, isopropyl ether and n-heptane, and most preferably isopropyl ether; the amount of antisolvent used is 2 to 7 times, preferably 3 to 6 times, most preferably 4 to 5 times the amount of solvent used in step ①.
According to the preparation method of the esomeprazole tenofovir hemifumarate compound crystal form B, the stirring time in the step ③ is 5-24 hours, preferably 8-20 hours and most preferably 10-18 hours.
In another aspect, a method for preparing crystalline form C of an esomeprazole tenofovir hemifumarate complex comprises the steps of:
① Weighing the esomeprazole tenofovir free base and fumaric acid in a mortar according to a molar ratio of 2:1;
② Adding solvent into a mortar for wetting and grinding;
③ And collecting the solid to obtain the crystalline form C of the esomeprazole tenofovir hemifumarate complex.
According to the preparation method of the esomeprazole tenofovir half fumaric acid compound crystal form C, the mass volume ratio of a mixture of the esomeprazole tenofovir free base and fumaric acid to a solvent in the step ② is 1g:2 ml-1 g:8ml, preferably 1g:3 ml-1 g:6ml, and most preferably 1g:4 ml-1 g:5ml; step ② solvent is selected from the group consisting of fatty alcohols, preferably C 1～C3 alcohol solvents, most preferably ethanol.
On the other hand, the invention also provides a preparation method of the esomeprazole tenofovir hemi-fumaric acid compound crystal form D, which comprises the following steps:
① Weighing the esomeprazole tenofovir free base and fumaric acid in a mortar according to a molar ratio of 2:1;
② Adding solvent into a mortar for wetting and grinding;
③ And collecting the solid to obtain the crystalline form D of the esomeprazole tenofovir hemifumarate compound.
In accordance with the above-described steps,
In a preferred embodiment of the present invention, the mass to volume ratio of the mixture of esomeprazole tenofovir free base and fumaric acid to the solvent of step ② is 1g:2ml to 1g:8ml, preferably 1g:3ml to 1g:6ml, most preferably 1g:4 ml to 1g:5ml; step ② the solvent is selected from the group consisting of fatty alcohols, preferably C 4～C7, alcoholic solvents, most preferably n-hexanol.
In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective dose of a crystalline form of an esomeprazole tenofovir hemifumarate complex and one or more pharmaceutically acceptable carriers, diluents or excipients. Pharmaceutically acceptable carriers refer to: one or more compatible solid or liquid fill or gel materials which are suitable for human use and must be of sufficient purity and low enough toxicity. Wherein compatibility herein means that the components of the composition are capable of being mixed with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients; pharmaceutically acceptable carriers include cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, 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, emulsifying agents such as tween series, wetting agents such as sodium dodecyl sulfate, gelatin, talc, colorants, flavoring agents, stabilizers and the like.
The pharmaceutical composition may be a tablet or a capsule.
In another aspect, the present invention relates to the use of crystalline forms of the esomeprazole tenofovir hemifumarate complex, or a pharmaceutically acceptable composition thereof, in the manufacture of a medicament for the treatment of hepatitis, preferably chronic hepatitis b.
The crystalline form of the esomeprazole tenofovir hemifumarate has the characteristics of good solubility, small hygroscopicity and high bioavailability, is beneficial to the processing of medicines and the use of the same in a medicine composition, and the preparation method is simple, convenient and easy to implement and has good reproducibility.
Drawings
Figure 1 is an X-ray diffraction pattern of crystalline form a of the esomeprazole tenofovir hemifumarate complex.
Fig. 1A is a DSC profile of crystalline form a of the esomeprazole tenofovir hemifumarate complex.
Fig. 1B is a TGA profile of crystalline form a of the esomeprazole tenofovir hemifumarate complex.
Fig. 1C is a 1 HNMR profile of esomeprazole tenofovir hemifumarate complex form a.
Figure 2 is an X-ray diffraction pattern of crystalline form B of the esomeprazole tenofovir hemifumarate complex.
Fig. 2A is a DSC profile of crystalline form B of the esomeprazole tenofovir hemifumarate complex.
Fig. 2B is a TGA profile of crystalline form B of the esomeprazole tenofovir hemifumarate complex.
Fig. 2C is a 1 HNMR profile of esomeprazole tenofovir hemifumarate complex form B.
Figure 3 is an X-ray diffraction pattern of crystalline form C of the esomeprazole tenofovir hemifumarate complex.
Fig. 3A is a DSC profile of crystalline form C of the esomeprazole tenofovir hemifumarate complex.
Fig. 3B is a 1 HNMR profile of esomeprazole tenofovir hemifumarate complex form C.
Fig. 4 is an X-ray diffraction pattern of crystalline form D of the esomeprazole tenofovir hemifumarate complex.
Fig. 4A is a DSC profile of crystalline form D of the esomeprazole tenofovir hemifumarate complex.
Fig. 4B is a 1 HNMR profile of esomeprazole tenofovir hemifumarate complex form D.
Fig. 5 is a dynamic moisture adsorption profile of crystalline form a of the esomeprazole tenofovir hemifumarate complex.
Fig. 6 is a dissolution profile of crystalline form a of esomeprazole tenofovir monofumarate and esomeprazole tenofovir hemifumarate complex.
Detailed Description
The following describes in further detail the embodiments of the present invention with reference to the drawings and examples. The following examples are illustrative of the invention and are not intended to limit the scope of the invention.
Example 1: preparation of esomeprazole tenofovir hemifumarate compound crystal form A
3G of esomeprazole tenofovir monofumarate and 3g of esomeprazole tenofovir free base are weighed and mixed with 18mL of tetrahydrofuran, the system temperature is controlled to be 60 ℃, stirring is started, the system is clarified, stirring is carried out for 2h under the heat preservation condition, 54mL of isopropyl ether is added into the system under the heat preservation condition, stirring is carried out for 12h, filtering is carried out, and the product is dried by blowing at 45 ℃ for 2h, so that the crystal form A of the esomeprazole tenofovir semi-fumaric acid compound with the molar yield of 92% and the purity of 98.3% is obtained.
Example 2: preparation of esomeprazole tenofovir hemifumarate compound crystal form A
6G of esomeprazole tenofovir monofumarate and 6.5g of esomeprazole tenofovir free base are weighed and mixed with 50 mL g of 1, 4-dioxane, the system temperature is controlled to be 65 ℃, stirring is started, the system is clarified, stirring is kept at 3: 3h, 120mL of methyl tertiary butyl ether is added to the system under the condition of keeping the temperature, stirring is carried out for 16 hours, filtering is carried out, and the product is placed at 40 ℃ for forced air drying for 18 hours, so that the crystal form A of the esomepiride hemifumarate compound is obtained, the molar yield is 91%, and the purity is 98.4%.
Example 3: preparation of esomeprazole tenofovir hemifumarate compound crystal form A
1G of esomeprazole tenofovir monofumarate and 1.1g of esomeprazole tenofovir free base are weighed and mixed with 10 mL tetrahydrofuran, the system temperature is controlled to be 60 ℃, stirring is started, the system is clarified, the temperature is kept for 2.5h, 45mL of n-heptane is added to the system under the heat-preserving condition, stirring is carried out for 12h, filtering is carried out, and the product is placed at 45 ℃ for blast drying for 24h, so that the crystal form A of the esomeprazole tenofovir semi-fumaric acid compound is obtained, the molar yield is 90%, and the purity is 9.8%.
Example 4: preparation of esomeprazole tenofovir hemifumarate compound crystal form A
2G of esomeprazole tenofovir monofumarate and 2g of esomeprazole tenofovir free base are weighed and mixed with 12mL of 1, 4-dioxane, the system temperature is controlled to be 55 ℃, stirring is started, the system is clarified, stirring is carried out for 2h at a temperature which is equal to or higher than that of the system, 40mL of methyl tertiary butyl ether is added to the system under the heat-preserving condition, stirring is carried out for 10h, filtering is carried out, and the product is dried for 20h at 40 ℃ by blowing, so that the crystal form A of the esomeprazole tenofovir half fumaric acid compound is obtained, the molar yield is 91%, and the purity is 98.3%.
Example 5: preparation of esomeprazole tenofovir hemifumarate compound crystal form A
Weighing 4g of esomeprazole tenofovir monofumarate and 4.5g of esomeprazole tenofovir free base, mixing with 40 mL g of tetrahydrofuran, controlling the temperature of the system to be 62 ℃, starting stirring, clarifying the system, stirring for 4h at a constant temperature, adding 180mL of isopropyl ether into the system under a constant temperature condition, stirring for 14h, filtering, and drying the product at 45 ℃ by blowing for 18h to obtain the crystal form A of the esomeprazole tenofovir hemifumarate compound with the molar yield of 92% and the purity of 9.6%.
Example 6: preparation of esomeprazole tenofovir hemifumarate compound crystal form B
3G of esomeprazole tenofovir monofumarate and 3.2g of esomeprazole tenofovir free base are weighed and mixed with 20 mL tetrahydrofuran, the system temperature is controlled to be 25 ℃, stirring is started, the system is clarified, the temperature is kept and stirred for 2 hours, 70mL of isopropyl ether is added to the system under the condition of keeping the temperature, stirring is carried out for 14 hours, filtering is carried out, and the product is dried by blowing at 30 ℃ for 24 hours, so that the crystal form B of the esomeprazole tenofovir semi-fumaric acid compound is obtained, the molar yield is 91%, and the purity is 98.4%.
Example 7: preparation of esomeprazole tenofovir hemifumarate compound crystal form B
1.5G of esomeprazole tenofovir monofumarate and 1.7g of esomeprazole tenofovir free base are weighed and mixed with 15 mL of 1, 4-dioxane, the temperature of the system is controlled to be 30 ℃, stirring is started, the system is clarified, the system is stirred for 2h in a heat preservation manner, 45mL of n-heptane is added to the system under the heat preservation condition, stirring is carried out for 12h, filtering is carried out, and the product is dried for 20h at 30 ℃ in a blasting manner, so that the crystal form B of the esomeprazole tenofovir hemifumarate compound is obtained, the molar yield is 90%, and the purity is 98.7%.
Example 8: preparation of esomeprazole tenofovir hemifumarate compound crystal form C
1G of esomeprazole tenofovir disoproxil free base and 0.12g of fumaric acid are weighed in a mortar, 4mL of ethanol is added for wetting and grinding, and the esomeprazole tenofovir hemi-fumaric acid compound crystal form C is obtained.
Example 9: preparation of esomeprazole tenofovir hemifumarate compound crystal form C
2G of esomeprazole tenofovir free base and 0.24g of fumaric acid are weighed in a mortar, 5.5mL of isopropyl alcohol is added for wetting and grinding, and the esomeprazole tenofovir hemi-fumaric acid compound crystal form C is obtained.
Example 10: preparation of esomeprazole tenofovir hemifumarate compound crystal form D
0.5G of esomeprazole tenofovir free base and 0.06g of fumaric acid are weighed in a mortar, 2mL of n-hexylalcohol is added for wetting and grinding, and the esomeprazole tenofovir hemi-fumaric acid compound crystal form D is obtained.
Example 11: preparation of esomeprazole tenofovir hemifumarate compound crystal form D
2G of esomeprazole tenofovir free base and 0.24g of fumaric acid are weighed in a mortar, 4.5mL of n-butyl alcohol is added for wetting and grinding, and the esomeprazole tenofovir hemi-fumaric acid compound crystal form D is obtained.
Experimental example 12: structure confirmation of esomeprazole tenofovir hemifumarate complex
The structural formula of the esomeprazole tenofovir hemi-fumaric acid compound is shown as formula II:
(1) Hydrogen nuclear magnetic resonance spectroscopy (1 H-NMR): 10mg of the crystal form A is weighed and placed in a nuclear magnetic tube with 5mm, 500 mu L of deuterated dimethyl sulfoxide is used for dissolving and uniformly mixing, a Bruker AVANCE400MHz full-digital nuclear magnetic resonance spectrometer is used for detecting a sample, a hydrogen nuclear magnetic resonance spectrogram is shown in figure 1C, and related data are shown in the following table:
chemical shift (ppm) Multiple of Proton number Proton attribution Remarks
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 a set of single peaks at delta 6.64ppm, corresponding to 1 proton, each 1/2 proton attributed to the olefin at the 31/31' position, confirming a 2:1 molar ratio of esomeprazole tenofovir to fumaric acid in the crystals.
The hydrogen nuclear magnetic resonance spectrograms of the crystal form B, the crystal form C and the crystal form D are respectively shown in the figure 2C, the figure 3B and the figure 4B, and are consistent with the hydrogen nuclear magnetic resonance spectrograms of the crystal form A, so that the molar ratio of the esomepiridine tenofovir to the fumaric acid in the crystal is proved to be 2:1.
(2) Acid-base titration method for measuring fumaric acid content: 0.2g of form A, form B, form C and form D are weighed respectively, precisely weighed and dissolved by adding 40mL of methanol. Potentiometric titration (rule 0701 in the fourth edition of China pharmacopoeia 2015) was used, titration was performed with sodium hydroxide titration solution (0.1 mol/L), and the titration result was corrected by blank test. The titrant of sodium hydroxide (0.1 mol/L) per 1ml corresponds to 5.80mg of C 4H4O4, the 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 esomeprazole tenofovir half-fumaric acid compound is 10.6%, the actual detection result of the content of 4 crystal forms of fumaric acid is basically consistent with the theoretical value, and the mol ratio of the esomeprazole tenofovir to the fumaric acid in the crystal is 2:1.
Experimental example 13: solubility of
The solubility of the crystalline form a of the idefenamide tenofovir disoproxil monofumarate and the idefenamide tenofovir hemifumarate complex were measured separately with reference to the solubility measurement method provided in pharmacopoeia of the people's republic of 2020 edition, and the results are shown in the following table:
Sample type Amount of water required to dissolve 1g of solute Solubility of
Eimerosamine tenofovir monofumarate 52mL Slightly soluble
Eimerosamine tenofovir hemifumarate complex crystal form A 24mL Dissolving
The result shows that the solubility of the crystal form A of the esomeprazole tenofovir hemifumarate compound is better than that of the esomeprazole tenofovir monofumarate, so that the compound has better bioavailability.
Experimental example 14: moisture permeability
The moisture absorption and weight gain of the crystalline form a of the eimeria tenofovir Wei Ban fumaric acid compound under different humidity conditions were examined by a dynamic moisture absorber (DVS INTRINSIC), and the results are shown in fig. 5.
The results show that the crystalline form a of the esomeprazole tenofovir hemifumarate complex has less hygroscopicity and is a desirable feature for pharmaceutical formulations.
Experimental example 15: interconversion relationship of forms A and B
(1) Phase change of solvent medium
Research shows that under the condition that no crystal seed is additionally 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 which are mixed with equal quality in a crystallization mother liquor system consisting of tetrahydrofuran/isopropyl ether is inspected, and the result is shown in the following table:
Raw material type Crystallization mother liquor system Temperature (temperature) Crystal form
Crystal form A/B (250 mg/250 mg) THF/IPE(5mL/15mL) 25℃ Crystal form B
Crystal form A/B (250 mg/250 mg) THF/IPE(5mL/15mL) 45℃ Crystal form A/B
Crystal form A/B (250 mg/250 mg) THF/IPE(5mL/15mL) 55℃ Crystal form A/B
Crystal form A/B (250 mg/250 mg) THF/IPE(5mL/15mL) 75℃ Crystal form A
The result shows that the crystal form B is a dominant crystal form at low temperature in the crystallization system, and the high Wen Xiajing type A is a dominant crystal form.
(2) Solid phase transition
The crystal form transformation conditions of the equal-mass mixed crystal forms A and B under the condition of different temperature blast drying are examined, and the results are shown in the following table:
Raw material type Drying temperature Crystal form
Crystal form A/B (250 mg/250 mg) 30℃ Crystal form A/B
Crystal form A/B (250 mg/250 mg) 40℃ Crystal form A/B
Crystal form A/B (250 mg/250 mg) 50℃ Crystal form A/B
Crystal form A/B (250 mg/250 mg) 60℃ Crystal form A
The results show that the crystal form B can be converted into the crystal form A under the high-temperature condition.
Experimental example 16: dissolution rate
Raw and auxiliary materials Prescription weight percentage
Active ingredient 24.1％
Lactose and lactose 30.6％
Carboxymethylcellulose calcium 25.4％
Talc powder 17.4％
Glyceryl behenate 2.5％
Taking into account the dissolution rates of the crystalline form a of the eimeric tenofovir monofumarate and the crystalline form a of the eimeric tenofovir hemifumarate in the powder direct compression formulation, mixing the raw materials and the auxiliary materials in an equal-increment manner according to the formulation shown in the table above, tabletting with a DP301 single-punch tablet press to 25mg, and taking into account the dissolution rates of the obtained tablets in a dissolution medium (ph=4.5 acetate buffer), the results of which are shown in fig. 6.
The result shows that the dissolution rate of the preparation product taking the crystalline form A of the esomeprazole tenofovir hemifumarate compound as an active ingredient is better than that of the tenofovir monofumarate.

Claims (13)

1. A crystal form A of an esomeprazole tenofovir hemifumarate compound shown in a formula (I) is characterized in that,
The X-ray powder diffraction pattern of the crystal form A has diffraction peaks at the angles of 5.1+/-0.2 DEG, 7.7+/-0.2 DEG, 13.0+/-0.2 DEG, 15.4+/-0.2 DEG, 20.9+/-0.2 DEG and 22.1+/-0.2 DEG of 2 theta.
2. Form a of the eimeril amine tenofovir hemifumarate complex according to claim 1, further comprising an X-ray powder diffraction pattern of form a at least one of 25.0 ± 0.2 ° or 10.2 ± 0.2 ° in 2Θ.
3. Form a of the eimeria tenofovir hemifumarate complex according to claim 2, wherein the X-ray powder diffraction pattern of form a optionally further comprises diffraction peaks at any 2, 3, 4,5,6,7 of 2Θ 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°.
4. A crystalline form a of an eimeria tenofovir hemifumarate complex of formula (I), characterized in that the X-ray powder diffraction pattern of form a has diffraction peaks at optionally 6, 8 or 10 of degrees 2Θ 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 °.
5. Form a of the esomeprazole tenofovir hemifumarate complex according to claim 4, characterized in that the X-ray powder diffraction pattern of form a comprises in 2Θ:
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°.
6. form a of the esomeprazole tenofovir hemifumarate complex according to claim 1, characterized by an X-ray powder diffraction pattern substantially as shown in figure 1.
7. Crystalline form a of the eimeric tenofovir hemi-fumaric acid complex according to any of claims 1-6, prepared by a process comprising the steps of:
① Mixing the esomeprazole tenofovir monofumarate and the esomeprazole tenofovir free base with a solvent at a certain temperature;
② Adding an antisolvent into the solution system to crystallize the solution system;
③ Stirring, filtering and collecting solids to obtain the crystalline form A of the esomeprazole tenofovir hemifumarate compound.
8. The process for the preparation of crystalline form a of esomeprazole tenofovir hemifumarate complex according to claim 7, characterized in that:
The temperature condition of the step ① is 55-70 ℃;
The molar ratio of the eimeric tenofovir monofumarate to the eimeric tenofovir free base is 1:1-1:3; the mass volume ratio of the mixture of the eimeric tenofovir monofumarate and the eimeric tenofovir free base to the solvent is 1g:2 ml-1 g:8ml;
The solvent is selected from cyclic ethers; the reaction time is 1-6 h;
Step ② the antisolvent is selected from a fatty ether or an alkane; the dosage of the antisolvent is 2-7 times of that of the solvent in the step ①;
and ③, stirring for 5-24 hours.
9. The process for the preparation of crystalline form a of esomeprazole tenofovir hemifumarate complex according to claim 7, characterized in that:
The temperature condition of the step ① is 60-65 ℃;
the molar ratio of the eimeric tenofovir monofumarate to the eimeric tenofovir free base is 1:1.1-1:2;
the mass volume ratio of the mixture of the eimeric tenofovir monofumarate and the eimeric tenofovir free base to the solvent is 1g:3 ml-1 g:6ml;
The solvent is selected from one of tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane;
The reaction time is 2-5 h;
Step ②, selecting an antisolvent from one of methyl tertiary butyl ether, isopropyl ether and n-heptane; the dosage of the antisolvent is 3-6 times of that of the solvent in the step ①;
And ③, stirring for 8-20 hours.
10. The process for the preparation of crystalline form a of esomeprazole tenofovir hemifumarate complex according to claim 7, characterized in that:
the temperature condition of the step ① is 65 ℃;
the molar ratio of the eimeric tenofovir monofumarate to the eimeric tenofovir free base is 1:1.2-1:1.5; the mass volume ratio of the mixture of the eimeric tenofovir monofumarate and the eimeric tenofovir free base to the solvent is 1g to 4ml;
the solvent is tetrahydrofuran; the reaction time is 2-3 h;
step ②, wherein the antisolvent is isopropyl ether; the dosage of the antisolvent is 4-5 times of that of the solvent in the step ①;
And ③, stirring for 10-18 hours.
11. A pharmaceutical composition comprising a therapeutically effective amount of crystalline form a of the eimeric tenofovir hemi-fumarate complex of any one of claims 1-6, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
12. Use of crystalline form a of the eimeril tenofovir hemi-fumarate complex according to any one of claims 1-6 or the pharmaceutical composition of claim 11 in the manufacture of a medicament for the treatment of hepatitis-related disorders.
13. Form a of the eimeric tenofovir hemifumarate complex according to any one of claims 1-6, or the use according to claim 12, wherein the hepatitis is chronic hepatitis b.
CN202110648580.5A 2021-06-10 2021-06-10 Eimerosamine tenofovir hemi-fumaric acid compound, crystal form, preparation method and application thereof Active CN113501846B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110648580.5A CN113501846B (en) 2021-06-10 2021-06-10 Eimerosamine tenofovir hemi-fumaric acid compound, crystal form, preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110648580.5A CN113501846B (en) 2021-06-10 2021-06-10 Eimerosamine tenofovir hemi-fumaric acid compound, crystal form, preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN113501846A CN113501846A (en) 2021-10-15
CN113501846B true CN113501846B (en) 2024-06-25

Family

ID=78010282

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110648580.5A Active CN113501846B (en) 2021-06-10 2021-06-10 Eimerosamine tenofovir hemi-fumaric acid compound, crystal form, preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN113501846B (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101778855A (en) * 2007-05-22 2010-07-14 阿尔迪默菲克斯技术有限责任公司 Tenofovir disoproxil hemi-fumaric acid co-crystal
CN103665043A (en) * 2012-08-30 2014-03-26 上海源力生物技术有限公司 Tenofovir prodrug and medical application thereof

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104045667A (en) * 2013-03-14 2014-09-17 上海卫思化学科技有限公司 Preparation method of tenofovir disoproxil fumarate hemifumarate
CN104558035B (en) * 2013-10-22 2017-12-19 连云港恒运药业有限公司 A kind of purification process of tenofovir prodrug
WO2017037608A1 (en) * 2015-08-28 2017-03-09 Laurus Labs Private Limited Solid forms of tenofovir alafenamide and salts thereof, processes for its preparation and pharmaceutical compositions thereof
CN106699812A (en) * 2015-11-12 2017-05-24 江苏豪森药业集团有限公司 Method for preparation and purification of tenofovir prodrug
WO2017203395A1 (en) * 2016-05-21 2017-11-30 Shilpa Medicare Limited Crystalline forms of tenofovir alafenamide hemi fumarate
CN111096954B (en) * 2018-10-29 2022-09-16 江苏豪森药业集团有限公司 A pharmaceutical composition for resisting viral infection and its preparation method

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101778855A (en) * 2007-05-22 2010-07-14 阿尔迪默菲克斯技术有限责任公司 Tenofovir disoproxil hemi-fumaric acid co-crystal
CN103665043A (en) * 2012-08-30 2014-03-26 上海源力生物技术有限公司 Tenofovir prodrug and medical application thereof

Also Published As

Publication number Publication date
CN113501846A (en) 2021-10-15

Similar Documents

Publication Publication Date Title
KR100661153B1 (en) Nucleotide analog composition and synthesis method
CN106414466B (en) Tenofovir Chinese mugwort draws phenol amine compound and its preparation method and application
JP4452034B2 (en) Process for preparing adefovir dipivoxil
CN105646584B (en) Tenofovir Chinese mugwort draws phenol amine fumarate crystal form and its preparation method and application
JP2010527996A (en) Tenofovir disoproxil-hemifumarate co-crystal
CN112142679B (en) Gefitinib and vanilloid eutectic methanol solvate and preparation method thereof
WO2011095059A1 (en) Polymorphs of dasatinib, preparation methods and pharmaceutical compositions thereof
CN111406056B (en) Crystalline 2-amino-2- (hydroxymethyl) propane-1, 3-diol salts of selective ACC inhibitors
CN113501846B (en) Eimerosamine tenofovir hemi-fumaric acid compound, crystal form, preparation method and application thereof
TWI718990B (en) A novel polymorphic form of tenofovir prodrug and its preparation as well as the use thereof
US20050182066A1 (en) Methods for the production of sildenafil base and citrate salt
CN101993417A (en) Stable novel crystal form of dimemorfan phosphate
CN106316964B (en) The polymorph of phenyl amino pyrimidine compounds or its salt
CN110128359B (en) Crystal of uric acid transporter 1 inhibitor and preparation method and application thereof
CN108948084B (en) Tenofovir di-L-amino acid ester and preparation method thereof
CA2954491C (en) Novel salt of tenofovir disoproxil
CN104844604A (en) Preparation method of high purity allopurinol sodium
CN116903658A (en) Nitrogen-containing fused heterocyclic compound crystal form, and preparation method and application thereof
CN113072583A (en) Crystal of tenofovir alafenamide hemifumarate and preparation method thereof
JP5589097B2 (en) Dasatinib polycrystal, preparation method thereof and drug composition
CN117510543A (en) Ai Miti Norafuro Wei Malai acid salt crystal form and preparation method and application thereof
CN110938001A (en) Chlorogenic acid ethanolamine salt and application thereof
CN1900078A (en) Entecavir potassium salt compound and its preparing method and medicine use
CN106316963A (en) Polymorphic substances of morpholinophenylaminopyrimidine compound or salts thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant