CN102153588A - Adefovir pharmaceutical co-crystal and preparation method thereof - Google Patents
Adefovir pharmaceutical co-crystal and preparation method thereof Download PDFInfo
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- CN102153588A CN102153588A CN2011100483037A CN201110048303A CN102153588A CN 102153588 A CN102153588 A CN 102153588A CN 2011100483037 A CN2011100483037 A CN 2011100483037A CN 201110048303 A CN201110048303 A CN 201110048303A CN 102153588 A CN102153588 A CN 102153588A
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- adefovir
- medicine
- crystal
- pharmaceutical
- eutectic
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- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 229960001997 adefovir Drugs 0.000 title claims abstract description 38
- 239000013078 crystal Substances 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 230000004323 axial length Effects 0.000 claims abstract description 4
- 238000001228 spectrum Methods 0.000 claims abstract description 3
- 239000003814 drug Substances 0.000 claims description 47
- 230000005496 eutectics Effects 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000011521 glass Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000006850 spacer group Chemical group 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000003760 magnetic stirring Methods 0.000 claims description 2
- 230000000630 rising effect Effects 0.000 claims description 2
- 238000002441 X-ray diffraction Methods 0.000 abstract description 4
- 239000008186 active pharmaceutical agent Substances 0.000 abstract 1
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 abstract 1
- 208000006454 hepatitis Diseases 0.000 abstract 1
- 231100000283 hepatitis Toxicity 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 239000000470 constituent Substances 0.000 description 4
- 208000002672 hepatitis B Diseases 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- MELHEUHXJKQZNC-UHFFFAOYSA-N 2-(6-aminopurin-9-yl)ethoxymethyl-[hydroxy(phosphonooxy)phosphoryl]oxyphosphinic acid Chemical compound NC1=NC=NC2=C1N=CN2CCOCP(O)(=O)OP(O)(=O)OP(O)(O)=O MELHEUHXJKQZNC-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- -1 adefovir ester Chemical class 0.000 description 2
- 230000001447 compensatory effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000003908 liver function Effects 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000001338 self-assembly Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 1
- 229950006790 adenosine phosphate Drugs 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- SUYVUBYJARFZHO-RRKCRQDMSA-N dATP Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-RRKCRQDMSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000004001 molecular interaction Effects 0.000 description 1
- 238000005232 molecular self-assembly Methods 0.000 description 1
- 239000006225 natural substrate Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical co-crystals, and particularly relates to a novel Adefovir pharmaceutical co-crystal and a preparation method thereof. An Adefovir molecule and a 2,6-dipicolinic acid molecule are bonded by a hydrogen bond to form a basic structural unit of the Adefovir pharmaceutical co-crystal. The space group of the Adefovir pharmaceutical co-crystal is a triclinic system, and the Adefovir pharmaceutical co-crystal has the following cell parameters: axial lengths: a=7.03-7.53, b=11.85-12.38, and c=11.99-12.49; and axial angles: alpha=76.35-76.85, beta=76.50-77.00, and gamma=77.16-77.66. The XRD (X-ray diffraction) spectrum characteristic peak appears at 12.00-12.50 degrees, 13.17-13.67 degrees, 13.98-14.48 degrees, 15.96-16.46 degrees, 17.72-18.22 degrees, 23.58-24.08 degrees and 25.46-25.96 degrees. The pharmaceutical co-crystal provided by the invention not only has the characteristics of the traditional active pharmaceutical ingredient in treating hepatitis b, but also obviously improves the solubility, stability and bioavailability.
Description
Technical field
The invention belongs to medicine eutectic technical field, be specifically related to the preparation method of a kind of novel Adefovir medicine eutectic and this medicine eutectic.
Background technology
1894, German E.Fischer proposed " lock-key " model based on the thought of " intermolecular selectivity effect ", promptly is the blank of modern supramolecule scientific theory.Nineteen thirty-seven, Germany K.L.Wolf etc. has created " supramolecule " speech, and the entity of the high-sequential that forms in order to describe molecular association is on universal significance, all there is interaction in the set of any molecule, so people usually are called " supramolecule " with this layer of structure of material aggregation attitude.Up to 1978, the J.M.Lehn professor of France just finally proposed the complete concept of " supramolecular chemistry " based on traditional Subjective and Objective architectural study that is planted in the organic chemistry.Supramolecular chemistry be the research molecular interaction conclude and form complicated in order and have a science of the molecule aggregates of ad hoc structure and function, it is " chemistry that surmounts the branch subcategory " and this molecule aggregates is called for short supramolecule.So the basis of supramolecular chemistry is intermolecular non-covalent interaction, by studying the science of the ergasia that a plurality of intermolecular non-covalent interactions not of the same race form.The strong bonding force that supramolecular chemistry has following notable feature: a. formation super molecular compound is weak interaction force stack and collaborative result between differing molecular, is the general performance of multiple reactive force; B. the super molecular compound that forms of differing molecular self-assembly demonstrates and the diverse new function of former self assembly molecule.And molecular recognition of being undertaken by the synergy of intermolecular weak interaction and supramolecule self-assembly are the cores of supramolecular chemistry research.Crystal engineering is applied to crystalline design and growth with the principle and the method for supramolecular chemistry, by the acting in conjunction of molecular recognition and self assembling process, obtains the Adjustable structure control, has the new crystal of specific physico-chemical property.
The approach of the Design Theory medicine eutectic of utilization crystal engineering is feasible, utilizes the principle of crystal engineering to be connected to form new crystal by active constituents of medicine and other eutectic precursor by hydrogen bond.Active constituents of medicine (API) so that crystalline form exists is confined to salt, polymorph and solvate (comprising hydrate) traditionally always.On intellecture property and bioavailability, API itself has very high utility value, and wherein structure and moiety are most important component.Britain Camb structural database (CSD) is the main source about the structure of matter microscopic information of molecular designing and material design.
Research of medicine crystal formation and the solid-state pharmacy industry that is characterized in of medicine have very important meaning.On the one hand, the same medicine of different crystal forms may there were significant differences aspect biochemical properties such as stability, solubleness and bioavailability, thereby influence the curative effect of medicine.If there is well assessment to select best medicine crystal formation to research and develop, may produces the variation of crystal formation in the clinical later stage, thereby cause the extension of medicine listing and produce enormous economic loss.
For imitation medicine company; thereby new crystal how to develop medicine can be broken the patent protection of original medicine company to crystal formation; ahead of time imitation medicine being introduced to the market, is vital problem in recent years, will directly have influence on imitation medicine and bulk drug company's market and international competitiveness.It has been comparative maturity and dark valued field that medicine crystal formation research and medicine solid-state is characterized in American-European pharmaceutical industry, but pharmaceutical industry still belongs to the starting stage at home.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of Adefovir medicine eutectic and this medicine eutectic thereof.
The selected bulk drug Adefovir of the present invention selects 2 for use as eutectic active constituents of medicine (API), and dipicolimic acid 2 is the eutectic presoma, thereby prepares the medicine eutectic of novel texture.
The mixed solvent that the selected solvent of the present invention is formed for the second alcohol and water, ethanol is lower as common nonpoisonous organic solvent and boiling point, and is more suitable for the room temperature diffusion process, and water is very clean resource.The preparation method who adopts is a backflow-room temperature dispensing volatile method, since Adefovir the second alcohol and water among both solvability do not include, carry out afterwards the room temperature dispensing volatile again so adopting earlier refluxes, after refluxing, filtering, promptly have crystal structure to come out in the process of solvent evaporates.
The active constituents of medicine of using among the present invention (API) is an Adefovir, and chemical name is: 9-[2-(phosphono methoxyl group) ethyl] VITAMIN B4, molecular formula is: C
8H
12N
5O
4P, its structural formula is shown in a formula.
The eutectic precursor of using among the present invention (cocrystal former) is 2, dipicolimic acid 2, and molecular formula is: C7H5NO4, its structural formula is shown in the b formula.
Adefovir medicine eutectic of the present invention, it is characterized in that: Adefovir molecule and one 2, the dipicolimic acid 2 molecule forms the basic structural unit of Adefovir medicine eutectic together by hydrogen bonded, wherein the two key oxygen on the phosphoric acid are as hydrogen-bond donor, 2 in the Adefovir structure, and the H in the dipicolimic acid 2 structure on the carboxylic acid is as hydrogen bond receptor; The spacer of Adefovir medicine eutectic is a triclinic(crystalline)system, its axial length a=7.03～7.53, b=11.85～12.38, c=11.99～12.49, shaft angle α=76.35～76.85, β=76.50～77.00, γ=77.16～77.66; Its XRD spectrum signature peak value appears at 12.00 °～12.50 °, and 13.17 °～13.67 °, 13.98 °～14.48 °, 15.96 °～16.46 °, 17.72 °～18.22 °, 23.58 °～24.08 °, 25.46 °～25.96 °.
The preparation method of Adefovir medicine eutectic of the present invention, its step is as follows:
(1) with Adefovir and 2, dipicolimic acid 2 placed round-bottomed flask in 1: 1 by volume～1.5: 1 in the lump by mass ratio 1: 1～3: 1, mixed solvent second alcohol and water, and the ratio of solute and solution is 10～20mg/ml in the system;
(2) at the round-bottomed flask reflux of having put on the shelf, the temperature to 90 of rising reaction system～95 ℃, reaction system begins to reflux, and opens water of condensation then and opens magnetic stirring apparatus simultaneously, stirs reaction 2～4h down;
(3) stir stop after with reacting liquid filtering, place the transparent glass bottle after room temperature environment is placed 20～50 hours down, to have crystal to generate filtrate after leaching insolubles, be described Adefovir medicine eutectic.
The instrument of detection of drugs eutectic structure and performance is as follows among the present invention:
1, eutectic structure is measured by Brooker Apex II CCD X-ray single crystal diffractometer, full name BrukerSMART-APEX CCD Diffractometer,
2, X-Ray DIFFRACTOMETER day island proper Tianjin company produces, and model is XRD-6000,
Tube voltage 40kV, tube current 30mA, 8 °/min of sweep velocity.
Adefovir is a kind of acyclic nucleotide analogue of single adenosine phosphate, and being phosphorylated to activated meta-bolites under the effect of cell kinase is the Adefovir diphosphate.The Adefovir diphosphate suppresses HBV DNA polymerase (reversed transcriptive enzyme) by following dual mode; The one, with the competition of natural substrate deoxyadenosine triphosphate, the 2nd, cause that the DNA chain extension stops after being incorporated into viral DNA.In addition, obtained China SFDA approval as the adefovir ester (Adefovir) of Adefovir oral preparations and be used for the treatment of chronic hepatitis B, its indication is the compensatory adult chronic hepatitis B patient of liver function.Adefovir ester is applicable to that treatment hepatitis B virus active replication and serum amino acid transferring enzyme continue the compensatory adult chronic hepatitis B patient of liver function that raises, and is particularly suitable for needing long-term prescription or lamivudine resistance thes take place the person.
The medicine eutectic of the present invention's preparation all has had tangible change having inherited the traditional raw material medicine outside the characteristic of treatment hepatitis B on its solvability, stability and bioavailability!
Description of drawings
The basic structural unit synoptic diagram of the medicine eutectic of Fig. 1: embodiment 1 preparation; Adefovir molecule and one 2, the dipicolimic acid 2 molecule forms the basic structural unit of Adefovir medicine eutectic together by hydrogen bonded, wherein the two key oxygen on the phosphoric acid are as hydrogen-bond donor, 2 in the Adefovir structure, and the H in the dipicolimic acid 2 structure on the carboxylic acid is as hydrogen bond receptor; This medicine eutectic spacer is a triclinic(crystalline)system, and its unit cell parameters is as follows: axial length a=7.03, b=11.85, c=11.99, shaft angle α=76.35, β=76.50, γ=77.16.
The XRD spectra of the medicine eutectic of Fig. 2: embodiment 1 preparation is with also consistent by the XRD of Materials Studio software simulation according to the crystal information data, the series of features peak appears at 12.13 °, 13.28 °, 13.46 °, 16.32 °, 18.20 °, 23.74 °, 25.50 °, this goes out the peak position and promptly is different from the bulk drug Adefovir and also is different from eutectic presoma 2, the XRD spectra of dipicolimic acid 2.
Embodiment
Embodiment 1:
Use Adefovir and 2, dipicolimic acid 2 is synthesized eutectic:
Weighing:
Reactant is pressed Adefovir: 2, and the mass ratio of dipicolimic acid 2=3: 2 feeds intake.Accurately take by weighing the 30.0mg Adefovir with analytical balance, 2 of 20.0mg, dipicolimic acid 2 is in round-bottomed flask;
The dissolving of bulk drug:
Accurately measure 2ml CH respectively with the 5ml transfer pipet
3CH
2OH and 2ml H
2O puts into the magnetic stir bar of 1cm size then in round-bottomed flask, the good reflux of frame, and with reaction system elevated temperature to 90 ℃, stirring and refluxing 3h.
Backflow-solvent room temperature hot the method for volatilizing:
Take out stirrer behind the backflow 3h, filter, filtrate is placed under the transparent glass bottle room temperature place.Slowly volatilize by the solvent room temperature afterwards, promptly have transparent tabular crystal to generate behind the 30h, be described Adefovir medicine eutectic.
Claims (2)
1. Adefovir medicine eutectic, it is characterized in that: Adefovir molecule and one 2, the dipicolimic acid 2 molecule forms the basic structural unit of Adefovir medicine eutectic together by hydrogen bonded, wherein the two key oxygen on the phosphoric acid are as hydrogen-bond donor, 2 in the Adefovir structure, and the H in the dipicolimic acid 2 structure on the carboxylic acid is as hydrogen bond receptor; The spacer of Adefovir medicine eutectic is a triclinic(crystalline)system, its unit cell parameters: axial length a=7.03～7.53, b=11.85～12.38, c=11.99～12.49, shaft angle α=76.35～76.85, β=76.50～77.00, γ=77.16～77.66; Its XRD spectrum signature peak value appears at 12.00 °～12.50 °, and 13.17 °～13.67 °, 13.98 °～14.48 °, 15.96 °～16.46 °, 17.72 °～18.22 °, 23.58 °～24.08 °, 25.46 °～25.96 °.
2. the preparation method of the described Adefovir medicine of claim 1 eutectic, its step is as follows:
(1) with Adefovir and 2, dipicolimic acid 2 placed round-bottomed flask in 1: 1 by volume～1.5: 1 in the lump by mass ratio 1: 1～3: 1, mixed solvent second alcohol and water, and the ratio of solute and solution is 10～20mg/ml in the system;
(2) at the round-bottomed flask reflux of having put on the shelf, the temperature to 90 of rising reaction system～95 ℃, reaction system begins to reflux, and opens water of condensation then and opens magnetic stirring apparatus simultaneously, stirs reaction 2～4h down;
(3) stir stop after with reacting liquid filtering, place the transparent glass bottle after room temperature environment is placed 20～50 hours down, to have crystal to generate filtrate after leaching insolubles, be described Adefovir medicine eutectic.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110048303 CN102153588B (en) | 2011-03-01 | 2011-03-01 | Adefovir pharmaceutical co-crystal and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110048303 CN102153588B (en) | 2011-03-01 | 2011-03-01 | Adefovir pharmaceutical co-crystal and preparation method thereof |
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| Publication Number | Publication Date |
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| CN102153588A true CN102153588A (en) | 2011-08-17 |
| CN102153588B CN102153588B (en) | 2013-03-06 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584818A (en) * | 2012-01-11 | 2012-07-18 | 吉林三善恩科技开发有限公司 | Novel paliperidone medicinal eutectic and preparation method thereof |
| CN102702266A (en) * | 2012-06-14 | 2012-10-03 | 中国药科大学 | Eutectic of adefovir dipivoxil and acetaminophen |
| CN102964384A (en) * | 2012-11-09 | 2013-03-13 | 中山大学 | Adefovir dipivoxil gallic acid eutectic, and preparation method and composition thereof |
| CN103864849A (en) * | 2014-03-20 | 2014-06-18 | 吉林大学珠海学院 | Adefovir drug cocrystal with para-aminobenzoic acid as former and preparation method thereof |
| CN105541701A (en) * | 2015-12-11 | 2016-05-04 | 吉林大学珠海学院 | Pharmaceutical cocrystal of deferiprone with maleic acid as precursor, and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1524865A (en) * | 2003-04-17 | 2004-09-01 | 北京德众万全药物技术开发有限公司 | Crystalline forms of adefovir dipivoxil ester |
| CN101020693A (en) * | 2007-02-05 | 2007-08-22 | 安徽师范大学 | Prepn process of Adefovir |
-
2011
- 2011-03-01 CN CN 201110048303 patent/CN102153588B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1524865A (en) * | 2003-04-17 | 2004-09-01 | 北京德众万全药物技术开发有限公司 | Crystalline forms of adefovir dipivoxil ester |
| CN101020693A (en) * | 2007-02-05 | 2007-08-22 | 安徽师范大学 | Prepn process of Adefovir |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584818A (en) * | 2012-01-11 | 2012-07-18 | 吉林三善恩科技开发有限公司 | Novel paliperidone medicinal eutectic and preparation method thereof |
| CN102702266A (en) * | 2012-06-14 | 2012-10-03 | 中国药科大学 | Eutectic of adefovir dipivoxil and acetaminophen |
| CN102702266B (en) * | 2012-06-14 | 2015-07-22 | 中国药科大学 | Eutectic of adefovir dipivoxil and acetaminophen |
| CN102964384A (en) * | 2012-11-09 | 2013-03-13 | 中山大学 | Adefovir dipivoxil gallic acid eutectic, and preparation method and composition thereof |
| CN102964384B (en) * | 2012-11-09 | 2015-06-24 | 中山大学 | Adefovir dipivoxil gallic acid eutectic, and preparation method and composition thereof |
| CN103864849A (en) * | 2014-03-20 | 2014-06-18 | 吉林大学珠海学院 | Adefovir drug cocrystal with para-aminobenzoic acid as former and preparation method thereof |
| CN103864849B (en) * | 2014-03-20 | 2016-01-20 | 吉林大学珠海学院 | Take para-amino benzoic acid as adefovir pharmaceutical co-crystal of presoma and preparation method thereof |
| CN105541701A (en) * | 2015-12-11 | 2016-05-04 | 吉林大学珠海学院 | Pharmaceutical cocrystal of deferiprone with maleic acid as precursor, and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN102153588B (en) | 2013-03-06 |
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