CN107226826A - Tenofovir Chinese mugwort draws phenol amine fumarate compound and its pharmaceutical composition - Google Patents
Tenofovir Chinese mugwort draws phenol amine fumarate compound and its pharmaceutical composition Download PDFInfo
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- CN107226826A CN107226826A CN201610179972.0A CN201610179972A CN107226826A CN 107226826 A CN107226826 A CN 107226826A CN 201610179972 A CN201610179972 A CN 201610179972A CN 107226826 A CN107226826 A CN 107226826A
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- chinese mugwort
- phenol amine
- amine fumarate
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- 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 System
- 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
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- 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
Abstract
The invention provides a variety of crystal formations that tenofovir Chinese mugwort draws phenol amine fumarate compound, including crystal formation I, II, III, IV and V, wherein crystal formation I, II and V has preferable stability, especially crystal formation I stability preferably, is especially suitable for preparation of preparation.The X ray powder diffractions that the crystal formation I is represented using Cu K α radiations with 2 θ angles are about 6.724 ± 0.2, have characteristic peak at 8.347 ± 0.2,10.785 ± 0.2,16.068 ± 0.2,17.446 ± 0.2,18.150 ± 0.2,20.028 ± 0.2,20.606 ± 0.2 degree.The present invention also provides the preparation method of above-mentioned crystal formation, simple to operate, is adapted to industrialized production and application.
Description
Technical field
The invention belongs to field of medicaments, and in particular to tenofovir Chinese mugwort draws novel crystal forms and its preparation side of phenol amine fumarate
Method, and the pharmaceutical composition containing tenofovir Chinese mugwort drawing phenol amine fumarate compound.
Background technology
Tenofovir Chinese mugwort draws phenol amine (tenofovir alafenamide, structural formula is as follows), chemical entitled 9-
[(R) -2- [[(S) -1- (isopropoxy carbonyl) ethyl] amino-benzene oxygen phosphinyl] methoxyl group] propyl group] adenine], it is by U.S.
A kind of novel nucleoside acids RTI of Gilead Sciences companies of state research and development.In U.S.'s listing, use within 2015
In treatment adult's HIV.The medicine also be used to treat hepatitis B, be currently in the III phases clinical.Rapid transformation after this product is oral
Into tenofovir, tenofovir diphosphate is phosphorylated in the presence of cell kinase, by competitively being taken off with natural
Oxygen ribose substrate, which is combined suppression varial polymerases and is inserted into after viral DNA, causes DNA extension termination, so as to suppress HIV
With HBV activity.
CN1291994C discloses tenofovir Chinese mugwort and draws the preparation method of phenol amine fumarate, but does not disclose any correlation
Crystal formation and data.CN103732594A discloses tenofovir Chinese mugwort and draws phenol amine hemifumarate and its crystal form.
CN104558036A discloses a kind of crystal form that tenofovir Chinese mugwort draws phenol amine hemifumarate.
Do not ended at present for tenofovir still and draw crystal formation and the correlative study of stability of phenol amine fumarate.Due to changing
The different crystal forms of compound can have difference in terms of stability, physical property, directly influence the steady of bulk drug and preparation
Qualitative and bioavilability, therefore crystal formation of the exploitation with stability and applicability is significant.
The content of the invention
It is an object of the invention to provide the crystal formation that the Chinese mugwort of the tenofovir shown in a kind of formula (I) draws the anti-fumarate of phenol amine,
The crystal formation has good stability, meets medicinal requirements, and preparation method is simple, is adapted to industrialized production.
To achieve these goals, the present invention provides following technical scheme：
The present invention provides a kind of tenofovir Chinese mugwort as shown in formula (I) and draws phenol amine fumarate compound, it is characterised in that
The tenofovir Chinese mugwort draws phenol amine fumarate compound to be I type crystal forms, and it is radiated using Cu-K α, is represented with 2 θ angles
X-ray powder diffraction collection about 6.724 ± 0.2,8.347 ± 0.2,10.785 ± 0.2,16.068 ± 0.2,17.446
± 0.2,18.150 ± 0.2,20.028 ± 0.2, have characteristic peak at 20.606 ± 0.2 degree, the wherein maximum peak of relative intensity is
6.724 ± 0.2 degree of characteristic peak.Further, the X-ray powder diffraction collection about 9.584 ± 0.2,11.829 ± 0.2,
12.010±0.2、13.627±0.2、21.192±0.2、21.469±0.2、22.930±0.2、24.855±0.2、
26.356 ± 0.2, there is characteristic peak at 27.598 ± 0.2 degree.Further, the tenofovir Chinese mugwort of above-mentioned I types crystal form draws phenol
The XRD of amine fumarate is basic as shown in figure 4, the 2 θ angles allow the error for having ± 0.2 degree.
The present invention also provides a kind of method that tenofovir Chinese mugwort as shown in formula (I) draws the I types crystallization of phenol amine fumarate,
Characterized in that, drawing phenol amine fumarate compound to be dissolved in the first solvent tenofovir Chinese mugwort, stirring is lower to add the second solvent, analysis
Crystalline substance, is filtered, and is dried, is produced；First solvent is selected from methanol, ethyl acetate, acetonitrile, tetrahydrofuran；The second solvent choosing
From isopropyl ether, methyl tertiary butyl ether(MTBE).For example, in a kind of exemplary embodiment, first solvent is methanol, described second
Solvent is isopropyl ether；Or first solvent is tetrahydrofuran, second solvent is methyl tertiary butyl ether(MTBE)；Or described
One solvent is acetonitrile, and second solvent is isopropyl ether；Or first solvent is ethyl acetate, second solvent is different
Propyl ether；Etc..
Tenofovir Chinese mugwort draws the ratio of phenol amine fumarate and the first solvent to be 0.01~1g/ml, such as 0.05~0.5g/
Ml, such as scope any number 0.05g/ml, 0.08g/ml, 0.1g/ml, 0.2g/ml, 0.3g/ml, 0.4g/ml etc.；The
The volume ratio of one solvent and the second solvent is 1:(3~20), such as 1:(4~15) or 1:(4~10).The compound is dissolved in
First solvent and/or it can be carried out in room temperature or heating (such as 50-70 DEG C) the step of add the second solvent, the crystallization can be with
It is that room temperature or low temperature (such as -20 DEG C~10 DEG C) are carried out.The drying can be room temperature or heat drying, and more preferably room temperature in vacuo is done
It is dry.
A kind of tenofovir Chinese mugwort as shown in formula (I) of the also offer of the present invention draws phenol amine fumarate compound, its feature
It is, the tenofovir Chinese mugwort draws phenol amine fumarate compound to be II type crystal forms, and it is radiated using Cu-K α, with 2 θ angles
Spend the X-ray powder diffraction collection represented about 4.380 ± 0.2,4.799 ± 0.2,13.385 ± 0.2,17.927 ± 0.2,
22.490 ± 0.2,24.529 ± 0.2,26.794 ± 0.2, have characteristic peak at 27.093 ± 0.2 degree, wherein relative intensity is maximum
Peak be 4.380 ± 0.2 degree of characteristic peak.Further, the X-ray powder diffraction collection is about 6.591 ± 0.2,9.258
±0.2、9.647±0.2、19.530±0.2、19.808±0.2、22.271±0.2、23.629±0.2、28.153±0.2、
There is characteristic peak at 31.735 ± 0.22 degree.Further, the tenofovir Chinese mugwort of above-mentioned II types crystal form draws phenol amine fumarate
XRD it is basic as shown in fig. 7, the 2 θ angles allow the error for having ± 0.2 degree.
The present invention also provides a kind of method that tenofovir Chinese mugwort draws the II type crystal forms of phenol amine fumarate, including will replace
Nuo Fuweiaila phenol amine fumarate is added in chloroform, is stirred at room temperature, crystallization, is filtered, and is dried, is produced.
A kind of tenofovir Chinese mugwort as shown in formula (I) of the also offer of the present invention draws phenol amine fumarate compound, its feature
It is, the tenofovir Chinese mugwort draws phenol amine fumarate compound to be type III crystal form, and it is radiated using Cu-K α, with 2 θ angles
Spend the X-ray powder diffraction collection represented about 4.524 ± 0.2,13.966 ± 0.2,16.566 ± 0.2,19.350 ± 0.2,
21.490 ± 0.2,22.269 ± 0.2,23.494 ± 0.2,28.317 ± 0.2, have characteristic peak at 33.197 ± 0.2 degree, wherein
The maximum peak of relative intensity is 23.494 ± 0.2 degree of characteristic peak.Further, the X-ray powder diffraction collection is about
9.231±0.2、10.646±0.2、14.228±0.2、14.804±0.2、17.083±0.2、19.911±0.2、20.550
±0.2、21.169±0.2、22.069±0.2、23.991±0.2、28.734±0.2、33.595±0.2、38.139±0.2
There is characteristic peak at degree.Further, the tenofovir Chinese mugwort of above-mentioned type III crystal form draws the XRD of phenol amine fumarate basic
As shown in figure 8, the 2 θ angles allow the error for having ± 0.2 degree.
The present invention also provides a kind of method that tenofovir Chinese mugwort draws the type III crystal form of phenol amine fumarate, including will
Tenofovir Chinese mugwort draws phenol amine fumarate to be placed in diffusion 1 day in trifluoroethanol solvent atmosphere at room temperature, and taking-up room temperature, which is dried, to be obtained.
The present invention also provides a kind of tenofovir Chinese mugwort as shown in formula (I) and draws phenol amine fumarate compound, and its feature exists
In the tenofovir Chinese mugwort draws phenol amine fumarate compound to be IV type crystal forms, and it is radiated using Cu-K α, with 2 θ angles
The X-ray powder diffraction collection of expression is about 4.438 ± 0.2,5.081 ± 0.2,10.863 ± 0.2,18.488 ± 0.2,
21.029 ± 0.2,21.392 ± 0.2,26.413 ± 0.2, have characteristic peak at 26.913 ± 0.2 degree, wherein relative intensity is maximum
Peak be 5.081 ± 0.2 degree of characteristic peak.Further, the X-ray powder diffraction collection is about 9.236 ± 0.2,9.525
±0.2、10.345±0.2、15.947±0.2、16.429±0.2、19.407±0.2、19.882±0.2、20.368±
0.2nd, there is characteristic peak at 25.555 ± 0.2 degree.Further, the tenofovir Chinese mugwort of above-mentioned IV types crystal form draws phenol amine fumaric acid
The XRD of salt is basic as shown in figure 9, the 2 θ angles allow the error for having ± 0.2 degree.
The present invention also provides a kind of method that tenofovir Chinese mugwort draws the IV type crystal forms of phenol amine fumarate, including will replace
Nuo Fuweiaila phenol amine fumarate is added in isopropanol, is stirred at room temperature, crystallization, is filtered, and is dried, is produced.
The sixth aspect of the present invention provides a kind of tenofovir Chinese mugwort as shown in formula (I) and draws phenol amine fumarate compound,
Characterized in that, the tenofovir Chinese mugwort draws phenol amine fumarate compound to be V-type crystal form, it is radiated using Cu-K α, with
The X-ray powder diffraction collection that 2 θ angles are represented about 4.880 ± 0.2,8.783 ± 0.2,9.321 ± 0.2,9.904 ±
0.2nd, 20.029 ± 0.2,25.150 ± 0.2,25.653 ± 0.2, there are characteristic peak, wherein relative intensity at 30.273 ± 0.2 degree
Maximum peak is 4.880 ± 0.2 degree of characteristic peak.Further, the X-ray powder diffraction collection about 10.549 ± 0.2,
14.100±0.2、15.784±0.2、16.083±0.2、17.969±0.2、18.370±0.2、20.652±0.2、
There is characteristic peak at 22.013 ± 0.2 degree.Further, the tenofovir Chinese mugwort of above-mentioned V-type crystal form draws phenol amine fumarate
XRD is substantially as shown in Figure 10, and the 2 θ angles allow the error for having ± 0.2 degree.
The present invention also provides a kind of method that tenofovir Chinese mugwort draws the V-type crystal form of phenol amine fumarate, including will replace
Nuo Fuweiaila phenol amine fumarates add the in the mixed solvent of acetonitrile and chloroform, 0~5 DEG C of stirring and crystallizing, mistake at room temperature
Filter, dries, produces.The volume ratio of acetonitrile and chloroform is 1：1.
The present invention also provides a kind of pharmaceutical composition, and its tenofovir Chinese mugwort for containing above-mentioned crystal form draws phenol amine fumaric acid
Salt compound and pharmaceutically acceptable carrier.Any formulation, preferably oral formulations, example can be made in described pharmaceutical composition
Such as tablet, capsule.
The invention provides a variety of crystal formations that tenofovir Chinese mugwort draws phenol amine fumarate, especially crystal formation I, it is high in high temperature
Under wet and solution environmental, stability very well, is adapted to prepare various formulations, and the preparation method of the crystal formation is simple, is adapted to industry
Metaplasia is produced.
Brief description of the drawings
Fig. 1 is the XRD that tenofovir Chinese mugwort draws phenol amine fumarate A crystal formations.
Fig. 2 is the TGA figures that tenofovir Chinese mugwort draws phenol amine fumarate A crystal formations.
Fig. 3 is the DSC figures that tenofovir Chinese mugwort draws phenol amine fumarate A crystal formations.
Fig. 4 is the DVS figures that tenofovir Chinese mugwort draws phenol amine fumarate A crystal formations.
Fig. 5 is the XRD that tenofovir Chinese mugwort draws phenol amine fumarate I crystal.
Fig. 6 is the TGA figures that tenofovir Chinese mugwort draws phenol amine fumarate I crystal.
Fig. 7 is the DSC figures that tenofovir Chinese mugwort draws phenol amine fumarate I crystal.
Fig. 8 is the DVS figures that tenofovir Chinese mugwort draws phenol amine fumarate I crystal.
Fig. 9 is the XRD that tenofovir Chinese mugwort draws phenol amine fumarate II crystal formations.
Figure 10 is the TGA figures that tenofovir Chinese mugwort draws phenol amine fumarate II crystal formations.
Figure 11 is the DSC figures that tenofovir Chinese mugwort draws phenol amine fumarate II crystal formations.
Figure 12 is the XRD that tenofovir Chinese mugwort draws phenol amine fumarate III crystal formations.
Figure 13 is the TGA figures that tenofovir Chinese mugwort draws phenol amine fumarate III crystal formations.
Figure 14 is the DSC figures that tenofovir Chinese mugwort draws phenol amine fumarate III crystal formations.
Figure 15 is the XRD that tenofovir Chinese mugwort draws phenol amine fumarate IV crystal formations.
Figure 16 is the TGA figures that tenofovir Chinese mugwort draws phenol amine fumarate IV crystal formations.
Figure 17 is the DSC figures that tenofovir Chinese mugwort draws phenol amine fumarate IV crystal formations.
Figure 18 is the XRD that tenofovir Chinese mugwort draws phenol amine fumarate V crystal formations.
Figure 19 is the TGA figures that tenofovir Chinese mugwort draws phenol amine fumarate V crystal formations.
Figure 20 is the DSC figures that tenofovir Chinese mugwort draws phenol amine fumarate V crystal formations.
Embodiment
The present invention is described in detail below by way of specific embodiment, it will be appreciated by those skilled in the art that following implement
Example is only purpose of explanation, without limiting the scope of the present invention in any way.Tenofovir Chinese mugwort draws phenol amine fumarate
Raw material can be prepared by art methods, can be any crystal formation.Unless otherwise instructed, the operating procedure in embodiment is
Routine operation room temperature, the crystallization time can be 3 hours to 3 days.
Method of testing：
XRD is tested：INSTRUMENT MODEL：Bruker D8Advance diffractometer, target：Cu-K α (40kV, 40mA),
Scanning range：3 ° -40 ° (2 θ values), step-length：0.02 ° of 2 θ, speed：0.2s.step-1
DSC is tested：INSTRUMENT MODEL：TA Instruments Q200DSC, temperature range：20-200 DEG C, sweep speed：10
DEG C/min, nitrogen flow rate：40ml/min
TGA is tested：INSTRUMENT MODEL：TA Instruments Q500TGA, temperature range：5-250 DEG C, sweep speed：10
DEG C/min, nitrogen flow rate：40ml/min
DVS is tested：INSTRUMENT MODEL：TA Instruments Q5000TGA, nitrogen flow rate：40ml/min,
Equilibrate at25℃；Humidity 0%；Isothermal for 180min；Abort next iso if
Weight (%)<0.0100for 15.00min
Preparation example：Tenofovir Chinese mugwort draws the preparation of phenol amine fumarate (with reference to ZL01813161.1 embodiments 4)
Tenofovir Chinese mugwort is drawn into phenol amine (5.2g), fumaric acid (1.15g), acetonitrile (100g) is added in reaction bulb, is heated to
65-70 DEG C is completely dissolved solid, filters while hot, is cooled to 5 DEG C and is kept for 16 hours.Product is filtered to isolate, is washed with acetonitrile
Wash, dry 5.6g white solids.The solid is anhydrous crystal forms after testing, calls crystal formation A in the following text.
In addition, drawing phenol amine fumarate to add in 3ml ethanol 100mg tenofovirs Chinese mugwort, 50ml is slowly added under stirring
Isopropyl ether, crystallization, centrifugal filtration, vacuum drying obtains solid, is still crystal formation A.
Using the XRD spectrum of Cu-K α actinometries as shown in figure 1, spectrum data is listed in the table below 1.TGA detection displays, sample
Product weightlessness 0.6% before 100 DEG C, is anhydride, decomposition temperature is about 175 DEG C (Fig. 2).DSC detections show the fusing point of sample
About 122 DEG C (Fig. 3).DVS/ isothermal adsorption figures show that weight change is about 0.8% (Fig. 4) in the range of 0%RH to 80%RH.
The tenofovir of table 1. Chinese mugwort draws the XRD modal data of the A crystal formations of phenol amine fumarate
Embodiment 1：Tenofovir Chinese mugwort draws the crystal formation I of phenol amine fumarate preparation
Method 1：Take 500mg tenofovirs Chinese mugwort to draw phenol amine fumarate, 10mL methanol is added at room temperature, stirring is lower to be added dropwise
200mL isopropyl ethers, a large amount of solids of precipitation, centrifugal filtration, room temperature in vacuo, which is dried overnight, to be obtained.
Method 2：Take 500mg tenofovirs Chinese mugwort to draw phenol amine fumarate, 8ml methyl tertiary butyl ether(MTBE)s, stirring are added at room temperature
Crystallization, centrifugal filtration, room temperature in vacuo is dried to obtain.
Method 3：Take 500mg tenofovirs Chinese mugwort to draw phenol amine fumarate, add in 15ml tetrahydrofurans and obtain dissolved clarification liquid, will
Solution is added in 200ml methyl isopropyl ethers, crystallization, centrifugal filtration, and room temperature in vacuo, which is dried overnight, to be obtained.
Using the XRD spectrum of Cu-K α actinometries as shown in figure 5, spectrum data is listed in the table below 2.TGA detections are shown in
Weightlessness 0.6% before 120 DEG C, sample is anhydride, and decomposition temperature is about 180 DEG C (Fig. 6).DSC detections show sample fusing point about
For 132 DEG C (Fig. 7).DVS/ isothermal adsorption figures show that weight change is about 0.4% (Fig. 8) in the range of 0%RH to 80%RH.
The tenofovir of table 2. Chinese mugwort draws the crystal formation I of phenol amine fumarate XRD modal data
| Sequence number | 2θ | D values | Relative intensity | Sequence number | 2θ | D values | Relative intensity |
| 1 | 6.724 | 12.1353 | 100.0 | 17 | 20.028 | 4.4297 | 27.5 |
| 2 | 8.347 | 10.5843 | 29.9 | 18 | 20.606 | 4.3067 | 55.5 |
| 3 | 9.584 | 9.2209 | 11.0 | 19 | 21.192 | 4.1889 | 11.9 |
| 4 | 10.785 | 8.1967 | 46.0 | 20 | 21.469 | 4.1356 | 5.2 |
| 5 | 11.829 | 7.4754 | 9.8 | 21 | 22.310 | 3.9815 | 5.1 |
| 6 | 12.010 | 7.3628 | 4.9 | 22 | 22.930 | 3.8753 | 12.6 |
| 7 | 13.627 | 6.4925 | 5.9 | 23 | 23.071 | 3.8518 | 5.8 |
| 8 | 14.510 | 6.0997 | 3.5 | 24 | 23.952 | 3.7121 | 5.3 |
| 9 | 14.666 | 6.0351 | 2.0 | 25 | 24.349 | 3.6525 | 7.3 |
| 10 | 15.304 | 5.7849 | 3.2 | 26 | 24.608 | 3.6147 | 5.1 |
| 11 | 15.671 | 5.6501 | 7.1 | 27 | 24.855 | 3.5794 | 12.2 |
| 12 | 16.068 | 5.5116 | 31.0 | 28 | 25.336 | 3.5124 | 5.8 |
| 13 | 16.925 | 5.2341 | 5.3 | 29 | 26.356 | 3.3787 | 13.9 |
| 14 | 17.446 | 5.0790 | 24.5 | 30 | 26.775 | 3.3269 | 3.9 |
| 15 | 18.150 | 4.8838 | 18.3 | 31 | 27.598 | 3.2294 | 11.1 |
| 16 | 19.403 | 4.5711 | 6.4 | 32 | 28.478 | 3.1317 | 6.3 |
Embodiment 2：Tenofovir Chinese mugwort draws the crystal formation II of phenol amine fumarate preparation
Take 500mg tenofovirs Chinese mugwort to draw phenol amine fumarate, 5mL chloroforms, room temperature magnetic agitation 3 are added at room temperature
My god, centrifugation is dried in vacuum overnight and obtained.
Using the XRD spectrum of Cu-K α actinometries as shown in figure 9, spectrum data is listed in the table below 3.TAG detections are shown in
Weightlessness 3.2% before 100 DEG C, about unifies a hydrone (theoretical weight ratio is 3.0%), decomposition temperature is about 174 DEG C, the crystalline substance
Type is monohydrate (Figure 10).DSC detections show that sample has a wide absworption peak between 40 DEG C~85 DEG C, 90 DEG C~105 DEG C it
Between have one turn of brilliant exothermic peak, occur to turn brilliant (Figure 11).
The tenofovir of table 3. Chinese mugwort draws the crystal formation II of phenol amine fumarate XRD modal data
| Sequence number | 2θ | D values | Relative intensity | Sequence number | 2θ | D values | Relative intensity |
| 1 | 4.380 | 20.1580 | 100.0 | 14 | 19.530 | 4.5414 | 12.6 |
| 2 | 4.799 | 18.3990 | 22.2 | 15 | 19.808 | 4.4785 | 11.6 |
| 3 | 6.591 | 13.4001 | 3.0 | 16 | 22.271 | 3.9884 | 31.5 |
| 4 | 9.258 | 9.5443 | 3.1 | 17 | 22.490 | 3.9501 | 60.1 |
| 5 | 9.647 | 9.1604 | 7.2 | 18 | 23.629 | 3.7622 | 9.3 |
| 6 | 10.753 | 8.2205 | 3.2 | 19 | 24.529 | 3.6261 | 19.6 |
| 7 | 12.226 | 7.2333 | 2.4 | 20 | 26.794 | 3.3246 | 17.6 |
| 8 | 13.385 | 6.6094 | 17.0 | 21 | 27.093 | 3.2885 | 62.4 |
| 9 | 14.147 | 6.2553 | 2.3 | 22 | 28.153 | 3.1670 | 15.6 |
| 10 | 15.218 | 5.8173 | 2.7 | 23 | 28.770 | 3.1005 | 6.4 |
| 11 | 16.661 | 5.3164 | 2.5 | 24 | 29.493 | 3.0262 | 5.9 |
| 12 | 17.927 | 4.9438 | 25.8 | 25 | 31.735 | 2.8173 | 16.2 |
| 13 | 18.471 | 4.7995 | 2.5 | 26 | 32.714 | 2.7352 | 2.4 |
Embodiment 3：Tenofovir Chinese mugwort draws the crystal formation III of phenol amine fumarate preparation
Take 500mg tenofovirs Chinese mugwort to draw phenol amine fumarate, be placed in trifluoroethanol solvent atmosphere and spread 1 day at room temperature,
Taking-up room temperature, which is dried 2 minutes, to be obtained.
As shown in figure 12 using the XRD spectrum of Cu-K α actinometries, spectrum data is listed in the table below 4.TGA collection of illustrative plates is shown in
14.0% weightlessness is there are about before 120 DEG C, about unifies a trifluoroethanol molecule, decomposition temperature is about 171 DEG C (Figure 13).DSC schemes
Spectrum display, has a desolventizing endothermic peak, fusing point is about 120 DEG C (Figure 14) between 50~105 DEG C.
The tenofovir of table 4. Chinese mugwort draws the crystal formation III of phenol amine fumarate XRD modal data
Embodiment 4：Tenofovir Chinese mugwort draws the crystal formation IV of phenol amine fumarate preparation
Take 500mg tenofovirs Chinese mugwort to draw phenol amine fumarate, 4mL isopropanols added at room temperature, are stirred at room temperature 3 days, centrifuge,
Room temperature in vacuo is dried overnight, and is produced.
As shown in figure 15 using the XRD spectrum of Cu-K α actinometries, spectrum data is listed in the table below 5.TGA collection of illustrative plates is shown in
Weightlessness 0.6% before 120 DEG C, sample is anhydride, and decomposition temperature is about 173 DEG C (Figure 16).DSC detections show the fusing point of sample
About 122 DEG C (Figure 17).
The tenofovir of table 5. Chinese mugwort draws the crystal formation IV of phenol amine fumarate XRD modal data
| Sequence number | 2θ | D values | Relative intensity | Sequence number | 2θ | D values | Relative intensity |
| 1 | 4.438 | 19.8952 | 20.0 | 14 | 18.488 | 4.7952 | 15.3 |
| 2 | 5.081 | 17.3765 | 100.0 | 15 | 19.407 | 4.5700 | 9.1 |
| 3 | 9.236 | 9.5672 | 3.2 | 16 | 19.882 | 4.4618 | 5.0 |
| 4 | 9.525 | 9.2779 | 4.3 | 17 | 20.368 | 4.3565 | 7.0 |
| 5 | 10.345 | 8.5439 | 11.2 | 18 | 21.029 | 4.2210 | 28.0 |
| 6 | 10.863 | 8.1377 | 20.5 | 19 | 21.392 | 4.1503 | 58.0 |
| 7 | 12.145 | 7.2815 | 5.0 | 20 | 22.650 | 3.9225 | 7.3 |
| 8 | 14.223 | 6.2218 | 4.9 | 21 | 25.555 | 3.4829 | 9.9 |
| 9 | 15.242 | 5.8084 | 4.7 | 22 | 26.413 | 3.3716 | 30.2 |
| 10 | 15.683 | 5.6458 | 5.8 | 23 | 26.913 | 3.3101 | 34.3 |
| 11 | 15.947 | 5.5529 | 9.9 | 24 | 30.116 | 2.9649 | 2.9 |
| 12 | 16.429 | 5.3911 | 10.1 | 25 | 31.854 | 2.8070 | 5.4 |
| 13 | 17.949 | 4.9379 | 11.4 | 26 | 32.435 | 2.7580 | 9.5 |
Embodiment 5：Tenofovir Chinese mugwort draws the crystal formation V of phenol amine fumarate preparation
Take 500mg tenofovirs Chinese mugwort to draw phenol amine fumarate, 10mL acetonitriles and 10mL chloroforms, 4 DEG C are added at room temperature
Stirring 3 days, centrifugal filtration, room temperature in vacuo is dried overnight, and is produced.
As shown in figure 18 using the XRD spectrum of Cu-K α actinometries, spectrum data is listed in the table below 6.TGA collection of illustrative plates is shown in
Weightlessness 0.2% before 120 DEG C, sample is anhydride, and decomposition temperature is about 175 DEG C (Figure 19).DSC collection of illustrative plates shows sample at 90 DEG C
There is a melting to turn brilliant peak between~112 DEG C, it is about 121 DEG C (Figure 20) to turn fusing point after crystalline substance.
The tenofovir of table 6. Chinese mugwort draws the crystal formation V of phenol amine fumarate XRD modal data
| Sequence number | 2θ | D values | Relative intensity | Sequence number | 2θ | D values | Relative intensity |
| 1 | 4.880 | 18.0928 | 100.0 | 13 | 16.083 | 5.5062 | 4.0 |
| 2 | 6.790 | 13.0072 | 1.5 | 14 | 17.969 | 4.9325 | 3.5 |
| 3 | 7.367 | 11.9898 | 3.5 | 15 | 18.370 | 4.8257 | 4.3 |
| 4 | 7.833 | 11.2780 | 2.0 | 16 | 20.029 | 4.4295 | 44.2 |
| 5 | 8.783 | 10.0599 | 6.5 | 17 | 20.652 | 4.2973 | 5.6 |
| 6 | 9.321 | 9.4797 | 10.7 | 18 | 22.013 | 4.0346 | 4.5 |
| 7 | 9.904 | 8.9235 | 22.1 | 19 | 22.447 | 3.9575 | 3.6 |
| 8 | 10.549 | 8.3794 | 4.4 | 20 | 22.631 | 3.9258 | 3.2 |
| 9 | 13.388 | 6.6079 | 2.9 | 21 | 25.150 | 3.5379 | 22.4 |
| 10 | 14.100 | 6.2759 | 4.0 | 22 | 25.653 | 3.4698 | 7.2 |
| 11 | 14.865 | 5.9546 | 2.1 | 23 | 28.650 | 3.1133 | 2.0 |
| 12 | 15.784 | 5.6098 | 7.9 | 24 | 30.273 | 2.9499 | 7.2 |
Embodiment 6：Tenofovir Chinese mugwort draws the polymorphous study on the stability of phenol amine fumarate
1st, high temperature drying is investigated
Tenofovir Chinese mugwort prepared by above-described embodiment draws the different crystal forms of phenol amine fumarate to be positioned over sealing clean
In vial, it is placed in 60 DEG C of thermostatic drying chambers, respectively at 0, sampling detection crystal formation change in 5,10 days.It the results are shown in Table 7.
The tenofovir of table 7. Chinese mugwort draws the polymorphous hot test of phenol amine fumarate
| Crystal formation | Testing result |
| A | 60 DEG C of dry placements, 10 days crystal formations are constant |
| I | 60 DEG C of dry placements, 10 days crystal formations are constant |
| II | Dry 5 days parts of placement for 60 DEG C and switch to Form A+Form I mixed crystal, Form A+Form I are switched within 10 days substantially |
| III | Dry to place 5 days for 60 DEG C and switch to Form A+Form I, rear discovery, which was placed less than 1 day, to be occurred turning brilliant |
| IV | Dry to place for 60 DEG C and switch within 5 days crystal formation A+ crystal formations I |
| V | Dry 5 days parts of placement for 60 DEG C and switch to Form A+Form I, Form A+Form I are switched within 10 days substantially |
Test result indicates that, under the conditions of high temperature drying, crystal formation A and crystal formation I stability are fine, crystal formation II, III, IV
With V less stable, easily it is changed into crystal formation A and crystal formation I mixed crystal；Crystal formation III stability is worst, is sent out less than 1 day
It is raw to turn crystalline substance.
2nd, room temperature high humidity is investigated
Tenofovir Chinese mugwort prepared by above-described embodiment draws the different crystal forms of phenol amine fumarate uniformly to share to opening training
Support in ware, thickness≤5mm is placed in room temperature (25 DEG C or so), relative humidity RH in 75 ± 5% constant incubator, respectively at
0th, 5, sampling detection crystal formation change in 10 days.It the results are shown in Table 8.
The tenofovir of table 8. Chinese mugwort draws the polymorphous high wet test of phenol amine fumarate
| Crystal formation | Testing result |
| A | It is constant that room temperature 75%RH places 10 days crystal formations |
| I | It is constant that room temperature 75%RH places 10 days crystal formations |
| II | Room temperature 75%RH 5 days crystal formations of placement are constant but peak intensity is changed, and Form A+Form I are switched within 10 days substantially |
| III | Room temperature 75%RH, which places 5 days crystal formations, significant change, switchs to Form A+Form I |
| IV | Room temperature 75%RH, which is placed, switchs to Form A+Form I for 5 days |
| V | It is constant that room temperature 75%RH places 10 days crystal formations |
Test result indicates that, under room temperature super-humid conditions, crystal formation A, crystal formation I, crystal formation V stability preferably, crystal formation II,
III and IV less stable, is easily changed into crystal formation A and crystal formation I mixed crystal；Crystal formation III stability is worst, very short time
It is interior to occur to turn crystalline substance.
3rd, mixed solvent competitive assay is investigated
Tenofovir, which is ended, draws crystal formation A, I and V sample of phenol amine fumarate to take about 200mg respectively, under the conditions of 25 DEG C
With 20ml stirring solvents, XRD signs are carried out to gained solid product.Experiment condition and result see the table below 9.
The stability of crystal form of table 9. compares (room temperature competition)
Test result indicates that, preferably, the two can coexist, crystal formation V less stable for crystal formation A, crystal formation I stability, hold
Easily it is changed into crystal formation A and crystal formation I mixed crystal.
4th, single solvent magma study on the stability
Tenofovir is ended and draws crystal formation A, the crystal formation I samples of phenol amine fumarate to take about 200mg respectively, coordinative solvent is added
Suspension is obtained, is stirred 3 days at 25 DEG C and 40 DEG C, XRD signs are carried out to gained solid product.Experiment condition and result are seen below
Table 10.
The stability of crystal form of table 10. compares (40 DEG C of investigations)
Test result indicates that, be placed under the conditions of 25 DEG C in solvent, crystal formation A, crystal formation I stability it is preferable；But 40
Under the conditions of DEG C, crystal formation A can occur to turn crystalline substance, partly switch to crystal formation I；Comprehensive normal temperature and hot conditions, crystal formation I stability>Crystal formation A
Stability.
The above-mentioned experimental result of the comprehensive present invention, tenofovir Chinese mugwort draws the crystal formation A and crystal formation I of phenol amine fumarate to be nothing
Crystal type, it is all more stable under the conditions of drying at room temperature, however, crystal formation A can switch to crystal formation A and crystalline substance at 40 DEG C in partial solvent
Type I mixed crystal, crystal formation I stability is more than crystal formation A under the high temperature conditions.In addition DVS investigates result and shown, crystal formation I moisture absorption
Property very little, will be significantly less than crystal formation A, preparation is easier to aoxidize, hydrolyzed especially for solid pharmaceutical preparation, after moisture absorption, go mouldy, have
Material increase is closed, the stability and security of product is influenceed.Therefore consider, crystal formation I stability is higher, be especially suitable for system
Standby tenofovir, which ends, draws the pharmaceutical composition and preparation of phenol amine fumarate.
Claims (10)
1. a kind of tenofovir Chinese mugwort as shown in formula (I) draws phenol amine fumarate compound,
Characterized in that, the tenofovir Chinese mugwort draws phenol amine fumarate compound to be I type crystal forms, it uses Cu-K α spokes
Penetrate, the X-ray powder diffraction collection represented with 2 θ angles is about 6.724 ± 0.2,8.347 ± 0.2,10.785 ± 0.2,
16.068 ± 0.2,17.446 ± 0.2,18.150 ± 0.2,20.028 ± 0.2, have characteristic peak at 20.606 ± 0.2 degree, wherein
The maximum peak of relative intensity is 6.724 ± 0.2 degree of characteristic peak.
2. tenofovir Chinese mugwort as claimed in claim 1 draws phenol amine fumarate compound, it is characterised in that the X-ray powder
Last diffracting spectrum further about 9.584 ± 0.2,11.829 ± 0.2,12.010 ± 0.2,13.627 ± 0.2,21.192 ±
0.2nd, 21.469 ± 0.2,22.930 ± 0.2,24.855 ± 0.2,26.356 ± 0.2, there is characteristic peak at 27.598 ± 0.2 degree.
3. tenofovir Chinese mugwort as claimed in claim 1 draws phenol amine fumarate compound, it is characterised in that the X-ray powder
Last diffracting spectrum is substantially as shown in Figure 4.
4. a kind of method that tenofovir Chinese mugwort prepared described in claim 1 draws phenol amine fumarate compound, it is characterised in that
Phenol amine fumarate is drawn to be dissolved in the first solvent tenofovir Chinese mugwort, stirring is lower to add the second solvent, and crystallization is filtered, dried, i.e.,
；First solvent is selected from methanol, ethyl acetate, acetonitrile, tetrahydrofuran；Second solvent is selected from isopropyl ether, methyl- tert
Butyl ether.
5. the ratio of method as claimed in claim 4, wherein tenofovir Chinese mugwort drawing phenol amine fumarate and the first solvent is
0.01~1g/ml；The volume ratio of first solvent and the second solvent is 1：(3~20).
6. the ratio of method as claimed in claim 4, wherein tenofovir Chinese mugwort drawing phenol amine fumarate and the first solvent is
0.05~0.5g/ml；The volume ratio of first solvent and the second solvent is 1：(4~15).
7. a kind of pharmaceutical composition, its tenofovir Chinese mugwort for containing described in any one of claims 1 to 3 of effective dose draws phenol amine rich
Horse phosphate compounds, and pharmaceutically acceptable carrier.
8. pharmaceutical composition as claimed in claim 6, wherein described pharmaceutical composition can be prepared into oral formulations.
9. the tenofovir Chinese mugwort described in claim 1 draws phenol amine fumarate compound preparing nucleotide reverse transcriptase suppression
Purposes in agent medicine.
10. purposes of the pharmaceutical composition in nucleotide reverse transcriptase inhibitor medicaments are prepared described in claim 6.
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| WO2019130354A1 (en) * | 2017-12-30 | 2019-07-04 | Cipla Limited | Polymorphic forms of (9-[(r)-2-[[(s)-[[(s)-1- (isopropoxycarbonyl)ethyl]amino]phenoxy phosphinyl]methoxy]propyl] adenine and pharmaceutically acceptable salts thereof |
| CN110452268A (en) * | 2019-08-21 | 2019-11-15 | 天地恒一制药股份有限公司 | A kind of preparation method of third phenol tenofovir, half fumaric acid monocrystalline |
| CN111989335A (en) * | 2018-06-12 | 2020-11-24 | 四川科伦博泰生物医药股份有限公司 | Phosphonamide ester compounds and salts and related crystal forms, preparation methods and uses thereof |
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Address after: 211112 Kejian Road 699, Jiangning District, Nanjing City, Jiangsu Province Applicant after: Jiangsu Aosaikang Pharmaceutical Co., Ltd. Address before: 211112 Kejian Road 699, Jiangning District, Nanjing City, Jiangsu Province Applicant before: Jiangsu Aosaikang Pharmaceutical Co., Ltd. |
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Application publication date: 20171003 |