CN107298681A - A kind of NVP novel crystal forms H and preparation method thereof - Google Patents
A kind of NVP novel crystal forms H and preparation method thereof Download PDFInfo
- Publication number
- CN107298681A CN107298681A CN201710487022.9A CN201710487022A CN107298681A CN 107298681 A CN107298681 A CN 107298681A CN 201710487022 A CN201710487022 A CN 201710487022A CN 107298681 A CN107298681 A CN 107298681A
- Authority
- CN
- China
- Prior art keywords
- nvp
- preparation
- crystal
- crystal formation
- diethylene glycol
- 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.)
- Pending
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 81
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 33
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000003756 stirring Methods 0.000 claims abstract description 13
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 239000012046 mixed solvent Substances 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 229910002483 Cu Ka Inorganic materials 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 2
- 238000001228 spectrum Methods 0.000 claims description 2
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- 238000000034 method Methods 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000002349 favourable effect Effects 0.000 abstract description 2
- 239000012453 solvate Substances 0.000 abstract description 2
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 129
- 229960000689 nevirapine Drugs 0.000 description 64
- 238000005755 formation reaction Methods 0.000 description 25
- 239000000047 product Substances 0.000 description 9
- 239000012043 crude product Substances 0.000 description 7
- 238000010583 slow cooling Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000000113 differential scanning calorimetry Methods 0.000 description 5
- 238000007599 discharging Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000002411 thermogravimetry Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000049 pigment Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000009102 absorption Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000004581 coalescence Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102100021202 Desmocollin-1 Human genes 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 101000968043 Homo sapiens Desmocollin-1 Proteins 0.000 description 1
- 101000880960 Homo sapiens Desmocollin-3 Proteins 0.000 description 1
- 208000022120 Jeavons syndrome Diseases 0.000 description 1
- -1 NVP compound Chemical class 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000004061 bleaching Methods 0.000 description 1
- 239000007844 bleaching agent Substances 0.000 description 1
- 229940126600 bulk drug product Drugs 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002389 environmental scanning electron microscopy Methods 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of novel crystal forms H of NVP and preparation method thereof.The crystal formation is the NVP solvate crystal formation of crystal habit that is characterized of X-ray powder diffraction in about 7.0 °, 9.2 °, 11.2 °, 13.1 °, 13.8 °, 18.3 °, 21.1 ° and 24.2 ° ± 0.2 ° of 2 θ, simultaneously there is provided the preparation method of the crystal formation, including NVP is added into diethylene glycol dimethyl ether or diethylene glycol dimethyl ether and the in the mixed solvent of other solvents, temperature control stirring, cold filtration, is dried.The features such as pointed novel crystal forms H has stability height, good fluidity in the present invention, while the features such as preparation of the crystal form has simple method, good impurity removing effect, favorable reproducibility, it is easy to the big production of commercialization, is worth with very high promotion and application.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to a kind of NVP novel crystal forms H and preparation method thereof.
Background technology
NVP (Nevirapine), the pyridos of chemical name 11- cyclopropyl -5,11- dihydro -4- methyl -6H- two [3,
2-B:2', 3'-E] [Isosorbide-5-Nitrae] diaza leather -6- ketone, its chemical structural formula is：
NVP by the Boehringer Ingelheim HIV-1 researched and developed the sweet class RTI of non-core, how
Wei Laping shares treatment HIV-1 infection with other antiretroviral drugs.1996.06.12 day U.S. FDA approval listing,
1997.12.23 ratify to list in Switzerland, 1998.02.05 Europe EMEA approval listings.In the country's listing of 52, the whole world.
This alone medicine can produce same drug-resistant virus quickly.Therefore, NVP should be other degeneration-resistant with more than at least two always
Retroviral agent is used together.The pregnant woman of ART is not used during for childbirth, can be pre- using NVP
Anti- HIV-1 mother-to-baby transmission.For Prevention of MTCT, this indication NVP can be used alone.Current Yuan Yan producers
Tablet lists Nevirapine anhydrous crystal formation, the semihydrate crystal formation of suspension formulations listing.
In recent years, successively with the presence of document report NVP polytropism, this is some molecules and molecular complex
The characteristic of thing.Single molecule, such as NVP, it is possible to create many crystal formations, they have different crystal structure and physical
Can, such as fusing point, X-ray diffractogram.Report NVP compound is Yuan Yan companies Boehringer Ingelheim earliest
Patent US 5366972, but the patent does not mention the crystal formation situation of the compound.Substantially, repeat to operate described in the patent
Process obtains crystal formation：Anhydrous NVP crystal formation I.Boehringer Ingelheim were in publication WO in 2000 simultaneously
1999009990, it was recently reported that NVP semihydrate.Patent US 20050059653 disclosed NVP in 2005
Form II and FormIII.Patent WO2011073907 reported NVP metastable-state crystal Form IV in 2011.
It is well known that production and curative effect of the quality of bulk drug product for formulation products have conclusive effect, lead to
Cross and constantly find that excellent drug purification method has great significance for improving product quality.Pass through patent and document
Analysis is it can be found that NVP reacts more in building-up process high temperature, and purity and the pigment impurity influence of product are larger,
In order to improve product quality, often purified using means such as multiple crystallization, charcoal absorptions.Grind US5366972 in its Central Plains
Compound patent is crystallized using ethyl acetate and hexamethylene, then uses recrystallize with dichloromethane.Original, which grinds patent EP 91117599, to be made
Crystallized, then recrystallized with pyridine and water with isopropanol.Patent CN102167699 is disclosed to be recrystallized using first alcohol and water, and is utilized
Activated carbon is decolourized.Patent CN102887898 is then recrystallized up to three times, and utilize using organic solvent to product
Bleaching agent bleaching etc..
Above-mentioned a variety of patents the problems of are embodied during NVP crude product refining, many using mixed solvent
Secondary recrystallization, recycled solvent is extremely difficult, product recrystallize often, loss it is big, complex process；Will using decolorising agent
A large amount of reluctant solid wastes are produced, while decolorising agent also can adsorption production, the refined receipts of reduction while adsorpting pigment impurity
Rate.
The present invention has found that NVP and diethylene glycol dimethyl ether can pass through molecule in research NVP crystallization process
Between hydrogen bond action form a kind of new crystal form, the crystal is in the octahedral volume morphing of rule, and the crystal is in nucleating growth
During can effectively avoid the entrance of pigment and other impurities, with excellent purity and high mobility.The present invention
In pointed novel crystal forms H have stability high, the features such as good fluidity, while the preparation of the crystal form has method letter
The features such as list, good impurity removing effect, favorable reproducibility, it is easy to the big production of commercialization, with very high promotion and application value.
The content of the invention
The present inventor is found that the novel crystal forms for the NVP reported different from existing literature in research process
H, NVP novel crystal forms H has stability good, good fluidity, and its preparation method is simple, and good impurity removing effect has
Reappearance.
Described NVP novel crystal forms H's has following feature：
A kind of novel crystal forms H of NVP, its X-ray diffracting spectrum (XRPD is radiated using Cu-Ka) is at 2 θ angles
There is characteristic peak at 7.0 °, 9.2 °, 11.2 °, 12.1 °, 13.1 °, 13.8 °, 15.2 °, 18.3 °, 21.1 ° and 24.2 ° ± 0.2 °.
Further, the novel crystal forms H of the NVP is radiated using Cu-Ka, its with the position at diffractive features peak (2 θ, with
Degree is represented), the X-ray powder diffraction collection parameter that represents of the relative intensity (I is represented with percentage %) at interplanar distance peak such as
Table 1 below.
The characteristic peak parameter of the NVP novel crystal forms H of table 1 X-ray powder diffraction figure
Also crystal of the 2 θ angle coincidence loss scopes at diffractive features peak within ± 0.2 ° is included.
There are two significantly near 130 DEG C, 245 DEG C in the novel crystal forms H of NVP of the present invention DSC collection of illustrative plates
Endothermic peak；
Diethylene glycol dimethyl ether rubs with NVP in the new solvate crystal forms of NVP of the present invention
Your ratio is 1：4；
In the novel crystal forms H of NVP of the present invention TGA collection of illustrative plates weightless about 11.2% near 130 DEG C；
The novel crystal forms H of NVP of the present invention solid shape is block octahedra.
It is a further object of the present invention to provide a kind of NVP novel crystal forms H preparation method.
Described NVP novel crystal forms H preparation method, step is as follows：
NVP is added into diethylene glycol dimethyl ether or diethylene glycol dimethyl ether and the in the mixed solvent of other solvents, temperature control is stirred
Mix, cold filtration, dry.
Other solvents described in the preparation method that the present invention is provided are following one or more：Methanol, ethanol, isopropanol,
Water, ethyl acetate, toluene, dimethylbenzene；
Percent by volume >=50% of in the mixed solvent diethylene glycol dimethyl ether described in the preparation method that the present invention is provided；
NVP quality and solvent volume ratio described in the preparation method that the present invention is provided are 1g：(1~100) ml, it is excellent
Elect 1g as：(3~8) ml；Temperature control stirring temperature described in the preparation method that the present invention is provided is 0~160 DEG C, preferably 50~120
℃；
The temperature control stirring time described in the preparation method that the present invention is provided is 0.1~10 hour, preferably 0.5~2 hour；
The chilling temperature described in preparation method that the present invention is provided is -10~30 DEG C, preferably -5~5 DEG C；
The drying temperature described in preparation method that the present invention is provided is 30~160 DEG C, preferably 60~100 DEG C；
The drying time described in preparation method that the present invention is provided is 1~48 hour, preferably 4~12 hours.
The technical scheme that a kind of preparation method for NVP novel crystal forms H that the present invention is provided is preferred is：
NVP is added in diethylene glycol dimethyl ether, 50~120 DEG C is heated to and stirs 0.5~2 hour, stirring is finished,
Slow cooling is to -5~5 DEG C, and cooling is finished, filtering, is dried 4~12 hours at 60~100 DEG C, obtains NVP novel crystal forms H.
The present invention is beneficial to be had the technical effect that：
1st, provide a kind of NVP stable new crystal form H；
2nd, the NVP novel crystal forms H that the present invention is provided is block octahedra, good fluidity；
The 3rd, a kind of NVP novel crystal forms H preparation method is provided；
4th, preparation method product purity height of the invention, high income, reproducible；
5th, preparation technology of the invention is simple to operate, it is easy to the big production of commercialization.
Brief description of the drawings
Fig. 1 is NVP novel crystal forms H prepared by the embodiment of the present invention 1 X-ray powder diffraction figure.
Fig. 2 is NVP novel crystal forms H prepared by the embodiment of the present invention 1 means of differential scanning calorimetry figure.
Fig. 3 is NVP novel crystal forms H prepared by the embodiment of the present invention 1 thermogravimetry.
Fig. 4 is NVP novel crystal forms H prepared by the embodiment of the present invention 1 microphotograph.
Fig. 5 is NVP novel crystal forms H prepared by the embodiment of the present invention 1 scanning electron microscope (SEM) photograph.
Fig. 6 is NVP novel crystal forms H prepared by the embodiment of the present invention 1 high-efficient liquid phase chromatogram.
Fig. 1 is the X-ray powder diffraction figure that embodiment 1 obtains NVP crystal formation H, from figure 1 it appears that in 2 θ
It is worth to have exclusive at 7.0 °, 9.2 °, 11.2 °, 12.1 °, 13.1 °, 13.8 °, 15.2 °, 18.3 °, 21.1 ° and 24.2 ° ± 0.2 °
Characteristic absorption peak.
Fig. 2 is the DSC collection of illustrative plates for the NVP crystal formation H that embodiment 1 is obtained, from fig. 2 it can be seen that at 130 DEG C and
There is absworption peak at 245 DEG C.
Fig. 3 is the TGA collection of illustrative plates for the NVP crystal formation H that embodiment 1 is obtained, it can be seen in figure 3 that near 130 DEG C
There are obvious weightlessness, weightlessness about 11.2%.
Fig. 4, Fig. 5 are the microphotograph and stereoscan photograph for the NVP crystal formation H that embodiment 1 is obtained respectively, from
It can be seen that the bulk octahedron in rule of the crystal formation in photo.
Fig. 6 is the high-efficient liquid phase chromatogram for the NVP crystal formation H that embodiment 1 is obtained, and as can be seen from the figure gained is produced
The high purity 99.97% of product.
Embodiment
In order to further appreciate that the present invention, the preferred embodiment of the invention is described with reference to embodiment, still
It should be appreciated that these descriptions are simply to further illustrate the features and advantages of the present invention, rather than to the claims in the present invention
Limitation.
Raw material and universal testing method：
NVP crude product used is prepared with reference to US5366972 embodiments 12 in embodiment.
X-ray powder diffraction (XRD) instrument：Dutch PANalytical X ' pert Pro types：Radiation source：Copper targetScan at ambient temperature：Voltage：45kv, electric current：40mA, originates 2 θ：2000 °, scanning range：
3.0000~50.0000 °, step-length：0.017 °, time of measuring：50.2 seconds/step；
Differential scanning calorimetry analyzes (DSC) instrument：Switzerland's plum Teller-support benefit DSC1 types, 30~300 DEG C of scopes, plus
Hot speed：10 DEG C/min, nitrogen flow rate：40ml/min；
Thermogravimetric analysis (TGA) instrument：U.S. TA Discovery 5500；
ESEM (SEM)：U.S. FEI, SIRION-100；
Electron microscope：Olympus CX41；
High performance liquid chromatography (HPLC) instrument：Japanese Shimadzu LC-20A types, Detection wavelength：220nm；
Embodiment 1：
NVP crude product 20g and 100ml diethylene glycol dimethyl ether is added into reaction bulb, 120 DEG C of stirrings 0.5 of temperature control are small
When, then slow cooling is to 0 DEG C, filtering, 70 DEG C of air blast of filter cake are dried 8 hours, and discharging obtains 21.8g NVP crystal formation H, given money as a gift
Yield is 95.0%, purity 99.97%.
Embodiment 2：
NVP crude product 20g, 80ml diethylene glycol dimethyl ether, 80ml water are added into reaction bulb, 90 DEG C of stirrings 1 of temperature control are small
When, then slow cooling is to 0 DEG C, filtering, 70 DEG C of air blast of filter cake are dried 10 hours, and discharging obtains 22.1g NVP crystal formation H, rolls over
Dry yield is 98.1%, purity 99.90%.
Embodiment 3：
NVP crude product 20g, 80ml diethylene glycol dimethyl ether, 60ml methanol, 70 DEG C of stirrings of temperature control are added into reaction bulb
1.5 hours, then slow cooling is to 0 DEG C, filtering, 70 DEG C of air blast of filter cake are dried 6 hours, and discharging obtains 20.8g NVP crystal formations
H, yield of giving money as a gift is 92.3%., purity 99.87%.
Embodiment 4：
NVP crude product 20g, 30ml diethylene glycol dimethyl ether, 30ml toluene, 110 DEG C of stirrings of temperature control are added into reaction bulb
1.0 hours, then slow cooling is to 0 DEG C, filtering, 80 DEG C of filter cake is dried in vacuo 6 hours, and discharging obtains 21.2g NVP crystal formations
H, yield of giving money as a gift is 94.1%, purity 99.91%.
Embodiment 5：
NVP crude product 20g, 60ml diethylene glycol dimethyl ether, 30ml ethyl acetate, 60 DEG C of temperature control are added into reaction bulb
Stirring 2.0 hours, then slow cooling is to 0 DEG C, filtering, 60 DEG C of filter cake is dried in vacuo 12 hours, and discharging obtains 21.5g NVPs
Crystal formation H, yield of giving money as a gift is 95.5%, purity 99.94%.
In order to illustrate the NVP crystal formation H of the present invention and other crystal formations of existing patent report difference, the present inventor
Crystal formation I and semihydrate are prepared for by US5366972, CN1268055A method respectively, and carried out with this patent crystal formation H
Compare, comparative result is as follows：
| Crystal formation title | Product form | Heap density | Mobility | Stability |
| Crystal formation I | Needle-like | 0.48g/cm3 | Poor fluidity, easily coalescence, viscous bag | Hygroscopic turn of crystalline substance is semihydrate |
| Semihydrate | Needle-like | 0.50g/cm3 | Poor fluidity, easily coalescence, viscous bag | Stable crystal form |
| This patent crystal formation H | It is block | 0.64g/cm3 | Mobility is fine | Stable crystal form, no hygroscopicity |
Above-mentioned result of the test shows, NVP crystal formation H of the invention stability height, good fluidity, bulk density are big,
Had a clear superiority in storage transporter mask.
NVP novel crystal forms H proposed by the present invention and preparation method thereof is described by embodiment, related skill
Art personnel substantially can be not departing from present invention, in spirit and scope to NVP novel crystal forms H as described herein and its system
Preparation Method is modified or suitably change is with combining, to realize the technology of the present invention.In particular, it is all similar
Replacement and change apparent to those skilled in the art, they be considered as being included in the present invention spirit,
In scope and content.
Claims (13)
1. a kind of novel crystal forms H of NVP, it is characterised in that：Described NVP crystal is diglyme solvent
Thing crystal, it is radiated using Cu-Ka, the X-ray powder diffraction represented with 2 θ angles about 7.0 °, 9.2 °, 11.2 °, 12.1 °,
13.1 °, 13.8 °, 15.2 °, 18.3 °, 21.1 ° and 24.2 ° ± 0.2 ° has characteristic peak.
2. the novel crystal forms H of NVP according to claim 1, it is characterised in that its X-ray diffracting spectrum (XRPD) is special
Levy peak parameter as follows：
3. NVP crystal formation as claimed in claim 1, it is characterised in that：Have in its DSC collection of illustrative plates near 130 DEG C, 245 DEG C
Two obvious endothermic peaks.
4. NVP crystal formation as claimed in claim 1, it is characterised in that：Diethylene glycol dimethyl in described NVP crystal
Ether is 1 with NVP molar ratio：4.
5. NVP crystal formation as claimed in claim 1, it is characterised in that：In its TGA collection of illustrative plates near 130 DEG C it is weightless about
11.2%.
6. NVP crystal formation as claimed in claim 1, it is characterised in that：Described NVP crystal solid shape is block
Shape is octahedra.
7. a kind of preparation method of the NVP crystal formation described in claim 1~6, it is characterised in that：NVP is added
The in the mixed solvent of diethylene glycol dimethyl ether or diethylene glycol dimethyl ether and other solvents, temperature control stirring, cold filtration is dried.
8. preparation method according to claim 7, it is characterised in that other described solvents are following one or more：
Methanol, ethanol, isopropanol, water, ethyl acetate, toluene, dimethylbenzene.
9. preparation method according to claim 7, it is characterised in that the body of described in the mixed solvent diethylene glycol dimethyl ether
Product percentage >=50%.
10. preparation method according to claim 7, it is characterised in that：Described NVP quality and solvent volume ratio
For 1g：(1~100) ml, preferably 1g：(3~8) ml.
11. preparation method according to claim 7, it is characterised in that：Described temperature control stirring temperature is 0~160 DEG C, excellent
Select 50~120 DEG C；The temperature control stirring time is 0.1~10 hour, preferably 0.5~2 hour.
12. preparation method according to claim 7, it is characterised in that：Described chilling temperature is -10~30 DEG C, preferably -
5~5 DEG C.
13. preparation method according to claim 7, it is characterised in that：Described drying temperature is 30~160 DEG C, preferably
60~100 DEG C；Drying time is 1~48 hour, preferably 4~12 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710487022.9A CN107298681A (en) | 2017-06-23 | 2017-06-23 | A kind of NVP novel crystal forms H and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710487022.9A CN107298681A (en) | 2017-06-23 | 2017-06-23 | A kind of NVP novel crystal forms H and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107298681A true CN107298681A (en) | 2017-10-27 |
Family
ID=60135897
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710487022.9A Pending CN107298681A (en) | 2017-06-23 | 2017-06-23 | A kind of NVP novel crystal forms H and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107298681A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050059653A1 (en) * | 2002-06-21 | 2005-03-17 | Dr. Reddy's Laboratories Limited | Novel crystalline forms of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b: 2',3'-e][1,4] diazepin-6-one (nevirapine) |
| WO2007010352A1 (en) * | 2005-07-19 | 2007-01-25 | Emcure Pharmaceuticals Limited | An improved process for industrial manufacture of nevirapine |
| US20130039987A1 (en) * | 2009-11-10 | 2013-02-14 | North-West University | Method for increasing the solubility of a transcriptase inhibitor composition |
-
2017
- 2017-06-23 CN CN201710487022.9A patent/CN107298681A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050059653A1 (en) * | 2002-06-21 | 2005-03-17 | Dr. Reddy's Laboratories Limited | Novel crystalline forms of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b: 2',3'-e][1,4] diazepin-6-one (nevirapine) |
| WO2007010352A1 (en) * | 2005-07-19 | 2007-01-25 | Emcure Pharmaceuticals Limited | An improved process for industrial manufacture of nevirapine |
| US20130039987A1 (en) * | 2009-11-10 | 2013-02-14 | North-West University | Method for increasing the solubility of a transcriptase inhibitor composition |
Non-Patent Citations (6)
| Title |
|---|
| BRUNO G. PEREIRA ET AL.: "Pseudopolymorphs and Intrinsic Dissolution of Nevirapine", 《CRYSTAL GROWTH & DESIGN》 * |
| MINO R.CAIRA ET AL.: "Solvent Inclusion by the Anti-HIV Drug Nevirapine: X-Ray Structures and Thermal Decomposition of Representative Solvates", 《CRYSTAL GROWTH & DESIGN》 * |
| RENU CHADHA ET AL.: "Solvated Crystalline Forms of Nevirapine: Thermoanalytical and Spectroscopic Studies", 《AAPS PHARMSCITECH》 * |
| RENU CHADHA ET AL.: "Thermoanalytical and spectroscopic studies on different crystal forms of nevirapine", 《J THERM ANAL CALORIM》 * |
| 徐晓辉等: "新型逆转录酶抑制剂Nevirapine 的合成", 《江西化工》 * |
| 李淑敏: "奈韦拉平合成工艺改进", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7220154B2 (en) | Crystalline forms of amino lipids | |
| CN108947891B (en) | Method for safely preparing pimavanserin and tartrate thereof by using triphosgene | |
| EP3337485B1 (en) | Crystalline forms of ibrutinib | |
| CN102448963A (en) | Useful pharmaceutical salts of 7-[(3r, 4r)-3-hydroxy-4-hydroxymethyl-pyrrolidin-1-ylmethyl]-3,5-dihydro-pyrrolo[3,2-d]pyrimidin-4-one | |
| KR20150036336A (en) | Crystalline form i of tyrosine kinase inhibitor dimaleate and preparation methods thereof | |
| CN108794351B (en) | Preparation method of pimavanserin key intermediate | |
| CN107980041A (en) | The polymorphic forms of Afatinib free alkali and its dimaleate | |
| CN114746412A (en) | Novel crystal form of KD-025 and preparation method thereof | |
| WO2005051925A1 (en) | Crystal of phenylalanine derivative and process for producing the same | |
| CN111718300A (en) | Novel crystal form of olaparib and preparation method thereof | |
| CN107814802A (en) | A kind of new method for preparing citric acid tropsch imatinib medicinal crystal-form | |
| US20120101273A1 (en) | Novel crystal forms of adefovir dipivoxil and processes for preparing the same | |
| KR101408370B1 (en) | Material containing aripiprazole and organic acid cocrystals and method for making thereof | |
| CN110041320B (en) | Preparation method of azilsartan crystals | |
| CN106279169B (en) | Novel crystal form of istradefylline and preparation method thereof | |
| CN107298681A (en) | A kind of NVP novel crystal forms H and preparation method thereof | |
| CN107540589B (en) | Elcalcitol crystal form, pharmaceutical composition, preparation method and application | |
| CN114008023B (en) | Crystal form of Sofos-piramide and preparation method thereof | |
| CN115925654A (en) | Tematataxel compound crystal form and preparation method and application thereof | |
| CN114364380A (en) | Solid forms of (S) -tert-butyl 2- ((2S,3R) -1-amino-3-hydroxy-1-oxobutan-2-yl) -1-oxo-2, 5-diazaspiro [3.4] octane-5-carboxylate and processes for their preparation | |
| CN113354626A (en) | Crystal form of enretinib and preparation method thereof | |
| CN108727417B (en) | Polycyclic compound sodium salt, and polycrystalline type, preparation method and application thereof | |
| CN110964017A (en) | Polymorph of Ribociclib monosuccinate and preparation method and application thereof | |
| CN111454318A (en) | Crystal form of antidepressant SAGE-217 and preparation method thereof | |
| CN106432197B (en) | Ledipasvir intermediate mono-p-toluenesulfonate, crystal form and preparation method 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 | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20171027 |
|
| RJ01 | Rejection of invention patent application after publication |