CN107556232A - A kind of Etoricoxib and the novel crystal forms and preparation method of hydrochloric acid forming salt - Google Patents
A kind of Etoricoxib and the novel crystal forms and preparation method of hydrochloric acid forming salt Download PDFInfo
- Publication number
- CN107556232A CN107556232A CN201710877317.7A CN201710877317A CN107556232A CN 107556232 A CN107556232 A CN 107556232A CN 201710877317 A CN201710877317 A CN 201710877317A CN 107556232 A CN107556232 A CN 107556232A
- Authority
- CN
- China
- Prior art keywords
- etoricoxib
- salt
- hydrochloric acid
- preparation
- acid forming
- 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
Abstract
A kind of Etoricoxib and the crystal formation and preparation method of hydrochloric acid forming salt, belong to crystal formation discovery and the preparing technical field of drug salts.The salt that Etoricoxib prepared by the present invention is formed with hydrochloric acid, through thermal weight loss（TGA）, X ray powder diffractions（P‑XRD）, X ray single crystal diffractions（S‑XRD）Means of differential scanning calorimetry（DSC）, ultraviolet spectra（UV）And nuclear-magnetism H spectrums（H‑NMR）Etoricoxib and the salt of hydrochloric acid formation are detected as etc. analysis method.Etoricoxib is a kind of insoluble drug, its salt formed with hydrochloric acid, has good solubility and stability during prepared by solid pharmaceutical preparation by test, is laid a good foundation for the exploitation and application of its novel form.
Description
Technical field
Salt crystalline substance formed the present invention relates to a kind of Etoricoxib and hydrochloric acid and preparation method thereof, and in particular to Etoricoxib and
Novel crystal forms of hydrochloric acid forming salt and preparation method thereof, belong to drug crystal forms discovery and preparing technical field.
Background technology
Etoricoxib is a kind of high selectivity Transitional cell carcinomas（COX-2）Depressant, English name are Etoricoxib, chemistry
Entitled [the chloro- 2- of 5-（The base of 6- picolines -3）-3-（4- sulfonyloxy methyl phenyl）Pyridine（5-Chloro-3-(4-
methanesulfonyl-phenyl)-6’-methyl-[2,3’]bipyridinyl）, molecular formula C18H15ClN2O2S。
Etoricoxib is used to treat osteoarthritis（OA）, rheumatoid arthritis and acute gouty arthritis.Etoricoxib
It is a kind of analgesic, its performance is compared with traditional NSAIDs（NSAIDs）Increase, be the treatment uniquely having confirmed
The effective former times dry goods medicine of acute gouty arthritis.In Mexico, the approved other idicatios of Brazil and Peru also at present
Have：Alleviate pain and primary dysmenorrhea after having tooth pulled out, alleviate chronic musculoskeletal pain, including chronic back pain etc..
During Etoricoxib is synthesized, some important intermediates may be incomplete due to removing, so as to influence
Pharmaceutical purity and quality.The relevant report of the crystal formation of the salt on Etoricoxib few so far, in view of this, the present invention
The technical issues that need to address are overcome the deficiencies in the prior art, there is provided a kind of Etoricoxib new salt form and preparation method, tool
There are good solubility and stability, laid a good foundation for the exploitation and application of its novel form.
The content of the invention
The present invention seeks to be related to the new salt form of a kind of Etoricoxib and hydrochloric acid and provide its preparation method, preparation side
Method is simple, favorable reproducibility.
The crystallographic features for being technically characterized in that the drug salts are brilliant of the present invention are：Crystallographic system belongs to rhombic system, and a=
10.915 (± 0.002), b=11.801 (± 0.002), c=14.059 (± 0.003), α=90o, β=90o, γ=90o；Thermal weight loss chromatogram characteristic：249.9 DEG C of fusing point, decomposable process is completed at 472.8 DEG C；X- ray Powder Diffraction pattern features：
8.1,12.5,14.6,15.0,16.2,16.7,18.2,18.9,20.6,21.2,21.9,
24.0,24.4,24.8,25.5,26.1,26.4,27.1,27.6,28.6,29.3,30.7,
There is diffraction maximum at 32.0,33.9,35.2,35.4,36.3,36.9；Uv atlas goes out peak position, in methanol
In solvent, maximum absorption band is 203.6nm and 235.4nm；Magnetic hydrogen spectrum signature is：1H-NMR (500 MHz, MeOD): δ
2.78 (s, 3H), 3.15(s, 3H), 7.59 (d, J = 8.5 Hz 2H),7.79 (d, J = 14 Hz, 1H),
7.97 (d, J = 14 2H), 8.11 (d, J = 3.5 Hz, 1H), 8.28(dd, J = 3 Hz, 1H), 8.68
(d, J = 3 Hz 1H), 8.82 (d, J = 4 Hz, 1H)
The invention further relates to Etoricoxib and the preparation method of the new salt form of hydrochloric acid, comprise the following steps：
(a) weigh hydrochloric acid and Etoricoxib ratio should be less than 1, be added to a certain amount of absolute methanol, and at low temperature（About 0~
15℃）Stirring, when there is turbid phenomenon stopping in solution, placed in environment of the room temperature less than 25 DEG C, solid can be separated out slowly.
(b) excess of solvent is filtered to remove, gained solid is placed in after methanol washs and is dried in vacuum overnight, and produces target salt
Type.
Beneficial effects of the present invention：Present invention discover that and be prepared for the new salt form of Etoricoxib and hydrochloric acid, exist by test
Solid pharmaceutical preparation has good solubility and stability during preparing, and base has been established for the exploitation and application of its novel form
Plinth.
Brief description of the drawings：Fig. 1：Single crystal diffraction figure of the Etoricoxib with hydrochloric acid into salt（H atom is omitted）；
Fig. 2:DSC the and TG schematic diagrames of Etoricoxib and hydrochloride crystalline substance；
Fig. 3：The powder diffraction schematic diagram of Etoricoxib and hydrochloride crystalline substance；
Fig. 4：The ultraviolet schematic diagram of Etoricoxib and hydrochloride crystalline substance；
Fig. 5：The nuclear-magnetism H spectrum schematic diagrames of Etoricoxib and hydrochloride crystalline substance；
Fig. 6：Relevant material contrasts chromatogram.
Form is described in further details to present disclosure again by the following examples, but not this should not be interpreted as with regard to this
Invent in above-mentioned subject area and be only limitted to following examples.It is general according to this area under the premise of the above-mentioned technology of the present invention is not departed from
The modification of corresponding replacement or change that logical technological know-how and customary means are made, is included in the present invention.
Embodiment 1
Under ice bath, by Etoricoxib (358mg, 1mmol) and hydrochloric acid（0.5mmol）It is added in 50ml conical flasks, adds
Enter 20ml methanol, add in batches, when solution has slight haze phenomenon, stopping adds, and after hour is done in stirring, being placed into room temperature is
In 10 degree of explosion-proof refrigerator, slowly separate out, obtain product.
Embodiment 2
Under ice bath, by Etoricoxib (350mg, 1mmol) and hydrochloric acid（1mmol）It is added in 50ml conical flasks, adds
20ml methanol, is added in batches, when solution has a slight haze phenomenon, stops adding, and after stirring half an hour, is placed on 0 DEG C anti-
In quick-fried refrigerator, slowly separate out, filtration drying, obtain product.
Embodiment 3：Hot test
Temperature selects 40 DEG C, 60 DEG C of two temperature levels respectively.Sample is placed 10 days at a temperature of 60 DEG C, in the 5th day and
Sample within 10 days, detected by stability high spot reviews project.If if sample is without significant change without the examination under the conditions of 40 DEG C
Test；If sample has significant change (such as content declines 5%, differentiates the change of unobvious appearance lusters greatly etc.), then must be under the conditions of 40 DEG C
Tested with method.
Embodiment 4：High wet test
Selection relative humidity is 75% ± 5%, 90% ± 5% two humidity level（T=25℃）.By sample be placed in relative humidity 90% ±
Under the conditions of 5%（In the drier for filling KNO3 saturated solutions, sealed with sealing compound）Place 10 days, sampled in the 5th day and the 10th day,
Detected by stability high spot reviews project demand, at the same before and after precise experiment sample weight, if sample without significant change,
Then without the experiment under the conditions of 75% ± 5%；If sample has significant change, (such as content declines 5%, differentiates unobvious, outward appearance color
Pool change is big, moisture absorption weighs 5% with first-class), then must be under the conditions of relative humidity 75% ± 5%（Drier equipped with NaCl saturated solutions
In, sealed with vaseline）Tested with method.
Embodiment 5：Strong illumination is tested
Sample opening is placed on equipped with the lighting box of fluorescent lamp or other suitable illumination apparatus, in illumination be 4500 lx ±
Placed 10 days under conditions of 500 lx, sampled in the 5th and the 10th day, detected, be important to by stability high spot reviews project
Pay attention to the cosmetic variation of sample.
The stability test of general condition：
HPLC testing results are as follows：
Relevant material comparative experiments data see the table below, and chromatogram is shown in Fig. 6.
In summary, the brilliant impurity content of salt and stability are all relatively preferable.
Claims (6)
- A kind of 1. new salt form of Etoricoxib and hydrochloric acid, it is characterised in that：The pharmaceutical co-crystals are lived using Etoricoxib as medicine Property composition, using hydrochloric acid as reactant, forming salt, its space group are rhombic system in methyl alcohol, and Etoricoxib and salt acid molecule are pressed 1：The Hydrogenbond that 1 ratio is formed into salt, during by into salt forms the elementary cell of Etoricoxib and hydrochloride, salt together Hydrogen bond is formed between acid molecule by hydroxyl to be combined, its crystallographic features is：Crystallographic system belongs to rhombic system, a=10.915 (± 0.002), b=11.801 (± 0.002), c=14.059 (± 0.003), α=90o, β=90o, γ=90 o。
- 2. Etoricoxib according to claim 1 and hydrochloric acid are into salt, it is characterised in that its thermal weight loss spectrogram fusing point 249.9 DEG C, complete decomposable process at about 472.8 DEG C.
- 3. Etoricoxib according to claim 1 and hydrochloric acid are into salt, it is characterised in that X- ray Powder Diffraction patterns are used Crystal face is represented 8.1,12.5,14.6,15.0,16.2,16.7,18.2,18.9,20.6 away from d values , 21.2,21.9,24.0,24.4,24.8,25.5,26.1,26.4,27.1,27.6,28.6 , have diffraction maximum at 29.3,30.7,32.0,33.9,35.2,35.4,36.3,36.9,.
- 4. Etoricoxib according to claim 1 and hydrochloric acid are into salt, it is characterised in that uv atlas goes out peak position, in first In alcoholic solvent, maximum absorption band is 203.6nm and 235.4nm.
- 5. salt according to claim 1 is brilliant, its nucleus magnetic hydrogen spectrum is characterised by：1H-NMR (500 MHz, MeOD): δ 2.78 (s, 3H), 3.15(s, 3H), 7.59 (d, J = 8.5 Hz 2H),7.79 (d, J = 14 Hz, 1H), 7.97 (d, J = 14 2H), 8.11 (d, J = 3.5 Hz, 1H), 8.28(dd, J = 3 Hz, 1H), 8.68 (d, J = 3 Hz 1H), 8.82 (d, J = 4 Hz, 1H)。
- 6. Etoricoxib and the new salt form preparation method of hydrochloric acid described in claim 1, it is characterised in that its hydrochloric acid is examined than support Former times proportioning is less than 1, and temperature control will be less than 25 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710877317.7A CN107556232A (en) | 2017-09-26 | 2017-09-26 | A kind of Etoricoxib and the novel crystal forms and preparation method of hydrochloric acid forming salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710877317.7A CN107556232A (en) | 2017-09-26 | 2017-09-26 | A kind of Etoricoxib and the novel crystal forms and preparation method of hydrochloric acid forming salt |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107556232A true CN107556232A (en) | 2018-01-09 |
Family
ID=60982499
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710877317.7A Pending CN107556232A (en) | 2017-09-26 | 2017-09-26 | A kind of Etoricoxib and the novel crystal forms and preparation method of hydrochloric acid forming salt |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107556232A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020042375A1 (en) * | 2000-07-05 | 2002-04-11 | Heimbrook David C. | Method of treating cancer |
| CN1152863C (en) * | 1996-07-18 | 2004-06-09 | 麦克弗罗斯特(加拿大)公司 | Substituted pyridines as selective cyclooxygenase-2 inhibitors |
| WO2012004677A1 (en) * | 2010-07-05 | 2012-01-12 | Actavis Group Ptc Ehf | Solid state forms of etoricoxib salts |
| EP2601952A1 (en) * | 2011-12-07 | 2013-06-12 | Zentiva, k.s. | Novel pharmaceutically acceptable salts and cocrystals of 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl and their therapeutic uses |
| WO2013105106A1 (en) * | 2011-11-03 | 2013-07-18 | Cadila Healthcare Limited | An improved process for the preparation of etoricoxib and polymorphs thereof |
| CN106632003A (en) * | 2015-12-31 | 2017-05-10 | 上海迈柏医药科技有限公司 | Method for preparing etoricoxib |
-
2017
- 2017-09-26 CN CN201710877317.7A patent/CN107556232A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1152863C (en) * | 1996-07-18 | 2004-06-09 | 麦克弗罗斯特(加拿大)公司 | Substituted pyridines as selective cyclooxygenase-2 inhibitors |
| US20020042375A1 (en) * | 2000-07-05 | 2002-04-11 | Heimbrook David C. | Method of treating cancer |
| WO2012004677A1 (en) * | 2010-07-05 | 2012-01-12 | Actavis Group Ptc Ehf | Solid state forms of etoricoxib salts |
| WO2013105106A1 (en) * | 2011-11-03 | 2013-07-18 | Cadila Healthcare Limited | An improved process for the preparation of etoricoxib and polymorphs thereof |
| EP2601952A1 (en) * | 2011-12-07 | 2013-06-12 | Zentiva, k.s. | Novel pharmaceutically acceptable salts and cocrystals of 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl and their therapeutic uses |
| CN106632003A (en) * | 2015-12-31 | 2017-05-10 | 上海迈柏医药科技有限公司 | Method for preparing etoricoxib |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2016184436A1 (en) | New crystal form of lenvatinib methanesulfonate salt and preparation method thereof | |
| TWI597277B (en) | Form i crystal of dimaleate salt of tyrosine kinase inhibitor and preparation method thereof | |
| CN105367552A (en) | Novel crystal form of neratinib maleate and preparation method thereof | |
| WO2016206534A1 (en) | New crystal form of apremilast and preparation method therefor | |
| WO2019228485A1 (en) | New crystal form of lenvatinib mesylate and preparation method therefor | |
| WO2020164565A1 (en) | New crystal form of oxypiperone hydrochloride and preparation method therefor | |
| CN107556232A (en) | A kind of Etoricoxib and the novel crystal forms and preparation method of hydrochloric acid forming salt | |
| CN105777655A (en) | Alpha crystal form of butenamide p-toluenesulfonate, preparation method and pharmaceutical composition containing the same | |
| JP2022508791A (en) | Dihydropyridine calcium channel blocker co-crystal, its production method and use | |
| CN107556233A (en) | A kind of Etoricoxib and the novel crystal forms and preparation method of thiophenic acid forming salt | |
| CN107417600A (en) | A kind of Etoricoxib and the novel crystal forms and preparation method of furancarboxylic acid forming salt | |
| CN107118153A (en) | A kind of Rui Gefeini monohydrate crystal forms and preparation method thereof | |
| WO2021000687A1 (en) | Preparation method for crystal form of pac-1 | |
| US10562855B2 (en) | Crystalline form of lenvantinib mesylate and process of preparation thereof | |
| CN103709156A (en) | Dasatinib polymorph medicine and preparation method thereof | |
| EP3272734A1 (en) | Ahu377 crystal form, preparation method and use thereof | |
| CN111032627B (en) | Crystal form of estrogen receptor inhibitor and preparation method thereof | |
| CN104557869B (en) | A kind of crystal formation of pyridinylamine compound fumarate | |
| WO2013075669A1 (en) | Crystal and amorphous substance of dapoxetine hydrochloride and preparation method therefor | |
| CN110143915A (en) | A kind of novel crystal forms and preparation method of Etoricoxib and p-methyl benzenesulfonic acid forming salt | |
| CN112174886A (en) | Preparation method of Levatinib mesylate crystal form X | |
| CN105859748B (en) | Polycyclic compound sodium salt and its polymorphic, preparation method and application | |
| WO2022253234A1 (en) | Crystal forms of glucosamine derivative, and preparation method therefor and use thereof | |
| WO2019120250A1 (en) | Novel crystal form of pimavanserin hemi-tartrate and method for preparing crystal form | |
| TW202408494A (en) | Novel crystalline form of isoxazole derivate and salt thereof and pharmaceutical composition including the same |
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: 20180109 |
|
| RJ01 | Rejection of invention patent application after publication |