CN107663193A - Pazopanib hydrochloride and its production and use - Google Patents
Pazopanib hydrochloride and its production and use Download PDFInfo
- Publication number
- CN107663193A CN107663193A CN201610601502.9A CN201610601502A CN107663193A CN 107663193 A CN107663193 A CN 107663193A CN 201610601502 A CN201610601502 A CN 201610601502A CN 107663193 A CN107663193 A CN 107663193A
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- CN
- China
- Prior art keywords
- pazopanib hydrochloride
- pazopanib
- room temperature
- crystal
- preparation
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical technology field, and in particular to crystal formation of pazopanib hydrochloride and preparation method thereof, the pazopanib hydrochloride for the novel crystal forms that the present invention obtains, have the advantage that：Purity is high, and maximum contaminant is less than 0.5 ‰；Stability is good；Method favorable reproducibility, is amplified to pilot-scale, and purity and crystal formation can reappear very well.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to crystal of pazopanib hydrochloride and preparation method thereof.
Background technology
Pazopanib hydrochloride is as needed for one kind that GlaxoSmithKline PLC company is researched and developed may interfere with obstinate tumor survival and growth
New vascular generation new oral angiogenesis inhibitors, targeting leads in vascular endothelial growth factor receptor (VEGFR)
Suppression is crossed to work to the new vascular generation of tumor feeding.Suitable for advanced renal cell carcinoma（One kind finds cancer in renal tubule
The kidney type of cell）, soft tissue sarcoma (STS), ovarian epithelial carcinoma and non-small cell lung cancer (NSCLC) treatment.
The structural formula of pazopanib hydrochloride is as follows：
Pazopanib hydrochloride is a kind of multi-crystalline compounds, and patent WO2011069053A1 discloses the ten of pazopanib hydrochloride
Several crystal formations and preparation method thereof, patent CN103232443A protect a kind of crystal formation L and preparation method thereof, patent CN
104130245A discloses a kind of pazopanib hydrochloride N crystal form.But no matter which kind of method, obtained pazopanib hydrochloride purity
Low, impurity content is high；Method poor reproducibility, it is difficult to pilot-scale is amplified to, so that content and crystal formation can not reappear.
The pazopanib hydrochloride for the novel crystal forms that the present invention obtains has the advantage that：Purity is high, and maximum contaminant is less than 0.5 ‰；
Stability is good；Method favorable reproducibility, is amplified to pilot-scale, and content and crystal formation can reappear very well.
The content of the invention
One object of the present invention, disclose a kind of crystal of pazopanib hydrochloride.
Another object of the present invention, disclose the preparation method of pazopanib hydrochloride crystal.
A further object of the present invention, disclose the pharmaceutical composition for including pazopanib hydrochloride crystal.
Present invention is specifically described in conjunction with the purpose of the present invention.
The invention provides a kind of pazopanib hydrochloride（Shown in formula I）Crystal,
The pazopanib hydrochloride crystal, determined using D/Max-2500.9161 types x-ray diffractometer, condition determination：Cu Ka
Target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction characteristic absorption peak（2θ）It is as follows with D values.
The measure of 2 θ values uses light source in the present invention, and precision is ± 0.2 °, therefore represents above-mentioned taken value and allow have certain conjunction
The error range of reason, its error range are ± 0.2 °.
Fusing point test：According to Pharmacopoeia of People's Republic of China（2010 editions, two）The first methods of C of annex VI determine fusing point, survey
The fusing point obtained is 290.5 DEG C -300.6 DEG C.Thermogravimetric analysis shows molten without recrystallisation solvent or absorption in pazopanib hydrochloride crystal
Agent.
Another object of the present invention, disclose the preparation method of pazopanib hydrochloride crystal.
Document report, pazopanib hydrochloride have a variety of preparation methods, and because its process for purification is different, purity is also different,
Crystal formation is also different.
The present inventor explores the relation of refining solvent and obtained pazopanib hydrochloride crystal, led to by largely testing
Cross and dissolve by heating pazopanib hydrochloride in the boiling solution containing ammonia, when naturally cooling to room temperature, then being incubated one section
Between obtain the present invention pazopanib hydrochloride crystal.The addition of ammoniacal liquor is required, and the amount of addition is very crucial.Ammoniacal liquor contains ammonia 28%
~29%.
It is specific as follows：Pazopanib hydrochloride adds 10-10.5 times（Weight or measurement (WM) ratio）Boiling-ammoniacal liquor=9：0.5-1：
In 1-1.2 mixed liquor, 60 DEG C -72 DEG C are heated to, the activated carbon of pazopanib hydrochloride 5% is added, insulated and stirred 30 minutes, takes advantage of
Heat filtering, room temperature is naturally cooled under filtrate stirring, then be incubated 5-6 hours, separated out crystallization, filtering, dry, obtain through room temperature in vacuo
To the above-mentioned pazopanib hydrochloride crystal of high-purity.
The product purity that this method obtains is high, and maximum contaminant is less than 0.5 ‰；Stability is good；It is amplified to pilot-scale, content
It can be reappeared very well with crystal formation.
Pazopanib hydrochloride used, the method provided according to document synthesize（Also can be obtained from commercial channel）, the salt of synthesis
The chemical constitution of sour pazopanib proves that chemical constitution is correct through nuclear magnetic resoance spectrum, elementary analysis.
A further object of the present invention, there is provided pharmaceutically acceptable comprising pazopanib hydrochloride crystal and one or more
Carrier composition pazopanib hydrochloride composition.
The pharmaceutical composition of the present invention prepares as follows：Using standard and conventional technique, make crystal and galenic pharmacy of the present invention
Upper acceptable liquid-carrier combines, and is allowed to arbitrarily be combined preparation with acceptable adjuvant and excipient on galenic pharmacy
Into particulate or microballoon.Said composition is used to prepare injection.
The active ingredient contained in pharmaceutical composition and unit dosage form（Crystal of the present invention）Amount can be according to patient's
The state of an illness, the situation of diagnosis are specifically applied, and the amount or concentration of compound used are adjusted in a wider scope
Section, the amount scope of reactive compound are the 0.1%~10% of composition（Weight）.
Stability test
According to a conventional method, investigate in 60 DEG C of high temperature, relative humidity 92.5%（RH）, strong illumination（4500Lx）Under, hydrochloric acid of the present invention
The relevant material of pazopanib crystal：
| 0 day | 5 days | 10 days | |
| 60 DEG C of high temperature | 0.04% | 0.04% | 0.04% |
| Relative humidity 92.5%（RH） | 0.04% | 0.04% | 0.05% |
| Strong illumination（4500Lx） | 0.04% | 0.05% | 0.05% |
As a result：In high temperature（60℃）, high humidity（RH, 92.5%）, strong illumination（4500Lx）Under, keep high purity, stability
Well, it is adapted to the manufacture of pharmaceutical preparation and long-term storage.
Embodiment：
With reference to embodiment, the present invention is described further, professional and technical personnel in the field is better understood from this hair
It is bright.Embodiment is only explanatory, is in no way intended to the scope that it limit the invention in any way.
Embodiment 1
In 50L reactors, add 3 kilograms of pazopanib hydrochlorides (purity 97.3%, HPLC) and 30.3L boiling-ammoniacal liquor=
9：0.8：In 1.1 mixed liquor, 60 DEG C -72 DEG C are heated to, 150 grams of activated carbons is added, insulated and stirred 30 minutes, filters while hot,
Room temperature is naturally cooled under filtrate stirring, then is incubated 5.5 hours, crystallization is separated out, filtering, is dried through room temperature in vacuo, obtain hydrochloric acid
2.81 kilograms of pazopanib crystal.Fusing point：290.5 DEG C -300.6 DEG C, purity 99.95%, single contaminant 0.04%, MS:349.13
(M+H) dissolvent residual detection meets the requirements.
Embodiment 2
Capsule containing pazopanib hydrochloride compound
Prescription：85 grams, propane diols 3.5ml of pazopanib hydrochloride, 145 grams of starch, is made 1000.
Technique：By pazopanib hydrochloride, starch, soaked with 20% aqueous solution of propylene glycol, granulation of being sieved after mixing, 55 DEG C dry
It is dry, whole grain, fill capsule.
Claims (4)
1. formula（Ⅰ）Pazopanib hydrochloride crystal formation,
（Ⅰ）
It is characterized in that：In being determined by the use of CuKa rays as characteristic X-ray powder, its collection of illustrative plates has the following 2 θ angles of diffraction and relative
Intensity,
The error of the 2 θ angles of diffraction is 0.2,
It is further characterized in that：290.5 DEG C -300.6 DEG C of fusing point.
2. the preparation method of pazopanib hydrochloride crystal described in claim 1, by the way that pazopanib hydrochloride is being contained into ammonia
Dissolved by heating in boiling solution, naturally cool to room temperature, then be incubated and obtain for a period of time.
3. the preparation method of pazopanib hydrochloride crystal described in claim 2, it is characterised in that comprise the following steps：Hydrochloric acid pa azoles
Pa Ni adds 10-10.5 times（Weight or measurement (WM) ratio）Boiling-ammoniacal liquor=9：0.5-1：In 1-1.2 mixed liquor, 60 are heated to
DEG C -72 DEG C, the activated carbon of pazopanib hydrochloride 5% is added, insulated and stirred 30 minutes, is filtered while hot, the lower natural cooling of filtrate stirring
To room temperature, then 5-6 hours are incubated, separate out crystallization, filtering, be dried to obtain through room temperature in vacuo.
4. one kind forms containing pazopanib hydrochloride crystal described in claim 1 and one or more pharmaceutically acceptable carriers
Composition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610601502.9A CN107663193A (en) | 2016-07-28 | 2016-07-28 | Pazopanib hydrochloride and its production and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610601502.9A CN107663193A (en) | 2016-07-28 | 2016-07-28 | Pazopanib hydrochloride and its production and use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107663193A true CN107663193A (en) | 2018-02-06 |
Family
ID=61113918
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610601502.9A Pending CN107663193A (en) | 2016-07-28 | 2016-07-28 | Pazopanib hydrochloride and its production and use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107663193A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10626110B2 (en) | 2018-08-07 | 2020-04-21 | Formosa Laboratories, Inc. | Polymorph of pazopanib hydrochloride and preparation process thereof |
-
2016
- 2016-07-28 CN CN201610601502.9A patent/CN107663193A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10626110B2 (en) | 2018-08-07 | 2020-04-21 | Formosa Laboratories, Inc. | Polymorph of pazopanib hydrochloride and preparation process thereof |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180206 |