CN104250230A - Erlotinib citrate, crystal form and preparation method of two - Google Patents
Erlotinib citrate, crystal form and preparation method of two Download PDFInfo
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- CN104250230A CN104250230A CN201410454321.9A CN201410454321A CN104250230A CN 104250230 A CN104250230 A CN 104250230A CN 201410454321 A CN201410454321 A CN 201410454321A CN 104250230 A CN104250230 A CN 104250230A
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- tarceva
- citrate trianion
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
Abstract
The invention relates to erlotinib citrate, a crystal form and a preparation method of the two. The preparation method comprises: using erlotinib hydrochloride as a raw material, dissolving in an ethyl acetate/water system or an acetone/water system, employing an alkali solution to adjust pH to be alkali, and adding citric acid to form a salt. The volume ratio of ethyl acetate to water in the ethyl acetate/ water system is 10:3, and the volume ratio of acetone to water in the acetone/water system is 15:4. The citrate of erlotinib and the specific crystal form of the erlotinib citrate have extremely good pharmacokinetic characteristics.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of Tarceva Citrate trianion and its crystal formation and their preparation method, also relate to described Tarceva Citrate trianion and the application of its crystal formation in pharmacy.
Background technology
Tarceva (Erlotinib) is first selectivity human epidermal growth factor acceptor (EGFR) the TYR kinase inhibitor developed by Roche Group of Switzerland (Roche Pharma), is applicable to two of the nonsmall-cell lung cancer of Locally Advanced or transfer, three line treatments.
Tarceva, chemical name is [6,7-bis-(2-methoxy ethoxy)-quinazoline-4-base]-(3-ethynyl phenyl) amine, and its structural formula is as follows:
Document CN1066142C discloses the preparation method of Tarceva and hydrochloride thereof, and after this US6900221, US7148231, US2009124642, CN101735156 etc. disclose the multiple crystallized form of Tarceva hydrochloride.CN1298396A discloses Tarceva mesylate and A, B, the C crystal form of anhydrous form.In addition, WO2008122776 and WO2011068403 discloses crystal formation and the preparation method of the multiple salt derivative of Tarceva, comprise vitriol, benzene sulfonate, oxalate, ethyl sulfonate, isethionate, hydrobromate, malonate, Pfansteihl salt, succinate, maleate also points out that part salt derivative has the water solubility more excellent than Tarceva hydrochloride and bioavailability, but does not provide concrete experimental data.
The report of Tarceva Citrate trianion is had no in currently available technology.
Summary of the invention
An object of the present invention is to provide a kind of Novel erlotinib derivative, is specially Tarceva Citrate trianion.
Another object of the present invention is to the crystal formation that a kind of Tarceva Citrate trianion is provided.
The present invention also provides the preparation method of described Tarceva Citrate trianion and crystal formation thereof.
Further aim of the present invention is to provide the pharmaceutical composition of the crystal formation comprising described Tarceva Citrate trianion or described Tarceva Citrate trianion.
Other objects of the present invention are also to provide the crystal formation of described Tarceva Citrate trianion or described Tarceva Citrate trianion preparing the application in human epidermal growth factor TYR kinase inhibitor.
Tarceva Citrate trianion provided by the present invention is specially formula 1,
Wherein HA is citric acid.
The crystal formation of Tarceva Citrate trianion of the present invention, when using X-ray diffraction CuK α to analyze, 4.04 in X-ray diffractogram, 6.62,8.04,16.4,19.9,22.0,23.3,24.0,25.8 there is X-ray diffraction peak.
The crystal formation of Tarceva Citrate trianion of the present invention,
| 2θ | d(A) | 2θ | d(A) | 2θ | d(A) |
| 4.04 | 21.8 | 14.3 | 6.14 | 24.0 | 3.69 |
| 6.24 | 14.1 | 14.7 | 6.00 | 24.6 | 3.60 |
| 6.62 | 13.3 | 16.0 | 5.51 | 25.5 | 3.47 |
| 7.36 | 11.9 | 16.4 | 5.38 | 25.8 | 3.44 |
| 8.04 | 10.9 | 17.7 | 4.98 | 26.3 | 3.37 |
| 9.56 | 9.24 | 18.0 | 4.90 | 26.9 | 3.29 |
| 9.83 | 8.99 | 18.8 | 4.69 | 28.9 | 3.08 |
| 10.3 | 8.50 | 19.9 | 4.45 | 29.5 | 3.01 |
| 10.9 | 8.08 | 20.1 | 4.4 | 29.8 | 2.98 |
| 12.0 | 7.33 | 20.9 | 4.24 | 31.0 | 2.87 |
| 12.3 | 7.16 | 21.9 | 4.04 | 31.7 | 2.81 |
| 12.6 | 6.96 | 22.0 | 4.02 | 33.0 | 2.70 |
| 13.1 | 6.74 | 22.8 | 3.88 | 33.6 | 2.65 |
| 14.2 | 6.22 | 23.3 | 3.80 | 34.6 | 2.58 |
When using X-ray diffraction CuK α to analyze, 2 θ, d (A) of X-ray diffractogram as shown above.
The crystal formation of Tarceva Citrate trianion of the present invention, when using X-ray diffraction CuK α to analyze, described X-ray diffractogram as shown in Figure 2 or Figure 3.
Present invention also offers the preparation method of the crystal formation of described Tarceva Citrate trianion or described Tarceva Citrate trianion, the method comprises: use Tarceva hydrochloride to be raw material, be dissolved in the mixed system of organic solvent and water, adopt basic solution to regulate pH to be after alkalescence, add citric acid salify.
According to specific embodiment of the invention scheme, in the preparation method of the crystal formation of described Tarceva Citrate trianion or described Tarceva Citrate trianion, the solvent that described organic solvent can be commonly used for organic chemistry filed is as ethyl acetate, methyl alcohol, ethanol, acetone, tetrahydrofuran (THF), toluene etc., ethyl acetate, acetone in the present invention, namely the method comprises: use Tarceva hydrochloride to be raw material, be dissolved in the system of ethyl acetate/aqueous systems or acetone/water, adopt basic solution to regulate pH to be after alkalescence, add citric acid salify.In the present invention, preferred organic solvent with the mixed volume ratio of water is: in ethyl acetate/aqueous systems, the volume ratio of ethyl acetate and water is 10:3, and in the system of acetone/water, the volume ratio of acetone and water is 15:4.
According to specific embodiment of the invention scheme, in the preparation method of the crystal formation of described Tarceva Citrate trianion or described Tarceva Citrate trianion, described basic solution can be this area lithium hydroxide solution usually used, sodium hydroxide solution, potassium hydroxide solution, cesium hydroxide solution, sodium carbonate solution, solution of potassium carbonate, cesium carbonate solution etc., its concentration is not construed as limiting, preferably 30-70% lithium hydroxide solution is used in the present invention, 30-70% sodium hydroxide solution, 30-70% potassium hydroxide solution, 30-70% cesium hydroxide solution, more preferably the sodium hydroxide solution of 50%.Described pH is that alkalescence refers to that pH is more than or equal to 7.0, and preferred pH is 8.0 ~ 9.0.
On the other hand, present invention also offers a kind of pharmaceutical composition, this pharmaceutical composition comprises: the crystal formation of Tarceva Citrate trianion of the present invention or described Tarceva Citrate trianion, and one or more pharmaceutically acceptable carrier or vehicle.The crystal formation of Tarceva Citrate trianion of the present invention or Tarceva Citrate trianion can make pharmaceutical field common formulations, as preparations such as tablet, capsule, injections with one or more pharmaceutically acceptable carriers or vehicle.
On the other hand, the crystal formation that present invention also offers described Tarceva Citrate trianion or described Tarceva Citrate trianion is preparing the application in human epidermal growth factor acceptor TYR kinase inhibitor.Described Tarceva Citrate trianion and specific crystal formation thereof have good Pharmacokinetic Characteristics.
Accompanying drawing explanation
Fig. 1 is X-ray diffractogram when using X-ray diffraction CuK α to analyze by prior art self-control Tarceva hydrochloride Form;
X-ray diffractogram when Fig. 2 is the CuK α analysis of embodiment 1 gained Tarceva Citrate trianion use X-ray diffraction;
X-ray diffractogram when Fig. 3 is the CuK α analysis of embodiment 2 gained Tarceva Citrate trianion use X-ray diffraction.
Embodiment
Further can be described the present invention by the following examples, but invention of the present invention is not limited to the following examples, the scope that these embodiments do not limit the present invention in any way.Those skilled in the art within the scope of the claims done some changes and adjustment also should be thought and belongs to scope of the present invention.
Embodiment 1: the preparation of Tarceva Citrate trianion
Get by prior art self-control Tarceva HCl, solid (using X-ray diffraction CuK α to analyze the X-ray diffractogram obtained as shown in Figure 1) 3g, add 50ml ethyl acetate and 15ml hydroecium temperature is stirred, be heated to 60 DEG C, add 50% aqueous sodium hydroxide solution, regulate aqueous phase pH8 ~ 9, solution is clarified, separatory while hot.Collect organic phase and wash with saturated sodium-chloride, organic phase 70 DEG C of heated and stirred 30 minutes, add 1.5g citric acid, system slightly muddiness is clearly not molten, and system becomes muddy gradually, stops heating after stirring 30min, system is white emulsion, and water-bath is cooled to stirring at room temperature crystallization 40min.Filter, obtain faint yellow solid, ethyl acetate is washed, and vacuum-drying, obtains Tarceva Citrate trianion 3.2g.Fusing point 155-158 DEG C, use X-ray diffraction CuK α to analyze the X-ray diffractogram obtained as shown in Figure 2, wherein 2 θ and d (A) value is as shown in the table:
| 2θ | d(A) | 2θ | d(A) | 2θ | d(A) |
| 4.04 | 21.8 | 14.3 | 6.14 | 24.0 | 3.69 |
| 6.24 | 14.1 | 14.7 | 6.00 | 24.6 | 3.60 |
| 6.62 | 13.3 | 16.0 | 5.51 | 25.5 | 3.47 |
| 7.36 | 11.9 | 16.4 | 5.38 | 25.8 | 3.44 |
| 8.04 | 10.9 | 17.7 | 4.98 | 26.3 | 3.37 |
| 9.56 | 9.24 | 18.0 | 4.90 | 26.9 | 3.29 |
| 9.83 | 8.99 | 18.8 | 4.69 | 28.9 | 3.08 |
| 10.3 | 8.50 | 19.9 | 4.45 | 29.5 | 3.01 |
| 10.9 | 8.08 | 20.1 | 4.4 | 29.8 | 2.98 |
| 12.0 | 7.33 | 20.9 | 4.24 | 31.0 | 2.87 |
| 12.3 | 7.16 | 21.9 | 4.04 | 31.7 | 2.81 |
| 12.6 | 6.96 | 22.0 | 4.02 | 33.0 | 2.70 |
| 13.1 | 6.74 | 22.8 | 3.88 | 33.6 | 2.65 |
| 14.2 | 6.22 | 23.3 | 3.80 | 34.6 | 2.58 |
Embodiment 2: the preparation of Tarceva Citrate trianion
Get the self-control Tarceva HCl, solid 3g identical with embodiment 1, add 15ml acetone and 4ml hydroecium temperature is stirred, be heated to 60 DEG C, add 50% aqueous sodium hydroxide solution, make aqueous phase pH8 ~ 9, solution is clarified, separatory while hot, organic phase saturated sodium-chloride washs, and collects organic phase and in 70 DEG C of heated and stirred 30 minutes, adds 1.5g citric acid, stirring and dissolving, system becomes muddy rear adularescent insolubles precipitation gradually by clarifying, and stops heating, last water-bath cooling and stirring crystallization 40min.Filter, obtain faint yellow solid, washing with acetone, vacuum-drying, obtain citric acid Tarceva 3.0g.Fusing point 155-158 DEG C, use X-ray diffraction CuK α to analyze the X-ray diffractogram obtained as shown in Figure 3, the Tarceva Citrate trianion that comparative example 1 obtains is known, and both are same crystal formation.
Embodiment 3: pharmacokinetics in beasle dog body of the Tarceva salt of different crystal forms and bioavailability study
Test method:
1, test drug: self-control erlotinid hydrochloride bulk drug and tablet (in Tarceva, containing 150mg Tarceva); The Tarceva Citrate trianion bulk drug prepared according to implementation column 2 and tablet (in Tarceva, containing 150mg Tarceva); By prior art homemade Tarceva maleate bulk drug (its crystal formation is different from Tarceva Citrate trianion of the present invention) and tablet (in Tarceva, containing 150mg Tarceva), the auxiliary material that the tablet of above-mentioned different Tarceva salt adopts is all identical with method, and above-mentioned three kinds of Tarceva salt tablets are substantially identical with its raw materials used medicine at the diffractogram of X-ray powder diffraction test gained, prove in film-making process, crystal formation does not change.
2, experimental animal and administration: 24 healthy beasle dogs, male and female half and half, 2 ~ 3 year old age, weight (14.85 ± 1.37) kg, adopt single dose dicycle trial design, 24 healthy beasle dogs are divided into 6 groups: A group intravenous injection self-control Tarceva HCI solution at random, the above-mentioned Tarceva hydrochloride sheet 1 prepared of A1 group gavage, the Tarceva citrate solution that B group intravenous injection embodiment 2 prepares, the above-mentioned Tarceva Citrate trianion sheet 1 prepared of B1 group gavage, C group intravenous injection self-control Tarceva maleate solution, the above-mentioned Tarceva maleate sheet 1 prepared of C1 group gavage, after 1 week, similar medicine intersection replaces another kind of route of administration, fasting during 4h after 12h and administration before test, only freely drink water.
3, blood specimen collection and mensuration: before administration (0 h) adopts blank blood, after administration in 1,2,3,4,6,8,10,12,24,36,48,72,96,120h foreleg vein takes a blood sample about 2mL, is placed in the centrifuge tube containing heparin, mixing, 3000rmin
-1centrifugal 10min, separated plasma ,-20 DEG C of conditions are saved to mensuration. and adopt LC-MS-MS method to measure dog plasma Tarceva concentration, result is as shown in the table:
1) in table, data are mean+SD.
Test-results shows that the gastric infusion bioavailability of Tarceva Citrate trianion tablet is apparently higher than Tarceva HCl tablets and Tarceva maleate tablet.Under same dose oral Tarceva Citrate trianion peak time and reach peak concentration comparatively other groups more fast and significantly, each group transformation period, test illustrated that oral Tarceva Citrate trianion has better Pharmacokinetic Characteristics without significant difference.
Claims (9)
1. the Tarceva Citrate trianion shown in formula 1,
Wherein HA is citric acid.
2. the crystal formation of Tarceva Citrate trianion according to claim 1, is characterized in that, when using X-ray diffraction CuK α to analyze, 4.04 in X-ray diffractogram, and 6.62,8.04,16.4,19.9,22.0,23.3,24.0,25.8 there is X-ray diffraction peak.
3. the crystal formation of Tarceva Citrate trianion according to claim 1, is characterized in that,
When using X-ray diffraction CuK α to analyze, 2 θ, d (A) of X-ray diffractogram as shown above.
4. the crystal formation of Tarceva Citrate trianion according to claim 1, is characterized in that, when using X-ray diffraction CuK α to analyze, X-ray diffractogram as shown in Figure 2 or Figure 3.
5. the preparation method of the crystal formation of Tarceva Citrate trianion according to claim 1 or Tarceva Citrate trianion according to claim 2, the method comprises: use Tarceva hydrochloride to be raw material, be dissolved in the system of ethyl acetate/aqueous systems or acetone/water, adopt basic solution to regulate pH to be after alkalescence, add citric acid salify.
6. preparation method according to claim 5, wherein, in ethyl acetate/aqueous systems, the volume ratio of ethyl acetate and water is 10:3, and in the system of acetone/water, the volume ratio of acetone and water is 15:4.
7. preparation method according to claim 5, wherein, described basic solution is 50% sodium hydroxide solution, and described pH is 8 ~ 9.
8. a pharmaceutical composition, this pharmaceutical composition comprises: the crystal formation of Tarceva Citrate trianion according to claim 1 or Tarceva Citrate trianion according to claim 2, and one or more pharmaceutically acceptable carrier or vehicle.
9. the crystal formation of Tarceva Citrate trianion according to claim 1 or Tarceva Citrate trianion according to claim 2 is preparing the application in human epidermal growth factor acceptor TYR kinase inhibitor.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410454321.9A CN104250230A (en) | 2014-09-05 | 2014-09-05 | Erlotinib citrate, crystal form and preparation method of two |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008122776A2 (en) * | 2007-04-04 | 2008-10-16 | Cipla Limited | Process for preparation of erlotinib and its pharmaceutically acceptable salts |
| CN103958483A (en) * | 2011-10-10 | 2014-07-30 | 埃吉斯药物私人有限公司 | Erlotinib salts |
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- 2014-09-05 CN CN201410454321.9A patent/CN104250230A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008122776A2 (en) * | 2007-04-04 | 2008-10-16 | Cipla Limited | Process for preparation of erlotinib and its pharmaceutically acceptable salts |
| CN103958483A (en) * | 2011-10-10 | 2014-07-30 | 埃吉斯药物私人有限公司 | Erlotinib salts |
Non-Patent Citations (1)
| Title |
|---|
| COMPOUND SUMMARY FOR CID 71584950: "N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine;2-hydroxypropane-1,2,3- tricarboxylic acid", 《PUBCHEM》 * |
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