CN104230824B - Erlotinib alkali crystal Form V and preparation method thereof - Google Patents
Erlotinib alkali crystal Form V and preparation method thereof Download PDFInfo
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- CN104230824B CN104230824B CN201410445259.7A CN201410445259A CN104230824B CN 104230824 B CN104230824 B CN 104230824B CN 201410445259 A CN201410445259 A CN 201410445259A CN 104230824 B CN104230824 B CN 104230824B
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- erlotinib
- alkali
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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 belongs to chemical pharmaceutical technical field, be specifically related to a kind of Erlotinib alkali crystal Form V and preparation method thereof.2 θ characteristic peaks in the X-ray powder diffraction of this crystal formation are positioned at 6.675 ± 0.2, and 8.677 ± 0.2,11.149 ± 0.2,13.028 ± 0.2,17.114 ± 0.2,18.115 ± 0.2,19.688 ± 0.2,21.609 ± 0.2,23.958 ± 0.2,25.756 ± 0.2,28.861 ± 0.2 degree.The present invention adopts hyperacoustic method to prepare the novel crystal forms Form V of Erlotinib alkali, preparation technology is simply controlled, operating time is short, be especially suitable for industrialized production, and the product crystal formation that the method is prepared is single, stable, by investigating the stability of Erlotinib alkali crystal Form V, find that this crystal formation has good heat stability and high humidity stability, and purity is high, it is especially suitable for long-time storage, and prepares highly purified erlotinib Hydrochloride.
Description
Technical field
The invention belongs to chemical pharmaceutical technical field, be specifically related to a kind of Erlotinib alkali crystal Form V and preparation method thereof.
Background technology
Erlotinib Hydrochloride is the oral antineoplastic agent of 4-aminophenyl quinazoline ditosylate salt that Osi Pharm Inc. of the U.S. (OSIPharmaceuticals) develops, and in 2004 in U.S.'s approval listing, is used for treating cancer of pancreas and Metastatic Nsclc.Erlotinib alkali, also known as Erlotinib, chemistry N-(3-acetylene phenyl)-[6,7-bis-(2-methoxyethoxy)] quinazoline-4-amine by name, structural formula is as follows:
The preparation method that patent US5747498 reports erlotinib Hydrochloride alkali at first, wherein the separation purification of Erlotinib alkali is to realize by the method for rapid column chromatography, refining Erlotinib alkali reacts with HCl in a solvent and generates erlotinib Hydrochloride, but the problem not mentioning Erlotinib alkali crystal formation in literary composition.
Patent WO2008012105 reports three kinds of novel crystal forms: FormI of Erlotinib alkali at first, FormII, FormIII, and disclose FormI, FormIII is hydrate forms, FormII is anhydride form, wherein FormII utilizes isopropanol to precipitate in Erlotinib alkali carrying out recrystallization or normal heptane joining the acetone soln of Erlotinib alkali to obtain in anhydrous conditions, FormI, the crystallization of FormIII is to obtain in moisture system, FormI be water/ethanol/acetone at ambient temperature mixture (2:1:1V/V/V) in crystallization, FormIII carries out crystallization from water/acetone (3:10V/V) at ambient temperature.
Patent WO2009024989 also reports a kind of Erlotinib aqueous alkali compound novel crystal forms (water content 1～10%), but can significantly find out from the XRD disclosed in patent, this patent obtained Erlotinib aqueous alkali compound crystal formation is the mixed crystal of FormI and FormII, is not the novel crystal forms that crystal formation is single.
Patent CN101914068 reports a kind of new Erlotinib alkali crystal Form IV, method disclosed in patent be by Erlotinib alkali thermosol in lipid solvent, cooling crystallize obtains FormIV, this preparation method there is no the participation of water, so the Erlotinib alkali crystal Form IV that this patent is reported exists with the form of anhydride.
Summary of the invention
It is an object of the invention to provide a kind of Erlotinib alkali crystal Form V, stable crystal form, purity are high, be particularly suited for industrialized production；The preparation method that invention also provides Erlotinib alkali crystal Form V, low-carbon environment-friendly, solvent used are cheap and easy to get, low toxicity, process route good stability, strong operability.
2 θ characteristic peaks in the X-ray powder diffraction of Erlotinib alkali crystal Form V of the present invention are positioned at 6.675 ± 0.2,8.677 ± 0.2,11.149 ± 0.2,13.028 ± 0.2,17.114 ± 0.2,18.115 ± 0.2,19.688 ± 0.2,21.609 ± 0.2,23.958 ± 0.2,25.756 ± 0.2,28.861 ± 0.2 degree.Wherein, in XRD figure, " ± 0.2 " is the measurement error scope allowed.
The DSC characteristic peak of described crystal formation is positioned at 152.17-154.96 DEG C.
The infrared absorption pattern characteristic peak of described crystal formation is positioned at 792,1030,1128,1208,1245,1461,1481,1512,1534,1569,1630,3283,3569cm-1。
The preparation method of Erlotinib alkali crystal Form V of the present invention, step is as follows:
(1) by Erlotinib alkali crude product, join in organic solvent, mix homogeneously；
(2) supersonic generator is opened, ultrasonic under ambient temperature；
(3) it is cooled to 0-5 DEG C after ultrasonic；
(4) sucking filtration, drip washing filter cake, vacuum drying, obtain Erlotinib alkali crystal Form V.
Organic solvent described in step (1) is one or more in methanol, ethanol, normal propyl alcohol, isopropanol or acetone, it is preferred to ethanol.
The ratio of the Erlotinib alkali described in step (1) and organic solvent is 1g:10-50ml, it is preferred to 1g:15-20ml.
The power of the supersonic generator described in step (2) is 500-1500W, it is preferred to 800-1200W；Frequency is 20-40KHz, it is preferred to 25-28KHz.
Ultrasonic time described in step (2) is 10-30min, it is preferred to 15-20min.
Vacuum drying temperature described in step (4) is 20-50 DEG C, it is preferred to 25-30 DEG C.
The present invention compared with prior art, has the advantages that
The present invention adopts hyperacoustic method to prepare the novel crystal forms FormV of Erlotinib alkali, preparation technology is simply controlled, operating time is short, be especially suitable for industrialized production, and the product crystal formation that the method is prepared is single, stable, by investigating the stability of Erlotinib alkali crystal Form V, find that this crystal formation has good heat stability and high humidity stability, and purity is high, it is especially suitable for long-time storage, and prepares highly purified erlotinib Hydrochloride.
Accompanying drawing explanation
Fig. 1 is the X-powder diffraction spectrum of the Erlotinib alkali crystal Form V of embodiment 1 preparation；
Fig. 2 is the DSC collection of illustrative plates of the Erlotinib alkali crystal Form V of embodiment 1 preparation；
Fig. 3 is the infared spectrum of the Erlotinib alkali crystal Form V of embodiment 1 preparation.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described further.
Embodiment 1
In the reaction bulb of the 250ml of clean dried, add 10.0g Erlotinib alkali, 100ml methanol, be uniformly mixed under room temperature, being put into by reaction bulb in 1500W supersonic generator, frequency is 40KHz, ultrasonic 10min, after ultrasonic, stir borehole cooling to 0～5 DEG C, sucking filtration, with 20ml methanol drip washing, filter cake is vacuum drying at 20 DEG C, obtains white solid, 9.5g, productivity 95.0%, HPLC purity 99.8%.
Embodiment 2
In the reaction bulb of the 250ml of clean dried, add 10.0g Erlotinib alkali, 300ml ethanol, be uniformly mixed under room temperature, being put into by reaction bulb in 1000W supersonic generator, frequency is 30KHz, ultrasonic 20min, after ultrasonic, stir borehole cooling to 0～5 DEG C, sucking filtration, use 20ml ethanol rinse, filter cake is vacuum drying at 25 DEG C, obtains white solid, 9.3g, productivity 93.0%, HPLC purity 99.9%.
Embodiment 3
In the reaction bulb of the 250ml of clean dried, add 10.0g Erlotinib alkali, 500ml isopropanol, be uniformly mixed under room temperature, being put into by reaction bulb in 500W supersonic generator, frequency is 20KHz, ultrasonic 30min, after ultrasonic, stir borehole cooling to 0～5 DEG C, sucking filtration, with 15ml isopropanol drip washing, filter cake is vacuum drying at 50 DEG C, obtains white solid, 8.9g, productivity 89.0%, HPLC purity 99.8%.
Embodiment 4
In the reaction bulb of the 250ml of clean dried, add 10.0g Erlotinib alkali, 150ml normal propyl alcohol, be uniformly mixed under room temperature, being put into by reaction bulb in 1000W supersonic generator, frequency is 28KHz, ultrasonic 15min, after ultrasonic, stir borehole cooling to 0～5 DEG C, sucking filtration, with 15ml normal propyl alcohol drip washing, filter cake is vacuum drying at 50 DEG C, obtains white solid, 8.8g, productivity 88.0%, HPLC purity 99.7%.
Embodiment 5
In the reaction bulb of the 250ml of clean dried, add 10.0g Erlotinib alkali, 500ml acetone, be uniformly mixed under room temperature, being put into by reaction bulb in 1000W supersonic generator, frequency is 28KHz, ultrasonic 15min, after ultrasonic, stir borehole cooling to 0～5 DEG C, sucking filtration, with 20ml acetone drip washing, filter cake is vacuum drying at 25 DEG C, obtains white solid, 9.2g, productivity 92.0%, HPLC purity 99.8%.
Embodiment 6
In the reaction bulb of the 250ml of clean dried, add 10.0g Erlotinib alkali, 500ml methanol, be uniformly mixed under room temperature, being put into by reaction bulb in 1500W supersonic generator, frequency is 20KHz, ultrasonic 20min, after ultrasonic, stir borehole cooling to 0～5 DEG C, sucking filtration, with 20ml methanol drip washing, filter cake is vacuum drying at 20 DEG C, obtains white solid, 9.1g, productivity 91.0%, HPLC purity 99.7%.
Embodiment 7
In the reaction bulb of the 250ml of clean dried, add 10.0g Erlotinib alkali, 100ml ethanol, be uniformly mixed under room temperature, being put into by reaction bulb in 1000W supersonic generator, frequency is 40KHz, ultrasonic 20min, after ultrasonic, stir borehole cooling to 0～5 DEG C, sucking filtration, use 20ml ethanol rinse, filter cake is vacuum drying at 25 DEG C, obtains white solid, 9.5g, productivity 95.0%, HPLC purity 99.8%.
The stability test of Erlotinib alkali crystal Form V
The Erlotinib alkali crystal Form V sample embodiment 2 and embodiment 5 prepared is airtight to be left in stability test case, temperature 40 DEG C, and humidity 75%, respectively at 30 days, 45 days, 60 days, 75 days, 90 days, sampling detected its change having related substance, and the related data of Erlotinib alkali purity is in Table 1.
The stability examination data of table 1 Erlotinib alkali crystal Form V
Taking study on the stability its XRD of the sample determination of 90 days, collection of illustrative plates contrasts consistent with Fig. 1, illustrates that Erlotinib alkali crystal Form V prepared by supercritical ultrasonics technology has good stability.
Claims (6)
1. an Erlotinib alkali crystal FormPreparation method, it is characterised in that X-ray powder diffraction such as Fig. 1 of this crystal formation；
Step is as follows:
(1) by Erlotinib alkali crude product, join in organic solvent, mix homogeneously；
(2) supersonic generator is opened, ultrasonic under ambient temperature；
(3) it is cooled to 0-5 DEG C after ultrasonic；
(4) sucking filtration, drip washing filter cake, vacuum drying, obtain Erlotinib alkali crystal Form；
Organic solvent described in step (1) is one or more in methanol, ethanol, normal propyl alcohol, isopropanol or acetone；
The power of the supersonic generator described in step (2) is 500-1500W, and frequency is 20-40KHz.
2. Erlotinib alkali crystal Form according to claim 1Preparation method, it is characterised in that the DSC characteristic peak of described crystal formation is positioned at 152.17-154.96 DEG C.
3. Erlotinib alkali crystal Form according to claim 1Preparation method, it is characterised in that the infrared absorption pattern of described crystal formation such as Fig. 3.
4. Erlotinib alkali crystal Form according to claim 1Preparation method, it is characterised in that the ratio of the Erlotinib alkali described in step (1) and organic solvent is 1g:10-50ml.
5. Erlotinib alkali crystal Form according to claim 1Preparation method, it is characterised in that the ultrasonic time described in step (2) is 10-30min.
6. Erlotinib alkali crystal Form according to claim 1Preparation method, it is characterised in that the vacuum drying temperature described in step (4) is 20-50 DEG C.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101914068A (en) * | 2010-08-14 | 2010-12-15 | 浙江华海药业股份有限公司 | Novel crystal form of erlotinib alkali and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101914068A (en) * | 2010-08-14 | 2010-12-15 | 浙江华海药业股份有限公司 | Novel crystal form of erlotinib alkali and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 声结晶技术的研究进展;杭方学等;《声学技术》;20070630;第26卷(第3期);第539-544页 * |
| 超声场强化溶液结晶研究进展;胡爱军等;《应用声学》;20021231;第21卷(第4期);第44-48页 * |
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Address after: 255129 Zichuan Economic Development Zone, Shandong, China, Zibo Applicant after: SHANDONG JINCHENG PHARMACEUTICAL CO., LTD. Address before: 255129 Zichuan Economic Development Zone, Shandong, China, Zibo Applicant before: Shandong Jincheng Pharmaceutical & Chemical Co., Ltd. |
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Address after: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee after: Shandong Jincheng Pharmaceutical Group Limited by Share Ltd Address before: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee before: SHANDONG JINCHENG PHARMACEUTICAL CO., LTD. |