CN101104591A - Polymorph of proparacaine hydrochloride and preparation method thereof - Google Patents
Polymorph of proparacaine hydrochloride and preparation method thereof Download PDFInfo
- Publication number
- CN101104591A CN101104591A CNA2006100365754A CN200610036575A CN101104591A CN 101104591 A CN101104591 A CN 101104591A CN A2006100365754 A CNA2006100365754 A CN A2006100365754A CN 200610036575 A CN200610036575 A CN 200610036575A CN 101104591 A CN101104591 A CN 101104591A
- Authority
- CN
- China
- Prior art keywords
- crystalline
- proxymetacaine
- hydrochloride
- proxymetacaine hydrochloride
- crystal
- 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
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to polymorphs and the making method of Proparacaine Hydrochloride (the chemical name is 3-amido-4 p propyl aminobenzoic acid-2-(ethylamino) ethyl ester mono hydrochloride). Two polymorphs of Proparacaine Hydrochloride can be obtained by choosing different solvent and different temperatures.
Description
Technical field
The present invention relates to proxymetacaine hydrochloride (Proparaeaine Hydrochloride, chemical name: polymorphic 3-amino-4-positive propoxy phenylformic acid-2-(ethylamino-) ethyl ester mono-hydrochloric salts) and preparation method thereof.By the selection of different solvents and temperature, obtain having the crystalline proxymetacaine hydrochloride of different crystal forms.
Background technology
The material that has identical chemical constitution but have different crystalline textures and a crystallized form is called as " polymorphic form ".Known many organic compound all have its polymorphic form, and this depends on the different of recrystallization solvent and recrystallization temperature, also are subjected to the influence of factors such as pH value and pressure sometimes.For medicinal compound, its chemistry and physically stable sex expression particularly important, the stability under room temperature, humidity and various storage requirement particularly, the medicinal compound of different crystal forms often shows different results on pharmacodynamics simultaneously, and all these character all are significant in the business development process of medicine.Therefore, it is significant to study those polymorphic forms that more help medicinal characteristic.
Proxymetacaine hydrochloride, chemistry " 3-amino-4-positive propoxy phenylformic acid-2-(ethylamino-) ethyl ester mono-hydrochloric salts " by name has following formula:
This compound is the medicine that is used for the treatment of various ophthalmologic operations and eye examination surface anesthesia.US1317250 and Clinton et al., J.Am.Chem.Soc.74,592 (1952), reported the synthetic method of this compound.Wherein also described mixed solvent with ethanol and ethyl acetate and the proxymetacaine hydrochloride crude product is carried out recrystallization prepared the method that fusing point is 175～185 ℃ a proxymetacaine hydrochloride, but above-mentioned patent does not all relate to the polymorphic problem of proxymetacaine hydrochloride.The invention provides the polymorphic form of proxymetacaine hydrochloride, the polymorphic form of this compound can be measured by the experiment of X-ray diffraction spectrographic and by other method such as differential scanning calorimetric (DSC) and distinguish.
Summary of the invention
The new crystalline proxymetacaine hydrochloride and preparation method thereof that relates to of the present invention.
Crystalline proxymetacaine hydrochloride (crystal formation I)
One of purpose of the present invention provides crystalline proxymetacaine hydrochloride (crystal formation I) and preparation method thereof.
The crystalline proxymetacaine hydrochloride of the present invention (crystal formation I), its with the X line powder diffraction spectrum of spending 2 θ and representing about 6.7 ± 0.2,9.8 ± 0.2,12.6 ± 0.2,13.5 ± 0.2,15.5 ± 0.2,17.3 ± 0.2,17.8 ± 0.2,17.9 ± 0.2,19.7 ± 0.2,19.9 ± 0.2,21.3 ± 0.2,24.6 ± 0.2,26.6 ± 0.2,26.9 ± 0.2 and 29.5 ± 0.2 have the peak.As shown in Figure 1.
The DSC collection of illustrative plates of the crystalline proxymetacaine hydrochloride of the present invention (crystal formation I) is seen accompanying drawing 2, and its endothermic transition is about 186 ℃.
Crystalline proxymetacaine hydrochloride of the present invention (crystal formation I) can prepare by the following method: proxymetacaine hydrochloride under 30～80 ℃ of conditions, is dissolved in C
1～C
5Straight-chain fatty alcohol, acetonitrile, and prepare in the mixed solvent of ethanol and ethyl acetate, ethanol and acetone.
Proxymetacaine hydrochloride should be in solvent all dissolvings, but temperature and concentration during dissolving are unrestricted, preferred proxymetacaine hydrochloride is dissolved in the above-mentioned solvent of mentioning fully, at the saturated solution of reflux state.
After proxymetacaine hydrochloride dissolved fully, by from the high temperature cooling crystallization, Tc was-20～25 ℃, and rate of cooling is 40 ℃/hour or littler, preferred room temperature naturally cooling crystallization.Last suction filtration separates obtaining crystalline proxymetacaine hydrochloride (crystal formation I).
Crystalline proxymetacaine hydrochloride (crystal form II)
Another object of the present invention provides crystalline proxymetacaine hydrochloride (crystal form II) and preparation method thereof.
The crystalline proxymetacaine hydrochloride of the present invention (crystal form II) is determined by its powder X-ray diffraction pattern, it is about 9.2 ± 0.2,14.5 ± 0.2,18.3 ± 0.2,18.6 ± 0.2,19.6 ± 0.2,20.4 ± 0.2,22.5 ± 0.2,23.5 ± 0.2,24.5 there is the peak at place, ± 0.2,27.0 ± 0.2 and 27.2 ± 0.2 degree 2 θ angles, as shown in Figure 3.
The DSC collection of illustrative plates of the crystalline proxymetacaine hydrochloride of the present invention (crystal form II) is seen accompanying drawing 4, and its endothermic transition is at about 173 ℃ and 200 ℃.
Crystalline proxymetacaine hydrochloride of the present invention (crystal form II) can prepare by the following method: proxymetacaine hydrochloride under 30～80 ℃ of conditions, is dissolved in the mixed solvent of Virahol, the trimethyl carbinol and tetrahydrofuran (THF) and ethanol, 4-methyl-2 pentanone and ethanol, methyl alcohol and ethyl acetate and prepares.
Proxymetacaine hydrochloride should be in solvent all dissolvings, but temperature and concentration during dissolving are unrestricted, preferred proxymetacaine hydrochloride is dissolved in the above-mentioned solvent of mentioning fully, is mixed with saturated solution under reflux state.After proxymetacaine hydrochloride dissolved fully, by from the high temperature cooling crystallization, Tc was-20～25 ℃, and rate of cooling is 40 ℃/hour or littler.Suction filtration separates obtaining crystalline proxymetacaine hydrochloride (crystal form II).
Description of drawings
Fig. 1 is the powder x-ray diffraction figure (XRD figure, trial-product are embodiment 1 product) of the crystalline proxymetacaine hydrochloride of the present invention (crystal formation I).
Fig. 2 is the differential scanning calorimetry figure (DSC figure, trial-product is embodiment 1 product) of the crystalline proxymetacaine hydrochloride of the present invention (crystal formation I).
Fig. 3 is the powder x-ray diffraction figure (XRD figure, trial-product are embodiment 4 products) of the crystalline proxymetacaine hydrochloride of the present invention (crystal form II).
Fig. 4 is the differential scanning calorimetry figure (DSC figure, trial-product is embodiment 4 products) of the crystalline proxymetacaine hydrochloride of the present invention (crystal form II).
Embodiment
Following embodiment only is to describe in detail the present invention, and unrestricted the present invention.
The preparation of embodiment 1 crystalline proxymetacaine hydrochloride (crystal formation I)
With 2.0 gram proxymetacaine hydrochloride and 12 milliliters of alcohol heating reflux, molten entirely.Suction filtration while hot, filtrate is cooled to room temperature with 40 ℃/hour speed, separates out white crystal.Decompress filter is used the small amount of ethanol flush cake, white crystal, 50 ℃ of drying under reduced pressure are to constant weight, crystalline proxymetacaine hydrochloride (crystal formation I) 1.6 grams, m.p.184.0～185.5 ℃.
The preparation of embodiment 2 crystalline proxymetacaine hydrochlorides (crystal formation I)
2.0 gram proxymetacaine hydrochlorides are joined in 32 milliliters of acetonitriles, reflux, molten entirely.Suction filtration while hot, filtrate is cooled to room temperature with 40 ℃/hour speed, separates out white crystal.Decompress filter is used the minor amounts of acetonitrile flush cake, white crystal, 50 ℃ of drying under reduced pressure are to constant weight, crystalline proxymetacaine hydrochloride (crystal formation I) 1.5 grams, m.p.183.7～184.5 ℃.
The preparation of embodiment 3 crystalline proxymetacaine hydrochlorides (crystal formation I)
2.0 gram proxymetacaine hydrochlorides are joined the mixed solvent (V of 30 milliliters of ethanol and ethyl acetate
Ethanol: V
Ethyl acetate=1: 1), reflux, molten entirely, suction filtration while hot, filtrate is cooled to room temperature with 40 ℃/hour speed, separates out white crystal.Decompress filter is used the small amount of ethanol flush cake, white crystal, 50 ℃ of drying under reduced pressure are to constant weight, crystalline proxymetacaine hydrochloride (crystal formation I) 1.4 grams, m.p.184.2～185.8 ℃.
The preparation of embodiment 4 crystalline proxymetacaine hydrochlorides (crystal form II)
2.0 gram proxymetacaine hydrochlorides are joined in 30 milliliters of Virahols, reflux, molten entirely.Suction filtration while hot, filtrate is cooled to room temperature with 40 ℃/hour speed, separates out white crystal.Decompress filter, with a small amount of Virahol flush cake, white crystal, 50 ℃ of drying under reduced pressure are to constant weight, crystalline proxymetacaine hydrochloride (crystal form II) 1.5 grams, m.p.198.7～199.5 ℃.
The preparation of embodiment 5 crystalline proxymetacaine hydrochlorides (crystal form II)
2.0 gram proxymetacaine hydrochlorides are joined the mixed solvent (V of 16 milliliters of ethanol and tetrahydrofuran (THF)
Ethanol: V
Tetrahydrofuran (THF)=1: 1), reflux, molten entirely, suction filtration while hot, filtrate is cooled to room temperature with 40 ℃/hour speed, separates out white crystal.Decompress filter, with small amount of ethanol alcohol flush cake, white crystal, 50 ℃ of drying under reduced pressure are to constant weight, crystalline proxymetacaine hydrochloride (crystal form II) 1.6 grams, m.p.198.8～200.1 ℃.
The preparation of embodiment 6 crystalline proxymetacaine hydrochlorides (crystal form II)
2.0 gram proxymetacaine hydrochlorides are joined 16 milliliters of 4-methyl-2 pentanones and ethanol mixed solvent (V
Ethanol: V
4-methyl-2 pentanone=1: 1), reflux, molten entirely, suction filtration while hot, filtrate is cooled to room temperature with 40 ℃/hour speed, separates out white crystal.Decompress filter is used the small amount of ethanol flush cake, white crystal, 50 ℃ of drying under reduced pressure are to constant weight, crystalline proxymetacaine hydrochloride (crystal form II) 1.5 grams, m.p.198.6～199.8 ℃.
Embodiment 7
The physical property of crystalline proxymetacaine hydrochloride (crystal formation I) characterizes (trial-product is embodiment 1 product)
Crystalline proxymetacaine hydrochloride (crystal formation I) X-ray powder diffraction (XRD) is analyzed: the result shows that it is about 6.7 ± 0.2,9.8 ± 0.2,12.6 ± 0.2,13.5 ± 0.2,15.5 ± 0.2,17.3 ± 0.2,17.8 ± 0.2,17.9 ± 0.2,19.7 ± 0.2,19.9 ± 0.2,21.3 ± 0.2,24.6 ± 0.2,26.6 ± 0.2,26.9 ± 0.2 and 29.5 ± 0.2 have peak (representing to spend 2 θ).See Fig. 1.
Crystalline proxymetacaine hydrochloride (crystal formation I) difference is looked scanning amount heat determination (DSC) condition determination: 50 ℃ of starting temperatures, 250 ℃ of final temperatures; Temperature rise rate: 10.0 ℃/min; Testing tool: NETZSCH DSC204.The result shows that its characteristic endothermic transition is at about 185.8 ℃.See Fig. 2.
Embodiment 8
The physical property of crystalline proxymetacaine hydrochloride (crystal form II) characterizes (trial-product is embodiment 4 products)
Crystalline proxymetacaine hydrochloride (crystal form II) X-ray powder diffraction (XRD): the result shows that it is about 9.2 ± 0.2,14.5 ± 0.2,18.3 ± 0.2,18.6 ± 0.2,19.6 ± 0.2,20.4 ± 0.2,22.5 ± 0.2,23.5 ± 0.2,24.5 ± 0.2,27.0 ± 0.2 and 27.2 ± 0.2 have peak (representing to spend 2 θ).See Fig. 3.
The difference of crystalline proxymetacaine hydrochloride (crystal form II) is looked scanning amount heat determination (DSC) condition determination: 50 ℃ of starting temperatures, 250 ℃ of final temperatures; Temperature rise rate: 10.0 ℃/min; Testing tool: NETZSCH DSC204.) measurement result shows that its characteristic endothermic transition is at about 172.7 ℃ and 199.6 ℃.See Fig. 4.
Claims (8)
1. a crystalline proxymetacaine hydrochloride (crystal formation I) is characterized in that using Cu-K.Radiation is to spend X line powder diffraction spectrum that 2 θ represent about 6.7 ± 0.2,9.8 ± 0.2,12.6 ± 0.2,13.5 ± 0.2,15.5 ± 0.2,17.3 ± 0.2,17.8 ± 0.2,17.9 ± 0.2,19.7 ± 0.2,19.9 ± 0.2,21.3 ± 0.2,24.6 ± 0.2,26.6 ± 0.2,26.9 ± 0.2 and 29.5 ± 0.2 have the peak.
2. as the crystalline proxymetacaine hydrochloride (crystal formation I) of claim 1, it is characterized in that its DSC endothermic transition is at about 186 ℃.
3. the preparation method of crystalline proxymetacaine hydrochloride as claimed in claim 1 (crystal formation I) is characterized in that comprising the following steps:
(a) with under 30～80 ℃ of conditions of proxymetacaine hydrochloride, in the dissolving organic solvent;
(b)-20～25 ℃ cooling crystallization;
(c) separation obtains crystalline proxymetacaine hydrochloride (crystal formation I).
4. the preparation method of crystalline proxymetacaine hydrochloride as claimed in claim 1 (crystal formation I) is characterized in that described organic solvent is selected from C
1～C
5The mixing solutions of mixed solution, ethanol and acetone of straight-chain fatty alcohol, acetonitrile, ethanol and ethyl acetate, the cooling rate of cooling crystallization is smaller or equal to 40 ℃/hour.
5. a crystalline proxymetacaine hydrochloride (crystal form II) is characterized in that using Cu-K
αRadiation, to spend X line powder diffraction spectrum that 2 θ represent about 9.2 ± 0.2,14.5 ± 0.2,18.3 ± 0.2,18.6 ± 0.2,19.6 ± 0.2,20.4 ± 0.2,22.5 ± 0.2,23.5 ± 0.2,24.5 ± 0.2,27.0 ± 0.2 and 27.2 ± 0.2 have the peak.
6. as the crystalline proxymetacaine hydrochloride (crystal form II) of claim 5, it is characterized in that its DSC endothermic transition is at about 173 ℃ and 200 ℃.
7. the preparation method of crystalline proxymetacaine hydrochloride as claimed in claim 5 (crystal form II) is characterized in that comprising the following steps:
(a) with under 30～80 ℃ of conditions of proxymetacaine hydrochloride, in the dissolving organic solvent;
(b)-20～25 ℃ cooling crystallization;
(c) suction filtration, separation obtain crystalline proxymetacaine hydrochloride (crystal form II).
8. the method for crystalline proxymetacaine hydrochloride as claimed in claim 5 (crystal form II), it is characterized in that described solvent is selected from the mixed solvent of Virahol, the trimethyl carbinol and tetrahydrofuran (THF) and ethanol, 4-methyl-2 pentanone and ethanol, methyl alcohol and ethyl acetate, the cooling crystallization cooling rate is no more than 40 ℃/hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100365754A CN101104591A (en) | 2006-07-14 | 2006-07-14 | Polymorph of proparacaine hydrochloride and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100365754A CN101104591A (en) | 2006-07-14 | 2006-07-14 | Polymorph of proparacaine hydrochloride and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101104591A true CN101104591A (en) | 2008-01-16 |
Family
ID=38998698
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006100365754A Pending CN101104591A (en) | 2006-07-14 | 2006-07-14 | Polymorph of proparacaine hydrochloride and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101104591A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102721775A (en) * | 2012-05-19 | 2012-10-10 | 泰州市产品质量监督检验所 | High performance liquid chromatography method for separating proparacaine hydrochloride intermediate IV from other intermediates |
| CN112961064A (en) * | 2021-02-02 | 2021-06-15 | 南京瑞年百思特制药有限公司 | Purification method and purification device of proparacaine hydrochloride |
-
2006
- 2006-07-14 CN CNA2006100365754A patent/CN101104591A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102721775A (en) * | 2012-05-19 | 2012-10-10 | 泰州市产品质量监督检验所 | High performance liquid chromatography method for separating proparacaine hydrochloride intermediate IV from other intermediates |
| CN102721775B (en) * | 2012-05-19 | 2016-06-01 | 泰州市产品质量监督检验所 | A kind of method that proxymetacaine hydrochloride intermediate IV is separated with the high performance liquid chromatography of other intermediate |
| CN112961064A (en) * | 2021-02-02 | 2021-06-15 | 南京瑞年百思特制药有限公司 | Purification method and purification device of proparacaine hydrochloride |
| CN112961064B (en) * | 2021-02-02 | 2021-10-08 | 南京瑞年百思特制药有限公司 | Purification method and purification device of proparacaine hydrochloride |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103974949B (en) | A kind of I type crystallization of 2-maleate of tyrosine kinase inhibitor and preparation method | |
| EP2517700B1 (en) | Pharmaceutically acceptable cocrystals of N-[2-(7-methoxy-1-naphthyl]acetamide and methods of their preparation | |
| US7491726B2 (en) | Crystalline forms of aripiprazole | |
| JP2014525470A (en) | A novel polymorphic form of pridopidine hydrochloride | |
| KR20150035585A (en) | 4-[5-(pyridine-4-yl)-1h-1,2,4-triazole-3-yl]pyridine-2-carbonitrile crystalline polymorph and production method therefor | |
| WO2014141292A2 (en) | Endoxifen citrate polymorph and process for preparing the same | |
| EP2542548A1 (en) | Process for preparation of polymorphic form and new polymorphic form of imatinib mesylate isolated in that process | |
| US20180002310A1 (en) | Crystalline forms of efinaconazole | |
| CN101104591A (en) | Polymorph of proparacaine hydrochloride and preparation method thereof | |
| CZ20023502A3 (en) | Novel stable crystalline form of thiazolidine derivative a process for preparing thereof | |
| TWI687412B (en) | Process for the preparation of polymorphs of imidacloprid | |
| Veverka et al. | Crystal habit modifications of imatinib mesylate under various precipitation conditions | |
| CN105523994B (en) | Methanesulfonic acid Lome Tapai crystal form III | |
| CN104558034A (en) | Novel crystal form of tedizolid phosphate disodium salt and preparation method of novel crystal form | |
| CN104788435A (en) | I-type crystal of dibenzenesulfonate of inhibitor of protein tyrosine kinase | |
| CN105294689B (en) | Tetra-substituted pyrazol isoquinoline compound and synthetic method thereof | |
| CN108727381A (en) | A kind of salt and preparation method thereof of alk tyrosine kinase inhibitor | |
| CN112830919B (en) | Benzopiperidine derivatives as pharmaceutical agents and process for preparing them | |
| WO2007072471A2 (en) | Novel crystalline forms of tiagabine hydrochloride and processes of preparing the same | |
| CN105461618A (en) | New crystal forms of lomitapide mesylate and preparation method thereof | |
| CN108463453A (en) | The method for being used to prepare the citric acid enclomifene with acicular crystal habit | |
| CN111704574A (en) | Preparation method of high-purity sorafenib tosylate crystal form III | |
| ITMI20111291A1 (en) | ALISKIREN EMIFUMARATE ETYL ACETATE SOLVATE | |
| CN104478854A (en) | Preparation method of imatinib mesylate of non-acicular crystal form |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20080116 |