CN103172658B - A kind of applicable medicinal prodrug crystal formation, preparation method and medicinal compositions - Google Patents
A kind of applicable medicinal prodrug crystal formation, preparation method and medicinal compositions Download PDFInfo
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Abstract
The invention discloses a kind of applicable medicinal water-soluble Disoprofol precursor compound hydrate crystal forms I, its preparation method and the medicinal compositions containing this crystal formation.Crystal formation of the present invention, can not there is crystal formation change in long-term placement, water absorbability is low, stable in properties, and solvability is good, is applicable to medicinal.In addition, the invention also discloses containing the treatment water-soluble Disoprofol precursor compound hydrate crystal forms I of effective dose and the composition of one or more medicinal acceptable pharmaceutical excipients.
Description
Technical field
The invention belongs to medicinal chemistry arts, specifically, relate to a kind of novel crystalline form of water-soluble Disoprofol precursor compound, and the method for this water-soluble Disoprofol precursor compound crystal formation of preparation.
Background technology
The propofol organic phosphate disodium salt of formula (1) structure is the Disoprofol water-soluble prodrug without water structure, enter human body by injection system etc. and discharge Disoprofol very soon and produce tranquilizing soporific or anesthetic action, all have been reported in the documents such as US Patent No. 6204257, US6451776, US6872838, WO03059255 and Chinese patent CN99811440.5.But because the water absorbability of propofol organic phosphate disodium salt in preparation of formula (1) is comparatively strong, result in the content being difficult to control its moisture and the difficulty formulated in its quality standard.
Formula (1)
For above-mentioned situation, publication number is the Chinese patent literature of CN101845057A, provides the propofol organic phosphate disodium salt hydrate of formula (1) structure, and X is the integer of 1-10.
Formula (2)
The invention provides control water-soluble Disoprofol precursor compound method with crystal water.But be difficult to keep agent of low hygroscopicity and stability in permanent stability are investigated by water-soluble Disoprofol precursor series compound prepared by usual way, be unfavorable for that the safety of drug quality is controlled.。
Summary of the invention
Contriver, through large quantifier elimination, is surprisingly found out that a kind of applicable medicinal water-soluble Disoprofol precursor compound hydrate crystal forms I, successfully overcomes the deficiency that prior art exists.
First object of the present invention there are provided a kind of good aqueous solubility and agent of low hygroscopicity is applicable to medicinal stable water soluble Disoprofol precursor compound hydrate crystal forms I.
Second object of the present invention is to provide the method preparing water-soluble Disoprofol precursor compound hydrate crystal forms I.
3rd object of the present invention is to provide the medicinal forms containing water-soluble Disoprofol precursor compound hydrate crystal forms I, or with the medicinal compositions that a kind of/multiple pharmaceutically acceptable auxiliary material is formed, can be used for clinically adult general anesthesia induction.
In the inventive solutions, described water-soluble Disoprofol precursor compound refers to following formula (1) compound:
Formula (1)
Specifically, water-soluble Disoprofol precursor compound hydrate crystal forms I provided by the present invention, its source of radiation-copper
x-ray powder diffraction figure, to spend 2 θ ± 0.2, characteristic peak has at least 5 following peaks: 4.709,5.356,9.393,13.290,14.100,14.981,15.894,18.291,18.833,19.451,21.632,22.419,23.042,24.051,25.626,26.719,27.658 and 28.387, preferably, there are at least 11 peaks, most preferably, there is all peaks.Particularly preferably, it has and the X-ray diffracting spectrum shown in Fig. 1.
In specific embodiment of the invention scheme, water-soluble Disoprofol precursor compound hydrate crystal forms I provided by the present invention, wherein, moisture content is weight percentage 5.1%-7.0%, preferably, is 5.4-6.0%, preferred 5.5%-5.8%.
In specific embodiment of the invention scheme, water-soluble Disoprofol precursor compound hydrate crystal forms I provided by the present invention, its thermogravimetric analysis collection of illustrative plates plays the large endothermic transition of performance at 210 DEG C, more preferably, has curve same as shown in Figure 3.
In specific embodiment of the invention scheme, water-soluble Disoprofol precursor compound hydrate crystal forms I provided by the present invention, the infrared spectra that its KBr pressed disc method measures, 3520,3300,3050,2964,2930,2890,1740 ~ 1600,1500 ~ 1350,1200 ~ 1050cm
-1place has infrared absorption band.More preferably, its infrared absorption spectrum as shown in Figure 4.
In specific embodiment of the invention scheme, water-soluble Disoprofol precursor compound hydrate crystal forms I provided by the present invention has agent of low hygroscopicity, and described crystal formation remained on 40 DEG C, and place 6 months under the condition of humidity 75%, moisture content is no more than 7%; Placing after dissolving under this condition is achromaticity and clarification liquid all the time; Related substance is constant, and content without reduction, and crystal formation change can not occur.
On the other hand, the invention provides the preparation method of water-soluble Disoprofol precursor compound hydrate crystal forms I, dissolved by water-soluble Disoprofol precursor compound completely, activated carbon decolorizing adopts cryodesiccated mode to obtain after filtering.
The invention provides the preparation method of water-soluble Disoprofol precursor compound hydrate crystal forms I, comprise the following steps:
A) by water-soluble Disoprofol precursor compound in solvent, optionally reflux, dissolves completely;
B), after water-soluble Disoprofol precursor compound dissolves completely, activated carbon decolorizing, essence filter is added;
C) lyophilize;
Here, described solvent is one or more solvent in water, Virahol, methyl alcohol, ethanol, acetone.
The invention provides the preparation method of water-soluble Disoprofol precursor compound hydrate crystal forms I, wherein, adopt as starting raw material water-soluble Disoprofol precursor compound can according to Chinese patent CN101845057 record method preparation, can be sterling or crude product, also can comprise different water content.
The invention provides the preparation method of water-soluble Disoprofol precursor compound hydrate crystal forms I, wherein, the described solvent adopted can be water, also can be the mixed system of water/Virahol, water/methyl alcohol, water/ethanol, water/acetone, volume ratio (V/V) is 20: 1-5, preferably 20: 1-2, be more preferably 20: 1.
The invention provides the preparation method of water-soluble Disoprofol precursor compound hydrate crystal forms I, wherein, the mass volume ratio that feeds intake (W/V) of raw material and described solvent is 1: 5-15, is preferably 1: 6-10, is particularly preferably 1: 8.Stir to obtain clear liquor, whether heat, depend on the boiling point of relied on solvent, stirring at normal temperature can obtain clear liquor without the need to heating.
The invention provides the preparation method of water-soluble Disoprofol precursor compound hydrate crystal forms I, wherein, appropriate injection gac (0.05 ~ 1.00%W/V) is decoloured 5-30 minute, is preferably 10-20 minute, be more preferably 15 minutes, collect filtrate.
The invention provides the preparation method of water-soluble Disoprofol precursor compound hydrate crystal forms I, wherein, described lyophilize, temperature controls at-60 DEG C ~ 40 DEG C, sublimation drying 29h ~ 57h; Be preferably temperature-55 DEG C ~ 30 DEG C, time 36h ~ 53h; Be particularly preferably-55 DEG C ~ 25 DEG C, time 45h ~ 47h.
The invention provides the preparation method of water-soluble Disoprofol precursor compound hydrate crystal forms I, wherein, described lyophilize pre-freezing temperature-5 DEG C ~-10 DEG C, 1 ~ 2 hour pre-freeze time, is preferably-5 DEG C, 1.5 hours; Then be cooled to-20 DEG C ~-30 DEG C to keep 2 ~ 5 hours, be preferably-25 DEG C and keep 4 hours; In 0.5 hour, be cooled to-40 DEG C ~-60 DEG C again keep 3 ~ 4 hours, be preferably-45 DEG C ~-55 DEG C and keep 3 ~ 4 hours, be particularly preferably-55 DEG C, keep 4 hours.Keep vacuum tightness at 10 ~ 30Pa, preferably 10 ~ 20Pa, particularly preferably 15Pa; Drying temperature-35 DEG C ~-10 DEG C, dry 15 ~ 24 hours, is preferably-20 ~-10 DEG C, dry 18 ~ 24 hours, particularly preferredly be-15 DEG C, drying 22 hours; Then improve temperature to-5 DEG C ~ 10 DEG C, 5 ~ 15 hours time of drying, be preferably-5 DEG C ~ 5 DEG C DEG C, dry 8 ~ 12 hours, particularly preferredly be-5 DEG C, drying 10 hours; Improve temperature to 15 DEG C ~ 40 DEG C again, dry 2 ~ 6 hours, be preferably 20 ~ 30 DEG C, dry 3 ~ 5 hours, particularly preferred was 25 DEG C, dry 4 hours.
The third aspect, the invention provides the pharmaceutical composition of a kind of medicine of water-soluble Disoprofol precursor compound hydrate crystal forms I comprising treatment significant quantity or/and pharmaceutical carrier/mixed with excipients formation, can be used for the induction of adult's general anesthesia, can be used for intravenous administration, can be that liquid drugs injection, lyophilized form are to patient's administration.
During to patient's administration, the heavy dose of infusion of Peripheral vein infusion device that is conventional, safety can be used, initial dosages scope is 10-20mg/kg, be preferably 20mg/kg, rapid intravenous infusion, in 5min, patient does not reach MOAA/S (improvement vigilance sedation score) and marks 4 grades, then add medicine by the predose of 50%.This product can be dissolved in following liquid: 5% glucose injection, 5% glucose and 0.2% sodium-chlor, 5% glucose and 0.45% sodium chloride injection, 0.9% sodium chloride injection, Lactated Ringer'S Solution, Lactated Ringer'S Solution and 5% glucose injection, 0.45% sodium chloride injection, 5% glucose, 0.45% sodium-chlor and 20mg equivalent Repone K.
The preparation method of the pharmaceutical composition of a kind of medicine of water-soluble Disoprofol precursor compound hydrate crystal forms I comprising treatment significant quantity provided by the invention or/and pharmaceutical carrier/mixed with excipients formation comprises the water-soluble Disoprofol precursor compound hydrate crystal forms I prepared by the present invention, water for injection is dissolved in after weighing, optional adds auxiliary material/vehicle or does not add, the direct canning means of rear employing makes liquid drugs injection, or adopts lyophilize mode to make freeze-dried preparation.
Accompanying drawing explanation
Fig. 1 represents the X-ray diffracting spectrum of sample (the lower abbreviation sample 1) crystal formation obtained by embodiment 1 mode.
Fig. 2 represents that the sample obtained by embodiment 1 mode is at 40 DEG C, places the X-ray diffracting spectrum after 6 months under the condition of humidity 75%.
Fig. 3 represents the TG figure of the sample obtained by embodiment 1 mode
Fig. 4 represents the infared spectrum of the sample crystal formation obtained by embodiment 1 mode
Fig. 5 represents the X-ray diffracting spectrum by existing document (note: existing document is the Chinese patent of publication number CN101845057A) water content 6% sample (lower abbreviation sample 2).
Embodiment
The analytical procedure that the present invention uses is as follows:
(1) X-ray powder diffraction test
Use Brooker company D8ADVANCE polycrystal X ray powder diffractometer.Sample spatula edge evenly crushes, and uses following instrument parameter: sweep limit 3.0 to 40.0 spends 2 θ, step-length 0.02 degree of 2 θ, often walks 0.5 second sweep time, source of radiation-copper
x-ray tube power 40KV/40mA.
(2) TG test
Use resistance to NETZSCHTG209 thermogravimetric analyzer of speeding, the sample that mensuration embodiment 1 obtains, the collection of illustrative plates obtained is as Fig. 3.TG figure shows, sample has large endothermic transition at 210 DEG C of places, and this is consistent with the fusing point of sample.
(3) infrared spectra test
Use the Varian660 Fourier transformation infrared spectrometer of Agilent company, the high-purity KBr powder of drying getting 1 ~ 3mg solid sample and 300mg is placed in mortar and mixes, transfer to again in the mould of tabletting machine, after being pressed into transparent thin slice, being placed in light path and measuring.
(4) wettability test
Use the T-50-DV705 current potential moisture titration of Mettler Toledo Inc., measure the sample moisture content that embodiment 1 mode obtains.Sample, temperature 40 DEG C, is placed 6 months under the condition of humidity 75%, and monthly timing working sample moisture content, observes outward appearance and aqueous solution proterties,
(5) stability test
Use the 1200S high performance liquid chromatography of Agilent company, analyze the sample that embodiment 1 obtains, temperature 40 DEG C, under the condition of humidity 75%, place related substance and the content of 6 months.
Embodiment 1
Getting publication number is in the Chinese patent literature of CN101845057, and water content is the sample 13.0g of 6%, and/Virahol (V/V=20: 1) the 104ml stirring at normal temperature that adds water is entirely molten, adds proper amount of active carbon and decolour 15 minutes after entirely molten, filters.Filtrate glove charging tray, in Freeze Drying Equipment, at-5 DEG C, pre-freeze 2 hours; Then be cooled to-25 DEG C, keep 4 hours; In 1 hour, be cooled to-55 DEG C, keep 4 hours.Keep vacuum tightness 15Pa, raised temperature extremely-15 DEG C, dry 22 hours; Then raised temperature is to-5 DEG C, dry 10 hours; Last raised temperature to 25 DEG C, dry 4 hours, obtains white crystals 12.29g, measures water content and is weight percentage 5.5%.
Sample 1, through combustion decomposition, is quantitatively changed, and uses ElementaVarioELIII type elemental analyser to detect, obtains the percentage composition of C, H, determination data and being analyzed as follows:
Results of elemental analyses
Embodiment 2
Getting publication number is in the Chinese patent literature of CN101845057, and water content is the sample 13.0g of 10%, and/the ethanol that adds water (V/V=10: 1) 104ml stirring at normal temperature is entirely molten, adds proper amount of active carbon and decolour 15 minutes after entirely molten, filters.Filtrate glove charging tray, in Freeze Drying Equipment, at-5 DEG C, pre-freeze 2 hours; Then be cooled to-25 DEG C, keep 4 hours; In 1 hour, be cooled to-55 DEG C, keep 4 hours.Keep vacuum tightness 15Pa, raised temperature extremely-15 DEG C, dry 22 hours; Then raised temperature is to-5 DEG C, dry 10 hours; Last raised temperature to 25 DEG C, dry 4 hours, obtains white crystals 10.32g, measures water content and is weight percentage 5.6%.
Embodiment 3
Getting publication number is in the Chinese patent literature of CN101845057, and water content is the sample 13.0g of 21%, and/acetone (V/V=20: 1) the 130ml stirring at normal temperature that adds water is entirely molten, adds proper amount of active carbon and decolour 15 minutes after entirely molten, filters.Filtrate glove charging tray, in Freeze Drying Equipment, at-8 DEG C, pre-freeze 1.5 hours; Then be cooled to-30 DEG C, keep 2.5 hours; In 1 hour, be cooled to-60 DEG C, keep 3 hours.Keep vacuum tightness 20Pa, raised temperature extremely-20 DEG C, dry 22 hours; Then raised temperature is to-5 DEG C, dry 10 hours; Last raised temperature to 25 DEG C, dry 4 hours, obtains white crystals 10.32g, measures water content and is weight percentage 5.5%.
Embodiment 4
Getting publication number is in the Chinese patent literature of CN101845057, and water content is the sample 13.0g of 35%, and/Virahol (V/V=20: 1) the 65ml stirring at normal temperature that adds water is entirely molten, adds proper amount of active carbon and decolour 15 minutes after entirely molten, filters.Filtrate glove charging tray, in Freeze Drying Equipment, at-5 DEG C, pre-freeze 1.5 hours; Then be cooled to-25 DEG C, keep 4 hours; In 1 hour, be cooled to-55 DEG C, keep 4 hours.Keep vacuum tightness 15Pa, raised temperature extremely-15 DEG C, dry 22 hours; Then raised temperature is to-5 DEG C, dry 10 hours; Last raised temperature to 25 DEG C, dry 4 hours, obtains white crystals 8.67g, measures water content and is weight percentage 5.5%.
Embodiment 5
By the sample that the method for embodiment 1 obtains, weigh by formula, by sample dissolution in water for injection, be stirred to and dissolve completely.Add proper amount of active carbon (0.05 ~ 1.00%W/V), stir 30 minutes, filter.Filtrate is degerming by 0.22 μm of filtering with microporous membrane, fillingly partly jumps a queue in cillin bottle or glass tube vial, puts on freeze drier dividing plate, at-30 DEG C, and pre-freeze 4 hours; Then at-10 DEG C, dry 10 hours; Last at 30 DEG C, dry 10 hours, vacuum or inflated with nitrogen tamponade, obtained sample redissolved rapidly, and solution is clarified.Pharmaceutical composition proportioning is as follows:
Embodiment 1 sample 0.5g (in anhydrous)
N.F,USP MANNITOL 0.1g
Water for injection is appropriate
The result of embodiment 1 gained sample X-ray powder diffraction is as following table 1
Table 1
| Scattering angle (2 θ) | D-spacing | Relative intensity (%) | |
| 1. | *4.709 | 18.749 | 100.0 |
| 2. | *5.356 | 16.487 | 3.2 |
| 3. | *9.393 | 9.408 | 2.6 |
| 4. | *13.290 | 6.657 | 2.5 |
| 5. | *14.100 | 6.276 | 6.0 |
| 6. | *14.987 | 5.906 | 4.0 |
| 7. | *15.894 | 5.571 | 2.8 |
| 8. | 16.221 | 5.460 | 1.5 |
| 9. | 17.090 | 5.184 | 0.7 |
| 10. | *18.291 | 4.846 | 1.7 |
| 11. | *18.833 | 4.708 | 3.1 |
| 12. | *19.451 | 4.560 | 4.2 |
| 13. | *21.632 | 4.105 | 2.1 |
| 14. | *22.419 | 3.963 | 0.9 |
| 15. | *23.042 | 3.857 | 1.3 |
| 16. | 23.665 | 3.757 | 1.3 |
| 17. | *24.051 | 3.697 | 1.6 |
| 18. | *25.626 | 3.473 | 1.9 |
| 19. | *26.719 | 3.334 | 1.9 |
| 20. | *27.658 | 3.223 | 2.1 |
| 21. | *28.387 | 3.142 | 2.8 |
| 22. | 29.774 | 2.998 | 1.4 |
| 23. | 31.856 | 2.807 | 1.5 |
| 24. | 34.169 | 2.622 | 1.0 |
| 25. | 35.756 | 2.509 | 0.7 |
| 26. | 37.520 | 2.395 | 1.2 |
The product that embodiment 2 to 4 is obtained, its PXRD collection of illustrative plates is identical with embodiment 1.
According to the sample that the mode of embodiment 1 obtains, there is similar PXRD experimental patterns, and at 6 months, temperature 40 DEG C, after the condition placement of humidity 75%, the PXRD experimental patterns that sample shows is consistent with crystal formation I (see Fig. 2), visible long-term placement, the crystal formation of this sample remains unchanged.
Embodiment 1 obtains the TG figure of crystal as shown in Figure 3, and sample has large endothermic transition at 210 DEG C of places.
Embodiment 1 obtains crystal infrared spectra as shown in Figure 4,3520,3300,3050,2964,2930,2890,1740 ~ 1600,1500 ~ 1350,1200 ~ 1050cm
-1the specific infrared absorption band at place.
The result of sample 2X-ray powder diffraction is as following table 2, and Fig. 5 is shown in by collection of illustrative plates
Table 2
| Scattering angle (2 θ) | D-spacing |
| 4.859 | 18.173 |
| 9.360 | 9.441 |
| 12.307 | 7.186 |
| 19.799 | 4.480 |
| 20.955 | 4.236 |
Sample moisture absorption and redissolve result as follows
Sample 1, sample 2 are temperature 40 DEG C, and place 6 months under the condition of humidity 75%, embodiment 1 moisture content is less than 7% all the time, the not easily moisture absorption, and more stable, situation is as shown in table 3,
Table 3
It is as follows that sample stability investigates result
Sample 1, sample 2, temperature 40 DEG C, are placed under the condition of humidity 75%, and sample 1 related substance is constant, and content is without reduction, and situation is as shown in table 4.
Table 4
Claims (10)
1. a water-soluble Disoprofol precursor compound hydrate crystal forms I, its source of radiation-copper
x-ray powder diffraction figure, to spend 2 θ ± 0.2, characteristic peak has following peak: 4.709,5.356,9.393,13.290,14.100,14.981,15.894,18.291,18.833,19.451,21.632,22.419,23.042,24.051,25.626,26.719,27.658 and 28.387;
Here, described water-soluble Disoprofol precursor compound hydrate crystal forms I, wherein, moisture content is weight percentage 5.1-7.0%;
Described water-soluble Disoprofol precursor compound refers to following formula (1) compound:
2. water-soluble Disoprofol precursor compound hydrate crystal forms I according to claim 1, it is characterized by X-ray diffracting spectrum, as shown in Figure 1.
3. water-soluble Disoprofol precursor compound hydrate crystal forms I according to claim 1, its thermal gravimetric analysis curve, plays the large endothermic transition of performance at 210 DEG C.
4. water-soluble Disoprofol precursor compound hydrate crystal forms I according to claim 1, infrared spectra is presented at 3520,3300,3050,2964,2930,2890,1740 ~ 1600,1500 ~ 1350,1200 ~ 1050cm
-1the specific infrared absorption band at place.
5. water-soluble Disoprofol precursor compound hydrate crystal forms I according to claim 1, wherein said crystal formation has agent of low hygroscopicity, described crystal formation remain on 40 DEG C, place 6 months under the condition of humidity 75%, moisture content is no more than 7% all the time.
6. the preparation method of water-soluble Disoprofol precursor compound hydrate crystal forms I described in arbitrary claim in claim 1 to 5, comprises the following steps:
A) by water-soluble Disoprofol precursor compound in solvent, optionally reflux, dissolves completely;
B), after water-soluble Disoprofol precursor compound dissolves completely, activated carbon decolorizing, essence filter is added;
C) lyophilize.
7. the preparation method of claim 6, wherein, step a) described solvent is one or more solvent in water, Virahol, methyl alcohol, ethanol, acetone.
8. the preparation method of claim 6, wherein, the mass volume ratio that feeds intake of step a) water-soluble Disoprofol precursor compound and solvent is 1:5 ~ 15.
9. the preparation method of claim 6, wherein, step c) described in lyophilize, oil temperature-60 DEG C ~ 40 DEG C, sublimation drying 29h ~ 57h.
10. the medicinal compositions containing water-soluble Disoprofol precursor compound hydrate crystal forms I described in arbitrary claim in claim 1 to 5.
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| CN101716149A (en) * | 2009-11-30 | 2010-06-02 | 宜昌人福药业有限责任公司 | New precursor medicinal preparation |
| CN101845057A (en) * | 2009-03-27 | 2010-09-29 | 四川大学 | Substituted phenol for methylal phosphate anesthetic and sedative drugs and preparation method thereof |
| EP2281565A2 (en) * | 2002-04-08 | 2011-02-09 | Eisai Inc. | Pharmaceutical compositions containing water-soluble prodrugs of propofol and methods of administering same |
| CN102351895A (en) * | 2011-08-08 | 2012-02-15 | 陕西合成药业有限公司 | Fospropofol disodium hydrate, preparation method and purpose thereof |
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| PL210812B1 (en) * | 2007-02-14 | 2012-03-30 | Inst Ciężkiej Syntezy Organicznej Blachownia | The manner of obtaining of bisphenol A |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1625414A (en) * | 2002-02-01 | 2005-06-08 | 施摩达生物技术有限公司 | Pharmaceutical composition |
| EP2281565A2 (en) * | 2002-04-08 | 2011-02-09 | Eisai Inc. | Pharmaceutical compositions containing water-soluble prodrugs of propofol and methods of administering same |
| CN101845057A (en) * | 2009-03-27 | 2010-09-29 | 四川大学 | Substituted phenol for methylal phosphate anesthetic and sedative drugs and preparation method thereof |
| CN101716149A (en) * | 2009-11-30 | 2010-06-02 | 宜昌人福药业有限责任公司 | New precursor medicinal preparation |
| CN102351895A (en) * | 2011-08-08 | 2012-02-15 | 陕西合成药业有限公司 | Fospropofol disodium hydrate, preparation method and purpose thereof |
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