CN106674269A - Fospropofol disodium tetrahydrate, crystal form of fospropofol disodium tetrahydrate, and preparation method and application of crystal form of fospropofol disodium tetrahydrate - Google Patents
Fospropofol disodium tetrahydrate, crystal form of fospropofol disodium tetrahydrate, and preparation method and application of crystal form of fospropofol disodium tetrahydrate Download PDFInfo
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- CN106674269A CN106674269A CN201510770626.5A CN201510770626A CN106674269A CN 106674269 A CN106674269 A CN 106674269A CN 201510770626 A CN201510770626 A CN 201510770626A CN 106674269 A CN106674269 A CN 106674269A
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Abstract
The invention provides a crystal form of fospropofol disodium tetrahydrate, and also provides a preparation method of the crystal form of fospropofol disodium tetrahydrate. In addition, a pharmaceutical composition containing the crystal form of fospropofol disodium tetrahydrate is applied to monitored anesthesia care (MAC) of an adult patient receiving diagnosis or treatment operations.
Description
Technical field
The invention belongs to one kind is phosphorus propofol sodium tetrahydrate and crystal formation and its preparation in compound crystal form preparation field
Method and purposes.
Background technology
In the anesthesia procedures of nearest 15 years, injectable anesthetis, especially propofol, induction for general anesthesia and
The application of maintenance oneself obtain extensive acceptance.There are several advantages compared with previous method with propofol intravenous anesthesia：As more
Easy-tolerated induction, because patient there is no concern that masking, the overpowering odor of asphyxia or volatile anesthetic；It is rapid and measurable
Recovery；The depth of anesthesia is can easily be accommodated by adjusting the dosage of propofol；Have low bad anti-compared with Splenectomy
Answer incidence rate；Anesthesia Restoration stage be reduced anxiety, nausea and vomiting [Padfield NL, Intrduction,
history and develpment,In:Padfield NL (Ed.) Ed.,Total Intravenous Anesthesia,
Butterwor th Heinemann, Oxford 2000].
In addition to its sedative and anesthetic effects, propofol also has a series of other biologys and medical application.For example, according to
Report that it was once used as Bendectin [McCollum JSC etc., Anesthesia 43 (1988) 239], antiepileptic medicine
[Chilvers CR, Laurie PS.Anesthesia 45 (1990) 995] and antipruritic [Borgeat etc.,
Anesthesiology 76 (1992) 510].The plasma concentration reached less than HD, i.e. propofol less than calm and
Emesis and antipruritic effect can be typically observed during the dosage of the required concentration of anesthesia.On the other hand, it is dense in wider blood plasma
It is observed that antiepileptic activity [Borgeat etc., Anesthesiology 80 (1994) 642] in the range of degree.Also it has been reported that
Short time intravenous injection is largely effective in terms of the migraine and non-migraine for the treatment of refractory less than the propofol of anaesthesia dosage
[224-230 of Krusz JC etc., Headache, 40 (2000)].Oneself further speculates that propofol can serve as antianxiety drugss
[973-7 of Kurt etc., Pol.J.Pharmacol. 55 (2003)], neuroprotective drug [Velly etc., Anesthesiology99
(2003) 368-75] and muscle relaxant [2322-7 of O'Shea etc., J.Neurosci. 24 (2004)], and due to it
There is antioxygenic property in living things system, thus can be further used for treating the inflammation at inflammation especially respiratory tract position, and
The treatment nerve injury relevant with nerve degeneration or wound.The generation that these diseases are considered as same active oxygen is relevant, therefore can use
Antioxidant is treating.For example, with reference to the United States Patent (USP) 6,254,853 of Hendler etc..
Propofol is typically configured to oil in water emulsion for clinical practice.Said preparation has limited storage life, and
To antibacterial and fungal contamination sensitivity, the antibacterial and fungal contamination cause postoperative infection [Bennett SN etc., N Engl J
Med333 (1995) 147].Because said preparation is in dense white, it is impossible to observe by the naked eye bottle first and detect antibacterial
Or the pollution of funguses.
Propofol is not only insoluble in water, and causes pain in injection site, it is often necessary to alleviated with local anaesthetics
[DolinSJ, Drugs and pharmacology,In:N.Padfield, Ed. Total Intravenous
Anesthesia, Butterworth Heinemann, Oxford 2000].Because its preparation is liplid emulsions, therefore vein gives
Medicine also causes the hypertriglyceridemia unfavorable to patient, especially over a long time receive infuse patient [Fulton B. and
Sorkin EM, Drugs 50 (1995) 636].The preparation of liplid emulsions makes it be more difficult to be shared with other medicines.The system
Any physical change of agent, the such as change of fat drips size, lead to the change of the pharmacological property of medicine and cause side effect,
Such as pulmonary infarction.
It has further been reported that the induction of anesthesia purposes of propofol is related to apneic high incidence, this seem according to
Rely in dosage, injection screening rate and premedicate [Reves JG, Glass, PSA, Lubarsky DA, Nonbarbiturate
intravenous anesthetics. In:The anti-Churchill of R.D.Miller etc., Eds, Anesthesia. 5LL
Livingstone, Philadephia, 2000].Reduce including tolerance using the breathing consequence of the propofol of anesthetic induction doses
And asphyxia, this occurs [Bryson etc., Drugs 50 (1995) 520] in up to 83% patient.Also oneself knows derivant
The propofol of amount has a significant hypotension effect, and the effect is dosage and plasma concentration-dependent [Reves etc. see on].With it is quick
The relevant hypotension of peak plasma after dense note propofol, sometimes requires that using controllable infusion pump or by the quick dense of induction
Injecting amount is dispersed into some little incremental dosage.And, the bolus dose of induction can cause unconsciousness in short-term, this
So that propofol is adapted only to simple treatment.For above-mentioned reasons, propofol is used for the induction of anesthesia and/or remains general necessary
Apply in the case where patient is by anesthesiology expert monitoring, and have been generally acknowledged that because non-narcotic expert is to revocable or day
The normal state of an illness is using being inappropriate.
In addition to it is used for the induction of anesthesia and maintains, it is auxiliary for conscious patient that propofol has been used successfully as tranquilizer
Local or regional anesthesia.Oneself is ground-breaking for conscious patient can be made to feel uneasy diagnosis aspect such as colon for its sedative properties
Spectroscopy or imaging operation.Also Zeng Zuowei is calm for acceptance imaging diagnosis or radiotherapy sunlight child for propofol.Nearest sends out
Exhibition is the calmness that propofol is used for Patients' rights.Have as the calmness that this skill more patient likes and implements with skilled anesthesia expert
Effect.
Compared with wide variety of sedative midazolam or other similar reagents, measure its calm quality and/or
Time of the patient in enough level of sedation, propofol provide it is similar or preferably sedation effect [referring to Fulton B and
Sorkin EM, Drugs 50 (1995) 636].What is be associated with propofol recovers faster and similar or less forgetful
Disease causes it to become the tranquilizer of the replacement other medicines for having attraction, especially for the patient for only requiring short time calmness.So
And, because current propofol formulations have the probability for causing hyperlipemia and easily tolerance of the development to its sedation effect,
Propofol is used for the method for the patient for needing long-time calm and does not also determine well.
Due to its very low oral administration biaavailability, it is generally recognized that the commercially available preparation of propofol is not suitable for removing
Other administering modes of parenteral, and typically must intravenous injection or input.When propofol it is quiet in a clinical setting
When arteries and veins gives, it is proposed that for certain indication, such as can be sucked by using spray by other non-oral routes
Administration, by the mucosa delivery of upper digestive tract epithelial cell, or [see, e.g. with suppository form rectally
Cozanitis, D.A. etc., the 575-7 of Acta Anaesthesiol. Scand. 35 (1991)；And 05 is specially opened referring to US.,
496,537 and 5,288,597].However, low bioavailability when propofol is administered by the alternate manner except intravenous route
Limit the development of the treatment.
Patent of the present invention provides phosphorus propofol sodium tetrahydrate and preparation method, and the phosphorus propofol sodium tetrahydrate is more general
Phosphorus propofol sodium prepared by circulation method has preferable stability in long-time stability investigation, and this ensures product for medicine
Stability it is safely controllable for clinical application.
The content of the invention
It is an object of the invention to provide a kind of phosphorus propofol sodium tetrahydrate and crystal formation, phosphorus propofol sodium tetrahydrate
Structural formula is as follows：
（Formula I）
Present invention also offers the preparation method of compound shown in formula I, concrete operations are as follows：
Make the phosphorus propofol sodium containing 30% moisture that dissolving is heated in the mixed solvent of organic solvent and water, add activated carbon
Decolourize, filter；Filtrate cooling crystallization, obtains the phosphorus propofol sodium tetrahydrate.
Above-mentioned organic solvent can for methanol, ethanol, isopropanol, normal propyl alcohol, positive ethanol, 2- butanol, 2- methyl isophthalic acids-propanol,
One or more of 2- methyl-2-propanols, acetone, butanone, methyl ethyl ketone.
Above-mentioned phosphorus propofol sodium is 1 with the mass volume ratio of mixed solvent：1-50；It is noted that quality volume herein
The unit magnitude of ratio can be the unit of g/mL, kg/L or other reciprocity magnitudes.
Above-mentioned recrystallization temperature is -20～40 DEG C, more preferably 0 DEG C.
Three aspects of the present invention, are that above-claimed cpd or its crystal formation are receiving diagnosis or treating the adult trouble of operating process
(MAC) is anaesthetized under the monitoring of person.
4th aspect of the invention, there is provided a kind of pharmaceutical composition, including aforesaid phosphorus propofol of the invention
Sodium tetrahydrate crystal formation.Said composition further includes one or more pharmaceutically acceptable carrier, excipient or diluent.
Said composition is suitable for the compositionss for preparing the sterile solution of parenteral routes or injectable sterile powder form.
Said composition is to include the unit dose containing phosphorus propofol sodium tetrahydrate of the invention, in an amount of from 1mg to 2000mg.
The fifth aspect of the invention, there is provided phosphorus propofol sodium tetrahydrate crystal formation, its X-ray powder diffraction figure is following
There is characteristic peak at 2 θ ± 0.2：4.1、4.5、8.9、13.4、17.8、22.3、26.8、31.2.The XRPD collection of illustrative plates of the crystal formation can be with
Further in above-mentioned 2 θ ± 0.2, Angle Position has characteristic peak：4.5、8.9、13.4、17.8、26.8、31.2.This patent crystal formation feature
Using the method for expressing that this area is conventional, allowable error is ± 0.2 to the angle at peak when being accurate to 0.1.And generally with reference to four houses
Five principles for entering.Used as the demonstration of other 2 θ degree of accuracy, the XRPD figures of the crystal formation can include following diffraction data：
6th aspect of the invention, there is provided a kind of phosphorus propofol sodium tetrahydrate structure cell, structure cell data are as follows：
Element proportioning is Na2(C13H19O5P) (H2O)4, the crystal formation is orthorhombic system, and space group is P21,
Crystal unit cell parameter
a = 12.2868(13) Å alpha= 90°
b = 8.0392(9) Å beta= 90°
c = 39.868(5) Å gamma= 90°
Z=4, unit cell volume is：3938.0(8) Å3。
By the following examples the specific embodiment of form, remakes further specifically to the above of the present invention
It is bright.But this scope for being interpreted as above-mentioned theme of the invention should not be only limitted to Examples below.It is all based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Description of the drawings
Fig. 1 is the XRPD collection of illustrative plates of embodiment of the present invention l gained phosphorus propofol sodium tetrahydrate crystal, and its abscissa represents 2 θ
The number of degrees, vertical coordinate represents peak intensity, and the 2TH data on figure represent 2 θ values, and D values represent interplanar distance, and percent represents diffraction maximum
Relative intensity.
X-ray powder diffraction of the present invention adopts Cu K α radiations source.
Fig. 2 is tied for the Advances in crystal X-ray diffraction (SXRD) of the gained phosphorus propofol sodium tetrahydrate crystal of the embodiment of the present invention 1
Composition.
Fig. 3 is the Advances in crystal X-ray diffraction (SXRD) two of the gained phosphorus propofol sodium tetrahydrate crystal of the embodiment of the present invention 1
Dimension structure chart.
Specific embodiment
The present invention is described in further detail with reference to embodiment, it should be understood that the scope of the present invention is non-to be only limitted to this
The scope of a little embodiments.
Embodiment 1：The preparation of phosphorus propofol sodium tetrahydrate
The phosphorus propofol sodium 10g containing 30% moisture is taken, 95% is added（v/v）Ethanol water 40ml, be heated to 60 DEG C stir to
Dissolving, adds 0.1g activated carbon decolorizings, and insulated and stirred is filtered for 10 minutes, and filtrate sets to 0 a DEG C crystallize, filters, and is dried, and obtains 8.6g phosphorus
Propofol sodium tetrahydrate, after testing, the XRPD of phosphorus propofol sodium crystal is schemed as shown in figure 1, SXRD structure charts are as shown in Figure 2.
Embodiment 2：The preparation of phosphorus propofol sodium tetrahydrate
The phosphorus propofol sodium 10g containing 30% moisture is taken, 95% is added（v/v）Methanol aqueous solution 20ml, be heated to 60 DEG C stir to
Dissolving, adds 0.2g activated carbon decolorizings, and insulated and stirred is filtered for 60 minutes, and filtrate puts -20 DEG C of crystallizes, filters, and is dried, and obtains 8.9g
Phosphorus propofol sodium tetrahydrate, after testing, the XRPD of phosphorus propofol sodium tetrahydrate crystal is schemed as shown in figure 1, SXRD structure charts
As shown in Figure 2.
Embodiment 3：The preparation of phosphorus propofol sodium tetrahydrate
The phosphorus propofol sodium 10g containing 30% moisture is taken, 90% is added（v/v）Isopropanol water 80ml, is heated to 60 DEG C and stirs to molten
Solution, adds 0.8g activated carbons, and insulated and stirred is filtered for 20 minutes, and filtrate stands 10 DEG C of crystallizes, filters, and is dried, and obtains final product 8.8g phosphorus
Propofol sodium tetrahydrate, after testing, the XRPD of phosphorus propofol sodium tetrahydrate crystal figure as shown in figure 1, SXRD structure charts such as
Shown in Fig. 2.
Embodiment 4：The preparation of phosphorus propofol sodium tetrahydrate
The phosphorus propofol sodium 50g containing 30% moisture is taken, ethanol methanol aqueous solution (v is added:v:v=90:5:5) 500 ml, heating
Stir to dissolving to 60 DEG C, add 5.0g activated carbons, insulated and stirred is filtered for 10 minutes, and filtrate stands 0 DEG C of crystallize, filters, and does
It is dry, 45.3g phosphorus propofol sodium tetrahydrates are obtained final product, after testing, the XRPD of phosphorus propofol sodium tetrahydrate crystal is schemed such as Fig. 1 institutes
Show, SXRD structure charts are as shown in Figure 2.
Embodiment 5：The preparation of phosphorus propofol sodium tetrahydrate
The phosphorus propofol sodium 20g containing 30% moisture is taken, ethanol methanol acetone aqueous solution (v is added:v:v=85:5：5:5) 80 ml,
It is heated to 60 DEG C to stir to dissolving, adds 1.0g activated carbons, insulated and stirred is filtered for 30 minutes, and filtrate stands 0 DEG C of crystallize, mistake
Filter, is dried, and obtains final product 18.9g phosphorus propofol sodium tetrahydrates, and after testing, the XRPD figures of phosphorus propofol sodium tetrahydrate crystal are as schemed
Shown in 1, SXRD structure charts are as shown in Figure 2.
Embodiment 6：The preparation of phosphorus propofol sodium tetrahydrate
The phosphorus propofol sodium 10g containing 30% moisture is taken, ethanol aqueous acetone solution (v is added:v:v=45:45:10) 80 ml, heating
Stir to dissolving to 60 DEG C, add 0.8g activated carbons, insulated and stirred is filtered for 30 minutes, and filtrate stands 10 DEG C of crystallizes, filters, and does
It is dry, obtain final product 8.8g phosphorus propofol sodium tetrahydrates, after testing, the XRPD of phosphorus propofol sodium tetrahydrate crystal figure as shown in figure 1,
SXRD structure charts are as shown in Figure 2.
Embodiment 7：The preparation of phosphorus propofol sodium tetrahydrate
The phosphorus propofol sodium 20g containing 30% moisture is taken, methanol acetone aqueous solution (v is added:v:v=45:45:10) 150 ml, plus
Heat to 60 DEG C are stirred to dissolving, add 1.5g activated carbons, and insulated and stirred is filtered for 30 minutes, and filtrate stands 0 DEG C of crystallize, filters,
It is dried, obtains final product 17.5g phosphorus propofol sodium tetrahydrates, after testing, the XRPD of phosphorus propofol sodium tetrahydrate crystal is schemed such as Fig. 1 institutes
Show, SXRD structure charts are as shown in Figure 2.
Embodiment 8：The preparation of phosphorus propofol sodium tetrahydrate
The phosphorus propofol sodium 20g containing 30% moisture is taken, Ethanol Isopropanol aqueous solution (v is added:v:v=45:45:10) 120 ml,
It is heated to 60 DEG C to stir to dissolving, adds 1.0g activated carbons, insulated and stirred is filtered for 30 minutes, and filtrate stands 20 DEG C of crystallizes, mistake
Filter, is dried, and obtains final product 18.0g phosphorus propofol sodium tetrahydrates, and after testing, the XRPD figures of phosphorus propofol sodium tetrahydrate crystal are as schemed
Shown in 1, SXRD structure charts are as shown in Figure 2.
Embodiment 9：The preparation of phosphorus propofol sodium tetrahydrate
The phosphorus propofol sodium 20g containing 30% moisture is taken, isopropanol aqueous acetone solution (v is added:v:v=45:45:10) 150 ml,
It is heated to 60 DEG C to stir to dissolving, adds 1.5g activated carbons, insulated and stirred is filtered for 30 minutes, and filtrate stands 5 DEG C of crystallizes, mistake
Filter, is dried, and obtains final product 18.3g phosphorus propofol sodium tetrahydrates, and after testing, the XRPD figures of phosphorus propofol sodium tetrahydrate crystal are as schemed
Shown in 1, SXRD structure charts are as shown in Figure 2.
Embodiment 10：The preparation of phosphorus propofol sodium tetrahydrate
The phosphorus propofol sodium 20g containing 30% moisture is taken, isopropanol methanol aqueous solution (v is added:v:v=45:45:10) 100 ml,
It is heated to 60 DEG C to stir to dissolving, adds 0.5g activated carbons, insulated and stirred is filtered for 30 minutes, and filtrate stands 30 DEG C of crystallizes, mistake
Filter, is dried, and obtains final product 17.2g phosphorus propofol sodium tetrahydrates, and after testing, the XRPD figures of phosphorus propofol sodium tetrahydrate crystal are as schemed
Shown in 1, SXRD structure charts are as shown in Figure 2.
Embodiment 11：It is as follows that the phosphorus propofol sodium tetrahydrate prepared by embodiment 1 determines structure cell data：
Embodiment 12：The phosphorus propofol sodium stability data that phosphorus propofol sodium tetrahydrate is prepared with commonsense method compares.
Sample accelerates to place 6 months at 30 DEG C, under conditions of humidity 70%, and data are as follows：
Sample 1 is phosphorus propofol sodium tetrahydrate
Sample 2 is phosphorus propofol sodium prepared by commonsense method
The above results show that homemade phosphorus propofol sodium tetrahydrate stability is compared with phosphorus propofol stable sodium prepared by commonsense method
Property is good.
Claims (10)
1. a kind of phosphorus propofol sodium tetrahydrate crystal and preparation method thereof, it is characterised in that phosphorus propofol sodium tetrahydrate is tied
Structure formula is as follows：
。
2. phosphorus propofol sodium tetrahydrate crystal according to claim 1 and preparation method thereof, it is characterised in that phosphorus third is moored
The X-ray powder diffraction figure of phenol sodium tetrahydrate has characteristic peak at 2 θ ± 0.2：4.1、4.5、8.9、13.4、17.8、22.3、
26.8、31.2。
3. X-ray powder diffraction figure according to claim 2, it is characterised in that X-ray powder diffraction figure is further in 2 θ
There is characteristic peak 4.5,8.9,13.4,17.8,26.8,31.2 at ± 0.2.
4. phosphorus propofol sodium tetrahydrate crystal according to claim 2, it is characterised in that the X-ray powder diffraction
Figure is substantially as shown in Figure 1.
5. the preparation method of the phosphorus propofol sodium tetrahydrate crystal according to any one of claim 1,2,3,4, including
It is as follows：
Make the phosphorus propofol sodium containing 30% moisture that dissolving is heated in the mixed solvent of organic solvent and water, add activated carbon
Decolourize, filter；Filtrate cooling crystallization, obtains the phosphorus propofol sodium tetrahydrate.
6. preparation method according to claim 5, it is characterised in that the organic solvent can be methanol, ethanol, isopropyl
Alcohol, normal propyl alcohol, positive ethanol, 2- butanol, 2- methyl isophthalic acids-propanol, 2- methyl-2-propanols, acetone, butanone, the one of methyl ethyl ketone
Plant or several.
7. preparation method according to claim 5, it is characterised in that the mass body of the phosphorus propofol sodium and mixed solvent
Product is than being 1：1-50.
8. preparation method according to claim 5, it is characterised in that described recrystallization temperature is -20～40 DEG C.
9. phosphorus propofol sodium tetrahydrate crystal according to claim 1, it is characterised in that the crystal formation is orthorhombic system,
Space group is P21, cell parameter is 90 ° of 90 ° of b=8.0392 (9) beta=of a=12.2868 (13) alpha=
C=39.868 (5) gamma=90 °, Z=4, unit cell volume is 3938.0 (8)3。
10. the phosphorus propofol sodium tetrahydrate crystal according to claim 1-3 any one is receiving diagnosis or is treating behaviour
Anaesthetize under the monitoring of the adult patients for making process.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6204257B1 (en) * | 1998-08-07 | 2001-03-20 | Universtiy Of Kansas | Water soluble prodrugs of hindered alcohols |
| CN101756913A (en) * | 2010-01-05 | 2010-06-30 | 陕西合成药业有限公司 | Preparation method for injection phosphorus propofol sodium |
| CN102382133A (en) * | 2011-12-02 | 2012-03-21 | 陕西合成药业有限公司 | Method for preparing and purifying fospropofol disodium |
| CN102558224A (en) * | 2012-01-11 | 2012-07-11 | 陕西合成药业有限公司 | Phosphorus propofol sodium hydrate and preparation method and purpose thereof |
-
2015
- 2015-11-11 CN CN201510770626.5A patent/CN106674269A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6204257B1 (en) * | 1998-08-07 | 2001-03-20 | Universtiy Of Kansas | Water soluble prodrugs of hindered alcohols |
| CN101756913A (en) * | 2010-01-05 | 2010-06-30 | 陕西合成药业有限公司 | Preparation method for injection phosphorus propofol sodium |
| CN102382133A (en) * | 2011-12-02 | 2012-03-21 | 陕西合成药业有限公司 | Method for preparing and purifying fospropofol disodium |
| CN102558224A (en) * | 2012-01-11 | 2012-07-11 | 陕西合成药业有限公司 | Phosphorus propofol sodium hydrate and preparation method and purpose thereof |
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Application publication date: 20170517 |