CN106674268A - Fospropofol disodium trihydrate, crystal form, preparation method and uses thereof - Google Patents
Fospropofol disodium trihydrate, crystal form, preparation method and uses thereof Download PDFInfo
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- CN106674268A CN106674268A CN201510768345.6A CN201510768345A CN106674268A CN 106674268 A CN106674268 A CN 106674268A CN 201510768345 A CN201510768345 A CN 201510768345A CN 106674268 A CN106674268 A CN 106674268A
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- phosphorus
- phosphorus propofol
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- propofol sodium
- sodium trihydrate
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- 239000013078 crystal Substances 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- LWYLQNWMSGFCOZ-UHFFFAOYSA-L disodium 2,6-bis(propan-2-yl)phenoxymethyl phosphate Chemical compound [Na+].[Na+].CC(C)C1=CC=CC(C(C)C)=C1OCOP([O-])([O-])=O LWYLQNWMSGFCOZ-UHFFFAOYSA-L 0.000 title abstract 3
- 229960001026 fospropofol disodium Drugs 0.000 title abstract 3
- 229960004134 propofol Drugs 0.000 claims description 95
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 claims description 91
- 229910052698 phosphorus Inorganic materials 0.000 claims description 71
- 239000011574 phosphorus Substances 0.000 claims description 71
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 67
- PAYGMRRPBHYIMA-UHFFFAOYSA-N sodium;trihydrate Chemical compound O.O.O.[Na] PAYGMRRPBHYIMA-UHFFFAOYSA-N 0.000 claims description 44
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 19
- 239000011734 sodium Substances 0.000 claims description 19
- 229910052708 sodium Inorganic materials 0.000 claims description 19
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- 238000003745 diagnosis Methods 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000012544 monitoring process Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical group CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical class CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- BFWWCEDATVMKEW-UHFFFAOYSA-N phenol;sodium;trihydrate Chemical compound O.O.O.[Na].OC1=CC=CC=C1 BFWWCEDATVMKEW-UHFFFAOYSA-N 0.000 claims 1
- 206010002091 Anaesthesia Diseases 0.000 abstract description 16
- 230000037005 anaesthesia Effects 0.000 abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 238000002405 diagnostic procedure Methods 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- 235000015424 sodium Nutrition 0.000 description 20
- 239000003814 drug Substances 0.000 description 12
- 238000000982 solution X-ray diffraction Methods 0.000 description 11
- 229940079593 drug Drugs 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 230000006698 induction Effects 0.000 description 8
- 239000012467 final product Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 230000001624 sedative effect Effects 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000000932 sedative agent Substances 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 206010039897 Sedation Diseases 0.000 description 3
- 230000003444 anaesthetic effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- -1 phosphorus propofol sodium trihydrates Chemical class 0.000 description 3
- 230000036280 sedation Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 208000001953 Hypotension Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 230000003474 anti-emetic effect Effects 0.000 description 2
- 230000003556 anti-epileptic effect Effects 0.000 description 2
- 230000002460 anti-migrenic effect Effects 0.000 description 2
- 230000001139 anti-pruritic effect Effects 0.000 description 2
- 239000002111 antiemetic agent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 208000012866 low blood pressure Diseases 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- YFVKHKCZBSGZPE-UHFFFAOYSA-N 1-(1,3-benzodioxol-5-yl)-2-(propylamino)propan-1-one Chemical compound CCCNC(C)C(=O)C1=CC=C2OCOC2=C1 YFVKHKCZBSGZPE-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 241001490312 Lithops pseudotruncatella Species 0.000 description 1
- 206010056677 Nerve degeneration Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 235000018936 Vitellaria paradoxa Nutrition 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000000049 anti-anxiety effect Effects 0.000 description 1
- 230000003026 anti-oxygenic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003908 antipruritic agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 208000008784 apnea Diseases 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 1
- AINBZKYUNWUTRE-UHFFFAOYSA-N ethanol;propan-2-ol Chemical compound CCO.CC(C)O AINBZKYUNWUTRE-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000002869 intravenous anesthetic agent Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- DGEYTDCFMQMLTH-UHFFFAOYSA-N methanol;propan-2-ol Chemical compound OC.CC(C)O DGEYTDCFMQMLTH-UHFFFAOYSA-N 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 1
- 229960003793 midazolam Drugs 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000002694 regional anesthesia Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000010911 splenectomy Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a fospropofol disodium trihydrate crystal form and a preparation method thereof, and applications of a pharmaceutical composition containing the fospropofol disodium trihydrate crystal form in monitored anesthesia care (MAC) of adult patients during diagnostic or therapeutic processes.
Description
Technical field
The invention belongs to one kind is phosphorus propofol sodium trihydrate 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 anesthetic, 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 VA；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；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 biology and medical application.For example, according to
Report that it was once used as antiemetic [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].In the PC reached less than HD, i.e. Propofol less than calmness
Antiemetic and antipruritic effect can be typically observed with anesthesia during the dosage of required concentration.On the other hand, in wider blood plasma
It is observed that antiepileptic activity [Borgeat etc., Anesthesiology 80 (1994) 642] in concentration range.Also
Report Propofol of the short time intravenous injection less than anaesthesia dosage in terms of the refractory antimigraine for the treatment of and non-antimigraine very
Effectively [224-230 of Krusz JC etc., Headache, 40 (2000)].Oneself further speculates that Propofol can serve as antianxiety
Medicine [973-7 of Kurt etc., Pol.J.Pharmacol. 55 (2003)], neuroprotective drug [Velly etc.,
Anesthesiology99 (2003) 368-75] and muscle relaxant [O'Shea etc., J.Neurosci. 24 (2004)
2322-7], and because it has antioxygenic property in living things system, thus treatment inflammation can be further used for and especially exhaled
The inflammation at road position is inhaled, and treats the neurotrosis relevant with nerve degeneration or wound.These illnesss are considered as same active oxygen
Generation is relevant, therefore can be treated with antioxidant.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 bacterium and fungal contamination sensitivity, the bacterium and fungal contamination cause POI [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 bacterium
Or the pollution of fungi.
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 embolism.
It has further been reported that the anesthesia induction 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 apnea, this occurs [Bryson etc., Drugs 50 (1995) 520] in up to 83% patient.Also oneself knows induction
The Propofol of dosage has a significant low blood pressure effect, and the effect is dosage and plasma concentration-dependent [Reves etc. see on].With it is fast
The relevant low blood pressure of the dense peak plasma noted after Propofol of speed, sometimes requires that using controllable infusion pump or quick by what is induced
Dense injecting amount is dispersed into some little incremental dosage.And, the bolus dose of induction can cause unconsciousness in short-term,
This causes Propofol to be adapted only to simple treatment.For above-mentioned reasons, Propofol is used for the induction of anesthesia and/or maintains typically must
Must apply in the case where patient is by anesthesiology expert monitoring, and have been generally acknowledged that due to non-narcotic expert to revocable or
The daily 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 sedative
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 children 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 is good for
Disease is forgotten so that it becomes the sedative of the replacement other medicines for having attraction, especially for only requiring short time calm patient.
However, because current propofol formulations have the possibility for causing hyperlipidemia and easily tolerance of the development to its sedation effect, institute
The method of the patient for being used to need long-time calm with Propofol 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 must typically be injected intravenously or be input into.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 UGI epithelial cell, or [see, e.g. with suppository form rectally
Cozanitis, D.A. etc., the 575-7 of Acta Anaesthesiol. Scand. 35 (1991)；And specially open referring to US.
05,496,537 and 5,288,597].However, low biological profit when Propofol is administered by the alternate manner except intravenous route
Expenditure limits the development of the treatment.
Patent of the present invention provides phosphorus propofol sodium trihydrate and preparation method, and the phosphorus propofol sodium trihydrate 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 trihydrate and crystal formation, phosphorus propofol sodium trihydrate
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 20% 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 trihydrate.
Above-mentioned organic solvent can for methyl alcohol, ethanol, isopropanol, normal propyl alcohol, positive ethanol, 2- butanol, 2- methyl isophthalic acids-propyl alcohol,
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 crystal.Said composition further includes one or more pharmaceutically acceptable carrier, excipient or diluent.
Said composition is suitable for the composition for preparing the sterile solution of parenteral routes or injection sterile powder form.
Said composition is to include the UD containing phosphorus propofol sodium of the invention, in an amount of from 1mg to 2000mg.
The fifth aspect of the invention, there is provided phosphorus propofol sodium trihydrate crystal formation, its X-ray powder diffraction figure is following
There is characteristic peak at 2 θ ± 0.2：4.4、4.7、9.4、13.3、14.1、17.8、18.9、22.9、23.6、24.0、26.8、28.4.Should
The XRPD collection of illustrative plates of crystal formation further can also have characteristic peak in above-mentioned 2 θ Angle Positions：4.4、4.7、9.4、14.1、18.9、28.4.
The angle of this patent crystal formation characteristic peak using the method for expressing that this area is conventional, is accurate to 0.1。.When allowable error for ±
0.2.And the principle that generally combination rounds up.As the demonstration of other 2 θ accuracy, the XRPD figures of the crystal formation can include with
Under diffraction data：
6th aspect of the invention, there is provided a kind of phosphorus propofol sodium trihydrate structure cell, structure cell data are as follows：
Element proportioning is Na2(C13H19O5P) (H2O)3, the crystal formation is orthorhombic system, and space group is P21,
Crystal unit cell parameter
a = 12.4836(14) Å alpha= 90°
b = 7.9351(9) Å beta= 90°
c = 37.656(4) Å gamma= 90°
Z=4, unit cell volume is：3730.2(7) 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 trihydrate crystal, and its abscissa represents 2 θ
The number of degrees, ordinate represents peak intensity, and the 2TH data on figure represent 2 θ values, and D values represent interplanar distance, and percentage 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 trihydrate 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 trihydrate 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 trihydrate
Phosphorus propofol sodium 10g is taken, 95% is added（v/v）Ethanol water 40ml, is heated to 60 DEG C and stirs to dissolving, adds
0.4g activated carbon decolorizings, insulated and stirred is filtered for 30 minutes, and filtrate sets to 0 a DEG C crystallization, is filtered, and is dried, and obtains 8.2g phosphorus propofol sodiums three
Hydrate, after testing, the XRPD of phosphorus propofol sodium trihydrate crystal schemes as shown in Figure l, and SXRD structure charts are as shown in Figure 2.
Embodiment 2：The preparation of phosphorus propofol sodium trihydrate
Phosphorus propofol sodium 10g is taken, 90% is added（v/v）Methanol aqueous solution 20ml, is heated to 60 DEG C and stirs to dissolving, adds
0.2g activated carbon decolorizings, insulated and stirred is filtered for 60 minutes, and filtrate puts -20 DEG C of crystallizations, is filtered, and is dried, and obtains 8.5g phosphorus propofol sodiums
Trihydrate, after testing, the XRPD of phosphorus propofol sodium trihydrate crystal schemes as shown in Figure l, and SXRD structure charts are as shown in Figure 2.
Embodiment 3：The preparation of phosphorus propofol sodium trihydrate
Phosphorus propofol sodium 10g is taken, 90% is added（v/v）Isopropanol water 60ml, is heated to 60 DEG C and stirs to dissolving, adds 1g work
Property charcoal, insulated and stirred 20 minutes filters, and filtrate stands 20 DEG C of crystallizations, filters, and is dried, and obtains final product the hydration of 8.2g phosphorus propofol sodiums three
Thing, after testing, the XRPD of phosphorus propofol sodium trihydrate crystal schemes as shown in Figure l, and SXRD structure charts are as shown in Figure 2.
Embodiment 4：The preparation of phosphorus propofol sodium trihydrate
Phosphorus propofol sodium 20g is taken, ethanol methanol aqueous solution (v is added:v:v=90:5:5) 80 ml, is heated to 60 DEG C and stirs to molten
Solution, adds 1.0g activated carbons, and insulated and stirred is filtered for 30 minutes, and filtrate stands 0 DEG C of crystallization, filters, and is dried, and obtains final product 18.3g phosphorus
Propofol sodium trihydrate, after testing, the XRPD of phosphorus propofol sodium trihydrate crystal schemes as shown in Figure l, and SXRD structure charts are such as
Shown in Fig. 2.
Embodiment 5：The preparation of phosphorus propofol sodium trihydrate
Phosphorus propofol sodium 20g is taken, ethanol aqueous acetone solution (v is added:v:v=45:45:10) 100 ml, be heated to 60 DEG C stir to
Dissolving, adds 1.0g activated carbons, and insulated and stirred is filtered for 30 minutes, and filtrate stands 0 DEG C of crystallization, filters, and is dried, and obtains final product 19.0g
Phosphorus propofol sodium trihydrate, after testing, the XRPD of phosphorus propofol sodium trihydrate crystal schemes as shown in Figure l, SXRD structure charts
As shown in Figure 2.
Embodiment 6：The preparation of phosphorus propofol sodium trihydrate
Phosphorus propofol sodium 20g is taken, the methanol acetone aqueous solution (v is added:v:v=45:45:10) 100 ml, be heated to 60 DEG C stir to
Dissolving, adds 1.0g activated carbons, and insulated and stirred is filtered for 30 minutes, and filtrate stands 0 DEG C of crystallization, filters, and is dried, and obtains final product 18.3g
Phosphorus propofol sodium trihydrate, after testing, the XRPD of phosphorus propofol sodium trihydrate crystal schemes as shown in Figure l, SXRD structure charts
As shown in Figure 2.
Embodiment 7：The preparation of phosphorus propofol sodium trihydrate
Phosphorus propofol sodium 20g is taken, the Ethanol Isopropanol aqueous solution (v is added:v:v=45:45:10) 100 ml, is heated to 60 DEG C of stirrings
To dissolving, 1.0g activated carbons are added, insulated and stirred is filtered for 30 minutes, and filtrate stands 0 DEG C of crystallization, filters, and is dried, and obtains final product
18.8g phosphorus propofol sodium trihydrates, after testing, the XRPD of phosphorus propofol sodium trihydrate crystal schemes as shown in Figure l, SXRD knots
Composition is as shown in Figure 2.
Embodiment 8：The preparation of phosphorus propofol sodium trihydrate
Phosphorus propofol sodium 20g is taken, isopropanol aqueous acetone solution (v is added:v:v=45:45:10) 150 ml, is heated to 60 DEG C of stirrings
To dissolving, 1.5g activated carbons are added, insulated and stirred is filtered for 30 minutes, and filtrate stands 0 DEG C of crystallization, filters, and is dried, and obtains final product
18.9g phosphorus propofol sodium trihydrates, after testing, the XRPD of phosphorus propofol sodium trihydrate crystal schemes as shown in Figure l, SXRD knots
Composition is as shown in Figure 2.
Embodiment 9：The preparation of phosphorus propofol sodium trihydrate
Phosphorus propofol sodium 20g is taken, isopropanol methanol aqueous solution (v is added:v:v=45:45:10) 100 ml, is heated to 60 DEG C of stirrings
To dissolving, 1.0g activated carbons are added, insulated and stirred is filtered for 30 minutes, and filtrate stands 0 DEG C of crystallization, filters, and is dried, and obtains final product
18.4g phosphorus propofol sodium trihydrates, after testing, the XRPD of phosphorus propofol sodium trihydrate crystal schemes as shown in Figure l, SXRD knots
Composition is as shown in Figure 2.
Embodiment 10：It is as follows that the phosphorus propofol sodium trihydrate prepared by embodiment 1 determines structure cell data：
Embodiment 11：The phosphorus propofol sodium stability data that phosphorus propofol sodium trihydrate 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 trihydrate
Sample 2 is phosphorus propofol sodium prepared by commonsense method
The above results show that homemade phosphorus propofol sodium trihydrate stability is compared with phosphorus propofol stable sodium prepared by commonsense method
Property is good.
Claims (10)
1. a kind of phosphorus propofol sodium trihydrate crystal and preparation method thereof, it is characterised in that phosphorus propofol sodium trihydrate is tied
Structure formula is as follows：
。
2. phosphorus propofol sodium trihydrate 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 trihydrate has characteristic peak at 2 θ ± 0.2：4.4、4.7、9.4、13.3、14.1、17.8、
18.9、22.9、23.6、24.0、26.8、28.4。
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 4.4,4.7,9.4,14.1,18.9,28.4 at ± 0.2.
4. phosphorus propofol sodium trihydrate crystal according to claim 2, it is characterised in that the X-ray powder diffraction
Figure is substantially as shown in Figure l.
5. the preparation method of the phosphorus propofol sodium trihydrate crystal according to any one of claim 1,2,3,4, including
It is as follows：
Make the phosphorus propofol sodium containing 20% 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 trihydrate.
6. preparation method according to claim 5, it is characterised in that the organic solvent can be methyl alcohol, ethanol, isopropyl
Alcohol, normal propyl alcohol, positive ethanol, 2- butanol, 2- methyl isophthalic acids-propyl alcohol, 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 trihydrate 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=7.9351 (9) beta=of a=12.4836 (14) alpha=
C=37.656 (4) gamma=90 °, Z=4, unit cell volume is 3730.2 (7)3。
10. the phosphorus propofol sodium trihydrate 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 |
| 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 |
| CN102397246A (en) * | 2011-11-18 | 2012-04-04 | 陕西合成药业有限公司 | Fospropofol sodium for injection and preparation method and application thereof |
| 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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2015
- 2015-11-11 CN CN201510768345.6A patent/CN106674268A/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 |
| CN102397246A (en) * | 2011-11-18 | 2012-04-04 | 陕西合成药业有限公司 | Fospropofol sodium for injection and preparation method and application thereof |
| 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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