CN106674270A - Fospropofol disodium pentahydrate, crystal form, preparation method and application thereof - Google Patents
Fospropofol disodium pentahydrate, crystal form, preparation method and application thereof Download PDFInfo
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- CN106674270A CN106674270A CN201510770629.9A CN201510770629A CN106674270A CN 106674270 A CN106674270 A CN 106674270A CN 201510770629 A CN201510770629 A CN 201510770629A CN 106674270 A CN106674270 A CN 106674270A
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- hydrate
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- phosphorus propofol
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- 239000013078 crystal Substances 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 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 4
- 229960001026 fospropofol disodium Drugs 0.000 title abstract 4
- 238000000034 method Methods 0.000 claims abstract description 11
- 238000003745 diagnosis Methods 0.000 claims abstract description 5
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 claims description 98
- 229960004134 propofol Drugs 0.000 claims description 98
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 74
- 229910052698 phosphorus Inorganic materials 0.000 claims description 74
- 239000011574 phosphorus Substances 0.000 claims description 74
- 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 66
- 239000011734 sodium Substances 0.000 claims description 66
- 229910052708 sodium Inorganic materials 0.000 claims description 66
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 12
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- 238000012544 monitoring process Methods 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
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 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
- NESLWCLHZZISNB-UHFFFAOYSA-M sodium phenolate Chemical compound [Na+].[O-]C1=CC=CC=C1 NESLWCLHZZISNB-UHFFFAOYSA-M 0.000 claims 1
- PAYGMRRPBHYIMA-UHFFFAOYSA-N sodium;trihydrate Chemical compound O.O.O.[Na] PAYGMRRPBHYIMA-UHFFFAOYSA-N 0.000 claims 1
- 206010002091 Anaesthesia Diseases 0.000 abstract description 15
- 230000037005 anaesthesia Effects 0.000 abstract description 15
- 239000003814 drug Substances 0.000 abstract description 11
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 235000015424 sodium Nutrition 0.000 description 63
- 238000000982 solution X-ray diffraction Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 239000012467 final product Substances 0.000 description 8
- 230000006698 induction Effects 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 206010039897 Sedation Diseases 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 230000036280 sedation Effects 0.000 description 3
- 230000001624 sedative effect Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 206010003497 Asphyxia Diseases 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 230000003556 anti-epileptic effect Effects 0.000 description 2
- 230000001139 anti-pruritic effect Effects 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 230000036543 hypotension Effects 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- DGEYTDCFMQMLTH-UHFFFAOYSA-N methanol;propan-2-ol Chemical compound OC.CC(C)O DGEYTDCFMQMLTH-UHFFFAOYSA-N 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- 229940125725 tranquilizer Drugs 0.000 description 2
- 239000003204 tranquilizing agent Substances 0.000 description 2
- 230000002936 tranquilizing effect Effects 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 241001490312 Lithops pseudotruncatella Species 0.000 description 1
- 206010056677 Nerve degeneration Diseases 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- SQPVQGHHSGWUEP-UHFFFAOYSA-N O.[P] Chemical compound O.[P] SQPVQGHHSGWUEP-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010067268 Post procedural infection Diseases 0.000 description 1
- 208000006193 Pulmonary infarction Diseases 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 235000018936 Vitellaria paradoxa Nutrition 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
- 210000001367 artery Anatomy 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000000481 breast Anatomy 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
- 238000007796 conventional method Methods 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
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 1
- YJVCRVPZGVVAEQ-UHFFFAOYSA-N ethanol;methanol;propan-2-one Chemical compound OC.CCO.CC(C)=O YJVCRVPZGVVAEQ-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
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 1
- 201000005577 familial hyperlipidemia Diseases 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003983 inhalation anesthetic agent Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000002869 intravenous anesthetic agent Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002632 lipids Chemical class 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
- DQMSBDXZGJIRDX-UHFFFAOYSA-N methanol;propan-2-ol;propan-2-one Chemical compound OC.CC(C)O.CC(C)=O DQMSBDXZGJIRDX-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
- 230000008764 nerve damage 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
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000007575 pulmonary infarction Effects 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-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
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- HQAITFAUVZBHNB-UHFFFAOYSA-N sodium;pentahydrate Chemical compound O.O.O.O.O.[Na] HQAITFAUVZBHNB-UHFFFAOYSA-N 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
- 210000003462 vein Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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 crystal form of fospropofol disodium pentahydrate and also provides a preparation method for the crystal form of the fospropofol disodium pentahydrate. Besides, a medicine compound containing the crystal form of the fospropofol disodium pentahydrate is applied to the monitored anesthesia care (MAC) for an adult patient who accepts diagnosis or is in a treatment operation process.
Description
Technical field
The invention belongs to one kind is phosphorus propofol sodium pentahydrate 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
IntravenousAnesthesia, Butterworth Heinemann, Oxford 2000].Because its preparation is lipid breast
Agent, therefore intravenously administrable also causes the hypertriglyceridemia unfavorable to patient, and the patient for infusing especially is received over a long time
[Fulton B. and Sorkin EM, Drugs 50 (1995) 636].The preparation of liplid emulsions makes it be more difficult to and other medicines
Thing is shared.Any physical change of said preparation, the such as change of fat drips size, lead to medicine pharmacological property change 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 without hydrate and preparation method, and the phosphorus propofol sodium is more general without hydrate
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 is without hydrate and crystal formation, phosphorus propofol sodium is without hydrate
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：
Phosphorus propofol sodium is heated in organic solvent dissolving, activated carbon decolorizing is added, is filtered；Filtrate cooling crystallization, obtains institute
Phosphorus propofol sodium is stated without hydrate.
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 organic 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 is without hydrate crystal forms.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 without hydrate containing phosphorus propofol sodium of the invention, in an amount of from 1mg to 2000mg.
The fifth aspect of the invention, there is provided, without hydrate crystal forms, its X-ray powder diffraction figure is following for phosphorus propofol sodium
There is characteristic peak at 2 θ ± 0.2：4.7、11.8、13.9、18.5、23.7、27.8.The angle of this patent crystal formation characteristic peak is using this
The conventional method for expressing in field, allowable error is ± 0.2 when being accurate to 0.1.And the principle that generally combination rounds up.As it
The demonstration of his 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 is without hydrate structure cell, and structure cell data are as follows：
Element proportioning is Na2(C13H19O5P), the crystal formation is monoclinic system, and space group is P21/ c,
Crystal unit cell parameter
a = 19.755(2) Å alpha= 90°
b = 5.7663(6) Å beta= 103.226(5)°
c = 15.425(2) Å gamma= 90°
Z=4, unit cell volume is：1710.5(3) 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 embodiment of the present invention l gained XRPD collection of illustrative plates of the phosphorus propofol sodium without hydrate 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 the gained phosphorus propofol sodium of the embodiment of the present invention 1 knot of the Advances in crystal X-ray diffraction (SXRD) without hydrate crystal
Composition.
Fig. 3 is Advances in crystal X-ray diffraction (SXRD) two of the gained phosphorus propofol sodium of the embodiment of the present invention 1 without hydrate crystal
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：Preparation of the phosphorus propofol sodium without hydrate
Phosphorus propofol sodium 10g is taken, ethanol methanol solution is added（v:v=95:5）40ml, is heated to 60 DEG C and stirs to dissolving, then adds
Enter 0.1g activated carbon decolorizings, insulated and stirred is filtered for 10 minutes, and filtrate puts 25 DEG C of crystallizes, filters, and is dried, and obtains 4.8g phosphorus propofol sodiums
Without hydrate, after testing, XRPD of the phosphorus propofol sodium without hydrate crystal is schemed as shown in figure 1, SXRD structure charts are as shown in Figure 2.
Embodiment 2：Preparation of the phosphorus propofol sodium without hydrate
Phosphorus propofol sodium 10g is taken, methanol solution 20ml is added, 60 DEG C is heated to and is stirred to dissolving, added 0.2g activated carbons and take off
Color, insulated and stirred is filtered for 10 minutes, and filtrate puts -20 DEG C of crystallizes, is filtered, and is dried, and obtains 7.3g phosphorus propofol sodiums without hydrate, Jing inspections
Survey, XRPD of the phosphorus propofol sodium without hydrate crystal is schemed as shown in figure 1, SXRD structure charts are as shown in Figure 2.
Embodiment 3：Preparation of the phosphorus propofol sodium without hydrate
Phosphorus propofol sodium 10g is taken, isopropanol methanol is added（v:v=95:5）100ml, is heated to 60 DEG C and stirs to dissolving, adds
0.8g activated carbons, insulated and stirred 20 minutes is filtered, and filtrate stands 10 DEG C of crystallizes, is filtered, and is dried, obtain final product 8.2g phosphorus propofol sodiums without
Hydrate, after testing, XRPD of the phosphorus propofol sodium without hydrate crystal is schemed as shown in figure 1, SXRD structure charts are as shown in Figure 2.
Embodiment 4：Preparation of the phosphorus propofol sodium without hydrate
Phosphorus propofol sodium 30g is taken, the ml of ethanol 300 is added, 60 DEG C is heated to and is stirred to dissolving, add 3.0g activated carbons, be incubated
Stirring is filtered for 10 minutes, and filtrate stands 0 DEG C of crystallize, is filtered, and is dried, and obtains final product 23.9g phosphorus propofol sodiums without hydrate, after testing,
XRPD of the phosphorus propofol sodium without hydrate crystal is schemed as shown in figure 1, SXRD structure charts are as shown in Figure 2.
Embodiment 5：Preparation of the phosphorus propofol sodium without hydrate
Phosphorus propofol sodium 20g is taken, ethanol methanol acetone (v is added:v:v=90:5:5) 100 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 crystallize, filters, and is dried, and obtains final product 18.0g phosphorus
Propofol sodium without hydrate, after testing, XRPD of the phosphorus propofol sodium without hydrate crystal figures as shown in figure 1, SXRD structure charts such as
Shown in Fig. 2.
Embodiment 6：Preparation of the phosphorus propofol sodium without hydrate
Phosphorus propofol sodium 10g is taken, ethanol acetone (v is added:v=45:45) 100 ml, is heated to 60 DEG C and stirs to dissolving, adds
0.5g activated carbons, insulated and stirred 30 minutes is filtered, and filtrate stands 10 DEG C of crystallizes, is filtered, and is dried, obtain final product 8.2g phosphorus propofol sodiums without
Hydrate, after testing, XRPD of the phosphorus propofol sodium without hydrate crystal is schemed as shown in figure 1, SXRD structure charts are as shown in Figure 2.
Embodiment 7：Preparation of the phosphorus propofol sodium without hydrate
Phosphorus propofol sodium 20g is taken, methanol acetone (v is added:v=45:45) 150 ml, is heated to 60 DEG C and stirs to dissolving, then adds
Enter 1.5g activated carbons, insulated and stirred is filtered for 30 minutes, and filtrate stands 0 DEG C of crystallize, filters, and is dried, and obtains final product 18.2g phosphorus propofol sodiums
Without hydrate, after testing, XRPD of the phosphorus propofol sodium without hydrate crystal is schemed as shown in figure 1, SXRD structure charts are as shown in Figure 2.
Embodiment 8：Preparation of the phosphorus propofol sodium without hydrate
Phosphorus propofol sodium 20g is taken, Ethanol Isopropanol (v is added:v=45:45) 150ml, is heated to 60 DEG C and stirs to dissolving, then adds
Enter 1.0g activated carbons, insulated and stirred is filtered for 30 minutes, and filtrate stands 20 DEG C of crystallizes, filters, and is dried, and obtains final product 18.7g phosphorus propofols
Without hydrate, after testing, XRPD of the phosphorus propofol sodium without hydrate crystal schemes as shown in figure 1, SXRD structure charts such as Fig. 2 institutes sodium
Show.
Embodiment 9：Preparation of the phosphorus propofol sodium without hydrate
Phosphorus propofol sodium 20g is taken, isopropanol acetone methanol (v is added:v:v=10:10:90) 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 5 DEG C of crystallizes, filters, and is dried, and obtains final product 17.4g
Without hydrate, after testing, XRPD of the phosphorus propofol sodium without hydrate crystal schemes as shown in figure 1, SXRD structure charts phosphorus propofol sodium
As shown in Figure 2.
Embodiment 10：Preparation of the phosphorus propofol sodium without hydrate
Phosphorus propofol sodium 20g is taken, isopropanol methanol/ethanol (v is added:v:v=20:60:20) 100 ml, be heated to 60 DEG C stir to
Dissolving, adds 0.5g activated carbons, and insulated and stirred is filtered for 30 minutes, and filtrate stands 0 DEG C of crystallize, filters, and is dried, and obtains final product 16.2g
Without hydrate, after testing, XRPD of the phosphorus propofol sodium without hydrate crystal schemes as shown in figure 1, SXRD structure charts phosphorus propofol sodium
As shown in Figure 2.
Embodiment 11：It is as follows that the phosphorus propofol sodium prepared by embodiment 1 determines structure cell data without hydrate：
Embodiment 12：Phosphorus propofol sodium compares without the phosphorus propofol sodium stability data that hydrate is prepared with commonsense method.
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 without hydrate
Sample 2 is phosphorus propofol sodium prepared by commonsense method
The above results show that homemade phosphorus propofol sodium is without hydrate stability compared with phosphorus propofol stable sodium prepared by commonsense method
Property is good.
Claims (9)
1. a kind of phosphorus propofol sodium is without hydrate crystal and preparation method thereof, it is characterised in that phosphorus propofol sodium is tied without hydrate
Structure formula is as follows：
。
2. phosphorus propofol sodium according to claim 1 is without hydrate crystal and preparation method thereof, it is characterised in that phosphorus third is moored
X-ray powder diffraction figure of the phenol sodium without hydrate has characteristic peak at 2 θ ± 0.2：4.7、11.8、13.9、18.5、23.7、
27.8。
3. 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.
4. preparation method of the phosphorus propofol sodium without hydrate crystal according to any one of claim 1,2,3, including such as
Under：
Take phosphorus propofol sodium and be heated to dissolving in organic solvent, add activated carbon decolorizing, filter；Filtrate cooling crystallization, obtains institute
Phosphorus propofol sodium is stated without hydrate.
5. preparation method according to claim 4, 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.
6. preparation method according to claim 4, it is characterised in that the mass body of the phosphorus propofol sodium and organic solvent
Product is than being 1：1-50.
7. preparation method according to claim 4, it is characterised in that described recrystallization temperature is -20～40 DEG C.
8. phosphorus propofol sodium according to claim 1 is without hydrate crystal, it is characterised in that the crystal formation is monoclinic system,
Space group is P21/ c, cell parameter is b=5.7663 (6) beta=of a=19.755 (2) alpha=90
103.226 (5) ° of c=15.425 (2) gamma=90 °, Z=4, unit cell volume is 1710.5 (3)3。
9. the phosphorus propofol sodium according to claim 1-3 any one is receiving diagnosis or is treating operation without hydrate crystal
Anaesthetize under the monitoring of the adult patients of process.
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| 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 |
-
2015
- 2015-11-11 CN CN201510770629.9A patent/CN106674270A/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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