CN106554377B - Morphine derivatives crystal form III and its preparation method and application - Google Patents
Morphine derivatives crystal form III and its preparation method and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention provides a kind of morphine derivatives crystal form III as shown in Equation 1, it is radiated using CuK α, its X powder diffraction figure is to have diffraction maximum at 9.36,13.24,14.74,15.22,16.22,17.50,19.90,20.92 and 22.98 in (2 θ ± 0.5) °.In addition, also disclosing the preparation method of the crystal form, medical composition and its use.Compared with known crystal form, the crystal form III of the application has the characteristics that solution rate is fast, bioavilability is high and is suitable for industrialization.
Description
Technical field
The present invention relates to field of medicaments, more particularly to morphine derivatives crystal form III and its preparation method and application.
Background technique
Morphine derivatives, structural formula are as shown in Equation 1:
The morphine derivatives early have turned out to be morphine in the intracorporal metabolite of people, and later to its research development, from
Nineteen fifty proves that it has higher analgesic activity than morphine by mouse test by Casparis, just recognize to the eighties
Unique active material in morphine metabolin is only to it, morphine analgesia effect in play critically important effect, so far just by
It is gradually known for clinician and medical science men, but its mechanism of action and clinical use only just start to open up in recent two decades
It opens, has a large amount of document now and it is reported, and its development is also opened by CeNes company, Britain from the last years of a dynasty or reign in last century
Begin to carry out, the derivative is in III phase clinical investigation phase at present, it has therefore proved that its analgesic effect is equal to morphine, and pair is made
With being substantially reduced, nausea and vomiting and respiration inhibition effect have clinical safety more preferably than morphine considerably less than morphine.
Structural formula is as shown in Figure 1:
United States Patent (USP) US6172206B1 discloses crystal form A of the morphine derivatives and preparation method thereof.However, the crystal form
It places at room temperature unstable, is also easy to produce degradation impurity A, impurity B, impurity C etc..The specific structure of impurity is as follows:
For the polymorphic of drug, different polymorphics can have different characteristics, and such as chemical stability melts
Point, apparent solubility, rate of dissolution and density etc..These properties can directly affect the processing and production of bulk pharmaceutical chemicals and preparation,
And it will affect the stability, solubility and bioavilability of preparation.In the solid pharmaceutical preparation made of the polymorphic of drug, dissolution
Degree directly affects bioavilability, in general, the drug that solubility is big, bioavilability can be higher.Therefore, the polymorphic of drug
All have great importance with the quality of pharmaceutical preparation, safety and validity.
Summary of the invention
The present inventor, which has developed one kind, has other peculiar properties relative to other solid-state forms of morphine derivatives shown in formula 1
Novel crystal forms, the stability of crystal form is good, and bioavilability is high, and is suitable for industrialization.
Integrity property of the invention is as described below, but for convenience's sake, morphine as shown in Equation 1 of the invention is spread out
Biological novel crystal forms are known as " crystal form III ".
The purpose of the present invention is to provide a kind of morphine derivatives crystal form III as shown in Equation 1.
Another object of the present invention is to provide the preparation methods of above-mentioned morphine derivatives crystal form III.
Third object of the present invention is to provide the pharmaceutical composition comprising above-mentioned morphine derivatives crystal form III.
Fourth object of the present invention is to provide application of the above-mentioned morphine derivatives crystal form III in drug.
The object of the present invention is achieved like this:
In embodiments of the invention, the present invention provides a kind of morphine derivatives crystal form III as shown in Equation 1:
Radiated using CuK α, X powder diffraction figure, in (2 θ ± 0.5) ° be 9.36,13.24,14.74,15.22,
16.22, there is at 17.50,19.90,20.92 and 22.98 its d-value of diffraction maximum to be respectively as follows: 9.4408,8.1549,
6.6816,6.0049,5.8165,5.4601,5.0635,4.4579,4.2428 and 3.8669；Its relative intensity is all larger than or waits
In 20%.
In a kind of preferred embodiment of the invention, crystal form III as shown in Equation 1 provided by the invention uses CuK α spoke
Penetrate, X powder diffraction figure, in (2 θ ± 0.2) ° be 9.36,13.24,14.74,15.22,16.22,17.50,19.90,
Have diffraction maximum at 20.92 and 22.98, d-value is respectively as follows: 9.4408,8.1549,6.6816,6.0049,5.8165,
5.4601,5.0635,4.4579,4.2428 and 3.8669；Its suitable intensity is all larger than or is equal to 20%.
In a kind of particularly preferred embodiment of the invention, morphine derivatives crystal form as shown in Equation 1 provided by the invention
III is radiated using CuK α, X powder diffraction figure, 2 θ ° for 7.56,8.50,9.36,10.04,10.34,10.84,11.44,
13.24、14.28、14.74、15.22、16.22、16.64、17.08、17.50、18.30、18.70、19.90、20.92、
22.04、22.98、23.38、23.94、24.56、25.44、26.06、26.74、27.18、27.52、28.76、29.10、
29.88, there is diffraction maximum at 30.54,31.82,32.52,33.30,35.48,37.44 and 38.92.
In a kind of particularly preferred embodiment of the invention, morphine derivatives crystal form as shown in Equation 1 provided by the invention
III is radiated using CuK α, X powder diffraction figure, and 2 θ, interplanar distance d value and the relative intensity percentage being expressed in degrees are such as
Under:
| 2θ° | d-value | I/I0 |
| 7.56 | 11.6841 | 5 |
| 8.50 | 10.3940 | 18 |
| 9.36 | 9.4408 | 100 |
| 10.04 | 8.8029 | 8 |
| 10.34 | 8.5481 | 6 |
| 10.84 | 8.1549 | 12 |
| 11.44 | 7.7285 | 10 |
| 13.24 | 6.6816 | 47 |
| 14.28 | 6.1972 | 11 |
| 14.74 | 6.0049 | 20 |
| 15.22 | 5.8165 | 23 |
| 16.22 | 5.4601 | 68 |
| 16.64 | 5.3232 | 27 |
| 17.08 | 5.1871 | 18 |
| 17.50 | 5.0635 | 51 |
| 18.30 | 4.8439 | 9 |
| 18.70 | 4.7412 | 11 |
| 19.90 | 4.4579 | 33 |
| 20.92 | 4.2428 | 28 |
| 22.04 | 4.0297 | 13 |
| 22.98 | 3.8669 | 33 |
| 23.38 | 3.8017 | 23 |
| 23.94 | 3.7140 | 21 |
| 24.56 | 3.6216 | 14 |
| 25.44 | 3.4983 | 20 |
| 26.06 | 3.4165 | 13 |
| 26.74 | 3.3311 | 11 |
| 27.18 | 3.2782 | 8 |
| 27.52 | 3.2384 | 7 |
| 28.76 | 3.1016 | 8 |
| 29.10 | 3.0661 | 11 |
| 29.88 | 2.9878 | 9 |
| 30.54 | 2.9247 | 8 |
| 31.82 | 2.8099 | 7 |
| 32.52 | 2.7510 | 6 |
| 33.30 | 2.6884 | 6 |
| 35.48 | 2.5280 | 6 |
| 37.44 | 2.4001 | 5 |
| 38.92 | 2.3121 | 5 |
In a kind of most preferred embodiment of the invention, morphine derivatives crystal form as shown in Equation 1 provided by the invention
III is radiated using CuK α, and X powder diffraction figure is as shown in Figure 1.
In one embodiment of the present invention, morphine derivatives crystal form III as shown in Equation 1 provided by the invention, uses KBr
The infrared absorption pattern that tabletting measures shows absorption peak in following wave number:
3399(cm-1)、2971(cm-1)、2726(cm-1)、1604(cm-1)、1504(cm-1)、1467(cm-1)、1407
(cm-1)、1317(cm-1)、1295(cm-1)、1256(cm-1)、1178(cm-1)、1158(cm-1)、1064(cm-1)、988(cm-1)、961(cm-1)、937(cm-1)、873(cm-1)、848(cm-1)、793(cm-1)、759(cm-1)、711(cm-1)、637(cm-1)、602(cm-1) and 528 (cm-1).It is highly preferred that its infrared spectrogram is as shown in Figure 2.
In one embodiment of the present invention, morphine derivatives crystal form III as shown in Equation 1 provided by the invention melts
Point peak temperature is 236.5 DEG C, which has differential scanning calorimeter (DSC) map as shown in Figure 3.
On the other hand, the present invention provides the preparation method of above-mentioned morphine derivatives crystal form III, include the following steps:
(1) will morphine derivatives as shown in Equation 1 be added acetonitrile in be made in suspension, temperature be 5-82 DEG C stirring 5~
15 hours；
(2) cooling, at 0~30 DEG C of temperature stirring and crystallizing 1~15 hour；
(3) it filters, filter cake is dried under reduced pressure in 20~80 DEG C.
In embodiments of the invention, the preparation method of above-mentioned morphine derivatives crystal form III provided by the invention, upper
It states in step (2), crystal, which about reached at 15 hours, turns Jinping's weighing apparatus.
In embodiments of the invention, the preparation method of above-mentioned morphine derivatives crystal form III provided by the invention, step
(1) preferably 30~45 DEG C of temperature described in.
In embodiments of the invention, the preparation method of above-mentioned morphine derivatives crystal form III provided by the invention, upper
It states in step (2), the temperature is preferably 0 DEG C~15 DEG C.
In embodiments of the invention, the preparation method of above-mentioned morphine derivatives crystal form III provided by the invention, step
(1) w/v of morphine derivatives and acetonitrile as shown in Equation 1 is 1:3~20 (g:ml) in.
In a preferred embodiment of the invention, the present invention provides the preparation method of above-mentioned morphine derivatives crystal form III,
Include the following steps:
(1) suspension is made by w/v for the morphine derivatives as shown in Equation 1 of 1:3~20 (g:ml) and with acetonitrile
Liquid is stirred at 30-45 DEG C；
(2) cooling, 0~15 DEG C stirring and crystallizing 1~15 hour；
(3) it filters；Colorless plate crystal is obtained, 20~80 DEG C are dried under reduced pressure, and obtain crystal form III.
The third aspect, the present invention provides a kind of pharmaceutical compositions, include morphine derivatives crystal form III shown in above-mentioned formula 1
With pharmaceutically acceptable auxiliary material.Here, tablet, powder, granule, glue is made according to different adaptation situations in the composition
The dosage forms such as wafer, injection, freeze-dried powder, pill, sustained-release and controlled release preparation.
Fourth aspect, the present invention provides morphine derivatives crystal form III shown in above-mentioned formula 1 in preparation treatment analgesic
Application, the preferably application after preparing iatrotechnics in analgesic.
Beneficial effects of the present invention:
The melting point peak temperature of morphine derivatives crystal form III of the present invention is 236.5 DEG C, and solution rate is fast in water,
Solubility >=100mg/mL in water, bioavilability is high, is suitble to that a variety of pharmaceutical compositions are made, can be made into several formulations such as piece
Agent, capsule, pill, sustained-release and controlled release preparation, freeze drying powder injection etc..In addition, morphine made from preparation method of the present invention
Derivative crystal form III purity is high, preparation method mild condition is easy to operate, places stablize at room temperature, and favorable reproducibility produced
Journey is easily controllable, highly-safe, is suitble to industrialized production.
Detailed description of the invention
Fig. 1 is the X powder diffraction map of crystal type morphine derivatives crystal form III.
Fig. 2 is the infrared spectrogram of crystal type morphine derivatives crystal form III.
Fig. 3 is differential scanning calorimeter (DSC) map of crystal type morphine derivatives crystal form III.
Specific embodiment
The present invention is specifically described below by embodiment, it is necessary to which indicated herein is that following embodiment is only used
In invention is further explained, it should not be understood as limiting the scope of the invention, person skilled in art can
To make some nonessential modifications and adaptations to the present invention according to aforementioned present invention content.
Infrared absorption spectrum (IR)
Measuring unit: Institute of Analysis, Peking University
Instrument: Spotlight200 Fourier transformation infrared spectrometer
Detect foundation: two annex IVC of Pharmacopoeia of People's Republic of China (version in 2010): infrared spectrophotometer
Pretreatment situation: the chromatographically pure potassium bromide powder for taking about 2mg sample and 100mg or so dry respectively is ground into carefully
After powder, it is packed into compression mold, translucent ingot piece is suppressed on tablet press machine.
Analyze parameter: infrared spectroscopy (KBr pressed disc method) test；Resolution ratio 4cm-1；Scanning times: 64 times
Powder x-ray diffraction
Measuring unit: Institute of Analysis, Peking University
Instrument: the full-automatic polycrystal X ray diffractometer of Dmax/2400
Detect foundation: two annex IXF:X ray powder diffraction methods of Pharmacopoeia of People's Republic of China (version in 2010)
It pre-processes situation: institute's test sample being taken out in right amount, is put into clean agate mortar and is ground
Analyze parameter: graphite monochromator；CuKα1；Scanning range: 2 θ: 3~40 °, scanning speed: 4 °/min,
Step-length: 0.02 °, pipe flow tube pressure: 40kV, 100mA；
Slit setting: (DS:1/2 °；SS:1/2°；RS:0.3mm)
Differential scanning calorimeter (DSC)
Measuring unit: Institute of Analysis, Peking University
Instrument: SDT Q600 thermogravimetric and differential scanning simultaneous determination instrument
Detect foundation: two annex VIIIQ of Pharmacopoeia of People's Republic of China (version in 2010): thermal analysis system
Pre-process situation: nothing
Analyze parameter: measuring temperature range: 20~245 DEG C；Heating rate: 10 DEG C/min；
High pure nitrogen flow: 50mL/min；Sampled point interval: 0.2 second/point
Embodiment 1
By morphine derivatives shown in 1g formula 1 (being prepared according to CN201410116005.0 the method) and 3ml acetonitrile
Suspension is made, 5 DEG C of stirring 15h, in 0 DEG C of stirring and crystallizing 10h, filtering, 60 DEG C are dried under reduced pressure.
Gained morphine derivatives θ ° of angle of diffraction 2 for 7.56,8.50,9.36,10.04,10.34,10.84,11.44,
13.24、14.28、14.74、15.22、16.22、16.64、17.08、17.50、18.30、18.70、19.90、20.92、
22.04、22.98、23.38、23.94、24.56、25.44、26.06、26.74、27.18、27.52、28.76、29.10、
29.88, there is absorption peak at 30.54,31.82,32.52,33.30,35.48,37.44,38.92, be crystal form III.Its X powder spreads out
It is as shown in Figure 1 to penetrate map.
Morphine derivatives crystal form III shown in crystalline form 1 of the invention, powder X-ray diffraction pattern is with 2 θ, d-value, I/I0
Equal parameter expressions III crystal form, as shown in the table:
| 2θ° | d-value | I/I0 |
| 7.56 | 11.6841 | 5 |
| 8.50 | 10.3940 | 18 |
| 9.36 | 9.4408 | 100 |
| 10.04 | 8.8029 | 8 |
| 10.34 | 8.5481 | 6 |
| 10.84 | 8.1549 | 12 |
| 11.44 | 7.7285 | 10 |
| 13.24 | 6.6816 | 47 |
| 14.28 | 6.1972 | 11 |
| 14.74 | 6.0049 | 20 |
| 15.22 | 5.8165 | 23 |
| 16.22 | 5.4601 | 68 |
| 16.64 | 5.3232 | 27 |
| 17.08 | 5.1871 | 18 |
| 17.50 | 5.0635 | 51 |
| 18.30 | 4.8439 | 9 |
| 18.70 | 4.7412 | 11 |
| 19.90 | 4.4579 | 33 |
| 20.92 | 4.2428 | 28 |
| 22.04 | 4.0297 | 13 |
| 22.98 | 3.8669 | 33 |
| 23.38 | 3.8017 | 23 |
| 23.94 | 3.7140 | 21 |
| 24.56 | 3.6216 | 14 |
| 25.44 | 3.4983 | 20 |
| 26.06 | 3.4165 | 13 |
| 26.74 | 3.3311 | 11 |
| 27.18 | 3.2782 | 8 |
| 27.52 | 3.2384 | 7 |
| 28.76 | 3.1016 | 8 |
| 29.10 | 3.0661 | 11 |
| 29.88 | 2.9878 | 9 |
| 30.54 | 2.9247 | 8 |
| 31.82 | 2.8099 | 7 |
| 32.52 | 2.7510 | 6 |
| 33.30 | 2.6884 | 6 |
| 35.48 | 2.5280 | 6 |
| 37.44 | 2.4001 | 5 |
| 38.92 | 2.3121 | 5 |
The melting point peak temperature of the crystal form III of morphine derivatives shown in crystalline form 1 is 236.5 DEG C, which has such as
Differential scanning calorimeter (DSC) map shown in Fig. 3.
The infrared spectroscopy that the crystal form III of morphine derivatives shown in crystalline form 1 is generated shows absorption peak in following wave number:
3399(cm-1)、2971(cm-1)、2726(cm-1)、1604(cm-1)、1504(cm-1)、1467(cm-1)、1407
(cm-1)、1317(cm-1)、1295(cm-1)、1256(cm-1)、1178(cm-1)、1158(cm-1)、1064(cm-1)、988
(cm-1)、961(cm-1)、937(cm-1)、873(cm-1)、848(cm-1)、793(cm-1)、759(cm-1)、711(cm-1)、637
(cm-1)、602(cm-1)、528(cm-1).Infrared spectrogram is as shown in Figure 2.
Embodiment 2
Morphine derivatives shown in 1g formula 1 and 5ml acetonitrile are made suspension, 10 DEG C of stirring 5h, in 5 DEG C of stirring and crystallizing 1h,
Filtering, 50 DEG C are dried under reduced pressure, and the characterizing method identification of gained morphine derivatives embodiment 1, is crystal form III.
Embodiment 3
Suspension, 65 DEG C of stirring 11h, in 20 DEG C of stirring and crystallizings are made in morphine derivatives shown in 1g formula 1 and 10ml acetonitrile
15h, filtering, 70 DEG C are dried under reduced pressure, and the characterizing method identification of gained morphine derivatives embodiment 1, is crystal form III.
Embodiment 4
Morphine derivatives shown in 1g formula 1 and 15ml acetonitrile are made suspension, 55 DEG C of stirring 10h, in 30 DEG C of crystallization 12h,
Filtering, 80 DEG C are dried under reduced pressure, and the characterizing method identification of gained morphine derivatives embodiment 1, is crystal form III.
Embodiment 5
Suspension, 35 DEG C of stirring 15h, in 30 DEG C of stirring and crystallizings are made in morphine derivatives shown in 1g formula 1 and 17ml acetonitrile
10h, filtering, 40 DEG C are dried under reduced pressure, and the characterizing method identification of gained morphine derivatives embodiment 1, is crystal form III.
Embodiment 6
Suspension, 45 DEG C of stirring 8h, in 25 DEG C of stirring and crystallizings are made in morphine derivatives shown in 1g formula 1 and 20ml acetonitrile
5h, filtering, 30 DEG C are dried under reduced pressure, and the characterizing method identification of gained morphine derivatives embodiment 1, is crystal form III.
Embodiment 7
Morphine derivatives shown in 1g formula 1 and 8ml acetonitrile are made suspension, 20 DEG C of stirring 6h, in 15 DEG C of stirring and crystallizing 3h,
Filtering, 20 DEG C are dried under reduced pressure, and the characterizing method identification of gained morphine derivatives embodiment 1, is crystal form III.
Embodiment 8
Suspension, 75 DEG C of stirring 9h, in 23 DEG C of stirring and crystallizings are made in morphine derivatives shown in 1g formula 1 and 15ml acetonitrile
8h, filtering, 45 DEG C are dried under reduced pressure, and the characterizing method identification of gained morphine derivatives embodiment 1, is crystal form III.
Embodiment 9
Suspension, 82 DEG C of stirring 13h, in 28 DEG C of stirring and crystallizings are made in morphine derivatives shown in 1g formula 1 and 16ml acetonitrile
3h, filtering, 35 DEG C are dried under reduced pressure, and the characterizing method identification of gained morphine derivatives embodiment 1, is crystal form III.
Embodiment 10:
Morphine derivatives shown in III crystal form formula 1 made from 1 the method for embodiment are according to 200mg/, lactose 80.8mg/
Grain, sodium carboxymethyl starch 72mg/, talcum powder 7.2mg/ and 10% polyvinylpyrrolidone 5.1mg/.
For morphine derivatives capsule shown in 1000 II crystal form formulas 1 is made, specific preparation method is: first will be former auxiliary
Expected 80 meshes, and weighed morphine derivatives shown in the III crystal form formula 1 of above-mentioned amount, lactose, sodium carboxymethyl starch and be uniformly mixed, add
10%PVP ethanol solution softwood is pelletized, and the talcum powder of above-mentioned amount is added into particle for drying, whole grain, is uniformly mixed, filling
Capsule.
Embodiment 11:
Morphine derivatives shown in III crystal form formula 1 made from 1 the method for embodiment are according to 200mg/ piece, starch 34mg/
Piece, microcrystalline cellulose 60mg/ piece, talcum powder 6mg/ piece and 2% hydroxypropyl methyl cellulose (K4M model) 6mg/ piece；
For morphine derivatives tablet shown in 1000 III crystal form formulas 1 is made, specific preparation method is: first will be former auxiliary
Expected 80 meshes, and weighed morphine derivatives shown in the III crystal form formula 1 of above-mentioned amount, starch, microcrystalline cellulose and be uniformly mixed, add suitable
2%HPMC aqueous solution softwood is measured, is pelletized, the talcum powder of recipe quantity is added into particle for drying, whole grain, is uniformly mixed, pressure
Piece.
Embodiment 12:
Morphine derivatives shown in III crystal form formula 1 made from 1 the method for embodiment are according to 50g, glucose 150g, 500ml
Water for injection is dissolved in dilute preparing tank, and temperature is controlled at 50~60 DEG C, and lysate is cooled to 25 up to being completely dissolved by stirring
DEG C, active carbon decoloring is added in the lysate that Xiang Shangshu is prepared, then active carbon therein is filtered to remove, phosphate-buffered is added
The pH value of the lysate is adjusted to 4.0 by liquid, adds water for injection to 5000ml, encapsulating sterilizes 30 minutes at 105 DEG C, obtains
To injection.
Testing example 1:
On the basis of measuring the LC-MS method of morphine in existing biological sample, experiment selects health Beagle dog 6, body
Weight is 8~10kg, is divided into two groups, every group 3, for observing life of the morphine derivatives shown in different crystal forms formula 1 to dog after oral
Object availability.It studies A crystal form and (prepares) morphine derivatives and III crystal form formula 1 shown in formula 1 according to embodiment 1 in US6172206B1
Shown morphine derivatives evaluate the life of A crystal form and III crystal form in the intracorporal pharmacokinetics of dog, and using morphine as reference preparation
Whether object availability is equivalent.And evaluation of bioequivalence is carried out to it by calculating its pharmacokinetic parameter.As a result: III is brilliant
Morphine derivatives shown in morphine derivatives shown in pattern 1 and A crystal form formula 1 are in the intracorporal main pharmacokinetic parameter of Beagle dog
As follows: peak time Tmax is respectively (1.572 ± 0.398), (1.498 ± 0.3988), up to Cmax Cmax is respectively
(197.176±80.461),(186.206±50.322)mg/ml；Eliminate relative half-lives T1/2 be respectively (0.915 ±
0.125),(0.909±0.112)h；The area under the curve AUC0- ∞ of Drug-time curve be respectively (456.358 ± 85.557),
(436.363±75.205)mg*h/ml.It can be seen that morphine derivatives shown in III crystal form formula 1 spread out with morphine shown in A crystal form formula 1
Biotinylated biomolecule availability is consistent.
Testing example 2
It is steady under the conditions of room temperature (25 ± 2 DEG C) to crystal form A (being prepared according to US6172206B1 embodiment 1) and III crystal form
It is qualitative to have carried out comparative study, and the research of the detecting and tracking in relation to substance has been carried out with HPLC, wherein the testing conditions of HPLC are such as
Under, using waters2695 type high performance liquid chromatograph (HPLC), chromatographic column is Agilent ZORBAX Eclipse XDB-
Phenyl, mobile phase are A:10mg potassium dihydrogen phosphate, phosphoric acid tune PH3.0；Mobile phase B: acetonitrile phase, using gradient elution, gradient
For
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 35 | 15 | 85 |
| 60 | 15 | 85 |
The concrete outcome of stability study is as follows:
Wherein, NA expression does not detect.
At 0 month, without A, B, C, these three degradations were miscellaneous for A crystal form and III crystal form it can be seen from the data of upper table
Matter, and after passing through 48 months, the impurity of A crystal form has increased separately 0.56%, 0.58%, 0.58%, and III crystal form difference is only
0.017%, 0.011%, 0.015% is increased, the degradation impurity of crystal form A is 30 times of crystal form III or so, it can be seen that
III crystal form is much than A stable crystal form at room temperature.
Claims (8)
1. a kind of morphine derivatives crystal form III as shown in Equation 1:
Radiated using CuK α, X powder diffraction figure, 2 θ ° for 7.56,8.50,9.36,10.04,10.34,10.84,11.44,
13.24、14.28、14.74、15.22、16.22、16.64、17.08、17.50、18.30、18.70、19.90、20.92、
22.04、22.98、23.38、23.94、24.56、25.44、26.06、26.74、27.18、27.52、28.76、29.10、
29.88, there is diffraction maximum at 30.54,31.82,32.52,33.30,35.48,37.44 and 38.92.
2. morphine derivatives crystal form III as described in claim 1, the infrared absorption pattern measured with KBr tabletting, in following wave
Digital display shows absorption peak:
3399cm-1、2971cm-1、2726cm-1、1604cm-1、1504cm-1、1467cm-1、1407cm-1、1317cm-1、1295cm-1、1256cm-1、1178cm-1、1158cm-1、1064cm-1、988cm-1、961cm-1、937cm-1、873cm-1、848cm-1、
793cm-1、759cm-1、711cm-1、637cm-1、602cm-1And 528cm-1。
3. morphine derivatives crystal form III as claimed in claim 1 or 2, endothermic transition temperature is at 236.5 DEG C.
4. the preparation method of morphine derivatives crystal form III as claimed any one in claims 1 to 3, includes the following steps:
(1) morphine derivatives as shown in Equation 1 are added in acetonitrile and suspension is made, stirred 5~15 hours at 5-82 DEG C of temperature；
(2) cooling, at 0~30 DEG C of temperature stirring and crystallizing 1~15 hour；
(3) it filters, filter cake is dried under reduced pressure in 20~80 DEG C.
5. preparation method as claimed in claim 4, wherein temperature described in step (1) is 30~45 DEG C.
6. preparation method as claimed in claim 4, wherein the weighing body of morphine derivatives and acetonitrile shown in step (1) Chinese style 1
Product is than being 1:3~20.
7. a kind of pharmaceutical composition, comprising morphine derivatives crystal form III described in any one of claims 1 to 3 and pharmaceutically
Acceptable auxiliary material.
8. application of the morphine derivatives crystal form III described in any one of claims 1 to 3 in preparation treatment analgesic.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997013775A1 (en) * | 1995-10-11 | 1997-04-17 | Nycomed Imaging As | New crystalline form of morphine-6-glucuronide |
| DE19541921A1 (en) * | 1995-11-10 | 1997-05-15 | Nycomed Arzneimittel Gmbh | New crystalline form of morphone-6-glucuronide, useful as analgesic |
| CN103864866A (en) * | 2014-03-26 | 2014-06-18 | 宜昌人福药业有限责任公司 | Synthesis method and intermediate compound of morphine-6-Beta-D-glucuronide |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997013775A1 (en) * | 1995-10-11 | 1997-04-17 | Nycomed Imaging As | New crystalline form of morphine-6-glucuronide |
| DE19541921A1 (en) * | 1995-11-10 | 1997-05-15 | Nycomed Arzneimittel Gmbh | New crystalline form of morphone-6-glucuronide, useful as analgesic |
| CN103864866A (en) * | 2014-03-26 | 2014-06-18 | 宜昌人福药业有限责任公司 | Synthesis method and intermediate compound of morphine-6-Beta-D-glucuronide |
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