CN106554377A - Morphine derivatives crystal formation III and its production and use - Google Patents
Morphine derivatives crystal formation III and its production and use Download PDFInfo
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Abstract
The invention provides a kind of morphine derivatives crystal formation III as shown in Equation 1, radiated using CuK α, its X powder diffraction figure, is 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) °.Additionally, also disclosing the preparation method of the crystal formation, medical composition and its use.Compared with known crystal formation, the crystal formation III of the application has the characteristics of dissolution velocity is fast, bioavailability is high and is suitable to industrialization.
Description
Technical field
The present invention relates to field of medicaments, more particularly to morphine derivatives crystal formation III and its preparation side
Method and purposes.
Background technology
Morphine derivatives, its structural formula are as shown in Equation 1：
The morphine derivatives early have turned out to be metabolite of the morphine in human body, and its research is opened
Exhibition is later, proves that it than morphine have higher pain relieving by mouse test by Casparis from nineteen fifty
Activity starts, and just recognizes that it is only in morphine metabolite unique active substance to the eighties,
Critically important effect is played in morphine analgesia effect, is so far gradually just clinician and medical science man
It is known, but its mechanism of action and Clinical practice are only just started to spread out in recent two decades, now
There is substantial amounts of document to report which, and its development is also by CeNes companies of Britain from last century
The last years of a dynasty or reign proceed by, and the derivant is in III phase clinical investigation phases at present, it has therefore proved that its analgesia
Effect is equal to morphine, and side effect is substantially reduced, and nausea and vomiting and respiration inhibition effect are notable
Less than morphine, with than morphine more preferably clinical safety.Structural formula is as shown in Figure 1：
United States Patent (USP) US6172206B1 discloses crystal formation A of the morphine derivatives and preparation method thereof.
However, the crystal formation places unstable at room temperature, degradation impurity A, impurity B, impurity C are also easy to produce
Deng.The concrete structure of impurity is as follows：
For the polymorphic of medicine, different polymorphics can have different characteristics, such as chemistry
Stability, fusing point, apparent solubility, rate of dissolution and density etc..These properties can be directly affected
The process and production of crude drug and preparation, and stability, dissolubility and the biology profit of preparation can be affected
Expenditure.In solid preparation made by polymorphic in medicine, dissolubility directly affects bioavailability,
Generally, the big medicine of dissolubility, bioavailability can be higher.Therefore, the polymorphic of medicine all with medicine
The quality of thing preparation, safety and effectiveness have great importance.
The content of the invention
The present inventor have developed one kind and have which relative to other solid-state forms of morphine derivatives shown in formula 1
The novel crystal forms of his peculiar property, the stability of crystal form are good, and bioavailability is high, and is suitable to industrialization.
The present invention integrity property as mentioned below, but for convenience's sake, by the present invention such as formula
Morphine derivatives novel crystal forms shown in 1 are referred to as " crystal formation III ".
It is an object of the invention to provide a kind of morphine derivatives crystal formation III as shown in Equation 1.
Another object of the present invention is to provide the preparation method of above-mentioned morphine derivatives crystal formation III.
Third object of the present invention is to provide the medicine group comprising above-mentioned morphine derivatives crystal formation III
Compound.
Fourth object of the present invention is to provide above-mentioned morphine derivatives crystal formation III answering in medicine
With.
The object of the present invention is achieved like this：
In embodiments of the invention, the invention provides a kind of morphine derivatives as shown in Equation 1 are brilliant
Type III：
Radiated using CuK α, its X powder diffraction figure, be 9.36 in (2 θ ± 0.5) °, 13.24,
14.74th, 15.22,16.22,17.50,19.90,20.92, and at 22.98 there is diffraction maximum its d-value
Respectively：9.4408、8.1549、6.6816、6.0049、5.8165、5.4601、5.0635、4.4579、
4.2428 with 3.8669；Its relative intensity is all higher than or equal to 20%.
In a kind of preferred embodiment of the present invention, the crystal formation III as shown in Equation 1 that the present invention is provided,
Radiated using CuK α, its X powder diffraction figure, be 9.36 in (2 θ ± 0.2) °, 13.24,14.74,
15.22nd, 16.22,17.50,19.90,20.92, and at 22.98 there is diffraction maximum, its d-value distinguishes
For：9.4408、8.1549、6.6816、6.0049、5.8165、5.4601、5.0635、4.4579、
4.2428 with 3.8669；Its suitable intensity is all higher than or equal to 20%.
In a kind of particularly preferred embodiment of the present invention, the morphine as shown in Equation 1 that the present invention is provided
Derivant crystal formation III, is radiated using CuK α, its X powder diffraction figure, 2 θ ° be 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、
30.54th, there is diffraction maximum at 31.82,32.52,33.30,35.48,37.44 and 38.92.
In a kind of particularly preferred embodiment of the present invention, the morphine as shown in Equation 1 that the present invention is provided
Derivant crystal formation III, is radiated using CuK α, its X powder diffraction figure, to spend 2 θ for representing, crystalline substance
Interplanar distance d value and relative intensity percentage ratio are as follows：
| 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 present invention, the morphine as shown in Equation 1 that the present invention is provided spreads out
Biological crystal formation III, is radiated using CuK α, and its X powder diffraction figure is as shown in Figure 1.
In one embodiment of the present invention, the morphine derivatives as shown in Equation 1 that the present invention is provided are brilliant
Type III, the infrared absorption pattern measured with KBr tablettings show absworption 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, the morphine derivatives as shown in Equation 1 that the present invention is provided are brilliant
Type III, its melting point peak temperature are 236.5 DEG C, and the crystal formation has differential scanning heat as shown in Figure 3
Analysis (DSC) collection of illustrative plates.
On the other hand, the invention provides the preparation method of above-mentioned morphine derivatives crystal formation III, including
Following steps：
(1) morphine derivatives as shown in Equation 1 are added and is made in suspension in acetonitrile, in temperature be
5-82 DEG C is stirred 5～15 hours；
(2) cool down, the stirring and crystallizing 1～15 hour in 0～30 DEG C of temperature；
(3) filter, filter cake is in 20～80 DEG C of drying under reduced pressure.
In embodiments of the invention, the system of the above-mentioned morphine derivatives crystal formation III that the present invention is provided
Preparation Method, in above-mentioned steps (2), crystal about reached at 15 hours and turns Jinping's weighing apparatus.
In embodiments of the invention, the system of the above-mentioned morphine derivatives crystal formation III that the present invention is provided
Preparation Method, preferably 30～45 DEG C of temperature described in step (1).
In embodiments of the invention, the system of the above-mentioned morphine derivatives crystal formation III that the present invention is provided
Preparation Method, in above-mentioned steps (2), the temperature is preferably 0 DEG C～15 DEG C.
In embodiments of the invention, the system of the above-mentioned morphine derivatives crystal formation III that the present invention is provided
Preparation Method, in step (1), morphine derivatives as shown in Equation 1 and the w/v of acetonitrile are 1:3～20 (g：
ml)。
In a preferred embodiment of the invention, the invention provides above-mentioned morphine derivatives crystal formation III
Preparation method, comprise the steps：
(1) by w/v be 1:3～20 (g：Ml morphine derivatives as shown in Equation 1) and
Suspension is made with acetonitrile, is stirred at 30-45 DEG C；
(2) cool down, 0～15 DEG C of stirring and crystallizing 1～15 hour；
(3) filter；Colorless plate crystal is obtained, 20～80 DEG C of drying under reduced pressure obtain crystal formation III.
The third aspect, the invention provides a kind of pharmaceutical composition, spreads out comprising morphine shown in above-mentioned formula 1
Biological crystal formation III and pharmaceutically acceptable adjuvant.Here, the compositionss are according to different adaptations
Situation makes tablet, powder, granule, capsule, injection, freeze-dried powder, drop pill, slow
Release the dosage forms such as controlled release preparation.
Fourth aspect, the invention provides morphine derivatives crystal formation III shown in above-mentioned formula 1 is controlled in preparation
Treat the application in analgesic, the preferably application after iatrotechnics are prepared in analgesic.
Beneficial effects of the present invention：
The melting point peak temperature of morphine derivatives crystal formation III of the present invention is 236.5 DEG C, molten in water
Solution speed is fast, and dissolubility >=100mg/mL in water, bioavailability are high, are adapted to make multi-medicament group
Compound, can be made into several formulations such as tablet, capsule, drop pill, sustained-release and controlled release preparation, lyophilized powder
Injection etc..Additionally, morphine derivatives crystal formation III purity obtained in preparation method of the present invention is high,
Preparation method mild condition, it is easy to operate, place stable under room temperature, favorable reproducibility, production process are easy
It is in control, safe, it is adapted to industrialized production.
Description of the drawings
X powder diffraction collection of illustrative plates of the Fig. 1 for crystal type morphine derivatives crystal formation III.
Infrared spectrograms of the Fig. 2 for crystal type morphine derivatives crystal formation III.
Differential scanning calorimeter (DSC) collection of illustrative plates of the Fig. 3 for crystal type morphine derivatives crystal formation III.
Specific embodiment
The present invention is specifically described below by embodiment, it is necessary to it is pointed out here that be following
Embodiment is served only for being further described the present invention, it is impossible to be interpreted as to the scope of the present invention
Limit, person skilled in art can make some non-according to the invention described above content to the present invention
The modifications and adaptations of matter.
Infrared absorption spectroscopy (IR)
Measuring unit：Institute of Analysis of Peking University
Instrument：Spotlight200 Fourier transformation infrared spectrometers
Detection foundation：Two annex IVC of Pharmacopoeia of People's Republic of China (version in 2010)：It is infrared
Spectrophotography
Pretreatment situation：The chromatographically pure bromination that about 2mg samples and 100mg or so are dried is taken respectively
Potassium powder mull into after fine powder loads in compression mold, translucent ingot piece is suppressed on tablet machine.
Analytical parameters：Infrared spectrum (KBr pressed disc methods) is tested；Resolution 4cm-1；Scanning times：
64 times
Powder x-ray diffraction
Measuring unit：Institute of Analysis of Peking University
Instrument：The full-automatic polycrystal X ray diffractometers of Dmax/2400
Detection foundation：Two annex IXF of Pharmacopoeia of People's Republic of China (version in 2010)：X is penetrated
Line powder diffraction method
Pretreatment situation：Institute's test sample is taken out into appropriate, grinding is mixed in being put into clean agate mortar
It is even
Analytical parameters：Graphite monochromator；CuKα1；Sweep limitss：2θ：3～40 °, scanning speed：4 °/min,
Step-length：0.02 °, pipe flow pipe pressure：40kV, 100mA；
Slit is arranged：(DS：1/2°；SS:1/2°；RS：0.3mm)
Differential scanning calorimeter (DSC)
Measuring unit：Institute of Analysis of Peking University
Instrument：SDT Q600 thermogravimetrics and differential scanning simultaneous determination instrument
Detection foundation：Two annex VIIIQ of Pharmacopoeia of People's Republic of China (version in 2010)：Heat
Analytic process
Pretreatment situation：Nothing
Analytical parameters：Temperature of the measurement scope：20～245 DEG C；Heating rate：10℃/min；
High pure nitrogen flow：50mL/min；Sampled point is spaced：0.2 second/point
Embodiment 1
By morphine derivatives shown in 1g formulas 1 (according to CN201410116005.0 methods described systems
It is standby) suspension is made with 3ml acetonitriles, 5 DEG C of stirring 15h, in 0 DEG C of stirring and crystallizing 10h, are filtered,
60 DEG C of drying under reduced pressure.
Gained morphine derivatives 2 θ ° of angle of diffraction be 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、30.54、31.82、32.52、
33.30th, there is absworption peak at 35.48,37.44,38.92, be crystal formation III.Its X powder diffraction collection of illustrative plates
As shown in Figure 1.
The present invention crystalline form 1 shown in morphine derivatives crystal formation III, its powder X-ray diffraction pattern with 2 θ,
d-value、I/I0It is Deng parameter expression III crystal formations, 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 formation III of morphine derivatives shown in crystalline form 1 is 236.5 DEG C, should
Crystal formation has differential scanning calorimeter (DSC) collection of illustrative plates as shown in Figure 3.
The infrared spectrum that the crystal formation III of morphine derivatives shown in crystalline form 1 is produced is aobvious in following wave number
Absworption peak is shown：
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 formulas 1 and 5ml acetonitriles are made into suspension, 10 DEG C are stirred 5h,
5 DEG C of stirring and crystallizings 1h, filter, 50 DEG C of drying under reduced pressure, gained morphine derivatives embodiment 1
Characterizing method is identified, is crystal formation III.
Embodiment 3
Morphine derivatives shown in 1g formulas 1 and 10ml acetonitriles are made into suspension, 65 DEG C are stirred 11h,
In 20 DEG C of stirring and crystallizings 15h, filter, 70 DEG C of drying under reduced pressure, gained morphine derivatives embodiment 1
Characterizing method identification, be crystal formation III.
Embodiment 4
Morphine derivatives shown in 1g formulas 1 and 15ml acetonitriles are made into suspension, 55 DEG C are stirred 10h,
In 30 DEG C of crystallize 12h, filter, 80 DEG C of drying under reduced pressure, gained morphine derivatives embodiment 1
Characterizing method is identified, is crystal formation III.
Embodiment 5
Morphine derivatives shown in 1g formulas 1 and 17ml acetonitriles are made into suspension, 35 DEG C are stirred 15h,
In 30 DEG C of stirring and crystallizings 10h, filter, 40 DEG C of drying under reduced pressure, gained morphine derivatives embodiment 1
Characterizing method is identified, is crystal formation III.
Embodiment 6
Morphine derivatives shown in 1g formulas 1 and 20ml acetonitriles are made into suspension, 45 DEG C are stirred 8h,
25 DEG C of stirring and crystallizings 5h, filter, 30 DEG C of drying under reduced pressure, gained morphine derivatives embodiment 1
Characterizing method is identified, is crystal formation III.
Embodiment 7
Morphine derivatives shown in 1g formulas 1 and 8ml acetonitriles are made into suspension, 20 DEG C are stirred 6h,
15 DEG C of stirring and crystallizings 3h, filter, 20 DEG C of drying under reduced pressure, gained morphine derivatives embodiment 1
Characterizing method is identified, is crystal formation III.
Embodiment 8
Morphine derivatives shown in 1g formulas 1 and 15ml acetonitriles are made into suspension, 75 DEG C are stirred 9h,
23 DEG C of stirring and crystallizings 8h, filter, 45 DEG C of drying under reduced pressure, gained morphine derivatives embodiment 1
Characterizing method is identified, is crystal formation III.
Embodiment 9
Morphine derivatives shown in 1g formulas 1 and 16ml acetonitriles are made into suspension, 82 DEG C are stirred 13h,
In 28 DEG C of stirring and crystallizings 3h, filter, 35 DEG C of drying under reduced pressure, gained morphine derivatives embodiment 1
Characterizing method is identified, is crystal formation III.
Embodiment 10：
Obtained in 1 methods described of embodiment, morphine derivatives shown in III crystal formations formula 1 are according to 200mg/
Grain, Lactose 80.8mg/ grain, carboxymethyl starch sodium 72mg/ grains, Pulvis Talci 7.2mg/ grains and 10% gather
Vinylpyrrolidone 5.1mg/ grains.
As a example by making morphine derivatives capsule shown in 1000 II crystal formations formulas 1, concrete preparation side
Method is：Supplementary material is crossed into 80 mesh sieves first, weigh morphine derivatives shown in the III crystal formations formula 1 of above-mentioned amount,
Lactose, carboxymethyl starch sodium mix homogeneously, plus 10%PVP ethanol solution soft materials, granulation, drying,
Granulate, adds the Pulvis Talci of above-mentioned amount, mix homogeneously, capsule charge in granule.
Embodiment 11：
Obtained in 1 methods described of embodiment, morphine derivatives shown in III crystal formations formula 1 are according to 200mg/
Piece, starch 34mg/ pieces, Microcrystalline Cellulose 60mg/ piece, Pulvis Talci 6mg/ pieces and 2% hydroxypropyl
Ylmethyl cellulose (K4M models) 6mg/ pieces；
As a example by making morphine derivatives tablet shown in 1000 III crystal formations formulas 1, concrete preparation method
It is：Supplementary material is crossed into 80 mesh sieves first, weigh morphine derivatives shown in the III crystal formations formula 1 of above-mentioned amount,
Starch, Microcrystalline Cellulose mix homogeneously, plus appropriate 2%HPMC aqueous solution soft materials, granulation, dry
Dry, granulate adds the Pulvis Talci of recipe quantity, mix homogeneously, tabletting in granule.
Embodiment 12：
Obtained in 1 methods described of embodiment, morphine derivatives shown in III crystal formations formula 1 are according to 50g, Portugal
Grape sugar 150g, 500ml waters for injection are dissolved in dilute preparing tank, and temperature control is stirred at 50～60 DEG C
Mix up to being completely dissolved, lysate is cooled to into 25 DEG C, activity is added in the above-mentioned lysate for preparing
Carbon decoloring, then activated carbon therein is filtered to remove, phosphate buffer is added by the pH of the lysate
Value is adjusted to 4.0, adds water for injection to 5000ml, embedding, sterilizes 30 minutes at 105 DEG C,
Obtain injection.
Testing example 1：
On the basis of the LC-MS methods of morphine are determined in existing biological sample, experiment is from health
Beagle Canis familiaris L.s 6, body weight are 8～10kg, are divided into two groups, 3 per group, for observing difference
Bioavailability of the morphine derivatives to Canis familiaris L. after oral shown in crystal formation formula 1.Research A crystal formations (according to
In US6172206B1 prepared by embodiment 1) shown in morphine derivatives shown in formula 1 and III crystal formations formula 1
Pharmacokineticss of the morphine derivatives in dog body, and with morphine as reference preparation, evaluate A crystal formations with
Whether the bioavailability of III crystal formations is equivalent.And which is given birth to by calculating its pharmacokinetic parameter
Thing equivalence is evaluated.As a result：Morphine derivatives shown in III crystal formations formula 1 and morphine shown in A crystal formations formula 1
Main pharmacokinetic parameter of the derivant in Beagle dog bodies is as follows：Peak time Tmax distinguishes
For (1.572 ± 0.398), (1.498 ± 0.3988), up to peak concentration Cmax be 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 curve AUC0- ∞ of Drug-time curve is respectively (456.358
±85.557)、(436.363±75.205)mg*h/ml.Morphine shown in III crystal formations formula 1 spreads out as can be seen here
It is biological consistent with morphine derivatives bioavailability shown in A crystal formations formula 1.
Testing example 2
To crystal formation A (being prepared according to US6172206B1 embodiments 1) and III crystal formations in room temperature (25
± 2 DEG C) under the conditions of stability carried out comparative study, and carried out relevant material with HPLC
Detecting and tracking is studied, wherein, the testing conditions of HPLC are as follows, using the efficient liquid of waters2695 types
Chromatography (HPLC), chromatographic column be Agilent ZORBAX Eclipse XDB-phenyl, mobile phase
For A：10mg potassium dihydrogen phosphates, phosphoric acid adjust PH3.0；Mobile phase B：Acetonitrile phase, is washed using gradient
De-, gradient is
| 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 is represented and is not detected.
By the data of upper table can be seen that at 0 month A crystal formations and the no A of III crystal formations, B,
C these three degradation impurity, and through 48 months afterwards, the impurity of A crystal formations increased 0.56% respectively,
0.58%th, 0.58%, and III crystal formations increase only 0.017%, 0.011%, 0.015% respectively, crystal formation
The degradation impurity of A is 30 times of crystal formation III or so, it can be seen that III crystal formations at ambient temperature
Much than A stable crystal form.
Claims (10)
1. a kind of morphine derivatives crystal formation III as shown in Equation 1：
Radiated using CuK α, its X powder diffraction figure, be 9.36 in (2 θ ± 0.5) °, 13.24,
14.74th, there is diffraction maximum at 15.22,16.22,17.50,19.90,20.92 and 22.98.
2. crystal formation III as claimed in claim 1, wherein, its X powder diffraction figure, (2 θ ±
° 0.2) be 8.50,9.36,10.84,13.24,14.74,15.22,16.22,17.50,19.90,
There is diffraction maximum at 20.92 and 22.98.
3. crystal formation III as claimed in claim 2, wherein, its X powder diffraction figure, at 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、
29.10th, have at 29.88,30.54,31.82,32.52,33.30,35.48,37.44 and 38.92 and spread out
Penetrate peak.
4. crystal formation III as claimed any one in claims 1 to 3, with KBr tablettings measure it is red
Outer absorption collection of illustrative plates, shows absworption 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)。
5. crystal formation III as claimed any one in claims 1 to 3, its endothermic transition temperature exist
236.5℃。
6. the preparation method of the morphine derivatives crystal formation III as any one of claim 1 to 5,
Comprise the steps：
(1) morphine derivatives as shown in Equation 1 are added in acetonitrile and makes suspension, in temperature 5-82 DEG C
Stirring 5～15 hours；
(2) cool down, the stirring and crystallizing 1～15 hour in 0～30 DEG C of temperature；
(3) filter, filter cake is in 20～80 DEG C of drying under reduced pressure.
7. preparation method as claimed in claim 6, wherein, described in step (1), temperature is preferred
For 30～45 DEG C.
8. preparation method as claimed in claim 6, wherein, morphine shown in step (1) Chinese style 1
Derivant is 1 with the w/v of acetonitrile：3～20.
9. a kind of pharmaceutical composition, comprising the morphine derivatives any one of claim 1 to 5
Crystal formation III and pharmaceutically acceptable adjuvant.
10. the morphine derivatives crystal formation III any one of claim 1 to 5 is preparing treatment town
Application in pain medicine.
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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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2015
- 2015-09-25 CN CN201510623686.4A patent/CN106554377B/en active Active
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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