CN108503557A - Osalmid crystal form III, preparation method and its application - Google Patents
Osalmid crystal form III, preparation method and its application Download PDFInfo
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- CN108503557A CN108503557A CN201710108168.8A CN201710108168A CN108503557A CN 108503557 A CN108503557 A CN 108503557A CN 201710108168 A CN201710108168 A CN 201710108168A CN 108503557 A CN108503557 A CN 108503557A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/42—Amides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/74—Biological properties of particular ingredients
- A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
- A61K2800/782—Enzyme inhibitors; Enzyme antagonists
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
Disclose Osalmid crystal form III, preparation method and its application.The X ray powder diffractions that the crystal form is indicated with 2 θ angles have characteristic peak at the angle of diffraction 7.51 ± 0.2,11.273 ± 0.2,15.068 ± 0.2,18.837 ± 0.2,19.386 ± 0.2,20.418 ± 0.2,22.118 ± 0.2,24.296 ± 0.2,26.337 ± 0.2,26.493 ± 0.2,27.236 ± 0.2,28.973 ± 0.2,30.349 ± 0.2,32.863 ± 0.2,36.06 ± 0.2,38.176 ± 0.2 degree.The crystal form has excellent physicochemical property and patent medicine performance, and preparation method is simple, and crystal form hygroscopicity is small, with good stability, favorable reproducibility.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to Osalmid crystal form III and its preparation method and answer
With.
Background technology
Polymorph in pharmaceuticals refers to that there are two kinds or more different crystal habits for active constituents of medicine (API).It is presently commercially available
Small-molecule drug in, about 90% or so drug is administered with crystal habit.This is because crystal habit is than other states,
Such as amorphous or liquid, the advantage with apparent physical and chemical performance and process has excellent physics and chemistry steady
It is qualitative can, can effective despumation composition, excellent processing performance.These advantages for drug quality and technical process all
Generate active influence.Therefore, crystal form research and control become the important research content in drug development process.
Crystal form research includes that crystal is found and crystal form preferably two stages.In crystal discovery phase, a variety of knots are mainly used
Brilliant means, such as fusion-crystallization, solution evaporation are quickly cooled down and the method for crystallising of suspension method, by change crystallization condition, solvent,
The external factor that temperature, speed and suspension solvent ratios etc. influence drug crystallization is made simultaneously using high-throughput sample preparation platform
Standby hundreds of secondary crystallization trials prepare and find new crystal form with micro-example technology of preparing and analysis means of testing.In crystal form
It is preferred that in the stage, will amplify new crystal form technique and preparation condition is groped, be spread out using many kinds of solids characterization method, such as X-ray
It penetrates, the means such as solid-state nuclear magnetic resonance, Raman spectrum, infrared spectrum carry out crystal form crystal characterization.In addition, will use DSC, TGA,
DVS, HPLC etc. carry out physical and chemical performance research to crystal form, and hygroscopicity, chemical stabilization, the physical state for comparing different crystal forms are stablized
Property, machinability etc. are studied.Preferred ground solid forms are finally selected to be developed.
General crystal form screening study includes following components：
(1) it is used for the property of the drug lot of research.
(2) it in order to carry out qualitative and detection solvent wherein that may be present or hydrated state to stable crystal form state, needs
Pair with different solvents balance after crystal occur variation be monitored.General synthesis is at 25 DEG C of temperature of reagent with analysis experiment
It carries out.But for evaluation temperature effect, partial condition selects 50 DEG C.
(3) it crystallizes or precipitates from selected solvent, to detect metastable state and stable state.Crystal study should include：
1. being quickly cooled down forced crystallization
2. slowly cooling slowly crystallization
3. slow isothermal volatile dry
4. rapidly joining poor solvent precipitation
5. state change under stress
4- hydroxyls salicylanilide (Osalmid), structural formula are：
For Osalmid currently used for cholecystitis, cholangitis, cholelithiasis, mechanism of action is similar to neocholan, can increase liver blood
Flow improves liver function, moisture in bile can be made to dramatically increase.Choleretic effect is strong compared with neocholan, and Oddi sphincters can be made loose
It relaxes.In addition still having reduces cholesterolemia effect.In the research of inventor's early period, it was found that Osalmid restores ribonucleotide
The inhibiting effect of enzyme (RR), can inhibit the growth of kinds of tumor cells, and independent medication or while being combined with Lamivudine can press down
The duplication of hepatitis B processed.In addition, inventor has found that Osalmid can also inhibit tyrosinase, there is potential white-skinned face function.Cause
This Osalmid can be not only used for medicine, it can also be used to cosmetics.
The report about Osalmid crystal form is not found at present.
Invention content
For the present invention on the basis of synthesis is using new crystallization nucleation mode and crystallization condition, research is prepared for a kind of willow amine
The novel crystal forms of phenol：Osalmid crystal form III.The study found that the crystal form hygroscopicity is small, stability is good, and can form regular crystalline substance
Build state, thus be conducive to the process of drug and the improvement of physical and chemical performance, improve patent medicine performance.
It is an object of the present invention to：The Osalmid crystal form III that a kind of hygroscopicity is small, stability is good is provided.
In order to solve the above technical problems, the technical scheme is that：
A kind of Osalmid crystal form III, the X-ray powder diffraction that the crystal form is indicated with 2 θ angles is in the angle of diffraction about 7.51
± 0.2, about 11.273 ± 0.2, about 15.068 ± 0.2, about 18.837 ± 0.2, about 19.386 ± 0.2, about 20.418 ± 0.2,
About 22.118 ± 0.2, about 24.296 ± 0.2, about 26.337 ± 0.2, about 26.493 ± 0.2, about 27.236 ± 0.2, about
28.973 ± 0.2, there is at about 30.349 ± 0.2, about 32.863 ± 0.2, about 36.06 ± 0.2, about 38.176 ± 0.2 degree spy
Levy peak.
Preferably, the Osalmid crystal form III have basically as in Figure 2 shown in X-ray powder diffraction collection.
Preferably, the differential scanning calorimetric analysis of the crystal form III at about 168 DEG C and about 176 DEG C (near) have feature
Endothermic peak.
Preferably, the decomposition temperature of the thermogravimetic analysis (TGA) of the Osalmid crystal form III is about 190 DEG C, in decomposition temperature
There is not weightlessness before degree.
Preferably, the infrared spectrum of the Osalmid crystal form III is in 3298.60cm-1、3158.85cm-1、1632.38cm-1、1577.24cm-1、1516.21cm-1、1460.92cm-1、1353.13cm-1、1232.01cm-1、1170.53cm-1、
1151.43cm-1、1132.54cm-1、1107.98cm-1、1090.86cm-1、1041.60cm-1、949.37cm-1、897.24cm-1、
827.47cm-1、783.42cm-1、749.44cm-1、658.88cm-1、552.38cm-1、521.03cm-1、496.35cm-1Place has
Characteristic peak.
Preferably, the Osalmid crystal form III is non solvate or non-hydrate.
Particularly, the Osalmid crystal form III is in 0~95% RH range, and crystal form does not change, moisture absorption
Property changes very little, and shows as moist almost without drawing.
The second object of the present invention is：The preparation method of Osalmid crystal form III is provided.
The preparation method is selected from one of following method：
(1) volatilization crystallization：Prepare Osalmid solid, solvent, mixing, dissolving is added；At 0~65 DEG C, preferably 15~30 DEG C
Or slowly evaporated at 40~65 DEG C it is dry, collect solid, obtain Osalmid crystal form III；Or
(2) antisolvent crystallisation
The small size vial equipped with the solvent very high to Osalmid solubility is taken, wherein by the dissolving of Osalmid solid, with
Afterwards, it takes equipped with the large size vial to the insoluble anti-solvent of Osalmid height, by the way of big bottle cover bottle, by small flint glass F
Bottle is put into large size vial, and the sealing of large size vial is stored at room temperature 3 days or more, so that poor solvent is constantly waved in solution, make
Precipitation obtains Osalmid crystal form III.
Wherein,
In method (1), it is preferable that the volatilization time slowly volatilized is more than for 24 hours.
In method (1), it is preferable that the solvent be selected from water, methanol, ethyl alcohol, isopropanol, isoamyl alcohol, acetone, methyl ethyl ketone,
Acetonitrile, methyl iso-butyl ketone (MIBK), ethyl acetate, isopropyl acetate, toluene, n-hexane, normal heptane, dichloromethane, petroleum ether, chlorine
The mixture of one or both of imitative, methyl tertiary butyl ether(MTBE), tetrahydrofuran or more；
Preferably, when volatilization temperature is 15~30 DEG C, the solvent is selected from methanol, methyl ethyl ketone, tetrahydrofuran, methyl- tert
Butyl ether, methyl iso-butyl ketone (MIBK), isopropyl acetate, acetone and the mixture of water, the mixture of methyl ethyl ketone and water, tetrahydrofuran and
The mixture of water, the mixture of acetone and toluene, methyl iso-butyl ketone (MIBK) and toluene mixture, isopropanol and n-hexane mixing
Object, the mixture of methyl iso-butyl ketone (MIBK) and n-hexane, the mixture of acetone and normal heptane, methyl ethyl ketone and normal heptane mixture,
The mixing of the mixture of tetrahydrofuran and normal heptane, the mixture of ethyl acetate and normal heptane, methyl iso-butyl ketone (MIBK) and normal heptane
Object, the mixture of acetone and dichloromethane, the mixture of tetrahydrofuran and dichloromethane, methyl tertiary butyl ether(MTBE) and dichloromethane
Mixture, the mixture of methyl iso-butyl ketone (MIBK) and dichloromethane, the mixture of acetone and chloroform, isopropyl acetate and chloroform it is mixed
Close object, tetrahydrofuran and the mixture of petroleum ether, the mixture of ethyl acetate and petroleum ether, methyl iso-butyl ketone (MIBK) and petroleum ether
Mixture.
When volatilization temperature be 40~65 DEG C when, the solvent be selected from methanol, ethyl alcohol, isopropanol, acetone, methyl ethyl ketone, acetonitrile,
The mixing of tetrahydrofuran, methyl tertiary butyl ether(MTBE), the mixture of second alcohol and water, the mixture of isoamyl alcohol and water, tetrahydrofuran and water
Mixture, the acetone of the mixture of object, methyl tertiary butyl ether(MTBE) and water and ethyl alcohol, the mixture of methanol and toluene, ethyl alcohol and toluene
With mixture, methyl iso-butyl ketone (MIBK) and the toluene of the mixture of toluene, the mixture of methyl ethyl ketone and toluene, tetrahydrofuran and toluene
Mixture, the mixture of isopropyl acetate and toluene, the mixture of methanol and n-hexane, ethyl alcohol and n-hexane mixture,
The mixture of isopropanol and n-hexane, the mixture of acetone and n-hexane, the mixture of methyl ethyl ketone and n-hexane, acetonitrile and just oneself
The mixture of alkane, the mixture of tetrahydrofuran and n-hexane, the mixture of ethyl acetate and n-hexane, isopropyl acetate and just oneself
The mixture of alkane, the mixture of methanol and normal heptane, the mixture of ethyl alcohol and normal heptane, isopropanol and normal heptane mixture,
The mixture of isoamyl alcohol and normal heptane, the mixture of methanol and dichloromethane, the mixture of ethyl alcohol and dichloromethane, isopropanol and
Mixture, acetonitrile and the dichloromethane of the mixture of dichloromethane, the mixture of isoamyl alcohol and dichloromethane, acetone and dichloromethane
Mixture, the methanol of the mixture of alkane, the mixture of methyl tertiary butyl ether(MTBE) and dichloromethane, methyl iso-butyl ketone (MIBK) and dichloromethane
With the mixture of chloroform, the mixture of ethyl alcohol and chloroform, isopropanol and the mixture of chloroform, the mixture of acetone and chloroform, second
Mixture, methanol and the oil of the mixture of nitrile and chloroform, the mixture of tetrahydrofuran and chloroform, methyl tertiary butyl ether(MTBE) and chloroform
The mixture of ether, the mixture of ethyl alcohol and petroleum ether, isopropanol and petroleum ether mixture, isoamyl alcohol and petroleum ether mixing
Object, the mixture of acetone and petroleum ether, methyl ethyl ketone and the mixture of petroleum ether, the mixture of acetonitrile and petroleum ether, ethyl acetate
With the mixture of petroleum ether, the mixture of methyl iso-butyl ketone (MIBK) and petroleum ether.
When the solvent is the mixture of two or more solvents, its volume ratio is not limited；For example, working as the solvent
For two kinds of solvents mixture when, volume ratio can be 2:1、1:1；When the solvent is the mixture of three kinds of solvents,
Volume ratio can be 1:1:1、2:1:1、2:2:1 etc..
In method (2), combination, methyl tertbutyl of the combination selected from tetrahydrofuran and n-hexane of the solvent and anti-solvent
The combination of ether and n-hexane, the combination of methyl ethyl ketone and petroleum ether, tetrahydrofuran and petroleum ether combination, methyl tertiary butyl ether(MTBE) and stone
The combination of oily ether, the combination of isopropyl acetate and petroleum ether.
The third object of the present invention is：There is provided the Osalmid crystal form III prepare for treat/or prevent gall-bladder
Inflammation, cholangitis, cholelithiasis, tumour, the drug of hepatitis B and the application in skin-lightening cosmetic.
By adopting the above-described technical solution, the beneficial effects of the invention are as follows：
In Osalmid crystal form III provided by the invention and preparation method thereof, preparation method is easy to operate, crystal form hygroscopicity
It is small, it is with good stability, thus be conducive to the process of drug and the improvement of physical and chemical performance, improve patent medicine performance.
Description of the drawings
The polarisation photo of Osalmid crystal form III obtained by Fig. 1 embodiments 1-1
X-ray powder diffraction (XRPD) figure of Osalmid crystal form III obtained by Fig. 2 embodiments 1-1
Thermogravimetic analysis (TGA) (TG) figure of Osalmid crystal form III obtained by Fig. 3 embodiments 1-1
Differential scanning calorimetric analysis (DSC) figure of Osalmid crystal form III obtained by Fig. 4 embodiments 1-1
Hygroscopicity analysis (DVS) figure of Osalmid crystal form III obtained by Fig. 5 embodiments 1-1
Infrared spectrum (IR) figure of Osalmid crystal form III obtained by Fig. 6 embodiments 1-1
Raman spectrum (Raman) figure of Osalmid crystal form III obtained by Fig. 7 embodiments 1-1
The stripping curve of Osalmid crystal form III obtained by Fig. 8 embodiments 1-1
Specific implementation mode
In order to make the purpose , technical scheme and advantage of the present invention be clearer, with reference to the accompanying drawings and embodiments, right
The present invention is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, and
It is not used in the restriction present invention.
Bulk pharmaceutical chemicals-Osalmid solid in embodiment is purchased from the smooth Science and Technology Co., Ltd. of upper Haitai.
Slowly volatilization refers to the volatilization time more than for 24 hours described in embodiment.
The preparation of 1 Osalmid crystal form III of embodiment
Embodiment 1-1
Osalmid solid about 3g is taken, 400ml methanol, mixing, dissolving is added.It slowly evaporates at 25 DEG C dry, then collects
Solid obtains Osalmid crystal form III, is yellow-white powder.
Embodiment 1-2
Osalmid solid about 3g is taken, 400ml isopropanols and 400ml n-hexanes, mixing, dissolving is added.It is slowly waved at 25 DEG C
It is sent to dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-3
Osalmid solid about 3g is taken, 400ml acetone and 400ml water, mixing, dissolving is added.Slowly evaporated at 25 DEG C it is dry,
Then solid is collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-4
Osalmid solid about 3g is taken, 400ml acetone and 400ml toluene, mixing, dissolving is added.It is slowly evaporated at 25 DEG C
It is dry, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-5
Osalmid solid about 3g is taken, 400ml acetone and 400ml normal heptanes, mixing, dissolving is added.In 25 DEG C of slowly volatilizations
To doing, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-6
Osalmid solid about 3g is taken, 400ml acetone and 400ml dichloromethane, mixing, dissolving is added.It is slowly waved at 25 DEG C
It is sent to dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-7
Osalmid solid about 3g is taken, 400ml acetone and 400ml chloroforms, mixing, dissolving is added.It is slowly evaporated at 25 DEG C
It is dry, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-8
Osalmid solid about 3g is taken, 400ml methyl ethyl ketone, mixing, dissolving is added.It slowly evaporates at 25 DEG C dry, then receives
Collect solid, obtain Osalmid crystal form III, is yellow-white powder.
Embodiment 1-9
Osalmid solid about 3g is taken, 400ml methyl ethyl ketone and 400ml water, mixing, dissolving is added.It is slowly evaporated at 25 DEG C
It is dry, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-10
Osalmid solid about 3g is taken, 400ml methyl ethyl ketone and 400ml normal heptanes, mixing, dissolving is added.It is slowly waved at 25 DEG C
It is sent to dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-11
Osalmid solid about 3g is taken, 400ml tetrahydrofurans, mixing, dissolving is added.Slowly evaporated at 25 DEG C it is dry, then
Solid is collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-12
Osalmid solid about 3g is taken, 400ml tetrahydrofurans and 400ml water, mixing, dissolving is added.In 25 DEG C of slowly volatilizations
To doing, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-13
Osalmid solid about 3g is taken, 400ml tetrahydrofurans and 400ml normal heptanes, mixing, dissolving is added.Slowly at 25 DEG C
It evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-14
Osalmid solid about 3g is taken, 400ml tetrahydrofurans and 400ml dichloromethane, mixing, dissolving is added.Delay at 25 DEG C
Then slow vaporization collects solid, obtains Osalmid crystal form III to doing, be yellow-white powder.
Embodiment 1-15
Osalmid solid about 3g is taken, 400ml tetrahydrofurans and 400ml petroleum ethers, mixing, dissolving is added.Slowly at 25 DEG C
It evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-16
Osalmid solid about 3g is taken, 400ml ethyl acetate and 400ml petroleum ethers, mixing, dissolving is added.Slowly at 25 DEG C
It evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-17
Osalmid solid about 3g is taken, 400ml methyl tertiary butyl ether(MTBE)s, mixing, dissolving is added.Slowly evaporated at 25 DEG C it is dry,
Then solid is collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-18
Osalmid solid about 3g is taken, 400ml methyl tertiary butyl ether(MTBE)s and 400ml dichloromethane, mixing, dissolving is added.25
It DEG C slowly evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-19
Osalmid solid about 3g is taken, 400ml methyl iso-butyl ketone (MIBK)s, mixing, dissolving is added.Slowly evaporated at 25 DEG C it is dry,
Then solid is collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-20
Osalmid solid about 3g is taken, 400ml methyl iso-butyl ketone (MIBK)s and 400ml toluene, mixing, dissolving is added.Delay at 25 DEG C
Then slow vaporization collects solid, obtains Osalmid crystal form III to doing, be yellow-white powder.
Embodiment 1-21
Osalmid solid about 3g is taken, 400ml methyl iso-butyl ketone (MIBK)s and 400ml n-hexanes, mixing, dissolving is added.At 25 DEG C
It slowly evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-22
Osalmid solid about 3g is taken, 400ml methyl iso-butyl ketone (MIBK)s and 400ml normal heptanes, mixing, dissolving is added.At 25 DEG C
It slowly evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-20
Osalmid solid about 3g is taken, 400ml methyl iso-butyl ketone (MIBK)s and 400ml dichloromethane, mixing, dissolving is added.25
It DEG C slowly evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-20
Osalmid solid about 3g is taken, 400ml methyl iso-butyl ketone (MIBK)s and 400ml petroleum ethers, mixing, dissolving is added.At 25 DEG C
It slowly evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-21
Osalmid solid about 3g is taken, 400ml isopropyls, mixing, dissolving is added.Slowly evaporated at 25 DEG C it is dry,
Then solid is collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-22
Osalmid solid about 3g is taken, 400ml isopropyls and 400ml chloroforms, mixing, dissolving is added.Delay at 25 DEG C
Then slow vaporization collects solid, obtains Osalmid crystal form III to doing, be yellow-white powder.
Embodiment 1-23
Osalmid solid about 3g is taken, 400ml methanol, mixing, dissolving is added.It slowly evaporates at 50 DEG C dry, then collects
Solid obtains Osalmid crystal form III, is yellow-white powder.
Embodiment 1-24
Osalmid solid about 3g is taken, 400ml methanol and 400ml toluene, mixing, dissolving is added.It is slowly evaporated at 50 DEG C
It is dry, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-25
Osalmid solid about 3g is taken, 400ml methanol and 400ml n-hexanes, mixing, dissolving is added.In 50 DEG C of slowly volatilizations
To doing, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-26
Osalmid solid about 3g is taken, 400ml methanol and 400ml normal heptanes, mixing, dissolving is added.In 50 DEG C of slowly volatilizations
To doing, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-27
Osalmid solid about 3g is taken, 400ml methanol and 400ml dichloromethane, mixing, dissolving is added.It is slowly waved at 50 DEG C
It is sent to dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-28
Osalmid solid about 3g is taken, 400ml methanol and 400ml chloroforms, mixing, dissolving is added.It is slowly evaporated at 50 DEG C
It is dry, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-29
Osalmid solid about 3g is taken, 400ml methanol and 400ml petroleum ethers, mixing, dissolving is added.In 50 DEG C of slowly volatilizations
To doing, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-30
Osalmid solid about 3g is taken, 400ml ethyl alcohol, mixing, dissolving is added.It slowly evaporates at 50 DEG C dry, then collects
Solid obtains Osalmid crystal form III, is yellow-white powder.
Embodiment 1-31
Osalmid solid about 3g is taken, 400ml ethyl alcohol and 400ml water, mixing, dissolving is added.Slowly evaporated at 50 DEG C it is dry,
Then solid is collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-32
Osalmid solid about 3g is taken, 400ml ethyl alcohol and 400ml toluene, mixing, dissolving is added.It is slowly evaporated at 50 DEG C
It is dry, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-33
Osalmid solid about 3g is taken, 400ml ethyl alcohol and 400ml n-hexanes, mixing, dissolving is added.In 50 DEG C of slowly volatilizations
To doing, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-34
Osalmid solid about 3g is taken, 400ml ethyl alcohol and 400ml normal heptanes, mixing, dissolving is added.In 50 DEG C of slowly volatilizations
To doing, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-35
Osalmid solid about 3g is taken, 400ml ethyl alcohol and 400ml dichloromethane, mixing, dissolving is added.It is slowly waved at 50 DEG C
It is sent to dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-36
Osalmid solid about 3g is taken, 400ml ethyl alcohol and 400ml chloroforms, mixing, dissolving is added.It is slowly evaporated at 50 DEG C
It is dry, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-37
Osalmid solid about 3g is taken, 400ml ethyl alcohol and 400ml petroleum ethers, mixing, dissolving is added.In 50 DEG C of slowly volatilizations
To doing, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-38
Osalmid solid about 3g is taken, 400ml isopropanols, mixing, dissolving is added.It slowly evaporates at 50 DEG C dry, then receives
Collect solid, obtain Osalmid crystal form III, is yellow-white powder.
Embodiment 1-39
Osalmid solid about 3g is taken, 400ml isopropanols and 400ml n-hexanes, mixing, dissolving is added.It is slowly waved at 50 DEG C
It is sent to dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-40
Osalmid solid about 3g is taken, 400ml isopropanols and 400ml normal heptanes, mixing, dissolving is added.It is slowly waved at 50 DEG C
It is sent to dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-41
Osalmid solid about 3g is taken, 400ml isopropanols and 400ml dichloromethane, mixing, dissolving is added.Slowly at 50 DEG C
It evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-42
Osalmid solid about 3g is taken, 400ml isopropanols and 400ml chloroforms, mixing, dissolving is added.In 50 DEG C of slowly volatilizations
To doing, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-43
Osalmid solid about 3g is taken, 400ml isopropanols and 400ml petroleum ethers, mixing, dissolving is added.It is slowly waved at 50 DEG C
It is sent to dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-44
Osalmid solid about 3g is taken, 400ml isoamyl alcohol and 400ml water, mixing, dissolving is added.It is slowly evaporated at 50 DEG C
It is dry, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-45
Osalmid solid about 3g is taken, 400ml isoamyl alcohol and 400ml normal heptanes, mixing, dissolving is added.It is slowly waved at 50 DEG C
It is sent to dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-46
Osalmid solid about 3g is taken, 400ml isoamyl alcohol and 400ml dichloromethane, mixing, dissolving is added.Slowly at 50 DEG C
It evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-47
Osalmid solid about 3g is taken, 400ml isoamyl alcohol and 400ml petroleum ethers, mixing, dissolving is added.It is slowly waved at 50 DEG C
It is sent to dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-48
Osalmid solid about 3g is taken, 400ml acetone, mixing, dissolving is added.It slowly evaporates at 50 DEG C dry, then collects
Solid obtains Osalmid crystal form III, is yellow-white powder.
Embodiment 1-49
Osalmid solid about 3g is taken, 400ml acetone and 400ml toluene, mixing, dissolving is added.It is slowly evaporated at 50 DEG C
It is dry, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-50
Osalmid solid about 3g is taken, 400ml acetone and 400ml n-hexanes, mixing, dissolving is added.In 50 DEG C of slowly volatilizations
To doing, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-51
Osalmid solid about 3g is taken, 400ml acetone and 400ml dichloromethane, mixing, dissolving is added.It is slowly waved at 50 DEG C
It is sent to dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-52
Osalmid solid about 3g is taken, 400ml acetone and 400ml chloroforms, mixing, dissolving is added.It is slowly evaporated at 50 DEG C
It is dry, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-53
Osalmid solid about 3g is taken, 400ml acetone and 400ml petroleum ethers, mixing, dissolving is added.In 50 DEG C of slowly volatilizations
To doing, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-54
Osalmid solid about 3g is taken, 400ml methyl ethyl ketone, mixing, dissolving is added.It slowly evaporates at 50 DEG C dry, then receives
Collect solid, obtain Osalmid crystal form III, is yellow-white powder.
Embodiment 1-55
Osalmid solid about 3g is taken, 400ml methyl ethyl ketone and 400ml toluene, mixing, dissolving is added.In 50 DEG C of slowly volatilizations
To doing, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-56
Osalmid solid about 3g is taken, 400ml methyl ethyl ketone and 400ml n-hexanes, mixing, dissolving is added.It is slowly waved at 50 DEG C
It is sent to dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-57
Osalmid solid about 3g is taken, 400ml methyl ethyl ketone and 400ml petroleum ethers, mixing, dissolving is added.It is slowly waved at 50 DEG C
It is sent to dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-58
Osalmid solid about 3g is taken, 400ml acetonitriles, mixing, dissolving is added.It slowly evaporates at 50 DEG C dry, then collects
Solid obtains Osalmid crystal form III, is yellow-white powder.
Embodiment 1-59
Osalmid solid about 3g is taken, 400ml acetonitriles and 400ml n-hexanes, mixing, dissolving is added.In 50 DEG C of slowly volatilizations
To doing, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-60
Osalmid solid about 3g is taken, 400ml acetonitriles and 400ml dichloromethane, mixing, dissolving is added.It is slowly waved at 50 DEG C
It is sent to dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-61
Osalmid solid about 3g is taken, 400ml acetonitriles and 400ml chloroforms, mixing, dissolving is added.It is slowly evaporated at 50 DEG C
It is dry, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-62
Osalmid solid about 3g is taken, 400ml acetonitriles and 400ml petroleum ethers, mixing, dissolving is added.In 50 DEG C of slowly volatilizations
To doing, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-63
Osalmid solid about 3g is taken, 400ml tetrahydrofurans, mixing, dissolving is added.Slowly evaporated at 50 DEG C it is dry, then
Solid is collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-64
Osalmid solid about 3g is taken, 400ml tetrahydrofurans and 400ml water, mixing, dissolving is added.In 50 DEG C of slowly volatilizations
To doing, solid is then collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-65
Osalmid solid about 3g is taken, 400ml tetrahydrofurans and 400ml toluene, mixing, dissolving is added.It is slowly waved at 50 DEG C
It is sent to dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-66
Osalmid solid about 3g is taken, 400ml tetrahydrofurans and 400ml n-hexanes, mixing, dissolving is added.Slowly at 50 DEG C
It evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-67
Osalmid solid about 3g is taken, 400ml tetrahydrofurans and 400ml chloroforms, mixing, dissolving is added.It is slowly waved at 50 DEG C
It is sent to dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-68
Osalmid solid about 3g is taken, 400ml ethyl acetate and 400ml n-hexanes, mixing, dissolving is added.Slowly at 50 DEG C
It evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-69
Osalmid solid about 3g is taken, 400ml ethyl acetate and 400ml petroleum ethers, mixing, dissolving is added.Slowly at 50 DEG C
It evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-70
Osalmid solid about 3g is taken, 400ml methyl tertiary butyl ether(MTBE)s, mixing, dissolving is added.Slowly evaporated at 50 DEG C it is dry,
Then solid is collected, Osalmid crystal form III is obtained, is yellow-white powder.
Embodiment 1-71
Osalmid solid about 3g is taken, 400ml methyl tertiary butyl ether(MTBE)s, 200ml water and 200ml ethyl alcohol, mixing, dissolving is added.
It is slowly evaporated at 50 DEG C dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-72
Osalmid solid about 3g is taken, 400ml methyl tertiary butyl ether(MTBE)s and 400ml dichloromethane, mixing, dissolving is added.50
It DEG C slowly evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-72
Osalmid solid about 3g is taken, 400ml methyl tertiary butyl ether(MTBE)s and 400ml chloroforms, mixing, dissolving is added.Delay at 50 DEG C
Then slow vaporization collects solid, obtains Osalmid crystal form III to doing, be yellow-white powder.
Embodiment 1-73
Osalmid solid about 3g is taken, 400ml methyl iso-butyl ketone (MIBK)s and 400ml toluene, mixing, dissolving is added.Delay at 50 DEG C
Then slow vaporization collects solid, obtains Osalmid crystal form III to doing, be yellow-white powder.
Embodiment 1-74
Osalmid solid about 3g is taken, 400ml methyl iso-butyl ketone (MIBK)s and 400ml dichloromethane, mixing, dissolving is added.50
It DEG C slowly evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-75
Osalmid solid about 3g is taken, 400ml methyl iso-butyl ketone (MIBK)s and 400ml petroleum ethers, mixing, dissolving is added.At 50 DEG C
It slowly evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-76
Osalmid solid about 3g is taken, 400ml isopropyl acetates and 400ml toluene, mixing, dissolving is added.Slowly at 50 DEG C
It evaporates into dry, then collects solid, obtain Osalmid crystal form III, be yellow-white powder.
Embodiment 1-77
Osalmid solid about 3g is taken, 400ml isopropyl acetates and 400ml n-hexanes, mixing, dissolving is added.Delay at 50 DEG C
Then slow vaporization collects solid, obtains Osalmid crystal form III to doing, be yellow-white powder.
Embodiment 1-78
It takes about 3mg bulk pharmaceutical chemicals to be dissolved in 200ml tetrahydrofurans in vial, then vial is put into and is contained
In the carboy of 6L n-hexanes, sealing is stored at room temperature one week, collects the solid of precipitation, obtains Osalmid crystal form III, for Huang
White powder.
Embodiment 1-79
It takes about 3mg bulk pharmaceutical chemicals to be dissolved in 200ml methyl tertiary butyl ether(MTBE)s in vial, then puts vial
In the carboy for entering the n-hexane containing 6L, sealing is stored at room temperature one week, collects the solid of precipitation, obtains Osalmid crystal form III,
For yellow-white powder.
Embodiment 1-80
It takes about 3mg bulk pharmaceutical chemicals to be dissolved in 200ml methyl ethyl ketone in vial, then vial is put into containing 6L
In the carboy of petroleum ether, sealing is stored at room temperature one week, collects the solid of precipitation, obtains Osalmid crystal form III, is yellowish-white
Color powder.
Embodiment 1-81
It takes about 3mg bulk pharmaceutical chemicals to be dissolved in 200ml tetrahydrofurans in vial, then vial is put into and is contained
In the carboy of 6L petroleum ethers, sealing is stored at room temperature one week, collects the solid of precipitation, obtains Osalmid crystal form III, for Huang
White powder.
Embodiment 1-82
It takes about 3mg bulk pharmaceutical chemicals to be dissolved in 200ml methyl tertiary butyl ether(MTBE)s in vial, then puts vial
In the carboy for entering the petroleum ether containing 6L, sealing is stored at room temperature one week, collects the solid of precipitation, obtains Osalmid crystal form III,
For yellow-white powder.
Embodiment 1-83
It takes about 3mg bulk pharmaceutical chemicals to be dissolved in 200ml isopropyl acetates in vial, is then put into vial
In the carboy of the petroleum ether containing 6L, sealing is stored at room temperature one week, collects the solid of precipitation, obtains Osalmid crystal form III, be
Yellow-white powder.
Osalmid crystal form III is confirmed by XRPD in above example, the XRPD collection of illustrative plates of each embodiment with embodiment 1-1
It is similar.
2 solubility experiment of embodiment
Embodiment 2-1
Take the Osalmid crystal form III that about 20mg embodiments 1-1 is prepared, under the conditions of 25 DEG C with 1mL deionized waters
Stirring balances at least for 24 hours, then, difference filtering solution.Solvent is volatilized surveyed using gravimetry in a vacuum by liquid portion
Determine the approximate solubility of bulk pharmaceutical chemicals in a solvent.Gravimetry：The accurate filtrate for taking certain volume (generally 0.5mL) is put into
In container that is dry and having weighed up weight, empty container weight is denoted as M0mg, volatilized in vacuum after solvent again precise its
Total weight is denoted as M1mg, then the solid masses being precipitated is M1-M0, and the volume of solvent is V mL, and raw material is in the solvent accordingly
Approximate solubility is X=(M1-M0)/V mg/mL.Obtaining the solubility of Osalmid crystal form III in deionized water is
0.413mg/mL。
Embodiment 2-2
Take the Osalmid crystal form III that about 20mg embodiments 1-1 is prepared, under the conditions of 25 DEG C with 1mL glycine-salt
Acid buffer (pH=2.0) stirring balances at least for 24 hours, then, difference filtering solution.Liquid portion in a vacuum volatilizes solvent
The approximate solubility of bulk pharmaceutical chemicals in a solvent is measured using gravimetry.Gravimetry：It is accurate to take certain volume (generally
Filtrate 0.5mL) is put into container that is dry and having weighed up weight, is denoted as M0mg, accurately claims again after solvent is volatilized in vacuum
Its total weight is measured, M1mg is denoted as, then the solid masses being precipitated is M1-M0, and the volume of solvent is V mL, and raw material is in the solvent accordingly
In approximate solubility be X=(M1-M0)/V mg/mL.Osalmid crystal form III is obtained in glycine-HCI buffer solution (pH=
2.0) solubility in is 0.365mg/mL.
Embodiment 2-3
Take the Osalmid crystal form III that about 20mg embodiments 1-1 is prepared, under the conditions of 25 DEG C with 1mLNa2HPO4Lemon
Lemon acid buffer (pH=4.6) stirring balances at least for 24 hours, then, difference filtering solution.Liquid portion in a vacuum waves solvent
It is dry to measure the approximate solubility of bulk pharmaceutical chemicals in a solvent using gravimetry.Gravimetry：It is accurate to take certain volume (general
For 0.5mL) filtrate be put into container that is dry and having weighed up weight, be denoted as M0mg, it is accurate again after solvent to be volatilized in vacuum
Its total weight is weighed, M1mg is denoted as, then the solid masses being precipitated is M1-M0, and the volume of solvent is V mL, and raw material is molten at this accordingly
Approximate solubility in agent is X=(M1-M0)/V mg/mL.Osalmid crystal form III is obtained in Na2HPO4Citrate buffer solution
(pH=4.6) solubility in is 0.343mg/mL.
The tests such as embodiment 3XRPD, TG, DSC, IR, Raman, DVS, stripping curve
Fig. 1-8 shows the polarisation photo for the Osalmid crystal form III that 1-1 of the embodiment of the present invention is prepared, is penetrated by X-
Line powder diffraction (XRPD), thermogravimetic analysis (TGA) (TG), differential scanning calorimetric analysis (DSC), infrared spectrum (IR), Raman spectrum
(Raman), hygroscopicity analysis (DVS), stripping curve characterization result.
Polarisation photo：It uses the XPV-400E petrographic microscopes of the rectangular optical instrument Co., Ltd in Shanghai to be tested,
It is 5 times to test amplification factor.Its analysis result is shown in Fig. 1.Polarisation photo shows, Osalmid crystal form made from above-described embodiment 1-1
III is off-white color crystal, has good shape characteristic.
XRPD is analyzed：Instrument model：Bruker D8advance, target：Cu K α (40kV, 40mA), sample to detector away from
From：30cm, scanning range：3 ° -40 ° (2theta values), scanning step diameter：0.05s.Its analysis result is shown in that Fig. 2, spectrogram show above-mentioned
Osalmid crystal form III made from embodiment has good crystallinity.
It is often characteristic by the diffraction spectrogram that specific crystal formation obtains in sample powder X-ray powder diffraction collection
's.Because of the difference of the relative amount of crystallization condition, grain size, mixture and other test conditions, diffraction spectrogram may will produce
Preferred orientation effect, the relative intensity so as to cause certain bands of a spectrum (especially in low angle) in spectrogram change.Therefore, spread out
The relative intensity for penetrating peak is not characteristic to targeted crystal, when judging whether identical as known crystal form, more should
It is to be noted that the position at peak rather than their relative intensity.In addition, judge crystal form whether when should be noted that holding Overall View
It reads, because being not that a diffracted ray represents an object phase, but a set of specific " d-1/ Π " data just represent a certain object phase.
It should be noted also that in the identification of mixture, since the factors such as content decline can cause the missing of part diffracted ray, at this point,
May also be characteristic to given crystal without relying on the whole bands of a spectrum observed in high-purity sample or even a bands of a spectrum.
TG is analyzed：Instrument model：Netzsch TG 209F3, temperature range：30-400 DEG C, sweep speed：10K/min,
Purge gass：25mL/min protects gas：15mL/min.Its analysis result is shown in Fig. 3.
Dsc analysis：Instrument number：Perkin Elmer DSC 1200, temperature range：- 40-400 DEG C, sweep speed：10
DEG C/min, nitrogen flow rate：50ml/min.Its analysis result is shown in Fig. 4.
DVS is analyzed：Instrument model：SMS DVS Intrinsic, 0~95%RH, temperature：25℃.Its analysis result is shown in figure
5.Moisture absorption ratio is 0.10% under 80%RH.
Draw it is moist be material medicine important physical properties, it directly influences the storage stability of drug, machinability
With technique preparation process.The application using Dynamic Water adsorption instrument (DVS) to sample at a temperature of 25 DEG C, investigate its 0~
95% relative humidity tests the adsorption and desorption of moisture content, draws wet performance with the various different crystal forms of determination.Following table is middle traditional Chinese medicines
Allusion quotation 2015 editions for drug after 25 DEG C, 80%RH balances, hygroscopic definition and range.
| It deliquesces | It absorbs enough moisture and forms liquid |
| It is great draw it is moist | Draw wet weightening and is not less than 15% |
| Have draw it is moist | Draw wet weightening less than 15% but is not less than 2% |
| Slightly draw moist | Draw wet weightening less than 2% but is not less than 0.2% |
| Nothing is moist almost without drawing | Draw wet weightening and is less than 0.2% |
IR is analyzed：Instrument model：Nicolet-Magna FT-IR 750, scanning range：4000to 350cm-1, differentiate
Rate：4cm-1.Its analysis result is shown in Fig. 6.
Raman is analyzed：Instrument model：Thermo Scientific DXR, optical maser wavelength：780nm, scanning range：
3500to 50cm-1, resolution ratio：2cm-1.Its analysis result is shown in Fig. 7.
Intrinsic dissolution experiment dissolves and absorbs test system using μ Diss (Pion Inc.) drug and is tested, with pH=
2.0 hydrochloric acid-glycine solution is as dissolution medium.
Crystal form IIIs of the 8mg from embodiment 1-1 is pressed onto 0.07cm in 3 minutes under 120bar pressure2Disk on, and
Disk is placed in the stripping rotor of 20mL afterwards, the hydrochloric acid-glycine solution for the pH=2.0 that dissolution medium is 37 DEG C, rotating speed is set as
50rpm。
Intrinsic dissolution (IDR) experimental result see the table below：
Dissolution concentration is accumulated in different time according to Osalmid crystal form III in upper table, linear fit obtains Osalmid crystal form
The stripping curve of III, as shown in Figure 8.
Related coefficient is 0.998, linear preferable.Its dissolution rate is 0.115 μ g/mL/min, is acquired according to following formula
Dissolution rates of the Osalmid crystal form III in hydrochloric acid-glycine solution that pH is 2.0 be：
Claims (10)
1. a kind of Osalmid crystal form III, which is characterized in that the X-ray powder diffraction that the crystal form is indicated with 2 θ angles is in diffraction
Angle about 7.51 ± 0.2, about 11.273 ± 0.2, about 15.068 ± 0.2, about 18.837 ± 0.2, about 19.386 ± 0.2, about
20.418 ± 0.2, about 22.118 ± 0.2, about 24.296 ± 0.2, about 26.337 ± 0.2, about 26.493 ± 0.2, about 27.236
± 0.2, about 28.973 ± 0.2, about 30.349 ± 0.2, about 32.863 ± 0.2, about 36.06 ± 0.2, about 38.176 ± 0.2 degree
Place has characteristic peak.
2. Osalmid crystal form III as described in claim 1, which is characterized in that the Osalmid crystal form III has substantially such as
X-ray powder diffraction collection shown in Fig. 2.
3. Osalmid crystal form III as described in claim 1, which is characterized in that the differential scanning amount of the Osalmid crystal form III
Heat analysis has feature endothermic peak at about 168 DEG C and about 176 DEG C.
4. Osalmid crystal form III as described in claim 1, it is characterised in that：The thermogravimetic analysis (TGA) of the Osalmid crystal form III
Decomposition temperature be about 190 DEG C.
5. Osalmid crystal form III as described in claim 1, it is characterised in that：The infrared spectrum of the Osalmid crystal form III exists
3298.60cm-1、3158.85cm-1、1632.38cm-1、1577.24cm-1、1516.21cm-1、1460.92cm-1、
1353.13cm-1、1232.01cm-1、1170.53cm-1、1151.43cm-1、1132.54cm-1、1107.98cm-1、
1090.86cm-1、1041.60cm-1、949.37cm-1、897.24cm-1、827.47cm-1、783.42cm-1、749.44cm-1、
658.88cm-1、552.38cm-1、521.03cm-1、496.35cm-1Place has characteristic peak.
6. the preparation method of Osalmid crystal form III according to any one of claims 1 to 5, which is characterized in that the preparation side
Method is selected from one of following method：
(1) volatilization crystallization：Prepare Osalmid solid, solvent is added, mixing dissolves, and at 0~65 DEG C, slowly evaporates into dry, collection
Solid obtains Osalmid crystal form III；Or
(2) antisolvent crystallisation
The small size vial equipped with the solvent very high to Osalmid solubility is taken, wherein by the dissolving of Osalmid solid, then, is taken
Small size vial is put by the way of big bottle cover bottle equipped with the large size vial to the insoluble anti-solvent of Osalmid height
Enter in large size vial, the sealing of large size vial is stored at room temperature 3 days or more, so that poor solvent is constantly waved in solution, make precipitation
It is precipitated, obtains Osalmid crystal form III.
7. preparation method as claimed in claim 6, which is characterized in that (1) volatilization crystallization is performed as follows：It is solid to prepare Osalmid
Body, is added solvent, mixing, dissolving, slowly evaporates at 15~30 DEG C or 40~65 DEG C dry, collects solid, obtains Osalmid crystalline substance
Type III.
8. preparation method as claimed in claims 6 or 7, which is characterized in that in method (1), the solvent is selected from water, first
Alcohol, ethyl alcohol, isopropanol, isoamyl alcohol, acetone, methyl ethyl ketone, acetonitrile, methyl iso-butyl ketone (MIBK), ethyl acetate, isopropyl acetate, toluene,
One or both of n-hexane, normal heptane, dichloromethane, petroleum ether, chloroform, methyl tertiary butyl ether(MTBE), tetrahydrofuran or more
The mixture of kind.
9. preparation method as claimed in claims 6 or 7, it is characterised in that
In method (1),
When volatilization temperature is 15~30 DEG C, the solvent is selected from methanol, methyl ethyl ketone, tetrahydrofuran, methyl tertiary butyl ether(MTBE), methyl
Isobutyl ketone, isopropyl acetate, acetone and the mixture of water, the mixture of methyl ethyl ketone and water, tetrahydrofuran and water mixture,
Mixture, the methyl tert-butyl of the mixture of acetone and toluene, the mixture of methyl iso-butyl ketone (MIBK) and toluene, isopropanol and n-hexane
The mixture of base ketone and n-hexane, the mixture of acetone and normal heptane, the mixture of methyl ethyl ketone and normal heptane, tetrahydrofuran and just
Mixture, acetone and the dichloro of the mixture of heptane, the mixture of ethyl acetate and normal heptane, methyl iso-butyl ketone (MIBK) and normal heptane
The mixture of methane, the mixture of tetrahydrofuran and dichloromethane, mixture, the methyl of methyl tertiary butyl ether(MTBE) and dichloromethane are different
Mixture, the tetrahydrofuran of the mixture of butyl ketone and dichloromethane, the mixture of acetone and chloroform, isopropyl acetate and chloroform
With the mixture of petroleum ether, the mixture of the mixture of ethyl acetate and petroleum ether, methyl iso-butyl ketone (MIBK) and petroleum ether；
When volatilization temperature is 40~65 DEG C, the solvent is selected from methanol, ethyl alcohol, isopropanol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrochysene
Mixture, the first of furans, methyl tertiary butyl ether(MTBE), the mixture of second alcohol and water, the mixture of isoamyl alcohol and water, tetrahydrofuran and water
Mixture, acetone and the toluene of the mixture of base tertbutyl ether and water and ethyl alcohol, the mixture of methanol and toluene, ethyl alcohol and toluene
Mixture, the mixture of methyl ethyl ketone and toluene, the mixture of tetrahydrofuran and toluene, methyl iso-butyl ketone (MIBK) and toluene mixing
Object, the mixture of isopropyl acetate and toluene, methanol and the mixture of n-hexane, the mixture of ethyl alcohol and n-hexane, isopropanol
It is mixed with the mixture of the mixture of n-hexane, the mixture of acetone and n-hexane, methyl ethyl ketone and n-hexane, acetonitrile and n-hexane
Close the mixed of object, tetrahydrofuran and the mixture of n-hexane, the mixture of ethyl acetate and n-hexane, isopropyl acetate and n-hexane
Close mixture, the isoamyl alcohol of object, methanol and the mixture of normal heptane, the mixture of ethyl alcohol and normal heptane, isopropanol and normal heptane
With mixture, isopropanol and the dichloromethane of the mixture of normal heptane, the mixture of methanol and dichloromethane, ethyl alcohol and dichloromethane
The mixture of alkane, the mixture of isoamyl alcohol and dichloromethane, the mixture of acetone and dichloromethane, acetonitrile and dichloromethane it is mixed
Close object, methyl tertiary butyl ether(MTBE) and the mixture of dichloromethane, the mixture of methyl iso-butyl ketone (MIBK) and dichloromethane, methanol and chloroform
Mixture, the mixture of ethyl alcohol and chloroform, the mixture of isopropanol and chloroform, acetone and chloroform mixture, acetonitrile and chlorine
Imitative mixture, the mixture of tetrahydrofuran and chloroform, the mixture of methyl tertiary butyl ether(MTBE) and chloroform, methanol and petroleum ether it is mixed
Close mixture, the acetone of object, ethyl alcohol and the mixture of petroleum ether, the mixture of isopropanol and petroleum ether, isoamyl alcohol and petroleum ether
With mixture, ethyl acetate and the petroleum ether of the mixture of petroleum ether, the mixture of methyl ethyl ketone and petroleum ether, acetonitrile and petroleum ether
Mixture, methyl iso-butyl ketone (MIBK) and petroleum ether mixture；
In method (2), the combination of the solvent and anti-solvent selected from the combination of tetrahydrofuran and n-hexane, methyl tertiary butyl ether(MTBE) and
The combination of n-hexane, the combination of methyl ethyl ketone and petroleum ether, tetrahydrofuran and petroleum ether combination, methyl tertiary butyl ether(MTBE) and petroleum ether
Combination, isopropyl acetate and petroleum ether combination.
10. any one of Claims 1 to 5 Osalmid crystal form III prepare for treat/or prevent cholecystitis, biliary tract
Inflammation, cholelithiasis, tumour, the drug of hepatitis B and the application in skin-lightening cosmetic.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112442062A (en) * | 2019-09-05 | 2021-03-05 | 中国科学院上海药物研究所 | Salinamide phenol organic silicon compound and anti-tumor application thereof |
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