CN107987065A - A kind of common amorphous substance of Puerarin niacinamide - Google Patents
A kind of common amorphous substance of Puerarin niacinamide Download PDFInfo
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- CN107987065A CN107987065A CN201711414869.0A CN201711414869A CN107987065A CN 107987065 A CN107987065 A CN 107987065A CN 201711414869 A CN201711414869 A CN 201711414869A CN 107987065 A CN107987065 A CN 107987065A
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- puerarin
- niacinamide
- amorphous substance
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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Abstract
The present invention relates to a kind of Puerarin niacinamide for being remarkably improved insoluble drug Puerarin dissolution rate to be total to amorphous substance.The common amorphous substance is a kind of amorphous state for being totally different from pueraria lobata cellulose crystal, and fusing point, x-ray diffractogram of powder spectrum, DSC spectrograms, the infrared spectrum from pueraria lobata cellulose crystal are different.Using Cu K α radiations, the X-ray powder diffraction spectrum represented with spending 2 θ does not have sharp diffraction maximum.Its glass transition temperature is about 64.1 DEG C.Dissolution test result indicates that, which can make the intrinsic dissolution rate of Puerarin improve about 78 times, and can when 24 is small the interior supersaturated state for being maintained above Puerarin Crystal solubility.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to Puerarin and niacinamide 1: 1 Pueraria lobota combined to form in molar ratio
Common amorphous substance of root element niacinamide and preparation method thereof.
Background technology
Puerarin (Puerarin), the entitled 8- β-D- glucopyanosyls-daidzein of chemistry, chemical constitution
It is as follows：
Puerarin has extensive pharmacological action, such as expands blood vessel, cardioprotection, protection nerve, anticancer, promotion bone shape
Into with reduce insulin resistance etc., available for treatment cardiovascular and cerebrovascular disease (such as angina pectoris, coronary heart disease), diabetes and diabetes simultaneously
Send out disease and cancer etc..Puerarin medicine source is enriched, and good effect, safe range is wide, has vast potential for future development, but it belongs to biology
IV class medicines in Biopharmaceutical Classification system, have the characteristics that low solubility, hypotonicity.Clinically Puerarin is unique at present
Method of administration is intravenous injection, but frequent and long term injections can cause the side effects such as delayed allergy, strongly limit
Its clinical practice.
Niacinamide is vitamin B3Derivative, belong to FDA approval GRAS (Generally Recognized as
Safe) small molecule auxiliary material, is widely used in medicine and food service industry.
We under study for action surprisingly it has been found that after Puerarin and niacinamide are made a kind of amorphous substance altogether jointly,
The dissolution rate of Puerarin obtains pole compared with bulk pharmaceutical chemicals and significantly improves.
The content of the invention
It is an object of the invention to provide a kind of Puerarin niacinamide that can significantly improve Puerarin dissolution rate altogether without fixed
Shape thing.
The common amorphous substance of the Puerarin niacinamide of the present invention, has following feature：
1st, powder x-ray diffraction
Instrument：D8Advance X-ray diffractometers (Bruker, Germany)
Target：Cu-K α are radiated
Wavelength：1.5406A
Pipe pressure：40KV
Guan Liu：40mA
Step-length：0.02°
Sweep speed：10°/min
The result shows that：The spectrogram of the common amorphous substance of Puerarin niacinamide does not have sharp diffraction maximum.
2nd, differential scanning calorimetry (DSC)
Instrument：Netzsch DSC 204F1Phoenix differential scanning calorimeters instrument (Netzsch, Germany)
Scope：Crystal and crystallophy mixture are 50-250 DEG C, and amorphous substance is 0-250 DEG C.
Programming rate：10℃/min
Broad peak of the Puerarin at 82.9 DEG C is its dehydration endotherm peaks, is endothermic fusion peak at 208.7 DEG C.
Niacinamide is endothermic fusion peak at 128.7 DEG C.
The glass transition temperature of the common amorphous substance of Puerarin niacinamide is at 64.1 DEG C.
3rd, infrared spectrum
Instrument：410 type infrared spectrometers of Nicolet Impact (Thermo Fisher Scientific, USA)
Puerarin niacinamide is total to the infrared spectrum wave number (cm of amorphous substance (pressing potassium bromide troche)-1) be：3305.3、
3205.8、2917.5、2687.5、1675.9、1628.6、1592.5、1514.2、1443.7、1392.2、1308.3、1255.2、
1211.9、1174.6、1082.0、1057.8、1041.6、1029.8、1012.6、888.3、833.1、795.8、782.6、
747.6、702.0、640.3、604.2、571.3、543.6、501.1、418.9cm-1。
Another object of the present invention is to provide the method for the common amorphous substance for preparing Puerarin niacinamide.
A kind of Puerarin niacinamide is total to the preparation method of amorphous substance, it includes Puerarin and niacinamide being dissolved in
In organic solvent, settled solution is obtained, rotary evaporation of solvent is depressurized at 35-70 DEG C, is dried in vacuo.
The organic solvent can be methanol, ethanol, isopropanol, n-butanol or their mixed solvent, preferably methanol or second
Alcohol.
The dosage of niacinamide is 0.5~2 times of molar equivalent of Puerarin, preferably 1 times of molar equivalent.
The temperature for depressurizing rotary evaporation of solvent is 35-70 DEG C, 45-55 DEG C of preferable temperature.
Puerarin niacinamide disclosed in the present invention is total to the pueraria lobata cellulose crystal and nicotinoyl of amorphous substance and existing patent report
The x-ray diffractogram of powder spectrum of amine crystal, DSC collection of illustrative plates, infrared spectrum are different, thus the solid forms be it is a kind of completely not
It is same as the Puerarin of the prior art and the form of niacinamide.
Brief description of the drawings
Fig. 1 is the x-ray diffractogram of powder of pueraria lobata cellulose crystal.
Fig. 2 is the x-ray diffractogram of powder of niacinamide crystal.
Fig. 3 is the x-ray diffractogram of powder of the crystallophy mixture of Puerarin and niacinamide.
Fig. 4 is the x-ray diffractogram of powder of the common amorphous substance of Puerarin niacinamide.
Fig. 5 is the DSC figures of pueraria lobata cellulose crystal.
Fig. 6 is the DSC figures of niacinamide.
Fig. 7 is the DSC figures of the crystallophy mixture of Puerarin and niacinamide.
Fig. 8 is the DSC figures of the common amorphous substance of Puerarin niacinamide.
The infrared spectrogram of Fig. 9 pueraria lobata cellulose crystals.
Figure 10 is the infrared spectrogram of niacinamide crystal.
Figure 11 is the infrared spectrogram of the crystallophy mixture of Puerarin and niacinamide.
Figure 12 is the infrared spectrogram of the common amorphous substance of Puerarin niacinamide.
Figure 13 be pueraria lobata cellulose crystal, Puerarin niacinamide common amorphous substance Puerarin in water intrinsic dissolution rate it is bent
Line contrasts.
Figure 14 be pueraria lobata cellulose crystal, Puerarin niacinamide common amorphous substance Puerarin in water supersaturated stripping curve
Contrast.
Embodiment
Embodiment
1st, powder x-ray diffraction
Instrument：D8Advance X-ray diffractometers (Bruker, Germany)
Target：Cu-K α are radiated
Wavelength：1.5406A
Pipe pressure：40KV
Guan Liu：40mA
Step-length：0.02°
Sweep speed：10°/min
The result shows that：The spectrogram of the common amorphous substance of Puerarin niacinamide does not have sharp diffraction maximum.
2nd, differential scanning calorimetry (DSC)
Instrument：204 F1 Phoenix differential scanning calorimeters instrument (Netzsch, Germany) of Netzsch DSC
Scope：Crystal and crystallophy mixture are 50-250 DEG C, and amorphous substance is 0-250 DEG C.
Programming rate：10℃/min
The glass transition temperature of the common amorphous substance of Puerarin niacinamide is at 64.1 DEG C.
3rd, infrared spectrum
Instrument：410 type infrared spectrometers of Nicolet Impact (Thermo Fisher Scientific, USA)
Puerarin niacinamide is total to the infrared spectrum wave number (cm of amorphous substance (pressing potassium bromide troche)-1) be：3305.3、
3205.8、2917.5、2687.5、1675.9、1628.6、1592.5、1514.2、1443.7、1392.2、1308.3、1255.2、
1211.9、1174.6、1082.0、1057.8、1041.6、1029.8、1012.6、888.3、833.1、795.8、782.6、
747.6、702.0、640.3、604.2、571.3、543.6、501.1、418.9cm-1。
Embodiment 1：Puerarin niacinamide is total to the preparation of amorphous substance
2.00g Puerarins and 0.58g niacinamide are added in 50mL methanol, room temperature ultrasonic dissolution obtains settled solution, by this
Settled solution depressurizes rotary evaporation of solvent at 35 DEG C, and 25 DEG C of vacuum drying 12h, obtain white powder 2.34g.
Embodiment 2：Puerarin niacinamide is total to the preparation of amorphous substance
2.00g Puerarins and 0.58g niacinamide are added in 50mL ethanol, room temperature ultrasonic dissolution obtains settled solution, by this
Settled solution depressurizes rotary evaporation of solvent at 50 DEG C, and 25 DEG C of vacuum drying 12h, obtain white powder 2.28g.
Embodiment 3：Puerarin niacinamide is total to the preparation of amorphous substance
2.00g Puerarins and 0.58g niacinamide are added into 50mL methanol/ethanols (50: 50, v/v) in the mixed solvent, room temperature
Ultrasonic dissolution obtains settled solution, this settled solution is depressurized rotary evaporation of solvent at 55 DEG C, 25 DEG C of vacuum drying 12h, obtain
White powder 2.32g.
Embodiment 4：Puerarin niacinamide is total to the preparation of amorphous substance
2.00g Puerarins and 0.58g niacinamide are added into 50mL methanol-isopropanols (50: 50, v/v) in the mixed solvent, room
Warm ultrasonic dissolution obtains settled solution, this settled solution is depressurized rotary evaporation of solvent at 65 DEG C, 25 DEG C of vacuum drying 12h, obtain
To white powder 2.21g.
Embodiment 5：Puerarin niacinamide is total to the preparation of amorphous substance
2.00g Puerarins and 0.58g niacinamide are added into 50mL methanol-n-butanol (50: 50, v/v) in the mixed solvent, room
Warm ultrasonic dissolution obtains settled solution, this settled solution is depressurized rotary evaporation of solvent at 70 DEG C, 25 DEG C of vacuum drying 12h, obtain
To white powder 2.19g.
Intrinsic dissolution rate measures
The common amorphous substance of pueraria lobata cellulose crystal, Puerarin niacinamide is crossed into 100 mesh sieves, precision weighs solid powder respectively
350mg, the fine and close regular tablets of a diameter of 13mm are pressed into hydraulic press, and ensure that the hardness of institute's tabletting is basically identical.Will
The bottom surface and side of tablet are wrapped up with beeswax model, make it only have a circular surface to be contacted with dissolution medium.Dissolution test side
Method according to《Chinese Pharmacopoeia》0,931 second method (paddle method) of version general rule in 2015, measure medium are water, medium volume 500mL, rotating speed
50rpm, 37 DEG C of dissolution medium temperature.After on-test, sampled respectively in 2,5,10,15,20,40,60,90,120min, every time
3mL is sampled, and supplements 3mL dissolution mediums.The solution of taking-up crosses 0.22 μm of miillpore filter, takes subsequent filtrate to carry out HPLC analyses.
The chromatographic condition of high performance liquid chromatography is as follows：
Instrument：Shimadzu LC-2010AHT high performance liquid chromatographs
Chromatographic column：Inertsil ODS-SP C18Column (4.6mm × 150mm, 5 μm)
Mobile phase：Methanol-water=35: 65 (V/V)
Flow velocity：1.0mL/min
Column temperature：30℃
Detection wavelength：250nm
The preparation of reference substance solution：Precision weighs Puerarin reference substance 10.0mg, puts in 10mL measuring bottles, with methanol dissolving simultaneously
Be diluted to scale, shake up, precision measures solution 1.0mL and puts in 10mL measuring bottles, adds mobile phase to be diluted to scale, shakes up, to obtain the final product.
Intrinsic dissolution rate passes through stripping quantity (mgcm-2The slope of)-time (min) regression curve is calculated and obtained.As a result
See attached drawing 13.
During characteristic dissolution test, pueraria lobata cellulose crystal is from the slow dissolution in slice, thin piece surface, until off-test exposed surface
Still to be complete circular；It is substantially all molten in 15min inner sheets and the dissolution that Puerarin niacinamide is total to amorphous substance is very fast
Complete, this shows that Puerarin niacinamide is total to the tablet that amorphous substance is formed under high pressure and still has very big dissolution rate, behind
Time point concentration deviate considerably from straight line, therefore use preceding 4 time points estimated performance dissolution rate.
With former Puerarin crystal phase ratio, which makes the intrinsic dissolution rate of Puerarin improve about 78 times.
Supersaturated dissolution determination
The common amorphous substance of pueraria lobata cellulose crystal, Puerarin niacinamide is crossed into 100 mesh sieves respectively, according to《Chinese Pharmacopoeia》2015
The 3rd method (small-radius curve track) device of year version general rule 0931, measure medium are water, dissolution medium volume 200mL, rotating speed 50rpm, dissolution
37 DEG C of medium temperature.Excessive above-mentioned sample is taken, is placed in dissolution medium, is sampled in 0.17,0.5,1,2,4,7,10,12,24h,
Per sub-sampling 2mL, 0.22 μm of miillpore filter is crossed, takes subsequent filtrate to carry out HPLC analyses after appropriate dilution.Chromatographic condition and characteristic
It is consistent under dissolution rate measure item.The result is shown in attached drawing 14.The result shows that the common amorphous substance of Puerarin niacinamide can quickly reach
To supersaturated state, and the solubility for being significantly higher than pueraria lobata cellulose crystal can be at least maintained in 24h, this supersaturation state has bigger
Membrane permeability driving force, be more advantageous to absorption of the medicine in enteron aisle.
Claims (5)
1. a kind of common amorphous substance of Puerarin niacinamide, it is characterised in that be by Puerarin and niacinamide 1: 1 knot in molar ratio
Close and formed, radiated using Cu-K α, the X-ray powder diffraction spectrum represented with spending 2 θ does not have sharp diffraction maximum；With KBr tablettings
Measure obtained infrared absorption spectroscopy 3305.3,3205.8,2917.5,2687.5,1675.9,1628.6,1592.5,
1514.2、1443.7、1392.2、1308.3、1255.2、1211.9、1174.6、1082.0、1057.8、1041.6、1029.8、
1012.6、888.3、833.1、795.8、782.6、747.6、702.0、640.3、604.2、571.3、543.6、501.1、
418.9cm-1There is absworption peak at place；Its glass transition temperature is about 64.1 DEG C.
2. Puerarin niacinamide according to claim 1 is total to the preparation method of amorphous substance, it is characterised in that is by pueraria lobata
Element is dissolved in organic solvent with niacinamide according to molar ratio 1: 1, and rotary evaporation of solvent is depressurized at 35-70 DEG C, is dried in vacuo,
Amorphous substance is total to up to Puerarin niacinamide.
3. Puerarin niacinamide as claimed in claim 2 is total to the preparation method of amorphous substance, it is characterised in that described organic molten
Agent is methanol, ethanol, isopropanol, n-butanol or their mixed solvent.
4. Puerarin niacinamide as claimed in claim 3 is total to the preparation method of amorphous substance, it is characterised in that described organic molten
Agent is preferably methanol or ethanol.
5. Puerarin niacinamide as claimed in claim 2 is total to the preparation method of amorphous substance, it is characterised in that the decompression rotation
The preferable temperature for turning evaporation solvent is 45-55 DEG C.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109053842A (en) * | 2018-10-11 | 2018-12-21 | 中国药科大学 | puerarin chelate and preparation method thereof |
| CN109180659A (en) * | 2018-09-18 | 2019-01-11 | 中国药科大学 | A kind of total amorphous substance of Puerarin saccharin and preparation method thereof |
| CN111848594A (en) * | 2020-08-04 | 2020-10-30 | 中国药科大学 | Puerarin anhydrous spherical crystal and preparation method and application thereof |
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Cited By (5)
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|---|---|---|---|---|
| CN109180659A (en) * | 2018-09-18 | 2019-01-11 | 中国药科大学 | A kind of total amorphous substance of Puerarin saccharin and preparation method thereof |
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| CN111848594A (en) * | 2020-08-04 | 2020-10-30 | 中国药科大学 | Puerarin anhydrous spherical crystal and preparation method and application thereof |
| CN111848594B (en) * | 2020-08-04 | 2022-03-11 | 中国药科大学 | Puerarin anhydrous spherical crystal and preparation method and application thereof |
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