CN106632024A - Preparation method of ibuprofen-nicotinamide eutectic through solvent - Google Patents
Preparation method of ibuprofen-nicotinamide eutectic through solvent Download PDFInfo
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- CN106632024A CN106632024A CN201610894814.3A CN201610894814A CN106632024A CN 106632024 A CN106632024 A CN 106632024A CN 201610894814 A CN201610894814 A CN 201610894814A CN 106632024 A CN106632024 A CN 106632024A
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- China
- Prior art keywords
- brufen
- eutectic
- preparation
- nicotinamide
- nicotinamide eutectic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
-
- 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
The invention relates to a preparation method of ibuprofen-nicotinamide eutectic with mole ratio of 1: 1 through solvent evaporation; the preparation method includes steps of commonly dissolving ibuprofen and nicotinamide in organic solvent; rotationally evaporating or naturally volatilizing solvent; acquiring the ibuprofen-nicotinamide eutectic. The prepared ibuprofen-nicotinamide eutectic is able to effectively add the water solubility of ibuprofen; the technical method is simple and cost is low; the quality is easy to control; the product yield is high (90-98%), and stability is good; the preparation method is good for industrial production.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to brufen and niacinamide by Hydrogenbond formed such as Formulas I
The preparation method of shown compound, i.e. 2- (4- isobutyl phenenyls) propionic acid niacinamide, improves the water of insoluble drug brufen
Dissolubility.
Background technology
Brufen (Ibuprofen), i.e. 2- (4- isobutyl phenenyls) is a kind of by suppressing Cycloxygenase reduction prostate
The NSAIDs of element synthesis.Compared to aspirin, brufen has higher anti-inflammatory, analgesia and refrigeration function, and right
Stomach, liver and hemopoietic system non-evident effect, are now widely used in treatment rheumatic arthritis, rheumatoid arthritis and tetanic
Property spondylitis etc..Brufen belongs to Biopharmaceutics Classification system BCS II class compounds, and its poorly water-soluble result in oral life
Thing availability is relatively low.Improving the method for drug solubility at present mainly has：By medicine preparation into salt, amorphous, solid dispersions,
Inclusion compound etc., the raising brufen solubility method of document report is mainly prepared into salt：CN103304401、CN
101190889th, CN 102617330, CN 101874794, CN 102557918, CN 1897925 disclose the smart ammonia of brufen
The preparation methods such as hydrochlorate, lysine salt, sodium salt, sylvite.In addition, the dissolving of brufen also can be improved by eutectic technology
Degree：CN103304476 discloses a kind of preparation method of brufen-nicotinamide eutectic.
Eutectic refers to bulk drug (API) and eutectic formation (coformer, CCF) in hydrogen bond or the work of other non-covalent bonds
Insoluble drug can be improved on the premise of medicines structure is not changed with single melting crystals with certain proportion formation with
Physicochemical property, such as solubility, dissolution rate, stability etc., and then improve its bioavilability.Except can be by ionic compound
Make outside eutectic, neutral compound also can with suitable CCF formed eutectic and improve solubility, the API for forming salt must be from
Subtype compound, therefore eutectic has broad prospects in drug development.
At present, only has a patent report with regard to brufen eutectic：CN 103304476 discloses a kind of application cooling analysis
Brufen-nicotinamide eutectic prepared by crystallization, will brufen and niacinamide in molar ratio for 1.4: 1～1.8: 1 ratio in
After dissolving in aqueous mixed solvent, cooling, in 0～5 DEG C of 1～3h of growing the grain, separates out crystal, filters, the Jing long periods (5～
Brufen-nicotinamide eutectic is obtained after 10h) being dried, fusing point is 94 DEG C, in diffraction in its x-ray diffractogram of powder spectrum (accompanying drawing 1)
Angle (2 θ) is have characteristic peak at 3.1,9.5,12.6,15.3,15.8,16.3,17.0,17.8,18.9,21.8 and 24.6 degree.So
And the method preparation time is long, program is loaded down with trivial details, yield relatively low (only 50～60%).
The invention provides a kind of method that brufen-nicotinamide eutectic is prepared by solvent evaporation method, simple process, into
This low, high income, it is easy to control, stability is high, is conducive to industrialized production.
The content of the invention
It is an object of the invention to provide a kind of method for preparing brufen-nicotinamide eutectic by solvent evaporation method.
A kind of preparation method of brufen-nicotinamide eutectic that brufen is formed with niacinamide, it is included cloth Lip river
It is fragrant to be fed intake in organic solvent with mol ratio as 1: 1 with niacinamide, settled solution is obtained in 5～40 DEG C of stirrings, in 10～65 DEG C
Under volatilize organic solvent, obtain brufen-nicotinamide eutectic.
The organic solvent can be ethanol, acetone, methyl alcohol, isopropanol, ethyl acetate and its mixed liquor, preferred alcohol,
Acetone, more preferably absolute ethyl alcohol.The consumption of organic solvent is 1-200 times, preferably 40-80 times of niacinamide consumption (weight)；
The bulk drug dissolving is generally carried out at 5～50 DEG C, and preferable temperature is 10～30 DEG C；
The organic solvent volatilizes temperature for 10～65 DEG C, preferably 20～40 DEG C.
The present invention prepare brufen-nicotinamide eutectic Jing high effective liquid chromatography for measuring, determine brufen therein with
Niacinamide mol ratio is 1: 1, with following feature：
1st, powder x-ray diffraction (PXRD) (accompanying drawing 2)：
Instrument：D8 Advance X-ray diffractometers (German Bruker)
Wavelength：
Target：Cu-K α are radiated
Pipe pressure：40kV
Guan Liu：40mA
Step-length：0.02°
Sweep speed：2°/min
2nd, differential scanning calorimetry (DSC) (accompanying drawing 4)：
Instrument：The differential scanning calorimeter instrument (Germany) of NETZSCH DSC 204
Scope：40～250 DEG C
Programming rate：10 DEG C/min
The endothermic fusion peak of novel crystalline form state is at about 91.1 DEG C.
3rd, fusing point：
Instrument：RY-1 melting point apparatus (Tianjin analytical instrument factory)
The fusing point of novel crystalline form state is 91.5～93.8 DEG C.With the fusing point (94 DEG C) of the crystal formation of the A of CN 103304476 reports
It is close to.
4th, infrared spectrum (FTIR) (accompanying drawing 6)：
Instrument：The type infrared spectrometers of Nicolet Impact 410 (Nicolet companies of the U.S.)
Infrared spectrum wave number (the cm of novel crystalline form state (KBr compressing tablets)-1) about：
3401,3180,2951,2483,1949,1706,1624,1514,1427,1401,1317,1232,1186,
1035,938,857,796,716,692,641,587,560,508,488,424.
Brufen-nicotinamide eutectic (accompanying drawing 2) and cloth that brufen disclosed in the present invention is combined to form with niacinamide
The PXRD (accompanying drawing 3) of ibuprofen bulk drug crystal formation, DSC (accompanying drawing 5), FTIR (accompanying drawing 7) collection of illustrative plates are different, therefore the crystal habit
It is a kind of crystal habit for being totally different from brufen bulk drug.The PXRD collection of illustrative plates of the eutectic and disclosed patent (accompanying drawing 1)
Unanimously, it is shown to be brufen-the nicotinamide eutectic of same crystal formation.
The simple process of the present invention, low cost, it is easy to control is conducive to industrialized production, using prepared by the method being total to
Brilliant high income (90～98%), good stability.
Description of the drawings
Fig. 1 is the x-ray diffractogram of powder spectrum for having reported brufen in patent-nicotinamide eutectic product.
Fig. 2 is the x-ray diffractogram of powder spectrum of brufen-nicotinamide eutectic product.
Fig. 3 is the x-ray diffractogram of powder spectrum of brufen bulk drug.
Fig. 4 is the differential scanning calorimetric thermogram spectrum of brufen-nicotinamide eutectic product.
Fig. 5 is the differential scanning calorimetric thermogram spectrum of brufen bulk drug.
Fig. 6 is brufen-nicotinamide eutectic product infrared spectrogram.
Fig. 7 is the infrared spectrogram of brufen bulk drug.
Fig. 8 is (accelerated test) stability setting-out powder X-ray under the conditions of brufen -40 DEG C/75%RH of nicotinamide eutectic product
X ray diffraction collection of illustrative plates (1. brufen-nicotinamide eutectic；2. brufen-nicotinamide eutectic accelerates January sample；3. brufen-nicotinoyl
Amine eutectic accelerates 2 months samples；4. brufen-nicotinamide eutectic accelerates March sample；5. brufen-nicotinamide eutectic accelerates 6 lunar samples
Product).
Fig. 9 is stripping curve contrast in brufen (■) and brufen-nicotinamide eutectic (△) water.
Specific embodiment
Embodiment 1：The preparation of brufen-nicotinamide eutectic
0.29g niacinamide and 0.50g brufens are added in 10ml absolute ethyl alcohols, 40 DEG C of stirred in water bath must clarify molten
Liquid.Resulting solution is placed in round-bottomed flask and volatilizes solvent in 50 DEG C of decompression rotary evaporations, collection obtains white needle-like crystals
0.73g, Jing PXRD (accompanying drawing 2), DSC (accompanying drawing 4), FTIR (accompanying drawing 6) are characterized and are defined as brufen-nicotinamide eutectic.Eutectic is produced
Rate is 92.4%, and fusing point is 92.5 DEG C, (accelerated test) setting-out 6 months under the conditions of 40 DEG C/75%RH, have good stability (plus
Speed 1,2,3, June eutectic sample P XRD spectrum is shown in accompanying drawing 8).
Embodiment 2：The preparation of brufen-nicotinamide eutectic
0.58g niacinamide and 1g brufens are added in the mixed solvent of 20ml absolute ethyl alcohols/methyl alcohol 1: 1,30 DEG C of water-baths
In stir to obtain settled solution.Resulting solution is placed in round-bottomed flask and volatilizes solvent in 30 DEG C of decompression rotary evaporations, collection is obtained
White needle-like crystals 1.47g, Jing PXRD, DSC and FTIR are characterized and are defined as brufen-nicotinamide eutectic.Eutectic yield is
93.1%, fusing point is 91.2 DEG C, and (accelerated test) setting-out 6 months, have good stability under the conditions of 40 DEG C/75%RH.
Embodiment 3：The preparation of brufen-nicotinamide eutectic
0.58g niacinamide and 1g brufens are added in 20ml ethyl acetate, clear transparent solutions are stirred at room temperature to obtain, shifted
To culture dish (φ：In 200mm), it is placed in fume hood and volatilizes naturally, collects and obtain white needle-like crystals 1.52g, Jing PXRD,
DSC and FTIR is characterized and is defined as brufen-nicotinamide eutectic.The product degree of crystallinity is high, and crystal size is big, any surface finish.Eutectic
Yield is 93.1%, and fusing point is 93.5 DEG C, and (accelerated test) setting-out 6 months, have good stability under the conditions of 40 DEG C/75%RH.
Embodiment 4：The preparation of brufen-nicotinamide eutectic
0.59g niacinamide and 0.99g brufens are added in 16ml acetone, clear is obtained in 10 DEG C of stirred in water bath molten
Liquid, is transferred to culture dish (φ：In 200mm), it is placed in fume hood and volatilizes (room temperature is 10 DEG C) naturally, collection obtains white needles
Crystal 1.54g, Jing PXRD, DSC and FTIR are characterized and are defined as brufen-nicotinamide eutectic.Eutectic yield is 97.5%, and fusing point is
93.8℃。
Embodiment 5：Eutectic solubility test
Brufen bulk drug is weighed respectively and brufen-nicotinamide eutectic (equivalent to brufen 20mg) puts 50ml deionizations
In water, magnetic stir bar stirring 24h, crosses 0.22 μm of filter membrane, using in high effective liquid chromatography for measuring solution at 25 DEG C/37 DEG C
The concentration of brufen.
The solubility of brufen bulk drug and brufen-nicotinamide eutectic in water, the results are shown in Table 1.
Brufen solubility in the water of table 1
*：P ＜ 0.05
With the independent crystal phase ratio of brufen, solubility of the brufen-nicotinamide eutectic in water is significantly increased.
Embodiment 5：Dissolution determination
Using ZRS-8G intelligence dissolving-out tester (Haiyida Science and Technology Co., Ltd., Tianjin), according to Chinese Pharmacopoeia, 2015 editions lead to
Then 0,931 second method (paddle method) determines the dissolution rate of brufen and the brufen-nicotinamide eutectic, brufen is weighed respectively former
Material medicine and brufen-nicotinamide eutectic (equivalent to brufen 15mg), in putting 900ml deionized waters, control water temperature for 37 DEG C, molten
Go out instrument rotating speed for 100 revs/min, sampled respectively at 5,10,15,20,40,60,90,120 minutes, filter and determined at 264nm
Absorbance, calculates dissolution rate.As a result accompanying drawing 9 is seen.
Brufen-nicotinamide eutectic is remarkably improved dissolution rate and degree of the brufen in water.
Embodiment 6：The brufen and niacinamide ratio measuring of crystal are separated out in solvent volatilization process
Precipitation eutectic is combined with equimolar with niacinamide to determine that solvent evaporation method prepares brufen during eutectic, rather than
Certain one pack system is first separated out, and is then separated out eutectic again and is affected eutectic purity, starts to separate out crystal until analysing completely in solvent volatilization
During going out, the crystal on our random acquisition chamber walls, using high effective liquid chromatography for measuring wherein brufen and nicotinoyl
Amine content, as a result shows that the mol ratio of brufen and niacinamide is 1: 1, explanation in solvent volatilizees the whole process for separating out crystal
Two components are to combine to form eutectic with equimolar ratio.
Claims (4)
1. a kind of preparation method of brufen-nicotinamide eutectic, it is characterised in that brufen and niacinamide are stirred together for into dissolving
After organic solvent, rotary evaporation or solvent being volatilized naturally, obtaining brufen-nicotinamide eutectic, the eutectic is by brufen
By hydrogen bond it is connected is formed at 1: 1 in molar ratio with niacinamide；Radiated using Cu-K α, the powder x-ray diffraction spectrum represented with 2 θ
Feature is as follows：
Compressing tablet determines the infrared absorption spectroscopy (cm for obtaining after mixing with KBr-1) about 3401,3180,2951,2483,1949,
1706,1624,1514,1427,1401,1317,1232,1186,1035,938,857,796,716,692,641,587,560,
There is absworption peak at 508,488 and 424；Solid-liquid transformation is on DSC collection of illustrative plates about 91.1 DEG C after its heat absorption.
2. the preparation method of brufen-nicotinamide eutectic as claimed in claim 1, it is characterised in that the organic solvent is
Ethanol, acetone, methyl alcohol, ethyl acetate, isopropanol and two or more mixed liquor, preferable organic solvent is absolute ethyl alcohol
And acetone, more preferably absolute ethyl alcohol.
3. the preparation method of brufen-nicotinamide eutectic as claimed in claim 1, it is characterised in that the dissolution of raw material temperature
Spend for 5～50 DEG C, preferably 10～30 DEG C.
4. the preparation method of brufen-nicotinamide eutectic as claimed in claim 1, it is characterised in that organic solvent volatilizes temperature
Spend for 10～65 DEG C, preferably 20～40 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610894814.3A CN106632024A (en) | 2016-10-11 | 2016-10-11 | Preparation method of ibuprofen-nicotinamide eutectic through solvent |
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| CN201610894814.3A CN106632024A (en) | 2016-10-11 | 2016-10-11 | Preparation method of ibuprofen-nicotinamide eutectic through solvent |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114031515A (en) * | 2021-11-29 | 2022-02-11 | 河北大学 | Paracetamol-ibuprofen pharmaceutical co-crystal and preparation method thereof |
| CN114409560A (en) * | 2022-01-26 | 2022-04-29 | 东南大学 | Actalli pharmaceutical co-crystal and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304476A (en) * | 2013-06-13 | 2013-09-18 | 天津大学 | Preparation method of ibuprofen-nicotinamide eutectic crystals |
-
2016
- 2016-10-11 CN CN201610894814.3A patent/CN106632024A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304476A (en) * | 2013-06-13 | 2013-09-18 | 天津大学 | Preparation method of ibuprofen-nicotinamide eutectic crystals |
Non-Patent Citations (4)
| Title |
|---|
| DAVID J.BERRY ET AL.: "Applying Hot-Stage Microscopy to Co-Crystal Screening: A Study of Nicotinamide with Seven Active Pharmaceutical Ingredients", 《CRYSTAL GROWTH & DESIGN》 * |
| FREDERICO L.F.SOARES ET AL.: "Green Synthesis of Ibuprofen−Nicotinamide Cocrystals and In-Line Evaluation by Raman Spectroscopy", 《CRYSTAL GROWTH & DESIGN》 * |
| KATRIN C. MÜLLERS ET AL.: "Simultaneous Formation and Micronization of Pharmaceutical Cocrystals by Rapid Expansion of Supercritical Solutions (RESS)", 《PHARMACEUTICAL RESEARCH》 * |
| SHING FUNG CHOW ET AL.: "Simultaneously Improving the Mechanical Properties,Dissolution Performance，and Hygroscopicity of Ibuprofen and Flurbiprofen by Cocrystallization with Nicotinamide", 《PHARMACEUTICAL RESEARCH》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114031515A (en) * | 2021-11-29 | 2022-02-11 | 河北大学 | Paracetamol-ibuprofen pharmaceutical co-crystal and preparation method thereof |
| CN114031515B (en) * | 2021-11-29 | 2022-10-21 | 河北大学 | Acetaminophen-ibuprofen pharmaceutical co-crystal and preparation method thereof |
| CN114409560A (en) * | 2022-01-26 | 2022-04-29 | 东南大学 | Actalli pharmaceutical co-crystal and preparation method thereof |
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