CN107286035A - A kind of 5 aminosalicylic acid pharmaceutical co-crystals and preparation method thereof - Google Patents
A kind of 5 aminosalicylic acid pharmaceutical co-crystals and preparation method thereof Download PDFInfo
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- CN107286035A CN107286035A CN201710355551.3A CN201710355551A CN107286035A CN 107286035 A CN107286035 A CN 107286035A CN 201710355551 A CN201710355551 A CN 201710355551A CN 107286035 A CN107286035 A CN 107286035A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/145—Maleic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
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- 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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- 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
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Abstract
The invention discloses a kind of 5 aminosalicylic acid pharmaceutical co-crystals and preparation method thereof, it is characterized in that, by 5 aminosalicylic acids and maleic acid, 2,6 dihydroxy-benzoic acids or 4 aminopyridines press 1:0.5 ~ 8 weight is than mixing, then it is complete to dissolving in methanol/acetone in the mixed solvent ultrasound, then 3 ~ 10 days are stood, the pale yellow transparent crystal of precipitation is 5 aminosalicylic acids and maleic acid, 2,6 dihydroxy-benzoic acids or 4 aminopyridine pharmaceutical co-crystals, the w/v of 5 aminosalicylic acid and maleic acid, 2,6 dihydroxy-benzoic acids or 4 aminopyridines and methanol/acetone mixed solvent is：1 mg:0.5~8 mg:2~5mL.The present invention is simply controllable with preparation method compared with prior art, and synthesis cycle is short, reproducible, not only remains outside the medicine speciality of nicotinic acid, and dissolubility is significantly improved, and extends the market cycle of original medicine, has broad application prospects.
Description
Technical field
The present invention relates to technical field of pharmaceutical co-crystal, specifically a kind of 5-aminosalicylic acid and maleic acid, 5- amino
Salicylic acid and 2,6- dihydroxy-benzoic acids or 5-aminosalicylic acid and 4-aminopyridine pharmaceutical co-crystals and preparation method thereof.
Background technology
Crystal engineering is in crystal, for designing according to the principle of supramolecular chemistry, method and control intermolecular interaction
With produce peculiar novel, of all shapes and colors, with specific physical property and chemical property crystal.These crystal are typically multidimensional
, the supramolecular aggregation spatially infinitely stretched, macromolecular architecture unit determines crystalline material in the ordered state of solid-state
Physics and chemical property.Thus, by selecting suitable macromolecular architecture primitive, these intermolecular phase interactions taken are grasped
With the information of (such as coordinate bond, hydrogen bond), the function between molecular components is obtained many-sided cooperation, optimize intermolecular varying strength
, orientation various interactions, it is possible to the material with particular configuration and physicochemical properties is obtained, so as to realize mesh
Mark controlledly synthesis.
At present, pharmaceutical co-crystals are in modification active constituents of medicine (active phaimaceutical ingredient, API)
Application in terms of physicochemical property receives much concern in recent years.Pharmaceutical activity molecule (API) generally has because containing various functional groups
Different bioactivity, these functional groups can be passed through using hydrogen bond or other non-covalent bond effects with other organic molecules
Intermolecular recognition reaction generation super molecular compound, i.e. pharmaceutical co-crystals, and the organic molecule being introduced into, are referred to as eutectic examination
Agent.The introducing of eutectic reagent, can improve crystal property, physico-chemical property and the drug effect of medicine in itself, be medical solid reagent
One new selection.Under normal temperature, active constituents of medicine (API) with many kinds of solids form exist, such as polycrystalline, solvate, hydrate,
Eutectic, amorphous and salt etc..The curative effect of one medicine is heavily dependent on API itself physicochemical property and its selection
Formulation, and solid forms different API have an impact to the solubility of medicine, stability, dissolution rate and bioavilability etc..
The research of API solid forms turns into an importance in new drug development, can be carried for the determination of optimal drug solid forms
Selective foundation.Each component can be neutral molecule in pharmaceutical co-crystals, thus pharmaceutical co-crystals can cover all API, including acid,
Alkali and non-ionized molecules, and the molecule that can be used to coordinate API to form eutectic is a lot, these materials potentially include food addition
Agent, preservative, pharmaceutic adjuvant, vitamin, mineral matter, amino acid and other bioactive molecules, or even others API, it is therefore, right
In given medicine, hundreds of pharmaceutical co-crystals can be generated, extend the market cycle of original medicine, with wide application
Prospect.
5-aminosalicylic acid is a kind of for treating antimicrobial lungy, also be used to treat IBD, passes through
Suppress NF- κ B and remove free radical and play a role, be mainly used in treating tuberculosis.5-aminosalicylic acid is important doctor simultaneously
Medicine and dye chemical industry raw material, are also a kind of primary raw material for treating chronic colitis medicine SASP, itself also has
Similar therapeutic action, clinically with various preparations of the 5-aminosalicylic acid (5-AS A) for main component.Maleic acid is also known as suitable
Butene dioic acid, it is mainly for the manufacture of unsaturated polyester resin and production tartaric acid, fumaric acid, butanedioic acid, DL-malic acid, dye
The compound such as color auxiliary agent and grease preservative, also has to compare and is widely applied in terms of medicine, agricultural chemicals, food.Maleic acid
Turn into the new acid in food_beverage industry.Appropriate maleic acid is added in food, beverage can strengthen special fruit flavor simultaneously
Improve mouthfeel.Current maleic acid be mainly used in fruit juice, drink tea, orange juice, sports drink and other various reinforcing fruit-flavored beverages
With food.2,6- dihydroxy-benzoic acids and 4-aminopyridine are the important intermediates in agricultural chemicals and medicine.
The pharmaceutical co-crystals of prior art, operation influence factor is more, and the requirement for cost and technology is all higher, and product
Easily by solvent effect, the crystal for obtaining high-purity is less susceptible to.
The content of the invention
The purpose of the present invention be in view of the shortcomings of the prior art and provide a kind of 5-aminosalicylic acid pharmaceutical co-crystals and its
Preparation method, is volatilized using the room temperature of methanol and acetone mixed solvent, by 5-aminosalicylic acid and maleic acid, 2,6- dihydroxy benzenes
Formic acid or 4-aminopyridine obtain 5-aminosalicylic acid and maleic acid, 2,6- of anorthic system P1 space groups by Hydrogenbond
Dihydroxy-benzoic acid or 4-aminopyridine pharmaceutical co-crystals, the solvent boiling point for synthesizing selection are relatively low, and preparation method is easy, not only retains
Outside the medicine speciality of 5-aminosalicylic acid, and dissolubility is significantly improved.
Realizing the concrete technical scheme of the object of the invention is：A kind of 5-aminosalicylic acid pharmaceutical co-crystals, are characterized in 5-
Aminosalicylic acid is as active constituents of medicine, and maleic acid, 2,6-DHBA or 4-aminopyridine are reactant, by medicine
Active component and the in the mixed solvent after reactant grinding in methanol and acetone, using solvent room temperature volatility process, make 5- amino water
Poplar acid, by Hydrogenbond, constitutes 5-aminosalicylic acid and Malaysia with maleic acid, 2,6-DHBA or 4-aminopyridine
The pharmaceutical co-crystals primitive of acid, 2,6-DHBA or 4-aminopyridine, the 5-aminosalicylic acid is total to maleic acid medicine
Crystalline substance is anorthic systemSpace group, its axial length is：A=3.7631~4.1631；B=12.4817~12.8817；C=
13.3246~13.7246；α=117.589~117.989 °；β=94.331~94.731 °；γ=94.041~94.441 °；
The 5-aminosalicylic acid is anorthic system with 2,6- dihydroxy-benzoic acids pharmaceutical co-crystalsSpace group, its axial length is：A=
6.9968~7.3968；B=13.8961~14.2961；C=15.1637~15.5637；α=98.422~98.822 °；β=
101.553~101.953 °；γ=99.790~100.190 °；The pharmaceutical co-crystals of the 5-aminosalicylic acid and 4-aminopyridine
For anorthic systemSpace group, its axial length is：A=8.671~9.671；B=10.330~10.730；C=24.681~
25.081；α=90 °；β=89.819~90.219 °；γ=90 °.
The 5-aminosalicylic acid is with the N (N1) and O in 5-aminosalicylic acid molecule by Hydrogenbond with maleic acid
(O2) atom as hydrogen bond donor, O (O4), O (O5), O (O6) and O (O7) atoms in the acid molecule of Malaysia as hydrogen bond by
Body, five intermolecular hydrogen bondings formed are：[N1-H1A ... O6 (- x ,-y+1 ,-z+1),D-H ... A=125.59 °；N1-H1A ... O7 (- x+1 ,-y+1 ,-z+1),D-H ... A=128.53 °；N1-H1B ... O4 (x+1, y-1, z-1),D-H ... A=167.07 °；N1-H1B ... O5 (x+1, y-1, z-1),D-H ... A=134.57 °；O2-H2B ... O7,D-H ... A=165.65 °].
The 5-aminosalicylic acid is with 5-aminosalicylic acid molecule by Hydrogenbond with 2,6- dihydroxy-benzoic acids
O (O2), O (O5), N (N1) and N (N2) atoms as the donor of hydrogen bond, O (O7), O in 2,6-DHBA molecule
(O8), O (O3W) atoms in O (O10) atoms and hydrone are as the acceptor of hydrogen bond, five intermolecular hydrogen bondings formed
For：[O2-H2B ... O3W,D-H ... A=177.51 °；N1-H1A ... O7,D-H ... A=144.80 °；N1-H1B ... O8 (- x+1 ,-y+1 ,-z),D-H ... A=145.25 °；O5-H5B ... O10,D-H ... A=169.20 °；N2-H2C ... O3W (x, y-1, z-1),D-H ... A=131.31 °].
The 5- aminobenzoic acids are with N (N3), the N in 5- aminobenzoic acids by Hydrogenbond with 4-aminopyridine
(N6) N (N1) in atom and 4-aminopyridine, N (N4) atoms are as hydrogen-bond donor, O (O2), O in 5- aminobenzoic acids
(O4), N (N1) atoms in O (O5), N (N3) atom and 4-aminopyridine are as hydrogen bond receptor, and seven formed are intermolecular
Hydrogen bond is：[N1-H1B ... O2 (- x ,-y+1 ,-z),D-H ... A=
171.70°；N1-H1C ... N3 (- x ,-y+3/2, z+1/2),D-H ... A=
166.72°；N3-H3B ... O4 (- x ,-y+1 ,-z),D-H ... A=
142.76°；N3-H3B ... N3 (- x ,-y+3/2, z-1/2),D-H ... A=
110.15°；N4-H4B ... O2,H ... A=2.076, D-H ... A=173.04 °；N4-H3C ... O5 (x ,-y
+ 1/2, z-1/2),D-H ... A=155.02 °；N6-H6A ... O2 (- x+1 ,-
Y+1 ,-z),D-H ... A=135.95 °].
A kind of preparation method of 5-aminosalicylic acid pharmaceutical co-crystals, is characterized in 5-aminosalicylic acid and maleic acid, 2,
6- dihydroxy-benzoic acids or 4-aminopyridine mixing, add methanol trituration to solvent after grinding is uniform and volatilize, then in methanol/the third
Ketone in the mixed solvent ultrasound is complete to dissolving, and stands 3~10 days, the block pale yellow transparent crystal of precipitation, is 5- aminosalicyclics
Acid and maleic acid, 5-aminosalicylic acid and 2,6-DHBA or 5-aminosalicylic acid and 4-aminopyridine pharmaceutical co-crystals,
The 5-aminosalicylic acid and maleic acid, 2,6- dihydroxy-benzoic acids or 4-aminopyridine, methanol and methanol/acetone mixed solvent
W/v be：1mg:0.5~8mg:5~30 μ L:2~5mL；The methanol/acetone in the mixed solvent methanol and acetone
Volume ratio be：0.5~2:1.
The present invention is simple, controllable with preparation method compared with prior art, and synthesis cycle is short, reproducible, synthesis
5-aminosalicylic acid pharmaceutical co-crystals, are remained outside the medicine speciality of 5-aminosalicylic acid, dissolubility is significantly improved, and are extended original
The market cycle of medicine, has broad application prospects.
Brief description of the drawings
Fig. 1 is 5-aminosalicylic acid and maleic acid pharmaceutical co-crystals construction unit schematic diagram：
Fig. 2 is the XRD spectrum of 5-aminosalicylic acid and maleic acid pharmaceutical co-crystals；
Fig. 3 is 5-aminosalicylic acid and maleic acid pharmaceutical co-crystals thermogravimetric collection of illustrative plates；
Fig. 4 is 5-aminosalicylic acid and the solubility curve figure of maleic acid pharmaceutical co-crystals in aqueous；
Fig. 5 is 5-aminosalicylic acid and solubility curve figure of the maleic acid pharmaceutical co-crystals in ethanol solution；
Fig. 6 is 5-aminosalicylic acid and 2,6 dihydroxy-benzoic acid pharmaceutical co-crystals construction unit schematic diagrames：
Fig. 7 is the XRD spectrum of 5-aminosalicylic acid and 2,6 dihydroxy-benzoic acid pharmaceutical co-crystals；
Fig. 8 is 5-aminosalicylic acid and 2,6 dihydroxy-benzoic acid pharmaceutical co-crystals thermogravimetric collection of illustrative plates；
Fig. 9 is the solubility curve figure of 5-aminosalicylic acid and 2,6 dihydroxy-benzoic acid pharmaceutical co-crystals in aqueous；
Figure 10 is the solubility curve figure of 5-aminosalicylic acid and 2,6 dihydroxy-benzoic acid pharmaceutical co-crystals in ethanol solution；
Figure 11 is 5-aminosalicylic acid and 4-aminopyridine pharmaceutical co-crystals construction unit schematic diagram：
Figure 12 is the XRD spectrum of 5-aminosalicylic acid and 4-aminopyridine pharmaceutical co-crystals；
Figure 13 is 5-aminosalicylic acid and 4-aminopyridine pharmaceutical co-crystals thermogravimetric collection of illustrative plates；
Figure 14 is 5-aminosalicylic acid and the solubility curve figure of 4-aminopyridine pharmaceutical co-crystals in aqueous；
Figure 15 is 5-aminosalicylic acid and solubility curve figure of the 4-aminopyridine pharmaceutical co-crystals in ethanol solution；
Embodiment
The present invention is with 5-aminosalicylic acid (C7H7O3N) it is pharmaceutical activity molecule, maleic acid (C4H4O4) it is reactant, its 5-
The synthesis of aminosalicylic acid and maleic acid pharmaceutical co-crystals is carried out by following structural response formula：
The present invention is with 5-aminosalicylic acid (C7H7O3N) it is pharmaceutical activity molecule, 2,6-DHBA (C7H6O4) be
Reactant, the synthesis of its 5-aminosalicylic acid and 2,6-DHBA pharmaceutical co-crystals is carried out by following structural response formula：
The present invention is with 5-aminosalicylic acid (C7H7O3N) it is pharmaceutical activity molecule, 4-aminopyridine (C5H6N2) it is reactant,
The synthesis of its 5-aminosalicylic acid and 4-aminopyridine pharmaceutical co-crystals is carried out by following structural response formula：
Below by way of specific embodiment, the present invention is described in further detail.
Embodiment 1
Weigh 30mg 5-aminosalicylic acids to be placed in agate mortar with 68.1mg maleic acids, 20 μ L are added after grinding is uniform
Methanol, is ground to rapidly solvent and volatilizes, then move to mixture in teat glass, adds the mixing of 2mL acetone and 2mL methanol
Solvent, ultrasound extremely dissolves complete, seals test tube mouthful and pricks aperture and stand and volatilize 6 days, test tube bottom starts to separate out crystal, obtains light
Yellow transparent bulk crystals 46mg is 5-aminosalicylic acid and maleic acid pharmaceutical co-crystals, and its yield is 89%.
Embodiment 2
Weigh 30mg 5-aminosalicylic acids to be placed in agate mortar with 30.2mg 2,6-DHBAs, grinding is uniform
After add 20 μ L methanol, solvent is ground to rapidly and is volatilized, then moves to mixture in teat glass, 2mL acetone and 2mL is added
The mixed solvent of methanol, ultrasound extremely dissolves complete, seals test tube mouthful and pricks aperture and stand and volatilize 3 days, test tube bottom starts to separate out
Crystal, it is 5-aminosalicylic acid and 2,6-DHBA pharmaceutical co-crystals to obtain pale yellow transparent bulk crystals 50mg, and it is produced
Rate is 83%.
Embodiment 3
Weigh 30mg 5-aminosalicylic acids to be placed in agate mortar with 18.4mg 4-aminopyridines, added after grinding is uniform
20 μ L methanol, are ground to rapidly solvent and volatilize, then move to mixture in teat glass, add 2mL acetone and 2mL methanol
Mixed solvent, ultrasound extremely dissolves complete, seals test tube mouthful and pricks aperture and stand and volatilize 5 days, test tube bottom starts to separate out crystal, obtains
It is 5-aminosalicylic acid and 4-aminopyridine pharmaceutical co-crystals to pale yellow transparent bulk crystals 27mg, its yield is 56%.
Pharmaceutical co-crystals prepared by the various embodiments described above carry out the detection of eutectic structure and its performance using following instruments to it：
(1), eutectic structure is determined by X-ray single crystal diffractometer, and full name is Bruker SMART Apex II
Diffractometer, Mo-K α
(2), PXRD diffraction is determined by powder diffractometer, model Rigaku (D/Max-Ultima IV)
diffractometer,Cu-KαTube voltage 35KV, tube current 5mA, 10 °/min of sweep speed；
(3), thermogravimetric curve is tested by TG-DSC analyzers, under model is Netzsch STA449F3, nitrogen atmosphere,
10 DEG C/min of heating rate.
Refering to accompanying drawing 1,5-aminosalicylic acid prepared by embodiment 1 with maleic acid pharmaceutical co-crystals after testing, its eutectic molecule
In 5-aminosalicylic acid molecule and Malaysia acid molecule by Hydrogenbond, constitute the substantially single of 5-aminosalicylic acid pharmaceutical co-crystals
Member.Wherein, in 5-aminosalicylic acid molecule N (N1), O (O2) atoms are as the donor of hydrogen bond, the O in the acid molecule of Malaysia
(O4), O (O5), O (O6), O (O7) atoms are as the acceptor of hydrogen bond, and five intermolecular hydrogen bondings formed are：[N1-H1A…O6
(- x ,-y+1 ,-z+1), D-H ... A=125.59 °；N1-H1A…O7(-x
+ 1 ,-y+1 ,-z+1),D-H ... A=128.53 °；N1-H1B…O4(x+
1, y-1, z-1),D-H ... A=167.07 °；N1-H1B ... O5 (x+1, y-
1, z-1),D-H ... A=134.57 °；O2-H2B ... O7,D-H ... A=165.65 °].
The pharmaceutical co-crystals of the 5-aminosalicylic acid and maleic acid are anorthic systemSpace group, its axial length is：A=
3.7631~4.1631；B=12.4817~12.8817；C=13.3246~13.7246；α=117.589~117.989 °；β
=94.331~94.731 °；γ=94.041~94.441 °.
Refering to accompanying drawing 2, as can be seen that 5-aminosalicylic acid and maleic acid prepared by embodiment 1 from X-ray diffraction peak
The characteristic peaks of pharmaceutical co-crystals are appeared in：7.76°、13.82°、14.68°、15.74°、16.48°、17.4°、20.28°、
21.18°、22.32°、23.92°、24.8°、27.02°、27.96°、31.24°、32.92°、33.08°、33.2。、38.2°、
38.96 ° and 40.02 °.
Refering to accompanying drawing 3,5-aminosalicylic acid prepared by embodiment 1 is with maleic acid pharmaceutical co-crystals in nitrogen atmosphere test condition
Under, its thermogravimetric curve starts to decompose at 141~226 DEG C, altogether weightlessness 57%.
The 5-aminosalicylic acid prepared to embodiment 1 carries out following solubility test with maleic acid pharmaceutical co-crystals：
(1) 52.7mg 5-aminosalicylic acids, are weighed and maleic acid pharmaceutical co-crystals (obtain 5- ammonia in eutectic by mono-crystalline structures
The metering of base salicylic acid and maleic acid is compared for 1：The quality of 5-aminosalicylic acid is 30mg in 1, therefore 52.7mg eutectics, has been ensured
The amount of 5-aminosalicylic acid is identical with blank group) be dissolved separately in as experimental group in 4mL water and 4mL ethanol, with eutectic is molten
Liquid.
(2), weigh 5-aminosalicylic acid 30mg to be dissolved separately in 4mL water and 4mL ethanol, 5-aminosalicylic acid solution is made
Compared for blank solution.
(3) the eutectic aqueous solution, is determined respectively with ultraviolet specrophotometer, eutectic ethanol solution, 5-aminosalicylic acid is water-soluble
Liquid, the absorbing state of 5-aminosalicylic acid ethanol solution is contrasted by the maximum absorption band with blank solvent, and observation medicine is formed
The situation of change of its solubility after pharmaceutical co-crystals.
Refering to accompanying drawing 4, a curves are the ultraviolet absorption curve of pharmaceutical co-crystals in figure, and b curves are the UV absorption of blank solution
Curve, from experimental result as can be seen that the solubility of pharmaceutical co-crystals in aqueous is significantly increased compared to blank solution.
Refering to accompanying drawing 5, a curves are the ultraviolet absorption curve of pharmaceutical co-crystals in figure, and b curves are the UV absorption of blank solution
Curve, from experimental result as can be seen that solubility of the pharmaceutical co-crystals in ethanol solution is significantly increased compared to blank solution.
Refering to accompanying drawing 6,5-aminosalicylic acid prepared by embodiment 2 with 2,6-DHBA pharmaceutical co-crystals after testing,
5-aminosalicylic acid molecule in its eutectic molecule passes through Hydrogenbond, structure with 2,6-DHBA molecule and hydrone
Into the elementary cell of 5-aminosalicylic acid pharmaceutical co-crystals.Wherein, in 5-aminosalicylic acid molecule O (O2), O (O5), N (N1), N
(N2) atom is used as the donor of hydrogen bond, O (O7), O (O8), O (O10) atoms in 2,6-DHBA molecule and free
O (O3W) atoms in hydrone are as the acceptor of hydrogen bond, and five intermolecular hydrogen bondings formed are：[O2-H2B ... O3W, D-H ... A=177.51 °；N1-H1A ... O7,D-H ... A=144.80 °；N1-H1B ... O8 (- x+1 ,-y+1 ,-z), D-H ... A=145.25 °；O5-H5B ... O10,D-H ... A=169.20 °；N2-H2C ... O3W (x, y-1, z-1),D-H ... A=131.31 °].
The 5-aminosalicylic acid is anorthic system with 2,6- dihydroxy-benzoic acids pharmaceutical co-crystalsSpace group, its axial length
For：A=6.9968~7.3968, b=13.8961~14.2961, c=15.1637~15.5637, α=98.422~
98.822 °, β=101.553~101.953 °, γ=99.790~100.190 °.
Refering to accompanying drawing 7, as can be seen that 5-aminosalicylic acid and 2,6- bis- prepared by embodiment 2 from X-ray diffraction peak
The characteristic peaks of hydroxybenzoic acid pharmaceutical co-crystals are appeared in：11.84°、12.4°、14.6°、15.24°、19.32°、20.7°、
22.04 °, 23.5 °, 23.82 °, 24.9 °, 26.04 °, 27.12 °, 27.72 ° and 34.54 °.
Refering to accompanying drawing 8,5-aminosalicylic acid prepared by embodiment 2 is with 2,6-DHBA pharmaceutical co-crystals in blanket of nitrogen
Enclose under test condition, its thermogravimetric curve starts to decompose at 163~218 DEG C, altogether weightlessness 37%.
The 5-aminosalicylic acid prepared to embodiment 2 carries out following solubility survey with 2,6- dihydroxy-benzoic acids pharmaceutical co-crystals
Examination：
(1) 60.2mg 5-aminosalicylic acids, are weighed and 2,6 dihydroxy-benzoic acid pharmaceutical co-crystals (are total to by mono-crystalline structures
The metering of 5-aminosalicylic acid and 2,6- dihydroxy-benzoic acids is compared for 1 in crystalline substance：5-aminosalicylic acid in 1, therefore 60.2mg eutectics
Quality be 30mg, ensured that the amount of 5-aminosalicylic acid is identical with blank group) as experimental group be dissolved separately in 4mL water and
In 4mL ethanol, with eutectic solution.
(2), weigh 5-aminosalicylic acid 30mg to be dissolved separately in 4mL water and 4mL ethanol, 5-aminosalicylic acid solution is made
Compared for blank solution.
(3) the eutectic aqueous solution, is determined respectively with ultraviolet specrophotometer, eutectic ethanol solution, 5-aminosalicylic acid is water-soluble
Liquid, the absorbing state of 5-aminosalicylic acid ethanol solution is contrasted by the maximum absorption band with blank solvent, and observation medicine is formed
The situation of change of its solubility after pharmaceutical co-crystals.
Refering to accompanying drawing 9, a curves are the ultraviolet absorption curve of pharmaceutical co-crystals in figure, and b curves are the UV absorption of blank solution
Curve, from experimental result as can be seen that the solubility of pharmaceutical co-crystals in aqueous is significantly increased compared to blank solution.
Refering to accompanying drawing 10, a curves are the ultraviolet absorption curve of pharmaceutical co-crystals in figure, and b curves are the ultraviolet suction of blank solution
Curve is received, from experimental result as can be seen that solubility of the pharmaceutical co-crystals in ethanol solution is significantly increased compared to blank solution.
Refering to accompanying drawing 11,5-aminosalicylic acid prepared by embodiment 3 with 4-aminopyridine pharmaceutical co-crystals after testing, its eutectic
5-aminosalicylic acid molecule in molecule, by Hydrogenbond, constitutes 5-aminosalicylic acid pharmaceutical co-crystals with 4-aminopyridine molecule
Elementary cell.N (N3) wherein in 5- aminobenzoic acids, the N (N1) in N (N6) atom and 4-aminopyridine, N (N4) atom
As hydrogen-bond donor, the N (N1) in O (O2), O (O4), O (O5), N (N3) atom and 4-aminopyridine in 5- aminobenzoic acids
Atom is as hydrogen bond receptor, and seven intermolecular hydrogen bondings formed are：[N1-H1B ... O2 (- x ,-y+1 ,-z), D-H ... A=171.70 °；N1-H1C ... N3 (- x ,-y+3/2, z+1/2), D-H ... A=166.72 °；N3-H3B ... O4 (- x ,-y+1 ,-z), D-H ... A=142.76 °；N3-H3B ... N3 (- x ,-y+3/2, z-1/2), D-H ... A=110.15 °；N4-H4B ... O2,H…A
A=173.04 ° of=2.076, D-H ...；N4-H3C ... O5 (x ,-y+1/2, z-1/2), D-H ... A=155.02 °；N6-H6A ... O2 (- x+1 ,-y+1 ,-z), D-H ... A=135.95 °].
The 5-aminosalicylic acid is anorthic system with 4-aminopyridine pharmaceutical co-crystalsSpace group, its axial length is：A=
8.671~9.671, b=10.330~10.730, c=24.681~25.081, α=90 °, β=89.819~90.219 °, γ
=90 °.
Refering to accompanying drawing 12, as can be seen that 5-aminosalicylic acid and 4- amino prepared by embodiment 3 from X-ray diffraction peak
The characteristic peaks of pyridine pharmaceutical co-crystals are appeared in：7.86°、15.92°、17.5°、20.3°、21.28°、22.48°、24.02°、
24.9 °, 27.12 °, 28.06 ° and 32.34 °.
Refering to accompanying drawing 13,5-aminosalicylic acid prepared by embodiment 3 is surveyed with 4-aminopyridine pharmaceutical co-crystals in nitrogen atmosphere
Under the conditions of examination, its thermogravimetric curve starts to decompose at 216~275 DEG C, altogether weightlessness 89%.
The 5-aminosalicylic acid prepared to embodiment 3 carries out following solubility test with 4-aminopyridine pharmaceutical co-crystals：
(1) 48.4mg 5-aminosalicylic acids, are weighed and 4-aminopyridine pharmaceutical co-crystals (are obtained in eutectic by mono-crystalline structures
The metering of 5-aminosalicylic acid and 4-aminopyridine is compared is for the quality of 5-aminosalicylic acid in 1: 1, therefore 48.4mg eutectics
30mg, has ensured that the amount of 5-aminosalicylic acid is identical with blank group) it is dissolved separately in as experimental group in 4mL water and 4mL ethanol,
With eutectic solution.
(2), weigh 5-aminosalicylic acid 30mg to be dissolved separately in 4mL water and 4mL ethanol, 5-aminosalicylic acid solution is made
Compared for blank solution.
(3) the eutectic aqueous solution, is tested respectively with ultraviolet specrophotometer, eutectic ethanol solution, 5-aminosalicylic acid is water-soluble
Liquid, the absorbing state of 5-aminosalicylic acid ethanol solution obtains pharmaceutical co-crystals molten for medicine by the contrast with blank solvent
Xie Du change situation.
Refering to accompanying drawing 14, a curves are the ultraviolet absorption curve of pharmaceutical co-crystals in figure, and b curves are the ultraviolet suction of blank solution
Curve is received, from experimental result as can be seen that the solubility of pharmaceutical co-crystals in aqueous is significantly increased compared to blank solution.
Refering to accompanying drawing 15, a curves are the ultraviolet absorption curve of pharmaceutical co-crystals in figure, and b curves are the ultraviolet suction of blank solution
Curve is received, from experimental result as can be seen that solubility of the pharmaceutical co-crystals in ethanol solution is significantly increased compared to blank solution.
Pharmaceutical co-crystals prepared by the present invention not only have outside 5-aminosalicylic acid medicine speciality, and dissolubility has and substantially carried
Height, extends the market cycle of original medicine.Various embodiments above is that the present invention will be further described, and is not used to limitation originally
Patent of invention, all is within equivalence enforcement of the present invention, the right for being intended to be limited solely by patent of the present invention.
Claims (5)
1. a kind of 5-aminosalicylic acid pharmaceutical co-crystals, it is characterised in that using 5-aminosalicylic acid as active constituents of medicine, Malaysia
Acid, 2,6-DHBA or 4-aminopyridine are reactant, by after active constituents of medicine and reactant grinding in methanol and
The in the mixed solvent of acetone, using solvent room temperature volatility process, make 5-aminosalicylic acid and maleic acid, 2,6-DHBA or
4-aminopyridine constitutes 5-aminosalicylic acid and maleic acid, 2,6-DHBA or 4-aminopyridine by Hydrogenbond
Pharmaceutical co-crystals primitive, the 5-aminosalicylic acid and maleic acid pharmaceutical co-crystals are anorthic systemSpace group, its axial length is：a
=3.7631~4.1631；B=12.4817~12.8817；C=13.3246~13.7246；α=117.589~
117.989°；β=94.331~94.731 °；γ=94.041~94.441 °；The 5-aminosalicylic acid and 2,6- dihydroxy
Benzoic acid pharmaceutical co-crystals are anorthic systemSpace group, its axial length is：A=6.9968~7.3968；B=13.8961~
14.2961；C=15.1637~15.5637；α=98.422~98.822 °；β=101.553~101.953 °；γ=
99.790~100.190 °；The pharmaceutical co-crystals of the 5-aminosalicylic acid and 4-aminopyridine are anorthic systemSpace group, its
Axial length is：A=8.671~9.671；B=10.330~10.730；C=24.681~25.081；α=90 °；β=89.819~
90.219°；γ=90 °.
2. 5-aminosalicylic acid pharmaceutical co-crystals according to claim 1, it is characterised in that the 5-aminosalicylic acid with
Maleic acid is to be used as the donor of hydrogen bond, Malaysia using the N (N1) and O (O2) atoms in 5-aminosalicylic acid molecule by Hydrogenbond
O (O4), O (O5), O (O6) and O (O7) atoms in acid molecule is as the acceptor of hydrogen bond, five intermolecular hydrogen bondings formed
For：[N1-H1A ... O6 (- x ,-y+1 ,-z+1),D-H ... A=
125.59°；N1-H1A ... O7 (- x+1 ,-y+1 ,-z+1),D-H ... A=
128.53°；N1-H1B ... O4 (x+1, y-1, z-1),D-H ... A=
167.07°；N1-H1B ... O5 (x+1, y-1, z-1),D-H ... A=
134.57°；O2-H2B ... O7,D-H ... A=165.65 °].
3. 5-aminosalicylic acid pharmaceutical co-crystals according to claim 1, it is characterised in that the 5-aminosalicylic acid with
2,6- dihydroxy-benzoic acids are with the O (O2) in 5-aminosalicylic acid molecule, O (O5), N (N1) and N (N2) by Hydrogenbond
Atom as hydrogen bond donor, in O (O7), O (O8), O (O10) atoms and the hydrone in 2,6-DHBA molecule
O (O3W) atoms as the acceptor of hydrogen bond, five intermolecular hydrogen bondings formed are：[O2-H2B ... O3W,D-H ... A=177.51 °；N1-H1A ... O7,D-H ... A=144.80 °；N1-H1B ... O8 (- x+1 ,-y+1 ,-z),D-H ... A=145.25 °；O5-H5B ... O10,D-H ... A=169.20 °；N2-H2C ... O3W (x, y-1, z-1),D-H ... A=131.31 °].
4. 5- aminobenzoic acids pharmaceutical co-crystals according to claim 1, it is characterised in that the 5- aminobenzoic acids with
4-aminopyridine is with the N in the N (N3) in 5- aminobenzoic acids, N (N6) atom and 4-aminopyridine by Hydrogenbond
(N1), N (N4) atoms are as hydrogen-bond donor, O (O2), O (O4), O (O5), N (N3) atoms and 4- ammonia in 5- aminobenzoic acids
N (N1) atoms in yl pyridines are as hydrogen bond receptor, and seven intermolecular hydrogen bondings formed are：[N1-H1B ... O2 (- x ,-y+
1 ,-z), D-H ... A=171.70 °；N1-H1C ... N3 (- x ,-y+3/2, z+
1/2), D-H ... A=166.72 °；N3-H3B ... O4 (- x ,-y+1 ,-z), D-H ... A=142.76 °；N3-H3B ... N3 (- x ,-y+3/2, z-1/2), D-H ... A=110.15 °；N4-H4B ... O2,
H ... A=2.076, D-H ... A=173.04 °；N4-H3C ... O5 (x ,-y+1/2, z-1/2), D-H ... A=155.02 °；N6-H6A ... O2 (- x+1 ,-y+1 ,-z), D-H ... A=135.95 °].
5. the preparation method of 5-aminosalicylic acid pharmaceutical co-crystals described in a kind of claim 1, it is characterised in that by 5- aminosalicyclics
Acid is mixed with maleic acid, 2,6-DHBA or 4-aminopyridine, and adding methanol trituration to solvent after grinding is uniform volatilizes,
Then it is complete to dissolving in methanol/acetone in the mixed solvent ultrasound, 3~10 days are stood, the block pale yellow transparent crystal of precipitation,
For 5-aminosalicylic acid and maleic acid, 5-aminosalicylic acid and 2,6- dihydroxy-benzoic acids or 5-aminosalicylic acid and 4- amino pyrroles
Pyridine pharmaceutical co-crystals, the 5-aminosalicylic acid and maleic acid, 2,6-DHBA or 4-aminopyridine, methanol and methanol/
The w/v of acetone mixed solvent is：1mg:0.5~8mg:5~30 μ L:2~5mL；The methanol/acetone mixed solvent
The volume ratio of middle methanol and acetone is：0.5~2:1.
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| CN115124532A (en) * | 2021-03-25 | 2022-09-30 | 中国医学科学院药物研究所 | Eutectic crystal of rhein and matrine, preparation method, composition and application thereof |
| CN115245487A (en) * | 2021-04-27 | 2022-10-28 | 中国医学科学院药物研究所 | Mesalazine and maleic acid eutectic crystal, preparation method, composition and application thereof |
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Cited By (5)
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| CN115124420A (en) * | 2021-03-25 | 2022-09-30 | 中国医学科学院药物研究所 | Rhein and matrine eutectic crystal hydrate, preparation method, composition and application thereof |
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| CN115124532B (en) * | 2021-03-25 | 2023-12-19 | 中国医学科学院药物研究所 | Rhein and matrine eutectic crystal, preparation method, composition and application thereof |
| CN115245487A (en) * | 2021-04-27 | 2022-10-28 | 中国医学科学院药物研究所 | Mesalazine and maleic acid eutectic crystal, preparation method, composition and application thereof |
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