CN102746153B - Chlorogenic acid compound and pharmaceutical composition thereof - Google Patents
Chlorogenic acid compound and pharmaceutical composition thereof Download PDFInfo
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- CN102746153B CN102746153B CN 201210236695 CN201210236695A CN102746153B CN 102746153 B CN102746153 B CN 102746153B CN 201210236695 CN201210236695 CN 201210236695 CN 201210236695 A CN201210236695 A CN 201210236695A CN 102746153 B CN102746153 B CN 102746153B
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Abstract
The invention belongs to the technical field of medicines, and in particular relates to a chlorogenic acid compound. The chlorogenic acid compound is crystal, which has the characteristic peaks in X-ray powder distraction pattern measured through Cu-K alpha ray at 2 theta of 7.9 degrees, 8.4 degrees, 8.8 degrees, 10.2 degrees, 12.0 degrees, 15.4 degrees, 16.9 degrees, 19.0 degrees, 21.9 degrees, 22.6 degrees, 25.9 degrees, 28.0 degrees, 29.6 degrees, and 35.1 degrees+/-0.2 degree. The invention further relates to a pharmaceutical composition which comprises honeysuckle extract and radix scutellariae extract, wherein the radix scutellariae extract contains the chlorogenic acid compound crystal. Peripherally, the pharmaceutical composition is honeysuckle and radix scutellariae dispersible tablet and honeysuckle and radix scutellariae dripping pill. The chlorogenic acid compound and the pharmaceutical composition thereof provided by the invention have good stability, and the contents of related substances are less for long-term storage, so the pharmaceutical safety of a patient is greatly improved.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of chlorogenic acid compound and pharmaceutical composition thereof.
Background technology
Chlorogenic acid, Chinese another name: (1S, 3R, 4R, 5R)-3-[[3-(3,4-dihydroxy phenyl)-1-oxo-2-propenyl] oxygen]-Isosorbide-5-Nitrae, 5-trihydroxy-naphthenic acid, English name: Chlorogenic acid, molecular formula is C
16H
18O
9, molecular weight is 354.31.Chlorogenic acid is a kind of important biologically active substance, has widely anti-microbial effect, cholagogic is arranged, stop blooding, increase white cell and antivirus action, has the blood clotting of shortening and the effect in bleeding time, is used for the treatment of upper respiratory tract infection, anti inflammation and heat resolution, cool blood heat radiation.Chlorogenic acid is the ester that is formed by coffic acid and quinic acid, and ester bond, unsaturated double-bond and three l fractions of polyphenol are arranged in its molecular structure, and poor stability under high temperature, high light effect the migration of molecule lactone group easily occurs and causes isomerization.
CN200510041298.1 discloses the preparation method of a kind of Flos Lonicerae extract and this extract, and the method comprises: the extracting honeysuckle medicinal material adds the water extraction 2～4 times of 8～20 times of volumes, each 0.5～1.5 hour, the pH that regulates extracting solution was 1～6, upper macroporous adsorptive resins, wash first impurity with water, use again 10～70% ethanol elution, collect ethanol eluate, Recycled ethanol, concentrated, regulating concentrated solution pH is 1～6, adds ethyl acetate extraction, reclaim ethyl acetate, concentrated, dry.The weight percentage of main active ingredient chlorogenic acid is at least 25% in this Flos Lonicerae extract.
CN200410035758.5 discloses a kind of technique of extracting the preparation chlorogenic acid from Japanese Honeysuckle, described technique comprises: Japanese Honeysuckle adds water or ethanol carries out refluxing extraction, filter, collect filtrate and reclaim solvent, add the ethanol precipitated impurities, spend the night, filter, decompression and solvent recovery adds water an amount of, standing over night, filter, macroporous resin column on the filtrate, concentrated with eluent, collection contains the component of chlorogenic acid, upper polyamide column is used the eluent wash-out, collects the component that contains chlorogenic acid, concentrated, the refining content that obtains is greater than 95% chlorogenic acid.Japanese Honeysuckle adds water or ethanol carries out refluxing extraction, filters, and collects filtrate and reclaims solvent, add the ethanol precipitated impurities, spend the night, filter, decompression and solvent recovery adds water an amount of, standing over night, filter, macroporous resin column on the filtrate, concentrated with eluent, collection contains the component of chlorogenic acid, and upper polyamide column is used the eluent wash-out, collection contains the component of chlorogenic acid, and is concentrated, and the refining content that obtains is greater than 95% chlorogenic acid.
CN201110046547.1 discloses the preparation method of a kind of Flos Lonicerae extract and chlorogenic acid extracting, the preparation process of this Flos Lonicerae extract is as follows: the extracting honeysuckle medicinal material, the water extraction 2～4 times that adds 8～20 times of volumes, each 0.5～1.5 hour, the pH value of regulating extracting solution is 1～6, upper macroporous adsorptive resins washes first impurity with water, uses 10～70% ethanol elution again, collect ethanol eluate, Recycled ethanol, concentrated, regulating concentrated solution pH value is 1～6, add ethyl acetate extraction, reclaim ethyl acetate, concentrated, drying.The percentage composition of main active ingredient chlorogenic acid is at least 30% in this Flos Lonicerae extract.
In above-mentioned patent and the prior art, although improved the content of activeconstituents chlorogenic acid, removed a large amount of impurity, and the problem of unresolved chlorogenic acid poor stability, in view of this, special proposition the present invention.
Summary of the invention
The object of the present invention is to provide a kind of chlorogenic acid compound, described chlorogenic acid compound has better stability, has greatly improved drug safety.
The second purpose of the present invention is to provide a kind of pharmaceutical composition that contains above-mentioned chlorogenic acid compound, particularly contains Lonicera and scutellaria drip pill and the dispersant tablets of honeysuckle flower and coptis of above-mentioned chlorogenic acid compound.
The 3rd purpose of the present invention is to provide a kind of preparation method who contains the Herba Leonuri extract of above-mentioned chlorogenic acid compound.
For realizing goal of the invention of the present invention, adopt following technical scheme:
A kind of chlorogenic acid compound of formula I, described chlorogenic acid compound is crystal, and the X-ray powder diffraction that described crystal uses the Cu-K alpha-ray to measure is 7.9 °, 8.4 °, 8.8 °, 10.2 °, 12.0 °, 15.4 °, 16.9 °, 19.0 °, 21.9 °, 22.6 °, 25.9 °, 28.0 °, 29.6 °, 35.1 ° ± 0.2 ° at 2 θ and locates to show characteristic peak;
Chlorogenic acid is the ester that is formed by coffic acid and quinic acid, and ester bond, unsaturated double-bond and three l fractions of polyphenol are arranged in its molecular structure, and poor stability under high temperature, high light effect the migration of molecule lactone group easily occurs and causes isomerization.The same compound, its inner solid-state structure of different crystal formations is different, and its lattice energy is also different, and the higher then constraint to compound molecule of lattice energy is larger, and crystalline structure is more stable.The contriver passes through experiment repeatedly, finally prepared foregoing chlorogenic acid compound crystal, its fusing point is 237 ~ 240 ℃, the stability experiment surface, compared with prior art, chlorogenic acid compound crystal provided by the invention has better stability, stores for a long time its related substances low, has greatly improved patient's drug safety.
The particle diameter of described chlorogenic acid compound crystal is 75 ~ 250 μ m.
The preparation method of described chlorogenic acid compound crystal comprises: the chlorogenic acid crude product is dissolved in acetone/isopropylcarbinol mixing solutions, wherein acetone and isopropylcarbinol are made into mixing solutions with the volume ratio of 2 ~ 3:1, and the volumetric usage of acetone/isopropylcarbinol mixing solutions is 6 ~ 9 times of chlorogenic acid crude product weight; Regulate pH to 3 ~ 4 with Glacial acetic acid, add again gac, whip attachment is filtered the decarburization degerming, reheats 55 ~ 65 ℃ and constant temperature and stirs after 2 ~ 3 hours, lower the temperature and the slow ether crystallization that adds under agitation condition with the speed of 0.7 ~ 1.2 ℃/min, be cooled to 0 ~ 5 ℃, filter drying under reduced pressure, washing obtains the chlorogenic acid crystal.
Among the preparation method of above-mentioned chlorogenic acid crystal, filter the decarburization degerming after, preferably be heated to 60 ~ 65 ℃ and constant temperature and stirred 2 hours.
Among the preparation method of above-mentioned chlorogenic acid crystal, preferably speed cooling and the while with 0.7 ~ 0.9 ℃/min slowly adds the ether crystallization.
Among the preparation method of above-mentioned chlorogenic acid crystal, the stir speed (S.S.) that adds the ether crystallization is preferably 12 ~ 16rmp.
Among the preparation method of above-mentioned chlorogenic acid crystal, the consumption of ether is 3 ~ 4 times of acetone/isopropylcarbinol mixed liquor volume.
The present invention also provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises Flos Lonicerae extract and Radix Scutellariae extract, and described Flos Lonicerae extract contains foregoing chlorogenic acid compound crystal.
The main active ingredient of Flos Lonicerae extract is chlorogenic acid, the migration of molecule lactone group easily occurs and causes isomerization in the prior art Content of Chlorogenic Acid under high temperature, high light effect, poor stability, contain the growth of the pharmaceutical composition of Flos Lonicerae extract along with the time of making the product, its active component content rapid drawdown, its related substances increases, and patient's drug risk is large.The present invention is by improving the physicochemical property of Flos Lonicerae extract Content of Chlorogenic Acid, and the medicinal compositions that comprises this Flos Lonicerae extract of preparation has better stability, has greatly improved patient's drug safety.
Preferably, the Lonicera and scutellaria drip pill of described pharmaceutical composition for being prepared from by Flos Lonicerae extract, Radix Scutellariae extract and Macrogol 4000, wherein the weight ratio of Flos Lonicerae extract and Radix Scutellariae extract is 5: 1 ~ 3, Flos Lonicerae extract with the weight ratio of polyoxyethylene glycol be 5: 9 ~ 12; Preferred described Flos Lonicerae extract is that 200 parts, Radix Scutellariae extract are that 80 parts, Macrogol 4000 are 420 parts.
Preferably, described pharmaceutical composition is dispersant tablets of honeysuckle flower and coptis, described dispersant tablets of honeysuckle flower and coptis by weight, contain Flos Lonicerae extract 80-120 part, Radix Scutellariae extract 30-50 part, low-substituted hydroxypropyl cellulose 15-25 part, Microcrystalline Cellulose 180-220 part, cross-linked polyvinylpyrrolidone 30-50 part; Preferably contain 100 parts of Flos Lonicerae extracts, 40 parts of Radix Scutellariae extracts, 20 parts of low-substituted hydroxypropyl celluloses, 200 parts of Microcrystalline Celluloses, 40 parts of cross-linked polyvinylpyrrolidones.
Among the present invention, the preparation of a Lonicera and scutellaria drip pill dispersant tablets of honeysuckle flower and coptis can be prepared with reference to the same dosage form of prior art, pays more creative work and need not those skilled in the art.
Described Flos Lonicerae extract adopts following method to be prepared from:
(1) extracting honeysuckle chopping adds the water boiling twice that 8-12 doubly measures, each 1.5 ~ 2.5 hours, filter, merging filtrate is regulated pH value to 10 ~ 12 with milk of lime (calcium oxide), after leaving standstill 20 ~ 30 hours, the leaching precipitation, throw out adds 2 ~ 3 times of amount ethanol suspendibles, transfer pH to 6 ~ 7 with sulfuric acid, stir evenly, filter, filtrate transfers to neutrality with hydrochloric acid, be concentrated into driedly, get the Flos Lonicerae extract crude product;
(2) be dissolved in the Flos Lonicerae extract crude product in the ethanol fully, filtering with microporous membrane, upper macroporous adsorbent resin, the ethanolic soln gradient elution with 60 ~ 80%, the independent collection of component and the drying under reduced pressure that will contain chlorogenic acid get the chlorogenic acid crude product, other component is merged collect;
(3) the chlorogenic acid crude product is dissolved in acetone/isopropylcarbinol mixing solutions, wherein acetone and isopropylcarbinol are made into mixing solutions with the volume ratio of 2 ~ 3:1, and the volumetric usage of acetone/isopropylcarbinol mixing solutions is 6 ~ 9 times of chlorogenic acid crude product weight; Regulate pH to 3 ~ 4 with Glacial acetic acid, add again gac, whip attachment is filtered the decarburization degerming, reheats 55 ~ 65 ℃ and constant temperature and stirs after 2 ~ 3 hours, lower the temperature and the slow ether crystallization that adds under agitation condition with the speed of 0.7 ~ 1.0 ℃/min, be cooled to 0 ~ 5 ℃, filter drying under reduced pressure, washing obtains the chlorogenic acid crystal;
(4) add gac to merging in other component of collecting, whip attachment is filtered the decarburization degerming, and drying under reduced pressure obtains white powder;
(5) white powder that chlorogenic acid crystal and step (4) is obtained mixes, and namely gets Flos Lonicerae extract.
Among the described Flos Lonicerae extract preparation method: in the step (1), add the water boiling of 12 times of amounts for the first time, add the water boiling of 10 times of amounts for the second time, each boiling 2 hours; Regulate pH value to 10 ~ 12 with 25% milk of lime; Sulphuric acid soln with 10% ~ 15% is transferred pH to 6 ~ 7.
Among the described Flos Lonicerae extract preparation method: in the step (2), the model of macroporous adsorbent resin is D101, and elution flow rate is 0.4 ~ 0.8ml/min.
Among the described Flos Lonicerae extract preparation method: in the step (3), filter the decarburization degerming after, preferably be heated to 60 ~ 65 ℃ and constant temperature and stirred 2 hours.
Among the described Flos Lonicerae extract preparation method: in the step (3), preferably speed cooling and the while with 0.7 ~ 0.9 ℃/min slowly adds the ether crystallization.
Among the described Flos Lonicerae extract preparation method: in the step (3), the stir speed (S.S.) that adds the ether crystallization is preferably 12 ~ 16rmp.
Among the described Flos Lonicerae extract preparation method: in the step (3), the consumption of ether is 3 ~ 4 times of acetone/isopropylcarbinol mixed liquor volume.
Chlorogenic acid compound provided by the invention and the pharmaceutical composition that contains this chlorogenic acid compound have following advantage:
(1) chlorogenic acid compound stability provided by the invention is good, stores for a long time its related substances few;
(2) pharmaceutical composition steady quality provided by the invention has improved patient's drug safety greatly, has higher bioavailability.
Description of drawings
The X-RD spectrogram of the chlorogenic acid compound that Fig. 1 provides for the embodiment of the invention 1.
Embodiment
Below with embodiment technical scheme of the present invention is further described; to help the advantage to technical scheme of the present invention; effect has further to be understood, and embodiment does not limit protection scope of the present invention, and protection scope of the present invention is decided by claim.
Embodiment 1
The preparation of chlorogenic acid compound crystal
The chlorogenic acid crude product is dissolved in acetone/isopropylcarbinol mixing solutions, and wherein acetone and isopropylcarbinol are made into mixing solutions with the volume ratio of 2:1, and the volumetric usage of acetone/isopropylcarbinol mixing solutions is 6 times of chlorogenic acid crude product weight; Regulate pH to 3 with Glacial acetic acid, add again gac, whip attachment, filter the decarburization degerming, reheat 55 ℃ and constant temperature and stir after 2 hours, with the speed cooling of 0.7 ℃/min and under agitation condition, slowly add the ether crystallization, be cooled to 0 ℃, the stir speed (S.S.) that adds the ether crystallization is preferably 12rmp, the consumption of ether is 3 times of acetone/isopropylcarbinol mixed liquor volume, filters drying under reduced pressure, washing obtains the chlorogenic acid crystal.
The particle diameter of described chlorogenic acid crystal is 75 ~ 250 μ m, yield 81.2%, HPLC content 99.65%.mp：237~240℃。
The X-ray powder diffraction collection of illustrative plates of the chlorogenic acid crystal that obtains locates to demonstrate characteristic diffraction peak at 7.9 °, 8.4 °, 8.8 °, 10.2 °, 12.0 °, 15.4 °, 16.9 °, 19.0 °, 21.9 °, 22.6 °, 25.9 °, 28.0 °, 29.6 °, 35.1 ° ± 0.2 °.
Embodiment 2
The preparation of chlorogenic acid compound crystal
The chlorogenic acid crude product is dissolved in acetone/isopropylcarbinol mixing solutions, and wherein acetone and isopropylcarbinol are made into mixing solutions with the volume ratio of 3:1, and the volumetric usage of acetone/isopropylcarbinol mixing solutions is 9 times of chlorogenic acid crude product weight; Regulate pH to 4 with Glacial acetic acid, add again gac, whip attachment, filter the decarburization degerming, reheat 65 ℃ and constant temperature and stir after 3 hours, with the speed cooling of 1.2 ℃/min and under agitation condition, slowly add the ether crystallization, be cooled to 5 ℃, the stir speed (S.S.) that adds the ether crystallization is preferably 16rmp, the consumption of ether is 4 times of acetone/isopropylcarbinol mixed liquor volume, filters drying under reduced pressure, washing obtains the chlorogenic acid crystal.
The particle diameter of described chlorogenic acid crystal is 75 ~ 250 μ m, yield 81.9%, HPLC content 99.71%.mp：237~240℃。
The X-ray powder diffraction collection of illustrative plates of the chlorogenic acid crystal that obtains and embodiment 1 product has identical parameters.
Embodiment 3
The preparation of chlorogenic acid compound crystal
The chlorogenic acid crude product is dissolved in acetone/isopropylcarbinol mixing solutions, and wherein acetone and isopropylcarbinol are made into mixing solutions with the volume ratio of 3:1, and the volumetric usage of acetone/isopropylcarbinol mixing solutions is 7 times of chlorogenic acid crude product weight; Regulate pH to 4 with Glacial acetic acid, add again gac, whip attachment, filter the decarburization degerming, reheat 60 ℃ and constant temperature and stir after 2 hours, with the speed cooling of 0.9 ℃/min and under agitation condition, slowly add the ether crystallization, be cooled to 3 ℃, the stir speed (S.S.) that adds the ether crystallization is preferably 15rmp, the consumption of ether is 4 times of acetone/isopropylcarbinol mixed liquor volume, filters drying under reduced pressure, washing obtains the chlorogenic acid crystal.
The particle diameter of described chlorogenic acid crystal is 75 ~ 250 μ m, yield 80.2%, HPLC content 99.79%.mp：237~240℃。
The X-ray powder diffraction collection of illustrative plates of the chlorogenic acid crystal that obtains and embodiment 1 product has identical parameters.
Embodiment 4
The preparation of Flos Lonicerae extract
The extracting honeysuckle chopping, the water boiling twice of 8 times of amounts of adding, each 2.5 hours, filter, merging filtrate is regulated pH value to 10 with milk of lime (calcium oxide), after leaving standstill 20 hours, the leaching precipitation, throw out adds 2 times of amount ethanol suspendibles, transfer pH to 6 with sulfuric acid, stir evenly, filter, filtrate transfers to neutrality with hydrochloric acid, be concentrated into driedly, get the Flos Lonicerae extract crude product.
Be dissolved in the Flos Lonicerae extract crude product in the ethanol fully, filtering with microporous membrane, upper macroporous adsorbent resin, the ethanolic soln gradient elution with 60%, the independent collection of component and the drying under reduced pressure that will contain chlorogenic acid get the chlorogenic acid crude product, other component is merged collection, add gac to merging in other component of collecting, whip attachment is filtered the decarburization degerming, drying under reduced pressure obtains white powder.
The chlorogenic acid crude product is dissolved in acetone/isopropylcarbinol mixing solutions, and wherein acetone and isopropylcarbinol are made into mixing solutions with the volume ratio of 2:1, and the volumetric usage of acetone/isopropylcarbinol mixing solutions is 6 times of chlorogenic acid crude product weight; Regulate pH to 3 with Glacial acetic acid, add again gac, whip attachment, filter the decarburization degerming, reheat 55 ℃ and constant temperature and stir after 2 hours, with the speed cooling of 0.7 ℃/min and under agitation condition, slowly add the ether crystallization, be cooled to 0 ℃, the stir speed (S.S.) that adds the ether crystallization is preferably 12rmp, the consumption of ether is 3 times of acetone/isopropylcarbinol mixed liquor volume, filters drying under reduced pressure, washing obtains the chlorogenic acid crystal.The particle diameter of described chlorogenic acid crystal is 75 ~ 250 μ m, yield 81.2%, HPLC content 99.65%.mp：237~240℃。The X-ray powder diffraction collection of illustrative plates of the chlorogenic acid crystal that obtains and embodiment 1 product has identical parameters.
Chlorogenic acid crystal and white powder are mixed, namely get Flos Lonicerae extract.
Embodiment 5
The preparation of Flos Lonicerae extract
The extracting honeysuckle chopping, the water boiling twice of 12 times of amounts of adding, each 1.5 hours, filter, merging filtrate is regulated pH value to 12 with milk of lime (calcium oxide), after leaving standstill 30 hours, the leaching precipitation, throw out adds 3 times of amount ethanol suspendibles, transfer pH to 7 with sulfuric acid, stir evenly, filter, filtrate transfers to neutrality with hydrochloric acid, be concentrated into driedly, get the Flos Lonicerae extract crude product.
Be dissolved in the Flos Lonicerae extract crude product in the ethanol fully, filtering with microporous membrane, upper macroporous adsorbent resin, the ethanolic soln gradient elution with 80%, the independent collection of component and the drying under reduced pressure that will contain chlorogenic acid get the chlorogenic acid crude product, other component is merged collection, add gac to merging in other component of collecting, whip attachment is filtered the decarburization degerming, drying under reduced pressure obtains white powder.
The chlorogenic acid crude product is dissolved in acetone/isopropylcarbinol mixing solutions, and wherein acetone and isopropylcarbinol are made into mixing solutions with the volume ratio of 3:1, and the volumetric usage of acetone/isopropylcarbinol mixing solutions is 9 times of chlorogenic acid crude product weight; Regulate pH to 4 with Glacial acetic acid, add again gac, whip attachment, filter the decarburization degerming, reheat 65 ℃ and constant temperature and stir after 3 hours, with the speed cooling of 1.2 ℃/min and under agitation condition, slowly add the ether crystallization, be cooled to 5 ℃, the stir speed (S.S.) that adds the ether crystallization is preferably 16rmp, the consumption of ether is 4 times of acetone/isopropylcarbinol mixed liquor volume, filters drying under reduced pressure, washing obtains the chlorogenic acid crystal.The particle diameter of described chlorogenic acid crystal is 75 ~ 250 μ m, yield 81.9%, HPLC content 99.71%.mp：237~240℃。The X-ray powder diffraction collection of illustrative plates of the chlorogenic acid crystal that obtains and embodiment 1 product has identical parameters.
Chlorogenic acid crystal and white powder are mixed, namely get Flos Lonicerae extract.
Embodiment 6
The preparation of Flos Lonicerae extract
The extracting honeysuckle chopping adds the water boiling of 12 times of amounts the first time, adds the water boiling of 10 times of amounts for the second time, merging filtrate is filtered in each boiling 2 hours, regulate pH value to 10 with 25% milk of lime (calcium oxide), leave standstill 20 hours after, leaching precipitates, throw out adds 2 times of amount ethanol suspendibles, and the sulphuric acid soln with 10% is transferred pH to 6, stirs evenly, filter, filtrate transfers to neutrality with hydrochloric acid, is concentrated into driedly, gets the Flos Lonicerae extract crude product.
The Flos Lonicerae extract crude product is dissolved in the ethanol fully, filtering with microporous membrane, upper macroporous adsorbent resin, the ethanolic soln gradient elution with 80%, the model of macroporous adsorbent resin is D101, elution flow rate is 0.4ml/min.The independent collection of component and the drying under reduced pressure that will contain chlorogenic acid get the chlorogenic acid crude product, other component is merged collect, and add gac in other component of merging collection, and whip attachment is filtered the decarburization degerming, and drying under reduced pressure obtains white powder.
The chlorogenic acid crude product is dissolved in acetone/isopropylcarbinol mixing solutions, and wherein acetone and isopropylcarbinol are made into mixing solutions with the volume ratio of 3:1, and the volumetric usage of acetone/isopropylcarbinol mixing solutions is 7 times of chlorogenic acid crude product weight; Regulate pH to 4 with Glacial acetic acid, add again gac, whip attachment, filter the decarburization degerming, reheat 60 ℃ and constant temperature and stir after 2 hours, with the speed cooling of 0.9 ℃/min and under agitation condition, slowly add the ether crystallization, be cooled to 3 ℃, the stir speed (S.S.) that adds the ether crystallization is preferably 12rmp, the consumption of ether is 3 times of acetone/isopropylcarbinol mixed liquor volume, filters drying under reduced pressure, washing obtains the chlorogenic acid crystal.The particle diameter of described chlorogenic acid crystal is 75 ~ 250 μ m, yield 80.2%, HPLC content 99.79%.mp：237~240℃。The X-ray powder diffraction collection of illustrative plates of the chlorogenic acid crystal that obtains and embodiment 1 product has identical parameters.
Chlorogenic acid crystal and white powder are mixed, namely get Flos Lonicerae extract.
Embodiment 7
The preparation of Flos Lonicerae extract
The extracting honeysuckle chopping adds the water boiling of 12 times of amounts the first time, adds the water boiling of 10 times of amounts for the second time, merging filtrate is filtered in each boiling 2 hours, regulate pH value to 12 with 25% milk of lime (calcium oxide), leave standstill 30 hours after, leaching precipitates, throw out adds 3 times of amount ethanol suspendibles, and the sulphuric acid soln with 15% is transferred pH to 7, stirs evenly, filter, filtrate transfers to neutrality with hydrochloric acid, is concentrated into driedly, gets the Flos Lonicerae extract crude product.
The Flos Lonicerae extract crude product is dissolved in the ethanol fully, filtering with microporous membrane, upper macroporous adsorbent resin, the ethanolic soln gradient elution with 60, the model of macroporous adsorbent resin is D101, elution flow rate is 0.8ml/min.The independent collection of component and the drying under reduced pressure that will contain chlorogenic acid get the chlorogenic acid crude product, other component is merged collect, and add gac in other component of merging collection, and whip attachment is filtered the decarburization degerming, and drying under reduced pressure obtains white powder.
The chlorogenic acid crude product is dissolved in acetone/isopropylcarbinol mixing solutions, and wherein acetone and isopropylcarbinol are made into mixing solutions with the volume ratio of 3:1, and the volumetric usage of acetone/isopropylcarbinol mixing solutions is 7 times of chlorogenic acid crude product weight; Regulate pH to 4 with Glacial acetic acid, add again gac, whip attachment, filter the decarburization degerming, reheat 65 ℃ and constant temperature and stir after 2 hours, with the speed cooling of 0.7 ℃/min and under agitation condition, slowly add the ether crystallization, be cooled to 3 ℃, the stir speed (S.S.) that adds the ether crystallization is preferably 16rmp, the consumption of ether is 4 times of acetone/isopropylcarbinol mixed liquor volume, filters drying under reduced pressure, washing obtains the chlorogenic acid crystal.The particle diameter of described chlorogenic acid crystal is 75 ~ 250 μ m, yield 80.6%, HPLC content 99.76%.mp：237~240℃。The X-ray powder diffraction collection of illustrative plates of the chlorogenic acid crystal that obtains and embodiment 1 product has identical parameters.
Chlorogenic acid crystal and white powder are mixed, namely get Flos Lonicerae extract.
Embodiment 8
The preparation of Lonicera and scutellaria drip pill
The Flos Lonicerae extract of getting the present invention's preparation is that 200g, Radix Scutellariae extract are that 40g, Macrogol 4000 are 360g, Macrogol 4000 is heated to molten state, the mixture that adds Flos Lonicerae extract and Radix Scutellariae extract, stir evenly, 85 ℃ of lower insulations 1 hour, splash in 0 ℃ the dimethyl silicone oil, take out, absorb phlegma, packing, and get final product.
Embodiment 9
The preparation of Lonicera and scutellaria drip pill
The Flos Lonicerae extract of getting the present invention's preparation is that 200g, Radix Scutellariae extract are that 80g, Macrogol 4000 are 420g, Macrogol 4000 is heated to molten state, the mixture that adds Flos Lonicerae extract and Radix Scutellariae extract, stir evenly, 85 ℃ of lower insulations 1 hour, splash in 0 ℃ the dimethyl silicone oil, take out, absorb phlegma, packing, and get final product.
The preparation of Lonicera and scutellaria drip pill
The Flos Lonicerae extract of getting the present invention's preparation is that 200g, Radix Scutellariae extract are that 120g, Macrogol 4000 are 480g, Macrogol 4000 is heated to molten state, the mixture that adds Flos Lonicerae extract and Radix Scutellariae extract, stir evenly, 85 ℃ of lower insulations 1 hour, splash in 0 ℃ the dimethyl silicone oil, take out, absorb phlegma, packing, and get final product.
Embodiment 11
The preparation of dispersant tablets of honeysuckle flower and coptis
Get Flos Lonicerae extract 80g, Radix Scutellariae extract 30g, the low-substituted hydroxypropyl cellulose 15g of the present invention's preparation, Microcrystalline Cellulose 180g, cross-linked polyvinylpyrrolidone 30g, mixing is that wetting agent is granulated with 95% ethanol, 60 ℃ of dryings, whole grain; After the passed examination, be pressed into 1000, packing.
Embodiment 12
The preparation of dispersant tablets of honeysuckle flower and coptis
Get Flos Lonicerae extract 120g, Radix Scutellariae extract 50g, the low-substituted hydroxypropyl cellulose 25g of the present invention's preparation, Microcrystalline Cellulose 220g, cross-linked polyvinylpyrrolidone 50g, mixing is that wetting agent is granulated with 95% ethanol, 60 ℃ of dryings, whole grain; After the passed examination, be pressed into 1000, packing.
Embodiment 13
The preparation of dispersant tablets of honeysuckle flower and coptis
Get Flos Lonicerae extract 100g, Radix Scutellariae extract 40g, low-substituted hydroxypropyl cellulose 20g, Microcrystalline Cellulose 200g, the cross-linked polyvinylpyrrolidone 40g of the present invention's preparation, mixing is that wetting agent is granulated with 95% ethanol, 60 ℃ of dryings, whole grain; After the passed examination, be pressed into 1000, packing.
Experimental example 1
This test example detects residual solvent in the prepared product of embodiment 1-7, and this test is according to 2010 editions second appendix VIII P of Chinese Pharmacopoeia residual solvent assay method, and it the results are shown in Table 1:
Table 1
| Group | Acetone | Isopropylcarbinol | Ether | Glacial acetic acid | Ethanol |
| Embodiment 1 | Up to specification | Up to specification | Up to specification | Up to specification | / |
| Embodiment 2 | Up to specification | Up to specification | Up to specification | Up to specification | / |
| Embodiment 3 | Up to specification | Up to specification | Up to specification | Up to specification | / |
| Embodiment 4 | Up to specification | Up to specification | Up to specification | Up to specification | Up to specification |
| Embodiment 5 | Up to specification | Up to specification | Up to specification | Up to specification | Up to specification |
| Embodiment 6 | Up to specification | Up to specification | Up to specification | Up to specification | Up to specification |
| Embodiment 7 | Up to specification | Up to specification | Up to specification | Up to specification | Up to specification |
Experimental example 2
This experimental example has been investigated the stability of chlorogenic acid crystal provided by the invention
This test is carried out according to 2005 editions second appendix XIX C of Chinese Pharmacopoeia medicine stability test governing principle, and the result is as follows:
Table 2, accelerated test result
Table 3, long-term test results
Sample 1 is the product of embodiment 1, and sample 2 is the product of embodiment 2, and sample 3 is the product of embodiment 3;
Sample 4 is commercially available chlorogenic acid bulk drug, originates from Anhua, sky, Hubei worker's raw material company limited;
Sample 5 is the chlorogenic acid elaboration that extracts preparation according to the method for embodiment 1 among the patent CN200410035758.5.
Accelerated test by this experimental example and test of long duration as can be known, compared with prior art, the stability of chlorogenic acid crystal provided by the invention is better.
Claims (11)
1. the chlorogenic acid compound of a formula I, it is characterized in that: described chlorogenic acid compound is crystal, and the X-ray powder diffraction that described crystal uses the Cu-K alpha-ray to measure is 7.9 °, 8.4 °, 8.8 °, 10.2 °, 12.0 °, 15.4 °, 16.9 °, 19.0 °, 21.9 °, 22.6 °, 25.9 °, 28.0 °, 29.6 °, 35.1 ° ± 0.2 ° at 2 θ and locates to show characteristic peak;
The formula I.
2. chlorogenic acid compound according to claim 1 is characterized in that, the particle diameter of described crystal is 75 ~ 250 μ m.
3. a pharmaceutical composition is characterized in that, described pharmaceutical composition comprises Flos Lonicerae extract and Radix Scutellariae extract, and described Flos Lonicerae extract contains chlorogenic acid compound crystal claimed in claim 1.
4. pharmaceutical composition according to claim 3, it is characterized in that, the Lonicera and scutellaria drip pill of described pharmaceutical composition for being prepared from by Flos Lonicerae extract, Radix Scutellariae extract and Macrogol 4000, wherein the weight ratio of Flos Lonicerae extract and Radix Scutellariae extract is 5: 1 ~ 3, and the weight ratio of Flos Lonicerae extract and polyoxyethylene glycol is 5: 9 ~ 12.
5. pharmaceutical composition according to claim 3, it is characterized in that, described pharmaceutical composition is dispersant tablets of honeysuckle flower and coptis, described dispersant tablets of honeysuckle flower and coptis by weight, contain Flos Lonicerae extract 80-120 part, Radix Scutellariae extract 30-50 part, low-substituted hydroxypropyl cellulose 15-25 part, Microcrystalline Cellulose 180-220 part, cross-linked polyvinylpyrrolidone 30-50 part.
6. pharmaceutical composition according to claim 5, it is characterized in that, described dispersant tablets of honeysuckle flower and coptis contains 100 parts of Flos Lonicerae extracts, 40 parts of Radix Scutellariae extracts, 20 parts of low-substituted hydroxypropyl celluloses by weight, 200 parts of Microcrystalline Celluloses, 40 parts of cross-linked polyvinylpyrrolidones.
7. each described pharmaceutical composition according to claim 3 ~ 6, it is characterized in that: described Flos Lonicerae extract adopts following method to be prepared from:
(1) extracting honeysuckle chopping adds the water boiling twice that 8-12 doubly measures, each 1.5 ~ 2.5 hours, filter, merging filtrate is regulated pH value to 10 ~ 12 with milk of lime, after leaving standstill 20 ~ 30 hours, the leaching precipitation, throw out adds 2 ~ 3 times of amount ethanol suspendibles, transfer pH to 6 ~ 7 with sulfuric acid, stir evenly, filter, filtrate transfers to neutrality with hydrochloric acid, be concentrated into driedly, get the Flos Lonicerae extract crude product;
(2) be dissolved in the Flos Lonicerae extract crude product in the ethanol fully, filtering with microporous membrane, upper macroporous adsorbent resin, the ethanolic soln gradient elution with 60 ~ 80%, the independent collection of component and the drying under reduced pressure that will contain chlorogenic acid get the chlorogenic acid crude product, other component is merged collect;
(3) the chlorogenic acid crude product is dissolved in acetone/isopropylcarbinol mixing solutions, wherein acetone and isopropylcarbinol are made into mixing solutions with the volume ratio of 2 ~ 3:1, and the volumetric usage of acetone/isopropylcarbinol mixing solutions is 6 ~ 9 times of chlorogenic acid crude product weight; Regulate pH to 3 ~ 4 with Glacial acetic acid, add again gac, whip attachment is filtered the decarburization degerming, reheats 55 ~ 65 ℃ and constant temperature and stirs after 2 ~ 3 hours, lower the temperature and the slow ether crystallization that adds under agitation condition with the speed of 0.7 ~ 1.0 ℃/min, be cooled to 0 ~ 5 ℃, filter drying under reduced pressure, washing obtains the chlorogenic acid crystal;
(4) add gac to merging in other component of collecting, whip attachment is filtered the decarburization degerming, and drying under reduced pressure obtains white powder;
(5) white powder that chlorogenic acid crystal and step (4) is obtained mixes, and namely gets Flos Lonicerae extract.
8. pharmaceutical composition according to claim 7 is characterized in that: in the described step (1), add the water boiling of 12 times of amounts for the first time, add the water boiling of 10 times of amounts for the second time, each boiling 2 hours; Regulate pH value to 10 ~ 12 with 25% milk of lime; Sulphuric acid soln with 10% ~ 15% is transferred pH to 6 ~ 7.
9. pharmaceutical composition according to claim 7, it is characterized in that: in the described step (2), the model of macroporous adsorbent resin is D101, and elution flow rate is 0.4 ~ 0.8ml/min.
10. pharmaceutical composition according to claim 7, it is characterized in that: in the described step (3), the stir speed (S.S.) during crystallization is 12～16rmp.
11. pharmaceutical composition according to claim 7 is characterized in that: in the described step (3), the consumption of ether is 3 ~ 4 times of acetone/isopropylcarbinol mixed liquor volume.
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| CN103951562B (en) * | 2014-05-09 | 2016-04-20 | 四川九章生物化工科技发展有限公司 | A kind of chlorogenic acid crystal formation and preparation method thereof |
| CN104352457A (en) | 2014-11-24 | 2015-02-18 | 四川九章生物科技有限公司 | Chlorogenic acid crystal form-containing preparation and application thereof |
| CN113214085A (en) * | 2021-04-14 | 2021-08-06 | 张洪胜 | Chlorogenic acid derivative with antioxidant activity and preparation method thereof |
Citations (3)
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|---|---|---|---|---|
| CN1506078A (en) * | 2002-12-11 | 2004-06-23 | 成都尚科药业有限公司 | Prepn of dispersive Yinhuang tablet |
| CN1768785A (en) * | 2005-10-25 | 2006-05-10 | 北京创立科创医药技术开发有限公司 | Honey suckle and scutellaria root pill and preparation thereof |
| CN102399146A (en) * | 2011-12-20 | 2012-04-04 | 广西大学 | Method for preparing high purity chlorogenic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1506078A (en) * | 2002-12-11 | 2004-06-23 | 成都尚科药业有限公司 | Prepn of dispersive Yinhuang tablet |
| CN1768785A (en) * | 2005-10-25 | 2006-05-10 | 北京创立科创医药技术开发有限公司 | Honey suckle and scutellaria root pill and preparation thereof |
| CN102399146A (en) * | 2011-12-20 | 2012-04-04 | 广西大学 | Method for preparing high purity chlorogenic acid |
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