CN109400598A - Berberine hydrochloride and lactic acid eutectic, preparation method and application - Google Patents
Berberine hydrochloride and lactic acid eutectic, preparation method and application Download PDFInfo
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Abstract
The invention belongs to pharmaceutical co-crystals fields, and in particular to Berberine hydrochloride and lactic acid eutectic, preparation method and application.The present invention is using Berberine hydrochloride and lactic acid eutectic made from dry milling processes, liquid feeding assisted milling method or suspension method, one molecule Berberine hydrochloride, a molecule lactic acid and a molecular water form the basic structural unit of Berberine hydrochloride and lactic acid eutectic by halogen key, hydrogen bond, are respectively formed halogen key between Berberine hydrochloride molecule and lactic acid molecules, between Berberine hydrochloride molecule and hydrone；Hydrogen bond is formed between lactic acid molecules and hydrone.Berberine hydrochloride prepared by the present invention and lactic acid eutectic, can reduce the hygroscopicity of Berberine hydrochloride, improve the solubility and dissolution rate of Berberine hydrochloride, improve its bioavilability；Improve the pharmacy and medical applications of Berberine hydrochloride.Preparation process of the present invention is simple and easy to control, yield and purity is high, is suitable for industrialized production, low in cost.
Description
Technical field
The invention belongs to technical field of pharmaceutical co-crystal, and in particular to Berberine hydrochloride and lactic acid eutectic, preparation method and
Using.
Background technique
In drug discovery process, the slightly solubility of active pharmaceutical ingredient (API), difficult dispersibility, low bioavilability and steady
The problems such as qualitative is still the development for perplexing medical industry, more restricts the exploitation and clinical application of drug.Drug-eluting rate is small
Lead to the reduction of drug bioavailability, this problem seems especially prominent for solid dosage medicine, and therefore, it is difficult to improve
Soluble drug dissolution rate is still drug development urgent problem and the problem of medicament research and development person increasingly pays close attention to, even more
An importance in the medicament research and development of the new solid-type of API.
Berberine hydrochloride C20H18ClNO4(formula I) is a kind of morphinane alkaloid, is existed usually in the form of dihydrate,
It is mainly used for treating enteric infections, eye conjunctivitis, the otitis media suppuratives such as gastroenteritis, bacillary dysentery etc., there are also block α receptor
Antiarrhythmic effect.Due to Berberine hydrochloride poorly water-soluble, cause its bioavilability low, faces to greatly limit it
Bed drug development.Therefore, the water solubility and dissolution rate for improving Berberine hydrochloride are still that Berberine hydrochloride pharmaceutical preparation is urgently to be resolved
The problem of.
In recent years, pharmaceutical co-crystals are prepared using supramolecular chemistry and crystal engineering and has become chemistry and medicine
Research hotspot, pharmaceutical co-crystals are gained great popularity due to its unique physicochemical properties.Pharmaceutical co-crystals refer to pharmaceutical activity group
Divide (active pharmaceutical ingredient, API) and other physiologically acceptable acid, alkali or nonionic chemical combination
The eutectics such as object formation (co-crystal former, CCF), it is non-by hydrogen bond, Van der Waals force, pi-pi accumulation effect, halogen key etc.
The crystal that covalent bond effect power is combined into.
Summary of the invention
The purpose of the present invention is to provide a kind of new solid forms of Berberine hydrochloride, i.e. Berberine hydrochloride and lactic acid is total
Crystalline substance, to be cocrystalization compound that basic structural unit is formed by a molecule Berberine hydrochloride, a molecule lactic acid and a molecular water, this
Cocrystalization compound can significantly reduce the hygroscopicity of Berberine hydrochloride, improve the solubility and dissolution rate of Berberine hydrochloride, enhance salt
The pharmacy and medical applications of sour jamaicin.
The present invention also provides the preparation methods of Berberine hydrochloride and lactic acid eutectic, and the preparation method is simple and easy to control, are suitable for work
Industry metaplasia produces, and low in cost.
To achieve the above object, the technical solution of the present invention is as follows: Berberine hydrochloride and lactic acid eutectic, are with Berberine hydrochloride
Active pharmaceutical ingredient, using lactic acid as presoma, the eutectic of formation；For anorthic system, space group P-1, cell parameter are as follows:α=70.047 (7) °, β=74.868 (7) °, γ=
84.194 (7) °,Z=2.
The PXRD of Berberine hydrochloride and lactic acid eutectic 2 θ of the angle of diffraction be 8.43 ° ± 0.2,14.82 ° ± 0.2,15.26 ° ±
0.2, there is characteristic peak at 18.86 ° ± 0.2,19.99 ° ± 0.2,24.93 ° ± 0.2,25.71 ° ± 0.2,26.33 ° ± 0.2.
The infrared spectrum of Berberine hydrochloride and lactic acid eutectic is in 1029 ± 5cm-1、1279±5cm-1、1585±5cm-1、
1711±5cm-1、3301±5cm-1Place has characteristic peak.
The structural formula of Berberine hydrochloride and lactic acid eutectic is C20H18ClNO4·C3H6O3·H2O, by a molecule hydrochloric acid barberry
Alkali, a molecule lactic acid and a molecular water form the basic structural unit of Berberine hydrochloride and lactic acid eutectic, salt by halogen key, hydrogen bond
The chlorine atom of sour barberry base molecule passes through Non-covalent binding with the hydrogen atom of the hydroxyl hydrogen atom of lactic acid molecules and hydrone respectively,
Halogen key is respectively formed between Berberine hydrochloride molecule and lactic acid molecules, between Berberine hydrochloride molecule and hydrone；In lactic acid molecules
Carboxyl oxygen atom is as hydrogen bond donor, and oxygen atom forms hydrogen as hydrogen bond receptor between lactic acid molecules and hydrone in hydrone
Key.
The present invention prepares the pharmaceutical co-crystals of Berberine hydrochloride and lactic acid using polishing or suspension method.Polishing passes through machine
Tool active force to generate halogen key, hydrogen bond or other intermolecular forces formation eutectic, polishing between compound molecule
Dry milling processes and liquid feeding assisted milling method.Suspension method is that brilliant formation or presoma mix in a solvent together by active pharmaceutical ingredient
After conjunction, abundant suspension effect forms eutectic so that generating halogen key, hydrogen bond or other intermolecular forces between compound molecule.
Grinding crystallization is blended with lactic acid for the preparation method of Berberine hydrochloride and lactic acid eutectic, Berberine hydrochloride.
The molar ratio of Berberine hydrochloride and lactic acid is 1:0.9~3, preferably 1:1~1.5, more preferably 1:1.
The method of grinding includes hand lapping, ball-milling method or mechanical lapping.
The speed of grinding is 10~800r/min, preferably 200~400r/min.
The temperature of grinding be 15 DEG C~35 DEG C, preferably room temperature.
Alternatively, preparation method further include: before grinding is blended, solvent, i.e. solvent is added into Berberine hydrochloride and lactic acid
Assisted milling.
When solvent assisted milling, the amount ratio of the gross mass and solvent of Berberine hydrochloride and lactic acid is 2~15g/ml, preferably
For 5~7g/ml, more preferably 6g/ml.The solvent includes methanol, ethyl alcohol, isopropanol, normal propyl alcohol or acetone etc..Grinding is formed
While eutectic, methanol, ethyl alcohol, isopropanol, normal propyl alcohol or acetone equal solvent also volatilize, conducive to the precipitation of eutectic.
Further include standing crystallization after grinding, stands in Crystallization Process, methanol, ethyl alcohol, isopropanol, normal propyl alcohol or acetone etc.
Solvent volatilization is easy to eutectic saturation and is precipitated.Stand crystallization temperature be 15 DEG C~35 DEG C, preferably room temperature.
Alternatively, preparation method can be with are as follows: Berberine hydrochloride is added in lactic acid to saturation or Berberine hydrochloride and lactic acid
Reach the mixed solution of saturation, suspension crystallization.
Specifically, Berberine hydrochloride and lactic acid are added into methanol to saturation is both reached, formed Berberine hydrochloride and
Lactic acid reaches the mixed solution of saturation.
Suspension active force (physical forces such as mechanicals efforts or sound wave such as stirring) makes Berberine hydrochloride and lactic acid
Between generate halogen key, hydrogen bond the effects of power formed eutectic, solvent volatilizees simultaneously during suspension, be conducive to eutectic saturation precipitation.
The mode of suspension crystallization is stirring or ultrasound etc..
The temperature of suspension crystallization be 15 DEG C~35 DEG C, preferably room temperature.
The time of suspension crystallization is 3~8 hours, preferably 4~8 hours, more preferably 6 hours.
Berberine hydrochloride prepared by the present invention and lactic acid eutectic, reduce the hygroscopicity of Berberine hydrochloride, are convenient for preparations shaping
The control of environmental parameter in the process, processing step and technological parameter is conducive to preparations shaping, the stabilization after improving preparations shaping
Property.
Berberine hydrochloride prepared by the present invention and lactic acid eutectic can be used for preparing pharmaceutical preparation, contain salt in the pharmaceutical preparation
Sour jamaicin and lactic acid eutectic active constituent.
The pharmaceutical preparation also contains any one or more pharmaceutically acceptable auxiliary material, described pharmaceutically acceptable auxiliary
Material has carrier, excipient, disintegrating agent, flavoring agent, lubricant, adhesive etc..
The pharmaceutical preparation is prepared into pharmaceutically acceptable any with prevention and/or therapeutic effect as needed
Dosage form.Pharmaceutically acceptable dosage form has liquid preparation, solid pharmaceutical preparation or semisolid preparation etc..Solid pharmaceutical preparation includes but unlimited
In granule, capsule, tablet or pulvis；Liquid preparation includes but is not limited to injection, suspension or electuary；Tablet includes
But it is not limited to sugar coated tablet, film coated tablet or enteric coated tablet；Capsule includes but is not limited to hard capsule and soft capsule.
Compared with the existing technology, the invention has the benefit that
(1) Berberine hydrochloride prepared by the present invention and lactic acid eutectic can reduce the hygroscopicity of Berberine hydrochloride, enhance hydrochloric acid
The stability of jamaicin；The solubility and dissolution rate for improving Berberine hydrochloride improve its bioavilability, improve hygroscopicity, mention
The preparations shaping and stability of high Berberine hydrochloride；Improve the pharmacy and medical applications of Berberine hydrochloride.
(2) preparation process of Berberine hydrochloride eutectic of the present invention is simple and easy to control, and yield is up to 90%~93%, and purity is up to
91%~96%, yield and purity is high are low in cost, are suitable for industrialized production.
Detailed description of the invention
Fig. 1 is the schematic arrangement of Berberine hydrochloride of the present invention and lactic acid cocrystalization compound.
Fig. 2 is that Berberine hydrochloride and lactic acid cocrystalization compound, Berberine hydrochloride and lactic acid eutectic simulate powder, hydrochloric acid barberry
The PXRD spectrogram of two hydrate of alkali.
The Berberine hydrochloride that Fig. 3 is Berberine hydrochloride dihydrate (a), prepared by embodiment 1 is infrared with lactic acid eutectic (b)
Spectrogram.
Fig. 4 is the TGA of Berberine hydrochloride dihydrate (a), Berberine hydrochloride prepared by embodiment 1 and lactic acid eutectic (b)
Curve graph.
Fig. 5 is the DSC of Berberine hydrochloride dihydrate (a), Berberine hydrochloride prepared by embodiment 1 and lactic acid eutectic (b)
Curve graph.
Fig. 6 be embodiment 1 prepare Berberine hydrochloride and lactic acid eutectic, two hydrate of Berberine hydrochloride (API) it is molten
Out-degree curve.
Fig. 7 is the dynamic water adsorption curve (a) of Berberine hydrochloride dihydrate (API), Berberine hydrochloride two at room temperature
The Dynamic Water of Berberine hydrochloride and lactic acid eutectic prepared by dynamic water desorption curve (b), the embodiment 1 of hydrate (API)
Divide the dynamic water desorption curve (d) of adsorption curve (c), Berberine hydrochloride prepared by embodiment 1 and lactic acid eutectic.
Specific embodiment
Polishing is respectively adopted in the present invention at room temperature and suspension method prepares Berberine hydrochloride and the drug of lactic acid is total
Crystalline substance, molecular structure is as shown in Figure 1, using Berberine hydrochloride as active pharmaceutical ingredient (API), using lactic acid (formula II) as forerunner
One molecule Berberine hydrochloride, a molecule lactic acid and a molecular water are combined together to form salt by intermolecular halogen key, hydrogen bond by body
The crystallography asymmetric cell of sour jamaicin and lactic acid eutectic, wherein chlorine atom in Berberine hydrochloride molecule respectively with
The hydroxyl hydrogen atom of lactic acid molecules and the hydrogen atom of hydrone are by noncovalent interaction, in Berberine hydrochloride molecule and lactic acid molecules
Between, between Berberine hydrochloride molecule and hydrone be respectively formed halogen key；The carboxyl oxygen atom of lactic acid molecules is as hydrogen bond donor, moisture
Oxygen atom forms hydrogen bond as hydrogen bond receptor between lactic acid molecules and hydrone in son.Specific embodiment is as follows:
Embodiment 1
Solution assisted milling: accurately weighing 408mg Berberine hydrochloride dihydrate (1mmol) and 100mg lactic acid, (quality is dense
Spend 90%, 1mmol), it feeds intake, is placed in agate mortar according to molar ratio=1:1, then to Berberine hydrochloride dihydrate and cream
1~2 drop ethyl alcohol (about 0.05~0.1mL) is added dropwise in acid to be fully ground under room temperature, prepares Berberine hydrochloride and lactic acid is total
Brilliant solid powder, yield 90.5%, purity 96.2%.In the process, assisted solution volatilizees, and is conducive to eutectic and is precipitated.In grinding
The assisted solution of dropwise addition can also be methanol, normal propyl alcohol, acetone or isopropanol other than ethyl alcohol.
Embodiment 2
Suspension method: it accurately weighs 408mg Berberine hydrochloride dihydrate (1mmol) and dissolves in 10mL lactic acid (mass concentration
90%) in, supersaturated Berberine hydrochloride lactic acid solution is made, is sufficiently stirred 6 hours, until faint yellow solid, forming salt is precipitated
Sour jamaicin and lactic acid eutectic.
Embodiment 3
Dry milling processes: 408mg Berberine hydrochloride dihydrate (about 1mmol) and 100mg lactic acid (mass concentration are accurately weighed
90%, 1mmol), it feeds intake, is placed in agate mortar according to molar ratio=1:1, under room temperature, be fully ground, it is small to prepare hydrochloric acid
Bark of a cork tree alkali and lactic acid eutectic solid powder, yield 90%, purity 93%.
Embodiment 4
At room temperature, by 100mg lactic acid (mass concentration 90%, 1mmol) and 408mg Berberine hydrochloride dihydrate
(1mmol) is added in 10mL methanol, obtains the mixed solution that lactic acid and Berberine hydrochloride reach saturation, stirs at room temperature
It mixes, until Berberine hydrochloride and lactic acid eutectic, yield 93%, purity 91% is precipitated.
Berberine hydrochloride prepared in the above embodiments characterizes respective diffracting spectrum by PXRD with lactic acid eutectic, by red
Outside, DSC/TG, DVS carry out respective single crystal structure analysis, and carry out different solutions (water, methanol, ethyl alcohol) solubility, water respectively
Middle dissolution determination.Detailed process is as follows:
(1) PXRD (powder X-ray diffractometry) of Berberine hydrochloride and lactic acid eutectic is identified
Instrument: X-ray diffractometer (German BRUKER company, D2 type)；
Testing conditions: Cu-Ka target, tube voltage 30kV, tube current 10mA, scanning range θ are 5 ° -45 °, and scanning speed is
8 °/min, step width 0.015.
Berberine hydrochloride prepared by embodiment 1 and lactic acid eutectic, Berberine hydrochloride and lactic acid eutectic simulation powder, hydrochloric acid are small
The PXRD spectrogram of two hydrate of bark of a cork tree alkali as shown in Fig. 2, Berberine hydrochloride and lactic acid eutectic prepared by embodiment 1 in 2 θ of the angle of diffraction
For 8.43 ° ± 0.2,14.82 ° ± 0.2,15.26 ° ± 0.2,18.86 ° ± 0.2,19.99 ° ± 0.2,24.93 ° ± 0.2,
There is characteristic peak at 25.71 ° ± 0.2,26.33 ° ± 0.2.Berberine hydrochloride dihydrate 2 θ of the angle of diffraction be 8.64 ° ± 0.2,
9.09°±0.2、12.98°±0.2、16.31°±0.2、25.40°±0.2、26.26°±0.2、26.86°±0.2、30.20°
There is characteristic peak at ± 0.2.
As shown in Figure 2, relative to two hydrate of Berberine hydrochloride, the characteristic diffraction peak of Berberine hydrochloride and lactic acid eutectic
And significant changes occur for diffraction peak intensity, illustrate to react between Berberine hydrochloride and lactic acid, generate new object phase, and
Occurs the characteristic peak of Berberine hydrochloride Yu lactic acid eutectic at 25.71 °.
The 2 θ characteristic peak of the PXRD angle of diffraction of Berberine hydrochloride and lactic acid eutectic prepared by embodiment 2 to embodiment 4 and implementation
Example 1 is identical.Illustrate that dry milling processes, suspension method can equally promote to react between Berberine hydrochloride and lactic acid, generates new object phase.
(2) cell parameter of Berberine hydrochloride and lactic acid eutectic is tested
Eutectic structure is measured by X-ray single crystal diffractometer (Bruker SMART Apex IIdiffractometer),
Mo-Ka is scanned at a temperature of 173K.
The crystal structure of Berberine hydrochloride and lactic acid eutectic prepared by embodiment 1 is anorthic system, and space group P-1 is brilliant
Born of the same parents' parameter are as follows:α=70.047 (7) °, β=74.868
(7) °, γ=84.194 (7) °,Z=2.
The cell parameter of embodiment 2 to Berberine hydrochloride and lactic acid eutectic prepared by embodiment 4 is same as Example 1.
(3) IR Characterization of Berberine hydrochloride and lactic acid eutectic
Instrument: Fourier Transform Infrared Spectrometer (German BRUKER company, 55 type of Equinox)；
Testing conditions: scanning wave band is 4000~400cm-1, sample is using KBr solid preform, resolution ratio: 1cm-1。
The infrared spectrum of Berberine hydrochloride dihydrate (a), Berberine hydrochloride prepared by embodiment 1 and lactic acid eutectic (b)
As shown in figure 3, Berberine hydrochloride dihydrate is at least in about 3421cm-1、1621cm-1、1504cm-1、1028cm-1There is feature at place
Peak, Berberine hydrochloride and lactic acid eutectic are at least in about 3301cm-1、1711cm-1、1585cm-1、1279cm-1、1029cm-1Place's tool
There is characteristic peak.From the figure 3, it may be seen that relative to Berberine hydrochloride dihydrate, the infrared signature peak of Berberine hydrochloride and lactic acid eutectic
Significant changes have occurred, illustrate to react between Berberine hydrochloride and lactic acid, generate new object phase.
The infrared spectrum characteristic peak and 1 phase of embodiment of Berberine hydrochloride prepared by embodiment 2 to embodiment 4 and lactic acid eutectic
Together.
(4) DSC/TG (differential scanning calorimetry/thermogravimetry) of Berberine hydrochloride and lactic acid eutectic is tested
Instrument: DSC/TGA synchronous solving (SDT-600Q series DSC/TGA/DTA synchronous solving)；
Testing conditions: nitrogen atmosphere, gas flow rate: 10mL/min, heating rate be 10 DEG C/min, test temperature section:
Room temperature~250 DEG C.
The TGA spectrogram of Berberine hydrochloride and lactic acid eutectic (b) prepared by Berberine hydrochloride dihydrate (a) and embodiment 1
As shown in Figure 4.It is 8.9% that Berberine hydrochloride dihydrate (a), which loses quality at 99.6 DEG C, with Berberine hydrochloride dihydrate
In the Theoretical Mass 8.8% of two molecular waters match, illustrate that raw materials used Berberine hydrochloride is dihydrate；Berberine hydrochloride with
Lactic acid eutectic (b) has 3.9% mass loss at 67.1 DEG C, hydrone content (3.8%) kissing with theoretical calculation
It closes, illustrates to contain a crystallization water in Berberine hydrochloride-lactic acid eutectic.
The DSC spectrogram of Berberine hydrochloride and lactic acid eutectic (b) prepared by Berberine hydrochloride dihydrate (a) and embodiment 1
As shown in Figure 5.Berberine hydrochloride and lactic acid eutectic (b) have an absorption peak at 67.1 DEG C, illustrate Berberine hydrochloride-lactic acid eutectic
In contain moisture；There are a sharp exothermic peak, the thermal decomposition temperature of the corresponding cocrystalization compound at 210 DEG C.
The DSC/TG test result and 1 phase of embodiment of Berberine hydrochloride prepared by embodiment 2 to embodiment 4 and lactic acid eutectic
Together.
(5) solubility test of Berberine hydrochloride and lactic acid eutectic
The determination of I, optimal absorption wavelength
The solubility test of Berberine hydrochloride and lactic acid eutectic uses calibration curve method, and instrument: Agilent-1260S is efficient
Liquid chromatograph；Testing conditions: Agilent-C18Chromatographic column (4.6mm × 150nm, 5 μm), mobile phase: -0.4% phosphoric acid of methanol
Solution gradient elution, flow velocity: 1ml/min, Detection wavelength: 230nm, column temperature are 30 DEG C, 10 μ L of sample volume.
There is stronger absorption peak at 230nm in Berberine hydrochloride dihydrate, therefore, selectes and carries out at 230nm wavelength
The solubility and dissolution determination of Berberine hydrochloride and lactic acid eutectic.
The elution program of II .HPLC
III, Specification Curve of Increasing
It is appropriate that precision weighs Berberine hydrochloride dihydrate, prepare respectively 0.0196mg/ml, 0.0492mg/ml,
0.0983mg/ml, 0.1966mg/ml, 0.2949mg/ml, 0.3932mg/ml, 0.4915mg/ml, 0.5898mg/ml standard
Liquid, standard solution is through 0.45 μ L membrane filtration, and sample introduction measures peak area, linear equation according to above-mentioned HPLC testing conditions respectively
For Y=40044X+20.191, related R2=1 > 0.995, illustrate Berberine hydrochloride mass concentration in 0.0196~0.5898mg/
Linear relationship is good within the scope of ml.
The solubility test of IV, Berberine hydrochloride and lactic acid eutectic
Berberine hydrochloride and lactic acid eutectic prepared by Berberine hydrochloride dihydrate (API), embodiment 1 is molten at 25 DEG C
Solution degree measurement result is as shown in table 1, and the results are shown in Table 2 for solubility test at 37 DEG C.
Berberine hydrochloride dihydrate (API), Berberine hydrochloride and lactic acid eutectic solubility results at 1 25 DEG C of table is (single
Position mg/ml)
Berberine hydrochloride dihydrate (API), Berberine hydrochloride and lactic acid eutectic solubility results at 2 37 DEG C of table is (single
Position mg/ml)
By the result of Tables 1 and 2 it is found that as the temperature rises, Berberine hydrochloride, Berberine hydrochloride and lactic acid eutectic exist
Solubility in solvent (water, methanol and ethyl alcohol) increases, under the conditions of mutually synthermal, same solvent (water, methanol and ethyl alcohol), salt
The solubility of sour jamaicin and lactic acid eutectic is greater than Berberine hydrochloride.Berberine hydrochloride, Berberine hydrochloride and lactic acid eutectic water,
Methanol is identical with the solubility size sequence of ethyl alcohol, and order is as follows: SMethanol>SWater>SEthyl alcohol。
The solubility test result and 1 phase of embodiment of Berberine hydrochloride prepared by embodiment 2 to embodiment 4 and lactic acid eutectic
Seemingly.
The dissolution determination of V, Berberine hydrochloride and lactic acid eutectic
Accurately weigh two hydrate 109mg of Berberine hydrochloride (hydrochloric jamaicin 100mg), Berberine hydrochloride and lactic acid
Eutectic 129mg (wherein the amount of Berberine hydrochloride is 100mg) is that dissolution is situated between with 900mL water according to dissolution rate and drug release determination method
Matter, using slurry processes, setting revolving speed is 50r/min, and measurement temperature is 37 DEG C, starts timing when feeding intake, respectively 5min, 10min,
15min, 20min, 30min, 45min, 60min, 90min, 120min take the molten of same volume until raw material all dissolves completely
Medium out, i.e. 5mL supplement the dissolution medium of same volume, by the dissolution medium of taking-up water system filter membrane mistake after taking every time
Filter, filtrate move in liquid phase bottle, measure content, the accumulation of Berberine hydrochloride and lactic acid eutectic according to above-mentioned HPLC testing conditions
Dissolution profiles are as shown in Figure 6.
It will be appreciated from fig. 6 that reach when being completely dissolved in water, the time used in two hydrate of Berberine hydrochloride (API) is
90min, Berberine hydrochloride prepared by embodiment 1 are 30min with the time used in lactic acid eutectic, and Berberine hydrochloride and lactic acid are formed altogether
After crystalline substance, the dissolution rate of Berberine hydrochloride is substantially improved.
The dissolution rate test result and 1 phase of embodiment of Berberine hydrochloride prepared by embodiment 2 to embodiment 4 and lactic acid eutectic
Seemingly.
(6) the dynamic vapor sorption method (DVS) of Berberine hydrochloride and lactic acid eutectic measures
(Surface Measurement Systems, Britain) has carried out DVS experiment on SMS DVS instrument.First to two water of Berberine hydrochloride
It closes object powder, Berberine hydrochloride and lactic acid eutectic powder to dry, a few houres is dried in nitrogen stream to establish balance dry weight, relatively
Humidity range is 0% -95% -0%, and with 10%RH increment, temperature is remained unchanged at 25 DEG C, the dynamic water of progress
Suction/desorption test.
Berberine hydrochloride dihydrate (API) intramolecular contains two molecular waters, dynamic water adsorption curve and desorption
Curve is as shown in Figure 7.In dynamic water adsorption process, in 10%~70% RH range, Berberine hydrochloride two is hydrated
Object relative mass changes small, basic held stationary；When relative humidity rises to 70% or more, Berberine hydrochloride starts to absorb water
Point；When relative humidity reaches 95%, Berberine hydrochloride intramolecular is further added by two molecular waters, at this point, Berberine hydrochloride contains four
Molecular water.Berberine hydrochloride containing four molecular waters is more stable, in dynamic water desorption process, only when relative humidity is small
When 20%, the Berberine hydrochloride containing four molecular waters just starts dehydration, when relative humidity is down to 0%, water in Berberine hydrochloride
Point content only has 1% or so.
By dynamic water suction/desorption curve of Fig. 7 Berberine hydrochloride dihydrate it is found that Berberine hydrochloride dihydrate exists
In 10%~95% range of relative humidity, there are water adsorption lag to enclose, and moisture absorption hysteresis quality is presented in Berberine hydrochloride dihydrate,
Berberine hydrochloride dihydrate is strong with the affinity of hydrone, and hygroscopicity is high.
Berberine hydrochloride and lactic acid eutectic intramolecular contain a molecular water, Berberine hydrochloride and lactic acid prepared by embodiment 1
The dynamic water adsorption curve and desorption curve of eutectic are as shown in Figure 7.In dynamic water adsorption process, increase with humidity, salt
Sour jamaicin and lactic acid eutectic slow-absorbing moisture, when relative humidity rises to 70%, Berberine hydrochloride and lactic acid eutectic start by
Gradually substantially absorb moisture；When humidity reaches 95%, the moisture of Berberine hydrochloride and lactic acid eutectic molecule re-absorption 8%.Dynamic
In state moisture desorption process, relative humidity from 95% drop to 70% during, Berberine hydrochloride and lactic acid eutectic are rapid
Lose two molecular waters；Relative humidity from 70% drop to 20% or less when, the relative mass of Berberine hydrochloride and lactic acid eutectic becomes
Change slowly, Berberine hydrochloride is held essentially constant with the moisture in lactic acid eutectic；When relative humidity drops to 20% or less, again
Rapid dehydration.By dynamic water suction/desorption curve of Fig. 7 Berberine hydrochloride and lactic acid eutectic it is found that illustrate Berberine hydrochloride with
Lactic acid eutectic is obviously reduced with the affinity of hydrone, and hygroscopicity significantly reduces.
After Berberine hydrochloride is combined in the form of eutectic with lactic acid, Berberine hydrochloride or Berberine hydrochloride two are significantly improved
The hygroscopicity of hydrate improves preparation convenient for the control of environmental parameter, processing step and technological parameter during preparations shaping
Stability and bioavilability after molding.
The Dynamic Vapor of Berberine hydrochloride prepared by embodiment 2 to embodiment 4 and lactic acid eutectic inhale/be desorbed test result with
Embodiment 1 is similar.
The above-mentioned description to embodiment is for ease of ordinary skill in the art to understand and use the invention.It is ripe
The personnel for knowing art technology obviously easily can make various modifications to these embodiments, and general original described herein
It ought to use in other embodiments without having to go through creative labor.Therefore, the present invention is not limited to the above embodiments, this field
Technical staff's announcement according to the present invention, improvement and modification made without departing from the scope of the present invention all should be in guarantors of the invention
Within the scope of shield.
Claims (10)
1. Berberine hydrochloride and lactic acid eutectic, which is characterized in that be forerunner with lactic acid using Berberine hydrochloride as active pharmaceutical ingredient
Body, the crystal of formation；For anorthic system, space group P-1, cell parameter are as follows: α=70.047 (7) °, β=74.868 (7) °, γ=84.194 (7) °,Z=2.
2. Berberine hydrochloride according to claim 1 and lactic acid eutectic, which is characterized in that PXRD is in 2 θ of the angle of diffraction
8.43°±0.2、14.82°±0.2、15.26°±0.2、18.86°±0.2、19.99°±0.2、24.93°±0.2、25.71°
There is characteristic peak at ± 0.2,26.33 ° ± 0.2.
3. Berberine hydrochloride according to claim 1 and lactic acid eutectic, which is characterized in that infrared spectrum is in 1029 ± 5cm-1、1279±5cm-1、1585±5cm-1、1711±5cm-1、3301±5cm-1Place has characteristic peak.
4. Berberine hydrochloride according to claim 1 and lactic acid eutectic, which is characterized in that a molecule Berberine hydrochloride, one
Molecule lactic acid and a molecular water form the basic structural unit of Berberine hydrochloride and lactic acid eutectic by halogen key, hydrogen bond, and hydrochloric acid is small
The chlorine atom of bark of a cork tree base molecule is respectively with the hydrogen atom of the hydroxyl hydrogen atom of lactic acid molecules and hydrone by Non-covalent binding, in salt
Halogen key is respectively formed between sour barberry base molecule and lactic acid molecules, between Berberine hydrochloride molecule and hydrone；Carboxyl in lactic acid molecules
Oxygen atom is as hydrogen bond donor, and oxygen atom forms hydrogen bond as hydrogen bond receptor between lactic acid molecules and hydrone in hydrone.
5. the preparation method of any one of claim the 1-4 Berberine hydrochloride and lactic acid eutectic, which is characterized in that hydrochloric acid barberry
Grinding crystallization is blended with lactic acid for alkali；Or Berberine hydrochloride is added in lactic acid to supersaturation, suspension crystallization；Or Berberine hydrochloride
Reach the mixed solution of saturation, suspension crystallization with lactic acid.
6. preparation method according to claim 5, which is characterized in that be blended in grinding system, Berberine hydrochloride and lactic acid
Molar ratio be 1:0.9~3, the temperature of grinding is 15 DEG C~35 DEG C.
7. preparation method according to claim 5, which is characterized in that before grinding is blended, to Berberine hydrochloride and lemon
Be added solvent in acid, the amount ratio of the gross mass and solvent of Berberine hydrochloride and lactic acid is 2~15g/ml, solvent include methanol,
Ethyl alcohol, isopropanol, normal propyl alcohol or acetone.
8. preparation method according to claim 5, which is characterized in that Berberine hydrochloride reaches the suspension of saturation with lactic acid
In crystallization system, solvent for use is methanol.
9. preparation method according to claim 5, which is characterized in that the mode of suspension crystallization is stirring or ultrasound, is mixed
The temperature of outstanding crystallization is 15 DEG C~35 DEG C.
10. a kind of pharmaceutical preparation, which is characterized in that total containing any one of Claims 1 to 4 Berberine hydrochloride and lactic acid
It is brilliant.
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