CN109212145A - A kind of novel high time resolution on-line checking drug-eluting process analysis method - Google Patents
A kind of novel high time resolution on-line checking drug-eluting process analysis method Download PDFInfo
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Abstract
The invention discloses a kind of novel high time resolution on-line checking drug-eluting process analysis method, it includes: 1) by the dissolution medium in dissolution medium holding bottle, the lower end for the flow cell being placed in water bath with thermostatic control is pumped by constant flow pump, make the ultrapure water in flow cell and the medicament contact on stainless steel tablet frame, and makes drug-eluting；2) drug dissolved out is flowed out from flow cell upper end through filter membrane, and sample a part of outflow enters waste liquid cup, and another part is entered by the back-pressure of pressure-regulating valve and draws sample capillary；3) draw sample capillary and separation capillary docking, high pressure is added at separation capillary both ends, sample described in step 2 is set to carry out electrophoresis from flowing door interface electricity into separation capillary, the continuous high time resolution of real-time online is carried out to sample with Capillary Electrophoresis UV detector and separates analysis detection, completes the process in leaching detection of sample；The real-time highly sensitive detection for realizing continuous automatic sampling and high time resolution, obtains accurate drug-eluting information.
Description
Technical field
A kind of drug-eluting technical field of analysis and detection of the present invention, and in particular to novel high time resolution on-line checking drug
Process in leaching analysis method.
Background technique
Oral administration solid vitro Drug stripping analysis typically refers under the liquid environment of simulation human body stomach, to tablet, glue
The dissolution rate and dissolution degree of the solid pharmaceutical preparations such as capsule, particle realize accurate detection, to reflect that drug collapses in vivo
The characteristic of solution and dissolution release, to evaluate the bioequivalence and bioavilability of drug.Drug-eluting analysis is that drug is facing
Bed fast and accurately measures the dissolution curve of different dosage forms drug using a preceding important indicator for evaluating its quality,
The speed and degree that objective rational evaluation active pharmaceutical ingredient is dissolved out from pharmaceutical preparation to medicament research and development, quality control and are commented
Valence, imitation medicine quality and curative effect Conformance Assessment etc. are of great significance.
Traditional solid dosage forms use basket, paddle, reciprocating cylinder method, mostly use hand sample, the behaviour such as are filtered, diluted
After work, using volumetric analysis, colorimetric method or ultraviolet-uisible spectrophotometer, high performance liquid chromatograph etc. to the molten of drug
Object carries out offline inspection out.The analysis of this hand sample is not only cumbersome, and human error is larger, and when being only capable of obtaining several
Between the drug-eluting information put, it is difficult to the accurate overall process for understanding drug-eluting.Therefore, it explores more time saving and more convenient automatic
Detection method is increasingly becoming the development trend of drug-eluting analysis.It has been reported molten to drug by constant flow pump or Autosampler
Liquid carries out on-line period out, and spectrometer or HPLC is combined to detect, and obtains drug-eluting curve, compared to manual sampling analysis,
Improve the accuracy and precision of test.But the problems such as there are still pipeline absorption, washing difficulty, so that analysis precision reduces,
And particular, it is important that these technical methods can not achieve the dynamic on-line monitoring of the drug-eluting overall process of high time resolution.
Currently, the situ process monitoring based on optical fiber operates drug-eluting analysis without sampling, filtering, fluid infusion etc., simple and easy,
Process analysis procedure analysis simultaneously also increases the information content of drug-eluting analysis.But it is only limitted to ultraviolet and visible absorbance drug, and
Excipient used in detection will affect the accuracy of reflection and the refractometric analysis of light, at the same the design of immersion cell and its
Position, light scattering effect, air bubble problem and auxiliary material sedimentary effect in stripping rotor etc. all limit optical fiber to a certain extent
The development of drug-eluting analysis.In addition, the compound medicinal formulation for various ingredients is analyzed, it is still necessary to using double-wavelength method, lead
The complex mathematicals separation method processing such as number spectroscopic methodology, K ratio method is to obtain drug-eluting information.
Summary of the invention
Object of the present invention is to analyze existing light scattering effect, air bubble problem and auxiliary material to solve existing drug-eluting
The problems such as sedimentary effect, and a kind of on-line analysis detection method of new oral solid drugs dissolution dynamic overall process is provided.
A kind of novel high time resolution on-line checking drug-eluting process analysis procedure analysis device: it includes: dissolution medium storage bottle
1, constant flow pump 2, flow cell 3, water bath device 4, to interface 5, pressure-regulating valve 6, draw sample capillary 7, flowing door interface 8, electromagnetism
Valve 9, syringe pump 10, separation capillary 11, buffer solution bottle 12；
The dissolution medium storage bottle 1 is connect with flow cell 3 by constant flow pump 2, and flow cell 3 is placed in water bath device 4, docking
Mouth 5 sets three ports, and port is separately connected flow cell 3 by conduit, draws sample capillary 7 and pressure-regulating valve 6, draws sample capillary
7 are connected and fixed with separation capillary 11 by flowing door interface 8, and drawing between sample capillary 7 and separation capillary 11 has slit, are divided
Buffer solution bottle 12 is connected from capillary 11, sets three ports on solenoid valve 9, the first and second port is separately connected stream by conduit
Dynamic door interface 8, syringe pump 10, third port connects waste collecting device by conduit；
Stainless steel tablet frame is equipped in the flow cell 3, upper end is equipped with two layers of filter that aperture is respectively 2.7 μm and 0.7 μm
Film；
45 ~ 55 μm of the internal diameter for drawing sample capillary 7,360 ~ 370 μm of outer diameter, 8 ~ 12cm of length, separation capillary 11 it is interior
45 ~ 55 μm of diameter, 360 ~ 370 μm of outer diameter, 18 ~ 22cm of length；
50 μm of the internal diameter for drawing sample capillary 7,365 μm of outer diameter, length 10cm separate 50 μm of the internal diameter, outer of capillary 11
365 μm of diameter, length 20cm；
The slot distances are 10 ~ 100 μm；
The slot distances are 50 μm.
A kind of novel high time resolution on-line checking drug-eluting process analysis method, it includes:
1) it by the dissolution medium in dissolution medium holding bottle, is pumped into and is placed under the flow cell in water bath with thermostatic control by constant flow pump
End makes the dissolution medium in flow cell and the medicament contact on stainless steel tablet frame, and makes drug-eluting；
2) drug dissolved out is flowed out from flow cell upper end through filter membrane, and sample a part of outflow enters waste liquid cup, another part
Entered by the back-pressure of pressure-regulating valve and draws sample capillary；
3) draw sample capillary and separation capillary docking, sample flows to from docking slit from sample capillary is drawn, and closes solenoid valve, delays
It rushes solution and flowing door interface is pumped by syringe pump, rinse the sample in slit；
4) opens solenoid valve accumulates sample at slit, and integration time is 1.5 ~ 2.5s, by application sample introduction voltage, makes sample
Product enter separation capillary, and sample injection time is 0.8 ~ 1.2s；Solenoid valve is closed, extra sample wash to waste liquid pool is rinsed
Time is 1.5 ~ 2.5s, applies separation high pressure, carries out online separation analysis detection to the sample of dissolution；
The 10mM ammonium acetate buffer solution or pH of dissolution medium described in step 1) is water, pH is 1.2 HCl solution, pH 4.5
For 6.8 10 mM phosphate buffer solutions, temperature is 36.5 ~ 37.5 DEG C；
Filter membrane described in step 2 is two layers of filter membrane, and aperture is respectively 2.7 μm and 0.7 μm；
Integration time described in step 4) is 2s, sample injection time 1s, washing time 2s；
The drug, dosage form are solid dosage forms.
The present invention provides a kind of novel high time resolution on-line checking drug-eluting process analysis procedure analysis devices: it includes: molten
Out medium storage bottle 1, constant flow pump 2, flow cell 3, water bath device 4, to interface 5, pressure-regulating valve 6, draw sample capillary 7, flowing
Door interface 8, solenoid valve 9, syringe pump 10, separation capillary 11, buffer solution bottle 12；A kind of novel high time resolution on-line checking
Drug-eluting process analysis method, it includes: that 1) dissolution medium in dissolution medium holding bottle is pumped by constant flow pump and is placed in
The lower end of flow cell in water bath with thermostatic control makes the ultrapure water in flow cell and the medicament contact on stainless steel tablet frame, and
Make drug-eluting；2) drug dissolved out is flowed out from flow cell upper end through filter membrane, and sample a part of outflow enters waste liquid cup, separately
A part is entered by the back-pressure of pressure-regulating valve and draws sample capillary；3) draw sample capillary and separation capillary docking, separating
Capillary both ends add high pressure, so that sample described in step 2 is carried out electrophoresis from flowing door interface electricity into separation capillary, with hair
Cons electrophoresis UV detector carries out the continuous high time resolution of real-time online to sample and separates analysis detection, completes the dissolution of sample
Process detection；The invention proposes a kind of circulation pool technologies of novel collection dynamic analog body fluid circulatory, automatic sequence sample introduction skill
The online process analysis method for the vitro Drug dissolution rate that art and high-speed video recorder separation detection technique are integrated, is opened
Open up the process analysis procedure analysis of high time resolution on-line checking drug-eluting rate and degree；For the process in leaching of different type drug,
The real-time highly sensitive detection for realizing continuous automatic sampling and high time resolution, obtains accurate drug-eluting information, has for science
It carries out to effect the evaluation quality of the pharmaceutical preparations and reference is provided.
Detailed description of the invention
A kind of novel high time resolution on-line checking drug-eluting process analysis procedure analysis structure drawing of device of Fig. 1, dissolution medium storage
Bottle 1, constant flow pump 2, flow cell 3, water bath device 4, to interface 5, pressure-regulating valve 6, draw sample capillary 7, flowing door interface 8, electricity
Magnet valve 9, syringe pump 10, separation capillary 11, buffer solution bottle 12；
Fig. 2 flows door interface figure and internal capillaries docking scheme, and (a) flows door interface, and (b) internal capillaries are to interface；
Fig. 3 difference dissolution medium flow velocity influences result to drug-eluting；
Fig. 4 flows door sample injection time cyclematics；
Fig. 5 different condition is to flowing door sample introduction-high-speed video recorder separation detection influence；(a) slit docks distance, (b)
Load sample time, (c) sample injection time (d) rinse the time of redundant sample, (e) flow door and draw sample speed, (f) rinse speed；Fig. 6
The reproducibility of dissolving device drug-eluting in the present invention；
Fig. 7 present invention is to acetparaminosalol tablet standard items (a) and Compound Chlorzoxazone tablet standard items (its two component difference
For Chlorzoxazone (b) and paracetamol (c)) on-line checking standard curve；
2 paracetamol tablet of Fig. 8 embodiment process in leaching real-time online high time resolution detection electrophoretic image and
Dissolution curve in four kinds of different dissolution mediums, the electrophoretic image of (A) real-time online high time resolution detection, four kinds of (B) not
With the dissolution curve in dissolution medium；
The process in leaching real-time online of 3 Compound Chlorzoxazone tablet of Fig. 9 embodiment separates the electrophoretic image of analysis detection and four
Dissolution curve in kind different dissolution mediums, A) detection of real-time online high time resolution electrophoretic image, (B) four kinds of differences are molten
Dissolution curve in medium out；
Figure 10 embodiment 3 be the on-line checking of paracetamol and Compound Chlorzoxazone tablet of the present invention dissolution curve and
The dissolution curve of offline inspection carries out data fitting result, (A) paracetamol, (B) Compound Chlorzoxazone.
Specific embodiment
The technical scheme of the invention is further explained by means of specific implementation.Those skilled in the art should be bright
, the described embodiments are merely helpful in understanding the present invention, should not be regarded as a specific limitation of the invention.
A kind of novel high time resolution on-line checking drug-eluting process analysis procedure analysis device of embodiment 1
A kind of novel high time resolution on-line checking drug-eluting process analysis procedure analysis device is as shown in Figure 1, it includes: dissolution medium storage
Deposit bottle 1, constant flow pump 2, flow cell 3, water bath device 4, to interface 5, pressure-regulating valve 6, draw sample capillary 7, flowing door interface 8,
Solenoid valve 9, syringe pump 10, separation capillary 11, buffer solution bottle 12；
The dissolution medium storage bottle 1 is connect with flow cell 3 by constant flow pump 2, and flow cell 3 is placed in water bath device 4, docking
Mouth 5 sets three ports, and port is separately connected flow cell 3 by conduit, draws sample capillary 7 and pressure-regulating valve 6, draws sample capillary
7 are connected and fixed with separation capillary 11 by flowing door interface 8, and drawing between sample capillary 7 and separation capillary 11 has slit, are divided
Buffer solution bottle 12 is connected from capillary 11, sets three ports on solenoid valve 9, the first and second port is separately connected stream by conduit
Dynamic door interface 8, syringe pump 10, third port connects waste collecting device by conduit；
Stainless steel tablet frame is equipped in the flow cell 3, upper end is equipped with two layers of filter that aperture is respectively 2.7 μm and 0.7 μm
Film；
50 μm of the internal diameter for drawing sample capillary 7,365 μm of outer diameter, length 10cm separate 50 μm of the internal diameter, outer of capillary 11
365 μm of diameter, length 20cm, efficiently separating distance is 5cm；
The slot distances are 50 μm.
Optimization (such as Fig. 3) to the device flow cell flow velocity；Paracetamol tablet different flow cell flow velocity (4,
8,16 mL/min) under dissolution curve it is as shown in Figure 3；When flow velocity is 16 mL/min, about 95% paracetamol drug
It is dissolved out after 15 min, and under the flow velocity of 4mL/min and 8mL/min, the dissolution rate of drug is only about 60% and 80%；These numbers
According to the increase shown with flow cell flow velocity, dissolution rate increases, therefore is made in next experiment using 16 mL/min
For flow cell flow velocity.
Flow door sample injection time programmed control process such as Fig. 4；Fig. 4 shows the flowing door sample introduction of automated procedures control
Time series chart.The sample obtained after dissolution flows to from docking slit from sample capillary 7 is drawn, and solenoid valve is in close state at this time
(9 closed state of solenoid valve: buffer solution is pumped into flowing door interface 8 by syringe pump 10 and rinses the sample in slit), prevents
Sample separates capillary 11 since diffusion enters when only applying separation high pressure.When starting sample introduction, computer is according in advance
The time series chart of setting follows the steps below: first turning on solenoid valve 9, sample is made to accumulate 2s at slit, then by applying
Sample voltage is added, sample injection time 1s, so that sample electrokinetic injection is closed solenoid valve 9 while entering separation capillary 11 will be extra
Sample wash to waste liquid pool, washing time 2s applies separation high pressure at this time and carries out online separation analysis inspection to the sample of dissolution
It surveys.
To the series of optimum (such as Fig. 5) of device flowing door strip part；As shown in Fig. 5 (a), when drawing sample capillary and separation
When the docking distance of capillary 11 too small (10 μm), it will be entered from the sample that sample capillary 7 flows out is drawn due to diffusion point
From in capillary 11.However, biggish docking distance (100 μm) is no when separating 11 both ends of capillary application separation high pressure
Sample electrokinetic injection can be entered to separation capillary 11.Therefore, optimum capillary docking distance selection is at 50 μm or so；
Fig. 5 (b) describes sample from the optimization electrophoretic image for drawing sample accumulated time of the outflow of sample capillary 7 full of slit.Sample
When product accumulated time is 3s, under the action of separating high pressure, in addition to entering separation extracapillary 11 also by the sample of electrokinetic injection
The sample slight spread being deposited at slit is had into separation capillary 11, two components is caused to be unable to baseline separation.When 2s, peak
Area peak height is constant, and peak shape is preferable, and it is narrow to illustrate that the sample accumulated time of 2s can be such that sample docks full of two capillaries just
Seam, makes sample completely instead of the dcq buffer solution at slit, but when 1s, since accumulated time is inadequate, peak-to-peak signal reduces.
Therefore, select best sample accumulated time for 2s；
As shown in Fig. 5 (c), sample injection time has been investigated based on peak shape and peak area.When sample injection time is greater than 1s(2s and 3s)
When, since the sample of electrokinetic injection is excessive, peak shape broadens and is unable to baseline separation.Therefore, the sample injection time set is 1s；
Fig. 5 (d) describes the optimization electrophoretic image investigated according to peak height and peak area and buffer molten washing time.Between when rinsing
When being set as 1s, peak shape broadens and is unable to baseline separation, illustrates that washing time not enough has the sample not rinsed out not adding sample
Diffused into when voltage separation capillary 11, but when rinsing between 2s ~ 3s when, there is similar peak shape and peak face
Product, illustrates that 2s washing time is enough to clean remaining sample, shortens the bulk analysis time；
When dcq buffer solution flow velocity is 100 μ L/min, different flowing doors draws electrophoretic image such as Fig. 5 (e) institute of sample flow velocity
Show.When drawing sample flow velocity less than 100 nL/min, the sample accumulated time of 2s is insufficient to allow sample to substitute flushing completely full of slit
Buffer solution.Select to draw sample flow velocity as 100 nL/min；
Fig. 5 (f) shows the electrophoretic image under different dcq buffer solution flow velocitys.When dcq buffer solution flow velocity is less than 20 μ
When L/min, sample can be diffused into separation capillary, can not achieve fast and effective flushing；Higher dcq buffer solution flow velocity
Can more efficiently prevent from sample during the separation process from slit electromigration to separation capillary.But too fast dcq buffer
Solution speed (being greater than 100 μ L/min) will receive the influence of bottleneck effect, while most of sample can be washed into waste liquid pool,
To reduce the sensitivity of sample analysis.Therefore selection 100 μ L/min of dcq buffer solution speed；
Based on the above results, optimal flowing door strip part is to draw sample capillary 7 and separate the slot distances that capillary 11 docks to be
50 μm, sample accumulated time 2s, sample injection time 1s, washing time 2s, sample draw sample flow velocity 100nL/min, dcq buffer solution
100 μ L/min of speed；
The reproduction Journal of Sex Research (such as Fig. 6) of apparatus of the present invention；As shown in fig. 6, using the method continuous sample introduction 30 μ g/mL of the present apparatus
Paracetamol standard solution (n=20).The results show this method favorable reproducibility, transit time, peak height, peak area
Relative standard deviation is respectively 1.56%, 2.42% and 0.93%.
A kind of novel high time resolution on-line checking drug-eluting process analysis method of embodiment 2
With a kind of novel high time resolution on-line checking drug-eluting process analysis method, the medicine of paracetamol tablet is realized
Object process in leaching real-time online continuously detects, and concrete operations are as follows:
By a large amount of fresh dissolution mediums of 37 ± 0.5 DEG C in dissolution medium holding bottle, it is pumped by constant flow pump in constant temperature
Open drug-eluting is realized in the lower end of flow cell in water-bath, make ultrapure water be located at stainless steel tablet frame on to second
The contact of acylamino- phenol tablet, the tablet of dissolution are respectively 2.7 μm and 0.7 μm of two layers of filter membrane stream by aperture from flow cell upper end
Out, the sample of outflow enters waste liquid cup all the way, and another way is entered by the back-pressure of pressure-regulating valve and draws sample capillary, draws sample capillary
Pipe and separation capillary docking add high pressure at separation capillary both ends, by sample from flowing door interface electricity into separation capillary
Electrophoresis is carried out, the continuous high time resolution of real-time online is carried out to paracetamol tablets with Capillary Electrophoresis UV detector and is separated
Analysis detection completes the process in leaching detection of paracetamol tablets；Therefore, the real-time continuous online of paracetamol is obtained
Electrophoretic image (Fig. 8 a), 80% or more acetparaminosalol phenol agents are dissolved out in 5 min or so, the medicine of 15 min or so 90% or more
Product are completely dissolved.
By converting accumulative dissolution rate for instantaneous dissolution rate, calculating real-time dissolution rate and drawing dissolution curve,
Formula is as follows:
In formula, Dissolved% ti The accumulative dissolution percentage of time drug, n are sample point number, ciFor tiTime circulation
The drug concentration of pond outflow, Dosage* are the effective component quality of drug, and flow rate is dissolution medium flow velocity；
The dissolution medium is respectively that water, the HCl solution of pH 1.2, the 10mM ammonium acetate buffer solution of pH 4.5 or pH are
6.8 10 mM phosphate buffer solutions；
Dissolution curve of the paracetamol dispersible tablet in four kinds of different dissolution mediums is as shown in Figure 8 (b), the results showed that, it is molten
The selection of medium has no significant effect the dissolution rate of paracetamol out, and dissolution curve is similar.
A kind of novel high time resolution on-line checking drug-eluting process analysis method of embodiment 3
With a kind of novel high time resolution on-line checking drug-eluting process analysis method, the medicine of Compound Chlorzoxazone tablet is realized
Object process in leaching real-time online continuously detects, and concrete operations are as follows:
By a large amount of fresh dissolution mediums of 37 ± 0.5 DEG C in dissolution medium holding bottle, it is pumped by constant flow pump in constant temperature
Open drug-eluting is realized in the lower end of flow cell in water-bath, makes ultrapure water and the compound on stainless steel tablet frame
The contact of Chlorzoxazone tablet, the tablet of dissolution are respectively 2.7 μm and 0.7 μm of two layers of filter membrane stream by aperture from flow cell upper end
Out, the sample of outflow enters waste liquid cup all the way, and another way is entered by the back-pressure of pressure-regulating valve and draws sample capillary, draws sample capillary
Pipe and separation capillary docking, add high pressure at separation capillary both ends, and sample is carried out electricity from interface electricity into separation capillary
Swimming carries out the continuous high time resolution separation analysis of real-time online to Compound Chlorzoxazone tablet with Capillary Electrophoresis UV detector
Detection is completed to detect (Fig. 9 a) to the dissolution rate of Compound Chlorzoxazone tablet, the absorbance of Chlorzoxazone and paracetamol
Reach maximum value in 6 min and 5 min or so respectively, 90% or more Chlorzoxazone and paracetamol is in 16 min or so
Dissolution.
By converting accumulative dissolution rate for instantaneous dissolution rate, calculating real-time dissolution rate and drawing dissolution curve,
Formula is as follows:
In formula, Dissolved% ti The accumulative dissolution percentage of time drug, n are sample point number, ciFor tiTime circulation
The drug concentration of pond outflow, Dosage* are the effective component quality of drug, and flow rate is dissolution medium flow velocity；
The dissolution medium is respectively that water, the HCl solution of pH 1.2, the 10mM ammonium acetate buffer solution of pH 4.5 and pH are
6.8 10 mM phosphate buffer solutions；
Dissolution curve of the COMPOUND CHLORZOXAZONE TABLETS in four kinds of different dissolution mediums is as shown in Figure 9 (b), the results showed that, not at 4 kinds
In same dissolution medium, there was no significant difference for the dissolution rate of paracetamol, but the dissolution rate of Chlorzoxazone is with dissolution medium
PH value increase and reduce, dissolution rate reaches maximum in the dissolution medium of 1.2 HCl of pH.
4 the method for the present invention of embodiment and offline hand sample testing result compare
Online process in leaching curve: with the dissolution rate of the method detection drug of flow cell series flow door sample introduction, being computed can be obtained
The online dissolution curve (Figure 10 A) of open flow cell drug, dissolution curve others preparation process is the same as embodiment 2 and 3.
Offline process in leaching curve: tablet being put into the flow cell in constant temperature water bath apparatus of the invention, with continuous pump
The 37 DEG C of dissolution mediums contact entered, constitutes open digestion series, it is made to carry out dissolution reaction, the sample of dissolution passes through circulation
Pond upper end after two layers of filter membrane that aperture is respectively 2.7 μm and 0.7 μm filters out, flow into sample divider, every 3min into
The primary offline sampling of row, sample carry out offline inspection with capillary ultraviolet detection, by calculate and draw to detect drug from
Line dissolution curve (Figure 10 B).
The data fitting of online process in leaching curve and offline dissolution dissolution curve: by following equation to online and offline
Dissolution data be fitted:
In formula, f2For the similar factors between two curves, n is sample time points, RjAnd TjFor online dissolution curve and offline molten
Average accumulated dissolution rate of the curve at jth time point out, if f2>=50, two dissolution curves are similar；f2< 50, two dissolutions are bent
Line is dissimilar.
It is computed, the online and offline dissolution curve similar factors f of paracetamol tablets and COMPOUND CHLORZOXAZONE TABLETS2
>=50, therefore it can prove that the online and offline dissolution curve of paracetamol tablets and COMPOUND CHLORZOXAZONE TABLETS is not obvious
Difference demonstrates the accuracy of this method.
In conclusion detection method proposed by the invention can carry out real-time online high score to one pack system and multicomponent pharmaceutical
It distinguishes separation analysis detection, does not need the pre-treatment and cumbersome artificial sampling process of sample, can obtain completely dissolving out data, people
It is small for error, integrate Dissolution experiments and analysis detection.In practical applications, have for the dissolution rate detection of drug latent
Application value.
Reagent instrument and equipment source used in the present invention:
1, paracetamol dispersible tablet:；Chinese medicines group Huanqiu Pharmaceutical Co., Ltd., Guangdong；
2, COMPOUND CHLORZOXAZONE TABLETS: Lunan Beite Pharmaceutical Co., Ltd.；
3, sodium dihydrogen phosphate/disodium hydrogen phosphate: Sigma-Aldrich；
4, ammonium acetate/acetic acid: Sigma-Aldrich；
5,12 mol/L hydrochloric acid: Sigma-Aldrich；
6,50 μm of internal diameters, 365 μm of outer diameter capillaries: the sharp Feng chromatography device Co., Ltd of Hebei Yongnian；
7, Capillary Electrophoresis UV detector: CoMetro Technology Co., Ltd. of the U.S.；
8, chromatographic work station: Shanghai everything Instrument Ltd.；
9, high voltage power supply: Tianjin Dongwen High Voltage Power Supply Factory；
10, syringe pump: Jiashan Rui Chuan Electronic Science and Technology Co., Ltd.；
11, constant flow pump: upper Industrial Co., Ltd. of Nereid section；
12, solenoid valve: Shanghai pellet can solenoid valve Co., Ltd.
The Applicant declares that the present invention illustrates the process method of the present invention through the above embodiments, but the present invention not office
It is limited to above-mentioned processing step, that is, does not mean that the present invention must rely on the above process steps to be carried out.Technical field
Technical staff is it will be clearly understood that any improvement in the present invention, to the equivalence replacement and drug ingedient of material selected by the present invention
Selection etc., all of which fall within the scope of protection and disclosure of the present invention.
Claims (10)
1. a kind of novel high time resolution on-line checking drug-eluting process analysis procedure analysis device, it includes: dissolution medium storage bottle
(1), constant flow pump (2), flow cell (3), water bath device (4), to interface (5), pressure-regulating valve (6), draw sample capillary (7), stream
Dynamic door interface (8), solenoid valve (9), syringe pump (10), separation capillary (11), buffer solution bottle (12)；
The dissolution medium storage bottle (1) is connect with flow cell (3) by constant flow pump (2), and flow cell (3) is placed in water bath device
(4) in, three ports are set to interface (5), port is separately connected flow cell (3) by conduit, draws sample capillary (7) and pressure tune
It saves valve (6), draws sample capillary (7) and separation capillary (11) and be connected and fixed by flowing door interface (8), draw sample capillary (7)
There are slit, separation capillary (11) connection buffer solution bottle (12) between separation capillary (11), solenoid valve sets three on (9)
Port, the first and second port are separately connected flowing door interface (8), syringe pump (10) by conduit, and third port is connected by conduit
Waste collecting device.
2. a kind of novel high time resolution on-line checking drug-eluting process analysis procedure analysis device according to claim 1, special
Sign is: stainless steel tablet frame is equipped in the flow cell 3, upper end is equipped with two layers that aperture is respectively 2.7 μm and 0.7 μm
Filter membrane.
3. a kind of novel high time resolution on-line checking drug-eluting process analysis procedure analysis device according to claim 1 or 2,
Be characterized in that: 45 ~ 55 μm of the internal diameter for drawing sample capillary (7), 360 ~ 370 μm of outer diameter, 8 ~ 12cm of length separate capillary
11 45 ~ 55 μm of internal diameter, 360 ~ 370 μm of outer diameter, 18 ~ 22cm of length.
4. a kind of novel high time resolution on-line checking drug-eluting process analysis procedure analysis device according to claim 3, special
Sign is: 50 μm of the internal diameter for drawing sample capillary 7,365 μm of outer diameter, length 10cm, separate capillary 11 50 μm of internal diameter,
365 μm of outer diameter, length 20cm.
5. a kind of novel high time resolution on-line checking drug-eluting process analysis procedure analysis device according to claim 4, special
Sign is: the slot distances are 10 ~ 100 μm.
6. a kind of novel high time resolution on-line checking drug-eluting process analysis procedure analysis device according to claim 5, special
Sign is: the slot distances are 50 μm.
7. a kind of novel high time resolution on-line checking drug-eluting process analysis method, it includes:
1) it by the dissolution medium in dissolution medium holding bottle, is pumped into and is placed under the flow cell in water bath with thermostatic control by constant flow pump
End makes the dissolution medium in flow cell and the medicament contact on stainless steel tablet frame, and makes drug-eluting；
2) drug dissolved out is flowed out from flow cell upper end through filter membrane, and sample a part of outflow enters waste liquid cup, another part
Entered by the back-pressure of pressure-regulating valve and draws sample capillary；
3) draw sample capillary and separation capillary docking, sample flows to from docking slit from sample capillary is drawn, and closes solenoid valve, delays
It rushes solution and flowing door interface is pumped by syringe pump, rinse the sample in slit；
4) opens solenoid valve accumulates sample at slit, and integration time is 1.5 ~ 2.5s, by application sample introduction voltage, makes sample
Product enter separation capillary, and sample injection time is 0.8 ~ 1.2s；Solenoid valve is closed, extra sample wash to waste liquid pool is rinsed
Time is 1.5 ~ 2.5s, applies separation high pressure, carries out online separation analysis detection to the sample of dissolution.
8. a kind of novel high time resolution on-line checking drug-eluting process analysis method according to claim 7, special
Sign is: the 10mM ammonium acetate buffer solution of dissolution medium described in step 1) is water, pH is 1.2 HCl solution, pH 4.5 or
The 10 mM phosphate buffer solutions that pH is 6.8, temperature are 36.5 ~ 37.5 DEG C.
9. a kind of novel high time resolution on-line checking drug-eluting process analysis method according to claim 7 or 8,
Be characterized in that: filter membrane described in step 2 is two layers of filter membrane, and aperture is respectively 2.7 μm and 0.7 μm.
10. a kind of novel high time resolution on-line checking drug-eluting process analysis method according to claim 9, special
Sign is: integration time described in step 4) is 2s, sample injection time 1s, washing time 2s；The drug, dosage form are solid
Body dosage form.
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