CN110296990B - Device and method for detecting content of polyvinyl alcohol in microsphere preparation - Google Patents
Device and method for detecting content of polyvinyl alcohol in microsphere preparation Download PDFInfo
- Publication number
- CN110296990B CN110296990B CN201910609899.XA CN201910609899A CN110296990B CN 110296990 B CN110296990 B CN 110296990B CN 201910609899 A CN201910609899 A CN 201910609899A CN 110296990 B CN110296990 B CN 110296990B
- Authority
- CN
- China
- Prior art keywords
- polyvinyl alcohol
- transparent container
- microspheres
- content
- liquid film
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/84—Systems specially adapted for particular applications
- G01N21/8422—Investigating thin films, e.g. matrix isolation method
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/84—Systems specially adapted for particular applications
- G01N2021/8405—Application to two-phase or mixed materials, e.g. gas dissolved in liquids
Landscapes
- Physics & Mathematics (AREA)
- Mathematical Physics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analysing Materials By Optical Means (AREA)
Abstract
The invention discloses a device and a method for detecting the content of polyvinyl alcohol in a microsphere preparation, wherein the device comprises the following components: a transparent container for holding the microsphere formulation and the organic solvent-water system; an emulsifier for emulsifying the microsphere preparation and the organic solvent-water system contained in the transparent container; the image collector is used for capturing the contour of the liquid film after emulsification treatment; and the image processor is connected with the image collector and used for receiving the liquid film contour, calculating the area of the liquid film contour and calculating the content of the polyvinyl alcohol in the microspheres according to an emulsion liquid film area-concentration standard curve formed by polyvinyl alcohol with known concentration. The detection method is to indirectly measure the concentration of the polyvinyl alcohol by using the emulsification effect of the polyvinyl alcohol. The detection device provided by the invention is simple to operate, good in repeatability and accurate in result, provides a specific measure for quantitatively detecting the content of polyvinyl alcohol in the microsphere preparation, and scientifically and effectively solves the problem of difficult quantification of polyvinyl alcohol.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a device and a method for detecting residual quantity of polyvinyl alcohol in a microsphere preparation.
Background
Polyvinyl Alcohol (PVA) is an artificially synthesized water-soluble compound, and is obtained by carrying out base-catalyzed alcoholysis on Polyvinyl acetate by using methanol as a solvent. The polyvinyl alcohol has no toxicity and side effect on human bodies, no irritation to skin and good biocompatibility, is an excellent pharmaceutic adjuvant and a process aid, and has wide application in the field of medicines. The molecular structure of polyvinyl alcohol contains hydrophilic alcoholic hydroxyl and lipophilic polyethylene long chain, can reduce water-oil interfacial tension to achieve a water-oil emulsification effect, and is often used as an emulsifier and a stabilizer in an emulsion polymerization process.
Microspheres refer to a dispersion of microparticles of a drug dispersed or adsorbed in a polymer matrix. The microspheres are usually prepared by emulsifying the immiscible polymer dispersed phase and continuous phase (external aqueous phase or organic phase) by mechanical stirring, homogenization or ultrasound, etc. to obtain a homogeneous emulsion, and then removing the organic solvent by solvent evaporation or solvent extraction. In the preparation process of the microsphere preparation, the surfactant can reduce the surface tension of a dispersed phase, form a film or an electric double layer on the surfaces of microdroplets, prevent the microdroplets from mutually aggregating and fully disperse in a medium to form emulsion.
The matrix material for preparing the microspheres is a lot and belongs to the hydrophobic high polymer class, such as polylactic-co-glycolic acid (PLGA). The hydrophilic-lipophilic Balance (HLB) value of the polyvinyl alcohol is 12.3, and is between 12 and 18, and the polyvinyl alcohol is an excellent oil-in-water (O/W) emulsifier. Polyvinyl alcohol and Poly (lactic-co-glycolic acid) (PLGA) copolymer affinity is better, and polyvinyl alcohol aqueous solution (0.1% -5%) is usually used as external water phase in the microsphere preparation process, and its hydrophilic/lipophilic ability is balanced, and can be directionally arranged on water-oil interface, and can reduce PLGA oil drop interface tension, but not be completely distributed in oil phase or water phase. Polyvinyl alcohol has no immunogenicity in vivo and no toxic or side effect on human body, but for local injection, the polyvinyl alcohol is not degradable in vivo, is accumulated in the organism for a long time and is not easy to be discharged, and the residual level needs to be strictly controlled and is not higher than the acceptable quantity level. Therefore, the content of the polyvinyl alcohol in the final product of the microsphere preparation needs to be strictly controlled, so that the development of a method for quantitatively analyzing the polyvinyl alcohol in the microsphere preparation is of great significance. The method is very limited at present for accurately and quantitatively detecting the content of polyvinyl alcohol with a series of different polymerization degrees, and even if the content can be quantitatively detected, the detection limit is higher and is not sensitive enough.
At present, research is carried out on the determination of the content of polyvinyl alcohol in an aqueous solution, mainly by a spectrophotometry and a liquid chromatography. Spectrophotometric method uses two adjacent hydroxyl groups of polyvinyl alcohol and iodine molecule to generate blue-green complex in boric acid medium, and has maximum absorption at 690nm [ l-lactate-co-glycolide) nanoparticles and cellulose ether ]. For example, CN109342650A discloses a method for determining the content of 1, 2-diol phase structure in polyvinyl alcohol, which comprises dissolving a polyvinyl alcohol sample to be determined in water, adding periodic acid to completely react, adding potassium iodide, standing in the dark for 5-15min, finally performing quantitative titration with sodium thiosulfate solution under the display of starch indicator until colorless is the end point, and recording the volume of the consumed sodium thiosulfate solution, thereby calculating and obtaining the content of 1, 2-diol phase structure in the polyvinyl alcohol to be determined. However, due to the relatively complex composition of the microspheres, various chemical substances carrying hydroxyl groups, such as water-soluble bulk drugs, mannitol serving as a freeze-drying protective agent, and the like, may exist, and all of the chemical substances interfere with the quantitative detection of polyvinyl alcohol. The limit of quantitation of the content of the polyvinyl alcohol detected by a spectrophotometric method is mu g/mL, and both the detection limit and the limit of quantitation are far insufficient for trace polyvinyl alcohol residue (< 1 mu g/mL) of the microsphere preparation.
Molecular exclusion chromatography-evaporative light scattering detection method for detecting polyvinyl alcohol content, adopting NaOH solution to crack microspheres, adopting HCl solution to neutralize, adopting dialysis bag to retain PLGA degradation products after neutralization, adopting signal-to-noise ratio method, using sample concentration with 3 times of noise peak as the lowest detection concentration, and detecting that the lowest detection limit is 10 mug/mL [ Quantitative analysis of polyvinyl alcohol on the surface of poly (d, l-lactate-co-glycolide) microscopic particles preparation by solution evaluation method: effect of particulate size and PVA concentration ]. In addition, by its principle, size exclusion chromatography cannot effectively distinguish a specific component, polyvinyl alcohol, when macromolecules of similar polarity and similar molecular weight are present in the microspheres. At present, the detection limits of spectrophotometry and liquid chromatography are both in the range of 0.1 mu g/mL-1 mg/mL, and the method is not suitable for analyzing trace polyvinyl alcohol residues.
At present, no method for accurately and quantitatively analyzing the content of the ultra-trace polyvinyl alcohol exists in the domestic medicament industry. Therefore, there is an urgent need to find a highly sensitive and effective quantitative detection method.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a detection device and a detection method for trace polyvinyl alcohol.
The invention adopts the following technical scheme to solve the technical problems in the prior art:
an apparatus for detecting polyvinyl alcohol content in a microsphere preparation, comprising: a transparent container for holding the microsphere formulation and the organic solvent-water system; an emulsifier for emulsifying the microsphere preparation and the organic solvent-water system contained in the transparent container; the image collector is used for capturing the contour of the liquid film after emulsification treatment; and the image processor is connected with the image collector and used for receiving the liquid film contour, calculating the area of the liquid film contour and calculating the content of the polyvinyl alcohol in the microspheres according to an emulsion liquid film area-concentration standard curve formed by polyvinyl alcohol with known concentration.
Preferably, the transparent container, the emulsifier and the image collector are supported by a support frame.
Preferably, the support frame comprises a horizontal base and a fixed support vertically connected with one side of the horizontal base, and an upper moving rod and a lower moving rod are vertically and respectively arranged on the fixed support.
Preferably, the bottom of the transparent container and the horizontal plane keep an included angle of 0 degree, namely the container is a flat bottom, and the bottom of the container is supported on the lower moving rod through the transparent plate.
Preferably, the transparent container is made of a material having high light transmittance and organic solvent resistance, and may be made of glass, organic glass, plastic, resin, or the like, and among them, a glass material is preferable.
Preferably, the transparent container is in a thin and high cylinder shape, and the height-diameter ratio of the transparent container is 2: 1-5: 1. The volume of the transparent container is 50-300 ml.
Preferably, the transparent plate is made of a material having high light transmittance and high strength, and may be made of glass, organic glass, plastic, resin, or the like, and among them, organic glass is preferable.
Preferably, the emulsifier comprises a motor fixedly connected with the upper moving rod and a dispersing cutter head positioned at the lower end of the motor and connected with the motor, and a stator and a rotor are mounted at the tail end of the dispersing cutter head and extend into the transparent container. The emulsifier is a high-shear dispersion emulsifier, the output power is not lower than 300W, and the adjustable range of the rotating speed comprises 3000-20000 rpm. The transparent container is filled with an organic solvent-water system, the middle part of the transparent container is a water-oil interface, and the stator and the rotor of the dispersing cutter head are just positioned at the water-oil interface after standing.
Preferably, the temperature control jacket is arranged outside the transparent container, the cooling circulating medium is introduced into the temperature control jacket, the temperature of the sample can be kept constant in the emulsification process after the cooling circulating medium is introduced into the temperature control jacket, the temperature control precision is +/-2 ℃, and the cooling circulating medium with high temperature reduction efficiency can be glycol aqueous solutions with different volume ratios.
Preferably, the image collector is positioned right below the transparent container and fixed on the horizontal base through the telescopic bracket, the height is adjusted to enable the image at the water-oil interface in the transparent container to be clearly captured, and the captured image is transmitted to the image processor through the data line.
Preferably, the organic solvent-water system should be two mutually incompatible phases, but the extraction system formed can dissolve all the ingredients in the formulation sample to form a clear, layered two-phase solution, with the dichloromethane-water system being preferred.
Preferably, the image collector is a digital camera capable of supporting on-line collection, the brand can be Canon, Nikon, Olympus, and the like, and the model of the camera with more than 1200 ten thousand pixels is preferred.
Preferably, the image processor is a computer system installed with irregular figure area calculation software, and the area calculation software may be CAD, Matlab, IPP, etc.
Another object of the present invention is to provide a method for detecting the content of polyvinyl alcohol in a microsphere preparation, which comprises the following steps:
(1) weighing microspheres and adding the microspheres into a transparent container, wherein an organic solvent-water system is added into the transparent container in advance, and the mass-volume ratio of the microspheres to the organic solvent-water system is as follows: (50-200): (30-60) mg/ml, starting an emulsifier, stirring until the microspheres are completely dissolved to obtain a transparent layered two-phase solution, and keeping the temperature to 25 ℃;
(2) starting the emulsifier again, emulsifying for 2-5 min, stopping emulsifying, removing the emulsifier, and standing until the microemulsion drops on the water-oil interface to form a continuous single-layer emulsion liquid film;
(3) opening an image collector positioned below the transparent container, adjusting the position relation between the image collector and the transparent container to enable the image collector to clearly capture the contour of the emulsion film from bottom to top, and transmitting the contour to the self-image processor through a data line;
(4) the image processor calculates the area of the contour of the emulsion film by adopting area software, and calculates the content of polyvinyl alcohol in the microsphere according to an emulsion film area-concentration standard curve formed by polyvinyl alcohol with known concentration, wherein the calculation formula of the content of residual polyvinyl alcohol in the microsphere is as follows:
P＝CVS1/MS2
in the formula:
c is the concentration of the polyvinyl alcohol aqueous solution with known concentration, and the unit is mu g/ml;
v is the volume of the aqueous phase in the organic solvent-water system, and the unit is ml;
m is the weighed mass of the microspheres, and the unit is mg;
p is the mass percent of the residual polyvinyl alcohol in the microspheres, and the unit is wt per mill;
S1the area of the emulsion liquid film formed for the microsphere sample, in cm2；
S2The area of an emulsion film formed by polyvinyl alcohol solution with known concentration is expressed in cm2。
The method belongs to an indirect measurement method, and the concentration of the polyvinyl alcohol is indirectly measured by utilizing the emulsification effect of the polyvinyl alcohol without depending on the molecular structure of the polyvinyl alcohol and the molecular weight distribution of the polyvinyl alcohol. The polyvinyl alcohol is almost insoluble in organic solvents, comprises benzene, toluene, dichloroethane, carbon tetrachloride, acetone, ethyl acetate and the like, has a molecular structure in which an aliphatic hydrocarbon unit is hydrophobic and a hydroxyl unit is hydrophilic, has an HLB value of between 12 and 18, and is a stable and excellent oil-in-water emulsifier. When the polyvinyl alcohol content is low (less than 0.01%), only a single-layer emulsion film is formed, and the emulsion films are gradually gathered together to form a continuous emulsion film which is laid on the water-oil interface. In addition, when a thin and tall container is selected, the water-oil interface area formed by the organic solvent-water system with the same volume is smaller, and a trace amount of polyvinyl alcohol in a large-volume solution can be enriched on the water-oil interface and form an emulsion film visible to naked eyes. When the concentration of the diluted polyvinyl alcohol exceeds 0.01%, the polyvinyl alcohol is diluted and then detected by the method.
Compared with the prior art, the invention has the beneficial effects that:
1. the detection device provided by the invention is simple to operate, good in repeatability and accurate in result, provides a specific measure for quantitatively detecting the content of polyvinyl alcohol in the microsphere preparation, and scientifically and effectively solves the problem of difficult quantification of polyvinyl alcohol;
2. when a thin and high type transparent container is selected, the area of a water-oil interface formed by the organic solvent-water system with the same volume is smaller, and a trace amount of polyvinyl alcohol in a large volume solution can be enriched on the water-oil interface to form a macroscopic emulsion film. Therefore, the detection method disclosed by the invention has low detection limit, and the detection limit of the polyvinyl alcohol can be reduced to the ng/ml level.
3. The detection principle of the invention is to indirectly measure the concentration of polyvinyl alcohol by using the emulsification effect of the polyvinyl alcohol, and the method avoids the interference of the residual substance carrying hydroxyl groups in the microsphere preparation on the detection result, for example, a large amount of mannitol serving as a freeze-drying protective agent is added during the freeze-drying of the microsphere, so that the great interference is caused on the measurement result, and the defects of inaccurate quantification of a spectrophotometry method, high quantification limit and the like are caused. The method also makes up the problems of high limit of quantitation and poor specificity of a molecular exclusion chromatography-evaporative light scattering detection method. The realization of the method fills the blank of an effective detection method for residual polyvinyl alcohol in the microsphere preparation in the field of medicine.
Drawings
FIG. 1 is a schematic diagram of a single-layer emulsion liquid film formed at an oil-water interface by polyvinyl alcohol measured by an emulsification method;
reference numbers in the figures: the device comprises a transparent container 1, an emulsifier 2, an image collector 3, an image processor 4, a horizontal base 5, a fixed support 6, an upper moving rod 7, a lower moving rod 8, a transparent plate 9, a motor 10, a dispersing cutter head 11, a stator and a rotor 12, a temperature control jacket 13 and a telescopic support 14.
Detailed Description
Reference will now be made in detail to the exemplary embodiments, examples of which are illustrated in the accompanying drawings. In the following description and in the drawings, the same numbers in different drawings identify the same or similar elements unless otherwise indicated. The embodiments described in the following exemplary embodiments do not represent all embodiments consistent with the present invention. Rather, they are merely examples of apparatus consistent with certain aspects of the invention, as detailed in the claims below. Various embodiments of the present description are described in an incremental manner.
It should be noted that all the directional indicators (such as up, down, left, right, front, and rear … …) in the embodiment of the present invention are only used to explain the relative position relationship between the components, the movement situation, etc. in a specific posture (as shown in the drawing), and if the specific posture is changed, the directional indicator is changed accordingly.
In addition, technical solutions between various embodiments may be combined with each other, but must be realized by a person skilled in the art, and when the technical solutions are contradictory or cannot be realized, such a combination should not be considered to exist, and is not within the protection scope of the present invention.
Example 1
As shown in fig. 1, the present invention provides a device for detecting the content of polyvinyl alcohol in a microsphere preparation, comprising: a transparent container 1 for holding a microsphere formulation and an organic solvent-water system; an emulsifier 2 for emulsifying the microsphere preparation and the organic solvent-water system contained in the transparent container 1; the image collector 3 is used for capturing the contour of the liquid film after emulsification treatment; and the image processor 4 is connected with the image collector 3 and used for receiving the liquid film contour, calculating the area of the liquid film contour and calculating the content of the polyvinyl alcohol in the microspheres according to an emulsion liquid film area-concentration standard curve formed by polyvinyl alcohol with known concentration.
The further technical scheme is that the transparent container 1, the emulsifier 2 and the image collector 3 are supported by a support frame. The support frame include horizontal base 5 and with 5 one side vertical continuous fixed bolster 6 of horizontal base, fixed bolster 6 goes up the perpendicular branch and is equipped with down and move pole 7 and move pole 8 down.
The further technical proposal is that the transparent container 1 is a flat-bottom container, and the bottom of the transparent container is supported on the lower moving rod 8 through a transparent plate 9. Preferably, the transparent container 1 is made of glass. The transparent plate 9 is preferably made of organic glass.
The further technical scheme is that the transparent container 1 is in a thin and tall cylindrical shape, and the height-diameter ratio ranges from 2:1 to 5: 1. The volume of the transparent container 1 is 50-300 ml.
The emulsifier 2 comprises a motor 10 fixedly connected with the upper moving rod 7 and a dispersing cutter head 11 positioned at the lower end of the motor 10 and connected with the motor, wherein a stator and a rotor 12 are installed at the tail end of the dispersing cutter head 11, and the stator and the rotor 12 extend into the transparent container 1. The emulsifier 2 is a high-shear dispersion emulsifier, the output power is not lower than 300W, and the adjustable range of the rotating speed comprises 3000-20000 rpm. An organic solvent-water system is arranged in the transparent container 1, a water-oil interface is arranged in the middle of the transparent container, and the stator and the rotor 12 of the dispersing tool bit 11 are just positioned at the water-oil interface after standing.
The further technical scheme is that a temperature control jacket 13 is arranged outside the transparent container 1, a cooling circulating medium is introduced into the temperature control jacket 13, the temperature of a sample can be kept constant in the emulsification process after the cooling circulating medium is introduced into the temperature control jacket 13, the temperature control precision is +/-2 ℃, and the cooling circulating medium with high temperature reduction efficiency can be glycol aqueous solutions with different volume ratios.
The further technical scheme is that the image collector 3 is positioned right below the transparent container 1 and fixed on the horizontal base 5 through the telescopic bracket 14, and the image at the water-oil interface in the transparent container 1 can be clearly captured by adjusting the height.
Example 2
(1) Weighing 100mg of leuprorelin acetate microspheres, adding into a transparent container, adding 30ml of organic solvent dichloromethane-water system (1:1), starting an emulsifier to 3000rpm, homogenizing until the microspheres are completely dissolved to obtain a transparent layered two-phase solution, and keeping the temperature to 25 ℃;
(2) starting the emulsifier to 10000rpm, emulsifying for 2min, stopping emulsifying when the residual polyvinyl alcohol can form stable microemulsion drops on the water-oil interface, removing the emulsifier, and standing until the microemulsion drops form a continuous single-layer emulsion liquid film on the water-oil interface;
(3) the image collector below the transparent container captures the contour of the emulsion film from bottom to top at the first time, the contour is transmitted to the image processor through a data line, the image processor calculates the area of the irregular graph by adopting CAD area software, and the residual amount of the polyvinyl alcohol in the microspheres is calculated according to the area of the emulsion film formed by the polyvinyl alcohol with known type and concentration.
(4) The calculation formula of the content of the residual polyvinyl alcohol in the microspheres is as follows:
P＝CVS1/MS2
in the formula:
c is the concentration of the polyvinyl alcohol aqueous solution with known concentration, and the unit is mu g/ml;
v is the volume of the aqueous phase in the organic solvent-water system, and the unit is ml;
m is the weighed mass of the microspheres, and the unit is mg;
p is the proportion of residual polyvinyl alcohol in the microspheres, and the unit is wt per thousand;
S1the area of the emulsion liquid film formed for the microsphere sample, in cm2；
S2The area of an emulsion film formed by polyvinyl alcohol solution with known concentration is expressed in cm2；
And (3) detection results: the residual quantity of polyvinyl alcohol in the microsphere is 0.035 per mill (w/w). (wherein C is 0.1. mu.g/ml, V is 15ml, S1Is 2.00cm2，S2Is 0.87cm2M is 100mg)
Example 3
(1) Weighing 50mg risperidone microspheres, adding into a transparent container, adding 30ml organic solvent dichloromethane-water system (1:1), starting an emulsifier to 3000rpm, homogenizing until the microspheres are completely dissolved to obtain a transparent layered two-phase solution, and keeping the temperature to 25 ℃;
(2) starting the emulsifier to 10000rpm, emulsifying for 2min, stopping emulsifying when the residual polyvinyl alcohol can form stable microemulsion drops on the water-oil interface, removing the emulsifier, and standing until the microemulsion drops form a continuous single-layer emulsion liquid film on the water-oil interface;
(3) the image collector below the transparent container captures the contour and area of the emulsion film from bottom to top at the first time, the contour and area are transmitted to the image processor through a data line, the image processor calculates the area of the irregular graph by adopting CAD area software, and the residual amount of the polyvinyl alcohol in the microspheres is calculated according to the area of the emulsion film formed by polyvinyl alcohol of known type and concentration.
(4) The calculation formula of the content of the residual polyvinyl alcohol in the microspheres is as follows:
P＝CVS1/MS2
in the formula:
c is the concentration of the polyvinyl alcohol aqueous solution with known concentration, and the unit is mu g/ml;
v is the volume of the aqueous phase in the organic solvent-water system, and the unit is ml;
m is the weighed mass of the microspheres, and the unit is mg;
p is the proportion of residual polyvinyl alcohol in the microspheres, and the unit is wt per thousand;
S1the area of the emulsion liquid film formed for the microsphere sample, in cm2；
S2The area of an emulsion film formed by polyvinyl alcohol solution with known concentration is expressed in cm2；
And (3) detection results: the residual quantity of polyvinyl alcohol in the microsphere is 0.085 per mill (w/w). (wherein C is 0.1. mu.g/ml, V is 15ml, S1Is 2.17cm2，S2Is 0.76cm2M is 50mg) (remarks: is different from PVA manufacturers used for leuprorelin microspheres. )
Example 4
Adding 15% (w/w) mannitol into the microspheres of example 1, lyophilizing, and detecting again by the method of example 1 to obtain the final product with polyvinyl alcohol residue of 0.028 ‰ (C is 0.1 μ g/ml, V is 15ml, and S is1Is 1.62cm2，S2Is 0.87cm2M is 100mg), about 0.033% o (0.028% divided by 85%) of the residue remained in the microspheres after conversion, except for the mannitol portion. For the same reasonThe detection results of the microspheres with the polyvinyl alcohol residual quantity in the examples 1 and 2 are consistent, which shows that the detection of the polyvinyl alcohol content by the emulsification method is not interfered by hydroxyl substances in the microsphere powder.
Example 5
The content of the residual polyvinyl alcohol in the microspheres of example 3 was measured by spectrophotometry, and the following steps were performed:
(1) weighing 20g of boric acid, adding water to dissolve the boric acid, and then fixing the volume to 500ml to prepare a boric acid solution;
(2) weighing 6.25g of potassium iodide and 3g of iodine, adding water to dissolve the potassium iodide and the iodine, and then fixing the volume to 250ml to prepare an iodine-potassium iodide solution;
(3) weighing 100mg of microspheres, adding water to a constant volume of 5ml, incubating in a water bath at 50-70 ℃ for 4h, cooling to room temperature, and centrifuging to obtain a supernatant;
(4) accurately measuring 1ml of polyvinyl alcohol aqueous solution to be detected by a pipette, sequentially adding 10ml of boric acid solution and 2ml of iodine-potassium iodide solution, reacting for 5-10min at room temperature, and measuring the absorbance of the solution at 640nm by an ultraviolet spectrophotometer.
The method determines that the concentration of polyvinyl alcohol and the absorbance have a linear relation, the response range is 1-20 mu g/mL, the content of the glycolide-lactide copolymer (PLG) in the microspheres is 90%, and the content of the water-soluble drug is 10%. The absorbance values of the blank excipients at the same ratio were measured by spectrophotometry as shown in table 1. The detection result shows that mannitol greatly interferes the detection of the content of the polyvinyl alcohol. TABLE 1 blank excipients and Absorbance values
Example 6
Detecting the content of polyvinyl alcohol in the solution by using a size exclusion chromatography-evaporative light scattering detection method, which comprises the following steps:
(1) mobile phase: 0.1% trifluoroacetic acid-water solution; column SWXL 2000; a detector: evaporative light scattering detector
(2) The sample size was 20. mu.L, and the flow rate was 1.0 ml/min.
(3) The results are shown in Table 2 below
TABLE 2 polyvinyl alcohol concentration and Peak area response
As can be seen from the above table, when the content of polyvinyl alcohol is detected by using size exclusion chromatography-evaporative light scattering detection method, when the content of polyvinyl alcohol in the aqueous solution of polyvinyl alcohol is 1mg/ml, the peak area response is extremely low, the baseline noise is large, the sensitivity is poor, and the detection limit is high.
Any modification or addition to the embodiments described herein by those skilled in the art will be within the scope of the invention without departing from the spirit of the invention or exceeding the scope of the claims.
Claims (11)
1. A device for detecting polyvinyl alcohol content in a microsphere preparation is characterized by comprising:
a transparent container for holding the microsphere formulation and the organic solvent-water system;
an emulsifier for emulsifying the microsphere preparation and the organic solvent-water system contained in the transparent container;
the image collector is used for capturing the contour of the liquid film after emulsification treatment;
and the image processor is connected with the image collector and used for receiving the liquid film contour, calculating the area of the liquid film contour and calculating the content of the polyvinyl alcohol in the microspheres according to an emulsion liquid film area-concentration standard curve formed by polyvinyl alcohol with known concentration.
2. The apparatus of claim 1, wherein the transparent container, emulsifier and image collector are supported by a support frame.
3. The device as claimed in claim 2, wherein the supporting frame comprises a horizontal base and a fixed bracket vertically connected with one side of the horizontal base, and the fixed bracket is vertically provided with an upper moving rod and a lower moving rod.
4. The apparatus according to claim 3, wherein the transparent container is a flat-bottomed container, the bottom of which is supported on the lower moving bar through a transparent plate.
5. The apparatus of claim 4, wherein the flat bottom container is made of a material that is highly transparent to light and resistant to organic solvents.
6. The apparatus of claim 4, wherein the emulsifier comprises a motor fixedly connected with the upper moving rod and a dispersing cutter head positioned at the lower end of the motor and connected with the motor, and a stator and a rotor are arranged at the tail end of the dispersing cutter head and extend into the transparent container.
7. The apparatus according to claim 6, wherein the transparent container is externally provided with a temperature-controlling jacket through which a cooling circulating medium is introduced.
8. The device of claim 7, wherein the image collector is positioned right below the transparent container and fixed on the horizontal base through a telescopic bracket.
9. The apparatus according to any one of claims 1 to 8, wherein the organic solvent-water system is two mutually incompatible phases.
10. The apparatus of claim 9, wherein the organic solvent-water system is a dichloromethane-water system.
11. A method for detecting the content of polyvinyl alcohol in a microsphere preparation is characterized by comprising the following steps:
(1) weighing microspheres and adding the microspheres into a transparent container, adding an organic solvent-water system into the transparent container in advance, starting an emulsifier, stirring until the microspheres are completely dissolved to obtain a transparent layered two-phase solution, and keeping the temperature to 25 ℃;
(2) starting the emulsifier again, emulsifying for 2-5 min, stopping emulsifying, removing the emulsifier, and standing until the microemulsion drops on the water-oil interface to form a continuous single-layer emulsion liquid film;
(3) opening an image collector positioned below the transparent container, adjusting the position relation between the image collector and the transparent container to enable the image collector to clearly capture the contour of the emulsion film from bottom to top, and transmitting the contour to the self-image processor through a data line;
(4) the image processor calculates the area of the contour of the emulsion film by adopting area software, and calculates the content of polyvinyl alcohol in the microsphere according to an emulsion film area-concentration standard curve formed by polyvinyl alcohol with known concentration, wherein the calculation formula of the content of residual polyvinyl alcohol in the microsphere is as follows:
P=CVS1/MS2
in the formula:
c is the concentration of the polyvinyl alcohol aqueous solution with known concentration, and the unit is mu g/ml;
v is the volume of the aqueous phase in the organic solvent-water system, and the unit is ml;
m is the weighed mass of the microspheres, and the unit is mg;
p is the mass percent of the residual polyvinyl alcohol in the microspheres, and the unit is wt%;
S1the area of the emulsion liquid film formed for the microsphere sample, in cm2；
S2The area of an emulsion film formed by polyvinyl alcohol solution with known concentration is expressed in cm2。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910609899.XA CN110296990B (en) | 2019-07-08 | 2019-07-08 | Device and method for detecting content of polyvinyl alcohol in microsphere preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910609899.XA CN110296990B (en) | 2019-07-08 | 2019-07-08 | Device and method for detecting content of polyvinyl alcohol in microsphere preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110296990A CN110296990A (en) | 2019-10-01 |
| CN110296990B true CN110296990B (en) | 2021-07-13 |
Family
ID=68030633
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910609899.XA Active CN110296990B (en) | 2019-07-08 | 2019-07-08 | Device and method for detecting content of polyvinyl alcohol in microsphere preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110296990B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112824892B (en) * | 2019-11-21 | 2023-06-06 | 浙江圣兆药物科技股份有限公司 | Method for detecting content of polyvinyl alcohol in microspheres |
| CN111583270B (en) * | 2020-04-10 | 2022-06-10 | 昆明理工大学 | Method for evaluating mixing effect of immiscible two phases |
| CN112485211B (en) * | 2020-11-13 | 2024-02-27 | 深圳善康医药科技股份有限公司 | Quantitative extraction and analysis method of trace polyvinyl alcohol in polylactic acid microspheres |
| CN113504196A (en) * | 2021-07-06 | 2021-10-15 | 珠海联邦制药股份有限公司 | Method for detecting content of polyvinyl alcohol by spectrophotometry |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7410744B2 (en) * | 2005-12-02 | 2008-08-12 | Fujifilm Corporation | Recording method |
| CN109800631A (en) * | 2018-12-07 | 2019-05-24 | 天津大学 | Fluorescence-encoded micro-beads image detecting method based on masked areas convolutional neural networks |
-
2019
- 2019-07-08 CN CN201910609899.XA patent/CN110296990B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7410744B2 (en) * | 2005-12-02 | 2008-08-12 | Fujifilm Corporation | Recording method |
| CN109800631A (en) * | 2018-12-07 | 2019-05-24 | 天津大学 | Fluorescence-encoded micro-beads image detecting method based on masked areas convolutional neural networks |
Non-Patent Citations (1)
| Title |
|---|
| 退浆废水中聚乙烯醇的分析检测研究;韩芳等;《干旱环境监测》;20170331;第31卷(第1期);全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110296990A (en) | 2019-10-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110296990B (en) | Device and method for detecting content of polyvinyl alcohol in microsphere preparation | |
| Aiedehe et al. | Chitosan microcapsules as controlled release systems for insulin | |
| CN1287774C (en) | Composition for inhalation | |
| Jana et al. | Interpenetrating hydrogels of O-carboxymethyl Tamarind gum and alginate for monitoring delivery of acyclovir | |
| Puoci et al. | New restricted access materials combined to molecularly imprinted polymers for selective recognition/release in water media | |
| Langham et al. | Mechanistic insights into the dissolution of spray-dried amorphous solid dispersions | |
| Kulkarni et al. | Novel interpenetrated polymer network microbeads of natural polysaccharides for modified release of water soluble drug: in-vitro and in-vivo evaluation | |
| Reich | Ultrasound-induced degradation of PLA and PLGA during microsphere processing: influence of formulation variables | |
| Woraphatphadung et al. | Synthesis and characterization of pH-responsive N-naphthyl-N, O-succinyl chitosan micelles for oral meloxicam delivery | |
| Kregar et al. | Development and validation of an in vitro release method for topical particulate delivery systems | |
| CN102232937A (en) | Nanometer preparation and preparation method thereof | |
| Ofokansi et al. | Formulation and evaluation of glutaraldehyde-crosslinked chitosan microparticles for the delivery of ibuprofen | |
| CN108079308B (en) | Coenzyme Q10Nano-structure lipid carrier compounded with octacosanol and preparation method thereof | |
| Tian et al. | Synthesis and evaluation of chitosan-vitamin C complex | |
| CN108670960A (en) | A kind of hyaluronic acid oligosaccharide-chitosan microball and the preparation method and application thereof containing Docetaxel | |
| Svirskis et al. | Development of mucoadhesive floating hollow beads of acyclovir with gastroretentive properties | |
| Kim | Soluplus-coated colloidal silica nanomatrix system for enhanced supersaturation and oral absorption of poorly water-soluble drugs | |
| Kilor et al. | Development of stable nanosuspension loaded oral films of glimepiride with improved bioavailability | |
| Okunlola et al. | Development of ibuprofen microspheres using acetylated plantain starches as polymer for sustained release | |
| Yan et al. | In vitro and in vivo evaluation of poly (acrylic acid) modified mesoporous silica nanoparticles as pH response carrier for β-elemene self-micro emulsifying | |
| CN112485211B (en) | Quantitative extraction and analysis method of trace polyvinyl alcohol in polylactic acid microspheres | |
| Wang et al. | Development and characterization of an amorphous curcumin-Eudragit® E100 solid dispersions with improved solubility, stability, and pharmacokinetic properties | |
| Vidyadhara | Development and characterization of a novel nanosuspension based drug delivery system of valsartan: A poorly soluble drug | |
| US20140256818A1 (en) | Nano-suspension process | |
| Ray et al. | pH sensitive interpenetrating network bio containers of gum ghatti for sustained release of glipizide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |