CN113768926A - Valsartan dispersion liquid, preparation method thereof and particle size determination method - Google Patents
Valsartan dispersion liquid, preparation method thereof and particle size determination method Download PDFInfo
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- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 2
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
- G01N15/02—Investigating particle size or size distribution
- G01N15/0205—Investigating particle size or size distribution by optical means, e.g. by light scattering, diffraction, holography or imaging
Abstract
The invention discloses a valsartan dispersion liquid, a preparation method thereof and a particle size determination method, wherein the valsartan dispersion liquid comprises an isoparaffin solvent and valsartan. The preparation method of the valsartan dispersion liquid is simple, easy to operate, good in reproducibility and free of requirements on equipment. The selection of the ultrasonic time and the ultrasonic frequency in the preparation method is crucial, if the ultrasonic time and the ultrasonic frequency are not up to the requirements, the valsartan particles can be aggregated, and if the ultrasonic time and the ultrasonic frequency exceed the ultrasonic time and the ultrasonic frequency in the invention, the valsartan particles are easy to break.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a valsartan dispersion liquid, a preparation method thereof and a particle size determination method.
Background
Valsartan is an angiotensin II receptor antagonist, is used for treating hypertension, congestive heart failure and post-myocardial infarction, has the characteristics of lasting and stable blood pressure reducing effect and small toxic and side effects, and has wide clinical application and huge market demand along with the increase of the number of people suffering from the diseases in recent years.
The valsartan is mostly a solid preparation, for the solid preparation, the drug dissolution speed directly influences the drug absorption and the curative effect, the dissolution speed of the solid drug is closely related to the particle size of the drug, according to the requirements of the dissolution rates of different solid preparations, the particle size of the raw material drug is controlled within a reasonable range so as to achieve the maximum drug effect, and the development of a proper particle size detection method of the raw material drug is very important.
In the current standard, the particle size control method is the particle size and particle size distribution measurement method recorded in the fourth part of the 'Chinese pharmacopoeia' 2020 edition: microscopy, sieving, laser scattering. Wherein the microscopic method can not control the limit of the particle size of the raw material medicine and requires no agglomeration phenomenon in the observed visual field, so the microscopic method can be used for assisting in observing the dispersion condition of the raw material medicine particles. The valsartan is white crystal or white and white-like powder in appearance and character, has hygroscopicity, is seriously pasted and sieved when the particle size distribution is measured by using a sieving method, has low sieving efficiency and cannot accurately control the particle size of the valsartan. Similarly, valsartan has a strong electrostatic adsorption effect, and when a dry method in laser scattering is attempted to be used for measurement, a valsartan sample cannot uniformly and stably pass through a detection window, so that valsartan is not suitable for dry measurement in a sieving method and a laser scattering method.
When the wet method is adopted for measurement, the dispersion method of the sample is the key point of the measurement, a proper dispersion medium is searched according to the dissolution property of the raw material medicine, valsartan is very soluble in ethanol, is soluble in methanol, is slightly soluble in ethyl acetate and is almost insoluble in water. Since valsartan is dissolved in an organic solvent to destroy the particle size of the raw material, the conventional organic solvent is not suitable, but the valsartan is hardly dissolved in water, so that water can be used as a good dispersion medium theoretically, but in actual sample dispersion, the fact that the sample floats on an upper layer to form a cluster when water is used as a dispersing agent is found due to the strong electrostatic adsorption effect of valsartan, and the sample cannot be uniformly dispersed by ultrasound (see figure 1).
In general, surfactants are substances which can reduce the surface tension of a liquid, and can play roles of solubilization, emulsification and wetting, and the surface tension of the liquid can be obviously reduced by adding a small amount of the substances, and documents report that 2% Sodium Dodecyl Sulfate (SDS) aqueous solution is used for dispersing valsartan raw material particles, but experiments show that the raw material with finer particles cannot be fully dispersed (see fig. 2), and in the measurement process, when 2% SDS aqueous solution is added to a sample injector to serve as a sample measurement medium, a stirring device is opened, so that a large amount of bubbles are easily generated to interfere with the background and influence the measurement result, if pure water is used as a dispersion medium in the sample injector, even if the dispersed valsartan dispersion liquid is added to the sample injector, the valsartan raw material particles are still re-aggregated after the stirring device is opened, and the true particle size distribution of the raw material cannot be measured (see fig. 3).
Disclosure of Invention
In order to solve the problems of the prior art, an object of the present invention is to provide a valsartan dispersion which has a good dispersing effect, is stable, and is less likely to aggregate.
Another object of the present invention is to provide a method for preparing a valsartan dispersion liquid, which can uniformly and stably disperse valsartan in an isoparaffin solvent.
The invention also aims to provide a method for measuring the particle size of the valsartan dispersion, which has good reproducibility and precision.
The invention has the following inventive concept: at present, the particle size of valsartan is not determined by a proper method, but the reason is that the valsartan particles have stronger electrostatic adsorption and the agglomeration of the particles cannot embody accurate particle size. If the particle size of the valsartan bulk drug is to be accurately determined, a proper dispersion medium is required to be found to ensure that the valsartan particles are fully dispersed under the laboratory condition, and the dispersion medium can be tolerated by an instrument, has no interference on the determination background, is nontoxic and environment-friendly, and has low cost.
The isomeric alkane solvent belongs to an extraction solvent oil, and its distillation range is 167-3And a viscosity of 1.49mm at a test temperature of 25 DEG C2The PVC resin has the surface tension of 23mN/m and the refractive index of 1.418 at the test temperature of 20 ℃, and is often used as an industrial cleaning solution, a PVC viscosity reducer and a PVC stabilizer carrier. Surprisingly, the reagent is used as a dispersion medium of a valsartan raw material, has low viscosity and good fluidity, meets the fluidity requirement of wet measurement of a laser particle analyzer, is almost non-toxic and odorless, has no pollution to the environment, is compatible with the surfaces of most electronic and electric appliances, has no loss to the instruments, and can effectively eliminate electrostatic adsorption among valsartan particles due to smaller surface tension and density.
The W/O type co-dispersant is soluble with isoparaffin with oil solubility, the isoparaffin is not soluble with valsartan, and the lecithin or hydrogenated lecithin is added as the co-dispersant to further improve the dispersion effect and stability of the valsartan dispersion.
Based on the above inventive concept, the present inventors have found that when isoparaffin added with a dispersion aid agent is used as a valsartan dispersion medium, valsartan has a good dispersion effect, is not easily agglomerated, and does not destroy the particle size.
The first purpose of the invention is realized by the following technical scheme:
a valsartan dispersion liquid comprises an isoparaffin solvent, valsartan and a dispersion aid.
Preferably, the mass volume ratio of the dispersion aid agent to the isoparaffin solvent is (0.02-0.07): 1.
preferably, the dispersion aid additive is at least one selected from lecithin and hydrogenated lecithin.
Preferably, the lecithin is selected from at least one of soybean lecithin, egg yolk lecithin, and rapeseed lecithin.
Preferably, the hydrogenated lecithin is at least one selected from the group consisting of hydrogenated soybean lecithin and hydrogenated egg yolk lecithin.
Preferably, the dispersion aid is soy lecithin.
Preferably, the mass-to-volume ratio of the soybean lecithin to the isoparaffin is (0.02-0.07): 1; further preferably, the mass-to-volume ratio of the soybean lecithin to the isoparaffin is (0.03-0.06): 1; still further preferably, the mass to volume ratio of soy lecithin to isoparaffin is from 0.05: 1.
preferably, the isoparaffin is selected from at least one of isoparaffin, dodecane, tetradecane, and hexadecane.
Preferably, the isoparaffin is isododecane.
Preferably, the concentration of the valsartan dispersion liquid is 3-18 mg/ml; further preferably, the concentration of the valsartan dispersion liquid is 5-15 mg/ml; more preferably, the concentration of the valsartan dispersion liquid is 8-12 mg/ml.
The second purpose of the invention is realized by the following technical scheme:
a preparation method of the valsartan dispersion comprises the following steps:
dispersing valsartan in an isoparaffin solvent to prepare a dispersed saturated solution;
dispersing the dispersion aid into an isoparaffin solvent to prepare a dispersion aid solution;
and mixing and dispersing the valsartan, the dispersion saturated solution and the dispersion aid solution to prepare the valsartan dispersion liquid.
Preferably, the concentration of the valsartan dispersion prepared by the method is 3-18 mg/ml.
Preferably, the volume ratio of the dispersion aid dispersant solution to the dispersion saturated solution is (10-20) to (80-90).
Preferably, the dispersing step in the preparation method employs at least one of ultrasound or agitation.
Preferably, the dispersion step in the preparation of the dispersion saturated solution employs at least one of ultrasound or stirring; and/or the dispersing step in the preparation of the dispersion aid solution adopts at least one of ultrasound or stirring; and/or the dispersing step in the preparation of the valsartan dispersion employs at least one of ultrasound or agitation.
Preferably, the dispersion is carried out using ultrasound.
Preferably, the ultrasound time is 5-25 min.
Preferably, the ultrasonic time in the preparation of the dispersion saturated solution is 15-25 min; further preferably, the ultrasonic time in the preparation of the dispersion saturated solution is 18-22 min.
Preferably, the ultrasonic time in the preparation of the valsartan dispersion is 5-10 min; further preferably, the ultrasound time in the preparation of the valsartan dispersion is 6-8 min.
Preferably, the ultrasonic frequency is 30-45 Hz.
The selection of the ultrasonic time and the ultrasonic frequency in the preparation method is crucial, if the ultrasonic time and the ultrasonic frequency are not up to the requirements, the valsartan particles can be aggregated, and if the ultrasonic time and the ultrasonic frequency exceed the ultrasonic time and the ultrasonic frequency in the invention, the valsartan particles are easy to break.
Preferably, the dispersion aid agent solution and the dispersion saturated solution are used after being filtered.
Preferably, the filtration is performed by using an organic filter membrane with the diameter of 0.3-0.6 μm; further preferably, the filtration is performed by using a 0.45 μm organic filter membrane.
Preferably, the preparation of the dispersion saturated solution further comprises a standing step.
Preferably, the preparation of the dispersion saturated solution further comprises a step of taking supernatant liquid by standing.
In the preparation process of the valsartan dispersion, the valsartan needs to be dispersed in isoparaffin to prepare a dispersion saturated solution of the valsartan. Although valsartan is insoluble in isoparaffin, the particle size test result can be influenced by the phenomenon that a very trace amount of valsartan is dissolved, so that the valsartan is firstly dispersed in the isoparaffin solvent and passes through a 0.45um filter membrane to prepare a dispersed saturated solution, and the phenomenon that a valsartan sample is very slightly soluble when dispersed is prevented from damaging the particle size distribution test result.
Lecithin is powder, and is added into an isoparaffin solvent to be dissolved and swelled into a gel block, and then slowly dissolved, and the mixture is stirred and then passes through a 0.45um filter membrane, so that the condition that the introduction of insufficiently dissolved lecithin particles influences the particle size distribution test result of valsartan is avoided.
And then, mixing a to-be-detected sample valsartan, a dispersion saturated solution and an auxiliary dispersing agent solution to prepare a valsartan dispersion liquid with the concentration of 3-18 mg/ml, wherein if the to-be-detected sample valsartan is directly mixed with an isoparaffin solvent and lecithin powder, the particle size of the valsartan sample can be damaged and impurity particles are introduced, so that the accuracy of particle size test data of the valsartan is influenced.
The third purpose of the invention is realized by the following technical scheme:
a method for determining the particle size of the valsartan dispersion comprises the following steps:
adding the dispersed saturated solution into a sample injection pool for background determination;
and adding the valsartan dispersion liquid into a sample injection pool to determine the particle size data.
Preferably, the determination method is determination by a laser particle sizer.
Preferably, the assay method comprises a system setting step and/or a method verification step.
Preferably, the system setup step is prior to background determination.
Preferably, the system setting step comprises setting optical parameters.
Preferably, the optical parameter includes at least one of a refractive index of the particles, an absorption rate, and a refractive index of the dispersion medium.
Preferably, the refractive index of the particles is set to 1.53 to 1.58.
Preferably, the particle absorption rate is set to 0.1-1.0.
Preferably, the particle absorptivity is set to be 0.1-1.0 and is a multiple of 10.
Preferably, the refractive index of the dispersion medium is set to 1.416.
Preferably, the system setting step includes setting a stirring speed.
Preferably, the stirring speed is 1200 and 2160 r/min; further preferably, the stirring speed is 1500-. In the particle size measurement method, the selection of the stirring speed affects the accuracy of the particle size measurement result, and if the stirring speed is low, large particles in valsartan particles are settled, so that the test result is smaller. The stirring speed in the invention can ensure that particles with different particle diameters in the valsartan dispersion liquid can simultaneously pass through the detection pool, thereby reducing the particle size measurement error and improving the test precision.
Preferably, the sample injection pool is a wet sample injection pool.
Preferably, the determination method further comprises a preheating step, wherein the preheating step is to preheat the instrument.
Preferably, the preheating step is to preheat the apparatus before the valsartan dispersion is added to the sample cell.
Preferably, the system setting step further comprises a shading degree setting step.
Preferably, the shade is set to 10% -20%.
Preferably, the assay method further comprises a method validation step.
Preferably, the method verification step comprises at least one of a step of evaluating the effect of model fitting, a repeatability verification step, and an intermediate precision verification step.
Preferably, the step of assessing the effect of model fitting comprises determining residuals and/or weighted residuals. Based on the optical parameters, the residual error is the least square fitting difference between the theoretical light intensity data and the actually measured light intensity data, and a small residual error value usually means that the measurement result is correct and reliable.
Preferably, the residual is less than 1%.
Preferably, the residuals are close to the weighted residuals.
Preferably, the reproducibility verification step comprises determining and calculating RSD, obtaining RSD results; further preferably, not less than 4 parts of valsartan dispersion is prepared and RSD is determined and calculated, which should correspond to: d10 is less than 15%, D50 is less than 10%, and D90 is less than 15%.
Preferably, not less than 6 parts of valsartan dispersion are prepared and determined to calculate RSD, which should correspond to D10 < 15%, D50 < 10%, D90 < 15%.
The invention has the beneficial effects that: the valsartan dispersion liquid disclosed by the invention is good in dispersion effect and stable in dispersion, a secondary aggregation phenomenon cannot occur, the problem that valsartan particles cannot be fully dispersed due to strong electrostatic adsorption in the prior art is solved, and meanwhile, organic solvents or slightly toxic surfactants such as dodecyl sulfuric acid and the like which are high in use cost and large in toxic and side stimulation are avoided.
The preparation method of the valsartan dispersion liquid is simple, easy to operate, good in reproducibility and free of requirements on equipment.
The method for determining the particle size of the valsartan dispersion liquid has strong pertinence, establishes a particle size detection method with good reproducibility and precision, is easy to popularize and popularize, has good application value, and avoids the problem that the results are inaccurate by a screening method and a direct dry method.
Drawings
FIG. 1 is a micrograph of the dispersion of valsartan in water;
FIG. 2 is a micrograph of the dispersion of valsartan in an aqueous solution of 2% SDS;
FIG. 3 is a micrograph of valsartan after dispersion in a 2% SDS aqueous solution and re-addition to water for dispersion;
FIG. 4 is a micrograph of a valsartan dispersion prepared by the method of example 1;
FIG. 5 is a plot of the particle size distribution of the valsartan dispersion of example 1;
FIG. 6 is a graph of particle size distribution using the valsartan dispersion of comparative example 1.
Detailed Description
In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples are given for illustration. It should be noted that the following examples are not intended to limit the scope of the claimed invention.
The starting materials, reagents or apparatus used in the following examples are conventionally commercially available or can be prepared by conventionally known methods, unless otherwise specified. The laser particle analyzer adopted in the invention has the following types: a laser particle size analyser, model Malvern Mastersizer 2000, a wet injector, model HYDRO2000MU (Malvern, uk).
Example 1
A valsartan dispersion comprising isododecane, valsartan and soy lecithin.
The valsartan dispersion in example 1 was prepared using the following preparation method:
the preparation method of the valsartan dispersion comprises the following steps:
1) preparing a dispersion saturated solution: adding 1.0g of valsartan into 1000ml of isododecane solvent, uniformly stirring, placing the mixture in an ultrasonic instrument for ultrasonic treatment for 20min, and filtering the mixture by using a 0.45-micron organic filter membrane for later use;
2) preparing a dispersion aid solution: weighing 1g to 20ml of isododecane solvent of soybean lecithin, slowly dissolving to prepare a soybean lecithin solution with the mass volume ratio of 5 percent, and filtering by using an organic filter membrane with the thickness of 0.45 mu m for later use;
3) preparation of a valsartan dispersion: 60mg of valsartan powder of a sample to be detected is taken and added into a 50ml volumetric flask, 2ml of soybean lecithin solution with the mass volume ratio of 5% and 20ml of dispersion saturated solution are added, the mixture is placed into an ultrasonic instrument for ultrasonic treatment, the ultrasonic treatment time is 7min, the ultrasonic frequency is 40Hz, and after the ultrasonic treatment is finished, the valsartan dispersion liquid with uniform dispersion is prepared.
The particle size of the valsartan dispersion in example 1 was determined using the following particle size determination method:
the particle size testing method comprises the following steps:
system setting: setting the refractive index of the particles to be 1.58, the absorptivity to be 0.1 and the refractive index of the dispersion medium to be 1.416;
and (3) sample determination: preheating a laser particle size analyzer for 30min, adding 100ml of dispersion saturated solution, wherein the analysis mode is a general mode, opening a stirring device to enable the stirring speed to be 1600r/min, adding the valsartan dispersion liquid to enable the light shading degree range to be 15% after background measurement is carried out, and starting to measure particle size data.
Example 2
A valsartan dispersion comprising isododecane, valsartan and soy lecithin.
The valsartan dispersion in example 2 was prepared using the following preparation method:
the preparation method of the valsartan dispersion comprises the following steps:
1) preparing a dispersion saturated solution: adding 1.0g of valsartan into 1000ml of isododecane solvent, uniformly stirring, placing in an ultrasonic instrument for ultrasonic treatment for 20min, and filtering by using a 0.45-micron organic filter membrane for later use;
2) preparing a dispersion aid solution: weighing 1g to 20ml of isododecane solvent of soybean lecithin, slowly dissolving to prepare a soybean lecithin solution with the mass volume ratio of 5 percent, and filtering by using an organic filter membrane with the thickness of 0.45 mu m for later use;
3) preparation of a valsartan dispersion: adding 60mg of valsartan powder of a sample to be detected into a 50ml volumetric flask, adding 2ml of soybean lecithin solution with the mass volume ratio of 5% and 20ml of dispersion saturated solution, placing the mixture into an ultrasonic instrument for ultrasonic treatment, wherein the ultrasonic treatment time is 8min, the ultrasonic frequency is 40Hz, and detecting after the ultrasonic treatment.
The particle size testing method comprises the following steps:
system setting: setting the refractive index of the particles to be 1.58, the absorptivity to be 1.0 and the refractive index of the dispersion medium to be 1.416;
and (3) sample determination: preheating a laser particle size analyzer for 30min, adding 100ml of dispersion saturated solution, opening a stirring device to enable the stirring speed to be 1700r/min, operating background measurement, adding valsartan dispersion to enable the light shading degree range to be 12%, and starting to measure particle size data, wherein the analysis mode is a general mode.
Comparative example 1
A valsartan dispersion liquid comprises Sodium Dodecyl Sulfate (SDS), valsartan and water.
The valsartan dispersion in comparative example 1 was prepared using the following preparation method:
1) preparation of 2% SDS dispersion medium: weighing 2g of SDS into 100ml of purified water, slowly dissolving to prepare an SDS solution with the mass-volume ratio of 2%, and filtering by using an organic filter membrane with the particle size of 0.45 mu m for later use;
2) preparation of a valsartan dispersion: putting 500mg of valsartan powder into a 50ml volumetric flask, adding 30ml of 2% SDS (sodium dodecyl sulfate) dispersion medium, putting the flask into an ultrasonic instrument for ultrasonic treatment for 120s at the ultrasonic frequency of 40Hz, and measuring after the ultrasonic treatment is finished.
The particle size of the valsartan dispersion in comparative example 1 was determined using the following particle size determination method:
the determination method comprises the following steps:
3) system setting: setting the refractive index of the particles to be 1.53, the absorptivity to be 0.01 and the refractive index of the dispersion medium to be 1.33;
4) and (3) sample determination: preheating for 30min, adding 100ml of 2% SDS dispersant solution, opening a stirring device to ensure that the stirring speed is 1800r/min, operating the background measurement, adding the valsartan dispersant to ensure that the light shading degree range is 10%, and starting the measurement.
Comparative example 2
A valsartan dispersion liquid comprises Sodium Dodecyl Sulfate (SDS), valsartan and water.
The valsartan dispersion in comparative example 2 was prepared using the following preparation method:
1) preparation of 2% SDS dispersion medium: weighing 2g of SDS into 100ml of purified water, slowly dissolving to prepare an SDS solution with the mass-volume ratio of 2%, and filtering by using an organic filter membrane with the particle size of 0.45 mu m for later use;
2) preparation of a valsartan dispersion: putting 500mg of valsartan powder into a 50ml volumetric flask, adding 30ml of 2% SDS (sodium dodecyl sulfate) dispersion medium, putting the flask into an ultrasonic instrument for ultrasonic treatment for 120s, and measuring after the ultrasonic treatment is finished.
The particle size of the valsartan dispersion in comparative example 2 was determined using the following particle size determination method:
3) system setting: setting the refractive index of the particles to be 1.53, the absorptivity to be 0.01 and the refractive index of the dispersion medium to be 1.33;
4) and (3) sample determination: preheating for 30min, adding 100ml of blank purified water, starting a stirring device to enable the stirring speed to be 1900r/min in an analysis mode of a general mode, operating background measurement, adding the valsartan dispersion to enable the light shading degree range to be 12%, and starting measurement.
Experimental example 1
(1) A microscopic image of a valsartan dispersion prepared by dispersing a valsartan powder using water as the dispersion medium is shown in fig. 1, from which fig. 1 it can be seen that: due to the electrostatic action among the valsartan particles, the valsartan particles are adsorbed and aggregated in water to form clusters;
(2) a microscopic image of a valsartan dispersion prepared by dispersing a valsartan powder using a 2% aqueous solution of Sodium Dodecyl Sulfate (SDS) as the dispersion medium is shown in fig. 2, from which fig. 2 it can be seen that: although the electrostatic interaction between the valsartan particles is improved, the valsartan particles still cannot be uniformly dispersed in a dispersion medium;
(3) firstly, dispersing the valsartan powder by using a 2% SDS aqueous solution, and then adding water for redispersion to prepare a valsartan dispersion liquid, wherein a micrograph of the valsartan dispersion liquid is shown in figure 3, and can be seen from figure 3: the valsartan particles, dispersed in a 2% aqueous SDS solution, reaggregate;
(4) the micrograph of the valsartan dispersion prepared in example 1 is shown in fig. 4, from which fig. 4 it can be seen that: the valsartan has obvious particle boundary and uniform dispersion.
Experimental example 2
The particle size distribution of the valsartan dispersion prepared in example 1 was determined using the particle size determination method in example 1 and is shown in fig. 5. The particle size distribution of the valsartan dispersion prepared in comparative example 1 was determined using the particle size determination method in comparative example 1 and is shown in fig. 6. As can be seen from fig. 5 and 6, the particle size measured by the particle size measuring method in comparative example 1 is larger than the particle size measured by the particle size measuring method in example 1.
Experimental example 3
And (3) verifying repeatability and precision:
6 parts of valsartan dispersion was repeatedly prepared as a test sample by the experimenter 1 according to the preparation method in example 1, and the particle sizes thereof were measured in units of μm using the particle size measurement method in example 1, calculating the RSD value and recording the calculation results in Table 1.
Table 1 example 1 method repeatability determination
| Sample name | D10 | D50 | D90 | Residual error | Weighted residual |
| 1-1 | 2.389 | 8.181 | 32.598 | 0.470 | 0.550 |
| 1-2 | 2.361 | 7.884 | 31.978 | 0.646 | 0.767 |
| 1-3 | 2.408 | 8.684 | 36.065 | 0.720 | 0.865 |
| 1-4 | 1.846 | 6.645 | 29.578 | 0.568 | 0.651 |
| 1-5 | 2.371 | 8.035 | 30.005 | 0.610 | 0.718 |
| 1-6 | 2.463 | 8.523 | 32.790 | 0.805 | 0.954 |
| Average | 2.306 | 7.992 | 32.169 | -- | -- |
| RSD(％) | 9.902 | 9.065 | 7.248 | -- | -- |
As can be seen from table 1: the test data has good fitting value, and the obtained D10 is less than 15%, D50 is less than 10%, and D90 is less than 15%, which all meet the requirements.
6 parts of valsartan dispersion were repeatedly prepared as a test sample by the experimenter 2 according to the preparation method of valsartan dispersion described in example 1, and 6 parts of the test sample were treated in parallel by the particle size test method in example 1, the particle sizes thereof were measured in units of μm, the RSD values were calculated, and the calculation results were recorded in table 2.
Table 2 example 1 method repeatability determination
| Sample name | D10 | D50 | D90 | Residual error | Weighted residual |
| 2-1 | 2.548 | 8.737 | 34.627 | 0.787 | 0.940 |
| 2-2 | 2.353 | 6.948 | 27.451 | 0.495 | 0.552 |
| 2-3 | 2.105 | 7.570 | 32.202 | 0.660 | 0.776 |
| 2-4 | 2.403 | 8.393 | 33.450 | 0.787 | 0.927 |
| 2-5 | 2.328 | 7.844 | 31.719 | 0.678 | 0.804 |
| 2-6 | 2.407 | 8.121 | 27.451 | 0.431 | 0.504 |
| Average | 2.357 | 7.963 | 31.971 | -- | -- |
| RSD(％) | 6.161 | 8.153 | 7.387 | -- | -- |
As can be seen from table 2: the test data has good fitting value, and the obtained D10 is less than 15%, D50 is less than 10%, and D90 is less than 15%, which all meet the requirements.
The test data of 6 parts of the valsartan dispersion sample prepared by the experimenter 1 and the test data of 6 parts of the valsartan dispersion sample prepared by the experimenter 2 were combined to calculate the intermediate precision, the unit of the particle size data measured in table 3 was μm, and the results were recorded in table 3.
Table 3 results of intermediate precision in example 1
| Sample name | D10 | D50 | D90 | Residual error | Weighted residual |
| 1-1 | 2.389 | 8.181 | 32.598 | 0.470 | 0.550 |
| 1-2 | 2.361 | 7.884 | 31.978 | 0.646 | 0.767 |
| 1-3 | 2.408 | 8.684 | 36.065 | 0.720 | 0.865 |
| 1-4 | 1.846 | 6.645 | 29.578 | 0.568 | 0.651 |
| 1-5 | 2.371 | 8.035 | 30.005 | 0.610 | 0.718 |
| 1-6 | 2.463 | 8.523 | 32.790 | 0.805 | 0.954 |
| 2-1 | 2.548 | 8.737 | 34.627 | 0.787 | 0.940 |
| 2-2 | 2.353 | 6.948 | 27.451 | 0.495 | 0.552 |
| 2-3 | 2.105 | 7.570 | 32.202 | 0.660 | 0.776 |
| 2-4 | 2.403 | 8.393 | 33.450 | 0.787 | 0.927 |
| 2-5 | 2.328 | 7.844 | 31.719 | 0.678 | 0.804 |
| 2-6 | 2.407 | 8.121 | 27.451 | 0.431 | 0.504 |
| Average | 2.332 | 7.964 | 31.659 | -- | -- |
| RSD(％) | 7.908 | 8.153 | 8.328 | -- | -- |
As can be seen from table 3: the obtained D10 of less than 15 percent, D50 of less than 10 percent and D90 of less than 15 percent meet the requirements, and the intermediate precision of the data measured by the particle size testing method in the example 1 is good.
3 parts of valsartan dispersion as a test article 1 were prepared by an experimenter 1 according to the preparation method in comparative example 1, then 3 parts of the test article 1 were treated in parallel, the particle size thereof was measured in units of μm, and the RSD value was calculated and the calculation result was recorded in table 4.
TABLE 4 repeatability of the method of comparative example 1
| Numbering | D10 | D50 | D90 | Residual error | Weighted residual |
| 1-1 | 15.549 | 51.174 | 110.030 | 0.300 | 0.208 |
| 1-2 | 13.907 | 59.443 | 116.936 | 0.308 | 0.222 |
| 1-3 | 28.201 | 81.326 | 146.290 | 0.243 | 0.217 |
| Average | 19.219 | 63.981 | 124.419 | -- | -- |
| RSD(％) | 40.69 | 24.35 | 15.47 | -- | -- |
As can be seen from table 4: comparative example 1 adopts 2% SDS-aqueous solution as dispersion medium and determination medium, and the fit is good, but the determination is disturbed by bubbles, and valsartan particles are not uniformly dispersed, and the result is obviously higher.
As a test article 2, 3 parts of valsartan dispersion was prepared by the experimenter 2 according to the preparation method in comparative example 1, and then the experimenter 2 treated 3 parts of the test article 1 and 3 parts of the test article 2 in parallel (total 6 test articles) according to the particle size measurement method in comparative example 2, measured the particle size data in μm, calculated the RSD value and recorded the calculation result in table 5.
TABLE 5 repeatability of comparative example 2 method
| Numbering | D10 | D50 | D90 | Residual error | Weighted residual |
| 1-1 | 17.363 | 65.743 | 127.099 | 0.265 | 0.235 |
| 1-2 | 17.695 | 71.693 | 132.570 | 0.280 | 0.224 |
| 1-3 | 18.466 | 67.766 | 124.645 | 0.273 | 0.219 |
| 1-4 | 12.598 | 71.375 | 132.108 | 0.308 | 0.282 |
| 1-5 | 15.235 | 71.839 | 130.386 | 0.265 | 0.224 |
| 1-6 | 24.728 | 74.211 | 143.197 | 0.266 | 0.222 |
| Average | 17.681 | 70.438 | 131.667 | -- | -- |
| RSD(％) | 22.93 | 4.391 | 4.872 | -- | -- |
As can be seen from table 5: comparative example 1 using 2% SDS-water solution as dispersion medium and pure water as determination medium, fitting was good, no bubble interference was measured but particle reaggregation and dispersion were not uniform, and the test results were also high.
In summary, the following steps: the valsartan dispersion liquid adopts the dispersion medium as isoparaffin solvent oil, and lecithin or hydrogenated lecithin is added as an auxiliary dispersing agent, so that the problems of strong electrostatic adsorption of valsartan, nonuniform aggregation or dispersion of raw material powder and lack of accuracy of a particle size measurement result are solved. The method has the advantages that the electrostatic adsorption aggregation among valsartan particles can be effectively reduced by adopting the valsartan dispersion liquid to measure by adopting a wet method in a laser scattering method under general experimental conditions, when the particle size measuring method is adopted, the optical parameter fitting is good, the real particle size of a valsartan raw material is reduced to the maximum extent, the problems that the valsartan is not provided with a proper dispersion medium and a proper particle size measuring method are solved, meanwhile, the dispersion medium is non-toxic and environment-friendly, the organic solvent pollution can be avoided, instruments in the measuring process are tolerant, easy to clean and maintain, and good application value is achieved.
Claims (10)
1. A valsartan dispersion characterized by: the valsartan dispersion comprises an isoparaffin solvent, valsartan and a dispersion aid.
2. The valsartan dispersion according to claim 1, characterised in that: the auxiliary dispersing agent is at least one of lecithin and hydrogenated lecithin.
3. The valsartan dispersion according to claim 1, characterised in that: the isoparaffin solvent is selected from at least one of isoparaffin, dodecane, tetradecane, and hexadecane.
4. A valsartan dispersion according to any one of claims 1-3 characterised in that: the concentration of the valsartan dispersion liquid is 3-18 mg/ml.
5. A process for preparing a valsartan dispersion according to any one of claims 1 to 4, characterised in that: the preparation method comprises the following steps:
dispersing valsartan in an isoparaffin solvent to prepare a dispersed saturated solution;
dispersing the dispersion aid into an isoparaffin solvent to prepare a dispersion aid solution;
and mixing and dispersing the valsartan, the dispersion saturated solution and the dispersion aid solution to prepare the valsartan dispersion liquid.
6. The process for preparing a valsartan dispersion according to claim 5, wherein: the volume ratio of the dispersion aid solution to the dispersion saturated solution is (10-20) to (80-90).
7. The process for preparing a valsartan dispersion according to claim 5, wherein: the dispersion step in the preparation method adopts at least one of ultrasound or stirring.
8. The process for preparing a valsartan dispersion according to claim 7, wherein: the ultrasonic time is 5-25 min; and/or the ultrasonic frequency is 30-45 Hz.
9. A method for determining the particle size of a valsartan dispersion prepared by the method of any one of claims 5 to 8, characterised in that: the determination method comprises the following steps:
adding the dispersed saturated solution into a sample injection pool for background determination;
and adding the valsartan dispersion liquid into a sample injection pool to determine the particle size data.
10. The method for determining the particle size of a valsartan dispersion according to claim 9, wherein: the determination method also comprises a system setting step and/or a method verification step.
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