CN103263394B - A kind of Cetirizine hydrochloride Tablets and related substance method of quality control thereof - Google Patents
A kind of Cetirizine hydrochloride Tablets and related substance method of quality control thereof Download PDFInfo
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Abstract
The object of the invention is to provide a kind of Cetirizine hydrochloride Tablets and related substance method of quality control thereof, in order to overcome cetirizine hydrochloride to thermally labile, supplementary material poor compatibility, the shortcoming such as easy jaundice in put procedure, first Macrogol 4000 is adopted, titanium dioxide and cetirizine hydrochloride and low-substituted hydroxypropyl cellulose mixing, adopt dry granulation by cetirizine and low-substituted hydroxypropyl cellulose parcel, it is made not to be subject to heat, its stripping is not affected again while the impact of light and other adjuvants, then by obtained granule and other adjuvant mixing direct compressions, shortened process, reduce energy and material consumption, improve cetirizine sheet yield.Adopt high performance liquid chromatography check the related substance of Cetirizine hydrochloride Tablets and formulate standard limits, better its quality of control, improves curative effect and safety simultaneously.
Description
Technical field
The present invention relates to medical art, is a kind of dosage form preparation and the related substance quality control thereof of antihistaminic cetirizine hydrochloride.
Background technology
At present, anaphylactic disease treated by the antihistaminic class medicine that adopts more clinically, as hismanal, Triprolidine Hydrochloride, chlorphenamine etc., though these medicines can suppress histamine releasing amount, but curative effect is very limited, effect is not played to many allergic symptoms, and some medicine also has larger side effect, make people dizzy, drowsiness after using, however cetirizine to show curative effect in these areas better.
Cetirizine hydrochloride is second filial generation antihistaminic, has good therapeutical effect to anaphylactic disease such as skin urticaria, allergic asthma, allergic rhinitis and the anaphylaxis conjunctivitis etc. of skin, respiratory system and eyes.At present, the dosage form of this medicine has a variety of, but great majority are all conventional dosage forms, and route of administration is also more conventional.Compared with other antihistaminics, although the central nervous system activity of cetirizine hydrochloride is lower, this medicine under the conditions such as heat, light extremely unstable and in production process yield lower.Simultaneously because taste is bitter, some patients is swallowed more difficult, particularly takes very inconvenient for child patient, Given this, therefore proposes the present invention.
Summary of the invention the object of the invention is to provide a kind of Cetirizine hydrochloride Tablets and related substance method of quality control thereof, in order to overcome cetirizine hydrochloride to thermally labile, supplementary material poor compatibility, the shortcoming such as easy jaundice in put procedure, first Macrogol 4000 is adopted, titanium dioxide and cetirizine hydrochloride and low-substituted hydroxypropyl cellulose mixing, adopt dry granulation by cetirizine and low-substituted hydroxypropyl cellulose parcel, it is made not to be subject to heat, its stripping is not affected again while the impact of light and other adjuvants, then by obtained granule and other adjuvant mixing direct compressions, shortened process, reduce energy and material consumption, improve cetirizine sheet yield.Adopt high performance liquid chromatography check the related substance of Cetirizine hydrochloride Tablets and formulate standard limits, better its quality of control, improves curative effect and safety simultaneously.
Technical problem to be solved by this invention realizes by the following technical solutions.
The weight percentage of each component of the present invention is:
The weight percentage of each component of the present invention is:
Preparation method step of the present invention is:
(1) percentage composition takes following component by weight:
(2) get the Macrogol 4000 of recipe quantity, titanium dioxide crosses 200 mesh sieves, mix homogeneously with the cetirizine hydrochloride of recipe quantity and low-substituted hydroxypropyl cellulose, for subsequent use;
(3) join in dry granulating machine by material in above-mentioned (2), setting pressure is 0.4 ~ 1.6Mpa, and feeding spiro rod speed is 25 ~ 35Hz, it is 18 ~ 26Hz that axle rotating speed is rolled in molding, and it is 12 ~ 22Hz that axle rotating speed is rolled in granulation, granulates with 18 mesh sieves, collecting granules, for subsequent use;
(4) mixed homogeneously with recipe quantity vertical compression mixture Ludipress, spray-dried lactose SuperTabSD, sodium stearyl fumarate by granule in above-mentioned (3), tabletting, control hardness is 5 ~ 8Kg, to obtain final product.
Preparation method step of the present invention is:
(1) percentage composition takes following component by weight:
(2) get 20.25g Macrogol 4000,0.065g titanium dioxide crosses 200 mesh sieves, mix homogeneously with 10.80g cetirizine hydrochloride and 10.80g low-substituted hydroxypropyl cellulose, for subsequent use;
(3) join in dry granulating machine by material in above-mentioned (2), setting pressure is 1.0Mpa, and feeding spiro rod speed is 25Hz, and it is 22Hz that axle rotating speed is rolled in molding, and it is 18Hz that axle rotating speed is rolled in granulation, granulates with 18 mesh sieves, and collecting granules is for subsequent use;
(4) mixed homogeneously with 33.75g vertical compression mixture Ludipress, 57.31g spray-dried lactose SuperTabSD, 2.025g sodium stearyl fumarate by granule in above-mentioned (3), control hardness is 6Kg, is pressed into 1000, obtains final product.
The method of quality control of related substance of the present invention is:
Determination of related substances
Measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; With acetonitrile-0.02% potassium dihydrogen phosphate (8: 92) for mobile phase A (by phosphoric acid adjust ph to 3.0), with acetonitrile-0.05% phosphoric acid solution (48: 52) for Mobile phase B, according to the form below carries out linear gradient elution; Flow velocity is 1.0ml per minute; Column temperature is 40 DEG C; Determined wavelength is 230nm.Get cetirizine hydrochloride, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G reference substance appropriate, accurately weighed, add the solution that mobile phase A is mixed with each 5 μ g/ml of hydrochloric cetirizine, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G, as system suitability solution.Precision measures in system suitability solution 20 μ l injection liquid chromatography, eluting order is followed successively by cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity G, cetirizine hydrochloride impurity B and cetirizine hydrochloride, and the separating degree at cetirizine hydrochloride peak and cetirizine hydrochloride impurity B peak must not be less than 2.0.
Algoscopy gets Cetirizine hydrochloride Tablets 20, is ground into fine powder, takes appropriate (being about equivalent to cetirizine hydrochloride 20mg), accurately weighed, put in 20ml measuring bottle, add mobile phase A 15ml, supersound process 5 minutes (power 250W, frequency 33kHz), lets cool, add mobile phase A and be settled to scale, shake up, filter, be diluted to scale, filter with 0.45 μm of filter membrane, get subsequent filtrate as need testing solution; Precision measures need testing solution 1.0ml, puts in 100ml measuring bottle, add mobile phase A and be diluted to scale, shake up, then precision measures 2.0ml, puts in 10ml measuring bottle, adds mobile phase A and is diluted to scale, shake up, in contrast solution.Precision measures need testing solution, each 20 μ l of contrast solution, injection liquid chromatography respectively, if any impurity peaks in need testing solution chromatogram, the peak area of cetirizine hydrochloride impurity A, B, G must not be greater than contrast solution main peak area 1.5 times (0.3%); The peak area of other single unknown impurities must not be greater than main peak area in contrast solution (0.2%); Each impurity peak area sum must not be greater than 4 times (0.80%) of contrast solution main peak area.In need testing solution chromatogram, can ignore in any peak being less than main peak area 0.1 times (0.02%) in contrast solution.
Accompanying drawing illustrates Related substances separation system suitability collection of illustrative plates.
Detailed description of the invention:
Embodiment 1 prepares Cetirizine hydrochloride tablet
Formula and proportioning:
Preparation method:
(1) percentage composition takes following component by weight:
(2) get 13.50g Macrogol 4000,0.015g titanium dioxide crosses 200 mesh sieves, mix homogeneously with 6.75g cetirizine hydrochloride and 6.75g low-substituted hydroxypropyl cellulose, for subsequent use;
(3) join in dry granulating machine by material in above-mentioned (2), setting pressure is 0.5Mpa, and feeding spiro rod speed is 30Hz, and it is 18Hz that axle rotating speed is rolled in molding, and it is 12Hz that axle rotating speed is rolled in granulation, granulates with 18 mesh sieves, and collecting granules is for subsequent use;
(4) mixed homogeneously with 40.50g vertical compression mixture Ludipress, 66.81g spray-dried lactose SuperTabSD, 0.675g sodium stearyl fumarate by granule in above-mentioned (3), control hardness is 5Kg, is pressed into 1000, obtains final product.
Embodiment 2 prepares Cetirizine hydrochloride tablet
Formula and proportioning:
Preparation method:
(1) percentage composition takes following component by weight:
(2) get 20.25g Macrogol 4000,0.065g titanium dioxide crosses 200 mesh sieves, mix homogeneously with 10.80g cetirizine hydrochloride and 10.80g low-substituted hydroxypropyl cellulose, for subsequent use;
(3) join in dry granulating machine by material in above-mentioned (2), setting pressure is 1.0Mpa, and feeding spiro rod speed is 25Hz, and it is 22Hz that axle rotating speed is rolled in molding, and it is 18Hz that axle rotating speed is rolled in granulation, granulates with 18 mesh sieves, and collecting granules is for subsequent use;
(4) mixed homogeneously with 33.75g vertical compression mixture Ludipress, 57.31g spray-dried lactose SuperTabSD, 2.025g sodium stearyl fumarate by granule in above-mentioned (3), control hardness is 6Kg, is pressed into 1000, obtains final product.
Embodiment 3 prepares Cetirizine hydrochloride tablet
Formula and proportioning:
Preparation method:
(1) percentage composition takes following component by weight:
(2) get 27.00g Macrogol 4000,0.13g titanium dioxide crosses 200 mesh sieves, mix homogeneously with 13.50g cetirizine hydrochloride and 10.80g low-substituted hydroxypropyl cellulose, for subsequent use;
(3) join in dry granulating machine by material in above-mentioned (2), setting pressure is 1.6Mpa, and feeding spiro rod speed is 35Hz, and it is 25Hz that axle rotating speed is rolled in molding, and it is 22Hz that axle rotating speed is rolled in granulation, granulates with 18 mesh sieves, and collecting granules is for subsequent use;
(4) mixed homogeneously with 37.67g vertical compression mixture Ludipress, 40.50g spray-dried lactose SuperTabSD, 2.70g sodium stearyl fumarate by granule in above-mentioned (3), control hardness is 8Kg, is pressed into 1000, obtains final product.
The determination of related substances of embodiment 4 Cetirizine hydrochloride Tablets
Measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; With acetonitrile-0.02% potassium dihydrogen phosphate (8: 92) for mobile phase A (by phosphoric acid adjust ph to 3.0), with acetonitrile-0.05% phosphoric acid solution (48: 52) for Mobile phase B, according to the form below carries out linear gradient elution; Flow velocity is 1.0ml per minute; Column temperature is 40 DEG C; Determined wavelength is 230nm.Get cetirizine hydrochloride, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G reference substance appropriate, accurately weighed, add the solution that mobile phase A is mixed with each 5 μ g/ml of hydrochloric cetirizine, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G, as system suitability solution.Precision measures in system suitability solution 20 μ l injection liquid chromatography, eluting order is followed successively by cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity G, cetirizine hydrochloride impurity B and cetirizine hydrochloride, and the separating degree at cetirizine hydrochloride peak and cetirizine hydrochloride impurity B peak must not be less than 2.0.
Cetirizine hydrochloride Tablets in algoscopy Example 1 20, is ground into fine powder, accurately weighed fine powder 400.11mg, put in 20ml measuring bottle, add mobile phase A 15ml, supersound process 5 minutes (power 250W, frequency 33kHz), let cool, add mobile phase A and be settled to scale, shake up, filter, be diluted to scale, filter with 0.45 μm of filter membrane, get subsequent filtrate as need testing solution; Precision measures need testing solution 1.0ml, puts in 100ml measuring bottle, add mobile phase A and be diluted to scale, shake up, then precision measures 2.0ml, puts in 10ml measuring bottle, adds mobile phase A and is diluted to scale, shake up, in contrast solution.Precision measures need testing solution, each 20 μ l of contrast solution, respectively injection liquid chromatography, record liquid chromatogram, be 0.08% according to collection of illustrative plates result of calculation impurity A, impurity B is 0.08%, and impurity G is 0.06%, and the separating degree of impurity peaks and cetirizine hydrochloride is all greater than 2.0.
The determination of related substances of embodiment 5 Cetirizine hydrochloride Tablets
Measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; With acetonitrile-0.02% potassium dihydrogen phosphate (8: 92) for mobile phase A (by phosphoric acid adjust ph to 3.0), with acetonitrile-0.05% phosphoric acid solution (48: 52) for Mobile phase B, according to the form below carries out linear gradient elution; Flow velocity is 1.0ml per minute; Column temperature is 40 DEG C; Determined wavelength is 230nm.Get cetirizine hydrochloride, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G reference substance appropriate, accurately weighed, add the solution that mobile phase A is mixed with each 5 μ g/ml of hydrochloric cetirizine, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G, as system suitability solution.Precision measures in system suitability solution 20 μ l injection liquid chromatography, eluting order is followed successively by cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity G, cetirizine hydrochloride impurity B and cetirizine hydrochloride, and the separating degree at cetirizine hydrochloride peak and cetirizine hydrochloride impurity B peak must not be less than 2.0.
Cetirizine hydrochloride Tablets in algoscopy Example 2 20, is ground into fine powder, accurately weighed fine powder 400.05mg, put in 20ml measuring bottle, add mobile phase A 15ml, supersound process 5 minutes (power 250W, frequency 33kHz), let cool, add mobile phase A and be settled to scale, shake up, filter, be diluted to scale, filter with 0.45 μm of filter membrane, get subsequent filtrate as need testing solution; Precision measures need testing solution 1.0ml, puts in 100ml measuring bottle, add mobile phase A and be diluted to scale, shake up, then precision measures 2.0ml, puts in 10ml measuring bottle, adds mobile phase A and is diluted to scale, shake up, in contrast solution.Precision measures need testing solution, each 20 μ l of contrast solution, respectively injection liquid chromatography, record liquid chromatogram, be 0.05% according to collection of illustrative plates result of calculation impurity A, impurity B is 0.10%, and impurity G is 0.07%, and the separating degree of impurity peaks and cetirizine hydrochloride is all greater than 2.0.
The determination of related substances of embodiment 6 Cetirizine hydrochloride Tablets
Measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; With acetonitrile-0.02% potassium dihydrogen phosphate (8: 92) for mobile phase A (by phosphoric acid adjust ph to 3.0), with acetonitrile-0.05% phosphoric acid solution (48: 52) for Mobile phase B, according to the form below carries out linear gradient elution; Flow velocity is 1.0ml per minute; Column temperature is 40 DEG C; Determined wavelength is 230nm.Get cetirizine hydrochloride, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G reference substance appropriate, accurately weighed, add the solution that mobile phase A is mixed with each 5 μ g/ml of hydrochloric cetirizine, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G, as system suitability solution.Precision measures in system suitability solution 20 μ l injection liquid chromatography, eluting order is followed successively by cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity G, cetirizine hydrochloride impurity B and cetirizine hydrochloride, and the separating degree at cetirizine hydrochloride peak and cetirizine hydrochloride impurity B peak must not be less than 2.0.
Cetirizine hydrochloride Tablets in algoscopy Example 3 20, is ground into fine powder, accurately weighed fine powder 400.07mg, put in 20ml measuring bottle, add mobile phase A 15ml, supersound process 5 minutes (power 250W, frequency 33kHz), let cool, add mobile phase A and be settled to scale, shake up, filter, be diluted to scale, filter with 0.45 μm of filter membrane, get subsequent filtrate as need testing solution; Precision measures need testing solution 1.0ml, puts in 100ml measuring bottle, add mobile phase A and be diluted to scale, shake up, then precision measures 2.0ml, puts in 10ml measuring bottle, adds mobile phase A and is diluted to scale, shake up, in contrast solution.Precision measures need testing solution, each 20 μ l of contrast solution, respectively injection liquid chromatography, record liquid chromatogram, be 0.11% according to collection of illustrative plates result of calculation impurity A, impurity B is 0.05%, and impurity G is 0.09%, and the separating degree of impurity peaks and cetirizine hydrochloride is all greater than 2.0.
The determination of related substances method contrast test of embodiment 7 Cetirizine hydrochloride Tablets and Method validation
System suitability contrast test, accurately weighed cetirizine hydrochloride impurity A 5.03mg, the volumetric flask being placed in 100ml adds mobile phase A dilution, powerful jolting, dissolves, adds mobile phase A and be diluted to scale, shake up, as cetirizine hydrochloride impurity A solution.Prepare successively according to the method, as follows:
The solution of hydrochloric cetirizine impurity B 5.05 μ g/ml;
The solution of hydrochloric cetirizine impurity G5.11 μ g/ml;
The solution of each 5.05 μ g/ml of hydrochloric cetirizine impurity A, cetirizine hydrochloride impurity B, cetirizine hydrochloride impurity G and cetirizine hydrochloride;
The solution of hydrochloric cetirizine impurity A and each 2.10 μ g/ml of cetirizine hydrochloride
Get above-mentioned solution, measure respectively according to related substance method of the present invention and existing related substance method thereof, record chromatogram, compares the separating effect of two kinds of methods by separating degree.
Existing related substance method:
Measure according to high performance liquid chromatography (Chinese Pharmacopoeia nineteen ninety-five version two annex VD).
Chromatographic condition and system suitability silica gel are filler; Dilute sulfuric acid-water-acetonitrile (0.4: 6.6: 93) is mixed flow phase; Isocratic clution; Flow velocity is 1.0ml/min; Survey wavelength is 230nm; Theoretical tray calculates should be not less than 1000 by cetirizine hydrochloride peak; Impurity A and main peak separating degree should meet the requirements.
Algoscopy is got this product and is added mobile phase and make containing the solution of 0.20mg in every 1ml, as need testing solution; Precision measures in right amount, adds mobile phase and makes the solution containing 2.0 μ l in every 1ml, solution (1) in contrast; Precision measures reference substance and each about 10mg of impurity A, adds mobile phase and makes the solution respectively containing 0.1mg in every 1ml, solution (2) in contrast.Precision measures contrast liquid (1) 10 μ l injection liquid chromatography and carries out prerun, regulates sensitivity, makes the peak height of main constituent chromatographic peak be 10 ~ 30% of full scale; Precision measures need testing solution and each 10 μ l of reference substance solution (2) sample introduction respectively again, and record chromatogram is to 3 times of main constituent peak retention time.If any impurity peaks in need testing solution chromatogram, its impurity peak area sum must not be greater than the main peak area (1.0%) of contrast solution (1).The results are shown in Table 1 and table 2.
Table 1 separating degree (R) comparing result
Result shows that test method separating effect of the present invention is better than art methods.
Related substance Detection capability contrast test
Need testing solution in Example 5 and contrast solution thereof, detect according to test method of the present invention and existing method thereof, more each method Related substances separation result.
Table 2 Detection capability comparative test result
It is sensitive that above-mentioned data show that the inventive method detects related substance, good separating effect.
Cetirizine hydrochloride Tablets determination of related substances method validation
Specificity investigates test
Get the Cetirizine hydrochloride Tablets 20 in above-described embodiment 2, be placed in mortar by its porphyrize powdered, precision takes fine powder 400.12mg, is placed in the volumetric flask of 20ml, add water shake well, dissolve, be diluted with water to scale, shake up, filter, make the solution of every 1ml containing 1.00mg, measure according to the chromatographic condition in above-described embodiment 5, in its chromatogram show sample, impurity is separated well with cetirizine.Separately get 6 parts, respectively 105 DEG C place 3 hours, irradiation under ultraviolet ray 24 hours, high light (4500Lx) irradiate 7 days, to destroy by 1N hydrochloric acid room temperature 2 hours, to destroy by 1N sodium hydroxide room temperature 2 hours, to destroy by 10% hydrogen peroxide room temperature and prepare according to the method described above for 30 minutes, measure, record chromatic graph spectrum.Result shows, and each catabolite destroying sample generation is all separated well with cetirizine hydrochloride.
Linear relationship is tested
The linear research range concentration of cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B, cetirizine hydrochloride impurity G is 0.3 μ g/ml ~ 4.5 μ g/ml.Precision takes reference substance in right amount respectively, is made into gradient solution, measures according to the chromatographic condition in above-described embodiment 5, record chromatogram, and measurement result is as following table:
Result investigated by table 3-1 cetirizine hydrochloride impurity A linear relationship
| Linear criterion solution | Percentage concentration ratio (%) | Concentration (μ g/ml) | Average peak area |
| L1 | 10 | 0.317 | 20480 |
| L2 | 25 | 0.793 | 51465 |
| L3 | 50 | 1.586 | 102817 |
| L4 | 75 | 2.379 | 154064 |
| L5 | 100 | 3.172 | 205898 |
| L6 | 150 | 4.758 | 300762 |
Conclusion: take concentration as abscissa respectively, peak area is vertical coordinate, and the regression equation obtaining cetirizine hydrochloride impurity A is: Y=63366x+1899; R=0.9996.Result shows, cetirizine hydrochloride impurity A concentration and peak area in the concentration range of 0.317 μ g/ml ~ 4.758 μ g/ml are good linear relation.
Result investigated by table 3-2 cetirizine hydrochloride impurity B linear relationship
Conclusion: take concentration as abscissa respectively, peak area is vertical coordinate, and the regression equation obtaining cetirizine hydrochloride impurity B is: Y=45594x+1350; R=0.9996.Result shows, cetirizine hydrochloride impurity B concentration and peak area in the concentration range of 0.273 μ g/ml ~ 4.097 μ g/ml are good linear relation.
Result investigated by table 3-3 cetirizine hydrochloride impurity G linear relationship
Conclusion: take concentration as abscissa respectively, peak area is vertical coordinate, and the regression equation obtaining cetirizine hydrochloride impurity G is: Y=47510x+1117; R=0.9996.Result shows, cetirizine hydrochloride impurity G concentration and peak area in the concentration range of 0.279 μ g/ml ~ 4.189 μ g/ml are good linear relation.
Detectability
The result of detectability (LOD) is determined according to signal to noise ratio, measures the dirt solution being diluted to variable concentrations with dilution method, when signal to noise ratio is about 3 be detectability concentration.
Conclusion: cetirizine hydrochloride detectability concentration is about 0.0042 μ g/ml, cetirizine hydrochloride impurity A detectability concentration is about 0.0047 μ g/ml, cetirizine hydrochloride impurity B detectability concentration is about 0.0082 μ g/ml, cetirizine hydrochloride impurity G detectability concentration is about 0.0083 μ g/ml, shows that chromatographic condition detection sensitivity is good.
Accuracy test
The accuracy studies response rate of the respective substance recorded in the mixture from known quantity cetirizine hydrochloride, adjuvant evaluates accuracy.Tested by cetirizine hydrochloride solution by measuring three groups of concentration known, test solution concentration is 25%, 100% and 150% of cetirizine hydrochloride 100% concentration.Measurement result sees the following form:
Table 4 Cetirizine hydrochloride Tablets accuracy test result
Conclusion: according to above-mentioned mensuration, the average recovery rate of cetirizine hydrochloride is 100.3%, RSD is 1.36%, shows that the result response rate is good.
Experimental example 1 antiallergic is tested
With this soil species white mice (body weight is 10 ~ 25g about) by gastric infusion approach, three dosage (5%, 10%, 20%) of Cetirizine hydrochloride Tablets and astemizole sheet (10%) are compared, carbon granules removing speed in serum in the unit of account time.
Result shows, Cetirizine hydrochloride Tablets obviously can increase foreign bodies removal rate value in serum, and three dosage (5%, 10%, 20%) of Cetirizine hydrochloride Tablets all have significant difference, and increases along with dosage and act on reinforcement.
Experimental example 2 anti-inflammation test
Get native country white mice in experiment each treated animal ear coating on the same day once, matched group is coated with mutually commensurability distilled water 0.05ml/20g.After 1 hour, each group washes away medicinal liquid with distilled water, cleans with dry cotton ball.Only dimethylbenzene 0.05ml/ is coated with to mouse right ear.Left ear compares, and puts to death animal after 15 minutes, is cut by ears with the card punch of diameter 6mm with position homalographic, with the difference of left and right auricle weight for swelling degree.Calculate each group of swelling degree, obtain inhibitory rate of intumesce (%).
Result shows, three dosage (5%, 10%, 20%) of Cetirizine hydrochloride tablet have the effect obviously suppressing mice auricle swelling, and suppression ratio is respectively 85.2%, 76.8%, 72.5%; Astemizole sheet also has same effect, and suppression ratio is 70.1%.
The antipruritic test of experimental example 3
By mice in test proxima luce (prox. luc), shave hair to each group of right back instep of mice, coating once.Test the same day, abrade right back instep with coarse sandpaper and shave hair place, area about 1 square centimeter, local again coating once, matched group gives equivalent distilled water.After last coating 10 minutes, at wound surface Chu Di 0.01% histamine phosphate 0.05ml/ only start, after this every 3 minutes by 0.01%, 0.02%, 0.03%, 0.04%...... progressive concentration, be only 0.05ml/ at every turn.Directly cause and occur that mice later licks right back foot, with finally occur mice later lick right back sufficient time histamine phosphate's total amount of giving be antipruritic valve.Record relatively each group cause valve of itching.
Result shows, the heavy dose of group of the Cetirizine hydrochloride tablet mice that is significantly improved causes the effect of valve of itching, causing valve of itching is 502.6 ± 79 μ g, and compare with matched group and have significant differences (P < 0.01), small dose group also improves and causes the effect of valve of itching.
Experimental example 4 stability test
Get the lower Cetirizine hydrochloride Tablets of the invention process 1 to 3, simulation listing packaging, place 6 months under being placed in 40 DEG C ± 2 DEG C and relative humidity 75% ± 5% condition, detection related substance is sampled respectively, compared with 0 month testing result 1st month, 2 months, 3 months, 6 the end of month at duration of test.Measurement result is in table 5.
Related substance measures according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; With acetonitrile-0.02% potassium dihydrogen phosphate (8: 92) for mobile phase A (by phosphoric acid adjust ph to 3.0), with acetonitrile-0.05% phosphoric acid solution (48: 52) for Mobile phase B, according to the form below carries out linear gradient elution; Flow velocity is 1.0ml per minute; Column temperature is 40 DEG C; Determined wavelength is 230nm.Get cetirizine hydrochloride, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G reference substance appropriate, accurately weighed, add the solution that mobile phase A is mixed with each 5 μ g/ml of hydrochloric cetirizine, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G, as system suitability solution.Precision measures in system suitability solution 20 μ l injection liquid chromatography, eluting order is followed successively by cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity G, cetirizine hydrochloride impurity B and cetirizine hydrochloride, and the separating degree at cetirizine hydrochloride peak and cetirizine hydrochloride impurity B peak must not be less than 2.0.
Algoscopy gets Cetirizine hydrochloride Tablets 20, is ground into fine powder, takes appropriate (being about equivalent to cetirizine hydrochloride 20mg), accurately weighed, put in 20ml measuring bottle, add mobile phase A 15ml, supersound process 5 minutes (power 250W, frequency 33kHz), lets cool, add mobile phase A and be settled to scale, shake up, filter, be diluted to scale, filter with 0.45 μm of filter membrane, get subsequent filtrate as need testing solution; Precision measures need testing solution 1.0ml, puts in 100ml measuring bottle, add mobile phase A and be diluted to scale, shake up, then precision measures 2.0ml, puts in 10ml measuring bottle, adds mobile phase A and is diluted to scale, shake up, in contrast solution.Precision measures need testing solution, each 20 μ l of contrast solution, injection liquid chromatography respectively, if any impurity peaks in need testing solution chromatogram, the peak area of cetirizine hydrochloride impurity A, B, G must not be greater than contrast solution main peak area 1.5 times (0.3%); The peak area of other single unknown impurities must not be greater than main peak area in contrast solution (0.2%); Each impurity peak area sum must not be greater than 4 times (0.80%) of contrast solution main peak area.In need testing solution chromatogram, can ignore in any peak being less than main peak area 0.1 times (0.02%) in contrast solution.
Table 5 Cetirizine hydrochloride Tablets stability test of the present invention related substance investigates result
Result of the test shows, the Cetirizine hydrochloride Tablets sample that the present invention obtains was through 6 months accelerated tests, and related substance, without significant difference, shows Product Process, steady quality.
Claims (5)
1. a Cetirizine hydrochloride Tablets, is characterized in that the component comprising following weight percentage:
Wherein, described Cetirizine hydrochloride Tablets prepares by the following method, first described Macrogol 4000, titanium dioxide and cetirizine hydrochloride and low-substituted hydroxypropyl cellulose are mixed, dry granulation is adopted described cetirizine hydrochloride and described low-substituted hydroxypropyl cellulose to be carried out being rolled into granule again, then by obtained described granule and other adjuvant mixing direct compressions.
2. a kind of Cetirizine hydrochloride Tablets according to claim 1, is characterized in that the component comprising following weight percentage:
3. a preparation method for Cetirizine hydrochloride Tablets, is characterized in that comprising following preparation process:
(1) percentage composition takes following component by weight:
(2) get the Macrogol 4000 of recipe quantity, titanium dioxide crosses 200 mesh sieves, mix homogeneously with the cetirizine hydrochloride of recipe quantity and low-substituted hydroxypropyl cellulose, for subsequent use;
(3) join in dry granulating machine by material in above-mentioned (2), setting pressure is 0.4 ~ 1.6Mpa, and feeding spiro rod speed is 25 ~ 35Hz, it is 18 ~ 26Hz that axle rotating speed is rolled in molding, and it is 12 ~ 22Hz that axle rotating speed is rolled in granulation, granulates with 18 mesh sieves, collecting granules, for subsequent use;
(4) mixed homogeneously with recipe quantity vertical compression mixture Ludipress, spray-dried lactose SuperTabSD, sodium stearyl fumarate by granule in above-mentioned (3), tabletting, control hardness is 5 ~ 8Kg, to obtain final product.
4. the preparation method of a kind of Cetirizine hydrochloride Tablets according to claim 3, is characterized in that comprising following preparation process:
(1) content takes following component by weight:
(2) get 20.25g Macrogol 4000,0.065g titanium dioxide crosses 200 mesh sieves, mix homogeneously with 10.80g cetirizine hydrochloride and 10.80g low-substituted hydroxypropyl cellulose, for subsequent use;
(3) join in dry granulating machine by material in above-mentioned (2), setting pressure is 1.0Mpa, and feeding spiro rod speed is 25Hz, and it is 22Hz that axle rotating speed is rolled in molding, and it is 18Hz that axle rotating speed is rolled in granulation, granulates with 18 mesh sieves, and collecting granules is for subsequent use;
(4) mixed homogeneously with 33.75g vertical compression mixture Ludipress, 57.31g spray-dried lactose SuperTabSD, 2.025g sodium stearyl fumarate by granule in above-mentioned (3), control hardness is 6Kg, is pressed into 1000, obtains final product.
5. a quality determining method for Cetirizine hydrochloride Tablets related substance, is characterized in that comprising the steps:
According to high effective liquid chromatography for measuring;
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; With acetonitrile-0.02% potassium dihydrogen phosphate (8:92) for mobile phase A, and with phosphoric acid by described mobile phase A adjust ph to 3.0, with acetonitrile-0.05% phosphoric acid solution (48:52) for Mobile phase B, according to the form below carries out linear gradient elution; Flow velocity is 1.0ml per minute; Column temperature is 40 DEG C; Determined wavelength is 230nm; Get cetirizine hydrochloride, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G reference substance appropriate, accurately weighed, described mobile phase A is added respectively in the described sour cetirizine taken, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G, be mixed with the solution of each 5 μ g/ml of hydrochloric cetirizine, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G respectively, as system suitability solution; Precision measures in system suitability solution 20 μ l injection liquid chromatography, eluting order is followed successively by described cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity G, cetirizine hydrochloride impurity B and cetirizine hydrochloride, and the separating degree at described cetirizine hydrochloride peak and described cetirizine hydrochloride impurity B peak must not be less than 2.0;
Algoscopy gets Cetirizine hydrochloride Tablets 20, is ground into fine powder, takes appropriate, namely the amount of taking is equivalent to cetirizine hydrochloride 20mg, accurately weighed, puts in 20ml measuring bottle, add described mobile phase A 15ml, supersound process 5 minutes, wherein, described ultrasonic power 250W, described supersonic frequency 33kHz, lets cool, add described mobile phase A and be settled to scale, shake up, filter, be diluted to scale, filter with 0.45 μm of filter membrane, get subsequent filtrate as need testing solution; Precision measures described need testing solution 1.0ml, puts in 100ml measuring bottle, adds described mobile phase A and is diluted to scale, shake up, then precision measures 2.0ml, put in 10ml measuring bottle, adds described mobile phase A and is diluted to scale, shake up, in contrast solution;
Precision measures described need testing solution, each 20 μ l of described contrast solution, injection liquid chromatography respectively, if any impurity peaks in described need testing solution chromatogram, the peak area of described cetirizine hydrochloride impurity A, B, G must not be greater than described contrast solution main peak area 1.5 times, and also namely the peak area of described cetirizine hydrochloride impurity A, B, G must not be greater than 0.3% of described contrast solution main peak area; The peak area of other single unknown impurities must not be greater than 0.2% of main peak area in described contrast solution; Each impurity peak area sum must not be greater than 4 times of described contrast solution main peak area, and also namely each impurity peak area sum must not be greater than 0.80% of described contrast solution main peak area; Anyly in described need testing solution chromatogram be less than main peak area 0.1 times in described contrast solution, also namely can ignore in any peak being less than 0.02% of main peak area in described contrast solution in described need testing solution chromatogram;
.
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| CN104569269A (en) * | 2015-01-05 | 2015-04-29 | 万特制药(海南)有限公司 | Method for testing related substances of levocetirizine hydrochloride intermediate |
| CN107782813B (en) * | 2016-08-26 | 2021-03-05 | 人福普克药业（武汉）有限公司 | Method for detecting related substances in cetirizine hydrochloride sample |
| CN110927308A (en) * | 2019-11-07 | 2020-03-27 | 徐州立兴佳正医药科技有限公司 | Method for determining concentration of cetirizine in blood plasma by liquid chromatography-mass spectrometry |
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Denomination of invention: A quality control method for cetirizine hydrochloride tablets and related substances Effective date of registration: 20230314 Granted publication date: 20160106 Pledgee: Science and Technology Branch of Torch Development Zone of Zhongshan Rural Commercial Bank Co.,Ltd. Pledgor: Guoyuan Guoyao (Guangdong) Pharmaceutical Group Co.,Ltd. Registration number: Y2023980034725 |