CN103263394A - Cetirizine hydrochloride tablet and related substance quality control method thereof - Google Patents
Cetirizine hydrochloride tablet and related substance quality control method thereof Download PDFInfo
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Abstract
The invention aims at providing a cetirizine hydrochloride tablet and a related substance quality control method thereof which are used for overcoming the shortcomings of thermal instability, low compatibility between raw and auxiliary materials, easy yellowing in a placing process and the like of cetirizine hydrochloride. The cetirizine hydrochloride tablet is prepared by the following steps of: mixing polyethylene glycol 4000, titanium dioxide, cetirizine hydrochloride and low-substituted hydroxypropyl cellulose; wrapping the cetirizine and low-substituted hydroxypropyl cellulose by dry granulation so as to avoid the influence of heat, light and other auxiliary materials and avoid influence on the dissolution; and mixing the prepared granules and other auxiliary materials, and directly tabletting, wherein the technological flow is shortened, energy consumption and material consumption are reduced, and the yield of the cetirizine hydrochloride tablet is improved. Meanwhile, the related substances of the cetirizine hydrochloride tablet are checked by a high performance liquid chromatography, and a standard limit is set so as to control the quality better and improve the curative effect and safety.
Description
Technical field
The present invention relates to medical technical field, is a kind of dosage form preparation and the related substance quality control thereof of antihistaminic cetirizine hydrochloride.
Background technology
At present, the antihistaminic class medicines that adopt are treated anaphylactic disease more clinically, as hismanal, quick, the chlorphenamine of gram etc., though these medicines can suppress histamine's burst size, but curative effect is very limited, and many allergic symptoms are not played effect, and some medicine also has bigger side effect, make people's dizziness, drowsiness etc. after the use, yet that cetirizine shows curative effect in these areas is better.
Cetirizine hydrochloride is second filial generation antihistaminic, and anaphylactic disease such as skin urticaria, allergic asthma, allergic rhinitis and the anaphylaxis conjunctivitis etc. of skin, respiratory system and eyes are had the good curing effect.At present, the dosage form of this medicine has a variety of, but great majority are all to be conventional dosage form, and route of administration is also relatively more conventional.Compare with other antihistaminics, though the central nervous system of cetirizine hydrochloride is active lower, this medicine under conditions such as heat, light extremely in instability and the production process yield lower.Simultaneously because the taste hardship, part patient's difficulty of swallowing, particularly take for child patient very inconvenient, Given this, so propose 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, the supplementary material compatibility is poor, easy shortcoming such as jaundice in the put procedure, at first adopt Macrogol 4000, titanium dioxide and cetirizine hydrochloride and low-substituted hydroxypropyl cellulose mix, adopt dry granulation with cetirizine and low-substituted hydroxypropyl cellulose parcel, make it not be subjected to heat, do not influence its stripping in the time of the influence of light and other adjuvants again, then with the granule and other adjuvant mixing direct compressions that make, shortened process, the material consumption that cuts down the consumption of energy has improved cetirizine sheet yield.Adopt the related substance of high performance liquid chromatography inspection Cetirizine hydrochloride Tablets simultaneously and formulate the standard limit, better control its quality, improve curative effect and safety.
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 by weighing following component by weight:
(2) Macrogol 4000, the titanium dioxide of getting recipe quantity is crossed 200 mesh sieves, and is with cetirizine hydrochloride and the low-substituted hydroxypropyl cellulose mix homogeneously of recipe quantity, standby;
(3) material in above-mentioned (2) is joined in the dry granulation machine, setting pressure is 0.4～1.6Mpa, and feeding spiro rod speed is 25～35Hz, and it is 18～26Hz that a rotating speed is rolled in molding, and it is 12～22Hz that a rotating speed is rolled in granulation, granulate with 18 mesh sieves, and collecting granules, standby;
(4) with granule and recipe quantity vertical compression mixture Ludipress, spray-dried lactose SuperTabSD, sodium stearyl fumarate mix homogeneously in above-mentioned (3), tabletting, control hardness is 5～8Kg, namely.
Preparation method step of the present invention is:
(1) percentage composition takes by weighing following component by weight:
(2) get the 20.25g Macrogol 4000,0.065g titanium dioxide is crossed 200 mesh sieves, and is with 10.80g cetirizine hydrochloride and 10.80g low-substituted hydroxypropyl cellulose mix homogeneously, standby;
(3) material in above-mentioned (2) is joined in the dry granulation machine, setting pressure is 1.0Mpa, and feeding spiro rod speed is 25Hz, and it is 22Hz that a rotating speed is rolled in molding, and it is 18Hz that a rotating speed is rolled in granulation, granulate with 18 mesh sieves, and collecting granules, standby;
(4) with granule and 33.75g vertical compression mixture Ludipress, 57.31g spray-dried lactose SuperTabSD, 2.025g sodium stearyl fumarate mix homogeneously in above-mentioned (3), control hardness is 6Kg, is pressed into 1000, namely.
The method of quality control of related substance of the present invention is:
Determination of related substances
Measure according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2010 D).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; Being mobile phase A (regulating pH value to 3.0 with phosphoric acid) with acetonitrile-0.02% potassium dihydrogen phosphate (8: 92), is Mobile phase B with acetonitrile-0.05% phosphoric acid solution (48: 52), and according to the form below carries out linear gradient elution; Flow velocity is per minute 1.0ml; Column temperature is 40 ℃; The detection wavelength is 230nm.It is an amount of to get cetirizine hydrochloride, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G reference substance, the accurate title, decide, 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 is measured system suitability solution 20 μ l and is injected chromatograph of liquid, 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 is got 20 of Cetirizine hydrochloride Tablets, is ground into fine powder, takes by weighing an amount of (being equivalent to cetirizine hydrochloride 20mg approximately), the accurate title, decide, and puts in the 20ml measuring bottle, adds mobile phase A 15ml, supersound process 5 minutes (power 250W, frequency 33kHz) is put cold, add mobile phase A and be settled to scale, shake up, filter, be diluted to scale, filter with 0.45 μ m filter membrane, get subsequent filtrate as need testing solution; Precision is measured need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase A and is diluted to scale, shakes up, and precision is measured 2.0ml again, puts in the 10ml measuring bottle, adds mobile phase A and is diluted to scale, shakes up, in contrast solution.Precision is measured need testing solution, each 20 μ l of contrast solution, injects chromatograph of liquid respectively, and if any impurity peaks, the peak area of cetirizine hydrochloride impurity A, B, G must not be greater than 1.5 times of contrast solution main peak areas (0.3%) in the need testing solution chromatogram; The peak area of other single unknown impurities must not be greater than main peak area (0.2%) in the contrast solution; Each impurity peak area sum must not be greater than 4 times (0.80%) of contrast solution main peak area.In the need testing solution chromatogram can ignore in any peak less than main peak area 0.1 times (0.02%) in the contrast solution.
Description of drawings related substance check system adaptability collection of illustrative plates.
The specific embodiment:
Embodiment 1 preparation Cetirizine hydrochloride Tablets agent
Prescription and proportioning:
Preparation method:
(1) percentage composition takes by weighing following component by weight:
(2) get the 13.50g Macrogol 4000,0.015g titanium dioxide is crossed 200 mesh sieves, and is with 6.75g cetirizine hydrochloride and 6.75g low-substituted hydroxypropyl cellulose mix homogeneously, standby;
(3) material in above-mentioned (2) is joined in the dry granulation machine, setting pressure is 0.5Mpa, and feeding spiro rod speed is 30Hz, and it is 18Hz that a rotating speed is rolled in molding, and it is 12Hz that a rotating speed is rolled in granulation, granulate with 18 mesh sieves, and collecting granules, standby;
(4) with granule and 40.50g vertical compression mixture Ludipress, 66.81g spray-dried lactose SuperTabSD, 0.675g sodium stearyl fumarate mix homogeneously in above-mentioned (3), control hardness is 5Kg, is pressed into 1000, namely.
Embodiment 2 preparation Cetirizine hydrochloride Tablets agent
Prescription and proportioning:
Preparation method:
(1) percentage composition takes by weighing following component by weight:
(2) get the 20.25g Macrogol 4000,0.065g titanium dioxide is crossed 200 mesh sieves, and is with 10.80g cetirizine hydrochloride and 10.80g low-substituted hydroxypropyl cellulose mix homogeneously, standby;
(3) material in above-mentioned (2) is joined in the dry granulation machine, setting pressure is 1.0Mpa, and feeding spiro rod speed is 25Hz, and it is 22Hz that a rotating speed is rolled in molding, and it is 18Hz that a rotating speed is rolled in granulation, granulate with 18 mesh sieves, and collecting granules, standby;
(4) with granule and 33.75g vertical compression mixture Ludipress, 57.31g spray-dried lactose SuperTabSD, 2.025g sodium stearyl fumarate mix homogeneously in above-mentioned (3), control hardness is 6Kg, is pressed into 1000, namely.
Embodiment 3 preparation Cetirizine hydrochloride Tablets agent
Prescription and proportioning:
Preparation method:
(1) percentage composition takes by weighing following component by weight:
(2) get the 27.00g Macrogol 4000,0.13g titanium dioxide is crossed 200 mesh sieves, and is with 13.50g cetirizine hydrochloride and 10.80g low-substituted hydroxypropyl cellulose mix homogeneously, standby;
(3) material in above-mentioned (2) is joined in the dry granulation machine, setting pressure is 1.6Mpa, and feeding spiro rod speed is 35Hz, and it is 25Hz that a rotating speed is rolled in molding, and it is 22Hz that a rotating speed is rolled in granulation, granulate with 18 mesh sieves, and collecting granules, standby;
(4) with granule and 37.67g vertical compression mixture Ludipress, 40.50g spray-dried lactose SuperTabSD, 2.70g sodium stearyl fumarate mix homogeneously in above-mentioned (3), control hardness is 8Kg, is pressed into 1000, namely.
The determination of related substances of embodiment 4 Cetirizine hydrochloride Tablets
Measure according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2010 D).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; Being mobile phase A (regulating pH value to 3.0 with phosphoric acid) with acetonitrile-0.02% potassium dihydrogen phosphate (8: 92), is Mobile phase B with acetonitrile-0.05% phosphoric acid solution (48: 52), and according to the form below carries out linear gradient elution; Flow velocity is per minute 1.0ml; Column temperature is 40 ℃; The detection wavelength is 230nm.It is an amount of to get cetirizine hydrochloride, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G reference substance, the accurate title, decide, 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 is measured system suitability solution 20 μ l and is injected chromatograph of liquid, 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 is got 20 of Cetirizine hydrochloride Tablets among the embodiment 1, is ground into fine powder, accurately claims to decide fine powder 400.11mg, put in the 20ml measuring bottle, add mobile phase A 15ml, 5 minutes (power 250W of supersound process, frequency 33kHz), put coldly, add mobile phase A and be settled to scale, shake up, filter, be diluted to scale, filter with 0.45 μ m filter membrane, get subsequent filtrate as need testing solution; Precision is measured need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase A and is diluted to scale, shakes up, and precision is measured 2.0ml again, puts in the 10ml measuring bottle, adds mobile phase A and is diluted to scale, shakes up, in contrast solution.Precision is measured need testing solution, each 20 μ l of contrast solution, injects chromatograph of liquid respectively, the 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 (two appendix V of Chinese Pharmacopoeia version in 2010 D).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; Being mobile phase A (regulating pH value to 3.0 with phosphoric acid) with acetonitrile-0.02% potassium dihydrogen phosphate (8: 92), is Mobile phase B with acetonitrile-0.05% phosphoric acid solution (48: 52), and according to the form below carries out linear gradient elution; Flow velocity is per minute 1.0ml; Column temperature is 40 ℃; The detection wavelength is 230nm.It is an amount of to get cetirizine hydrochloride, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G reference substance, the accurate title, decide, 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 is measured system suitability solution 20 μ l and is injected chromatograph of liquid, 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 is got 20 of Cetirizine hydrochloride Tablets among the embodiment 2, is ground into fine powder, accurately claims to decide fine powder 400.05mg, put in the 20ml measuring bottle, add mobile phase A 15ml, 5 minutes (power 250W of supersound process, frequency 33kHz), put coldly, add mobile phase A and be settled to scale, shake up, filter, be diluted to scale, filter with 0.45 μ m filter membrane, get subsequent filtrate as need testing solution; Precision is measured need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase A and is diluted to scale, shakes up, and precision is measured 2.0ml again, puts in the 10ml measuring bottle, adds mobile phase A and is diluted to scale, shakes up, in contrast solution.Precision is measured need testing solution, each 20 μ l of contrast solution, injects chromatograph of liquid respectively, the 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 (two appendix V of Chinese Pharmacopoeia version in 2010 D).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; Being mobile phase A (regulating pH value to 3.0 with phosphoric acid) with acetonitrile-0.02% potassium dihydrogen phosphate (8: 92), is Mobile phase B with acetonitrile-0.05% phosphoric acid solution (48: 52), and according to the form below carries out linear gradient elution; Flow velocity is per minute 1.0ml; Column temperature is 40 ℃; The detection wavelength is 230nm.It is an amount of to get cetirizine hydrochloride, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G reference substance, the accurate title, decide, 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 is measured system suitability solution 20 μ l and is injected chromatograph of liquid, 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 is got 20 of Cetirizine hydrochloride Tablets among the embodiment 3, is ground into fine powder, accurately claims to decide fine powder 400.07mg, put in the 20ml measuring bottle, add mobile phase A 15ml, 5 minutes (power 250W of supersound process, frequency 33kHz), put coldly, add mobile phase A and be settled to scale, shake up, filter, be diluted to scale, filter with 0.45 μ m filter membrane, get subsequent filtrate as need testing solution; Precision is measured need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase A and is diluted to scale, shakes up, and precision is measured 2.0ml again, puts in the 10ml measuring bottle, adds mobile phase A and is diluted to scale, shakes up, in contrast solution.Precision is measured need testing solution, each 20 μ l of contrast solution, injects chromatograph of liquid respectively, the 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 methodology checking
The system suitability contrast test, the accurate title, decided cetirizine hydrochloride impurity A 5.03mg, places the volumetric flask of 100ml to add the mobile phase A dilution, powerful jolting, dissolving adds mobile phase A and is diluted to scale, shakes 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 each 2.10 μ g/ml of hydrochloric cetirizine impurity A and 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, come the separating effect of two kinds of methods of comparison by separating degree.
Existing related substance method:
Measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia nineteen ninety-five version).
Chromatographic condition and system suitability silica gel are filler; Dilute sulfuric acid-water-acetonitrile (0.4: 6.6: 93) is the mixed flow phase; The isoconcentration eluting; Flow velocity is 1.0ml/min; The survey wavelength is 230nm; Theoretical tray calculates by the cetirizine hydrochloride peak should be not less than 1000; Impurity A and main peak separating degree should meet the requirements.
Algoscopy is got this product and is added mobile phase and make the solution that contains 0.20mg among every 1ml, as need testing solution; Precision is measured in right amount, adds mobile phase and makes the solution that contains 2.0 μ l among every 1ml, in contrast solution (1); Precision is measured reference substance and each about 10mg of impurity A, adds mobile phase and makes the solution that contains 0.1mg among every 1ml, in contrast solution (2).Precision is measured contrast liquid (1) 10 μ l and is injected chromatograph of liquid and carry out prerun, regulates sensitivity, and the peak height that makes the main constituent chromatographic peak is 10～30% of full scale; Precision is measured need testing solution and each 10 μ l difference sample introduction of reference substance solution (2) again, and the record chromatogram is to 3 times of main constituent peak retention time.If any impurity peaks, its impurity peak area sum must not be greater than the main peak area (1.0%) of contrast solution (1) in the need testing solution chromatogram.The results are shown in Table 1 and table 2.
Table 1 separating degree (R) comparing result
The result shows that test method separating effect of the present invention is better than art methods.
Related substance detects the ability contrast test
Get need testing solution and contrast solution thereof among the embodiment 5, detect according to test method of the present invention and existing method thereof, relatively each method related substance check result.
Table 2 detects the ability comparative test result
Above-mentioned data show that the inventive method detects related substance sensitivity, good separating effect.
Cetirizine hydrochloride Tablets determination of related substances method validation
Specificity is investigated test
Get 20 of Cetirizine hydrochloride Tablets in above-described embodiment 2, place mortar with its porphyrize powdered, precision takes by weighing fine powder 400.12mg, places the volumetric flask of 20ml, add the water shake well, dissolving, thin up shakes up to scale, filter, make the solution that every 1ml contains 1.00mg, measure according to the chromatographic condition in above-described embodiment 5, impurity separates well with cetirizine in its chromatogram show sample.Other gets 6 parts, respectively 105 ℃ place 3 hours, irradiation under ultraviolet ray 24 hours, high light (4500Lx) irradiation 7 days, with 1N hydrochloric acid room temperature destroy 2 hours, with 1N sodium hydroxide room temperature destroy 2 hours, destroy with 10% hydrogen peroxide room temperature and to prepare according to the method described above in 30 minutes, measure record chromatic graph spectrum.The result shows that each catabolite that destroys the sample generation all separates well with cetirizine hydrochloride.
The linear relationship test
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.It is an amount of that precision takes by weighing reference substance respectively, is made into gradient solution, measure according to the chromatographic condition in above-described embodiment 5, and the record chromatogram, measurement result such as following table:
Table 3-1 cetirizine hydrochloride impurity A linear relationship is investigated the result
| Linear standard solution | Percentage concentration is than (%) | Concentration (μ g/ml) | Average peak area |
| L1 | 10 | 0.317 | 20480 |
| |
25 | 0.793 | 51465 |
| |
50 | 1.586 | 102817 |
| L4 | 75 | 2.379 | 154064 |
| L5 | 100 | 3.172 | 205898 |
| L6 | 150 | 4.758 | 300762 |
Conclusion: be abscissa with concentration respectively, peak area is vertical coordinate, and the regression equation that obtains the cetirizine hydrochloride impurity A is: Y=63366x+1899; R=0.9996.The 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 the good linear relation.
Table 3-2 cetirizine hydrochloride impurity B linear relationship is investigated the result
Conclusion: be abscissa with concentration respectively, peak area is vertical coordinate, and the regression equation that obtains the cetirizine hydrochloride impurity B is: Y=45594x+1350; R=0.9996.The 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 the good linear relation.
Table 3-3 cetirizine hydrochloride impurity G linear relationship is investigated the result
Conclusion: be abscissa with concentration respectively, peak area is vertical coordinate, and the regression equation that obtains cetirizine hydrochloride impurity G is: Y=47510x+1117; R=0.9996.The 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 the good linear relation.
Detectability
The result of detectability (LOD) recently determines according to noise, with dilution method the impurity solution that is diluted to variable concentrations is measured, when signal to noise ratio is about 3 to 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 the chromatographic condition detection sensitivity is good.
Accuracy test
Accuracy studies uses the response rate of the respective substance that records from the mixture of known quantity cetirizine hydrochloride, adjuvant to estimate accuracy.To test by the cetirizine hydrochloride solution of 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 that 100.3%, RSD is 1.36%, shows that the response rate is good as a result.
The test of experimental example 1 antiallergic
(body weight about 10～25g) is pressed the gastric infusion approach, three dosage (5%, 10%, 20%) and the astemizole sheet (10%) of Cetirizine hydrochloride Tablets is compared carbon granules removing speed in the serum in the unit of account time with this soil species white mice.
The result shows that Cetirizine hydrochloride Tablets can obviously increase foreign bodies removal rate value in the serum, and three dosage (5%, 10%, 20%) of Cetirizine hydrochloride Tablets all have significant difference, and along with dosage increases and the effect reinforcement.
The test of experimental example 2 antiinflammatories
Get the native country white mice in experiment each treated animal ear coating on the same day once, matched group is coated with same amount distilled water 0.05ml/20g.Each group is cleaned with dry cotton ball with distilled water flush away medicinal liquid after 1 hour.With dimethylbenzene 0.05ml/ only be coated with to mouse right ear.Left side ear compares, and puts to death animal after 15 minutes, with the card punch of diameter 6mm ears are downcut with the position homalographic, and be the swelling degree with the difference of left and right auricle weight.Calculate and respectively organize the swelling degree, obtain inhibitory rate of intumesce (%).
The result shows that three dosage (5%, 10%, 20%) of Cetirizine hydrochloride Tablets agent have the effect of obvious inhibition mice auricle swelling, and suppression ratio is respectively 85.2%, 76.8%, 72.5%; The astemizole sheet also has same effect, and suppression ratio is 70.1%.
Experimental example 3 antipruritic tests
Mice in the test proxima luce (prox. luc), is shaved hair to each right back instep of group mice, and coating once.Test same day abrades right back instep with coarse sandpaper and shaves hair place, about 1 square centimeter of area, the part again coating once, matched group gives the equivalent distilled water.Behind the last coating 10 minutes, beginning was only dripped 0.01% 0.05ml/ of histamine phosphate at the wound surface place, after this every 3 minutes by 0.01%, 0.02%, 0.03%, the 0.04%...... progressive concentration, only be 0.05ml/ at every turn.Directly cause and mice occurs and later lick right back foot, later to lick the right back histamine phosphate's total amount that is given when sufficient be antipruritic valve to occur mice at last.Record and relatively each group cause the valve of itching.
The result shows that Cetirizine hydrochloride Tablets agent heavy dose is organized the effect that the mice that is significantly improved causes the valve of itching, and causing the valve of itching is 502.6 ± 79 μ g, with matched group significant differences (P＜0.01) is arranged relatively, and small dose group also improves and causes the effect of the valve of itching.
Experimental example 4 stability tests
Get 1 to 3 following Cetirizine hydrochloride Tablets of the invention process, simulation listing packing, place under 40 ℃ ± 2 ℃ and relative humidity 75% ± 5% condition and placed 6 months, at the duration of test detection related substance of taking a sample respectively 1st month, 2 months, 3 months, 6 the end of month, and detected the result in 0 month and compare.Measurement result sees Table 5.
Related substance is measured according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2010 D).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; Being mobile phase A (regulating pH value to 3.0 with phosphoric acid) with acetonitrile-0.02% potassium dihydrogen phosphate (8: 92), is Mobile phase B with acetonitrile-0.05% phosphoric acid solution (48: 52), and according to the form below carries out linear gradient elution; Flow velocity is per minute 1.0ml; Column temperature is 40 ℃; The detection wavelength is 230nm.It is an amount of to get cetirizine hydrochloride, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G reference substance, the accurate title, decide, 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 is measured system suitability solution 20 μ l and is injected chromatograph of liquid, 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 is got 20 of Cetirizine hydrochloride Tablets, is ground into fine powder, takes by weighing an amount of (being equivalent to cetirizine hydrochloride 20mg approximately), the accurate title, decide, and puts in the 20ml measuring bottle, adds mobile phase A 15ml, supersound process 5 minutes (power 250W, frequency 33kHz) is put cold, add mobile phase A and be settled to scale, shake up, filter, be diluted to scale, filter with 0.45 μ m filter membrane, get subsequent filtrate as need testing solution; Precision is measured need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase A and is diluted to scale, shakes up, and precision is measured 2.0ml again, puts in the 10ml measuring bottle, adds mobile phase A and is diluted to scale, shakes up, in contrast solution.Precision is measured need testing solution, each 20 μ l of contrast solution, injects chromatograph of liquid respectively, and if any impurity peaks, the peak area of cetirizine hydrochloride impurity A, B, G must not be greater than 1.5 times of contrast solution main peak areas (0.3%) in the need testing solution chromatogram; The peak area of other single unknown impurities must not be greater than main peak area (0.2%) in the contrast solution; Each impurity peak area sum must not be greater than 4 times (0.80%) of contrast solution main peak area.In the need testing solution chromatogram can ignore in any peak less than main peak area 0.1 times (0.02%) in the contrast solution.
Table 5 Cetirizine hydrochloride Tablets stability test of the present invention related substance is investigated the result
Result of the test shows that the Cetirizine hydrochloride Tablets sample that the present invention makes was through 6 months accelerated tests, and related substance does not have significant difference, shows product technology, steady quality.
Claims (5)
1. Cetirizine hydrochloride Tablets is characterized in that comprising following components in weight percentage content:
2. a kind of Cetirizine hydrochloride Tablets according to claim 1 is characterized in that comprising following components in weight percentage content:
3. the preparation method of a Cetirizine hydrochloride Tablets is characterized in that comprising being prepared as follows step:
(1) percentage composition takes by weighing following component by weight:
(2) Macrogol 4000, the titanium dioxide of getting recipe quantity is crossed 200 mesh sieves, and is with cetirizine hydrochloride and the low-substituted hydroxypropyl cellulose mix homogeneously of recipe quantity, standby;
(3) material in above-mentioned (2) is joined in the dry granulation machine, setting pressure is 0.4～1.6Mpa, and feeding spiro rod speed is 25～35Hz, and it is 18～26Hz that a rotating speed is rolled in molding, and it is 12～22Hz that a rotating speed is rolled in granulation, granulate with 18 mesh sieves, and collecting granules, standby;
(4) with granule and recipe quantity vertical compression mixture Ludipress, spray-dried lactose SuperTabSD, sodium stearyl fumarate mix homogeneously in above-mentioned (3), hardness processed is 5～8Kg, is pressed into 1000, namely.
4. the preparation method of a kind of Cetirizine hydrochloride Tablets according to claim 3, it is characterized in that comprising being prepared as follows step: (1) percentage composition by weight takes by weighing following component:
(2) get the 20.25g Macrogol 4000,0.065g titanium dioxide is crossed 200 mesh sieves, and is with 10.80g cetirizine hydrochloride and 10.80g low-substituted hydroxypropyl cellulose mix homogeneously, standby;
(3) material in above-mentioned (2) is joined in the dry granulation machine, setting pressure is 1.0Mpa, and feeding spiro rod speed is 25Hz, and it is 22Hz that a rotating speed is rolled in molding, and it is 18Hz that a rotating speed is rolled in granulation, granulate with 18 mesh sieves, and collecting granules, standby;
(4) with granule and 33.75g vertical compression mixture Ludipress, 57.31g spray-dried lactose SuperTabSD, 2.025g sodium stearyl fumarate mix homogeneously in above-mentioned (3), control hardness is 6Kg, is pressed into 1000, namely.
5. the method for quality control of a Cetirizine hydrochloride Tablets related substance is characterized in that comprising the steps:
Measure according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2010 D).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; Being mobile phase A (regulating pH value to 3.0 with phosphoric acid) with acetonitrile-0.02% potassium dihydrogen phosphate (8: 92), is Mobile phase B with acetonitrile-0.05% phosphoric acid solution (48: 52), and according to the form below carries out linear gradient elution; Flow velocity is per minute 1.0ml; Column temperature is 40 ℃; The detection wavelength is 230nm.It is an amount of to get cetirizine hydrochloride, cetirizine hydrochloride impurity A, cetirizine hydrochloride impurity B and cetirizine hydrochloride impurity G reference substance, the accurate title, decide, 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 is measured system suitability solution 20 μ l and is injected chromatograph of liquid, 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 is got 20 of Cetirizine hydrochloride Tablets, is ground into fine powder, takes by weighing an amount of (being equivalent to cetirizine hydrochloride 20mg approximately), the accurate title, decide, and puts in the 20ml measuring bottle, adds mobile phase A 15ml, supersound process 5 minutes (power 250W, frequency 33kHz) is put cold, add mobile phase A and be settled to scale, shake up, filter, be diluted to scale, filter with 0.45 μ m filter membrane, get subsequent filtrate as need testing solution; Precision is measured need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase A and is diluted to scale, shakes up, and precision is measured 2.0ml again, puts in the 10ml measuring bottle, adds mobile phase A and is diluted to scale, shakes up, in contrast solution.Precision is measured need testing solution, each 20 μ l of contrast solution, injects chromatograph of liquid respectively, and if any impurity peaks, the peak area of cetirizine hydrochloride impurity A, B, G must not be greater than 1.5 times of contrast solution main peak areas (0.3%) in the need testing solution chromatogram; The peak area of other single unknown impurities must not be greater than main peak area (0.2%) in the contrast solution; Each impurity peak area sum must not be greater than 4 times (0.80%) of contrast solution main peak area.In the need testing solution chromatogram can ignore in any peak less than main peak area 0.1 times (0.02%) in the contrast solution.
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| CN104458932A (en) * | 2014-10-23 | 2015-03-25 | 广东东阳光药业有限公司 | Method for detecting relevant substances of cetirizine hydrochloride granules |
| 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 |
| CN107782813A (en) * | 2016-08-26 | 2018-03-09 | 人福普克药业（武汉）有限公司 | Detect the method about material 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104458932A (en) * | 2014-10-23 | 2015-03-25 | 广东东阳光药业有限公司 | Method for detecting relevant substances of cetirizine hydrochloride granules |
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| CN107782813A (en) * | 2016-08-26 | 2018-03-09 | 人福普克药业（武汉）有限公司 | Detect the method about material 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 |
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