CN1971258A - Method for evaluating stability of cefoperazone sodium leechdom - Google Patents
Method for evaluating stability of cefoperazone sodium leechdom Download PDFInfo
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Abstract
The invention provides an evaluating method of stableness of cefoperazone sodium medicine; the crystal analysis is preceded by powder X-ray diffraction technology, the diffraction characteristic parameters which express the different crystal sample is selected as the quantizing index, the different crystal samples can be partied into different monoids by the statistical analysis. Based on the above, different sample monoids are associated with its stability to build the correlation relationship of the diffraction characteristic parameters and the stability, so the evaluation of stability can be rapidly realized with the diffraction characteristic parameters. The method is quick, convenient and accurate, it compensates for the disadvantages of traditional method, can do quick evaluation for the stability of the cefoperazone sodium medicine, and can be used to guide the company to produce the production and improve the process.
Description
Technical field
The present invention relates to a kind of method of quick evaluating stability of cefoperazone sodium leechdom, specifically, relate to a kind of application powder x-ray diffraction technology and carry out the crystallinity analysis, set up diffractive features parameter and stable correlationship, thereby realize estimating its stability fast with the diffractive features parameter of sample.
Background technology
Stability is one of important indicator of estimating drug quality, is a main standard weighing drug safety, validity." Chinese pharmacopoeia (version was two ones in 2005) appendix XIXC " bulk drug and pharmaceutical preparation stability test governing principle " and " international technology of ICH medicine registration requires " (mass fraction) " new raw material medicine and stability of formulation test ICH three parts coordinate and direct principle " are set forth the aspects such as purpose, basic demand, method step and high spot reviews project of stability of drug products test and are stipulated.
In the drug quality research work, according to above-mentioned two governing principles, formed the test method of the traditional evaluation stability of drug products of a cover gradually, and generally accepted by people and adopt.According to traditional evaluation method, bulk drug need carry out influence factor test, accelerated test and long-term stable experiment.The influence factor test comprises hot test (condition: 60 ℃ or 40 ℃ of temperature; Time: 10 days), high humility test (condition: 25 ℃ of temperature, relative humidity 90 ± 5% or 75 ± 5%; Time: 10 days) and strong illumination test (condition: 4500 ± 500lx; Time: 10 days), influence its stable factor and possible degradation pathway and catabolite, for preparation production technique, packing, storage requirement and foundation explanation product analysis method provide scientific basis in order to inherent stability, the understanding of inquiring into medicine.The test condition of accelerated test is 40 ± 2 ℃ of temperature, relative humidity 75 ± 5%, test period is 6 months, its objective is by quickening the chemistry or the physical change of medicine, inquire into stability of drug, for preparation designs, packs, transports, stores the data that provides necessary.The test condition of long-term stable experiment is 25 ± 2 ℃ of temperature, relative humidity 60 ± 10%, and test period is 12 months, its objective is that the term of validity for formulating medicine provides foundation.
According to traditional evaluation method, need repeatedly sampling (influence factor test: 0 day, 5 days, 10 days in the test period of every test determination; Accelerated test: 0 month, January, February, March, June; Long-term stable experiment: 0 month, March, June, September, Dec), carry out the mensuration of projects such as proterties, content, related substance.Defectives such as seen traditional evaluation method exists the test period to grow, workload is big, waste time and energy can't satisfy the requirement of estimating fast in the pharmaceutical production process modification.Therefore, need provide a kind of evaluation method more fast and accurately.
Cefoperazone sodium belongs to third generation cephalosporin class microbiotic.Chemical name is (6R, 7R)-and 3-[[(1-methyl isophthalic acid H-tetrazolium-5 base) sulphur] methyl]-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazine carbon acylamino)-2-p-hydroxybenzene-acetylamino]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid sodium salt.Advantages such as cefoperazone sodium has has a broad antifungal spectrum, and antibacterial action is strong now have been widely used in clinical.China is from the research of beginning cefoperazone sodium synthesis technique in 1981, domestic so far existing tens tame preparation manufacturing enterprises, and the manufacturer of raw material only has that Dalian Pfizer, Zhuhai federation, east, Suzhou are auspicious, the Shandong peace is for than several families such as Austria, part material still needs import.
Nat'l Pharmaceutical ﹠ Biological Products Control Institute has carried out the emphasis examination at random in 2000 to it in the microbiotic chamber, the sample of this examination at random is distributed in 17 provinces from 28 manufacturing enterprises, and total lot number is 112 batches, wherein 72 batches are directly extracted by manufacturing enterprise, account for 64.3% of total lot number; 40 batches are extracted from the circulation field, account for 35.7%.According to Chinese Pharmacopoeia nineteen ninety-five version the sample that extracts is tested, it is as follows that the result adds up: the disqualification rate of this examination at random is 11.6%, wherein content is defective is to cause the underproof main cause of homemade cefoperazone for inj sodium product, and 8 batches of against regulation products of this inspection are all taken out from the circulation field.Do correlation analysis by effect phase and content to product, find that total trend is: the sample of approaching more effect phase, content are low more.The prompting cefoperazone sodium decomposes in the storage life gradually, and the main factor that promptly influences the cefoperazone sodium quality is its stability, so, still need product processes to instruct and transform.
Summary of the invention
(1) technical matters that will solve
Purpose of the present invention aims to provide a kind of evaluation method of stability of drug products fast and accurately, to overcome long, defective such as workload big, waste time and energy of traditional evaluation method test period, simultaneously cefoperazone sodium pharmaceutical production process modification is instructed.
(2) technical scheme
For addressing the above problem, the invention provides a kind of fast appraisement method of stability of cefoperazone sodium leechdom, method of the present invention may further comprise the steps:
(1) gets the cefoperazone sodium sample, adopt the positive platen press compressing tablet of glass plate;
(2) utilize the powder x-ray diffraction technology that the crystallinity of sample is analyzed, searching can characterize the diffractive features parameter of different crystallinity samples;
(3) be index with the diffractive features parameter, adopt clustering methodology that the different sample of crystallinity is carried out monoid and divide;
(4) in different monoids, select representational sample, adopt influence factor test, accelerated test and long-term stable experiment to estimate the stability of cefoperazone sodium leechdom;
(5) sample monoid division result is associated with the result of stability test, sets up diffractive features parameter and stable correlationship;
(6) the powder x-ray diffraction characteristic parameter that utilizes sample is estimated the stability of cefoperazone sodium leechdom fast as quantizating index, guide product production and technological transformation.
Wherein described in the step (1) sample can be selected from various processes, different batches simultaneously, compressing tablet respectively.
Wherein the diffractive features parameter described in the step (2) is diffraction peak position (2 θ) and diffraction peak relative intensity (I/I
0), or diffraction peak position (2 θ) and diffraction peak intensity (I).
Wherein the cluster analysis described in the step (3) (Cluster analysis) claims cluster analysis again, being a kind of multivariate statistical method of research " things of a kind come together, people of a mind fall into the same group ", is to utilize mathematical measure that a collection of object or variable are classified in the degree of close and distant distance in nature according to them.Adopt pedigree clustering method (Hierarchicalclustering method) a sample set can be divided into several inferior collection.Monoid is divided the cardinal rule follow: between each things according to qualitative classification; Nature difference between the things of the like description is less; The nature difference of things is bigger between class and the class.The arrangement mode of this method cluster is that group is included in the big class, and the typical consequence of its analysis is a pedigree chart (Dendrogram).Now existing various software can reach this purpose, as SPSS software.
Wherein the influence factor test period described in the step (4) is 10 days, comprise hot test (60 ℃ or 40 ℃ of temperature), high humility test (25 ℃ of temperature, relative humidity 90 ± 5% or 75 ± 5%) and strong illumination test (light intensity: 4500 ± 500lx), respectively at the 0th day, 5 days, 10 days sampling and measuring after the setting-out; The accelerated test time is 6 months, under 40 ± 2 ℃ of temperature, relative humidity 75 ± 5% conditions, respectively at after the setting-out the 0th month, January, February, March, June sampling and measuring; The long-term stable experiment time is 12 months, under 25 ± 2 ℃ of temperature, relative humidity 60 ± 10% conditions, respectively at after the setting-out the 0th month, March, June, September, Dec sampling and measuring.The mensuration project is the color of proterties, content, related substance, fusing point, hydroscopicity, solution and clarity, polymkeric substance, moisture etc., is proterties, content and related substance but mainly detect assessment item.Estimate the stability of cefoperazone sodium leechdom with measurement result.
Wherein characteristic index is adjusted, optimized to step (5) in case of necessity, because the science of characteristic index, reasonable, appropriate selection are that this method is set up key one ring in the process, to a certain extent to the practicality decisive role of method.Need when selecting characteristic index the diffractive features parameter of different crystallinity samples and the result of its stability test are fully taken into consideration.Sometimes the characteristic index that primary election obtains can be proved appropriate inadequately by the subsequent experimental result, and just need adjust and optimize this moment it.For example certain feature peak position (2 θ) of determining in primary election is located, and subsequent experimental finds that the fluctuation of the strong measurement result in peak is bigger, illustrate in the stability and the reappearance of this peak position place experimental data relatively poorly, and this peak position is not suitable for being elected to be the feature peak position, needs change or rejecting.And for example primary election is determined with strong (I) parameter in peak as another characteristic index, and follow-up experimental result shows that the strong parameter in peak is subjected to the influence of instrument state bigger, by comparison strong (the I/I in peak relatively
0) parameter is subjected to the influence of instrument state hardly, can reduce the systematic error of method, therefore adjust when optimizing characteristic index strong (I) parameter in peak with the strong (I/I in relative peak
0) parameter substitutes.In a word, adjusting with the purpose of optimizing characteristic index is to make selected index can characterize out the difference of the diffractive features of different crystallinity samples to greatest extent.
Wherein utilize the powder x-ray diffraction characteristic parameter of sample as quantizating index in the step (6), estimate the stability of cefoperazone sodium leechdom fast, be meant that a certain cefoperazone sodium sample to be analyzed is carried out powder x-ray diffraction to be measured, and obtains diffracting spectrum and diffraction parameter.With sample at the relative peak of feature that given several features peak position (2 θ) is located strong (I/I
0) or above-mentioned two diffractive features parameters of peak strong (I) and known each hypotype sample of A crystal formation cefoperazone sodium compare, determine the hypotype ownership of sample to be analyzed.In conjunction with each known hypotype stability of sample conclusion, estimate stability of sample to be analyzed.Again according to the concrete production technology of different stability sample, the production technology of product is instructed.
According to crystallographic sorting technique, medicine can be divided into crystal type and unformed two big classes.For the crystal type medicine, different along with crystallization solvent and process conditions may produce different crystal formations with a kind of medicine, are called the polymorphism of medicine.The polymorphism of medicine all has considerable influence to drug quality and clinical effectiveness, and wherein one of main influence aspect drug quality is the influence to the medicine physical and chemical stability.
On the other hand, for a kind of medicine, even mutually isomorphous product, because the change of production technology, the crystallinity of its product and crystalline characteristics are also incomplete same, and then cause stability there are differences.For example, the present application people finds in the research to the beta-lactam antibiotic cefoperazone sodium, be all A crystal formation product, but the crystallinity between the product, crystalline characteristics and stability is all different.
The method of medicine polymorphic research is commonly used at present hot stage microscope inspection technique, thermal analysis system (comprising differential thermal analysis, differential scanning calorimetry and thermogravimetry), infrared spectrophotometer, solubility test method, powder x-ray diffraction method and a monocrystalline X-ray diffraction method etc., and wherein the powder x-ray diffraction method is the technology that a kind of powder x-ray diffraction collection of illustrative plates that utilizes monochromatic X-ray to shine to produce on the polycrystalline sample solves problems such as relevant sample crystallinity and crystal structure.This technology is special, accurate, quick with it, advantages of simple operation is subject to people's attention day by day, more and more is widely used in the Pharmaceutical Analysis field, is to carry out the most frequently used of medicine polymorphic research and effective method at present.
Utilize the powder x-ray diffraction technology can distinguish unformed and crystal type intuitively from the powder x-ray diffraction collection of illustrative plates of sample: unformed sample does not have the obvious diffraction peak; And the crystal type sample has sharp-pointed diffraction peak.To the crystal type sample, the powder x-ray diffraction collection of illustrative plates of the every kind of crystal formation almost fingerprint with the people is the same simultaneously, the distributing position of its diffraction peak (2 θ) and intensity height (I, I/I
0) oneself feature all arranged.When comprising several crystal formation in the sample, the collection of illustrative plates that its powder x-ray diffraction collection of illustrative plates is added and obtained by the diffracting spectrum of the various crystal formations of forming it.
On the other hand, for the mutually isomorphous product with a kind of medicine, the nuance of its production technology also can show by the powder x-ray diffraction collection of illustrative plates of sample, thereby distinguishes mutually.Method of the present invention can utilize the powder x-ray diffraction characteristic parameter of sample as quantizating index, estimates the stability of cefoperazone sodium leechdom fast, and then estimates the quality of various processes, guide product production and technological transformation.
(3) beneficial effect
This method first with quick, easy, the powder x-ray diffraction technology is applied in the estimation of stability of medicine accurately, many defectives of traditional evaluation method have been remedied, can carry out the quick evaluation of stability of cefoperazone sodium leechdom, also can be used for instructing manufacturing enterprise to carry out production and technological transformation with clearly defined objectively.
Embodiment
The following examples can further be expressly understood the present invention, but following embodiment is not a limitation of the invention.
One, cefoperazone sodium present situation
Nat'l Pharmaceutical ﹠ Biological Products Control Institute has carried out the emphasis examination at random in 2000 to it in the microbiotic chamber.The sample of this examination at random is distributed in 17 provinces from 28 manufacturing enterprises, and total lot number is 112 batches, and wherein 72 batches are directly extracted by manufacturing enterprise, account for 64.3% of total lot number; 40 batches are extracted from the circulation field, account for 35.7%.According to Chinese Pharmacopoeia nineteen ninety-five version the sample that extracts is tested, it is as follows that the result adds up:
1, total qualification rate of this examination at random is 88.4%; 13 batch samples are against regulation, and disqualification rate is 11.6%.
2, from Interventions Requested, the color of proterties, clarity, solution, crystallinity are all up to specification, and the assay item is against regulation in the substandard product 8 batches (dividing 5 producers), accounts for 61.5% of defective sum; Clarity is underproof 2 batches (dividing 2 producers), accounts for 15.4%; Moisture is underproof 3 batches (1 producer), accounts for 23.1%.
See on the sample source that 3, from have 8 batches of the field of circulation, account for 61.5% of defective sum in the substandard product, it is against regulation to be the assay item; And clarity and moisture failure all take out from production producer (totally 5 batches, account for defective sum 38.5%).
The result shows that content is defective to be to cause the underproof main cause of homemade cefoperazone for inj sodium product, and 8 batches of against regulation products of this inspection are all taken out from the circulation field.Do correlation analysis by effect phase and content to certain enterprise product, find that total trend is: the sample of approaching more effect phase, content are low more.The prompting cefoperazone sodium decomposes in the storage life gradually.In view of the above, this examination at random can be reached a conclusion: the main factor that influences the cefoperazone sodium quality is its stability.
Two, the classification of cefoperazone sodium crystal type sample and stability are relatively
1. the classification of crystal type sample
Carry out finding when powder x-ray diffraction is analyzed that be all the crystal type sample but have two kinds of different diffracting spectrums, diffraction peak distributing position of the two and intensity are all inequality at 112 batches of homemade cefoperazone for inj sodium to this examination at random.Prompting cefoperazone sodium crystal type sample may have two kinds of different crystal formations, and we are referred to as A crystal formation and B crystal formation respectively.I/I with A crystal formation and B crystal formation feature top eight spectral line separately
0, 2 θ, d/n value (the d/n value is calculated by Bragg equation 2d sin θ=n λ) list in the table 1 respectively.As seen the d/n value of A crystal formation and B crystal formation is obviously different, further specifies the crystal type cefoperazone sodium and has two kinds of different crystal formations.
The powder x-ray diffraction data of the cefoperazone sodium of two kinds of different crystal forms of table 1
| Crystal form | A | B | ||||
| Peak line | 2θ | d/n() | I/I 0 | 2θ | d/n() | I/I 0 |
| 1 2 3 4 5 6 7 8 | 14.36 3.32 19.82 20.40 21.52 17.96 7.52 13.94 | 6.16 26.59 4.48 4.35 4.13 4.93 11.75 6.35 | 100 86 62 54 54 46 44 42 | 10.44 20.86 16.20 14.46 19.28 18.96 22.58 22.26 | 8.47 4.25 5.47 6.12 4.60 4.68 3.93 3.99 | 100 58 48 44 38 34 34 32 |
2.A the comparison of crystal formation and B stable crystal form
2.1 lattice stability
2.1.1 high temperature powder X-ray diffraction experiment
Utilize high temperature powder X-ray diffraction method that two kinds of crystal formations of cefoperazone sodium A, B are measured to compare the difference between the different crystal forms lattice stability.The result shows that when the A crystal formation was heated to 120 ℃, the peak of diffraction peak began by force to weaken; To be 28.58,28.30 diffraction peak then be divided into two diffraction peaks that intensity is less again from acromion is synthetic unimodal to 2 θ; During to 140 ℃, each diffraction peak position and the variation of intensity in its diffracting spectrum are all little, show that too big change does not take place lattice.And the B crystal formation is when being heated to 80 ℃, and 2 θ are that 7.2 diffraction peak has become very weak, but other diffraction peak does not change substantially; During to 100 ℃, each diffraction peak peak position begins bigger change takes place, and shows that its lattice changes.
2.1.2 thermal analysis experiment
The medicine of the same race that crystal formation is different, fusing point often there are differences, and having only a kind of crystal formation usually is the most stable on thermodynamics, and it is higher to show as fusing point, and chemical stability is better.Carry out DSC by cefoperazone sodium and measure, find that the A crystal formation does not change substantially under higher temperature A, two kinds of crystal formations of B; And the B crystal formation has the endothermic peak (the possibility of result has time delay) of a broad about 110 ℃.The cefoperazone sodium that shows two kinds of crystal formations has different stability, judges that tentatively the A crystal formation is than the B stable crystal form.
2.1.3 interpretation of result
The crystal formation difference of medicine, the stability of its lattice are also different.By contrast, amplification to the local collection of illustrative plates of high temperature powder X-ray diffraction, the cefoperazone sodium that can clearly find out A, two kinds of crystal formations of B is with the difference on its lattice variations of rising of temperature.Simultaneously, crystal formation in transition process also usually with the variation on the heat.Dsc analysis is the result show, B crystal formation (100 ℃) its original lattice under higher temperature may expand, though diffraction peak still exists position and shape all to change, and has an endothermic process to take place near this temperature; And the diffraction peak of A crystal formation changes not quite, and its DSC curve is also milder, does not have tangible thermal change process.Show that the A crystal formation is more stable to higher temperature than its lattice of B crystal formation.
2.2 accelerated stability test
2.2.1 Temperature Influence
Select A crystal formation, B crystal formation and unformed cefoperazone sodium sample to carry out 40 ℃, 60 ℃, 70 ℃ and 80 ℃ of accelerated tests respectively, investigate two kinds of different crystal type samples and unformed stability of sample.
2.2.1.1 compare the time dependent trend of different crystal forms stability of sample with 80 ℃ of test figures
The result shows that cefoperazone sodium is to thermally labile.In preceding 3 days, the slope maximum of unformed sample degradation curve; To the 6th day, the content fall of B crystal form samples surpassed unformed sample.Do respectively the three after 6 days Trendline and provide the Trendline equation: the A crystal formation is y=-0.7679x+89.344; The B crystal formation is y=-2.77x+85.572; Unformed is y=-0.9975x+69.846.As seen, the degraded slope is followed successively by B crystal formation, unformed, A crystal formation by arranging from big to small.The stability order that shows the three is: A crystal formation＞unformed＞B crystal formation.
2.2.1.2 at each temperature the test figure temperature variant trend of different crystal forms stability of sample relatively during with the 5th day
The result shows, cefoperazone sodium is with the rising of the temperature acceleration of degrading, but temperature is to the difference that influences of different crystal forms cefoperazone sodium stability.(below 60 ℃) at a lower temperature, the more unformed sample of crystal type sample is stable, and three's stability order is: A crystal formation＞B crystal formation＞unformed; And under the hot conditions (more than 70 ℃), the B crystal form samples is least stable, and three's stability order is: A crystal formation＞unformed＞B crystal formation, and along with the rising of temperature, the degradation rate increase of B crystal form samples is the fastest.Whether relevant the stability that shows cefoperazone sodium is not only with crystallization, and relevant with the crystallization type.
Usually crystal type sample more unformed sample under the situation that keeps its lattice perfection is stable.But under extreme conditions (as high temperature) is when its lattice is destroyed, because of the generally more unformed sample of crystal type sample contains more moisture, so can show than the more unsettled characteristic of unformed sample.When temperature more than 70 ℃ the time, may be because the lattice of B crystal formation be destroyed, water of crystallization is overflowed, and causes its stability less than unformed sample.
2.2.2 the influence of humidity
Select A crystal formation, B crystal formation and unformed cefoperazone sodium sample to carry out the stability test of 40 ℃ of following different humidity conditions respectively, investigate two kinds of different crystal type samples and unformed stability of sample.
2.2.2.1 the content data with sample under each humidity compare the trend that the different crystal forms stability of sample changes with humidity
The result shows that along with the increase of humidity, the degraded of cefoperazone sodium is accelerated.Three's stability order is: A crystal formation＞B crystal formation＞unformed.Unformed stability of sample is subjected to having the greatest impact of humidity: along with the increase of humidity, and its stability decreases, degraded is accelerated.Though the crystal type sample also has this trend, change also not obvious.
Increase trend 2.2.2.2 compare the moisture of different crystal forms sample with the time dependent data of moisture in the sample under high (75%), low (30%) two humidity
The result shows that drawing that the cefoperazone sodium tool is higher is moist, but the crystal type sample is significantly less than unformed sample.Than (30%) under the low humidity, the moisture of crystal type sample and unformed sample all reaches an equilibrium value very soon and keeps constant substantially; And when higher levels of humidity (75%), the moisture of unformed sample also has the trend that slowly rises in the back that raises rapidly, and the amplitude of its rising is higher than the crystal type sample far away, and content descends also faster simultaneously.Prove that thus thereby the motility that moisture could participate in and improve the solid molecule quickens its chemical degradation.
3. conclusion
The powder x-ray diffraction analysis shows that there are two kinds of different crystal formations in the crystal type cefoperazone sodium: A crystal formation and B crystal formation.The experiment of high temperature powder X-ray diffraction, thermal analysis experiment and accelerated stability test confirm that further A crystal formation cefoperazone sodium is more stable than the B crystal form samples.
Three, the classification of cefoperazone sodium A crystal form samples characterizes
1.A the hypotype of crystal form samples classification
A crystal formation cefoperazone sodium sample is repeated powder x-ray diffraction to be measured, spectrogram is analyzed with RISM.Qualitative Analysis software at random, obtain corresponding with it peak strong (I) in the average diffraction peak (2 θ) at the last 10 peak and each the sample collection of illustrative plates, the results are shown in Table 2-1, and the strong (I/I in relative peak
0), the results are shown in Table 2-2.The hierarchical clustering method that utilization SPSS software provides is classified to the A crystal form samples, and A crystal formation cefoperazone sodium sample can further be divided into 5 hypotypes: being numbered 13,14,15,6 and 7 sample is the I hypotype; Being numbered 4,17,12,19,11,8,10,1,2,3,16 and 24 sample is the II hypotype; Being numbered 5,20 and 18 sample is the III hypotype; Being numbered 9 sample is the IV hypotype; Being numbered 21,23 and 22 sample is the V hypotype.
Table 2-1 cefoperazone sodium A crystal form samples diffractive features cluster data
| Sample number into spectrum | 2θ | |||||||||
| 7.5-7.6 | 10.1-10.2 | 13.9-14.0 | 14.4-14.5 | 18.0-18.1 | 18.6-18.7 | 19.8-19.9 | 20.4-20.5 | 21.5-21.6 | 25.1-25.2 | |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 | 1037 955 933 402 633 683 705 835 698 756 1038 894 965 949 989 675 455 481 720 747 2080 2068 1978 418 | 871 889 852 386 0 718 685 711 613 526 757 844 595 631 732 544 539 0 682 0 0 0 0 410 | 971 1004 992 615 800 883 807 837 0 719 937 922 793 868 944 835 785 685 798 761 0 0 0 602 | 2087 2030 2106 1350 1901 1956 2053 1928 1463 1656 2526 2596 2133 2245 2327 1538 1673 1657 2165 2188 2338 2163 2146 1153 | 1387 1393 1348 736 880 886 857 1267 914 1116 1553 1366 996 990 1067 928 999 953 1257 1210 1229 1042 1110 799 | 1133 1035 1075 622 703 702 665 934 0 886 1170 1078 785 843 867 756 795 753 957 879 0 0 0 648 | 1906 1850 1928 1039 1257 1196 1297 1644 1400 1398 1942 1918 1385 1469 1419 1367 1395 1384 1651 1632 1795 1564 1579 1016 | 1587 1634 1587 899 1104 1113 1048 1394 1127 1201 1613 1652 1233 1282 1249 1095 1176 1122 1365 1343 1501 1379 1417 851 | 1274 1302 1361 812 1001 1008 949 1211 1008 1062 1418 1464 1165 1169 1231 903 1059 1054 1355 1313 1348 1215 1208 601 | 745 691 812 480 558 595 0 679 0 636 726 861 589 635 621 477 537 0 692 728 0 0 0 364 |
Table 2-2 cefoperazone sodium A crystal form samples diffractive features cluster data
| Sample number into spectrum | 2θ | |||||||||
| 7.5-7.6 | 10.1-10.2 | 13.9-14.0 | 14.4-14.5 | 18.0-18.1 | 18.6-18.7 | 19.8-19.9 | 20.4-20.5 | 21.5-21.6 | 25.1-25.2 | |
| 1 | 50 | 42 | 47 | 100 | 66 | 54 | 91 | 76 | 61 | 36 |
| 2 | 47 | 44 | 49 | 100 | 69 | 51 | 91 | 80 | 64 | 34 |
| 3 | 44 | 40 | 47 | 100 | 64 | 51 | 92 | 75 | 65 | 39 |
| 4 | 30 | 29 | 46 | 100 | 55 | 46 | 77 | 67 | 60 | 36 |
| 5 | 33 | 0 | 42 | 100 | 46 | 37 | 66 | 58 | 53 | 29 |
| 6 | 35 | 37 | 45 | 100 | 45 | 36 | 61 | 57 | 52 | 30 |
| 7 | 34 | 33 | 39 | 100 | 42 | 32 | 63 | 51 | 46 | 0 |
| 8 | 43 | 37 | 43 | 100 | 66 | 48 | 85 | 72 | 63 | 35 |
| 9 | 48 | 42 | 0 | 100 | 62 | 0 | 96 | 77 | 69 | 0 |
| 10 | 46 | 32 | 43 | 100 | 67 | 54 | 84 | 73 | 64 | 38 |
| 11 | 41 | 30 | 37 | 100 | 61 | 46 | 77 | 64 | 56 | 29 |
| 12 | 34 | 33 | 36 | 100 | 53 | 42 | 74 | 64 | 56 | 33 |
| 13 | 45 | 28 | 37 | 100 | 47 | 37 | 65 | 58 | 55 | 28 |
| 14 | 42 | 28 | 39 | 100 | 44 | 38 | 65 | 57 | 52 | 28 |
| 15 | 43 | 31 | 41 | 100 | 46 | 37 | 61 | 54 | 53 | 27 |
| 16 | 44 | 35 | 54 | 100 | 60 | 49 | 89 | 71 | 59 | 31 |
| 17 | 27 | 32 | 47 | 100 | 60 | 48 | 83 | 70 | 63 | 32 |
| 18 | 29 | 0 | 41 | 100 | 58 | 45 | 84 | 68 | 64 | 0 |
| 19 | 33 | 32 | 37 | 100 | 58 | 44 | 76 | 63 | 63 | 32 |
| 20 | 34 | 0 | 35 | 100 | 55 | 40 | 75 | 61 | 60 | 33 |
| 21 | 89 | 0 | 0 | 100 | 53 | 0 | 77 | 64 | 58 | 0 |
| 22 | 96 | 0 | 0 | 100 | 48 | 0 | 72 | 64 | 56 | 0 |
| 23 | 92 | 0 | 0 | 100 | 52 | 0 | 74 | 66 | 56 | 0 |
| 24 | 36 | 36 | 52 | 100 | 69 | 56 | 88 | 74 | 52 | 32 |
Four, crystallinity and cefoperazone sodium A crystal form samples stability relationship
1. the comparison of each hypotype sample room crystallinity and chemical stability
Crystallinity is defined as the number percent of crystalline portion and unformed part in the sample, and its numerical value has reflected the quality of sample crystallization degree to a certain extent.Account for the relative crystallinity of each sample of percentage calculation of total peak integral area with the diffraction peak area sum of each sample of A crystal formation cefoperazone sodium, the result shows, the average crystallite degree difference of each hypotype sample.Simultaneously, the result of 80 ℃ of accelerated stability tests shows that stability and its crystallinity of A crystal formation cefoperazone sodium are proportionate, and along with reducing of crystallinity, stability reduces.In 5 hypotypes, the crystallinity of I hypotype sample is the highest, infers its chemical stability the best.
2. the relation of same hypotype sample room crystallinity and chemical stability
Select in the same hypotype two batches of crystallinity to differ the sample of big (crystallinity is respectively 16.24 and 29.46) and carry out stability test under the same terms respectively, under same test conditions, the increase of impurity peaks in the big sample chromatogram figure of crystallinity of the little sample of crystallinity is more also more obvious.
The two stability is compared as index with two batch samples impurity number percent (normalization method) in the stability test under 70 ℃ and 40 ℃ of conditions, the results are shown in Table 3.
Table 3-1 crystallinity and stability relationship test (70 ℃)
| The sample lot number | Crystallinity | Number percent (%)/impurity peaks that impurity peak area accounts for total peak area detects number (individual) | Impurity recruitment (%) | ||||
| 0 day | 3 days | 6 days | 11 days | 14 days | |||
| 95835064 | 16.24 | 0.5/1 | 5.0/4 | 6.1/4 | 7.3/4 | 7.7/4 | 7.2 |
| 0004020 | 29.46 | 0.3/1 | 2.8/2 | 3.4/2 | 4.0/2 | 4.4/2 | 4.1 |
Table 3-2 crystallinity and stability relationship test (40 ℃)
| The sample lot number | Crystallinity | Number percent (%)/impurity peaks that impurity peak area accounts for total peak area detects number (individual) | Impurity recruitment (%) | ||||
| 0 day | 30 days | 42 days | 52 days | 57 days | |||
| 95835064 | 16.24 | 0.5/1 | 0.6/1 | 0.7/1 | 2.1/3 | 2.3/2 | 1.8 |
| 0004020 | 29.46 | 0.3/1 | 0.5/1 | 0.6/1 | 0.7/1 | 0.9/1 | 0.6 |
As seen, no matter be that high temperature quickens or long-term stable experiment, the number percent that its impurity level of sample that crystallinity is little increases all is higher than the big sample of crystallinity, and impurity peaks to detect number also more.
3. conclusion
The medicine of same crystal formation not necessarily has identical chemical stability.Some nuance that can reflect crystalline material structure cell inside to the research of crystallinity and chemically stable sexual intercourse to a certain extent.The result shows, the crystallinity difference of A crystal formation cefoperazone sodium different subtype sample; There is certain relation in its stability with the crystallinity size: the sample that the sample that crystallinity is big is little than crystallinity is stable.
Five, set up the meaning of the fast appraisement method of stability of cefoperazone sodium leechdom
Institute's construction method can be used for estimating fast the stability of cefoperazone sodium leechdom, can also estimate the quality of various processes on this basis fast, further instructs the production and the technological transformation of cefoperazone sodium product.
Claims (4)
1, a kind of evaluation method of stability of cefoperazone sodium leechdom may further comprise the steps:
(1) gets the cefoperazone sodium sample, adopt the positive platen press compressing tablet of glass plate;
(2) utilize the powder x-ray diffraction technology that the crystallinity of sample is analyzed, searching can characterize the diffractive features parameter of different crystallinity samples;
(3) be index with the diffractive features parameter, adopt clustering methodology that the different sample of crystallinity is carried out monoid and divide;
(4) in different monoids, select representational sample, adopt influence factor test, accelerated test and long-term stable experiment to estimate the stability of cefoperazone sodium leechdom;
(5) sample monoid division result is associated with the result of stability test, sets up diffractive features parameter and stable correlationship;
(6) the powder x-ray diffraction characteristic parameter that utilizes sample is estimated the stability of cefoperazone sodium leechdom, guide product production and technological transformation as quantizating index.
2, evaluation method as claimed in claim 1, it is characterized in that wherein described in the step (1) sample be selected from various processes, different batches simultaneously, compressing tablet respectively.
3, evaluation method as claimed in claim 1, it is characterized in that wherein diffractive features parameter described in the step (2) is meant: peak position is strong with relative peak.
4, evaluation method as claimed in claim 1, it is characterized in that wherein diffractive features parameter described in the step (2) is meant: peak position and peak are strong.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103951679A (en) * | 2014-04-29 | 2014-07-30 | 悦康药业集团有限公司 | Cefoperazone sodium compound and medicine composition thereof |
| CN104165919A (en) * | 2014-08-29 | 2014-11-26 | 四川制药制剂有限公司 | Method for determining contents of effective components in cefoperazone sodium and tazobactam sodium for injection |
| CN104198549A (en) * | 2014-08-29 | 2014-12-10 | 四川制药制剂有限公司 | Method for determining content of cefoperazone sodium of cefoperazone sodium and tazobactam sodium for injection |
| CN107255646A (en) * | 2017-07-11 | 2017-10-17 | 华南理工大学 | A kind of method of fast quantification Predicting Stability of Drugs |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1040250C (en) * | 1994-08-01 | 1998-10-14 | 华南师范大学 | Method for measurement of material heat expansion in X-ray powder diffraction meter |
| CN1209628C (en) * | 2002-07-25 | 2005-07-06 | 浙江大学 | Chinese medicine quality control and evaluation method |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103951679A (en) * | 2014-04-29 | 2014-07-30 | 悦康药业集团有限公司 | Cefoperazone sodium compound and medicine composition thereof |
| CN103951679B (en) * | 2014-04-29 | 2016-04-27 | 悦康药业集团有限公司 | A kind of cefoperazone sodium compound and pharmaceutical composition thereof |
| CN104165919A (en) * | 2014-08-29 | 2014-11-26 | 四川制药制剂有限公司 | Method for determining contents of effective components in cefoperazone sodium and tazobactam sodium for injection |
| CN104198549A (en) * | 2014-08-29 | 2014-12-10 | 四川制药制剂有限公司 | Method for determining content of cefoperazone sodium of cefoperazone sodium and tazobactam sodium for injection |
| CN107255646A (en) * | 2017-07-11 | 2017-10-17 | 华南理工大学 | A kind of method of fast quantification Predicting Stability of Drugs |
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