CN112505225A - Method for predicting validity period of medicine - Google Patents
Method for predicting validity period of medicine Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims abstract description 79
- 238000000034 method Methods 0.000 title claims abstract description 30
- 229940079593 drug Drugs 0.000 claims abstract description 53
- 230000005855 radiation Effects 0.000 claims abstract description 34
- 238000005070 sampling Methods 0.000 claims abstract description 24
- 239000000843 powder Substances 0.000 claims abstract description 19
- 238000005303 weighing Methods 0.000 claims abstract description 17
- 238000012360 testing method Methods 0.000 claims abstract description 15
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 11
- 239000012085 test solution Substances 0.000 claims abstract description 10
- 238000012417 linear regression Methods 0.000 claims abstract description 9
- 238000007865 diluting Methods 0.000 claims abstract description 8
- XWSCOGPKWVNQSV-UHFFFAOYSA-N 5-bromo-2,3-dichloropyridine Chemical group ClC1=CC(Br)=CN=C1Cl XWSCOGPKWVNQSV-UHFFFAOYSA-N 0.000 claims description 64
- 229960005111 zolpidem tartrate Drugs 0.000 claims description 64
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 10
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 239000012488 sample solution Substances 0.000 claims description 9
- 230000005251 gamma ray Effects 0.000 claims description 8
- 230000005865 ionizing radiation Effects 0.000 claims description 8
- 239000000523 sample Substances 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000001514 detection method Methods 0.000 claims description 5
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 239000012528 membrane Substances 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- GUTLYIVDDKVIGB-OUBTZVSYSA-N Cobalt-60 Chemical compound [60Co] GUTLYIVDDKVIGB-OUBTZVSYSA-N 0.000 claims description 2
- 238000001471 micro-filtration Methods 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 5
- 229940127557 pharmaceutical product Drugs 0.000 claims 5
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- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 2
- 206010022437 insomnia Diseases 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
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- 238000013112 stability test Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
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- 210000002784 stomach Anatomy 0.000 description 1
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- 229940125725 tranquilizer Drugs 0.000 description 1
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
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Abstract
The application provides a method for predicting the validity period of a medicine, which comprises the following steps: (1) carrying out an accelerated test: setting the medicines of each group in accelerated degradation environments with different radiation intensities, relative humidity and sampling time; (2) preparation of a test solution: precisely weighing each group of medicines, grinding into fine powder, precisely weighing a certain amount of fine powder, placing into a 50ml measuring flask, quantitatively diluting with mobile phase to constant volume, and making into test solution. (3) Establishing an effective period equation: and (3) performing content measurement by using a high performance liquid chromatography, calculating the effective period of the medicine under the conditions of different relative humidity, radiation intensity and sampling time, and performing a linear regression model to construct an equation for predicting the effective period of the medicine. The prediction method is simple to operate, good in repeatability, labor-saving, simple in theoretical derivation, short in test period, consistent in prediction result with the actual effective period of the medicine and high in accuracy.
Description
Technical Field
The invention relates to the technical field of medicine validity period prediction, in particular to a method for predicting the medicine validity period.
Background
In general, astronauts carry various complete medicines in the outer space, and can effectively treat common diseases.
Various diseases easily produced by astronauts in the outer space include the diseases related to the environmental factors of the outer space and the common clinical diseases similar to those on the ground. The types of drugs that astronauts carry when entering space involve almost every clinical department, including cardiovascular, respiratory, digestive, urinary, neuro-oral, surgical, etc. The medicament has rich dosage forms, such as tablets, injections, sprays, suppositories, liniments and the like. The medicine can be tens of kinds such as analgesic, stomach medicine, antidepressant, anti-dizziness medicine, antiinflammatory medicine, and tranquilizer. The medicine chest on the international space station is also provided with sedative and medicines for treating melancholy, anxiety and psychological diseases.
Zolpidem tartrate tablets are clinically and widely used mental drugs, are mainly used for occasional insomnia and temporary insomnia, have the effective period of 36 months, and are one of necessary chemical drugs for astronauts in space environment. Research shows that the storage temperature of the medicine in the space environment is similar to the earth, and the biggest factors influencing the stability of the medicine are space radiation and relative humidity, wherein the space radiation comprises non-ionizing radiation and ionizing radiation, the non-ionizing radiation can be shielded by spacecrafts, space stations, medicine packages and the like, and the electromagnetic waves of gamma rays, X rays and the like of the ionizing radiation, electrons, protons, high-energy Z particles and the like are difficult to completely shield, so that the structure of the medicine is changed to a certain extent. Therefore, space environment stability research on space drugs is needed to predict the effective period of zolpidem tartrate tablets.
In addition, on earth, some medicines are sterilized and disinfected by radiation, and the sterilization mode can accelerate the degradation of the medicines to a certain extent, so that the effective period of the medicines is shortened.
If a stability test method specified by pharmacopoeia is adopted, the time is long, the cost is high, and manpower and material resources are consumed. The existing zolpidem tartrate tablet validity period prediction method comprises the methods of a classical constant temperature method, software prediction, an initial uniform velocity method, an Arrhenius equation prediction method of humidity correction and the like, and the prediction result has the defects of poor repeatability, large error and the like. However, the effective period of the medicine in the space environment has many and uncontrollable influence factors, so that a method for predicting the effective period of the medicine (such as zolpidem tartrate tablets) in the environment of accelerating medicine degradation is in the present stage.
Disclosure of Invention
In order to solve the problem that a method for predicting the effective period of a medicine under an accelerated medicine degradation environment is lacked, which has good repeatability and small error, the invention aims to provide a method for predicting the effective period of the medicine, which comprises the following steps:
(1) carrying out an accelerated test: randomly dividing the medicines into a plurality of groups, respectively carrying out ionizing radiation with the radiation intensity of 0-100kgy on each group of medicines, respectively placing each group of irradiated medicines into different incubators, wherein the relative humidity of each incubator is 30-80%, and the sampling time of the medicines is 0-504 hours;
(2) preparing a test solution and measuring the content: precisely weighing each group of the medicines processed in the step (1), grinding into fine powder, precisely weighing a certain amount of fine powder, placing the fine powder into a 50ml measuring flask, adding a proper amount of a mobile phase, diluting to a scale, shaking up, filtering, precisely weighing 1ml of a subsequent filtrate, placing the subsequent filtrate into the 50ml measuring flask, quantitatively diluting with the mobile phase to a constant volume, and filtering with a microporous filter membrane to obtain a sample solution; and (3) carrying out content determination on each sample solution by using a high performance liquid chromatography, wherein the conditions of the high performance liquid chromatography are as follows: the instrument is LC-20A (SHIMADZU), the chromatographic column is an octadecylsilane bonded silica gel column (150mm multiplied by 4.6mm, 5 μm, SHIMADZU), and the mobile phase: acetonitrile-methanol-0.05 mo1/L phosphoric acid solution, wherein the acetonitrile and the methanol are pure solutions, the 0.05mo1/L phosphoric acid solution is adjusted to pH value of 5.4-5.6 by triethylamine, and the ratio of acetonitrile: methanol: the proportion of the phosphoric acid solution is (10-20): (20-30): (50-60), the column temperature is 40 ℃, and the detection wavelength is 254 nm; the injection volume is 20 mu L; the flow rate is 1 mL/min;
(3) establishing an effective period equation: and (3) calculating different relative humidities, radiation intensities and corresponding drug expiration dates under the sampling time conditions in the step (1) according to the content of each test sample measured in the step (2), and performing a linear regression model to construct an equation for predicting the drug expiration dates.
Further, the ionizing radiation in step (1) is γ -ray.
Further, the dose of the gamma-ray is 0 to 80 KGy.
Further, the gamma-ray is emitted from the cobalt 60.
Further, the sampling time in the step (1) is 3 to 366 hours.
Further, the relative humidity of the incubator in the step (1) is 40% to 70%.
Further, the medicine is zolpidem tartrate tablets, and the invention further provides a method for predicting the effective period of the zolpidem tartrate tablets, wherein the zolpidem tartrate tablets are under accelerated test conditions. The expiration date refers to the longest period of time that the drug content is greater than 80% of the labeled amount under the accelerated test conditions of step (1).
Further, in the step (2), a plurality of zolpidem tartrate tablets in each group in the step (1) are taken, precisely weighed, ground into fine powder, precisely weighed into fine powder equivalent to 25mg of zolpidem tartrate, placed in a 50ml measuring flask, added with a proper amount of mobile phase, shaken to dissolve the fine powder, diluted to a scale by the mobile phase, shaken up and filtered, 1ml of subsequent filtrate is precisely weighed, placed in a 50ml measuring flask, quantitatively diluted by the mobile phase to a constant volume, and filtered by a 0.45 mu m microfiltration membrane to prepare a sample solution of 10 mu g/ml.
Further, the equation for predicting the drug expiration date in step (3) is: t ═ K1·RIM+K2·RH+K3T + b, wherein K1In the range of (-0.12 to-0.16), K2In the range of (1.1 to 1.5), K3The range is (-0.01 to-0.014), the range of b is (32 to 36), wherein RH is relative humidity, and the unit is%; RIM is the radiation intensity in kgy; t is sampling time and has a unit of h; t is the validity period and the unit is month.
After the technical scheme is adopted, compared with the prior art, the method has the following beneficial effects:
according to the method, the humidity condition, the radiation intensity and the sampling time are set to simulate the environment for accelerating the degradation of the drug, the deterioration of the zolpidem tartrate tablet is accelerated, the high-efficiency liquid phase content of the drug is used as an index, a relevant linear regression equation is obtained by adopting a multivariate linear model method, and the equation is used for predicting the validity period of the zolpidem tartrate tablet in the environment for accelerating the degradation. When the drug content is reduced to 80% of the labeled amount (10 mg/tablet), the zolpidem tartrate tablet loses the drug effect, so the time point when the drug content is lower than 80% of the labeled amount is used as the judgment basis of the drug validity period. The method has the advantages of simple prediction operation, good repeatability, labor saving, simple theoretical derivation, short test period, high accuracy and the predicted result is consistent with the actual effective period of the medicine.
Drawings
FIG. 1 is a high performance liquid chromatogram of group 1 zolpidem tartrate tablets;
FIG. 2 is a high performance liquid chromatogram of a zolpidem tartrate tablet of group 2;
FIG. 3 is a high performance liquid chromatogram of group 3 zolpidem tartrate tablets;
FIG. 4 is a high performance liquid chromatogram of zolpidem tartrate tablets from group 4.
Detailed Description
The advantages of the invention are further illustrated in the following description of specific embodiments in conjunction with the accompanying drawings.
Reference will now be made in detail to the exemplary embodiments, examples of which are illustrated in the accompanying drawings. When the following description refers to the accompanying drawings, like numbers in different drawings represent the same or similar elements unless otherwise indicated. The implementations described in the exemplary embodiments below are not intended to represent all implementations consistent with the present disclosure. Rather, they are merely examples of apparatus and methods consistent with certain aspects of the present disclosure, as detailed in the appended claims. The terminology used in the present disclosure is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. As used in this disclosure and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.
Example 1:
1. carrying out an accelerated test: dividing zolpidem tartrate tablets into four groups of ten tablets at random, respectively carrying out gamma-ray radiation of 0kgy, 8kgy, 25kgy and 80kgy on the four groups of medicines, respectively placing the four groups of medicines after radiation into different stable incubators, setting the relative humidity of the incubators to be 40-70%, and the sampling time of each group of medicines to be 3-336h, wherein the specific experimental conditions are shown in table 1.
TABLE 1 accelerated test conditions adopted for four groups of zolpidem tartrate tablets respectively
2. The high performance liquid chromatography conditions for content determination of zolpidem tartrate tablets are as follows:
the instrument comprises the following steps: LC-20A (SHIMADZU)
A chromatographic column: octadecylsilane chemically bonded silica gel column; (150 mm. times.4.6 mm, 5 μm, SHIMADZU)
Mobile phase: acetonitrile-methanol-0.05 mo1/L phosphoric acid solution (pH adjusted to 5.5 with triethylamine) (18:23: 59); column temperature: 40 deg.C
Detection wavelength: 254 nm;
sample introduction volume: 20 mu L of the solution;
flow rate: 1 mL/min;
3. preparing a test solution and measuring the content: taking ten zolpidem tartrate tablets from each group, taking 40 tablets from four groups in total, precisely weighing four groups of medicines respectively, grinding into fine powder, precisely weighing a proper amount of fine powder (about 25mg of zolpidem tartrate) from each group, respectively placing into a 50ml measuring flask, adding a mobile phase to dilute to a scale, shaking up, filtering, precisely weighing 1ml of subsequent filtrate, placing into a 50ml measuring flask, quantitatively diluting with the mobile phase to a constant volume, filtering with a 0.45 mu m microporous membrane, and respectively preparing the four groups of medicines into 10 mu g/ml test solution.
4. Establishing an effective period equation: analyzing the four groups of 10 mu g/ml sample solutions to be tested by high performance liquid chromatography, wherein a 1 st group zolpidem tartrate high performance liquid chromatogram is shown in figure 1, a 2 nd group zolpidem tartrate high performance liquid chromatogram is shown in figure 2, a 3 rd group zolpidem tartrate high performance liquid chromatogram is shown in figure 3, a 4 th group zolpidem tartrate high performance liquid chromatogram is shown in figure 4, the content of each group of samples is taken as an index, the time t when the content of the samples is reduced to 80% of a labeled amount (650 mg/tablet) is calculated, namely the relative humidity, the radiation intensity and the effective period of the zolpidem tartrate under the sampling time, and a linear regression model is performed according to the time t and an equation for predicting the effective period of the zolpidem tartrate is established: t is 34.89399323-0.14205588 RIM +1.359329593 RH-0.012589264T, where T is the expiration date in months and RH is the relative humidity in months; RIM is the radiation intensity in kgy; t is the sampling time in h.
The fit of the model is shown in the multiple linear regression model of table 2, with a coefficient of determination of 0.82240831, indicating that 82.24% of the change in expiration date can be explained by the change in radiation intensity, relative humidity, and sampling time. The more the coefficient value of the decision coefficient is close to 1, the more the prediction of the validity period by the model is close to the true value. Taking the radiation intensity as an example, the partial regression coefficient is-0.14205588, which shows that under the condition of no change of other factors, the effective period is reduced by 0.14 month when the radiation intensity is increased by 1 Kgy.
TABLE 2 multiple Linear regression model of zolpidem tartrate tablets
The zolpidem tartrate tablets with the relative humidity of 50 percent, the radiation intensity of 8kgy and the sampling time of 100h are substituted into the validity period prediction equation in the example 1: the effective period of zolpidem tartrate tablets under the condition is predicted to be 33.18 months in T-34.89399323-0.14205588. RIM + 1.359329593. RH-0.012589264. T.
And (3) verification: 30 zolpidem tartrate tablets are randomly divided into 3 groups, 10 tablets are taken in each group, the zolpidem tartrate tablets are irradiated with 8kgy, the zolpidem tartrate tablets are respectively placed in a stability incubator with the relative humidity of 50% for 100 hours, the content of the zolpidem tartrate tablets is 92.38% of the marked amount according to the content measurement method of example 1, and the effective period is 33 months.
Example 2:
1. carrying out an accelerated test: dividing zolpidem tartrate tablets into four groups of ten tablets at random, respectively carrying out gamma-ray radiation of 0kgy, 8kgy, 25kgy and 80kgy on the four groups of medicines, respectively placing the four groups of medicines after radiation into different stable incubators, setting the relative humidity of the incubators to be 40-70%, and the sampling time of each group of medicines to be 3-336h, wherein the specific experimental conditions are shown in table 3.
TABLE 3 accelerated test conditions adopted for four groups of zolpidem tartrate tablets respectively
2. The high performance liquid chromatography conditions for content determination of zolpidem tartrate tablets are as follows:
the instrument comprises the following steps: LC-20A (SHIMADZU)
A chromatographic column: octadecylsilane chemically bonded silica gel column; (150 mm. times.4.6 mm, 5 μm, SHIMADZU)
Mobile phase: acetonitrile-methanol-0.05 mo1/L phosphoric acid solution (pH adjusted to 5.5 with triethylamine) (10: 30: 60); column temperature: 40 deg.C
Detection wavelength: 254 nm;
sample introduction volume: 20 mu L of the solution;
flow rate: 1 mL/min;
3. preparing a test solution and measuring the content: taking ten zolpidem tartrate tablets from each group, taking 40 tablets from four groups in total, precisely weighing four groups of medicines respectively, grinding into fine powder, precisely weighing a proper amount of fine powder (about 25mg of zolpidem tartrate) from each group, respectively placing into a 50ml measuring flask, adding a mobile phase to dilute to a scale, shaking up, filtering, precisely weighing 1ml of subsequent filtrate, placing into a 50ml measuring flask, quantitatively diluting with the mobile phase to a constant volume, filtering with a 0.45 mu m microporous membrane, and respectively preparing the four groups of medicines into 10 mu g/ml test solution.
4. Establishing an effective period equation: analyzing the four groups of 10 mu g/ml sample solutions through high performance liquid chromatography, calculating the time t when the sample content is reduced to 80% of the labeled amount (10 mg/tablet) by taking the content of each group of samples as an index, namely the effective period of the zolpidem tartrate tablet under the relative humidity, the radiation intensity and the sampling time, performing a linear regression model according to the time t, and establishing an equation for predicting the effective period of the zolpidem tartrate tablet: t-32-0.12. RIM + 1.1. RH-0.01. T, wherein T is the expiration date in months and RH is the relative humidity in months; RIM is the radiation intensity in kgy; t is the sampling time in h. Taking the radiation intensity as an example, the validity period is reduced by 0.12 month when the radiation intensity is increased by 1Kgy under the condition that other factors are not changed.
The zolpidem tartrate tablet with the relative humidity of 50 percent, the radiation intensity of 8kgy and the sampling time of 100h is substituted into the prediction equation of the validity period in example 2, wherein T is 32-0.12. RIM + 1.1. RH-0.01. T, and the validity period of the zolpidem tartrate tablet under the condition is predicted to be 30.59 months.
30 zolpidem tartrate tablets are randomly divided into 3 groups, 10 tablets are taken in each group, the zolpidem tartrate tablets are irradiated with 8kgy, the zolpidem tartrate tablets are respectively placed in a stability incubator with the relative humidity of 50% for 100 hours, the content of the zolpidem tartrate tablets is 92.38% of the marked amount according to the content measurement method of example 2, and the effective period is 33 months.
Example 3
1. Carrying out an accelerated test: dividing zolpidem tartrate tablets into four groups of ten tablets at random, respectively carrying out gamma-ray radiation of 0kgy, 8kgy, 25kgy and 80kgy on the four groups of medicines, respectively placing the four groups of medicines after radiation into different stable incubators, setting the relative humidity of the incubators to be 40-70%, and the sampling time of each group of medicines to be 3-336h, wherein the specific experimental conditions are shown in table 4.
TABLE 4 accelerated test conditions adopted for four groups of zolpidem tartrate tablets respectively
2. The high performance liquid chromatography conditions for content determination of zolpidem tartrate tablets are as follows:
the instrument comprises the following steps: LC-20A (SHIMADZU)
A chromatographic column: octadecylsilane chemically bonded silica gel column; (150 mm. times.4.6 mm, 5 μm, SHIMADZU)
Mobile phase: acetonitrile-methanol-0.05 mo1/L phosphoric acid solution (pH adjusted to 5.5 with triethylamine) (20: 30: 50);
column temperature: 40 deg.C
Detection wavelength: 254 nm;
sample introduction volume: 20 mu L of the solution;
flow rate: 1 mL/min;
3. preparing a test solution and measuring the content: taking ten zolpidem tartrate tablets from each group, taking 40 tablets from four groups in total, precisely weighing four groups of medicines respectively, grinding into fine powder, precisely weighing a proper amount of fine powder (about 20mg of zolpidem tartrate) from each group, respectively placing into a 50ml measuring flask, adding a mobile phase to dilute to a scale, shaking up, filtering, precisely weighing 1ml of subsequent filtrate, placing into a 50ml measuring flask, quantitatively diluting with the mobile phase to a constant volume, filtering with a 0.45 mu m microporous membrane, and respectively preparing the four groups of medicines into 10 mu g/ml test solution.
4. Establishing an effective period equation: analyzing the four groups of 10 mu g/ml sample solutions through high performance liquid chromatography, calculating the time t when the sample content is reduced to 80% of the labeled amount (10 mg/tablet) by taking the content of each group of samples as an index, namely the effective period of the zolpidem tartrate tablet under the relative humidity, the radiation intensity and the sampling time, performing a linear regression model according to the time t, and establishing an equation for predicting the effective period of the zolpidem tartrate tablet: t-36-0.16. RIM + 1.5. RH-0.014. T, wherein T is the expiration date in months and RH is the relative humidity in months; RIM is the radiation intensity in kgy; t is the sampling time in h. Taking the radiation intensity as an example, the validity period is reduced by 0.16 month when the radiation intensity is increased by 1Kgy under the condition that other factors are not changed.
The zolpidem tartrate tablets with the relative humidity of 50 percent, the radiation intensity of 8kgy and the sampling time of 100h are substituted into the prediction equation of the validity period in example 1, wherein T is 36-0.16. RIM + 1.5. RH-0.014. T, and the validity period of the zolpidem tartrate tablets under the condition is predicted to be 34.07 months.
30 zolpidem tartrate tablets are randomly divided into 3 groups, each group comprises 10 tablets, the zolpidem tartrate tablets are irradiated with 8kgy, the zolpidem tartrate tablets are respectively placed in a stability incubator with the relative humidity of 50% for 100 hours, the content of the zolpidem tartrate tablets is detected to be 92.38% of the marked amount, and the effective period is 33 months.
The embodiment 1-3 shows that the validity period prediction equation in the embodiment 1 is most consistent with the actually detected validity period time, the validity period prediction equation is optimal, the accuracy is high, the repeatability is good, and a rapid and reliable method is provided for predicting the validity period of zolpidem tartrate tablets.
It should be noted that the embodiments of the present invention have been described in terms of preferred embodiments, and not by way of limitation, and that those skilled in the art can make modifications and variations of the embodiments described above without departing from the spirit of the invention.
Claims (9)
1. A method of predicting the expiration date of a pharmaceutical product, comprising the steps of:
(1) carrying out an accelerated test: randomly dividing the medicines into a plurality of groups, respectively carrying out ionizing radiation with the radiation intensity of 0-100kgy on each group of medicines, respectively placing each group of irradiated medicines into different incubators, wherein the relative humidity of each incubator is 30-80%, and the sampling time of the medicines is 0-504 hours;
(2) preparing a test solution and measuring the content: precisely weighing each group of the medicines processed in the step (1), grinding into fine powder, precisely weighing a certain amount of fine powder, placing the fine powder into a 50ml measuring flask, adding a proper amount of a mobile phase, diluting to a scale, shaking up, filtering, precisely weighing 1ml of a subsequent filtrate, placing the subsequent filtrate into the 50ml measuring flask, quantitatively diluting with the mobile phase to a constant volume, and filtering with a microporous filter membrane to obtain a sample solution; and (3) carrying out content determination on each sample solution by using a high performance liquid chromatography, wherein the conditions of the high performance liquid chromatography are as follows: the instrument is LC-20A (SHIMADZU), the chromatographic column is an octadecylsilane bonded silica gel column (150mm multiplied by 4.6mm, 5 μm, SHIMADZU), and the mobile phase: acetonitrile-methanol-0.05 mo1/L phosphoric acid solution, wherein the acetonitrile and the methanol are pure solutions, the 0.05mo1/L phosphoric acid solution is adjusted to pH value of 5.4-5.6 by triethylamine, and the ratio of acetonitrile: methanol: the proportion of the phosphoric acid solution is (10-20): (20-30): (50-60), the column temperature is 40 ℃, and the detection wavelength is 254 nm; the injection volume is 20 mu L; the flow rate is 1 mL/min; and
(3) establishing an effective period equation: and (3) calculating different relative humidities, radiation intensities and corresponding drug expiration dates under the sampling time conditions in the step (1) according to the content of each test sample measured in the step (2), and performing a linear regression model to construct an equation for predicting the drug expiration dates.
2. The method for predicting expiration date of a pharmaceutical product according to claim 1, wherein the ionizing radiation in step (1) is a gamma ray.
3. The method of predicting drug expiration as claimed in claim 2, wherein the dose of gamma rays is 0-80 KGy.
4. The method of predicting drug expiration as claimed in claim 3, wherein said gamma ray is emitted from cobalt 60.
5. The method for predicting expiration date of drugs according to claim 1, wherein the sampling time in step (1) is 3 to 366 hours.
6. The method for predicting expiration date of drugs according to claim 1, wherein the relative humidity of the incubator in the step (1) is 40% to 70%.
7. The method for predicting the expiration date of a pharmaceutical product according to any one of claims 1 to 6, wherein the pharmaceutical product is zolpidem tartrate tablets.
8. The method for predicting the expiration date of a pharmaceutical product according to claim 7, wherein in the step (2), a plurality of tablets in each set of zolpidem tartrate tablets in the step (1) are taken, precisely weighed, ground into fine powder, precisely weighed fine powder containing 25mg of zolpidem tartrate is placed in a 50ml measuring flask, diluted to a scale by a mobile phase, shaken up and filtered, precisely measured to obtain 1ml of subsequent filtrate, placed in a 50ml measuring flask, quantitatively diluted to a constant volume by the mobile phase, and filtered by a 0.45 μm microfiltration membrane to prepare a sample solution of 10 μ g/ml.
9. The method of predicting a drug expiration date of claim 8, wherein the equation of predicting a drug expiration date in step (3) is: t ═ K1·RIM+K2·RH+K3T + b, wherein K1Is-0.12 to-0.16, K21.1 to 1.5, K3 is-0.01 to-0.014, b is 32 to 36, wherein RH is relative humidity, unit is%; RIM is the intensity of radiation, aloneThe bit is kgy; t is sampling time and has a unit of h; t is the validity period and the unit is month.
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Application publication date: 20210316 |