CN109632931B - Analysis method of midazolam preparation - Google Patents
Analysis method of midazolam preparation Download PDFInfo
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- CN109632931B CN109632931B CN201811640781.5A CN201811640781A CN109632931B CN 109632931 B CN109632931 B CN 109632931B CN 201811640781 A CN201811640781 A CN 201811640781A CN 109632931 B CN109632931 B CN 109632931B
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
The invention provides an analysis method of midazolam preparation, which comprises the following steps: s1: preparing a sample solution, namely taking the midazolam preparation, digesting the midazolam preparation for 30-90min by using a digesting agent to obtain a midazolam mother solution; diluting with dilute nitric acid serving as a diluent to obtain a sample solution; s2: and (3) ICP-MS testing, wherein the digesting agent is selected from nitric acid and/or hydrogen peroxide. The detection method provided by the application avoids interference of elements such as C, F and improves atomization efficiency, thereby improving detection accuracy.
Description
Technical Field
The invention relates to the field of analysis and detection, and particularly relates to an analysis method of a midazolam preparation.
Background
The chemical name of midazolam is 1-methyl-8-chloro-6- (2-fluorophenyl) -4H-imidazo [ l, 5-a][l,4]Benzodiazepine
The drug has typical benzodiazepine
Has similar pharmacological activity, and can produce anxiolytic, sedative, hypnotic, anticonvulsant and muscle relaxing effects. After intramuscular or intravenous injection, transient antegrade memory deficits can occur, leaving the patient unable to recall what happened during the drug spike. The medicine has the advantages of rapid action and short duration. After the medicine is taken, the time for falling asleep can be shortened (generally only 20 minutes are needed from the taking to the falling asleep), the total sleep time is prolonged, the fast wave sleep (REM) is not influenced, and a patient can feel energetic, relaxed and happy after waking up the next morning. No drug resistance and withdrawal symptoms or rebound. Low toxicity and wide safety range.
The methods for measuring the content of the midazolam organic matter and controlling the quality are more, but the research on measuring the content of elements in the midazolam injection is less. Among the 92 natural elements currently known to exist in nature, 81 elements are known to exist in the organism in addition to inert elemental gas and technetium, francium, actinium, protactinium, astatine, etc. At present, limited by sample processing methods and detection conditions, the sample to be detected is generally small in sampling amount when element detection is carried out, so that the detection value of the sample in the detection process is low, some components are difficult to detect or the detection error is large. However, when the sampling amount of the sample to be measured is increased, the sample often has the problems of gelatinization, nonuniform digestion or insufficient digestion and the like in the digestion process, so that the measurement is difficult to carry out or the error is large.
And known digestion methods of the samples, such As microwave digestion method, ashing digestion, acid digestion and the like, are adopted, wherein the ashing digestion efficiency is low, the precision is poor, and the volatilization of elements to be detected (such As Pb, Hg and As) is often caused. Although microwave digestion is convenient, the cost is too high, the sample amount is small, potential safety hazards exist, and the range of measurable elements is small. Acid digestion is the most widely applied method, but the most serious problem of the traditional acid digestion is incomplete digestion, and the residual and excessive acid in digestion liquid can influence the determination result.
Disclosure of Invention
In order to solve the technical problems, the invention provides an analysis method of midazolam preparation.
As a preferred technical solution, the method for analyzing the midazolam formulation comprises the following steps:
s1: preparation of sample solution
Digesting the midazolam preparation with a digesting agent for 30-90min to obtain a midazolam mother solution; diluting with dilute nitric acid serving as a diluent to obtain a sample solution;
s2: ICP-MS testing
The digesting agent is selected from nitric acid and/or hydrogen peroxide.
As a preferable technical scheme, the digestion is divided into three steps:
the first step is as follows: adding mixed solution of concentrated nitric acid and hydrogen peroxide as digesting agent, and digesting for 10-30 min;
the second step is that: adding a digesting agent concentrated nitric acid, and digesting for 10-30 min;
the third step: adding a digesting agent concentrated nitric acid, and digesting for 10-30 min.
The three digestion steps are all in a closed environment, and the heating deacidification is an open environment.
As a preferable technical scheme, the weight ratio of the concentrated nitric acid to the hydrogen peroxide in the mixed solution is 1: 1.
the applicant finds that digestion is decomposed into three steps, wherein in the first step, concentrated nitric acid and hydrogen peroxide are adopted according to the weight ratio of 1: 1, the digesting agent can decompose and generate high-energy active oxygen which has strong destructive effect on organic substances; the organic matter can completely decompose and release metal elements, and the interference of C, F elements is reduced; clear up through the cubic, can effectually prevent to once clear up that time is long, sour volatile lead to clearing up the appearance of the incomplete problem of process, in addition, will clear up and decompose into 3 times, clear up the in-process digestion temperature and can be less than once clear up, prevent volatilizing of elements such As Hg, As, Sb to the degree of accuracy that detects has been improved.
As a preferable technical scheme, the weight ratio of the digesting agent added in the first step, the digesting agent added in the second step and the digesting agent added in the third step is 2: 1: 1.
as a preferable technical scheme, before dilution, heating is firstly carried out to remove acid for 10-30 min.
As a preferred technical solution, the parameters of the ICP-MS test include:
the output power of the high-frequency generator is 1100-1300W, and the flow rate of the atomizer is 0.8-0.9 mL/min.
The applicant finds that when the flow rate of the atomizer is 0.8-0.9L/min and the plasma gas is 15-20L/min, the amount of water entering the plasma can be reduced, and therefore the probability of the elements to be detected being generated into oxides is reduced. Meanwhile, the contact time of O and H elements and the element to be detected is reduced, and the probability of generating oxide is further reduced. When the flow rate is too small, the amount of the generated oxide increases, and when the flow rate is too large, the average residence time of the sample in the ICP torch is short, resulting in a decrease in the line intensity.
As a preferred technical scheme, the parameters of the ICP-MS test further comprise 15-20L/min of plasma gas, 0.8-1.6L/min of auxiliary gas and 44-52rpm of sample flushing speed; internal standard elements: sc, Y and Bi.
As a preferable technical scheme, 20-50 wt% of ethanol is added into the sample mother liquor before dilution.
As a preferable technical scheme, 35 wt% of ethanol is added into the sample mother liquor before dilution.
In the application, the mixed solution of concentrated nitric acid and hydrogen peroxide can increase the surface tension of the solution, and is not beneficial to the evaporation and ionization of elements to be detected; a certain content of ethanol is added into the sample solution, so that the surface tension of the solution can be reduced; however, the addition of ethanol can increase the viscosity of the solution, which is not beneficial to the increase of the lifting amount of the sample; the applicant unexpectedly finds that when the plasma gas is 18L/min and the flow rate of the atomizer is 0.87L/min, the detection accuracy and precision are improved; the possible reasons are guessed that when the flow rates of the plasma gas and the atomizer are in a certain value, the viscosity of the sample is reduced, the amount of the sample entering the plasma torch is increased, and the sample atomization efficiency is improved.
As a preferred technical scheme, the steps further comprise preparing Hg element standard mother liquor, 7 element mixed standard mother liquor, 15 element mixed standard mother liquor and 3 element mixed internal standard solutions; seven elements in the 7-element mixed standard mother liquor are As, Cd, Co, Ni, Pb, Sb and V; 15 elements in the 15 element mixed standard mother liquor are Al, B, Li, Mn, Ba, Cr, Cu, Ti, Na, Mg, K, Ca, Fe, Zn and Si; the mixed internal standard solution of the 3 elements is Sc, Y and Bi.
The invention has the beneficial effects that:
the detection method provided by the application avoids interference of elements such as C, F and improves atomization efficiency, thereby improving detection accuracy.
Detailed Description
For purposes of the following detailed description, it is to be understood that the invention may assume various alternative variations and step sequences, except where expressly specified to the contrary. Moreover, other than in any operating examples, or where otherwise indicated, all numbers expressing, for example, quantities of ingredients used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
Moreover, it should be understood that any numerical range recited herein is intended to include all sub-ranges subsumed therein. For example, a range of "1 to 10" is intended to include all sub-ranges between (and including) the recited minimum value of 1 and the recited maximum value of 10, i.e., having a minimum value equal to or greater than 1 and a maximum value of equal to or less than 10.
No mention is made in the present invention of the availability of the pharmaceutical product or the components for purchase or preparation.
In order to solve the technical problems, the invention provides an analysis method of midazolam preparation.
In a specific embodiment, the method for analyzing the midazolam formulation comprises the following steps:
s1: preparation of sample solution
Digesting the midazolam preparation with a digesting agent for 30-90min to obtain a midazolam mother solution; diluting with dilute nitric acid serving as a diluent to obtain a sample solution;
s2: ICP-MS testing
The digesting agent is selected from nitric acid and/or hydrogen peroxide.
The concentration of the diluent dilute nitric acid is 2 wt%.
In a specific embodiment, the digestion is divided into three steps:
the first step is as follows: adding mixed solution of concentrated nitric acid and hydrogen peroxide as digesting agent, and digesting for 10-30 min;
the second step is that: adding a digesting agent concentrated nitric acid, and digesting for 10-30 min;
the third step: adding a digesting agent concentrated nitric acid, and digesting for 10-30 min.
The CAS number of the concentrated nitric acid is 7697-37-2, and the CAS number of the hydrogen peroxide is 7722-84-1.
In a preferred embodiment, the digestion is divided into three steps:
the first step is as follows: adding mixed solution of concentrated nitric acid and hydrogen peroxide as digesting agent, and digesting for 20 min;
the second step is that: adding a digesting agent concentrated nitric acid, and digesting for 20 min;
the third step: adding digestive concentrated nitric acid, and digesting for 20 min.
In a specific embodiment, the weight ratio of the concentrated nitric acid to the hydrogen peroxide in the mixed solution is 1: 1.
in a specific embodiment, the weight ratio of the digesting agent added in the first step, the second step and the third step is 2: 1: 1.
in a specific embodiment, the acid is removed by heating for 10-30min before the dilution.
In a specific embodiment, the parameters of the ICP-MS test comprise:
the output power of the high-frequency generator is 1100-1300W, and the flow rate of the atomizer is 0.8-0.9 mL/min.
In a preferred embodiment, the parameters of the ICP-MS test comprise:
the high-frequency generator output power is 1200W, and the flow rate of the atomizer is 0.85 mL/min.
In a specific embodiment, the parameters of the ICP-MS test further comprise 15-20L/min of plasma gas, 0.8-1.6L/min of auxiliary gas and 44-52rpm of sample flushing speed; internal standard elements: sc, Y and Bi.
In a preferred embodiment, the parameters of the ICP-MS test further comprise 17L/min of plasma gas, 1.2L/min of auxiliary gas and 48rpm of sample flushing speed; internal standard elements: sc, Y and Bi.
In a specific embodiment, the auxiliary gas is an inert gas; in a preferred embodiment, the auxiliary gas is argon.
In a specific embodiment, 20-50 wt% ethanol is added to the sample mother liquor before dilution.
In a preferred embodiment, 35 wt% ethanol is added to the sample mother liquor before dilution.
The ethanol has CAS number 64-17-5 and does not need dilution.
In a specific embodiment, the steps further comprise preparing Hg element standard mother liquor, 7 element mixed standard mother liquor, 15 element mixed standard mother liquor and 3 element mixed internal standard solutions; seven elements in the 7-element mixed standard mother liquor are As, Cd, Co, Ni, Pb, Sb and V; 15 elements in the 15 element mixed standard mother liquor are Al, B, Li, Mn, Ba, Cr, Cu, Ti, Na, Mg, K, Ca, Fe, Zn and Si; the mixed internal standard solution of the 3 elements is Sc, Y and Bi.
The following description will be given by way of specific examples.
Examples
Example 1
Example 1 provides an analytical method for midazolam formulations, comprising the steps of:
s1: preparation of sample mother liquor
Taking 2mL of midazolam preparation, adding 2mL of nitric acid and hydrogen peroxide according to a weight ratio of 1: 1, digesting the combined mixed solution for 20 minutes; supplementing 1mL of nitric acid, and digesting for 20 minutes; then 1mL of nitric acid is supplemented, and digestion is carried out for 20 minutes; heating for 20min to remove acid to obtain a sample mother solution.
S2: preparation of sample solution
And (3) sampling 400 mu L of the mother solution into a 10mL volumetric flask, adding 35 wt% of ethanol into the mother solution, diluting the mother solution to a scale with a diluent of 2% nitric acid, and shaking up to obtain the product.
S3: preparation of blank solution
Taking 400 mu L of the solution after the midazolam is digested, putting the solution into a 10mL volumetric flask, diluting the solution to a scale with a diluent of 2% nitric acid, and shaking up to obtain the midazolam.
S4: accuracy solution
Low concentration level: and putting 400 mu L of sample solution into a 10mL volumetric flask, adding 10 mu L of 15 element mixed standard mother liquor and 10 mu L of 7 element mixed standard mother liquor 10 mu L, Hg element standard mother liquor, diluting to a scale with a diluent, shaking uniformly to obtain 3 parts of sample solution in parallel by the same method. The standard concentration of As, Cd, Co, Ni, Pb, Sb, V and Hg elements is 0.1 mug/L, the standard concentration of Al, B, Ba, Cr, Cu, Li and Mn elements is 10 mug/L, and the standard concentration of Fe, Zn and Si elements is 100 mug/L.
The medium concentration level: and putting 400 mu L of sample solution into a 10mL volumetric flask, adding 50 mu L of 15 element mixed standard mother liquor and 100 mu L of 7 element mixed standard mother liquor 100 mu L, Hg element standard mother liquor, diluting to a scale with a diluent, and shaking uniformly to obtain the product. A total of 3 sample solutions were prepared in parallel. The standard concentration of As, Cd, Co, Ni, Pb, Sb, V and Hg elements is 1 mug/L, the standard concentration of Al, B, Ba, Cr, Cu, Li and Mn elements is 50 mug/L, and the standard concentration of Fe, Zn and Si elements is 500 mug/L.
High concentration level: and putting 400 mu L of sample solution into a 10mL volumetric flask, adding 100 mu L of 15 element mixed standard mother liquor and 150 mu L of 7 element mixed standard mother liquor 200 mu L, Hg element standard mother liquor, diluting to a scale with a diluent, and shaking up to obtain the product. A total of 3 sample solutions were prepared in parallel. The standard concentration of As, Cd, Co, Ni, Pb, Sb and V elements is 2 mug/L, the standard concentration of Hg element is 1.5 mug/L, the standard concentration of Al, B, Ba, Cr, Cu, Li and Mn elements is 100 mug/L, and the standard concentration of Fe, Zn and Si elements is 1000 mug/L.
S5: preparation of repetitive solutions
And putting 400 mu L of sample solution into a 10mL volumetric flask, adding 50 mu L of 15 element mixed standard mother liquor and 100 mu L of 7 element mixed standard mother liquor 100 mu L, Hg element standard mother liquor, diluting to a scale with a diluent, and shaking uniformly to obtain the product. 6 replicate solutions were prepared in parallel in the same way. The standard concentration of As, Cd, Co, Ni, Sb, Pb, V and Hg elements is 1 mug/L, the standard concentration of Al, B, Ba, Cr, Cu, Li and Mn elements is 50 mug/L, and the standard concentration of Fe, Zn and Si elements is 500 mug/L.
S6: intermediate precision solution
On different days, different analysts sample 400 mul of solution into a 10mL volumetric flask, adding 50 mul of 15-element mixed standard mother liquor and 100 mul of 7-element mixed standard mother liquor 100 mul L, Hg-element standard mother liquor, diluting to scale with diluent, and shaking uniformly to obtain the product. 6 portions of intermediate precision solution were prepared in parallel in the same manner. The standard concentration of As, Cd, Co, Ni, Sb, Pb, V and Hg elements is 1 mug/L, the standard concentration of Al, B, Ba, Cr, Cu, Li and Mn elements is 50 mug/L, and the standard concentration of Fe, Zn and Si elements is 500 mug/L.
S7: ICP-MS testing
The parameters of the ICP-MS test comprise:
the output power of the high-frequency generator is 1200W, the flow rate of the atomizer is 0.85mL/min, the plasma gas is 17L/min, the auxiliary gas is 1.2L/min, and the sample washing speed is 48 rpm.
Example 2
Example 2 provides an analytical method for midazolam formulations, comprising the steps of:
s1: preparation of sample mother liquor
Taking 2mL of midazolam preparation, adding 2mL of nitric acid and hydrogen peroxide according to a weight ratio of 1: 1, digesting the combined mixed solution for 20 minutes; supplementing 1mL of nitric acid, and digesting for 20 minutes; then 1mL of nitric acid is supplemented, and digestion is carried out for 20 minutes; heating for 20min to remove acid to obtain a sample mother solution.
S2: preparation of sample solution
And (3) sampling 400 mu L of the mother solution into a 10mL volumetric flask, adding 35 wt% of ethanol into the mother solution, diluting the mother solution to a scale with a diluent of 2% nitric acid, and shaking up to obtain the product.
S3: preparation of blank solution
Taking 400 mu L of the solution after the midazolam is digested, putting the solution into a 10mL volumetric flask, diluting the solution to a scale with a diluent of 2% nitric acid, and shaking up to obtain the midazolam.
S4: accuracy solution
Low concentration level: and putting 400 mu L of sample solution into a 10mL volumetric flask, adding 10 mu L of 15 element mixed standard mother liquor and 10 mu L of 7 element mixed standard mother liquor 10 mu L, Hg element standard mother liquor, diluting to a scale with a diluent, shaking uniformly to obtain 3 parts of sample solution in parallel by the same method. The standard concentration of As, Cd, Co, Ni, Pb, Sb, V and Hg elements is 0.1 mug/L, the standard concentration of Al, B, Ba, Cr, Cu, Li and Mn elements is 10 mug/L, and the standard concentration of Fe, Zn and Si elements is 100 mug/L.
The medium concentration level: and putting 400 mu L of sample solution into a 10mL volumetric flask, adding 50 mu L of 15 element mixed standard mother liquor and 100 mu L of 7 element mixed standard mother liquor 100 mu L, Hg element standard mother liquor, diluting to a scale with a diluent, and shaking uniformly to obtain the product. A total of 3 sample solutions were prepared in parallel. The standard concentration of As, Cd, Co, Ni, Pb, Sb, V and Hg elements is 1 mug/L, the standard concentration of Al, B, Ba, Cr, Cu, Li and Mn elements is 50 mug/L, and the standard concentration of Fe, Zn and Si elements is 500 mug/L.
High concentration level: and putting 400 mu L of sample solution into a 10mL volumetric flask, adding 100 mu L of 15 element mixed standard mother liquor and 150 mu L of 7 element mixed standard mother liquor 200 mu L, Hg element standard mother liquor, diluting to a scale with a diluent, and shaking up to obtain the product. A total of 3 sample solutions were prepared in parallel. The standard concentration of As, Cd, Co, Ni, Pb, Sb and V elements is 2 mug/L, the standard concentration of Hg element is 1.5 mug/L, the standard concentration of Al, B, Ba, Cr, Cu, Li and Mn elements is 100 mug/L, and the standard concentration of Fe, Zn and Si elements is 1000 mug/L.
S5: preparation of repetitive solutions
And putting 400 mu L of sample solution into a 10mL volumetric flask, adding 50 mu L of 15 element mixed standard mother liquor and 100 mu L of 7 element mixed standard mother liquor 100 mu L, Hg element standard mother liquor, diluting to a scale with a diluent, and shaking uniformly to obtain the product. 6 replicate solutions were prepared in parallel in the same way. The standard concentration of As, Cd, Co, Ni, Sb, Pb, V and Hg elements is 1 mug/L, the standard concentration of Al, B, Ba, Cr, Cu, Li and Mn elements is 50 mug/L, and the standard concentration of Fe, Zn and Si elements is 500 mug/L.
S6: intermediate precision solution
On different days, different analysts sample 400 mul of solution into a 10mL volumetric flask, adding 50 mul of 15-element mixed standard mother liquor and 100 mul of 7-element mixed standard mother liquor 100 mul L, Hg-element standard mother liquor, diluting to scale with diluent, and shaking uniformly to obtain the product. 6 portions of intermediate precision solution were prepared in parallel in the same manner. The standard concentration of As, Cd, Co, Ni, Sb, Pb, V and Hg elements is 1 mug/L, the standard concentration of Al, B, Ba, Cr, Cu, Li and Mn elements is 50 mug/L, and the standard concentration of Fe, Zn and Si elements is 500 mug/L.
S7: ICP-MS testing
The parameters of the ICP-MS test comprise:
the output power of the high-frequency generator is 1100W, the flow rate of the atomizer is 0.8mL/min, the plasma gas is 15L/min, the auxiliary gas is 0.8L/min, and the sample washing speed is 44 rpm.
Example 3
Example 3 provides an analytical method for midazolam formulations, comprising the steps of:
s1: preparation of sample mother liquor
Taking 2mL of midazolam preparation, adding 2mL of nitric acid and hydrogen peroxide according to a weight ratio of 1: 1, digesting the combined mixed solution for 20 minutes; supplementing 1mL of nitric acid, and digesting for 20 minutes; then 1mL of nitric acid is supplemented, and digestion is carried out for 20 minutes; heating for 20min to remove acid to obtain a sample mother solution.
S2: preparation of sample solution
And (3) sampling 400 mu L of the mother solution into a 10mL volumetric flask, adding 35 wt% of ethanol into the mother solution, diluting the mother solution to a scale with a diluent of 2% nitric acid, and shaking up to obtain the product.
S3: preparation of blank solution
Taking 400 mu L of the solution after the midazolam is digested, putting the solution into a 10mL volumetric flask, diluting the solution to a scale with a diluent of 2% nitric acid, and shaking up to obtain the midazolam.
S4: accuracy solution
Low concentration level: and putting 400 mu L of sample solution into a 10mL volumetric flask, adding 10 mu L of 15 element mixed standard mother liquor and 10 mu L of 7 element mixed standard mother liquor 10 mu L, Hg element standard mother liquor, diluting to a scale with a diluent, shaking uniformly to obtain 3 parts of sample solution in parallel by the same method. The standard concentration of As, Cd, Co, Ni, Pb, Sb, V and Hg elements is 0.1 mug/L, the standard concentration of Al, B, Ba, Cr, Cu, Li and Mn elements is 10 mug/L, and the standard concentration of Fe, Zn and Si elements is 100 mug/L.
The medium concentration level: and putting 400 mu L of sample solution into a 10mL volumetric flask, adding 50 mu L of 15 element mixed standard mother liquor and 100 mu L of 7 element mixed standard mother liquor 100 mu L, Hg element standard mother liquor, diluting to a scale with a diluent, and shaking uniformly to obtain the product. A total of 3 sample solutions were prepared in parallel. The standard concentration of As, Cd, Co, Ni, Pb, Sb, V and Hg elements is 1 mug/L, the standard concentration of Al, B, Ba, Cr, Cu, Li and Mn elements is 50 mug/L, and the standard concentration of Fe, Zn and Si elements is 500 mug/L.
High concentration level: and putting 400 mu L of sample solution into a 10mL volumetric flask, adding 100 mu L of 15 element mixed standard mother liquor and 150 mu L of 7 element mixed standard mother liquor 200 mu L, Hg element standard mother liquor, diluting to a scale with a diluent, and shaking up to obtain the product. A total of 3 sample solutions were prepared in parallel. The standard concentration of As, Cd, Co, Ni, Pb, Sb and V elements is 2 mug/L, the standard concentration of Hg element is 1.5 mug/L, the standard concentration of Al, B, Ba, Cr, Cu, Li and Mn elements is 100 mug/L, and the standard concentration of Fe, Zn and Si elements is 1000 mug/L.
S5: preparation of repetitive solutions
And putting 400 mu L of sample solution into a 10mL volumetric flask, adding 50 mu L of 15 element mixed standard mother liquor and 100 mu L of 7 element mixed standard mother liquor 100 mu L, Hg element standard mother liquor, diluting to a scale with a diluent, and shaking uniformly to obtain the product. 6 replicate solutions were prepared in parallel in the same way. The standard concentration of As, Cd, Co, Ni, Sb, Pb, V and Hg elements is 1 mug/L, the standard concentration of Al, B, Ba, Cr, Cu, Li and Mn elements is 50 mug/L, and the standard concentration of Fe, Zn and Si elements is 500 mug/L.
S6: intermediate precision solution
On different days, different analysts sample 400 mul of solution into a 10mL volumetric flask, adding 50 mul of 15-element mixed standard mother liquor and 100 mul of 7-element mixed standard mother liquor 100 mul L, Hg-element standard mother liquor, diluting to scale with diluent, and shaking uniformly to obtain the product. 6 portions of intermediate precision solution were prepared in parallel in the same manner. The standard concentration of As, Cd, Co, Ni, Sb, Pb, V and Hg elements is 1 mug/L, the standard concentration of Al, B, Ba, Cr, Cu, Li and Mn elements is 50 mug/L, and the standard concentration of Fe, Zn and Si elements is 500 mug/L.
S7: ICP-MS testing
The parameters of the ICP-MS test comprise:
the output power of the high-frequency generator is 1300W, the flow rate of the atomizer is 0.9mL/min, the plasma gas is 20L/min, the auxiliary gas is 1.6L/min, and the sample washing speed is 52 rpm.
Example 4
Example 4 provides an analytical method for midazolam formulations, similar to example 1, except that step S1 is as follows:
s1: preparation of sample mother liquor
Taking 2mL of midazolam preparation, adding 4mL of nitric acid, and digesting for 60 minutes to obtain a sample mother solution.
Example 5
Example 5 provides an analytical method for midazolam formulations, similar to example 1, except that in the first step, the weight ratio of nitric acid to hydrogen peroxide in the mixed solution of nitric acid and hydrogen peroxide is 1.5: 0.5.
example 6
Example 6 provides an analytical method for midazolam formulations, similar to example 1, except that step S1 is as follows:
taking 2mL of midazolam preparation, adding 2mL of nitric acid and hydrogen peroxide according to a weight ratio of 1: 1, digesting the combined mixed solution for 10 minutes; supplementing 1mL of nitric acid, and digesting for 10 minutes; then 1mL of nitric acid is supplemented, and digestion is carried out for 20 minutes; heating for 40min to remove acid to obtain a sample mother solution.
Example 7
Example 7 provides an analytical method for midazolam formulations, similar to example 1, except that step S1 is as follows:
taking 2mL of midazolam preparation, adding 2mL of nitric acid and hydrogen peroxide according to a weight ratio of 1: 1, digesting the combined mixed solution for 20 minutes; supplementing 1mL of nitric acid, and digesting for 20 minutes; then 1mL of nitric acid is supplemented, and digestion is carried out for 20 minutes to obtain a sample mother liquor.
Example 8
Example 8 provides an analytical method for midazolam formulations, prepared in a similar manner to example 1, except that the parameters of the ICP-MS test comprise:
the output power of the high-frequency generator is 900W, the flow rate of the atomizer is 1.9mL/min, the plasma gas is 15L/min, the auxiliary gas is 0.8L/min, and the sample washing speed is 44 rpm.
Example 9
Example 9 provides an assay for midazolam formulations without the addition of ethanol in step S2.
Example 10
Example 10 provides an assay for midazolam formulations comprising the steps of:
s1: preparation of sample mother liquor
Taking 2mL of midazolam preparation, adding 4mL of nitric acid, and digesting for 60 minutes to obtain a sample mother solution.
S2: preparation of sample solution
And (3) sampling 400 mu L of the mother solution, diluting the mother solution to a scale with a diluent of 2% nitric acid in a 10mL volumetric flask, and shaking up to obtain the product.
S3: preparation of blank solution
The same as in example 1.
S4: accuracy solution
The same as in example 1.
S6: intermediate precision solution
The same as in example 1.
S7: ICP-MS testing
The parameters of the ICP-MS test comprise:
the output power of the high-frequency generator is 800W, the flow rate of the atomizer is 1.9mL/min, the plasma gas is 15L/min, the auxiliary gas is 0.5L/min, and the sample washing speed is 56 rpm.
Evaluation of Performance test
One or more performance tests
1) Linearity
Sampling and analyzing the linear solution, and automatically calculating the correlation coefficient (r) of the linear equation by an instrument by taking the concentration of the standard solution as the abscissa and the intensity as the ordinate, wherein the correlation coefficient (r) is not lower than 0.995. The correlation coefficient of the equation is greater than 0.995 and the correlation coefficient and slope are shown in table 1.
TABLE 1
2) Accuracy of
The recovery of all accuracy solutions was between 70% and 150%, the RSD did not exceed 20%, and the accuracy results are shown in table 2.
TABLE 2
3) Quantitative Limit (LOQ)
The recovery rates of the LOQ solutions were all between 70-150% and the RSD was less than 20%, and the results of the recovery rates of the LOQ solutions are shown in Table 3.
4) Specificity
The detection value of the blank solution in the process is not more than LOQ, the concentration level recovery rate in the accuracy solution is 70-150%, the RSD is not more than 20%, and the specific reference is shown in Table 3.
TABLE 3
5) Precision degree
The RSD calculated for 6 replicate solutions was less than 20%, see table 4.
TABLE 4
6) Precision-intermediate precision
RSD of calculation results of 6 repetitive solutions and 6 intermediate precision solutions were less than 25%, and RSD of intermediate precision was shown in table 5.
TABLE 5
2) Accuracy testing
The midazolam formulations were tested as provided in examples 1-10, with the accuracy RSD/% of the test results shown in table 6.
TABLE 6
The foregoing examples are merely illustrative and serve to explain some of the features of the method of the present invention. The appended claims are intended to claim as broad a scope as is contemplated, and the examples presented herein are merely illustrative of selected implementations in accordance with all possible combinations of examples. Accordingly, it is applicants' intention that the appended claims are not to be limited by the choice of examples illustrating features of the invention. Also, where numerical ranges are used in the claims, subranges therein are included, and variations in these ranges are also to be construed as possible being covered by the appended claims.
Claims (5)
1. An analytical method of midazolam formulation, characterized in that it comprises the following steps:
s1: preparing a sample solution;
digesting the midazolam preparation with a digesting agent for 30-90min to obtain a midazolam mother solution; diluting with dilute nitric acid serving as a diluent to obtain a sample solution;
s2: ICP-MS testing;
adding 35 wt% of ethanol into the sample mother liquor before dilution;
the parameters of the ICP-MS test comprise:
the output power of the high-frequency generator is 1100-1300W, and the flow rate of the atomizer is 0.8-0.9 mL/min;
the parameters of the ICP-MS test also comprise 15-20L/min of plasma gas, 0.8-1.6L/min of auxiliary gas and 44-52rpm of sample flushing speed; internal standard elements: sc, Y, Bi;
the digestion is divided into three steps:
the first step is as follows: adding mixed solution of concentrated nitric acid and hydrogen peroxide as digesting agent, and digesting for 10-30 min;
the second step is that: adding a digesting agent concentrated nitric acid, and digesting for 10-30 min;
the third step: adding a digesting agent concentrated nitric acid, and digesting for 10-30 min.
2. The analytical method of claim 1, wherein the weight ratio of the concentrated nitric acid to the hydrogen peroxide in the mixed solution is 1: 1.
3. the analytical method according to claim 1, wherein the weight ratio of the digesting agent added in the first, second and third steps is 2: 1: 1.
4. the assay of claim 1, wherein said dilution is preceded by heating to remove acid for 10-30 min.
5. The assay of any one of claims 1-4, wherein the steps further comprise formulating Hg elemental standard stock, 7 elemental mixed standard stock, 15 elemental mixed standard stock and 3 elemental mixed internal standard solutions; seven elements in the 7-element mixed standard mother liquor are As, Cd, Co, Ni, Pb, Sb and V; 15 elements in the 15 element mixed standard mother liquor are Al, B, Li, Mn, Ba, Cr, Cu, Ti, Na, Mg, K, Ca, Fe, Zn and Si; the mixed internal standard solution of the 3 elements is Sc, Y and Bi.
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