Method for detecting impurities in 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone
1. A method for detecting impurities in 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one comprises the following steps:
1) mixing 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one with an aqueous solution of acetonitrile to obtain a test solution a;
respectively mixing impurities to be detected with acetonitrile to obtain impurity stock solutions;
mixing appropriate amount of each impurity stock solution with acetonitrile water solution to obtain each impurity reference solution;
mixing 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone, a proper amount of impurity stock solutions and an acetonitrile aqueous solution to obtain a system applicability solution b;
2) respectively detecting acetonitrile aqueous solution, impurity reference substance solution, test solution a and system applicability solution b by adopting HPLC, wherein the detection conditions are as follows:
octadecylsilane chemically bonded silica is used as a stationary phase;
the mobile phase comprises a mobile phase A and a mobile phase B, sodium dihydrogen phosphate solution and acetonitrile are used as the mobile phase A, and methanol and acetonitrile are used as the mobile phase B, and equal gradient elution is carried out;
3) and (3) obtaining the detection result of the impurity by calculation according to the HPLC map obtained in the step 2).
2. The detection method according to claim 1, wherein in the step 3), the volume ratio of the sodium dihydrogen phosphate solution to the acetonitrile in the mobile phase A is 950: 50;
the concentration of the potassium dihydrogen phosphate solution is 0.005-0.1 mol/L, and the pH value is 5.5-8.5;
in the mobile phase B, the volume ratio of methanol to acetonitrile is 500: 500.
3. the detection method according to claim 1, wherein in the step 3), the volume ratio of the mobile phase A to the mobile phase B is 20-97: 3 to 80.
4. The detection method according to claim 1, wherein in the step 3), the flow rate of the mobile phase is 0.7-0.9 mL/min;
the temperature of the detected chromatographic column is 20-50 ℃.
5. The detection method according to claim 1, wherein in step 3), the flow rate of the mobile phase is 0.8 mL/min;
the column temperature of the detected chromatographic column is 40 ℃;
the chromatographic column for detection is YMC-Triart C18, the column length is 250mm, the inner diameter is 4.6mm, and the particle size of the filler is 5 μm;
the wavelength of the detection is 230 nm.
6. The detection method according to claim 1, wherein in step 3), the volume ratio of the mobile phase A to the mobile phase B in the gradient elution process is:
7. the detection method according to claim 1, wherein each impurity stock solution comprises a stock solution of an impurity of formula (1), a stock solution of an impurity of formula (2), a stock solution of an impurity of formula (3), a stock solution of an impurity of formula (4), and a stock solution of an impurity of formula (5);
8. the detection method according to claim 7, wherein the concentration of the impurity in the stock solution of each impurity is 1 to 1000 μ g/mL;
in each impurity reference substance solution, the concentration of impurities is 0.05-50 mu g/mL.
9. The detection method according to claim 1, wherein the concentration of 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one in the sample solution a is 0.05 to 5 mg/mL.
10. The detection method according to claim 1, wherein in the system-compatible solution b, the concentration of the 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one is 0.05 to 5mg/mL, and the concentration of impurities is 0.05 to 50 μ g/mL.
Background
1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone serving as a starting material or an intermediate of various anti-cancer drugs such as Nilotinib (Nilotinib), Imatinib (Imatinib), and the like has a molecular formula of C10H12N2O, molecular weight 176.2151. The preparation method has stable market supply and low price, and is particularly suitable for the synthesis of raw material medicines. At present, the national requirements on the raw material medicine are higher and higher, and 1- (3-pyridyl) -3- (diThe methylamino) -2-propen-1-one is used as a starting reaction material or an intermediate for synthesizing various anti-cancer drugs, potential impurities existing in the methylamino) -2-propen-1-one can be introduced into the API, and in order to reduce potential risks of the API, the quality of the 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one needs to be monitored. The chemical structural formulas of nilotinib and imatinib are as follows:
disclosure of Invention
In view of this, the technical problem to be solved by the present invention is to provide a method for detecting impurities in 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one, which can effectively detect impurities in 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one, and the separation degree of the impurities from 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one is high.
The invention provides a method for detecting impurities in 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone, which comprises the following steps:
1) mixing 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one with an aqueous solution of acetonitrile to obtain a test solution a;
respectively mixing impurities to be detected with acetonitrile to obtain impurity stock solutions;
mixing appropriate amount of each impurity stock solution with acetonitrile water solution to obtain each impurity reference solution;
mixing 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone, a proper amount of impurity stock solutions and an acetonitrile aqueous solution to obtain a system applicability solution b;
2) respectively detecting acetonitrile aqueous solution, impurity reference substance solution, test solution a and system applicability solution b by adopting HPLC, wherein the detection conditions are as follows:
octadecylsilane chemically bonded silica is used as a stationary phase;
the mobile phase comprises a mobile phase A and a mobile phase B, sodium dihydrogen phosphate solution and acetonitrile are used as the mobile phase A, and methanol and acetonitrile are used as the mobile phase B, and equal gradient elution is carried out;
3) and (3) obtaining the detection result of the impurity by calculation according to the HPLC map obtained in the step 2).
Preferably, in step 3), the volume ratio of the sodium dihydrogen phosphate solution to the acetonitrile in the mobile phase a is 950: 50;
the concentration of the potassium dihydrogen phosphate solution is 0.005-0.1 mol/L, and the pH value is 5.5-8.5;
in the mobile phase B, the volume ratio of methanol to acetonitrile is 500: 500.
preferably, in the step 3), the volume ratio of the mobile phase A to the mobile phase B is 20-97: 3 to 80.
Preferably, in the step 3), the flow rate of the mobile phase is 0.7-0.9 mL/min;
the temperature of the detected chromatographic column is 20-50 ℃.
Preferably, in the step 3), the flow rate of the mobile phase is 0.8 mL/min;
the column temperature of the detected chromatographic column is 40 ℃;
the chromatographic column for detection is YMC-Triart C18, the column length is 250mm, the inner diameter is 4.6mm, and the particle size of the filler is 5 μm;
the wavelength of the detection is 230 nm.
Preferably, in step 3), during the gradient elution, the volume ratio of the mobile phase a to the mobile phase B is:
preferably, each impurity stock solution comprises a stock solution of the impurity of formula (1), a stock solution of the impurity of formula (2), a stock solution of the impurity of formula (3), a stock solution of the impurity of formula (4), and a stock solution of the impurity of formula (5);
preferably, the concentration of the impurities in the stock solution of each impurity is 1-1000 mug/mL;
in each impurity reference substance solution, the concentration of impurities is 0.05-50 mu g/mL.
Preferably, in the test solution a, the concentration of 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one is 0.05-5 mg/mL.
Preferably, in the system suitability solution b, the concentration of the 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one is 0.05-5 mg/mL, and the concentration of impurities is 0.05-50 μ g/mL.
The invention provides a method for detecting impurities in 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone, which comprises the following steps: 1) mixing 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one with an aqueous solution of acetonitrile to obtain a test solution a; respectively mixing impurities to be detected with acetonitrile to obtain impurity stock solutions; mixing appropriate amount of each impurity stock solution with acetonitrile water solution to obtain each impurity reference solution; mixing 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone, a proper amount of impurity stock solutions and an acetonitrile aqueous solution to obtain a system applicability solution b; 2) respectively detecting acetonitrile aqueous solution, impurity reference substance solution, test solution a and system applicability solution b by adopting HPLC, wherein the detection conditions are as follows: octadecylsilane chemically bonded silica is used as a stationary phase; the mobile phase comprises a mobile phase A and a mobile phase B, sodium dihydrogen phosphate solution and acetonitrile are used as the mobile phase A, and methanol and acetonitrile are used as the mobile phase B, and equal gradient elution is carried out; 3) and (3) obtaining the detection result of the impurity by calculation according to the HPLC map obtained in the step 2). The method for detecting the impurities in the 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-one, which is provided by the invention, is an external standard method, can accurately detect all the impurities in the 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-one, has higher separation degree of the impurities and the 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-one, has higher separation degree among all the impurities, meets all indexes, is simple and convenient to operate, has low cost, and is suitable for wide application.
Drawings
FIG. 1 is an HPLC chromatogram of an aqueous solution of acetonitrile at a volume concentration of 10%;
FIG. 2 is an HPLC chromatogram of a system suitability solution b of example 1 of the present invention;
FIG. 3 is an HPLC chromatogram of the test solution a in example 1 of the present invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a method for detecting impurities in 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone, which comprises the following steps:
1) mixing 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one with an aqueous solution of acetonitrile to obtain a test solution a;
respectively mixing impurities to be detected with acetonitrile to obtain impurity stock solutions;
mixing appropriate amount of each impurity stock solution with acetonitrile water solution to obtain each impurity reference solution;
mixing 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone, a proper amount of impurity stock solutions and an acetonitrile aqueous solution to obtain a system applicability solution b;
2) respectively detecting acetonitrile aqueous solution, impurity reference substance solution, test solution a and system applicability solution b by adopting HPLC, wherein the detection conditions are as follows:
octadecylsilane chemically bonded silica is used as a stationary phase;
the mobile phase comprises a mobile phase A and a mobile phase B, sodium dihydrogen phosphate solution and acetonitrile are used as the mobile phase A, and methanol and acetonitrile are used as the mobile phase B, and equal gradient elution is carried out;
3) and (3) obtaining the detection result of the impurity by calculation according to the HPLC map obtained in the step 2).
The invention mixes 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone and acetonitrile water solution to obtain a test solution a.
In certain embodiments of the invention, the aqueous solution of acetonitrile has a concentration of 10% by volume.
In some embodiments of the present invention, the concentration of 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one in the test solution a is 0.05-5 mg/mL. In certain embodiments, the concentration of 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one in the test solution a is 0.5 mg/mL.
The invention mixes the impurity to be measured with acetonitrile respectively to obtain each impurity stock solution.
In certain embodiments of the invention, each of the impurity stock solutions comprises a stock solution of the impurity of formula (1), a stock solution of the impurity of formula (2), a stock solution of the impurity of formula (3), a stock solution of the impurity of formula (4), and a stock solution of the impurity of formula (5);
in some embodiments of the invention, the concentration of each impurity in the stock solution is 1-1000. mu.g/mL. In certain embodiments, the concentration of each impurity in the stock solution is 100 μ g/mL.
In certain embodiments of the invention, the aqueous solution of acetonitrile has a concentration of 10% by volume.
In certain embodiments of the invention, the concentration of impurities in each impurity stock solution is the same.
In the invention, proper amount of each impurity stock solution is taken and respectively mixed with acetonitrile water solution to obtain each impurity reference substance solution.
The amount of each impurity stock solution used is not particularly limited, and the required amount can be used according to actual conditions.
In certain embodiments of the invention, the concentration of the impurity in each impurity control solution is 0.05-50 μ g/mL. In certain embodiments, the concentration of the impurity in each impurity control solution is 5 μ g/mL.
In certain embodiments of the invention, the aqueous solution of acetonitrile has a concentration of 10% by volume.
In certain embodiments of the invention, the concentration of the impurity in each of the impurity control solutions is the same.
The invention mixes 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone, a proper amount of impurity stock solutions and acetonitrile aqueous solution to obtain a system applicability solution b.
The amount of each impurity stock solution mentioned herein is not particularly limited, and may be selected as needed in accordance with the actual circumstances.
In certain embodiments of the invention, the aqueous solution of acetonitrile has a concentration of 10% by volume.
In certain embodiments of the present invention, in the system-applicable solution b, the concentration of the 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one is 0.05 to 5mg/mL and the concentration of impurities is 0.05 to 50. mu.g/mL. In certain embodiments, the system suitability solution b, the concentration of 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one is 0.5 mg/mL. In certain embodiments, the concentration of impurities in the system suitability solution b is 5 μ g/mL.
After obtaining each impurity stock solution, each impurity reference substance solution, the test solution a and the system applicability solution b, the acetonitrile aqueous solution, the impurity reference substance solution, the test solution a and the system applicability solution b are respectively detected by HPLC.
In certain embodiments of the invention, the aqueous solution of acetonitrile has a concentration of 10% by volume.
The detection conditions are as follows:
octadecylsilane chemically bonded silica is used as a stationary phase;
the mobile phase comprises a mobile phase A and a mobile phase B, wherein sodium dihydrogen phosphate solution and acetonitrile are used as the mobile phase A, and methanol and acetonitrile are used as the mobile phase B, and the equal gradient elution is carried out.
In the invention, the mobile phase comprises a mobile phase A and a mobile phase B, wherein sodium dihydrogen phosphate solution and acetonitrile are used as the mobile phase A, and methanol and acetonitrile are used as the mobile phase B, and the equal gradient elution is carried out.
In certain embodiments of the present invention, the volume ratio of the sodium dihydrogen phosphate solution to the acetonitrile in the mobile phase a is 950: 50. in some embodiments of the invention, the concentration of the potassium dihydrogen phosphate solution is 0.005-0.1 mol/L, and the pH value is 5.5-8.5. In certain embodiments, the potassium dihydrogen phosphate solution has a concentration of 0.01mol/L and a pH of 7.0.
In certain embodiments of the present invention, the volume ratio of methanol to acetonitrile in the mobile phase B is 500: 500.
in certain embodiments of the present invention, the volume ratio of the mobile phase a to the mobile phase B is 20 to 97: 3 to 80.
In certain embodiments of the present invention, during the gradient elution, the volume ratio of mobile phase a to mobile phase B is:
in certain embodiments of the present invention, the flow rate of the mobile phase is 0.7-0.9 mL/min. In certain embodiments, the flow rate of the mobile phase is 0.8 mL/min.
In some embodiments of the invention, the column temperature of the detected chromatographic column is 20-50 ℃. In certain embodiments, the column temperature of the chromatographic column being tested is 40 ℃.
In certain embodiments of the invention, the chromatographic column tested was YMC-Triart C18, the column length was 250mm, the inner diameter was 4.6mm, and the packing particle size was 5 μm.
In certain embodiments of the present invention, the wavelength of the detection is 230 nm.
And after the detection is finished, obtaining the detection result of the impurity by calculation according to the HPLC map obtained in the step.
In the invention, the known impurities are calculated by adopting an external standard method, and the unknown impurities are calculated by adopting a 0.5 percent self-pairing method.
The source of the above-mentioned raw materials is not particularly limited in the present invention, and may be generally commercially available.
The method for detecting the impurities in the 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-one, which is provided by the invention, is an external standard method, can accurately detect all the impurities in the 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-one, has higher separation degree of the impurities and the 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-one, has higher separation degree among all the impurities, meets all indexes, is simple and convenient to operate, has low cost, and is suitable for wide application.
In order to further illustrate the present invention, the following examples are provided to describe the method for detecting impurities in 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one of the present invention in detail, but should not be construed as limiting the scope of the present invention.
In the examples, the known impurities were calculated by the external standard method, and the unknown impurities were calculated by the 0.5% self-alignment method.
Example 1
Instruments and conditions:
a detector: a UV detector;
a chromatographic column: YMC-Triart C18, with column length of 250mm, inner diameter of 4.6mm, and filler particle diameter of 5 μm;
detection wavelength: 230 nm;
mobile phase:
a0.01 mol/L potassium dihydrogen phosphate solution (pH 7.0) -acetonitrile (volume ratio 950: 50)
B, methanol-acetonitrile (the volume ratio is 500: 500);
column temperature: 40 ℃;
flow rate: 0.8 mL/mim;
time program:
solvent: acetonitrile water solution with volume concentration of 10 percent;
sample introduction amount: 10 μ L.
The experimental steps are as follows:
taking 10mg of 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone, precisely weighing, adding a solvent to dissolve and dilute into a test solution a containing 0.5mg of the test solution in every 1 mL;
taking 10mg of each impurity formula (1), formula (2), formula (3), formula (4) and formula (5), precisely weighing, and respectively adding acetonitrile to dissolve and dilute into impurity stock solution containing 100 mu g of impurities per 1 mL; precisely measuring 1.0mL of each impurity stock solution, and diluting with solvent to obtain 5 μ g of each impurity reference solution per 1 mL; 10mg of 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one was weighed out precisely, dissolved in an appropriate amount of solvent, and 1.0mL of each impurity stock solution was weighed out precisely and added, and diluted with a solvent to give a system-compatible solution b containing 0.5mg of 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one, impurities of formulae (1), (2), (3), (4) and (5) 5. mu.g each per 1 mL.
Precisely sucking 10 μ L acetonitrile aqueous solution with volume concentration of 10%, injecting into high performance liquid chromatograph for detection, and recording map. Precisely absorbing 10 μ L of each impurity reference substance solution, injecting into a high performance liquid chromatograph for detection, and recording the map. Precisely sucking 10 μ L of the sample solution, injecting into high performance liquid chromatograph, detecting, and recording the chromatogram. Precisely sucking 10 μ L of the system applicability solution b, injecting into a high performance liquid chromatograph for detection, and recording the map. Wherein, the impurity formula (1) corresponds to the impurity A, the impurity formula (2) corresponds to the impurity B, the impurity formula (3) corresponds to the impurity C, the impurity formula (4) corresponds to the impurity D, and the impurity formula (5) corresponds to the impurity E.
And (4) obtaining the detection result of the impurity by calculation according to the HPLC map obtained in the step.
FIG. 1 is an HPLC chromatogram of an aqueous solution of acetonitrile at a volume concentration of 10%.
FIG. 2 is an HPLC chromatogram of a system suitability solution b of example 1 of the present invention.
FIG. 3 is an HPLC chromatogram of the test solution a in example 1 of the present invention.
The results of the experiments are summarized in tables 1 and 2.
TABLE 1 HPLC DETECTION AND CALCULATION OF SYSTEM APPLICABILITY SOLUTION B OF EXAMPLE 1
Name (R)
RT(min)
RRT
Tailing factor
Degree of separation
Number of plates
Impurity A
20.669
0.824
1.019
44.751
49541.5
Impurity E
21.817
0.870
0.908
3.012
49974.6
Impurity C
25.081
1.000
1.083
9.549
116870.9
Main peak
25.842
1.030
1.147
2.602
126305.8
Impurity D
27.341
1.090
0.988
4.274
70941.8
Impurity B
28.579
1.139
1.250
3.338
119167.8
TABLE 2 HPLC DETECTION AND CALCULATION OF TEST SOLUTION A IN EXAMPLE 1
As can be seen from Table 1, the main peak and each impurity reach baseline separation, the tailing factors are all between 0.9 and 1.5, the theoretical plate number is more than 10000, and the peak type of each peak is good. And the separation degrees between the main peak and the adjacent impurities and between the impurities are all larger than 1.5, thereby meeting the requirements. The method meets the requirement of measuring related substances of 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone, and has good system applicability.
As is clear from Table 2, the purity of the batch of sample 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one was 99.72%, the mass content of the largest other single impurities was 0.1%, and the mass content of the total impurities was 0.28%.
And (3) testing precision:
sample introduction precision: taking 1 part of test solution a for continuous sample introduction for 6 needles; and (3) repeatability test: taking 2 parts of mixed impurity reference substance solution (prepared by taking 1ml of stock solutions of five impurities respectively, putting the stock solutions into a 20ml measuring flask together, adding acetonitrile aqueous solution to dilute and fix the volume), respectively taking two needles, taking 6 parts of test solution a, respectively taking one needle, carrying out middle medium density and repeatability tests, and only carrying out people replacement and instrument rework tests on different dates.
The results of the precision measurement are shown in Table 3.
TABLE 3 results of precision measurement
As can be seen from Table 3, the repeatability, the intermediate precision and the injection precision are all known impurities, the maximum single impurity and total impurity are 0.10 wt% and 0.28 wt%, each RSD value is less than 1.0%, the method meets the requirement, and the method has good precision.
Testing detection limit and quantification limit:
and respectively injecting the test solution a and each impurity reference substance solution into a liquid chromatograph for detection, and gradually diluting according to the result until the response value of each substance is detected, wherein S/N is approximately equal to 10 and is used as a quantitative limit, and S/N is approximately equal to 3 and is used as a detection limit. The results are shown in Table 4.
TABLE 4 detection Limit and quantitation Limit test results
As can be seen from Table 4, the main peak and the limit concentration of each impurity are both between 20ng/mL and 85ng/mL, the limit concentration of quantitation is both between 70ng/mL and 280ng/mL, and the method has good detection sensitivity.
The good linear relation between the test sample and each impurity shows that the method can detect the impurity in the range of linear concentration, and the detection result is accurate and reliable, and cannot be detected because the test sample contains trace impurities.
And (3) testing accuracy:
taking 2 parts of mixed impurity reference substance solution (1 ml of stock solutions of five impurities are respectively taken and put in a 20ml measuring flask together, and acetonitrile aqueous solution is added for dilution and volume fixing to obtain the mixed impurity reference substance solution) into 2 needles respectively; 1 part of test solution a is put into 1 needle; adding samples with the limit of 80% impurities into 3 parts of test solution a, and respectively putting the samples into 1 needle; adding samples with 100% impurity limit into 3 parts of test solution a, and respectively putting the samples into 1 needle; 3 samples of the sample solution a to which 120% of impurities were added were inserted into 1 needle each (3 samples of solutions to which different impurities were added, and the results of the following recovery rates were merely average values).
The results of the accuracy test are shown in table 5.
TABLE 5 accuracy test results
As can be seen from Table 5, the recovery rates of the impurities are respectively 92-105%, and the RSD values of the recovery rates are respectively less than 5%, which meets the requirements. The method has good accuracy.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
