Method for detecting content of potassium ions in Milsartan potassium and application of method

Abstract

The invention belongs to the technical field of pharmaceutical analysis, and particularly provides a method for detecting the content of potassium ions in Milsartan potassium, which comprises the following steps: S1, preparing a potassium ion reference solution and a Milsartan potassium test solution; s2, respectively detecting the reference substance and the test sample by adopting HPLC-CAD (High Performance Liquid Chromatography-Computer Aided Design), recording a chromatogram, and calculating the content of potassium ions; wherein the conditions of the high performance liquid chromatography are as follows: a mixed mechanism chromatographic column is adopted, an ammonium formate aqueous solution is used as a mobile phase A, acetonitrile is used as a mobile phase B, and isocratic elution is performed. According to the method for detecting the content of the potassium ions in the Milsartan potassium, provided by the invention, the potassium ions in the Milsartan potassium are controlled by adopting an external standard method according to the characteristics of the Milsartan potassium. The method is accurate, reliable, high in sensitivity and good in repeatability, can rapidly and efficiently measure the content of the potassium ions in the Milsartan potassium, provides an effective technical means and data support for subsequent Milsartan potassium content detection, and can be used for evaluating the quality of Milsartan potassium drugs.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for detecting the potassium ion content in potassium valsartan and its application. Background Art

[0002] Potassium valsartan is a prodrug that can be rapidly converted into the active ingredient azilsartan after oral absorption. The latter can block the action of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in various tissues. Its structure is shown as follows:

[0003]

[0004] Since the potassium ion content directly affects the content of valsartan, accurate quantitative determination is extremely important. To ensure the safety and reliability of drug quality, it is necessary to conduct in-depth quantitative research on the potassium ion content in potassium valsartan for subsequent further research on the content of potassium valsartan.

[0005] In traditional pharmaceutical analysis, the potassium ion content is usually determined by an IC system (ion chromatograph) or chemical titration method. The former instrument is relatively expensive and requires the preparation of special anion and cation chromatographic columns, with high usage costs. The latter titration method, although low in cost, lacks specificity.

[0006] Liquid phase detection technology has become a core analytical tool in the fields of chemistry, biomedicine, environmental monitoring, etc. due to its separation efficiency, sensitivity, and automation advantages. However, potassium ions in potassium valsartan have no absorption in an ultraviolet detector, so it is a difficult point to control the potassium content in potassium valsartan by traditional liquid phase means. Summary of the Invention

[0007] The purpose of the present invention is to overcome the problem that the existing detection methods are difficult to accurately detect the potassium ion content in potassium valsartan.

[0008] To this end, the present invention provides a method for detecting the potassium ion content in potassium valsartan, including the following steps:

[0009] S1. Prepare a potassium ion reference solution and a test solution of potassium valsartan.

[0010] S2. Use HPLC-CAD to detect the reference and the test sample respectively, record the chromatogram, and calculate the potassium ion content.

[0011] Among them, the conditions for high performance liquid chromatography are: use a mixed mechanism chromatographic column, use an aqueous ammonium formate solution as mobile phase A, use acetonitrile as mobile phase B, and perform isocratic elution.

[0012] Specifically, the preparation method of the potassium ion reference solution in step S1 above is as follows: Transfer the potassium ion standard solution, dissolve and dilute it with an acidic diluent, and make up the volume to a preset scale, then shake well to obtain it; the preparation method of the mearsartan potassium test solution is as follows: Take mearsartan potassium, dilute it with an acidic diluent to the preset scale, and shake well to obtain it.

[0013] Specifically, the above-mentioned acidic diluent includes acetic acid.

[0014] Specifically, the injection volume for HPLC-CAD detection in step S2 above is 5 - 10 μl.

[0015] Specifically, the CAD atomization temperature in step S2 above is 50 °C.

[0016] Specifically, the flow rate of the mobile phase during HPLC-CAD detection in step S2 above is 0.8 - 1.2 ml / min.

[0017] Specifically, the column temperature of the chromatographic column in step S2 above is set to 20 - 30 °C.

[0018] Specifically, the isocratic elution condition in step S2 above is: the volume ratio of mobile phase A to mobile phase B is 35:65.

[0019] Specifically, the total isocratic elution time in step S2 above is 8 - 15 min.

[0020] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0021] The method for detecting the potassium ion content in mearsartan potassium provided by the present invention controls the potassium ions in mearsartan potassium by using the external standard method according to the characteristics of mearsartan potassium itself. It is accurate, reliable, highly sensitive, and has good repeatability. It can quickly and efficiently determine the potassium ion content in mearsartan potassium, providing an effective technical means and data support for the subsequent content detection of mearsartan potassium, and can be used to evaluate the quality of mearsartan potassium drugs.

[0022] The following will further elaborate on the present invention in detail with reference to the accompanying drawings. Description of the Drawings

[0023] Figure 1 It is the chromatogram of the blank solution in Example 2 of the present invention.

[0024] Figure 2 It is the chromatogram of the reference solution in Example 2 of the present invention.

[0025] Figure 3 It is the chromatogram of the test solution in Example 2 of the present invention.

[0026] Figure 4It is the chromatogram of the test solution under the electrospray detector test at 35 °C (low mode) in Example 3 of the present invention.

[0027] Figure 5 It is the chromatogram of the test solution under the electrospray detector test at 50 °C (high mode) in Example 3 of the present invention.

[0028] Figure 6 It is K in Example 7 of the present invention + Correlation diagram of peak area and concentration - linear function.

[0029] Figure 7 It is K in Example 7 of the present invention + Correlation diagram of peak area and concentration - power function. Detailed implementation manners

[0030] The technical solutions in the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Although the representative embodiments of the present invention have been described in detail, those of ordinary skill in the technical field to which the present invention belongs will understand that various modifications and changes can be made to the present invention without departing from the scope of the present invention. Therefore, the scope of the present invention should not be limited to the embodiments, but should be defined by the appended claims and their equivalents.

[0031] The present invention provides a method for detecting the potassium ion content in potassium valsartan, comprising the following steps:

[0032] S1. Prepare a potassium ion reference solution: Transfer a potassium ion standard solution, dissolve and dilute it with an acidic diluent, and make it up to a preset scale, then shake well to obtain.

[0033] Prepare a test solution of potassium valsartan: The preparation method of the test solution of potassium valsartan is as follows: Take potassium valsartan, dilute it with an acidic diluent to a preset scale, and shake well to obtain.

[0034] Among them, the acidic diluent is preferably acetic acid.

[0035] S2. Use HPLC-CAD to detect the reference and the test sample respectively, record the chromatogram, and calculate the potassium ion content;

[0036] Among them, the conditions of the high performance liquid chromatography method are as follows: Use a mixed mechanism chromatographic column, preferably Comixsil HAC (4.6×150 mm, 3 μm); Flow rate: 0.8 - 1.2 ml / min; Column temperature: 20 - 30 °C; Injection volume: 5 - 10 μl; Use ammonium formate aqueous solution as mobile phase A and acetonitrile as mobile phase B. Mobile phase A is preferably 100 mM ammonium formate adjusted to pH 2.7±0.2 with formic acid;

[0037] The isocratic elution procedure is as follows:

[0038] Time (min) A％ B％ 0 35 65 8-15 35 65

[0039] The total elution time is 8 - 15 min, preferably 10 min; the flow rate is 0.5 ml per minute; the column temperature is 25 °C;

[0040] The detector conditions are an electrospray detector (CAD), the injection tray temperature is 15 °C, and the atomization temperature is 50 °C.

[0041] The effects of the method for detecting the potassium ion content in mealixartan potassium of the present invention are studied through specific examples below.

[0042] The reagents used in the examples of the present invention can all be purchased from the market or can be prepared by the methods described in the present invention. Unless otherwise specified, the analytical reagents and solutions used in the present invention meet the requirements of the appendix of the Chinese Pharmacopoeia 2020 Edition.

[0043] (1) Instruments and Reagents

[0044] Vanquish Thermo Fisher high performance liquid chromatograph (Thermo Fisher Scientific Inc., USA);

[0045] Thermo Fisher Corona Ultra electrospray detector (CAD detector) (Thermo Fisher Scientific Inc., USA);

[0046] The chromatographic column is a size exclusion chromatographic column Comixsil HAC (4.6×150 mm, 3 μm);

[0047] Acetonitrile is of chromatographic grade (Fisher Limited);

[0048] Water is ultrapure water;

[0049] Potassium ion standard solution (1 mg / ml in 0.005% HNO3).

[0050] Example 1: Selection of Diluent and Test Sample Concentration

[0051] 1. Detection Parameters

[0052] Chromatographic column: Comixsil HAC (4.6×150 mm, 3 μm); Flow rate: 1.0 ml / min; Column temperature: 25 °C; Injection volume: 5 μl; Mobile phase: 100 mM ammonium formate (pH = 2.7) - acetonitrile.

[0053] The atomization temperature of the electrospray detector is 50 °C;

[0054] An isocratic elution method is adopted in the mobile phase. The ratio of 100 mM ammonium formate - acetonitrile in the mobile phase is 35:65, the total elution time is 10 min; the flow rate is 0.5 ml per minute; the column temperature is 25 °C;

[0055] The temperature of the sample injection tray is 15 °C;

[0056] Concentration of the test sample: 1 mg / ml;

[0057] Sample injection volume: 5 μl.

[0058] 2. Experimental procedures

[0059] Prepare the reference solution: Accurately pipette 1 ml of the potassium ion standard solution (1 mg / ml) into a 10-ml volumetric flask, dissolve and dilute to the mark with the diluent, and shake well. Take 6 ml of the above solution, place it in a 10-ml volumetric flask, dilute with acetic acid and make up to the mark, and shake well to obtain;

[0060] Prepare the test sample solution: Take 10 mg of potassium medoxomil, place it in a 10-ml volumetric flask, dilute to the mark with the diluent, and shake well to obtain.

[0061] According to the above preparation method, prepare the reference and test sample solutions using different diluents. Using the above chromatographic detection parameters, detect for different diluents, and take the peak shape as the inspection index.

[0062] 3. Experimental results

[0063] The test results of the diluents are shown in Table 1.

[0064] Table 1 Test results of diluents

[0065]

[0066] 4. Conclusion

[0067] Alcohols may react with the stationary phase to cause esterification reactions, resulting in changes in reproducibility and retention. Alcohols such as methanol and non-volatile salts cannot be used in this system. As can be seen from Table 1, when acetic acid is selected as the diluent, the sample has good solubility and good peak shape.

[0068] Example 2: Specificity test and system test

[0069] 1. Detection parameters

[0070] Chromatographic column: Comixsil HAC (4.6×150 mm, 3 μm); Flow rate: 1.0 ml / min; Column temperature: 25 °C; Sample injection volume: 5 μl; Mobile phase: 100 mM ammonium formate (pH = 2.7) - acetonitrile.

[0071] The atomization temperature of the electrospray detector is 50 °C;

[0072] An isocratic elution method was adopted in the mobile phase. The ratio of 100 mM ammonium formate - acetonitrile in the mobile phase was 35:65, the total elution time was 10 min; the flow rate was 0.5 ml per minute; the column temperature was 25 °C;

[0073] The temperature of the sample injection tray was 15 °C;

[0074] The injection volume was 5 μl.

[0075] 2. Experimental procedures

[0076] Prepare the reference stock solution: Accurately pipette 1 ml of the potassium ion standard solution into a 10 ml volumetric flask, dissolve it with acetic acid and dilute to the mark, shake well, and you will get it;

[0077] Prepare the reference solution: Accurately pipette 6 ml of the reference stock solution into a 10 ml volumetric flask, add acetic acid to dilute and make up to the mark, shake well, and you will get it;

[0078] Prepare the test solution: Take 10 mg of potassium medoxomil, put it into a 10 ml volumetric flask, add acetic acid to dilute to the mark, shake well to get it.

[0079] 3. Experimental results

[0080] Inject a blank (acetic acid) sample, measure it, and record the chromatogram ( Figure 1 ), and the blank has no interference with the detection.

[0081] Inject a reference solution sample, measure it, and record the chromatogram ( Figure 2 ). The retention time of the potassium ion peak is 2.765 min, and the retention time of the nitrate ion peak is 3.912 min; all known components do not interfere with each other.

[0082] Inject a test solution sample, measure it, and record the chromatogram ( Figure 3 ). The retention time of the potassium ion peak in the test solution is the same as that of the reference solution; it indicates that the potassium ion in the sample can elute independently without interference.

[0083] 4. Conclusion

[0084] The analytical method provided by the present invention can be used to detect the content of potassium ions in potassium medoxomil. This method has strong specificity, high sensitivity and convenient operation.

[0085] Example 3: Electrospray detector test

[0086] 1. Detection parameters

[0087] Chromatographic column: Comixsil HAC (4.6×150 mm, 3 μm); Flow rate: 1.0 ml / min; Column temperature: 25 °C; Injection volume: 5 μl; Mobile phase: 100 mM ammonium formate (pH = 2.7) - acetonitrile.

[0088] An isocratic elution method was used in the mobile phase. The ratio of 100 mM ammonium formate - acetonitrile in the mobile phase was 35:65, the total elution time was 10 min; the flow rate was 0.5 ml per minute; the column temperature was 25 °C;

[0089] The temperature of the injection tray was 15 °C;

[0090] The injection volume was 5 μl.

[0091] 2. Experimental procedure

[0092] Using the above chromatographic conditions, different atomization temperatures were adjusted, and the peak shape was used as a reference index for optimization.

[0093] 3. Experimental results

[0094] When the atomization temperature was 35 °C (low mode), the peak shape was poor. See the liquid chromatography diagram in Figure 4 . When the atomization temperature was 50 °C (high mode), the peak shape was good. See the liquid chromatography diagram in Figure 5 .

[0095] 4. Conclusion

[0096] The atomization temperature of the CAD detector has an impact on the detection of the potassium ion content in potassium valsartan. When the atomization temperature is 50 °C, the peak shape is good.

[0097] Example 4: Selection of injection volume

[0098] 1. Detection parameters

[0099] Chromatographic column: Comixsil HAC (4.6×150 mm, 3 μm); flow rate: 1.0 ml / min; column temperature: 25 °C; mobile phase: 100 mM ammonium formate (pH = 2.7) - acetonitrile.

[0100] An isocratic elution method was used in the mobile phase. The ratio of 100 mM ammonium formate - acetonitrile in the mobile phase was 35:65, the total elution time was 10 min; the flow rate was 0.5 ml per minute; the column temperature was 25 °C;

[0101] The temperature of the injection tray was 15 °C; the atomization temperature was 50 °C.

[0102] 2. Experimental procedure

[0103] Using the above chromatographic conditions, different injection concentrations were adjusted, and the peak shape was used as a reference index for optimization.

[0104] 3. Experimental results

[0105] The experimental results of the injection volume are shown in Table 2.

[0106] Table 2 Results of injection volume experiment

[0107] Injection volume Peak shape Background noise 3 μl Poor peak shape 30 - 40 PA 5 μl Good peak shape 40 - 50 PA 10 μl Good peak shape 70 - 80 PA

[0108] 4. Conclusion:

[0109] The injection volume of the CAD detector has an impact on the detection of potassium ion content in potassium valsartan. When the injection volume is 5 μl - 10 μl, the peak shape is good, and when the injection volume is 5 μl, the background noise is small.

[0110] Example 5: Spike recovery experiment

[0111] 1. Detection parameters

[0112] Chromatographic column: Comixsil HAC (4.6×150 mm, 3 μm); Flow rate: 1.0 ml / min; Column temperature: 25 °C; Injection volume: 5 μl; Mobile phase: 100 mM ammonium formate (pH = 2.7) - acetonitrile.

[0113] Isocratic elution method is adopted in the mobile phase. The ratio of 100 mM ammonium formate - acetonitrile in the mobile phase is 35:65, and the total elution time is 10 min; The flow rate is 0.5 ml per minute; The column temperature is 25 °C;

[0114] The injection tray temperature is 15 °C; The nebulization temperature is 50 °C;

[0115] Injection volume 5 μl.

[0116] 2. Experimental procedure

[0117] Prepare the test solution: Take 10 mg of potassium valsartan sample, place it in a 10 ml volumetric flask, dilute it to the mark with acetic acid, and shake well to obtain;

[0118] Prepare the reference stock solution: Precisely pipette 1 ml of potassium ion standard solution into a 10 ml volumetric flask, dissolve it with acetic acid and dilute it to the mark, and shake well to obtain;

[0119] Prepare the reference solution: Precisely pipette 6 ml of the reference stock solution into a 10 ml volumetric flask, dilute it with acetic acid and make up the volume to the mark, and shake well to obtain;

[0120] Prepare the recovery solution: Weigh 10 mg of potassium valsartan sample, place it in a 10 ml volumetric flask, dilute it to the mark with the reference solution, and shake well to obtain;

[0121] Inject the reference solution continuously for 6 needles, measure, and record the chromatogram. Inject the test solution for 2 needles, measure, and record the chromatogram. Inject the recovery solution for 1 needle, measure, and record the chromatogram, and calculate the recovery rate.

[0122] 3. Experimental results

[0123] Table 3 Results of Six Consecutive Standard Solutions

[0124]

[0125] As can be seen from Table 3, the precision of the instrument is good.

[0126] Table 4 Results of the Recovery Test

[0127] <![CDATA[K in the sample + content]]> <![CDATA[Add K + content]]> <![CDATA[Measured K + content]]> Recovery rate 1 63.9 μg / ml 60.0 μg / ml 124.9 μg / ml 101.7％

[0128] The concentration of the sample solution was 1.077 mg / ml, and the average peak area of potassium ions in two injections of the sample was 6.394 PA*min. In the recovery solution, the concentration of the sample solution was 1.054 mg / ml, and the peak area of potassium ions was 12.217 PA*min. The recovery rate was 101.7%.

[0129] 4. Conclusion

[0130] The results of the recovery test were in the range of 80%-120%, indicating that the method had good accuracy.

[0131] Example 6: Repeatability Test

[0132] 1. Detection Parameters

[0133] Chromatographic column: Comixsil HAC (4.6×150 mm, 3 μm); Flow rate: 1.0 ml / min; Column temperature: 25 °C; Injection volume: 5 μl; Mobile phase: 100 mM ammonium formate (pH = 2.7) - acetonitrile.

[0134] Isocratic elution was used in the mobile phase. The ratio of 100 mM ammonium formate - acetonitrile in the mobile phase was 35:65, and the total elution time was 10 min; The flow rate was 0.5 ml per minute; The column temperature was 25 °C;

[0135] The injection tray temperature was 15 °C; The nebulization temperature was 50 °C;

[0136] Injection volume: 5 μl.

[0137] 2. Experimental Procedure

[0138] Prepare the test solution: Take 10 mg of potassium medoxomil sample, place it in a 10 ml volumetric flask, dilute it to the mark with acetic acid, and shake well to obtain; Prepare 6 portions in parallel.

[0139] Inject the test solution continuously for 6 injections, measure, record the chromatogram, calculate the potassium ion content in the 6 injections of the sample, and calculate the repeatability results of the sample.

[0140] 3. Experimental Results

[0141] Table 5 Repeatability Results of the Sample

[0142]

[0143]

[0144] 4. Conclusions

[0145] As can be seen from Table 5, using this method, the RSD% of potassium ion content is 2.0, indicating good repeatability.

[0146] Example 7: Correlation Experiment

[0147] 1. Detection Parameters

[0148] Chromatographic column: Comixsil HAC (4.6×150 mm, 3 μm); Flow rate: 1.0 ml / min; Column temperature: 25 °C; Injection volume: 5 μl; Mobile phase: 100 mM ammonium formate (pH = 2.7) - acetonitrile.

[0149] In the mobile phase, an isocratic elution method is adopted. The ratio of 100 mM ammonium formate - acetonitrile in the mobile phase is 35:65, and the total elution time is 10 min; The flow rate is 0.5 ml per minute; The column temperature is 25 °C;

[0150] The injection tray temperature is 15 °C; The atomization temperature is 50 °C;

[0151] Injection volume: 5 μl.

[0152] 2. Experimental Procedures

[0153] Prepare 150% linear solution: Pipette 9 ml of the reference stock solution into a 10-ml volumetric flask, dilute to the mark with acetic acid, and shake well to obtain;

[0154] Prepare 100% linear solution: Pipette 6 ml of the reference stock solution into a 10-ml volumetric flask, dilute to the mark with acetic acid, and shake well to obtain;

[0155] Prepare 80% linear solution: Pipette 4.8 ml of the reference stock solution into a 10-ml volumetric flask, dilute to the mark with acetic acid, and shake well to obtain;

[0156] Prepare 50% linear solution: Pipette 3 ml of the reference stock solution into a 10-ml volumetric flask, dilute to the mark with acetic acid, and shake well to obtain;

[0157] Prepare 30% linear solution: Pipette 1.8 ml of the reference stock solution into a 10-ml volumetric flask, dilute to the mark with acetic acid, and shake well to obtain;

[0158] Inject one needle of each of the above solutions, measure, record the chromatogram, and calculate. Using the reference concentration as the abscissa and the peak area as the ordinate, plot the standard curve.

[0159] 3. Experimental Results

[0160] Table 6 Linear relationship results

[0161]

[0162]

[0163] The detection principle of the CAD detector is based on the fact that the change in concentration with the change in particle concentration follows an exponential power law due to the change in particle size distribution, and the diameter of the particles determines the final average charge amount. The electrometer detects all the charges carried on the particle surface, and thus a current signal with a power-law function relationship with the concentration can be obtained. Therefore, it is necessary to use the power-law function value to correct and fit the standard curve.

[0164] Considering that the signal of the CAD detector has a good linear range, its response value is only related to the injection mass, and the linear slope will only slightly decrease when the injection concentration is too high. The linear functions of concentration versus response value in this linear experiment are calculated as shown in Figure 6 and the power function as shown in Figure 7 . A good correlation between potassium ions and the peak area is obtained in the range of 6 ug / ml - 90 ug / ml.

[0165] 4. Conclusion

[0166] Under the method provided by the present invention, a good correlation between potassium ions and the peak area is obtained in the range of 6 ug / ml - 90 ug / ml.

[0167] The above examples are only illustrative of the present invention and do not constitute a limitation on the protection scope of the present invention. Any design identical or similar to the present invention falls within the protection scope of the present invention.

Claims

1. A method for detecting the potassium ion content in valsartan potassium, characterized in that, It includes the following steps: S1. Prepare a potassium ion reference solution and an irbesartan potassium for test solution; S2. Detect the reference and the test sample by HPLC-CAD respectively, record the chromatogram, and calculate the potassium ion content; Among them, the conditions of the high performance liquid chromatography method are as follows: a mixed mechanism chromatographic column is used, an aqueous solution of ammonium formate is used as mobile phase A, and acetonitrile is used as mobile phase B, and isocratic elution is carried out.

2. The method for detecting the potassium ion content in meallasartan potassium as described in claim 1, wherein The preparation method of the potassium ion reference solution in step S1 is as follows: Transfer a potassium ion standard solution, dissolve and dilute it with an acidic diluent, and make up the volume to a preset scale, and shake well to obtain it; The preparation method of the irbesartan potassium for test solution is as follows: Take irbesartan potassium, dilute it with an acidic diluent to a preset scale, and shake well to obtain it.

3. The method for detecting the potassium ion content in meallasartan potassium according to claim 2, wherein: The acidic diluent includes acetic acid.

4. The method for detecting the potassium ion content in meallasartan potassium according to claim 1, characterized in that: The injection volume for HPLC-CAD detection in step S2 is 5-10 μl.

5. The method for detecting the potassium ion content in meallasartan potassium as described in claim 1, wherein: The atomization temperature of CAD in step S2 is 50 °C.

6. The method for detecting the potassium ion content in meallasartan potassium as described in claim 1, characterized in that: The flow rate of the mobile phase during HPLC-CAD detection in step S2 is 0.8-1.2 ml / min.

7. The method for detecting the potassium ion content in meallasartan potassium as described in claim 1, characterized in that: The column temperature of the chromatographic column in step S2 is set at 20-30 °C.

8. The method for detecting the potassium ion content in meallasartan potassium as described in claim 1, wherein, The isocratic elution condition in step S2 is as follows: the volume ratio of mobile phase A to mobile phase B is 35:

65.

9. The method for detecting the potassium ion content in meallasartan potassium as described in claim 1, wherein: The total time of isocratic elution in step S2 is 8-15 min.

10. Application of the method for detecting the potassium ion content in irbesartan potassium according to any one of claims 1-9 in evaluating the quality of irbesartan potassium drugs.

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