TN-1084 APPLICATIONS...done using high performance liquid chromatography (HPLC), while...
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TN-1084 Introduction Ranitidine hydrochloride is used to treat stomach disorders such as ulcers and esophageal reflux disease. As this drug is now a ge- neric, the United States Pharmacopeia (USP) and European Phar- macopoeia (Ph. Eur.) or (EP) have developed monographs to sup- port its formulation. The USP lists several different procedures for determination of ranitidine depending on the dosage form - oral solution, tablets, capsules, or injectables. The assay for ranitidine is done using high performance liquid chromatography (HPLC), while chromatographic purity is established using thin layer chromatog- raphy (TLC). The lack of a robust protocol that can be used for both assay and purity with all dosage forms has been a major limitation of the cur- rent monographs. The USP has received a significant amount of feedback on the current protocol, but no suitable alternative has been provided. This work represents what we believe to be the solution that has been needed - a single HPLC procedure that is suitable for all testing requirements and dosage forms. Materials and Methods Agilent ® 1100 Series HPLC (Agilent Technologies Inc., Santa Clara, CA, USA) equipped with quaternary pump, column oven, and stan- dard UV/VIS flow cell. APPLICATIONS For additional technical notes, visit www.phenomenex.com An Improved HPLC Method for the Determination of Ranitidine Suitable for All Dosage Forms using Kinetex ® Core-Shell Technology Columns Philip J. Koerner, Sky Countryman, Deborah Jarrett, and Jeff Layne Phenomenex, Inc., 411 Madrid Ave., Torrance, CA 90501 USA A new and improved HPLC method based on core-shell technology has been developed to replace the various testing protocols in the existing Ranitidine HCl monographs for various dosage forms. Results and Discussion The current HPLC procedure in the USP monograph is similar to the EP monograph utilizing a fully porous Waters ® XTerra ® 3.5 µm 100 x 4.6 mm column 1 . In previous publications we have demonstrated improved performance for monograph methods by making adjustments that are within the allowable limits as defined in USP General Chapter <621> 2, 3 . However, in this case the changes being proposed are great enough that they require a full revalidation of the methodology. The USP Ranitidine Resolution Mixture reference standard contains ranitidine hydrochloride and four related impurities: ranitidine amino alcohol hemifumarate, ranitidine diamine hemifumarate, ranitidine N-oxide, and ranitidine complex nitroacetamide. This was prepared as indicated in the current monograph. Ranitidine S-oxide (ranitidine impurity C) was obtained from USP and added to the resolution mixture for method development. The overall chromatographic separation of the new method is improved. In the previous method (Figure 1A), peak shape for Ranitidine Impurity A was very poor, which caused problems with quantitation. The new method (Figure 1B) improved peak shape allowing for an increase in signal-to-noise from 11.6 on the Waters XTerra column to 77 on the Kinetex core-shell column, which represented >700 % increase. Resolution of different excipients found in the various dosage forms was also difficult using the old method. Due to the higher efficiency obtained using the Kinetex core-shell particle technology, peak capacity for this gradient method was increased from 136 to 211. The increased peak capacity provides increased chromatographic resolution, allowing for improved separation of additional impurities or product degradants. The required resolution for the old method between ranitidine N-oxide and ranitidine complex nitroacetamide was 1.5, and this is easily achieved (resolution = 5.0) with the new method. In order to verify applicability of this new method, several important validation parameters outlined in USP General Chapter <1225> were performed including linearity, range, precision and accuracy. Method ruggedness and robustness were also evaluated to further demonstrate method stability. The range of the assay was set from 10-200 % of the test concentration (Figure 2). Six replicate injections were made at the 75, 100, and 125 % concentrations and the relative standard deviation (RSD) was calculated to be 0.15, 0.10, and 0.13 %, respectively. These low RSD values were well within the stated requirement of the current monograph of not more than 1.0 %. Method robustness was investigated by intentionally adjusting the pH of the phosphate buffer solution ±0.3 units. At pH 6.8, Column: Kinetex 2.6 μm C18 100 Å Dimensions: 100 x 4.6 mm Part No.: 00D-4462-E0 Mobile Phase: A: 40 mM Potassium phosphate (pH 7.1) / Acetonitrile (98:2) B: 40 mM Potassium phosphate (pH 7.1) / Acetonitrile (78:22) Gradient: Time: (min) A (%) B (%) 0 100 0 10.0 0 100 15.0 0 100 Flow Rate: 1.5 mL/min Temperature: 35 °C Injection Volume 25 µL Detection: UV @ 230 nm (ambient) Sample: Analyte Retention Time, min 1. Ranitidine amino alcohol hemifumarate 2.05 2. Ranitidine diamine hemifumarate (Impurity A) 2.99 3. Ranitidine S-oxide (Impurity C) 3.53 4. Ranitidine N-oxide 4.24 5. Ranitidine complex nitroacetamide 4.71 6. Ranitidine HCl 6.19 Mobile Phase Preparation To a 250 mL volumetric flask, 0.5 g of sodium dodecyl sulfate (SDS) was dissolved in 18 mL of 0.15 M phosphoric acid, 90 mL of acetonitrile and 90 mL of methanol was added, and diluted with water to the 250 mL mark, mixed, and filtered (≤ 0.5 μm porosity). (continued on page 2)
Transcript of TN-1084 APPLICATIONS...done using high performance liquid chromatography (HPLC), while...
TN-1084
IntroductionRanitidine hydrochloride is used to treat stomach disorders such as ulcers and esophageal reflux disease. As this drug is now a ge-neric, the United States Pharmacopeia (USP) and European Phar-macopoeia (Ph. Eur.) or (EP) have developed monographs to sup-port its formulation. The USP lists several different procedures for determination of ranitidine depending on the dosage form - oral solution, tablets, capsules, or injectables. The assay for ranitidine is done using high performance liquid chromatography (HPLC), while chromatographic purity is established using thin layer chromatog-raphy (TLC).
The lack of a robust protocol that can be used for both assay and purity with all dosage forms has been a major limitation of the cur-rent monographs. The USP has received a significant amount of feedback on the current protocol, but no suitable alternative has been provided. This work represents what we believe to be the solution that has been needed - a single HPLC procedure that is suitable for all testing requirements and dosage forms.
Materials and MethodsAgilent® 1100 Series HPLC (Agilent Technologies Inc., Santa Clara, CA, USA) equipped with quaternary pump, column oven, and stan-dard UV/VIS flow cell.
APPLICATIONS
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An Improved HPLC Method for the Determination of Ranitidine Suitable for All Dosage Forms using Kinetex® Core-Shell Technology ColumnsPhilip J. Koerner, Sky Countryman, Deborah Jarrett, and Jeff LaynePhenomenex, Inc., 411 Madrid Ave., Torrance, CA 90501 USA
A new and improved HPLC method based on core-shell technology has been developed to replace the various testing protocols in the existing Ranitidine HCl monographs for various dosage forms.
Results and DiscussionThe current HPLC procedure in the USP monograph is similar to the EP monograph utilizing a fully porous Waters® XTerra® 3.5 µm 100 x 4.6 mm column1. In previous publications we have demonstrated improved performance for monograph methods by making adjustments that are within the allowable limits as defined in USP General Chapter <621> 2, 3. However, in this case the changes being proposed are great enough that they require a full revalidation of the methodology.
The USP Ranitidine Resolution Mixture reference standard contains ranitidine hydrochloride and four related impurities: ranitidine amino alcohol hemifumarate, ranitidine diamine hemifumarate, ranitidine N-oxide, and ranitidine complex nitroacetamide. This was prepared as indicated in the current monograph. Ranitidine S-oxide (ranitidine impurity C) was obtained from USP and added to the resolution mixture for method development.
The overall chromatographic separation of the new method is improved. In the previous method (Figure 1A), peak shape for Ranitidine Impurity A was very poor, which caused problems with quantitation. The new method (Figure 1B) improved peak shape allowing for an increase in signal-to-noise from 11.6 on the Waters XTerra column to 77 on the Kinetex core-shell column, which represented >700 % increase.
Resolution of different excipients found in the various dosage forms was also difficult using the old method. Due to the higher efficiency obtained using the Kinetex core-shell particle technology, peak capacity for this gradient method was increased from 136 to 211. The increased peak capacity provides increased chromatographic resolution, allowing for improved separation of additional impurities or product degradants. The required resolution for the old method between ranitidine N-oxide and ranitidine complex nitroacetamide was 1.5, and this is easily achieved (resolution = 5.0) with the new method.
In order to verify applicability of this new method, several important validation parameters outlined in USP General Chapter <1225> were performed including linearity, range, precision and accuracy. Method ruggedness and robustness were also evaluated to further demonstrate method stability.
The range of the assay was set from 10-200 % of the test concentration (Figure 2). Six replicate injections were made at the 75, 100, and 125 % concentrations and the relative standard deviation (RSD) was calculated to be 0.15, 0.10, and 0.13 %, respectively. These low RSD values were well within the stated requirement of the current monograph of not more than 1.0 %.
Method robustness was investigated by intentionally adjusting the pH of the phosphate buffer solution ±0.3 units. At pH 6.8,
Column: Kinetex 2.6 μm C18 100 ÅDimensions: 100 x 4.6 mm
Part No.: 00D-4462-E0Mobile Phase: A: 40 mM Potassium phosphate (pH 7.1) / Acetonitrile (98:2)
B: 40 mM Potassium phosphate (pH 7.1) / Acetonitrile (78:22)Gradient: Time: (min) A (%) B (%)
0 100 0 10.0 0 100 15.0 0 100
Flow Rate: 1.5 mL/minTemperature: 35 °C
Injection Volume 25 µL Detection: UV @ 230 nm (ambient)
Sample: Analyte Retention Time, min1. Ranitidine amino alcohol hemifumarate 2.052. Ranitidine diamine hemifumarate (Impurity A) 2.993. Ranitidine S-oxide (Impurity C) 3.534. Ranitidine N-oxide 4.245. Ranitidine complex nitroacetamide 4.716. Ranitidine HCl 6.19
Mobile Phase PreparationTo a 250 mL volumetric flask, 0.5 g of sodium dodecyl sulfate (SDS) was dissolved in 18 mL of 0.15 M phosphoric acid, 90 mL of acetonitrile and 90 mL of methanol was added, and diluted with water to the 250 mL mark, mixed, and filtered (≤ 0.5 μm porosity).
(continued on page 2)
TN-1084
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ranitidine Impurity A (peak 2) and ranitidine S-oxide (ranitidine impurity C, peak 3) co-eluted, as did ranitidine N-oxide (peak 4) and ranitidine complex nitroacetamide (peak 5). At pH 7.4, co-elution of ranitidine Impurity A and ranitidine S-oxide occurred. This highlights the importance of controlling the phosphate buffer pH for obtaining reproducible results; therefore the working pH should be 7.1 ± 0.1. The mobile phase gradient rate was also adjusted by ±10 %, which produced very small shifts in retention time, but had no impact on resolution.
Method ruggedness was demonstrated by having two analysts run the ranitidine method on two different HPLC systems and on different days. The results indicate that the method is stable and provides reproducible results (Figure 3). Small changes in retention time are due to differences in system configuration; however, quantitative results were similar. In addition, the gradient
was adjusted to be a bit steeper (0-100 % B in 9 minutes) and shallower (0-100 % B in 11 minutes). Changes in gradient, while affecting retention time slightly, did not affect resolution between the target analytes.
This method was applied to the assay of ranitidine in one readily available dosage form, Zantac 75® mg tablets, with the resulting chromatogram shown in Figure 4A. This method was also applied to a sample that had been degraded by refluxing in 0.1 N NaOH for 24 hours (Figure 4B). The resulting chromatograms show an increase in the diamine hemifumarate (Impurity A) and complex nitroacetamide impurities. No degradation was observed after refluxing the tablets in 0.1 N HCl for 24 hours (Figure 4C), but ranitidine was completely absent with significant degradation products produced following oxidation with 3 % hydrogen peroxide (H2O2) (Figure 4D).
App
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Figure 1. Comparison of the current USP method (A) using the fully porous 3.5 μm column (Waters® XTerra®) with the method (B) described here using the 2.6 μm core-shell column (Phenomenex® Kinetex®).
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19538Column: Kinetex 2.6 µm C18 100 Å
Dimensions: 100 x 4.6 mmPart No.: 00D-4462-E0
Mobile Phase: A: 40 mM Potassium phosphate pH 7.1 / Acetonitrile (98:2)B: 40 mM Potassium phosphate pH 7.1 / Acetonitrile (78:22)
Gradient: (100:0) A/B to (0:100) A/B over 10 minFlow Rate: 1.5 mL/min
Temperature: 35 °CDetection: UV @ 230 nm (ambient)
Sample: 1. Ranitidine amino alcohol hemifumarate2. Ranitidine diamine hemifumarate (Impurity A)3. Ranitidine S-oxide (Impurity C)4. Ranitidine N-oxide5. Ranitidine complex nitroacetamide6. Ranitidine HCl
19534Column: Waters® XTerra® 3.5 µm MS C18 125 Å
Dimensions: 100 x 4.6 mmMobile Phase: A: 40 mM Potassium phosphate pH 7.1 / Acetonitrile (98:2)
B: 40 mM Potassium phosphate pH 7.1 / Acetonitrile (78:22)Gradient: (100:0) A/B to (0:100) A/B over 10 min
Flow Rate: 1.5 mL/minTemperature: 35 °C
Detection: UV @ 230 nm (ambient)Sample: 1. Ranitidine amino alcohol hemifumarate
2. Ranitidine diamine hemifumarate (Impurity A) 3. Ranitidine S-oxide (Impurity C) 4. Ranitidine N-oxide 5. Ranitidine complex nitroacetamide 6. Ranitidine HCl
Comparative separations may not be representative of all applications.
B.A.
TN-1084
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APPLICATIONSTN-1084
Figure 2. Linearity (area counts versus Ranitidine load) for the analysis of Ranitidine over the range 10–200 % of target sample loading.
Figure 3. Method ruggedness was demonstrated by running the Ranitidine analysis on two different HPLC systems, on different days, by two analysts.
Figure 4. Assay for Ranitidine in Zantac 75® mg tablet dosage form (A), forced degradation using 0.1 N NaOH (B), forced degradation using 0.1 N HCl (C), and forced degradation by oxidation with 3 % H2O2 (D).
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19540Column: Kinetex 2.6 µm C18 100 Å
Dimensions: 100 x 4.6 mmPart No.: 00D-4462-E0
Mobile Phase: A: 40 mM Potassium phosphate pH 7.1 / Acetonitrile (98:2)B: 40 mM Potassium phosphate pH 7.1 / Acetonitrile (78:22)
Gradient: (100:0) A/B to (0:100) A/B over 10 minFlow Rate: 1.5 mL/min
Temperature: 35 °CDetection: UV @ 230 nm (ambient)
Sample: 1. Ranitidine amino alcohol hemifumarate 2. Ranitidine diamine hemifumarate (Impurity A) 3. Ranitidine S-oxide (Impurity C) 4. Ranitidine N-oxide 5. Ranitidine complex nitroacetamide 6. Ranitidine HCl
19542Column: Kinetex 2.6 µm C18 100 Å
Dimensions: 100 x 4.6 mmPart No.: 00D-4462-E0
Mobile Phase: A: 40 mM Potassium phosphate pH 7.1 / Acetonitrile (98:2)B: 40 mM Potassium phosphate pH 7.1 / Acetonitrile (78:22)
Gradient: (100:0) A/B to (0:100) A/B over 10 minFlow Rate: 1.5 mL/min
Temperature: 35 °CDetection: UV @ 230 nm (ambient)
Sample: 6. Ranitidine HCl
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TN-1084
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19543Column: Kinetex® 2.6 µm C18 100 Å
Dimensions: 100 x 4.6 mmPart No.: 00D-4462-E0
Mobile Phase: A: 40 mM Potassium phosphate pH 7.1 / Acetonitrile (98:2)B: 40 mM Potassium phosphate pH 7.1 / Acetonitrile (78:22)
Gradient: (100:0) A/B to (0:100) A/B over 10 minFlow Rate: 1.5 mL/min
Temperature: 35 °CDetection: UV @ 230 nm (ambient)
Sample: 2. Ranitidine diamine hemifumarate (Impurity A) 5. Ranitidine complex nitroacetamide 6. Ranitidine HCl
19684Column: Kinetex 2.6 µm C18 100 Å
Dimensions: 100 x 4.6 mmPart No.: 00D-4462-E0
Mobile Phase: A: 40 mM Potassium phosphate pH 7.1 / Acetonitrile (98:2)B: 40 mM Potassium phosphate pH 7.1 / Acetonitrile (78:22)
Gradient: (100:0) A/B to (0:100) A/B over 10 minFlow Rate: 1.5 mL/min
Temperature: 35 °CDetection: UV @ 230 nm (ambient)
Sample: 6. Ranitidine HCl
19685Column: Kinetex 2.6 µm C18 100 Å
Dimensions: 100 x 4.6 mmPart No.: 00D-4462-E0
Mobile Phase: A: 40 mM Potassium phosphate pH 7.1 / Acetonitrile (98:2)B: 40 mM Potassium phosphate pH 7.1 / Acetonitrile (78:22)
Gradient: (100:0) A/B to (0:100) A/B over 10 minFlow Rate: 1.5 mL/min
Temperature: 35 °CDetection: UV @ 230 nm (ambient)
Sample: 1. Ranitidine amino alcohol hemifumarate2. Ranitidine diamine hemifumarate (Impurity A)3. Ranitidine S-oxide (Impurity C)4. Ranitidine N-oxide
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B. 0.1 N NaOH Degradation
D. 3 % H2O2 Oxidation
C. 0.1 N HCI Degradation
Figure 4. (cont’d)
TN-1084
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ConclusionWe are suggesting that the testing protocols in the existing Ranitidine HCl monographs be replaced with this new and improved method. While we are currently evaluating this new method for dif-ferent ranitidine dosage forms, we have limited access to impurities that may be unique to each company’s manufacturing process. We are encouraging current producers of ranitidine to test this method for applicability to their dosage forms and provide us feedback.
References1. USP33-NF28, Monograph for Ranitidine Hydrochloride.
2. Phenomenex Technical Note TN-1071: Determination of Impurities and Related Substances for Acetylsalicylic Acid.
3. Phenomenex Technical Note TN-1073: Determination of Impurities and Related Substances for Glibenclamide.
UHPLC / HPLC Sure-Lok™ High Pressure PEEK™ Male Nut FittingsPart No. Description UnitAQ0-8503 Sure-Lok High Pressure PEEK 1-Pc Nut 10-32,
for 1/16 in. Tubing, 12,000 psi (827 bar)10/pk
AQ0-8530 Sure-Lok Fitting Tightening Tool, Aluminum ea
2.6 μm MidBore™ Columns (mm)KrudKatcher Ultra In-Line Filter*
30 x 3.0 50 x 3.0 75 x 3.0 100 x 3.0 150 x 3.0 /3pkXB-C18 00A-4496-Y0 00B-4496-Y0 00C-4496-Y0 00D-4496-Y0 –– AF0-8497
C18 00A-4462-Y0 00B-4462-Y0 00C-4462-Y0 00D-4462-Y0 00F-4462-Y0 AF0-8497
C8 00A-4497-Y0 00B-4497-Y0 00C-4497-Y0 00D-4497-Y0 –– AF0-8497
PFP 00A-4477-Y0 00B-4477-Y0 00C-4477-Y0 00D-4477-Y0 00F-4477-Y0 AF0-8497
HILIC 00A-4461-Y0 –– –– –– 00F-4461-Y0 AF0-8497
Kinetex® Ordering Information 2.6 μm Analytical Columns (mm)
KrudKatcher™ Ultra In-Line Filter*
30 x 4.6 50 x 4.6 75 x 4.6 100 x 4.6 150 x 4.6 /3pkXB-C18 –– 00B-4496-E0 00C-4496-E0 00D-4496-E0 00F-4496-E0 AF0-8497
C18 00A-4462-E0 00B-4462-E0 00C-4462-E0 00D-4462-E0 00F-4462-E0 AF0-8497
C8 –– 00B-4497-E0 00C-4497-E0 00D-4497-E0 00F-4497-E0 AF0-8497
PFP 00A-4477-E0 00B-4477-E0 00C-4477-E0 00D-4477-E0 00F-4477-E0 AF0-8497
HILIC –– 00B-4461-E0 00C-4461-E0 00D-4461-E0 00F-4461-E0 AF0-8497
1.7 μm Minibore Columns (mm)KrudKatcher Ultra In-Line Filter*
50 x 2.1 100 x 2.1 150 x 2.1 /3pkXB-C18 00B-4498-AN 00D-4498-AN –– AF0-8497
C18 00B-4475-AN 00D-4475-AN 00F-4475-AN AF0-8497
C8 00B-4499-AN 00D-4499-AN –– AF0-8497
PFP 00B-4476-AN 00D-4476-AN 00F-4476-AN AF0-8497
HILIC 00B-4474-AN –– –– AF0-8497
2.6 μm Minibore Columns (mm)KrudKatcher Ultra In-Line Filter*
30 x 2.1 50 x 2.1 100 x 2.1 150 x 2.1 /3pkXB-C18 00A-4496-AN 00B-4496-AN 00D-4496-AN 00F-4496-AN AF0-8497
C18 00A-4462-AN 00B-4462-AN 00D-4462-AN 00F-4462-AN AF0-8497
C8 00A-4497-AN 00B-4497-AN 00D-4497-AN 00F-4497-AN AF0-8497
PFP 00A-4477-AN 00B-4477-AN 00D-4477-AN 00F-4477-AN AF0-8497
HILIC –– 00B-4461-AN 00D-4461-AN 00F-4461-AN AF0-8497
*KrudKatcher Ultra requires 5/16 in. wrench. Wrench not provided.
TN-1084
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TN83
9212
10_L
Terms and Conditions Subject to Phenomenex Standard Terms and Conditions which may be viewed at http://www.phenomenex.com/TermsAndConditions.
Trademarks Kinetex is a registered trademark of Phenomenex, Inc. in the United States, European Union, and other jurisdictions. KrudKatcher, MidBore and Sure-Lok are trademarks of Phenomenex, Inc. Waters and XTerra are registered trademarks of Waters Corporation. Agilent is a registered trademark of Agilent Technologies, Inc. Zantac 75 is a registered trademark of the GlaxoSmithKline (GSK) group of companies. PEEK is a trademark of Victrex plc.
Disclaimer Phenomenex is in no way affiliated with Waters Corporation, Agilent Technologies, GSK, or Victrex plc. All columns used for comparisons were new and manufactured by Waters Corp. Dimensions and chromatographic conditions are the same for all columns unless otherwise noted. Comparative separations may not be representative of all applications.
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If Kinetex® core-shell technology columns do not provide at least an equivalent separation as compared to other products of the same phase and dimensions, return the column with comparative data within 45 days for a FULL REFUND.
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