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1

Stress testing of linaclotide: Development of a validated stability-indicating RP-HPLC method

Pyla S. R. M., Sahu P. K., Srinivas K.

Acta Chromatographica

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2017

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Vol. 29, no. 2

207--217

EN

Linaclotide, a first-in-class guanylate cyclase-C agonist, was recently approved by US Food and Drug Administration (FDA) as a promising pharmacotherapy for the management of constipation-predominant irritable bowel syndrome (IBS). In this communication, we present a novel stability-indicating reverse-phase high-performance liquid chromatography (RP-HPLC) method for the quantitative determination of linaclotide along with its degradation products. During the International Conference on Harmonization (ICH) prescribed stress study, linaclotide was found susceptible to degrade under hydrolytic (acid and base) and oxidative (peroxide) conditions. The separation of the degradants from the analyte was achieved on a Zorbax Eclipse XDB C8 Column (250 mm × 4.6 mm, 5 μm) using 0.01 N potassium dihydrogen orthophosphate buffer and acetonitrile (80:20 v/v) as mobile phase at a flow rate of 1.00 mL min−1 at column temperature of 40 °C. The detection of the column effluents was realized on a photodiode array detector set at 220 nm. Under the above optimal condition, the method was validated with respect to specificity, linearity, range, precision, robustness, and sensitivity in compliance to the regulatory requirements.

2

A stability-indicating capillary electrophoresis method for the determination of emtricitabine and tenofovir disoproxil fumarate in pharmaceutical tablets

Al-Johar, H. I. H. I., Maher H. M., Al-Zoman N. Z., Al-Shammary D. J., Al-Showiman H.

Acta Chromatographica

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2017

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Vol. 29, no. 4

469--476

EN

A stability-indicating capillary electrophoresis method coupled to a diode array detector (DAD) was developed and validated for the simultaneous determination of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) in combined tablets. This proposed method utilized a fused silica capillary (effective length, 62 cm; internal diameter [ID], 75 μm) and a background electrolyte (BGE) consisting of phosphate solution (pH 9.5, 50 mM). The separation was achieved at a voltage of 25 kV and a temperature of 21 °C using paracetamol as an internal standard. The described method was linear over the range of 5–200 μg/mL for both drugs (r = 0.9992). Intra- and inter-day relative standard deviation (RSD) (n = 9) was 0.41%. The limits of detection for FTC and TDF were 1.25 and 1.00 μg/mL, respectively. The average percentage recoveries of FTC and TDF from their tablet formulations were 99.66 ± 0.73 and 99.48 ± 0.33, respectively. The two drugs were subjected to thermal, photolytic, hydrolytic, and oxidative stress conditions, and then the stressed samples were analyzed by the proposed method. Degradation products produced as a result of stress studies did not interfere with the detection of FTC and TDF. The assay can thus be considered stability indicating.

3

Development of a stability-indicating HPLC method and a dissolution test for rivaroxaban dosage forms

Souri E., Mottaghi S., Zargarpoor M., Ahmadkhaniha R., Jalalizadeh H.

Acta Chromatographica

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2016

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Vol. 28, no. 3

347--361

EN

Rivaroxaban is an inhibitor of factor Xa, which is used as an oral anticoagulant for the prevention of thromboembolism. The objective of this study was to develop a stability-indicating high-performance liquid chromatographic method for the quantitative determination of rivaroxaban in pharmaceutical dosage forms. Rivaroxaban was subjected to acidic, basic, oxidative, photolytic, and thermal conditions for forced stress degradation studies. Considerable degradation was observed in all stress degradation tests. Rivaroxaban and its degradation products were separated on a Nova-Pak C8 column utilizing a mixture of acetonitrile and KH2PO4 50 mM (pH 3.0) (40:60, v/v) as the mobile phase, and the chromatogram was recorded at 270 nm using a general ultraviolet (UV) detector. The developed method was linear over the concentration range of 1–50 μg mL−1 showing acceptable within-day and between-day precision and accuracy values (CV <2% and Error <2%). The dissolution profile of rivaroxaban tablets was also studied in the presence of a surfactant using optimized conditions. The validated method was successfully used for the determination of rivaroxaban in dosage forms and also in dissolution medium indicating the specificity of the assay method.

4

Development and validation of a stability-indicating RP-LC method for the estimation of process-related impurities and degradation products of oxcarbazepine in pharmaceutical formulation

Reddy P. S., Babu K. S., Kumar N.

Acta Chromatographica

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2014

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Vol. 26, no. 2

267--282

EN

A stability-indicating gradient reverse-phase liquid chromatographic method was developed for the quantitative determination of process-related impurities and forced degradation products of oxcarbazepine in pharmaceutical formulation. The method was developed by using Inertsil cyano (250 × 4.6 mm) 5 μm column with mobile phase containing a gradient mixture of solvent A (0.01 M sodium dihydrogen phosphate, pH adjusted to 2.7 with orthophosphoric acid and acetonitrile in the ratio of 80:20 v/v) and B (50:40:10 v/v/v mixture of acetonitrile, water, and methanol). The flow rate of mobile phase was 1.0 mL min−1. Column temperature was maintained at 25°C and detection wavelength at 220 nm. Developed reverse-phase high-performance liquid chromatography (RP-HPLC) method can adequately separate and quantitate five impurities of oxcarbazepine, namely imp-A, imp-B, imp-C, imp-D, and imp-E. Oxcarbazepine was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal, and photolytic degradation. Oxcarbazepine was found to degrade significantly in acid, base, and oxidative stress conditions. The degradation products were well resolved from oxcarbazepine and its impurities. The developed method was validated as per International Conference on Harmonization (ICH) guidelines with respect to specificity, linearity, limit of detection and quantification, accuracy, precision, and robustness.

5

Stability-indicating densitometric determination of some angiotensin II receptor antagonists in presence of their degradation products

El-Shaboury S. R., Hussein A. S., Mohamed Niveen A., El-Sutohy Mohamed M.

Acta Chromatographica

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2013

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Vol. 25, no. 1

79--95

EN

A simple, selective, precise, and stability-indicating thin-layer chromatographic method has been developed and validated for analysis of some angiotensin II receptor antagonists (AIIRAs), namely, Losartan potassium (Los-K), Irbesartan (Irb), and Candesartan cilexetil (Cand) in the bulk drug and in pharmaceutical formulations (tablets). The method was based on using TLC plates pre-coated with silica gel G 60 on aluminum sheets as stationary phase and the development system was performed using chloroform:methanol (9:1) giving well separated and compact spots for all the studied drugs (RF values 0.41–0.53). The separated spots were characterized by viewing under the UV lamp, then visualized as orange spots by spraying with Dragendorff’s reagent and measured by densitometry. Under the optimum chromatographic conditions, linear relationships were obtained between response and concentrations of each studied drug with high correlation coefficients (0.9985–0.9994). Good accuracy and precision were successfully obtained for the analysis of tablets containing each drug alone or combined with diuretic drug hydrochlorothiazide (HCTZ). No interferences could be observed from the co-formulated HCTZ, commonly encountered excipients present in tablets as well as the degradation products. The results were compared successfully with reported methods and can be used as a stability-indicating assay.

6

A validated stability-indicating RP-LC method for the estimation of process-related impurities and degradation products of quetiapine fumarate in solid oral dosage form

Kumar N., Sangeetha D, Goyal R, Reddy P. S.

Acta Chromatographica

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2013

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Vol. 25, no. 2

393--409

EN

A simple, selective, and stability-indicating reverse phase liquid chromatographic method has been developed and validated for the simultaneous determination of impurities and forced degradation products of quetiapine fumarate. The chromatographic separation was achieved on Inertsil-3 C8, 150 mm × 4.6 mm, 5 μm column at 35°C with UV detection at 217 nm using gradient mobile phase at a flow rate of 1.0 mL/min. Mobile phase A contains a mixture of 0.01 M di-potassium hydrogen orthophosphate (pH 6.8) and acetonitrile in the ratio of 80:20 (v/v), respectively, and mobile phase B contains a mixture of 0.01 M di-potassium hydrogen orthophosphate (pH 6.8) and acetonitrile in the ratio of 20:80 (v/v), respectively. The drug product was subjected to the stress conditions of oxidative, hydrolysis (acid and base), hydrolytic, thermal, and photolytic degradation. Quetiapine fumarate was found to degrade significantly in acid, base, and oxidative stress conditions. The degradation products were well resolved from main peak and its impurities. The mass balance was found to be in the range of 96.6–102.2% in all the stressed conditions, thus proved the stability-indicating power of the method. The developed method was validated as per ICH guidelines with respect to specificity, linearity, limit of detection and quantification, accuracy, precision, and robustness.

7

Development and validation of stability-indicating HPLC method for solifenacin succinate: Isolation and identification of major base degradation product

Desai D, Patel G, Shukla N., Rajput S

Acta Chromatographica

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2012

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Vol. 24, no. 3

399--418

EN

Stability-indicating HPLC method was developed for determination of solifenacin succinate (SLN) as bulk drug and from pharmaceutical formulation. The HPLC separation of SLN from its degradation products was achieved using Oyster BDS C8 (250 mm × 4.6 mm i.d., 5 μm particle size) column with a flow rate 0.7 mL min-1 and using a UV detector to monitor the eluate at 210 nm. The mobile phase was composed of 10 mM ammonium formate buffer (adjusted pH 3 with formic acid)-acetonitrile-methanol (52.5:37.5:10, v/v/v). The linear regression analysis data for the calibration plots showed good linear relationship with r2 = 0.9999 in the working concentration range of 2–100 μg mL-1. The limit of detection (LOD) and limit of quantification (LOQ) were 0.07 and 0.21 μg mL-1, respectively. API and formulation of SLN were subjected to acid and alkali hydrolysis, oxidation, thermal and photodegradation. Standard drug peak was well resolved from the peaks of degradation products with significantly different retention time values. Also, isolation and identification of major base degradation product were carried out. The method is simple, accurate, specific, repeatable, stability-indicating, reduces the duration of the analysis and is suitable for routine determination of SLN in pharmaceutical formulation.

8

Development and application of stability-indicating HPLC method for the determination of nevirapine and its impurity in combination drug product

Navaneethan G, Karunakaran K., Elango K. P

Acta Chromatographica

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2012

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Vol. 24, no. 4

575--587

EN

A stability-indicating reversed-phase high-performance liquid chromatography method has been developed and validated for the estimation of nevirapine and its impurity, namely the related compound A and the related compound B in combination drug product. The separation was carried out on SUPELCOSIL ABZ (150 mm × 4.6 mm, 5 µm) column. Tablet was admitted to the stress conditions of acid, base, peroxide, thermal, humidity, and photolytic degradation. The degradation products were well resolved from nevirapine, and its impurities peaks and the peak homogeneity of compound were obtained using photo diode array detector, hence proving the stability-indicating nature of the method. Moreover, to prove the selectivity of the method, individual lamivudine, zidovudine, and their main impurities were injected. The developed method was linear for nevirapine from 120 to 360 µg mL-1, and the linear regression obtained was >0.999. Recovery data were in the range 98.2–101.5%. The limit of quantification for related compound A and related compound B was found to be 0.02%. The proposed method was validated according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines and proved suitable for stability testing and quality control of these drugs in pharmaceutical preparations.

9

A validated stability-indicating isocratic LC method for levofloxacin in the presence of degradation products and its process-related impurities

Sateesh J. N., Subba Reedy G. V., Jayaveera K. N., Dhayalamurthi S

Acta Chromatographica

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2012

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Vol. 24, no. 1

23--36

EN

The objective of the current study is to develop a validated specific stability-indicating isocratic reversed-phase liquid chromatographic method for the quantitative determination of levofloxacin and its related substances in pharmaceutical dosage forms in the presence of degradation products and its process-related impurities. Forced degradation studies were performed on levofloxacin as per the International Conference on Harmonisation (ICH)-prescribed stress conditions using acid, base, oxidative, water hydrolysis, thermal stress and photolytic degradation to show the stability-indicating power of the method. Significant degradation was observed during oxidative stress; minor degradation was observed in acidic stress and no degradation was observed in other stress conditions. The chromatographic method was optimized using the samples generated from forced degradation studies and the spiked impurity solution. The analysis was carried out with a 50 mm length × 4.6 mm i.d., 3.0 μm particle size YMC Pack Pro-C18 column using the mobile phase consisting of a mixture of 1.0% (v/v) triethylamine in water with pH adjusted to 6.30, using orthophosphoric acid, methanol and acetonitrile (7.7:1.3:1.0) pumped at a flow rate of 0.8 mL min−1 with ultraviolet (UV) detection at 235 nm. The limit of detection and the limit of quantification for the levofloxacin and its process-related impurities were established. The stressed test solutions were assayed against the qualified working standard of levofloxacin and the mass balance in each case was in between 99.1% and 99.9%, indicating that the developed liquid chromatography (LC) method was a stability-indicating technique. Validation of the developed LC method was carried out as per ICH requirements.

10

Stress degradation studies on cefpodoxime proxetil and development of a validated stability-indicating HPLC method

Patel G, Rajput S

Acta Chromatographica

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2011

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Vol. 23, no. 2

215--234

EN

A simple, sensitive, specific, precise, and stability-indicating high-performance liquid chromatographic (HPLC) method for determination of cefpodoxime proxetil as bulk drug and as pharmaceutical formulation was developed and validated as per the International Conference on Harmonization (ICH) guidelines. An isocratic separation was achieved using a Phenomenex Luna C18 (250 mm × 4.6 mm i.d., 5 μm particle size) column with a flow rate of 1 mL min-1 and a UV detector to monitor the eluate at 254 nm. The mobile phase consisted of acetonitrile and 50 mM ammonium acetate pH 6 (pH was adjusted with o-phosphoric acid) in the ratio of 45:55 (υ/υ). The linear regression analysis data for the calibration plots showed good linear relationship with r2 = 0.9998 in the working concentration range of 1–80 μg mL-1 The LOD and LOQ were 0.17 and 0.5 μg mL-1, respectively. The drug was subjected to acid and alkali hydrolysis, oxidation, dry heat, wet heat treatment, and photodegradation. The standard drug peaks were well resolved from the degradation products’ peaks with significantly different retention time (tR), and the resolution factor for cefpodoxime proxetil was found to be greater than 1.7. As the method could effectively measure the drug in the presence of all degradation products and excipients expected to be present in the formulation, it can be employed as a specific stability-indicating method. Moreover, the proposed HPLC method was utilized to investigate the kinetics of the acidic and oxidative degradation processes at different temperatures. An Arrhenius plot was constructed and the apparent pseudo-first-order rate constant, half-life and activation energy were calculated.

11

Development and validation of a simple, stability-indicating high-performance liquid chromatographic method for analysis of tolterodine tartrate in the bulk drug and in its tablet formulation

Sinha V. R, Jindal V, Kumar R. V, Bhinge J. R, Goel H

Acta Chromatographica

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2011

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Vol. 23, no. 1

133--143

EN

A stability-indicating HPLC method has been developed for analysis of tolterodine tartrate in the bulk drug and in formulations. Acceptable separation of the drug and its degradation products was achieved at 40°C on a 4.6 mm i.d. × 250 mm, 5-μm particle, C18 column with 40:60 (υ/υ) buffer solution-methanol containing 0.5% (υ/υ) triethylamine as mobile phase. The pH of the mobile phase was adjusted to 7.0 ± 0.1 with orthophosphoric acid. The flow rate was 1.2 mL min -1and the detection wavelength 220 nm. The method was validated for linearity, precision, accuracy, specificity, and robustness. Response was a linear function of concentration over the range 1–100 μg mL-1. The slope of the calibration plot was 17.82 mV s -1ppm-1, the correlation coefficient 0.999, and the relative standard deviation (RSD) 0.23%. Assessment of precision revealed method RSD was low — from 1.59 to 1.88% for intra-day precision and from 0.59 to 1.90% for inter-day precision. Stress degradation studies showed tolterodine tartrate was stable to acidic and neutral hydrolysis, oxidative stress, photolytic stress, and thermal stress but labile to alkaline hydrolysis.

12

UPLC separation and quantification of related substances of varenicline tartrate tablet

Satheesh B, Kumarpulluru S, Raghavan V, Saravanan D

Acta Chromatographica

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2010

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Vol. 22, no. 2

207--218

EN

A new ultra-performance liquid chromatographic (UPLC) method has been developed and validated for quantification of substances related to varenicline tartrate, process-related and degradation products, in pharmaceutical formulations. Chromatographic separation of six impurities was performed on a reversed phase column. The method was validated for linearity, limits of detection and quantification, accuracy, precision, and selectivity. The calibration plots obtained for the six impurities were linear over the range 0.005–0.30%. The relative standard deviations ( s r ) of intra and inter-day experiments were less than 1.0%. The detection limits ranged between 0.002 and 0.004%, depending on the impurity. The proposed UPLC method was successfully applied to quantification of varenicline impurities in its pharmaceutical formulation.

13

Development and validation of a stability-indicating UHPLC method for assay of felbamate and related substances

Shetty S. K, Surendranath K. V, Kaja R. K., Satish J, Jogul J, Manitripathi U

Acta Chromatographica

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2010

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Vol. 22, no. 2

161--172

EN

A new, sensitive, stability-indicating, and cost and time-effective isocratic reversed-phase UHPLC method has been developed for quantitative analysis of felbamate, an antiepileptic drug, both in the bulk drug and in pharmaceutical dosage forms. Chromatographic separation of felbamate and its two impurities was achieved on a C 18 column with a simple buffer-methanol mobile phase; the run time was 8 min. Quantification was achieved by ultraviolet detection. Resolution between the impurities was >2.0. Response was a linear function of concentration over the range 0.1–3.0 μg mL -1, correlation coefficient >0.999, for felbamate and the impurities. The method is capable of detecting the two impurities at levels of 0.002% (0.02 μg mL -1) of the test concentration of 1.0 mg mL -1 (1 μL injection). The same sensitivity was achieved for all the degradation products formed during stress studies in which the drug was subjected to hydrolysis, oxidation, photolysis, and thermal degradation. Substantial degradation occurred under acidic and basic conditions. The stressed test solutions were assayed against felbamate working standard and the mass balance in each case was close to 100%, indicating the method is stability-indicating. The method was validated for linearity, accuracy, precision, and robustness in accordance with ICH Guidelines.

14

Application of a stability-indicating HPTLC method for quantitative analysis of amtolmetin guacil in a pharmaceutical dosage form

Bhusari V. K., Mahadik M. V., Dhaneshwar S. R.

Acta Chromatographica

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2009

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Vol. 21, no. 2

299--317

EN

A sensitive, selective, precise, and stability-indicating HPTLC method has been established for analysis of amtolmetin guacil both as the bulk drug and in a formulation. Aluminum foil-backed silica gel 60F 254 plates were used with toluene-ethyl acetate 4:6 ( υ/υ ) as mobile phase, and densitometric analysis was performed in absorbance mode at 320 nm. The method was validated for linearity, precision, accuracy, selectivity, and specificity in accordance with ICH guidelines. Amtolmetin guacil was subjected to acidic and alkaline hydrolysis, oxidation, dry heat treatment, and photo-degradation. The method was used to study the kinetics of degradation of amtolmetin guacil by acid and alkali.

15

Development and validation of a stability-indicating HPTLC method for analysis of 3-acetyl-11-keto-β-boswellic acid in a herbal extract and a nanoparticles formulation

Goel A., Goel R., Jain G. K., Singh R. M., Ahmad F. J., Singh G. N.

Acta Chromatographica

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2008

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Vol. 20, no. 3

497-511

EN

A new, specific, sensitive, selective, precise, and reproducible high-performance thin-layer chromatographic (HPTLC) method has been established for study of the stability of 3-acetyl-11-keto-β-boswellic acid (AKBA). HPTLC was performed on aluminium foil plates coated with 200 µm silica gel 60F 254 . Linear ascending development with toluene-ethyl acetate 7:3 ( v/v ) was performed at room temperature (25 š 2°C) in a twin-trough glass chamber saturated with mobile phase vapour. Compact bands ( R 0.52 š 0.02) were obtained for AKBA. Spectrodensitometric scanning was performed in absorbance mode at 250 nm. Linear regression analysis of the calibration plots showed there was a good linear relationship ( r 2 = 0.9989 š 0.0002) between peak area and concentration in the range 200-1200 ng band -1 . The method was validated for precision, recovery, robustness, specificity, and detection and quantification limits, in accordance with ICH guidelines. The limits of detection and quantification were 3.06 and 9.29 ng band -1, respectively. The recovery of the method was 99.35-100.21%. AKBA was subjected to various stress test conditions - acid and alkali hydrolysis, oxidation, photodegradation, and dry and wet heat treatment. Degradation products were well resolved from the pure drug with significantly different R F values. Statistical analysis showed the method could be successfully applied for the estimation of AKBA in herbal extract and in nanoparticles. Because the method could effectively separate the drug from its degradation products, it can be regarded as stability-indicating.

16

Development and validation of a stability-indicating HPTLC method for analysis of rupatadine fumarate in the bulk drug and tablet dosage form

Shirkhedkar A. A., Thorve R. R., Fursule R. A., Surana S. J.

Acta Chromatographica

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2008

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Vol. 20, no. 3

423-437

EN

A simple, selective, precise and stability-indicating high-performance thin-layer chromatographic method for analysis of rupatadine fumarate, both as the bulk drug and in a tablet formulation, has been developed and validated. Aluminium foil TLC plates precoated with silica gel 60F 254 were used as stationary phase and toluene-methanol-triethylamine 4:1:0.2 ( v/v ) as mobile phase. A compact band ( R F 0.61 š 0.02) was obtained for rupatadine fumarate. Densitometric analysis was performed in absorbance mode at 264 nm. Linear regression analysis revealed a good linear relationship ( r 2 = 0.9992 š 0.0001) between peak area and concentration in the range 400-1400 ng band -1. The mean values š SD of the slope and intercept were 2.5471 š 0.005 and 1055.2 š 4.20, respectively. The method was validated for precision, recovery, and robustness. The limits of detection and quantitation were 66.63 and 201.91 ng band -1, respectively. Rupatadine fumarate was subjected to acid and alkaline hydrolysis, oxidation, and photochemical and thermal degradation and underwent degradation under all these conditions. Statistical analysis proved the method enables repeatable, selective, and accurate analysis of the drug. It can be used for identification and quantitative analysis of rupatadine fumarate in the bulk drug and in tablet formulations.