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ISSN (Online): 0975-8232,
ISSN (Print): 2320-5148

International Journal Of
Pharmaceutical Sciences And Research

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IVABRADINE AND METOPROLOL: A REVIEW OF ANALYTICAL METHODS FOR PHARMACEUTICAL QUALITY CONTROL AND MONITORING

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IVABRADINE AND METOPROLOL: A REVIEW OF ANALYTICAL METHODS FOR PHARMACEUTICAL QUALITY CONTROL AND MONITORING

K. Gandhi * and S. B. Ezhava

Department of Pharmaceutical Chemistry, L. M. College of Pharmacy, Ahmedabad, Gujarat, India.

ABSTRACT: Beta-blockers are widely used in combination with Ivabradine in people with coronary heart disease (CHD), one of the leading causes of death. Thus, monitoring of these drugs is important because it is accessible to manage heart failure amongst people with CHD. In addition, its quality control is fundamental to provide quality medicines. Method of analysis can be the first step in the rational use of pharmaceuticals. In this context, a detailed study of literature and official compendia for the pharmaceutical quality control of Ivabradine and Metoprolol were done. Among the analytical methods in the evaluation of Ivabradine and Metoprolol, HPLC is predominantly followed by HPTLC and UV. It was found that in the literature that analysis of Ivabradine and Metoprolol-based pharmaceutical products are more common than analysis of Ivabradine and Metoprolol in biological matrices. Pharmaceutical analyses have an impact on analytical decisions as well as effective and reliable results. The method must be suitable for the intended investigation. Although, there is a lack of Analytical Methods for estimation of Ivabradine and Metoprolol in their combined dosage form.

Keywords: Ivabradine, Metoprolol, Spectrophotometry, Chromatography

INTRODUCTION: Coronary heart disease (CHD), also known as ischemic heart disease, is one of the leading causes of death. CHD develops because of the build-up of fatty deposits (plaque) on the walls of the coronary arteries. When arteries are blocked or narrowed, the heart does not receive enough blood to function properly, which can cause pain and tightness in the chest (angina). There are several types of angina, the most common being stable angina pectoris (AP). When you exercise or become stressed, the heart needs to work harder in order to pump enough oxygen around the body. When a person is suffering from AP, this extra stress on the heart causes severe pain in the chest.

This type of angina is usually treated using medications and changing a person’s lifestyle so that they do not put unnecessary strain on the heart. There is a wide range of drugs that can be prescribed to help people with (anti-anginal agents) 1. Beta-blockers (beta-blockers, β-blockers, etc.) are a class of medications that are predominantly used to manage abnormal heart rhythms and to protect the heart from a second heart attack (myocardial infarction) after a first heart attack (secondary prevention).

They are also widely used to treat high blood pressure (hypertension). Beta-blockers widely used in combination with Ivabradine in people with heart failure with LVEF (Left ventricular ejection fraction is the measurement of how much blood is pumped out of the left ventricle of the heart) lower than 35 percent (in Angina Pectoris LVEF lowers than 35%) inadequately controlled by beta blockers alone and whose heart rate exceeds 70 beats per minute. In people not sufficiently managed with beta-blockers for their heart failure adding Ivabradine decreases the risk of hospitalization for heart failure.

Ivabradine selectively inhibits the pacemaker If current. Blocking this channel reduces cardiac pacemaker activity, selectively slowing the heart rate and allowing more blood flow to flow to the myocardium. (Beta Blocker) Metoprolol Succinate blocks β1 adrenergic receptors in heart muscle cells. So, Ivabradine with Metoprolol safely and effectively reduces the heart rate and makes the heart more efficient at pumping blood throughout the body 2.

The Newly developed combination of beta-blocker (Metoprolol) with Ivabradine is safely and effectively treating Coronary Heart Disease. So, this combination is more widely used in Angina Pectoris. Therefore, the quality control of this pharmaceutical product is fundamental to provide quality medicines to the population 3.

Thus, A review of existing analytical methods in the literature and in official compendia for evaluation of Ivabradine and Metoprolol was made in this paper.

Ivabradine: 4, 5

FIG. 1: STRUCTURE OF IVABRADINE

Chemical Name: 3-[3-({[(7S)-3,4-dimethoxybicyclo [4.2.0]octa-1,3,5-trien-7-yl] methyl} (methyl) amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one

Molecular Formula: C27H36N2O5

Molecular Weight: 468.594 g/mol

Mechanism of Action: Ivabradine lowers heart rate by selectively inhibiting If channels ("funny channels") in the heart in a concentration-dependent manner without affecting any other cardiac ionic channels (including calcium or potassium).

Ivabradine binds by entering and attaching to a site on the channel pore from the intracellular side and disrupts If ion current flow, which prolongs diastolic depolarization, lowering heart rate.

The If currents are located in the sinoatrial node and are the home of all cardiac pacemaker activity. Ivabradine, therefore, lowers the pacemaker firing rate, consequently lowering heart rate and reducing myocardial oxygen demand. This allows for an improved oxygen supply and therefore mitigation of ischemia, allowing for a higher exercise capacity and reduction in angina episodes.

Metoprolol: 6-10

FIG. 2: STRUCTURE OF METOPROLOL

Chemical Name: 1-[4-(2-methoxyethyl)phenoxy]-3-[(propan-2-yl)amino]propan-2-ol

Molecular Formula: C15H25NO3

Molecular Weight: 267.364 g/mol

Mechanism of Action: Metoprolol competes with adrenergic neurotransmitters such as catecholamines for binding at beta(1)-adrenergic receptors in the heart.

Beta(1)-receptor blockade results in a decrease in heart rate, cardiac output, and blood pressure.

Marketed form of Metoprolol: Metoprolol succinate, Metoprolol tartrate, Metoprolol fumarate

Mechanism of Action (in Combination): Ivabradine selectively inhibits the pacemaker If current. Blocking this channel reduces cardiac pacemaker activity, selectively slowing the heart rate and allowing more time for blood to flow to the myocardium. (Beta Blocker) Metoprolol Succinate blocks β1 adrenergic receptors in heart muscle cells.

So, Ivabradine with Metoprolol safely and effectively reduces the heart rate and makes the heart more efficient at pumping blood throughout the body.

Applications: Ivabradine and Metoprolol tartrate in combination is marketed in the form of tablets. The typical dose is 5 mg Ivabradine and 25/50 mg Metoprolol tartrate.

Methods for Analysis: Quality control is essential to certify the quality, safety, and efficacy of pharmaceutical products.

Therefore, Analytical Methods are used to check quality. The methods found in the literature for evaluation of Ivabradine and Metoprolol were Titrimetric, UV, Visible spectroscopy, dissolution study using HPLC, IR, HPLC, HPLC coupled with MS (LC-MS), HPTLC, UPLC, UPLC coupled to MS, UPLC-MS/MS. UPLC-MS method is the most used in the analysis of biological samples, whereas the HPLC method is the most used in the analysis of pharmaceutical samples shown in the figure.

FIG. 3: METHODS FOUND IN LITERATURE FOR EVALUATION OF IVABRADINE    

FIG. 4: METHODS FOUND IN LITERATURE FOR EVALUATION OF METOPROLOL

Literature reveals that Ivabradine is estimated in combination with various drugs like Carvedilol, Metoprolol, Roboxetine whereas Metoprolol is estimated in combination with Amlodipine, Clinidipine, Metformin, Olmesartan, Telmisartan, Atorvastatin, Ramipril, Caffeine, Tolbutamine, Dapson.

Various articles are available on the analysis of pharmaceutical samples of Ivabradine and Metoprolol alone.

Very few articles are reported for the analysis of Ivabradine and Metoprolol in biological matrices.

DISCUSSION: Ivabradine and Metoprolol in pharmaceutical or biological matrixes can be evaluated by different methods of analysis.

Pharmaceutical analyses have an impact on making analytical decisions as well as getting effective and reliable results. The method must be suitable for the intended investigation.

Ivabradine is a newly approved drug, so the analytical method is not available in any official compendia, whereas Metoprolol is official in IP(IP 2018)6and USP (USP 40 NF 35)7.

In Official compendia analytical methods for Metoprolol are available in various salt form like succinate, tartrate and fumarate.

The official method for analysis of Metoprolol tablet uses HPLC wherein buffer and acetonitrile are used as a mobile phase. A dissolution study was performed in phosphate buffer.

Titration was done using perchloric acid. Reported Methods for Estimation of Ivabradine and Metoprolol are given in the table.

TABLE 1: REPORTED METHOD FOR ESTIMATION OF IVABRADINE

S. no. Drug Description Ref no.
1 Ivabradine in controlled-release formulations by UV Spectrophotometric Method Detection Wavelength: 286 nm

Solvent: Phosphate Buffer (pH 6.8)

Linearity Range:10-50 μg/mL

Correlation co-efficient:0.9994

 11
2 Ivabradine in controlled-release formulations by UV Spectrophotometric and RP-HPLC methods for dissolution study UV Method:

Detection Wavelength: 286 nm, Solvent: Water, HCl Buffer (pH 1.2), Phosphate Buffer (pH 6.8)

Linearity Range:

In Water: 5-60 μg/mL, In HCl Buffer (pH 1.2): 5-60 μg/mL

In Phosphate Buffer (pH 6.8): 5-60 μg/mL

Correlation co-efficient:

In Water: 0.9998, In HCl Buffer (pH 1.2): 0.9998

In Phosphate Buffer (pH 6.8): 0.9999

RP-HPLC Method:

Mobile phase: Phosphate buffer pH 7.4: Methanol (35:65)

Solvent: Phosphate Buffer (pH 6.8), Phosphate buffer (pH 7.4): methanol (35:65)

Stationary Phase: 250 mm × 4.6 mm, 5µm, C18, 100Aº Kromasil column

Linearity Range:

In Phosphate Buffer (pH 6.8): 5-60μg/mL

In phosphate buffer pH 7.4: methanol (35:65): 40-60 μg/mL

Retention Time: 7.4 min, Flow Rate: 1 ml/min

Correlation co-efficient:

In Phosphate Buffer (pH 6.8): 0.9992

In phosphate buffer pH 7.4: methanol (35:65): 0.9993

LOD:0.05 µg/mL, LOQ:0.2 µg/ml

 12
3 Ivabradine Hydrochloride in Bulk and Pharmaceutical dosage form by RP-HPLC method Detection Wavelength: 286 nm

Solvent: Methanol: ACN (80:20 v/v) further dilution in Methanol, Mobile phase: Methanol: ACN (80:20 v/v)

Stationary Phase: ZorbaxEclipsPlus C18, 250×4.6 mm, 5 μm column

Linearity Range: 2.5-50 μg/mL, Retention Time: 5.8 min

Flow Rate: 1 ml/min, Correlation co-efficient: 0.9998

LOD: 0.0216 μg/mL, LOQ: 0.06537 μg/mL

 13
4 Ivabradine Hydrochloride in Tablets by RP-HPLC method Detection Wavelength: 285 nm, Mobile phase: Methanol:25 mM phosphate buffer (60:40 v/v) pH 6.5

Stationary Phase: SS Wakosil C18AR, 250×4.6 mm, 5 μm column

Linearity Range: 30-210 μg/mL, Retention Time: 7.4 min

Flow Rate: 0.8 ml/min, Correlation co-efficient: 0.9998

 14
5 Ivabradine HCl in Pharmaceutical Dosage Form by Stability Indicating UV Spectrophotometric Method and RP-HPLC Method UV Method:

Detection Wavelength: 286 nm, Solvent: Methanol

Linearity Range: 4.2-31. 6μg/mL LOD: 0.06 μg/ml, LOQ: 0.2 μg/ml, Correlation co-efficient: 0.99974

RP-HPLC Method:

Detection Wavelength: 286 nm, Solvent: Water: Acetonitrile (50: 50 v/v). Further dilution was made in Methanol

Mobile phase: 0.5% Formic Acid (pH=7.0): Acetonitrile (65: 35 v/v), Stationary Phase: Inertsil ODS-3V [250 mm x 4.6mm] 5µcolumn, Linearity Range: 4.2-31. 6 μg/mL, Retention Time: 7 min, Flow Rate: 0.7 ml/min, Correlation co-efficient: 0.9989, LOD: 0.06 μg/ml, LOQ: 0.2 μg/ml

Degradation:

Thermal: 105º C for 24 Hrs, UV: 254 nm for 48 Hrs

Acid:2 mL 5 N HCl (60°C for 30 min) %Degradation: 10.96%, Alkali:2 mL 5 N NaOH (60°C for 30 min)

Oxidation:3% H2O2 (60°C for 30 min), %Degradation: 3.71%, Humidity: 40°C/75%RH for 24 h Marked Degradation observed in acid hydrolysis and Oxidation condition

 15
6 Ivabradine HCl in Solid Oral Dosage Form by Stability Indicating RP-HPLC Method

 

 Detection Wavelength: 285 nm

Solvent: Water

Mobile phase: 10 mM ammonium acetate buffer pH 6.0: Methanol (50:50) (v/v)

Stationary Phase:Phenomenex KinetexC18 column (150 × 4.6 mm, 5 μm

Retention Time: 3.1 min, Linearity Range: 70 - 130μg/ml.

Flow Rate: 1 ml/min, Correlation co-efficient: 0.9997

Degradation:

Thermal: 105º C for 24 Hrs, %Degradation: 13%

Photolytic: 1.2 million lux h & 200 W h / sq. m

Acid:1 N hydrochloric acid (10% / 75°C for 6 h)

Alkali:1 N sodium hydroxide (10% / 75°C for 6 h)

Oxidation:3% H2O2 (10% /75°C for 6 h), %Degradation: 3%

Humidity:92%RH at 25°C for 48 h

Marked Degradation observed in acid Thermal and Oxidation condition

 16
7 Ivabradine in Bulk and Pharmaceutical Dosage Form by RP HPTLC Method Solvent: DMSO, Detection Wavelength:254 nm, 366 nm

Mobile phase: Acetonitrile: Water (60:40, v/v)

Stationary Phase: Kieselgel 60 F254 S

Linearity Range: 0.2–1.2 µg/spot

Rf Value:0.26, Correlation co-efficient: 0.999

 17
8 Ivabradine in Bulk and Pharmaceutical Dosage Form by Stability Indicating HPTLC Method Detection Wavelength:287 nm

Mobile phase: Ethyl acetate: 0.389 M Ammonium acetate in Methanol (1:5, v/v)

Stationary Phase: silica gel 60F254 aluminum plates

Linearity Range: 1200-2800 ng/spot, Rf Value:0.36 ± 0.01

LOD: 255.86 ng/spot, LOQ: 775.33 ng/spot

Correlation co-efficient: 0.9956

 18
9 Ivabradine in Bulk and Pharmaceutical Dosage Form by Stability Indicating HPTLC Method Solvent: Methanol, Detection Wavelength:286 nm

Mobile phase: Chloroform: Methanol (1:1 v/v)

Stationary Phase: Aluminum Plate precoated with Silica Gel 60 F254

Linearity Range: 400–2000 ng/band, Rf Value:0.63 ± 0.02

LOD: 20.73 ng/band, LOQ: 62.83ng/band

Correlation co-efficient: 0.997

Degradation:

Photolytic: 1.2 million lux h & 200 W h / sq. m

Acid:1 N hydrochloric acid (10% / refluxed at 60°C for 30 min), Alkali: 0.1 N sodium hydroxide (10% / room temperature for 24 h), Oxidation:3% H2O2 (10% / room temperature for 24 h), Dry Heat: In Oven 80°C for 6 hr

No Degradation peak observed

 19
10 Ivabradine in Human Plasma by LC-MS/MS-ESI Method Solvent: Methanol

Mobile phase: 0.1% formic acid: Methanol (60:40, v/v)

Stationary Phase: Aglient Eclipse XDB C8 column (150 × 4.6 mm, 5 μm)

Linearity Range:0.1–200 ηg/mL, Flow Rate: 1 ml/min

Correlation co-efficient: 0.9970

 20
11 Ivabradine and N-desmethylivabradine in Urine and in Human Plasma by LC-MS/MS Method Solvent: Methanol

Internal Standard: Diazepam

Mobile phase: Methanol and Aqueous 5 mM Ammonium acetate buffer containing 0.2% formic acid (80:20, v/v)

Stationary Phase: Diamonsil C18 column (150 mm 4.6 mm, 5 mm

Linearity Range:

In Plasma: Ivabradine: 0.1013–101.3 ng/mL,

N-desmethylivabradine: 0.085–25.5 ng/mL

In Urine:Ivabradine: 10.13–6078 ng/mL

N-desmethylivabradine: 8.5–850 ng/mL

Flow Rate: 0.6 ml/min, Correlation co-efficient: 0.999

 21
12 Ivabradine

Impurity 3,3'-

(propane-1,3-diyl) bis(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one) by Spectroscopic and Volumetric Method

 Spectroscopic Method:

Detection Wavelength: 479 nm, Solvent: Distilled water

Oxidation of drug impurity by excess cerium (IV) sulphate in acidic medium and the subsequent reaction of the remaining Ce (IV) with a known amount of ferrous ammonium sulphate. The resultant ferric ion is then made to react with thiocyanate in acid medium to form a brown coloured complex which is analyzed spectrophotometrically against the reagent blank.

Linearity Range:0.5–100 mg/lCorrelation co-efficient:0.9984, LOD: 0.14, LOQ: 0.42

Volumetric Method:

un-reacted Ce (IV) is titrated against standard ferrous ammonium sulphate to estimate the quantity of IVA-9.

 22
13 Ivabradine and Carvedilol in their fixed dose combination by RP- HPLC Method Wavelength: 275 nm

Solvent: 50:50 (v/v) methanol/water further dilution by using 85:15:0.1 (v/v/v) acetonitrile/water/formic acid

Mobile phase: Acetonitrile: Phosphate Buffer (pH 3) (75:25)

Stationary Phase: Hypersil ODS C18, Flow Rate: 1 ml/min

Linearity Range:

Ivabradine: 50-300 µg/ml, Carvedilol: 150-400 µg/ml

Retention Time:Ivabradine: 8.40 min, Carvedilol: 12.14 min

Correlation co-efficient:Ivabradine:0.9983, Carvedilol:0.9999

LOD:Ivabradine: 3.64, Carvedilol: 4.83

LOQ:Ivabradine: 11.03, Carvedilol: 14.64

 23

TABLE 2: REPORTED METHOD FOR ESTIMATION OF METOPROLOL

S. no. Drug Description Ref no.
1 Metoprolol succinate in Bulk and in Pharmaceutical dosage forms by UV Spectrophotometric method In Distilled water:

Detection Wavelength: 221 nm, Linearity Range: 5-25 μg/mL

Correlation coefficient: 0.995

LOD: 1.389 µg/mL, LOQ: 4.2084 µg/ml

In phosphate buffer pH 6.8:

Detection Wavelength: 223 nm, Linearity Range: 5-25μg/mL

Correlation coefficient: 0.995

LOD: 0.1399 µg/mL, LOQ: 0.4240 µg/ml

 24
2 Metoprolol tartrate in Pharmaceutical dosage forms byUV Spectrophotometric and Complexation method UV Spectrophotometric method:

Detection Wavelength: 274 nm, Linearity Range: 68.4-205.4 μg/mL,  Correlation coefficient: 0.998

LOD: 8.10 µg/mL, LOQ:26.98 µg/ml

Complexation method:

Complexation withcopper (II) at pH 6.0, using Britton-Robinson buffer solution, Detection Wavelength: 675 nm

Linearity Range: 8.5-70μg/mL, Correlation coefficient: 0.998

LOD: 5.56 µg/mL, LOQ: 7.11 µg/ml

 25
3 Metoprolol succinate in Bulk and Pharmaceutical Dosage Form by RP-HPLC Method Detection Wavelength: 280 nm

Mobile phase: Acetonitrile: water: 1 % ortho phosphoric acid (70:27:3 v/v/v)

Stationary Phase: Aligent C-8, RP column (4.6 mm i.d x 250 mm), Linearity Range:10–200 µg/mL

Retention Time: 6.84 min, Flow Rate: 1 ml/min

LOD:0.0284 µg/mL, LOQ:0.094 µg/ml

 26
4 Metoprolol tartrate in Human Plasma by RP-HPLC Method Internal Standard: Pinacidil monohydrate

Detection Wavelength: 275 nm

Mobile phase: Acetonitrile: Water: Triethylamine 18:81:1 (v/v) pH 11, Stationary Phase:250 mm × 4 mm, 10-μm particle, Novapack C18 column, Linearity Range: 20–200 µg/mL, Retention Time: 6.84 min, Flow Rate: 1 ml/min

 27
5 Metoprolol Tartrate and Hydrochlorothiazide in Bulk and in Pharmaceutical dosage forms by RP-HPLC Method Detection wavelength: 226 nm, Solvent: Methanol

Mobile phase: Phosphate buffer:  Methanol (60:40) (v/v)

Stationary Phase: Inertsil ODS-3, 250 mm, 4.6 mm ID, packed with 5 μ particle size, Flow Rate:1.0 ml/min

Linearity Range: Metoprolol tartrate: 100 to 600 ppm, Hydrochlorthiazide: 12.5 to 75 ppm

Retention Time:

Metoprolol tartrate: 10.81, Hydrochlorthiazide: 4.13

Correlation coefficient:

Metoprolol tartrate: 0.9995, Hydrochlorthiazide: 0.9998

 28
6 Metformin, Metoprolol and its Metabolites in Rat Plasma by LC–MS-MS Method Mobile phase: Methanol: Water containing 0.1% formic acid (39:61, v/v)

Stationary Phase: Agilent HC-C18 column (4.6 × 250 mm, 5 µm), Flow Rate: 0.2 ml/min

Linearity Range: Metoprolol: 19.53–40,000 ng/mL, Metformin: 3.42–7,000 ng/mL, α-hydroxymetoprolol (HMT): 2.05–4,200 ng/mL, O-desmethylmetoprolol (DMT): 1.95–4,000 ng/mL

Retention Time:

Metoprolol: 6.9 min, Metformin: 3.6 min, α-hydroxymetoprolol(HMT): 3.8 min, O-desmethylmetoprolol (DMT): 3.1 min

 29
7 Metoprolol Succinate and Olmesartan Medoxomil in Tablet Dosage Form by Stability Indicating RP-HPLC Method Detection wavelength: 228 nm, Solvent: Methanol

Mobile phase: Methanol: 0.05% v/v O-phosphoric acid in water (50:50 v/v) , Stationary Phase: Chromasil 250 × 4.6 mm, i.d 5 µm C-18 column, Flow Rate: 1ml/min

Linearity Range: Metoprolol Succinate: 5-80 µg/ml, Olmesartan Medoxomil: 5-70 µg/ml

Retention Time:Metoprolol Succinate: 3.485 min, Olmesartan Medoxomil: 7.085 min

Correlation coefficient:

Metoprolol Succinate: 0.9990, Olmesartan Medoxomil: 0.9993

Degradation:

Thermal: 80º C for 48 Hrs in oven, Photodegradation:(U.V.) in Photostability chamber equipped with UV ligt with energy of not less than 200watt hours/square meter, (Fluroscence light)in Photostability chamber equipped with Fluroscence light illumination not less than 1.2 million lux hours

Acid: 10 mL 1 N HCL and heated for 30 min at 60º C, 2 impurities that is at Rt 2.950, 5.033

Alkali: 10 mL 1 N NaOH and refluxed for 30 min at 60º C 2 impurities that is at Rt 2.893, 5.030

Oxidation: (i) 30 % H2O2 heated for 2 hrs at 60º C in water bath

Neutral: 10 ml distilled water and refluxed for 2 hrs at 60º C

Degradation was observed in Acidic and Alkaline condition

 30
8 Metoprolol Succinate and Olmesartan Medoxomil in Tablet Dosage Form by Stability Indicating RP-HPLC Method Detection wavelength: 220 nm, Solvent: ACN: Water (1:1)

Mobile phase: 0.05% Trifluoro acetic acid (TFA): Acetonitrile (70:30 v/v) , Stationary Phase: YMC-Pack CN 250 x 4.6 mm, i.d 5 µm C-18 column, Flow Rate: 1ml/min

Linearity Range: Metoprolol Succinate: 5-35 µg/ml, Olmesartan Medoxomil: 5-35 µg/ml

Retention Time:

Metoprolol Succinate: 4.1 min, Olmesartan Medoxomil: 7.9 min

Correlation coefficient:

Metoprolol Succinate: 0.998, Olmesartan Medoxomil: 0.999

LOD:Metoprolol Succinate: 1.05 µg/ml,

Olmesartan Medoxomil: 0.085 µg/ml

LOQ:Metoprolol Succinate: 3.19 µg/ml

Olmesartan Medoxomil: 0.259 µg/ml

Degradation:

Thermal: (Dry heat): heated at 105º C for 24 Hrs in oven impurities that is at Rt 8.4, 8.6 min for OLM and 4.8, 6.1, 6.7, 6.8 min for MET Humidity: 75% RH for 24 hrs impurities that is at Rt 8.4, 8.6 min for OLM and 4.8, 6.1, 6.7

min for MET Photodegrdation:(U.V.) in UV light at 254 nm for 24 hrs impurities that is at Rt 8.4, 8.6 min for OLM and 4.8, 5.3, 6.1, 6.7 min for MET(In Sun light)for 24 hrs impurities that is at Rt 8.4, 8.6 min for OLM and 4.8, 5.3, 6.1, 6.7 min for MET, Acid: 0.1 N HCl and heated for 1 hr at 100º C, impurities that is at Rt 5.8 min for OLM and 4.9, 5.3 min for MET

Alkali: 0.1 N NaOH heated for 1 hr at 100º C impurities that is at Rt 5.9 min for OLM and 4.9, 5.3 min for MET

Oxidation: (i) 0.1 % H2O2 heated for 24 hrs at 100º C impurities that is at Rt 5.8 min for OLM and 5.3 min for MET

Degradation was observed in Acidic, Alkaline and Oxidation Condition

 31
9 Olmesartan Medoximil and Metoprolol Succinate in Tablet Dosage Form by HPTLC Method Solvent: Methanol, Detection Wavelength: 233 nm

Mobile phase: Water: Methanol: Ammonium sulphate (4.5:4.5:1.5 v/v/v)

Stationary Phase: Precoated silica gel aluminium plate 60 F254

Linearity Range: Olmesartan: 100-700 ng/spot, Metoprolol succinate: 100-700 ng/spot

Rf Value: Olmesartan: 0.65, Metoprolol succinate: 0.78

Correlation co-efficient:

Olmesartan: 0.9991, Metoprolol succinate: 0.9992

LOD: Olmesartan: 12.07 ng, Metoprolol succinate: 17.3 ng

LOQ: Olmesartan: 37 ng, Metoprolol succinate: 51.7 ng

 32
10 Caffeine, Tolbutamide, Metoprolol, and Dapsone in Rat Plasma by UPLC–MS-MS Method Detection wavelength: 220 nm, Internal Standard: Phenacetin

Solvent: Methanol: Water (5:5, v/v)

Extraction: Dichloromethane: Butanol (10:1, v/v)

Mobile phase: Acetonitrile: Water (containing 0.1% formic acid) (15:85, v/v)Stationary Phase: Waters Acquity UPLC BEH HILIC C18 column (2.1 3 50 mm, 1.7 mm), Flow Rate: 0.25 mL/min Linearity Range: Metoprolol: 2.5–250 ng/mL, Caffeine: 2.5–1,000 ng/ml,Dapson: 2.5–1,000 ng/ml, Tolbutamide: 5–5,000 ng/mL

Retention Time: Metoprolol: 2.31 min, Caffeine: 1.15 min

Dapson: 3.10 min, Tolbutamide: 2.31 min

Correlation coefficient: Metoprolol: 0.9998, Caffeine: 0.9936

Dapson: 0.9966, Tolbutamide: 0.9990

 33
11 Cilnidipine and Metoprolol succinate in bulk drugs and combined dosage form by UV spectrophotometric method (Q-Absorbance Ratio) Solvent: Methanol, Detection Wavelength: 230.60 nm and 223.40 nm, i.e. isoabsorptive point

Linearity Range:

Clinidipine: 2-10 μg/mL, Metoprolol succinate: 10-50 μg/ml

At 230.60 nm wavelength:

Correlation coefficient: Clinidipine: 0.9991, Metoprolol succinate: 0.9986LOD: Clinidipine: 0.0529 µg/ml, Metoprolol succinate: 0.1647 µg/mlLOQ:Clinidipine: 0.16058 µg/ml, Metoprolol succinate: 0.4993 µg/ml

At 223.40 nm wavelength:

Correlation coefficient: Clinidipine: 0.9995, Metoprolol succinate: 0.9998LOD: Clinidipine: 0.0909 µg/ml, Metoprolol succinate: 0.1281 µg/mlLOQ:Clinidipine: 0.2757 µg/ml, Metoprolol succinate: 0.3884 µg/ml

 34
12 Clnidipine and Metoprolol succinate in bulk drugs and Tablet dosage form by RP-HPLC Method

 

 Detection wavelength: 225 nm Solvent: Water and Methanol (50:50) Mobile phase: Buffer (0.1%OPA): Methanol (45:55 v/v)

Stationary Phase: Altima C18 (4.6 × 150mm, 5μm) column

Flow Rate: 1 ml/min Linearity Range: Metoprolol Succinate: 12.5-75μg/ml, Clnidipine: 5-30μg/ml

Retention Time:

Metoprolol Succinate: 2.249 min, Clnidipine: 3.062 min

Correlation co-efficient:

Metoprolol succinate: 0.9995, Clnidipine: 0.9992

 35
13 Clnidipine and Metoprolol succinate in combined dosage form by HPTLC Method Solvent: Methanol, Detection Wavelength: 231 nm

Mobile phase: Toluene: Chloroform: Methanol: Glacial acetic acid (45: 25: 25: 5 v/v/v/v)

Stationary Phase: Silica Gel G60 F254 TLC plate

Linearity Range: Clnidipine: 100-500μg/ml, Metoprolol succinate: 500-2500 μg/ml

Rf Value: Clnidipine: 0.70 ± 0.01, Metoprolol succinate: 0.34 ± 0.005Correlation co-efficient: Clnidipine: 0.9954, Metoprolol succinate: 0.9991LOD: Clnidipine: 4.936001 μg/ml,

Metoprolol succinate: 4.936001μg/mlLOQ: Clnidipine: 27.18213 μg/ml, Metoprolol succinate: 82.3701μg/ml

 36
14 Metoprolol Succinate and Amlodipine in Tablet Dosage Form by RP-HPLC Method Detection wavelength: 221 nmSolvent: 0.02 M phosphate buffer solution: acetonitrile (70:30v/v, pH 3.0)

Mobile phase: 0.02 M phosphate buffer solution: acetonitrile (70:30v/v, pH 3.0) Stationary Phase: KromasilC18 (250 x 4.6 mm, 5 µm) columnFlow Rate: 1 ml/min

Linearity Range: Metoprolol Succinate: 10-110 µg/ml, Amlodipine: 10-110 µg/mlRetention Time: Metoprolol Succinate: 4.49 min, Amlodipine: 2.57 minCorrelation coefficient: Metoprolol Succinate: 0.9992, Amlodipine: 0.9991

LOD: Metoprolol succinate: 0.025 µg/ml, Amlodipine: 0.029 µg/mlLOQ: Metoprolol succinate: 0.075 µg/ml, Amlodipine: 0.090 µg/ml

 37
15 Amlodipine besylate and Metoprolol succinate in bulk and Tablets by HPTLC Method Solvent: Methanol, Detection Wavelength: 254 nm,

Mobile phase: Toluene: Ethyl acetate: Methanol: Triethylamine (4:1:1:0.4 v/v/v)Stationary Phase: Precoated silica gel aluminium plate 60 F254 (10×10 cm)Linearity Range: Amlodipine besylate: 400-1400 ng/spot, Metoprolol succinate: 3800-13300 ng/spot

Rf Value: Amlodipine besylate: 0.39, Metoprolol succinate: 0.59

Correlation co-efficient: Amlodipine besylate: 0.9990±0.0013

Metoprolol succinate: 0.9993±0.0013LOD: Amlodipine besylate: 39.99 ng/spot, Metoprolol succinate: 121.20 ng/spot

LOQ: Amlodipine besylate: 234.31 ng/spot, Metoprolol succinate: 710.03 ng/spot

 38
16 Telmisartan and Metoprolol Succinate in Tablet Dosage Form by Stability Indicating HPLC Method Solvent: Methanol, Detection Wavelength: 223 nm

Mobile phase: Methanol: 10 mM potassium dihydrogen phosphate buffer: 10 mM hexane sulphonic acid (80:10:10 v/v/v)

Stationary Phase: HiQ Sil C18 (250 × 4.6 mm, 5 µm) column

Linearity Range: Telmesartan:5-60 µg/mL, Metoprolol succinate: 5-80 µg/mL Flow rate: 1 ml/min

Retention time:

Telmesartan: 5.653 min, Metoprolol succinate: 3.067 min

Correlation co-efficient:

Telmesartan: 0.9980, Metoprolol succinate: 0.9990

 39
17 Telmisartan and Metoprolol succinate in Pharmaceutical formulation by Normal and Reversed-Phase HPTLC Method Normal Phase HPTLC Method:

Solvent: Methanol, Detection Wavelength: 242 nm

Linearity Range: Telmisartan: 800–3200 ng/band,

Metoprolol succinate: 1600– 6400 ng/spot

Mobile phase: Toluene: Propanol: Methanol: Triethylamine (8: 1: 1: 0.5 v/v)

Stationary Phase: Precoated silica gel aluminium plate 60 F254

Rf Value:

Telmisartan: 0.45 ± 0.02, Metoprolol succinate: 0.70 ± 0.02

Correlation co-efficient:

Telmisartan: 0.997, Metoprolol succinate: 0.997

LOD:

Telmisartan: 2.79 ng/spot, Metoprolol succinate: 58.69 ng/spot

LOQ:

Telmisartan: 8.45 ng/spot, Metoprolol succinate: 177.86 ng/spot

Reversed-Phase HPTLC Method

Solvent: Methanol,Detection Wavelength: 242 nm

Linearity Range: Telmisartan: 800–3200 ng/band,

Metoprolol succinate: 1600– 6400 ng/spot

Mobile phase: Methanol: Water: Triethylamine (6: 4: 0.5 v/v)

Stationary Phase: RP-18 silica gel 60 F254S

Rf Value:

Telmisartan: 0.55 ± 0.02, Metoprolol succinate: 0.41 ± 0.02

Correlation co-efficient:

Amlodipine besylate: 0.996, Metoprolol succinate: 0.998

LOD: Amlodipine besylate: 43.97 ng/spot,

Metoprolol succinate: 64.18 ng/spot

LOQ: Amlodipine besylate: 133.26 ng/spot

Metoprolol succinate: 194.49 ng/spot

 40
18 Atorvastatin Calcium and Metoprolol Succinate in Capsules by HPTLC Method Solvent: Methanol,Detection Wavelength: 276 nm

Mobile phase: Toluene: Methanol: Ethyl acetate: Glacial acetic acid (7: 1.5: 1: 0.5 v/v/v/v)

Stationary Phase: Precoated silica gel aluminium plate 60 F254

Linearity Range: Atorvastatin: 500–3000 ng/band

Metoprolol succinate: 1000-6000 ng/spot

Rf Value:

Atorvastatin: 0.28 ± 0.1, Metoprolol succinate: 0.58 ± 0.1

Correlation co-efficient:

Atorvastatin: 0.9974, Metoprolol succinate: 0.9927

LOD:

Atorvastatin: 15.001 ng, Metoprolol succinate: 45.457 ng

LOQ:

Atorvastatin: 78.736 ng, Metoprolol succinate: 238.595 ng

 41
19 Atorvastatin Calcium and Metoprolol Succinate, Ramipril in Capsules by Stability-Indicating RP-UPLC Method Solvent: Methanol, Detection Wavelength: 210 nm

Mobile phase: 0.0045 M Sodium lauryl sulphate as buffer, at ratio of buffer: Acetonitrile (50:50 v/v)

Stationary Phase: Zorbax® XDB-C18 (4.6 mm × 50 mm, 1.8 μm) column Flow rate: 1 ml/min

Retention time: Ramipril: 2.6 min, Atorvastatin: 2.1 min, Metoprolol succinate: 1.3 min

Degradation:

Thermal: (Dry heat): heated at 105º C for 15 Hrs, %Degradation: 33.5% for RAM, 32.3% ATV

Humidity: 25 º C, 90% RH for 7 days

Photo degradation:(U.V.) in Photostability chamber equipped with UV light with energy of 200 Watt-hours/square meter for 24 hr(In Visible light)in Photostability chamber equipped with Fluorescence light illumination not less than 1.2 million lux hours for 24 hrs

Acid: 0.1 N HCl Refluxed at 60 º C

for 30 min, %Degradation: 2.7% for MET

Alkali: 0.1 N NaOH Refluxed at 60 º C for 30 min, %Degradation: 2.6% for RAM

Oxidation: 3 % H2O2Refluxed at 60 º C for 30 min, %Degradation: 4.8% for RAM, 2.2% ATV

Purified Water: 60 º C for 1 hr

Degradation was not observed in visible light, UV, humidity and water hydrolysis stress studies. Significant degradation was not shown in acid hydrolysis, base hydrolysis and oxidative conditions.  However, thermal stress showed significant degradation.

 42
20 Ivabradine, Roboxetine and Metoprolol in Human plasma by UPLC-MS/MS Method Internal Standard:Deuterium-labeled drugs (d3- ivabradine, d5-reboxetine and d7-metoprolol), Flow rate: 0.5 ml/min

Mobile phase: mixture of water and methanol, each containing 2 mM ammonium acetate

Stationary Phase: Waters ACQUITY BEH C18 column (50 mm × 2.1 mm i.d., 1.7 m particle size)

Linearity Range:

Ivabradine: 1 ng/mL to 500 ng/mL, Metoprolol: 1 ng/mL to 500 ng/mL,Roboxetine: 1 ng/mL to 500 ng/mL

Retention time:

Ivabradine: 2.1 min, Metoprolol: 1.8 min, Roboxetine: 2.6 min

 43
21 Ivabradine and Metoprolol in bulk and tablet dosage form by Stability Indicating RP-HPLC Method Detection wavelength: 260 nm, Solvent: ACN: Water (60:40)

Mobile phase: Orthophosphoric acid (0.1%) buffer: acetonitrile (60:40 V/V)

Stationary Phase: Denali C18 column of dimension 150 mm × 4.6 mm, 5 μm

Flow Rate: 0.8 ml/min, Run Time: 6 min

Linearity Range:

Ivabradine: 5-30 µg/mL, Metoprolol: 25-150 µg/mL

Retention Time:

Ivabradine: 2.290 min, Metoprolol: 3.520 min

Correlation coefficient:

Ivabradine: 0.9993, Metoprolol Succinate: 0.999

LOD: Ivabradine: 0.38 µg/ml, Metoprolol: 0.27 µg/ml

LOQ: Ivabradine: 0.69 µg/ml, Metoprolol: 0.71 µg/ml

Degradation:

Dry heat: heated at 90º C for 1Hr Acid: 2 N HCl boil for 1 hr

%Degradation: 0.455% Rt: 2.655 min

Alkali: 2 N NaOH boil for 1 hr

%Degradation: 0.586% Rt: 4.05 min

Oxidation: 30 % H2O2 boil for 1 hr, %Degradation: 1.453% Rt: 2.655 min and 3.327% Rt: 5.072

Marked Degradation was observed in Acidic, Alkaline and Oxidation condition

 44

CONCLUSION: This review depicts the reported Spectroscopic and Chromatographic methods developed and validated for the estimation of Ivabradine and Metoprolol. Literature review reveals that there are various spectroscopic and chromatographic methods available for the estimation of Ivabradine and Metoprolol alone and in combination with other drugs. HPLC and HPTLC methods were found to be very common. Ivabradine in combination with Metoprolol and Roboxetine was estimated by UPLC/MS-MS method in human plasma. Recently an article on the stability-indicating HPLC method was published for estimation of Ivabradine and Metoprolol in their combined dosage form. There is only one reported method for Ivabradine and Metoprolol in their combined dosage form. So, there will be a great scope for the development of highly precise, accurate and simple analytical methods for newly developed combined dosage form of Ivabradine and Metoprolol.

ACKNOWLEDGEMENT: Nil

CONFLICTS OF INTEREST: Nil

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    How to cite this article:

    Gandhi NK and Ezhava SB: Ivabradine and metoprolol: a review of analytical methods for pharmaceutical quality control and monitoring. Int J Pharm Sci & Res 2021; 12(12): 6221-32. doi: 10.13040/IJPSR.0975-8232.12(12).6221-32.

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IJPSR

N. K. Gandhi * and S. B. Ezhava

Department of Pharmaceutical Chemistry, L. M. College of Pharmacy, Ahmedabad, Gujarat, India.

noopursana@gmail.com

09 December 2020

05 May 2021

28 May 2021

10.13040/IJPSR.0975-8232.12(12).6221-32

01 December 2021

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