1. INTRODUCTION:

Hypertension is a condition in which the force of blood against the artery wall is too high usually systolic blood pressure greaterthan 140mm Hg or diastolic blood pressure greater than 90mm Hg or both over a sustained period. Hypertension is habitual heart disease; it is generally increased with ageing. Pre-hypertension produce pathological changes in the vascularization and hypertrophy of the left ventricle. Stroke and Heart failure is the main risk factor of hypertension. Increase Peripheral resistance gives increase blood pressure.

The more chances of heart disease in adults are moderate with systolic BP <120mm Hg and diastolic BP <80mm Hg and High rising systolic and diastolic BP is increasing gradually. Hypertension is common disease all over the world¹.

1.1 Analytical method development:

In the Pharmaceutical industry Qualitative and Quantitative determination of drugs, API, Raw materials, and biological samples, there are Analytical methods used such asspectrometry and chromatography. These methods used to ensure the identity, purity, potency and performance of drugs. Analytical method development plays the main roles in the development and manufacture of pharmaceuticals.

Basic requirements for new method development for drugs analysis are the drug or drugs should not be official in any pharmacopoeia, a proper analytical process for the drugs must be not available in the literature due to patent regulations., Analytical methods for a drug in combination with other drugs must not be available and the exiting analytical procedure may require costly reagents and solvents.

The number of drugs entered in the market is growing every year. These drugs can be either new established or limited structural modification of the leaving one. Usually, there is a delay from the launch of a drug into the market to its addition in pharmacopoeias. This occurs because of the possible unpredictability in the continuous and broad utilization of these drugs, reports of new toxicities, growth of patient resistance and development of greater drugs by the challenger. So, standards and analytical procedures for these drugs may not be available in the pharmacopoeias. Hence, it needed to develop the latest analytical methods for such drugs². Scope of development of the analytical method is generally dealing with a detailed explanation of the analytical procedure. An analytical method covers all dominant operational parameters and specific requirements³.

There are several steps included in method development:

· Physiochemical properties of drugs

· Extraction of analyte

· Set up instrumental conditions

· Sample preparation

· Method optimization

· Validation of the developed method

1.2 Validation of analytical method:

Validation plays rolea in demonstrating that any procedure, process, method, equipment, material, activityas expected under a given set of circumstances. The process by which it’s developed, by laboratory studies that the performance specifications of the process connect the need for the deliberatedanalytical application. Analytical procedure mentions that how to perform the analysis. It gives details about every step to conduct all analytical tests. The purpose of validation is that an analytical procedure is to demonstrate that is suitable for its intended use. There is main four types of procedure to be validated are Identification test, Quantitative test, limit test and qualitative test^4,5. According to ICH Q2 (R1) guidelines analytical method was developed and validated by using various parameters^,6. Method development is a moderate and very difficult procedure. For method development labs require estimating a combination of mobile phase, temperature, pH, column and gradient to produce precise and accurate separation for all activity⁷.

The characteristicsof analytical method validation are⁵:

· Accuracy

· Specificity

· Linearity

· Range

· Precision

· Limit of detection

· Limit of quantification

· Robustness

1.3 Introduction of Stability Study:

Stability study provides evidence on how the quality of drugs varies with time under the influence of temperature, light and humidity. It develops a re-test period for the drugs or shelf life for the drug product. It suggested storage conditions as well as to identify degradation products with the help of stress study, which can in turn support to develop the degradation pathways and the intrinsic stability of the molecule and developing and validating suitable analytical procedures. Stress testing is performed on an individual batch of the drug substance. It must coverthe effect of temperatures [in 10°C increments (e.g., 50°C, 60°C, etc.) above that for accelerated testing], humidity (e.g., 75% RH or greater), oxidation, photolysis and also to check the susceptibility to hydrolysis over a broad range of Ph values wherein solution or suspension. The essential part of the stability study is the photostability study, which is explained in ICH Q1B⁸. The ICH guideline defined that stress testing is a device that enhance the divination of stability problems, development of analytical methods, as well as, the identification of the degradation products and pathways⁹.

Generally forced degradation/stress testing is employed to get the samples for stability-indicating assay methods. It is stability testing for drug material and pharmaceutical products under specific conditions those useful for accelerated stability testing is called as forced degradation study or stress testing¹⁰. In this step, forced degradation studies have been initiated to degrade the sample such as pharmaceutical drugs or API or drug material deliberating¹¹.

Forced degradation studies depend upon the product and the type of dosage forms. Solid, liquid and injection dosage forms have a different process for the stability study. It helps to know about the impurities during the storage of drug products in various environmental conditions¹². To demonstrate the method which can be accomplished to estimate accurately active pharmaceutical ingredient in exitance of degradants which are anticipated to be formed during different types of degradations applied to the drug sample¹³.9Various stress conditions are explained in ICH guidelines like Acid/Base hydrolysis, Heat, Oxidation, Humidity and light exposure. The limit of degradation is 5-20%, more than 20% degradation is abnormal and must be investigated¹⁴.

Telmisartan is widely used antihypertensive drug, belongs to a group of Angiotensin II Receptor Blockers (ARBs)¹⁵. Telmisartan isan angiotensin II receptor antagonist agent. It blocks vasocontraction and aldosterone secretion. Telmisartan is a non-peptide molecule and chemically described as 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d]imidazol]-3'-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid¹⁶. The structure is illustrated in figure 1.

Figure 1 Structure of Telmisartan

Azelnidipine is a novel calcium channel blocking agent. In hypertension treatment calcium channel blockers (eg.Azelnidipine) are play important role¹⁷. It chemically described as 3-(1-benzhydrylazetidin-3-yl) 5-isopropyl 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, it is a new dihydropyridine derivative with calcium antagonistic activity. Azelnidipine has blocked trans membrane Ca+2 influx through the voltage-dependent channels of smooth muscle in vascular walls and gives angiogenesis. It is indicated in the treatment of hypertension and angina pectoris¹⁸. The structure is illustrated in figure 2.

Figure 1 Structure of Azelnidipine

2.1 Mechanism of action of Azelnidipine (AZEL):

Azelnidipine is a novel Ca+2 channel blocker thatsuppresses transmembrane Ca+2 influx in vascular walls. It increases the level of Ca2+ gives increases contraction and blood pressure Normally, calcium induces smooth muscle contraction, contributing to hypertension. When calcium channels are blocked, then it producing decreased BP. Azelnidipine is induced NF-κB activation. Azelnidipine induced protein kinase C (PKC) activation, which then increases the secretion of VEGF, VEGF secretion directly induced HCEC tube formation via KDR/FIK-I. Azelnidipine have molecular effects with ANGIOGENESIS²².

2.2 Mechanism of action of Telmisartan (TEL):

Telmisartan is an AT1 blocker. It suppresses the activities of angiotensin II. When angiotensin II binds to AT1 receptors in the heart then it stimulates the heart.

Figure 3 Mechanism action of Azelnidipine

In the case of in blood vessel it gives vasoconstriction, in the case of in kidney then it causes renal sodium and fluid retention, in case of in adrenal cortex then it releases of aldosterone, these activities cause an increase in blood pressure. Angiotensin I forming Angiotensin II is catalyzed byACE, kininase II. It has a PPAR-y agonist activity²³. Telmisartan is a non peptide molecule. It has considerable affinity for AT1 receptor than AT2 receptor²⁴.

Figure 3 Mechanism action of Telmisartan

2.3 Active pharmaceutical ingredient

Table 2 Active pharmaceutical ingredient

Sr. No	API	Manufacture
1	Azelnidipine	Kimia Biosciences ltd Delhi
2	Telmisartan	Vasudha Pharmaceutical ltd, Hyderabad

2.4 Marketed formulation:

Table 3 Marketed Formulation

Sr. No	Marketed formulation (Tablet)	Manufacturer
1	Azelnidipine + Telmisartan (Telma-AZ)	Glenmark Pharmaceuticals, Dahej, Gujarat

3. COMPENDIAL METHODS:

Azelnidipine is official in Indian pharmacopoeia (IP-2018) described chromatographic method, Japanese pharmacopoeia (2016) described potentiometric titration. Telmisartan is official in US Pharmacopeia (Revision bulletin official in Dec 1, 2014).

4. ANALYTICAL METHODS:

(LITERATURE REVIEW):

These all are the methods that are used for the estimation of Azelnidipine and Telmisartan in the marketed formulation and pharmaceutical dosage forms. Analytical methods are described which are identified during the literature survey. Various U.V, NMR, MASS, IR spectroscopic, HPLC, UPLC, HPTLC, TLC, LC/MS, and other analytical methods for simultaneous estimation of Azelnidipine, Telmisartan in single determination and its combination with other drugs have been reported. Below describes the several methods with the method description and condition which are reported on review literature.

Reported methods:

UV Spectroscpic and Chromatographic methods:

Various U.V. spectroscopic and chromatographic methods for determination of Azelnidipine and Telmisartan single and its combination with other drugs have been reported:

Rele R. V, Patil S.P, Specifies that “Ultra-Violet Spectrophotometric Method for Estimation of Azelnidipine from Bulk Drug and Pharmaceutical Formulation”. Methanol is used as a solvent. It was estimated at 224nm for the UV- spectrophotometric method^25.

D. Prabhakar, J. Shreekanth, K.N. Jatveera specifies that “Method Development and Validation of Azelnidipine by RP-HPLC”. The methanol is used as a solvent. It was estimated at 254nm for the UV-spectrophotometric method²⁶.

Akshaya R Rane, Dr Sunil K Mahajan specifies that “Validation and forced stability indicating HPTLC method for determination of Azelnidipine”. The Chloroform, Ethyl Acetate and Methanol is used as a solvent. It was estimated at 255nm for the UV-spectrophotometric method²⁷.

Janisha Modi, Shivangi K Patel reveals that “Stability indicating analytical method development and validation for estimation of Azelnidipine”. The Sodium diabasic Phosphate Buffer, Acetonitrile and Methanol is used as a solvent. It was estimated at 257 nm for the UV-spectrophotometric method. The flow rate is 1ml/min²⁸.

S. Junehha, P. Venkateshvarlu, P.S.S Prasad specifies that Sensitive Analysis of Azelnidipine and Related Derivative in Human Plasma by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry. Ammonium acetate and formic acid are used as a solvent. The flow rate is 0.1ml/min²⁹.

Ravindra Babu Ganduri, Jaychandra Raddy, Himabindu Virumindi, Ramprakash, specifies that Stability indicating LC method for determination of Azelnidipine and Olmesartan medoximil incombine tablet dosage form. The Potassium dihydrogen phosphate buffer and Acetonitrile (20 :80) is used as a solvent. It was estimated at 255nm for UV-spectrophotometric method. The flow rate is 2ml/min³⁰.

Alaa El Sayed Ahmed Amin, Mounir Zaky Saad, Mohamed Aly Amin Ahmed, specifies that Simultaneous Determination of Azelnidipine and Olmesartan Medoxomil in Pharmaceutical Dosage Forms by UFLC Method. Methanol is used as a solvent. It was estimated at 257nm for UV-spectrophotometric method. The flow rate is 1ml/min³¹.

Nilam Patela, Jayvadan K. Patelb reveals that Simultaneous Determination of Azelnidipine and Olmesartan medoxomil by First Derivative Spectrophotometric Method. Methanol is used as a solvent. It was estimated at 239.4nm of Azelnidipine and 217nm of Olmesartan Medoxomil³².

Kishanta Kumar Pradhan, Uma Shankar Mishra, Aurobindo Sahoo, Kanhu Charana Sahu, Debananda Mishra, Ranjit Dash specifies that Method development and validation of Telmisartan in bulk and pharmaceutical dosage forms by UV Spectrophotometric method. Methanol is used as a solvent. It was estimated at 298nm for UV-spectrophotometric method³³.

M. Lakshmi Surekha, G. Kumara Swamy, G. Lakshmi Ashwini specifies that Development and Validation of RP-HPLC method for the estimation of Telmisartan inbulk and tablet dosage Form. The Triethyl amine and Methanol (40:60) is used as solvent. It was estimated at 230nm. The flow rate is 1.2ml/min³⁴.

Chitra Prabhu, Ganesa Sundararajan Subramanian, Arumugam Karthik, Suvarna Kini, Mallayasamy Surulivel Rajan, Nayanabhirama Udupa specifies that Determination of Telmisartan by HPTLC–A Stability Indicating Assay. The chloroform and methanol (8.6:1.4) is used as solvent. It was estimated at 297 nm³⁵.

Lalit Thakare, Sufiyan Ahmad reveals that UV spectrophotometric method for the determination of Cilnidipine (CIL) and Telmisartan (TEL) in bulk drug and pharmaceutical dosage form. The solvent Acetonitrile and water (90:10) is used as solvent³⁶.

Reema H. Rupareliya and Hitendra S. Joshi specifies that “HPTLC method for the determination of Cilnidipine and Telmisartan in bulk drug and pharmaceutical dosage form”. The Toluene, Methanol and Ethylacetate (8:2:1) is used as solvent. It was estimated at 230nm³⁷.

A.R. Chabukswar, S.C. Jagdale, S.V. Kumbhar, D.J. Desai, B.S. Kuchekar, P.D. Lokhande specifies that “Stability Indicating Simultaneous Validation of Telmisartan and Cilnidipine with Forced Degradation behavior Study by RP-HPLC in Tablet Dosage Form”. The monobasic dehydrate buffer pH 3.0 and phosphoric acid (68:32). It was estimated at 245nm. The flow rate is 1ml/min³⁸.

Santosh Kumar M, Venkanteshwar Rao Jupally specifies that HPLC Method Development for Telmisartan and Amlodipine, The Acetonitrile, Methanol and Triethylamine buffer, PH 5.0 adjusted with O-Phosphoric acid is used as a solvent. It was estimated at 237nm. The flow rate is 1.5ml/min. TheTailing factor was found to be amlodipine and telmisartan was 1.85 and 1.48³⁹.

Kaliappan Ilango1 and Pushpangadhan S. Shiji Kumar specify that Development and Validation of RP – HPLC method for the estimation of Telmisartan and amlodipine in bulk and tablet dosage form. The Buffer and Acetonitrile (60:40) is used as a solvent. It was estimated at 234nm. The flow rate is 1ml/min⁴⁰.

P. Gayathr, K.N. Jayaveera, Sasikiran Goud and N. Sravan Reddy specifies that Development and Validation of Stability Indicating HPTLC and HPLC Methods for Simultaneous Determination of Telmisartan and Atorvastatin in Their Formulations. In the HPLC Mobile Phase was taken acetonitrile and 0.025M ammonium acetate (38:52), Detection Wavelength was estimated at 281nm and the Flow rate is 1ml/min. In HPTLC method, Mobile Phase was toluene, methanol, ethyl acetate and acetic acid (5: 1: 1: 0.3), Detection Wavelength was estimated at 279nm and Rf value was found 0.37±0.02 TLM and 0.63±0.01 ATR⁴¹.

A. Shashi Kumari, P. Sunil Kumar Chaitanya, G. Rohini Reddy and Jomol Joseph P. Naga Haritha specifies that Development and Validation of RP -HPLC method for the estimation of Telmisartan andmetformin in bulk and tablet dosage form. The Mobile Phase was taken Buffer, Acetonitrile and Methanol (35:55:1), Detection Wavelength was estimated at 237nm and Flow rate was kept at 1ml/min⁴².

Binalben S. Patel, Dr. Shailesh V. Luhar, Dr. Sachin B. Narkhede specifies that “Development and validation of an analytical method for simultaneous estimation of telmisartan and ramipril using reverse phase HPLC in bulk and dosage form”. The Mobile Phase was taken mixed phosphate buffer (pH3.0), CAN and Methanol (20:50:30v/v/v%), Detection Wavelength was estimated at 220nm, Flow rate: 1ml/min and Retention Time was observed in Telmisartan: 3.033 and Ramipril: 4.003⁴³.

RlcSasidhari, S. Vidyadharai, B. Deepti, K. Tejaswi and J. Suhasinispecifies that Method Development and Validation of RP–HPLC method for the estimation of Telmisartan, Clinidipine and metoprolol succinate in bulk and tablet dosage form. The mobile phase was taken a mixture of Phosphate buffer (pH3.0), Acetonitrile and pH adjusted with 0.5% orthophosphoric acid, Detection Wavelength was found in CIL: 241 nm, TEL: 296 nm and MET: 224nm and Flow rate were kept at 1ml/min⁴⁴.

Bhoomi D. Patel, Ankit Chaudhary, Sudhir Gami specifies that Development and Validation of RP - HPLC Method for the Simultaneous Determination of Hydrochlorothiazide, Amlodipine Besylate and Telmisartan in Bulk and Pharmaceutical Formulation. The acetonitrile and acetate buffer (60:40v/v%) is used as a solvent. It was estimated at 333nm. The flow rate was kept at 1ml/min⁴⁵.

N. Vanaja, Ch. Preethi, Dr. S.Y. Manjunath, Krishanu Pal specifies that RP-HPLC method for simultaneous estimation of Chlorthalidone, Telmisartan and Benidipine HCl in their Combined Dosage Form. The Buffer (pH 3.0) and Methanol (50:50 v/v) is used as a solvent. It was estimated at 230nm. The flow rate was kept at 1ml/min⁴⁶.

Shah Binal B, Patel Bhoomi B, Gohil Kirtan N, Patel Piyush M specifies that Method Development and Validation for Simultaneous Estimation of Telmisartan and Chlorthalidone by RP-HPLC in Pharmaceutical Dosage Form. The Potassium di hydrogen orthophosphate buffer, Acetonitrile and Methanol (35:45:20 pH 3.5 adjusted with OPA) is used as solvent. It was estimated at 333nm. The flow rate was kept at 0.8ml/min. Retention Time was observed of Telmisartan: 4.937 min and Chlorthalidone: 3.640min⁴⁷.

Jain Nilesh, Sharma Bhupendra Kumar, Jain Ruchi, Jain Deepak Kumar andJain Surendra, specifies that Difference Spectrophotometric Method Development and Validation for Simultaneous Estimation of Rosuvastatin Calcium and Telmisartan in Bulk and Combined Dosage Form. Methanol is used as solvent⁴⁸.

Aashka Joshi, Dr. C. N. Patel specifies that RP-HPLC Method Development and Validation form Quantitative Estimation of Metoprolol Succinate and Telmisartan in Bulk Drug and Their Dosage Forms. The acetonitrile, methanol and phosphate buffer pH-5 (35:35:30 % v/v/v) is used as a solvent. It was estimated at 225nm. The flow rate was set at a 1ml/min. Retention Time was observed for Telmisartan: 4.68±0.5 min and Metoprolol succinate:2.57±0.5 min⁴⁹.

Dharmendra Damor, Karan Mittal, Bhoomi Patel, RajashreeMashru specifies that stability indicating RP-HPLC method developed for the determination of Nebivolol and Telmisartan in its combined pharmaceutical dosage form. The Acetonitrile and 0.05M (pH 6.5) Disodiumhydrogen buffer are used as a solvent. It was estimated at 235nm. The flow rate was set at a 1ml/min⁵⁰.

Zeel T. Doshi, Jignesh S. Shah1, Dilip G. Maheshwari specifies that UV-Visible methods were developed and validated for the estimation of Cilostazol and Telmisartan in synthetic mixture. The water, acetonitrile and methanol are used as a solvent. CIT and TEL were found to be at 258nm and 237.5nm⁵¹.

Dhanalakshmi K, Tatineni Vasuki, Nagarjuna reddy, Jotheiswari D specifies that Development and Validation RP-HPLC Method for Simultaneous Estimation of Telmisartan and Nifedipine In Synthetic Mixture. The CAN, Water and Methanol (10:20:70 v/v/v) is used as a solvent. It was estimated at 234nm. The flow rate was kept at 1ml/min⁵².

Jayesh G. Panchal, Ravindra V. Patel, Bhoomika R. Mistry, Shobhana K. Menon specifies that RP-HPLC method has been developed and validated for the analysis of Telmisartan and Hydrochlorothiazide in tablet formulation. The solvent was used as Ammonium phosphate buffer and Acetonitrile (60:40 v/v). It was estimated at 270nm. The flow rate was set at 1.5ml/min⁵³.

Hassan A. Alhazmi, Ahmed M. Alnami, Mohammed A. A. Arishi, Raad K. Alameer, Mohammed Al Bratty, Zia ur Rehman, Sadique A. Javed, smail A. Arbab, specifies that Development and Validation of Reversed-Phase LC Method for Simultaneous Determination Telmisartan, Amlodipine and Their Degradation Products in Fixed Dose Combination Tablets. The potassium di-hydrogen orthophosphate buffer and acetonitrile (65:35 v/v) is used as a solvent. It was estimated at 238nm. The flow rate was kept at 1ml/min⁵⁴.

Jenisha Modi, Shivangi K Patel, A Fast and Validated Reversed-Phase HPLC Method for Simultaneous Determination ofSimvastatin, Atorvastatin, Telmisartan and Irbesartan in Bulk Drugs and Tablet formulations. The ammonium acetate buffer and acetonitrile (40:60) is used as a solvent. It was estimated at 220nm. The flow rate was set at a 1ml/min⁵⁵.

5. DISCUSSION:

The presented review highlights various analytical methods reported for estimation of Azelnidipine and Telmisartan alone or in combination with Other drugs in marketed formulation. RP-HPLC and UV methods were found to be the most widely used methods. These methods are found to be rapid, accurate, sensitive, economical and reproducible for the determination of Azelnidipine and Telmisartan in various marketed formulations.

6. CONCLUSION:

So, from all the above information it should be concluded that numerous spectroscopic methods, chromatographic methods and other methods were used for the estimation of Azelnidipine and Telmisartan alone or in combination with other drugs. But no any analytical method is available till date for the simultaneous estimation of Azelnidipine and Telmisartan combination. So there is an ample opportunity to develop and validate an analytical mehod for simultaneous estimation of this combination and also researcher can also develop stability indicating method for this combination.

7. CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 17.04.2021 Modified on 07.05.2021

Asian J. Pharm. Ana. 2021; 11(3):227-234.

DOI: 10.52711/2231-5675.2021.00040

	AZELNIDIPINE	TELMISARTAN
Molecular Weight	582.646 g/mol	514.6169 g/mol
Molecular formula	C₃₃H₃₄N₄O₆	C₃₃H₃₀N₄O₂
Drug Category	Calcium channel blocker	Angiotensin-II receptor antagonists
Chemical name	3-(1-benzhydrylazetidin-3-yl) 5-isopropyl 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate	4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d]imidazol]-3'-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid
Melting point	122 – 123°C	261-263 °C
PKa	7.89	4.45
LogP	5.23	8.42
Λmax	255 nm	234 nm
Uses	Used as an antihypertensive agent	Used as an antihypertensive agent