METHOD DEVELOPMENT AND VALIDATION

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Slide 1 : SIMULTANEOUS ESTIMATION OF VALSARTAN AND HYDROCHLOROTHIAZIDE BY RP-HPLC By Ashish kumar gaur M.Pharm(p.Chem)
Slide 2 : CONTENTS INTRODUCTION LITERATURE REVIEW RESEARCH ENVISAGH PLAN OF WORK REFERENCES
Slide 3 : (1) INTRODUCTION Introduction of validation Introduction of hypertension Introduction of Drug profile
Slide 4 : INTRODUCTION OF VALIDATION Method validation is defined as the process of defining and proving an analytical method acceptable for its intended use. Method validation is the process used to confirm that the analytical procedure employed for a specific test is suitable for its intended use. The results obtained from method validation can be used for the quality improvement, reliability and consistency of analytical results. Analytical methods need to be validated before introduction into routine use. There are various parameters studied for Method Validation:- Precision / Reproducibility Accuracy Linearity Specificity / Selectivity Limit of detection Limit of quantitation Robustness / Ruggedness
Slide 5 : Precision:-  The precision of each method was ascertained separately from the peak areas. Accuracy: The accuracy of the method was established by studying the recovery.  Linearity & Range: The calibration curve showed good linearity in the range of 10 – 100 µg/ml. Specificity The specificity of the HPLC method was ascertained by analyzing standard drug and sample solutions.  LOD & LOQ: The Minimum concentration level at which the analyte can be reliable detected (LOD) & quantified (LOQ) were determined from the calibration curve and based on the standard deviation of intercepts and slope of the calibration curve. Method Robustness: Influence of small changes in chromatographic conditions such as change in flow rate (0.1ml/min), Temperature (200C), Wavelength of detection (2nm) & methanol content in mobile phase (2%) studied to determine the robustness of the method.
Slide 6 : High Performance Liquid Chromatography HPLC is a form of column chromatography used frequently in biochemistry and analytical chemistry to separate, identify and quantify compounds. HPLC utilizes a column that holds chromatographic packing material (stationary phase), a pump that moves the mobile phase through the column and a detector that shows the retention times (RT) of the molecules. RT variation depends on the interaction of stationary phase with the molecules being analyzed and use of different type of solvents to develop chromatogram. HPLC particularly RP-HPLC is the most popular analytical technique in the pharmaceutical industry. It is widely used for assay and impurity analysis in pharmaceutical quality control. The detector for method development is PDA detector because it can be used for both quantitative and qualitative analysis. The use of a PDA detector is to determine the peak purity of the active ingredient in the samples which greatly facilitates the method development.
Slide 7 : Figure 1.2: Waters HPLC System
Slide 8 : CHROMATOGRAPHY Chromatography is an analytical method that used for the separation, identification and determination of chemical components in complex mixtures. This technique is based on the separation of components in a mixture (the solute) due to the difference in migration rates of the components through a stationary phase by a gaseous or liquid mobile phase. Classification of chromatographic techniques :-
Slide 9 : Types of HPLC:- Normal Phase-HPLC Reverse Phase –HPLC Ion-Exchange Chromatography (IEC) Size-Exclusion Chromatography (SEC) Applications of hplc:- HPLC is used for chemistry and biochemistry research analyzing complex mixtures, purifying chemical compounds, and developing processes for synthesizing chemical compounds, isolating natural products, or predicting physical properties. HPLC can be used for particle separation based on the polarity of the elements in a sample. HPLC is a highly sensitive method of detection and quantification of any chemicals in a particular sample using ultraviolet and visible absorbance.
Slide 10 : INTRODUCTION OF HYPERTENSION:- Hypertension (HTN) or high blood pressure, sometimes called arterial hypertension, is a chronic medical condition in which the blood pressure in the arteries is elevated. This requires the heart to work harder than normal to circulate blood through the blood vessels. Hypertension is classified as either primary (essential) hypertension or secondary hypertension. (1) Primary (essential) hypertension:-It is the most common form of hypertension, accounting for 90–95% of all cases of hypertension. Hypertension results from a complex interaction of genes and environmental factors. Lifestyle factors that lower blood pressure, include reduced dietary salt intake, increased consumption of fruits and low fat products (Dietary Approaches to Stop Hypertension (DASH diet)), exercise, weight loss and reduced alcohol intake. (2) Secondary hypertension:- It results from an identifiable cause. Renal disease is the most common secondary cause of hypertension. Hypertension can also be caused by endocrine conditions, such as Cushing's syndrome, hyperthyroidism, hypothyroidism, acromegaly, Conn's syndrome or hyperaldosteronism, hyperparathyroidism and pheochromocytoma. Other causes of secondary hypertension include obesity, sleep apnea, pregnancy, excessive liquorice consumption and certain prescription medicines, herbal remedies and illegal drugs.
Slide 11 : Classification of antihypertensive drugs:-          
Slide 12 : Introduction of Drug profile Valsartan:-It is a drug comes under the category of angiotensin-II receptor antagonist. Angiotensin II receptor antagonist:- Angiotensin II receptor antagonists, also known as angiotensin receptor blockers (ARBs), AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system. Their main uses are in the treatment of hypertension (high blood pressure), diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure. Mechanism of action:- They act by blocking the activation of angiotensin II AT1 receptors. Blockage of AT1 receptors directly causes vasodilatation, reduces secretion of vasopressin, and reduces production and secretion of aldosterone, amongst other actions. The combined effect reduces blood pressure. Hydrochlorothiazide:-It is a drug comes under the category of thiazide diuretics. Diuretic:- A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.  Mechanism of action:- The antihypertensive actions of some diuretics (thiazides and loop diuretics in particular) are independent of their diuretic effect. That is, the reduction in blood pressure is not due to decreased blood volume resulting from increased urine production, but occurs through other mechanisms and at lower doses than that required to produce diuresis.
Slide 13 : Fig. I Structure of Valsartan  Chemical name- (S)-N-(1-Oxopentyl)-N-[[2’-(1H-tetrazol-5-yl)[1,1’biphenyl]-4-yl]methyl]-L-valine. It is non-peptide highly selective, a potent, orally active Angiotensin II receptor type 1 antagonist ( acting on the AT1Subtype) which causes reduction in blood pressure and is used in treatment of hypertension. It was first developed by Novartis Company. It is also available in combination with other antihypertensive drugs. Valsartan is soluble in acetonitrile and methanol. It is soluble in the neutral pH range. Monotherapy with Valsartan with 80 mg as the starting dose has shown considerable efficacy in patients with CHF and renal impairment along with hypertension. Fig. II Structure of Hydrochlorothiazide  Chemical name- 6-chloro-3, 4-dihydro-2H-1, 2, 4- benzothiadiazine- 7-sulfonamide-1, 1- dioxide.   It is a diuretic of the class of benzothiadiazines widely used in antihypertensive pharmaceutical formulations, alone or in combination with other drugs, which reduces blood volume by acting on the kidneys to reduce sodium (Na) reabsorption in the distal convoluted tubule. The major site of action in the nephron appears on an electroneutral Na+-Cl- co-transporter by competing for the chloride site on the transporter. Simultaneous determination of both drugs is highly desirable as this would allow more efficient generation of clinical data and could be more cost-effective than separate assays.
Slide 14 : (2) LITERATURE REVIEW In 2012, Gananadhamu Samanthula et al have done Development and Validation of a New RP-HPLC Method for the Estimation of Valsartan and Hydrochlorothiazide in Tablets and develop a simple, reproducible and efficient Reverse Phase High Performance Liquid Chromatography (RP-HPLC) method for the simultaneous estimation of Valsartan and Hydrochlorothiazide in tablets and the separation was achieved on Hypersil C18 column (250 cm length, 4.6 mm internal diameter and 5 µm particle size) with a mobile phase having a fixed composition of acetonitrile: 0.1M ammonium acetate buffer in the ratio of 55:45 v/v and at a flow rate was 1.0 ml/min and the effluent was monitored with UV detector at 254 nm in which the retention times for Valsartan and Hydrochlorothiazide were found to be 2.38 and 2.97 min. respectively. The linearity range for Valsartan and Hydrochlorothiazide were found 32-160 and 5-25 µg/ml respectively and the developed method was applied for quantitative determination of above drugs in tablet dosage forms and the method was found to be accurate, precise and selective for simultaneous estimation of Valsartan and Hydrochlorothiazide in tablets.  In 2011, Lakshmana Rao A.et al have done SIMULTANEOUS ESTIMATION OF VALSARTAN AND HYDROCHLOROTHIAZIDE IN TABLETS BY RP-HPLC METHOD and was developed a simple, reproducible and efficient reverse phase high performance liquid chromatographic method for simultaneous determination of valsartan and hydrochlorothiazide in tablets by using column having 100mmx4.6mm i.d. in isocratic mode with mobile phase containing Acetonitrile: Phosphate buffer (50:50; adjusted to pH 3.0) and the flow rate was 0.8 ml/min and effluent was monitored at 225 nm. The retention time (min) and linearity range (µg/ml) for valsartan and hydrochlorothiazide were found (5.59, 2.36) and (10-50, 10-50), respectively and the developed method was found to be accurate, precise and selective for simultaneous determination of valsartan and hydrochlorothiazide in tablets.
Slide 15 : (3) RESEARCH ENVISAGH The present study is based on the combination of two newer drugs of different class, which is angiotensin-II receptor antagonist and diuretics class drugs used in hypertension. These two drugs are given in combination to release the hypotension/ antihypertensive effect because renin is a enzyme which is responsible for the conversion of angiotensinogen to angiotensin-I (octapeptide) and further process and in this process angiotensin-II is prepared which is heptapeptide and responsible for sodium water retention which increases the blood volume and causes hypertension. The diuretics class of drugs acts on the rennin angiotensin system and angiotensin-II antagonist acts on the angiotensin-II receptor to produce the antihypertensive effect. So, this combination (valsartan & hydrochlorothiazide) is used to produce synergistic effect in hypertension.  After going through a literature review, it was observed that no HPLC analytical method has been developed for this combination till now. So, the present study is used to develop a method which is simple, précised, accurate and applicable for the studies of pharmaceutical dosages form of these two drugs.
Slide 16 : (4) PLAN OF WORK Method development Method Validation Method Application
Slide 17 : Method development      
Slide 18 : Method Validation
Slide 19 : Method Application To check the utility of developed and validated HPLC assay method by applying in analysis of valsartan and hydrochlorothiazide.
Slide 20 : REFERENCES (1) Patnaik Arabinda, “A New Rp-hplc Method For The Determination Of Valsartan In Bulk And Its Pharmaceutical Formulations With It’s Stability Indicative Studies”, Pharma Science Monitor An International Journal Of Pharmaceutical Sciences, vol-2, issue-3, 43-53, july-2011.   (2)Lakshmana Rao A., “Simultaneous Estimation Of Valsartan And Hydrochlorothiazide In Tablets By Rp-hplc Method”, International Journal Of Pharmacy & Industrial Research, vol-1,170-174,sept-2011   (3)Chaudhary Ankit B., “Estimation Of Valsartan And Hydrochlorothiazide In Pharmaceutical Dosage Forms By Absorption Ratio Method”, International Journal Of Applied Biology And Pharmaceutical Technology, volume: i: issue-2: 455-464, aug-oct-2010.   (4)Jothieswari D., “Design And Rp - Hplc Method For The Simultaneous Determination Of Valsartan And Hydrochlorothiazide In Bulk And In Pharmaceutical Formulation”, Internationl Journal Of Novel Trends In Pharmaceutical Scicences, volume 1 number 1 oct- 2011.  
Slide 21 : (5) Gananadhamu S., “Development And Validation Of A New Rp-hplc Method For The Estimation Of Valsartan And Hydrochlorothiazide In Tablets”, Ijpi’s Journal Of Analytical Chemistry, vol 2:8 ,13-19,oct-2012.   (6)Reddy N. Bodela, “Rp-hplc Method Development And Validation Of Valsartan Tablet Dosage Form”, Journal Of Chemical And Pharmaceutical Research,vol-2:4, 878-886,oct-2010.   (7)Pradhan K. Kishanta, “Method Development And Validation Of Valsartan In Bulk And Pharmaceutical Dosage Forms By Isocratic Rp- Hplc Technique”, International Journal Of Pharmaceutical Research & Development, vol 3(7), 201-208,2011.
Slide 22 : THANK YOU

 


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