REVIEW ARTICLE AN OVERVIEW OF IMPURITY PROFILING ON ANTIHYPERTENSIVE LIFE SAVING DRUGS BY USING RECENT HYPHENATED TECHNIQUE ABSTRACT: An extensive

survey of literature revealed for analytical methods published in various

analytical and pharmaceutical chemistry journals as well as reported in official compendia which have been employed to determination of known ,unknown, total impurities and degradation product of life saving antihypertensive drugs is discussed . All reported impurities and degradation products of antihypertensive drugs have been conducted by integrated approach of hyphenated technique such as HPLC-UV, LC-MS,LC-MS\MS and LC-NMR based on elucidate structure confirmation through differences in the retention time or elution behaviour with respect to the UV peak are proof of a coeluting impurity in HPLC and using LC-MS A change in the m/z ratio, resulting in peaks with identical retention to get correct molecular weight and mass fragmentation can even be attributed to impurities if they cannot be explained by the drug substance itself. Special attention is given on impurity profiling of pharmaceuticals since presence of impurity can have significant effect on their quality, safety and efficacy ,the testing and evaluation of impurities are important regulatory requirement which is mandatory to identify and characterize for pharmaceutical industries according to ICH requirements.

INTRODUCTION :Hypertension is one of the most prevalent diseases with an estimated one billion cases world wide . It is one of major common cardiovascular disorder in modern times with a multitude of etiological factors of various diseases like myocardial ischemia, cardiac failure, renal failure and stroke. According to WHO one third of Men and two fifth of Women over 40 years of age are hypertensive because as age increases there is pari-pasu increase in blood Pressure According to Food and Drug administration(FDA) Impurity may be defined as component found in drug that are neither drug substance nor excipients. It can arises either from manufacturing synthetic process or by degradation of finished product. So impurity

Profiling is excellent means to determine purity of final product and works as key function to the production of high purity of drug.[1] Whereas In term of degradation product are degradation of others compounds or decomposition material of interest or active ingredient that may present as impurity in drug substance. So identication of degradation products is also very effective for estimating the causes and pathways of the degradation of drug substances in pharmaceuticals.

The main purpose to write this review article on impurity profiling and degradation products of antihypertensive drugs because the presently critical attention is given on these aspect of pharmaceuticals by regulatory agencies as well by pharmaceutical industries As antihypertensive drugs are life saving drugs and its proper and correct dose is mandatory to get relief from hypertension. So impurity profiling is very essential for such class of drugs to assure safety and efficacy of drug product.[2] Till date no comprehensive review article has been published on the impurities and degradation products of antihypertensive drugs of different classes. Review also covers different analytical method which have been published in articles as well as reported in official compendia (Indian pharmacopeia ,United States Pharmacopeia , European pharmacopeia and British pharmacopeia). Moreover a comparative study also has been carried out on each type impurities such as specified impurity, unidentified other detectable and total impurities which have been identified by using HPLC, LC-MS\MS and LC-NMR hyphenated techniques

REGULATORY ASPECT OF IMPURITY AND DEGRADATION STUDY IN PHARMCEUTICAL PRODUCT

Most of pharmaceutical industry are following ICH guideline .This guideline has more than 20 quality guidelines.ICH Q3A(R)\Q3B(R) prescribes thresholds for reporting, qualification and identification of impurity in new drug substance and products based on the total daily intake of the relevant drug. Identification of impurities above 0.1% level in drug substance and 0.2% level in new drug product (for 50 mg max. daily dose ) has become an obligation It is mandatory for the manufacturer to identify and characterize all the unknown impurities that are present in it at a level as low as 0.05% [3-4] According to ICH , Any unspecified impurity with an acceptance criterion of not more than () in the identification threshold in table 1. Ma Less >2g. daily dose Rep Less or equal to 2g\day 0.05 > 2g\day 0.03 Reporting threshold Identiification threshold Identfication threshold Ide Qual 0.05% 0.10 0.10% or 1.0 mg\day 0.15 0.15% or 1.0 mg\day 0.03% (whi (whenever lower) 0.05 0.05% 0.0 s 0.05%

ICH Guidelines for identification and qualification of impurity in Bulk drug formulation table 2. Dose <1 <1mg 1-10 1-10mg 10-1 10-100mg 1001 100mg-2g >2g > 2g Thre Threshold for identification (%) ual Q 1.0d 1.0 1.0d 0.5 0.5 1.0h 0.2 h 0.2 0.5 c 0.1d 0.1 0.2d 0.1h 0.1 0.1d Qualification (%) 1.0 1.0 0.5 0.2 0.1

Threshold for reporting degradation products in a new drug product table 3. Max. daily dose 1g >1g Threshold for identification 0.1% 0.05%

For force degradation study ICH Q1A suggests such following condition can be employed [5-6] (i) (ii) 10 C increments above the accelerated temperatures (e.g. 50 C, 60 C,etc.), humidity where appropriate (e.g. 75% or greater),

(iii) hydrolysis across a wide range of pH values, (iv) oxidation and (v) photolysis.

IMPORTANCE OF IMPURITY IN PHARMCEUTICAL PRODUCT DEVELOPMENT

1.Controlling impurities in drug substance is an essential part of pharmaceutical development since presence of impurities in a drug substance may have significant impact on toxicology studies and drug safety. 2.The data obtained from impurity analyses are used to help the understanding of chemical reactions and processes, as well as to ensure conformance to specification 3.The discrepancy between the assay and impurity profile result are used further investigation to determine the cause of the low assay. 4. It is particularly important to investigate batches to be used in clinical trials and from the scale-up in order to maintain a state of constant impurity qualification. 5. Structured based approach, such as the presented impurity concept in combination with an integrated quality system may facilitate GMP aspect for an efficient drug development process[8]

SYSTEMATIC APPROACH FOR IDENTIFICATION OF IMPURITY AND DEGRADATION STUDY BY USING HYPHENATED TECHNIQUE

Most of active pharmaceutical ingredient (APIs) are produced by synthetic process so there may be chances of unwanted chemicals that may remains with APIs and could be generated at any stage during synthetic process like as impurity in last and start intermediate of synthesis, originate from solvent reactions and degradation product. The organic impurities present in the API could be process related impurities such as starting materials, intermediates, by-products, reagents, ligands, and process degradation products. They could also be formed as a result of degradation experienced under storage conditions. So many unidentified impurity could be produced at any stage during synthesis process and can be present in final drug substance which may cause unexpected side effects. But final intermediate stage may become rigorous during synthetic process since it is major source of potentials impurities which can entail with residual solvent as well as process related impurities which are demonstrated as degradant product. So it is very formidable to distinguish between the process-related impurities and degradation products in drug substance.[9]

So highly selective analytical technique is required which is capable to separate and quantify closely eluting impurities or degradation products .Different types of detectors are available for detection of impurities and degradation products. forced degradation studies are conducted by using different stress condition such as acid, neutral and alkaline hydrolysis, thermal and photo degradation according to ICH requirements to distinguish between process related impurity from degradation product. Finally Such type of impurity structure and degradation product can be predicted with the help of hyphenated techniques like LC-MS, LC-MS/MS and LC-NMR The data can be interpreted based on the fragmentation pattern for particular compound and structure can be confirmed by NMR and IR data. After confirmation of degradant produced by stress studies can be elucidate through matching Retention times in HPLC and by using LC-MS concerns about Msn fragment pattern and mass spectra according to change in m\z ratio can be attributed impurity even if do not explained by drug substance itself.[10]

UTILIZATION OF RECENT HYPHENATED ANALYTICAL TECHNIQUE IN IMPURITY MONITORING PROFILE

There has been various publication articles published on impurity profile and degradation study of antihypertensive drug using HPLC and hyphenated technique such as LC-MS\MS, LC-NMR technique which have been employed to identify and confirmation of known and unknown impurity and degradation product. HPLC is most frequently utilized as analytical technique is a well-established reliable technique used in controlling the quality and consistency of APIs.. It has detection limit of drug related impurity and degradation product are 0.1% or lower and result can be interpreted by difference retention times or elution behavior through U.V chromatograms for confirmation of co-eluted peak. [10] U.V. diode array detector or LCMS detections is used to check impurity peak co-elution with the main compound peak which having similar structure features, In Case of positional isomers , diastereomers, oxidative degradation products then there may be two condition of co-eluted peak .It may be either dissimilar UV spectra from two structural closely related compounds in un-saturated rings and oxidative of un-saturated rings Or similar UV spectra from two structural closely related compounds in most cases diastereomer or an N-oxidative on a saturated ring. then such type co-eluting impurities can be checked for peak purity [11] HPLC also provide facility for method optimizing change in mobile phase ratio, pH, Gradient elution , flow rate , temp., columns and its type for different class of drugs. Which are important for the development of an accurate, precise, reproducible, and rugged RP-HPLC impurity method [13]. However, sometimes impurities exhibit very weak or no response when detection is carried out by UV detection. To overcome this problems hyphenated technique are using in pharmaceutical industry LC-MS and LC-NMR. based on high sensitivity, resolution capacity, specificity and selectivity to Characterize ,identify and quantify individual impurity in order to make sure that assign molecular Weight of component ,structure confirmation by tacking mass spectra at different position of U.V chromatograms for interpretation of peak. LC-MS\MS (Tandom) spectroscopy used to generate mass spectra by using collision activation of protonated molecules of impurity with argon gas which induce fragmentation of component. So Msn

fragmentation does not only provide unique molecular fingerprinting in tracking but also ensures structure confirmation to elucidate degradant structure. When impurity level is too low to be determined by LC-NMR structure based approach is extremly powerful tool to isolate isomers and distinguish isomeric and oxidative degradant product to obtain more clearly structure confirmation by wide application of 1H,13C and 2D NMR spectroscopy. . To accommodate NMR detection, the LC method is optimised to provide enhanced separation at higher column loadings in order to increase the sensitivity of the LC-NMR experiment.[14-16]

ANTIHYEPRTENSIVE DRUGS
Antihypertensive drugs are classified according to mechanism or the site of action in which max. used Class of calcium channel blockers, Angiotensin Converting Enzyme inhibitors, Angiotensin II antagonist and alpha , beta blockers . All impurities and degradation product of antihypertensive drugs of each class with structure and analytical method are summarized in respective table .

(A)CALCIUM CHANNEL BLOCKER DRUGS

It has been a major advance class in treatment of Antihypertensive, angina and other cardiovascular drugs. Calcium antagonist are a heterogeneous group of cardiovascular drugs used to block the entry of calcium ions in to nerve cells producing a reduction in peripheral vascular resistance. So these are commonly used in treatment of chronic hypertensive in adults and children . First generation calcium blockers are verapamil, nifedipine (dihydropyridine class ) and diltiazem (benzothiazepine ) and second generation are felodipine ,nitrendipine, nimodipine and third generation lacidipine Impurities and degradation products are described each one by one .[17]

NIFEDIPINE : It is prototype compound of 1, 4 dihydropyridine calcium channel blocker class and used as arterial dilator and angina pectoris. Process related impurity of nifedipine A, B, C, D are officialy reported in EP ,IP,BP

and however impurity only reported in USP. Nifedipine is photosensitive compound which degraded exposure to UV and Visible light converted to respectively nitrosophenyl and nitropyridine which are similar to A and B official impurity. photodegradation study is published by mojtaba et.al. and also reported in official compendia.[19-20] NITRENDIPINE : It is long acting second generation calcium blocker , it acts by inhibit movement of calcium though the slow channel of cardiac and vascular smooth muscles thus inducing peripheral vasodilation with consequent reduction in elevated blood pressure . Enantiomeric separation I, II ,III and IV process related impurity is carried out by V.marinkovic et.al . Impurity I, II, and III are reported in EP whereas III , IV are official in B P. Major degradation product is observed by oxidation and found faster in acidic condition.. Oxidative degradation compound dehydronitrendipine is determined by D.N tipre et. al . For oxidation drug is placed in methanol, acetone, ethyl acetate, chloroform and dichloromethane and exposed to sunlight from 08:00 to 17:00 h for 2 days at 30C.[25-26] NIMODIPINE : Isocratic RP-HPLC method to separate impurities A, B, C is reported by panagiotos et.al .These impurities are officially reported EP and BP and impurity A official in USP.[27] AMLODIPINE : It is one of the calcium channel blocker acts primarily on arterial muscle .Six process related impurities are detected by simple RP-HPLC method and LC-MS method is used to identify structures of impurity is published by P. sudhakat et. al. .Impurity I to IV are similar A,B,C,D reported in EP and other impurity E,F,G,H also reported in BP in which Impurity III and IV are polar and II, V and VI are non polar[28]

FELODIPINE ::

It is newer hypertensive drug requiring only once daily therapy to attain maximum efficacy and tolerability .it is used in combination with beta blocker which is suitable to mild to moderate hypertension. Process related impurity A , B, C are official in EP AND BP .

LACIDIPINE : It is a recently highly vasoselective third generation dehydropyridine antagonist that can be administered once daily. It possess one of the highest known membrane partition coefficient which allow it to position more deeply within the vascular cell membrane lipid bilayer. Lacidipine belongs to dihydropyridine class and its structure is characterised by the presence of a cinnamate moiety; the active trans form is used in therapy.Process related impurity A, B,C are reported official in BP. Lacidipine is photosensitive drug degraded in cis-isomer and a photocyclic isomer which is the main photodegradation product when solutions exposed to UV-A radiations .Photoexposure tests (up to 20 h) is carried out with monochromatic photon sources at_=365 and 313 nm in ethanolic (0.5% w/v) .Lacidipine solution photoexposed is showed that lacidipine photodegradation rate is higher when the drug is irradiated at 365 nm than at313 nm, under the conditions of equivalent absorbed photon number.[30] ISARADIPINE : Isaradipine impurity B, D are specific and other detectable A.C,E are only reported in E.P Isaradipine degradation study is carried out under all stress condition but it is susceptible to degradation exposure to UV light and oxidation process published by Michael et.al . One degradation product from basic condition and another one from UV degradation . Seven degradation (A ,B,C,D, E,F, G) are observed as result of peroxide degradation in which G similar to UV degradation product. For base degradation studies is carried out in 0.1 N NaOH and solution is left at ambient temperature or heated at 60C for 6 h in sealed scintillation vial to prevent evaporation of solvent during heating. And for acid degradation studies, 0.1 N HCl is added to this solution and left solution similar at ambient temperature or heated at 60C for 6 h.. For oxidative degradation studies, 3% hydrogen peroxide solution is added often temperature or heated at 60C for 6 h..For UV degradation studies, placed in a scintillation vial, which is then placed inside a cabinet under held 254 nm UV lamp for up to 24 h. Exposure to UV Radiation

is

caused 20% of the sample is degraded whereas exposure to oxidizing conditions caused extensive

degradation of the sample.[31] DILTIAZEM (DTZ) : It is less potent vasodilator than nifedipine and has a modest action direct inhibit chronotropic, ionotropic and dromotropic action .it produces modest fall in blood pressure with no change in heart rate .It is optical active compound due to having asymmetric carbon at position 2 and 3. Therefore it forms cis and trans isomers and cis. DTZ configuration (2s,3s) drug used in therapy and this streoisomers may be present in raw material reported in USP. All impurities of DTZ B, C, D, E, F has (+) Cis forms except A which has (+) -trans forms .Al these impurities are cited both in EP and BP.[32] VERAPAMIL : Antihypertensive effect of verapamil stems from a decrease in peripheral vascular resistance without an increase in heart rate as a reflex response. It is important class used in management of angina and atrial Tachyarrhythmias. HPLC method developed to determine related substance of verapamil by L.volvo et. al. it enables resolution of related compound from parent compound and each other by Comparing HPLC test for chromatographic impurity in USP.. we found potential impurity as precursors or by degradation products A,B,E,F,G,H,I,L,M in which F,I are related USP A and USP B impurity. These official impurities A , B, C, D, E, F, G, H, I, J, K, L, M and other N ,O, P are reported in EP and BP as related substance[33]

(B)ANGIOTENSIN II ANTAGONIST
Non peptide Ang. Receptor antagonist are used in hypertension by inhibit rennin release which rise in blood pressure by vasoconstriction . LOSARTAN : Losartan is the first nonpeptidic angiotensin II type-1 (AT1) receptor antagonist BP reported specified D,F,K, L, M and other control substances B,C,E,F,G,H,I as official impurity in which G impurity triphenyl methnol is also reported in IP .Two major photo degradates are produced when exposure to light (UV or visible) and the presence of oxygen. Losartan stress study we observed I (aldehyde derivative ) and II ,III degradant which are identified as dimeric degradant . Besides losartan in suspension dosage form observed formation of 7 degradant in which 2 or 3 major and 4-7 relatively minor product study is carried out by Randal et. al [34-35] CANDESARTAN :

It block vasoconstrictor and ADH secreting effect of ANG II by selecting blocking binding of ANG II to sAT1 receptors found in vascular smooth muscle and adrenal gland There is not yet reported official impurity in any official compendia. Drug degradation study is carried out by surbhi Mehta et. al. drug degraded in water hydrolytic condition as DP-III,IV, V,VI and VIII are formed whereas one degradant product each DP-1 is observed in under basic as well as DP-III in acidic condition. photodegradation from exposure base photolysis DP-VII and III are formed in which III is a major degradant .characterization of each degradant product by complete mass fragmentation pathway using MSn and MS\TOF mass studies. For hydrolytic stress studies is conducted at 80 C as well as oxidative study is carried out in 30% H 2O2 out at room temperature for 2 day .For photostability testing is carried out by exposing the solutions of drug in 0.01N HCl, 0.01N NaOH and water to light for 8 days and for thermal stress testing, the drug is sealed in glass vials and placed in a thermostatic block at 50 C for 21 days.we found maximum degradation is observed on hydrolysis, especially in the neutral condition and also degraded signicantly under photolytic conditions.[36] VALSARTAN Valsartan is a potent highly selective and orally active antagonist at the angiotensin II AT1 receptor that is used for the treatment of hypertension..Valsartan is a US pharmacopeia listed drug substance and three impurities are reported in this pharmacopeia. Five impurities (related substances) are detected by A. Sampath et. Al which are different from reported USP method due to different reported synthetic scheme of valsartan .Seven impurities and degradant product in APIs are separated and described by Ch. krishnaiah et. al using RP-UPLC quantitative determination of valsartan impurity.. When valsartan is subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation then we get Valsartan degraded significantly in acid and oxidative stress conditions while stable to all other conditions. We observed such type similar impurity during stress condition which are impurity A,C,D in base condition A,B,C,D in water hydrolysis, A,B,C,D,E in oxidative degradant and acid degradation A,C,D by using LCMS\MS technique.[37-38] EPROSARTAN

Eprosartan is used in treatment congestive heart failure and renal failure and also used to treat hypertension disease effectively with good tolerance due to small hazard of serious ill reactions. Eprosartan related substance unknown dimmer impurity is identified by cuirong et.al using sensitive HPLC\MSn method .eprosartan impurity is not yet reported in any official compendia[39] . IRBESARTAN : Drug action similar with candesartan which block vasoconstrictor and ADH secreting effect of ANG II by selecting blocking binding of ANG II to AT1 receptors. Drug is found to be degraded in DP-I, II AND III from exposure to acid, base and photo acidic stress condition which is published by Ravi p. shah et.al. photoexposure of solid drug, and dry heating at 80 C. Any official impurity is not yet reported in pharmacopoeia.[40] . OLMESARTAN : : When drug Olmesartan medoxomil stored at 40 C and 75% R.H , 2 major degradant product are formed . One degradant product as OL ester hydrolysate and another one as unknown degradation product dehydrated dimer of olmesartan . Official impurity is not yet reported in any compendia.[41] TELMISARTAN Its action independent of the pathway for angiotensin II synthesis. It has more affinity for AT1 receptor than for AT2 receptor . process related substance specified A, B,C,D and other control substance E,F,G,H are reported in BP. Drug is only sensitive to photoacidic condition while stable to other stress condition One major degradant product I formed under photostability study is published by Ravi p.shah et. al. is carried out in out in 0.1N HCl by exposing for 13 days to a combination of uorescent and UV light in a photostability chamber at 8500 lx and 0.05 W/m2[42]

(C)ACE INHIBITORS

The most prominent action of ACE II is vasoconstriction produced directly as well as by releasing adrenaline from adrenal medulla and by increasing central sympathetic outflow. These drugs specifically block enzyme ACE and thereby decrease ANG II which is responsible for vaso- constriction and ADH secretion .it causes vasodilation increased sodium and water retention leading to decrease in blood pressure . ENALPRIL Enalapril is an ethyl ester of a long-acting orally active ACE inhibitor .It is basically a pro-drug, which after oral administration undergoes hydrolysis to yield enalaprilat and is used as its maleate salt in therapeutic indications. It is an ideal drug for hypertension who are intolerant to beta blockers. Impurity of enalpril A ,B,C,D,E ,H are specific and other detectable impurity F,G ,I. reported in EP AND BP. Enalapril degraded to one or two degradation products in most of the stress conditions, except acidic hydrolysis, where a total of ve degradation products are produced. . It degrades to two major degradation products enalaprilat and diketopiperazine derivative are formed in solutions of pH above and below 3 Respectively. Enalapril is also show photolabile in solution and again yielding diketopiperazine derivative as the main degradation product .This degradant product is also observed due to heat induced which reported in USP. For degradation study of enalapril maleate is subjected to acid (0.1N HCl), neutral and alkaline (0.1N NaOH) hydrolytic conditions at 80 C, as well as to oxidative decomposition at room temperature which is carried out in 0.1N HCl, water and 0.1N NaOH at 40 C. for 2 mg ml1 in 3% H2 O2 and 20 mg ml1 in 30% H2 O2 and kept for 8 days at room temperature. For photolysis exposing the solutions at 40 C to 1.25 106 lx h of uorescent light and 210 W h m2 of UV light but drug degraded only in acidic conditions under light [43] RAMIPRIL : It is highly lipophilic long acting ACE inhibitor. it is effectively reduce both supine and standing blood pressure without significant alteration in pulse rate .Specific impurity A, B, C, D and other detectable impurity E ,F,G,H,I,K,L,M, N as Official impurity reported in EP and other impurity O reported in BP. stability of ramipril is carried out by L. hanysova et. al in the buffer solution with different pH and also inuence of acid, alkaline and oxidative medium . drug substance is dissolved in the ammonium phosphate buffer (pH 3, 5 and 8) and these solutions are stored at 90 C for 1 h. and also dilution in acid (0.1 M HCl), alkaline (0.1 M NaOH) and oxidative (hydrogen peroxide solution) medium. Impurity D (ramipril diketopiperazine) is detected in the buffer of pH 3 and pH 5 and impurity E (ramiprildiacid) is detected in

buffer of pH 8 which both are similar with official impurity in European pharmacopoeia.. we found same impurity D in heat stress degradation as well as both D and E are also observed in oxidation condition.[44]

CAPTOPRIL it is being used in moderate to severe essential hypertension generally in combination with diuretic or beta blocker and causes both arteriolar and vasodilation which reduce preload and after load. captopril disulphide related substance impurity is reported in both EP and USP. LISINOPRIL Drug inhibit ACE by drug reduce plasma ANG II levels which lead to vasodilation and reduction of ADH secretion lowering blood pressure. EP and BP similar reported official impurity A, B, C,D, E, F and degradation product is found as lisinoril DKPZ published in literature.[45] PERINDOPRIL It is an orally active ACE inhibitor considered very valuable in treatment of conjestive heart failure. In European pharmacopeia process related impurity of perindopril A,B,C,D,E,F,G,H,I are reported and other control substance specified k,L,M,N,O,P ,Q,R,S,T,U,V,W,X,Y,Z are also reported in BP .

(D)DIURETICS
It may be considered as first line of drugs for treatment of mild hypertension Efficacy of these agents as antihypertension are not directly related to diuretic potency. However Loop diuretics are potent diuretics but possess only modest effect on blood pressure and used in combination with vasodilators or ACE inhibitors in severe resistant hypertension . Moreover, thiazides are weak diuretics but useful hypertensive HCTZ ,CHLORTHALIDONE and INDAPAMIDE as preferred Antihypertensive diuretics. HYDROCHLORTHIAZIDE Hydrochlorothiazide (HCTZ) is a common diuretic that is utilized singularly or in combination with other drugs for the treatment of hypertension .Hctz acts by inhibit absorption of sodium and chloride at the begning of distal convoluted tubes .Typically it contains chlorothiazide(CTZ) as a process impurity and 4amino-6-chloro-1,3-benzenedisulfonamide (DSA) as a degradation product. Both these impurities along with an additional impurity HCTZDSA is reported in European Pharmacopoeia , BP and USP.[46]

INDAPAMIDE It is a vasodilator and diuretic related to thiazides ,it reduces BP at dose which cause little or no diuresis. It act probably by interfering with ionic fluxes including that of calcium across vascular smooth muscle cells. Indapamide related substance A,B official impurity in BP and EP. CHLORTHALIDONE It is used as weak diuretic. Chlorthalidone consists specified process related impurity A,B,C,D,E,F,G,H,I which are officially reported in both EP and BP. SPIRANOLACTONE spiranolactone acts as Aldosterone-antagonist is widely used Potassium-sparing diuretic. It is safe and efficacious in treatment of refractory oedema associated with heart failure and cirrhosis of liver (with or without ascites), or the nephritic syndrome, and in ascites associated with malignancy. Three known(3,4,5) and five noval [47] AMILORIDE AND TRIAMETERENE They are two nonsteroidal organic ashes which act on distal tubule by blocking sodium potassium , and hydrogen exchange and decrease potassium excretion. Related substance A impurity of Amiloride is reported in EP and BP whereas triameterene A, B, C official impurity only in BP. FUROSEMIDE Furosemide is high ceiling diuretic which has a distinct action on renal tubular function and inhibit sodium and chloride re-absorption in ascending limb of Loop of henle. and produce venodilator action in hypertension. Furosemide has A, B ,C, D ,E process related substances which are official impurity in only EP and BP. impurities (6,7,8,9,10) have been identified in spiranolactone by Huachen et. al. there is not yet reported official impurity in any official compendia.(IP,USP ,BP And EP)

(E)BETA ADRENERGIC BLOCKERS

beta adrenorecptor are less well tolerated than ACE inhibitor or AT1 antagonist and the evidence supporting their routine use is less strong than other classes of antihypertensive drug. These drugs are used in chronic treatment of hypertensive patients results in slow reduction of blood pressure .

PRPPRANOLOL It has beta blocker activity without symhathomimetic action and decrease heart rate and prolong systole by retarding contraction of ventricular fibres. Ppnl consists A, B , C impurity are reported in EP and BP in which B,C reported in IP. ATENOLOL It has also beta blocker activity without symhathomimetic action It is one of most commonly used beta blocker for hypertension and angina . There is A, B, C, D , E, F,G, H impurity are official in EP and BP. .photostability of Atenolol is carried out at pH 9, 7.4 and 4.0 when exposed to UVB (290320 nm) and UVA (320400nm) radiations (xenon arc lamp) for 17 h, equivalent to doses of 184.00 J/cm2 (UVA) and 29.6 J/cm2 (UVB). We found increase with the pH value decreasing photodegradation photodegradation product is identied at pH 7.4.[48] TIMOLOL It is used in hypertension having beta blocker activity without membrane stabilizing activity . Timolol Consist related substance A as official impurity in EP. and major

(F)Beta and alpha adrenergic blockers

LABETALOL It is unique among adrenergic antagonist in blocking both alpha and beta receptors . it is orally effective and undergoes considerable first pass metabolism .It is a 5 times moderately potent hypotensive and specially useful in pheochromocytoma, clonidine withdrawal can also be used in essential hypertension .it has equal parts of each isomer displays beta 1 +beta 2 and alpha 1 bloking as well as weak beta 2 agonistic activity. Labetolol process related impurity A, B are reported in both EP and BP. photodegradation is carried out under forced conditions by vincenza andrisano et.al. Forced photodegradation of labetalol in aqueous solutions has been conducted under exposure to UVAUVB radiations (xenon arc lamp) at the doses of 150 mJ / cm 2 / min for UVA radiation and 24 mJ / cm 2 / min for UVB radiation15 h in pH 7.4. For oxidative photolysis Labetalol solution in diluted ammonium hydroxide (pH 9) is subjected to UVAUVB radiation for 6 h, equivalent to a total dose of 54 J / cm 2 for UVA radiation and 8.6 J / cm 2 for UVB radiation. Labetalol under UV-254 and UVBUVA radiations gives similar I,II photodegradation respectively.[49] photoproducts

CARVEDILOL CV is an aryl ethylamine non specific beta adreno recptor antagonist with alpha 1 blocking activity. It exerts antihypertensive effect partly by reducing total peripheral resistance and vasodilation by blocking alpha 1 adreno recptors and by inhibit beta adrenorecptor mediated compensating mechanism..CV is widely prescribed for the treatment of cardiovascular diseases such as hypertension, ischemic heart diseases, myocardial infractions and congestive heart failures. Impurity A, B ,C are official in EP and BP and one potential degradant product is similar with impurity B. Stability study has been published by Olgagalanpqulou et al and detected unknown impurity E, F and one unknown degradant product when exposed to moisture.[50] (G)ALPHA ADRENERGIC BLOCKERS (PERIPHERAL ANTIADRENERGIC DRUGS) All alpha 1 adrenergic blockers produce a significant fall of blood pressure in patients with essential hypertension. PRAZOSINE It is a selective competitive antagonist of the classical alpha 1 receptors. This is quinazoline derivative possessing a potent vasodilation action and more often it is employed in combination with betaadrenorecptor blockers or diuretics. Prazosine process related impurity A, B in IP and A, B, C, D, E are reported in EP and BP.[51] DOXAZOSINE Doxazosin is a new quinazoline derivative with a selective inhibition of alpha 1 subtype of adrenergic recptor as potent antihypertensive agent and It is very effective when administered orally or intravenously. Doxazosin mesylate is a postsynaptic -1 adrenoreceptor antagonist used either alone or in combination with diuretics or adrenergic-receptor-antagonist. .S-(+) enantiomer of DXZN is offered both reduced side effects (e.g. asthma, dizziness), and improved efficacy over the racemate for the treatment of BPH (benign prostatic hyperplasia ) process related impurity is published by R.Nages et. al and also reported in BP and USP A ,B,C,D,E And F in which G similar to A and H similar to C.[52]

TERAZOSINE It is an alpha -1 adrenorecptor antagonist used in treatment of hypertension. Process related substance are reported A,B,C,D,E,F,G,,H,I,K,L,M ,N in BP and k impurity is similar with prazosine structure. PHENTOLAMINE MESILATE It is short acting alpha blocker Process related impurity A is official in EP and BP.

(H)DIRECT VASODILATORS
These drugs lower the blood pressuer in normal and antihypertensive subjects due to selective arteriolar Vasodilations. many vasodilators are clinically important being used to treat common condition including hypertension , cardiac failure and angina pectoris. MINOXIDIL: Minoxidil is very potent and long acting vasodilator used as a drug of last resort in treating severe hypertension unresponsive to other drugs.It is powerful arterial vasodilator relax smooth muscle by selectively increasing the membrane permeability by KATP potassium channel opening and seldom used except in the therapy of Resistant hypertension. Minoxidil impurity A, B, C, D, E are reported in European pharmacopeia.

(I)CENTRALLY ACTING AGENT CLONIDINE : clonidine is a centrally acting alpha 2 agonist which is now seldom used. Clonidine when given i.v. produce short time hypertension followed by prolong decrease in systolic and diastolic pressure. When it given orally, it produces fall in blood pressure and addition diuretic enhances antihypertensive action., clonidine A,B, C official impurity reported in .BP and acetyl clonidine impurity in USP.

Conclusion
Thus we conclude that by systematic approach most of reported impurity in literature survey and official compendia have just shown separation of drug from known synthetic impurity or potential degradation product with or without subjecting it stress. Determination of its quality is quite important not only for safety but also to prove its efficacy for the benefit of the patients who ultimately receives it in different dosages during the treatment of hypertension. Most of antihypertensive drugs are enantiomers such as DTZ, nitrendipine ,isaradipine , indapamide and carvedilol etc as sterioisomerism . Determination of enantiomeric purity has become an important issue in the analysis of chiral drugs in drug development and quality control.Because of the fact that only one of the enantiomers fully contributes to the desired therapeutic activity while the other may be an unwanted by product since control of the unwanted enantiomers in the drug substances is necessary and it must be determined at the levels prescribed by the regulatory authorities. All reported impurities and degradation of Anti-hypertensive drugs are highlighted in tables but It does not mean comprehensive coverage of all literature survey reports .Now a days by conducting integrated approach has become provide rapid and unambiguous to Identification of impurities and several degradation at one time by application of hyphenated techniques such like LC-MS,LC-MS\MS, LC-NMR using (1H,13C and 2D) to get correct molecular Weight and mass fragmentation to verify structure confirmation. So we can say it has been pointed out that hyphenated technique has become an essential part of the comprehensive Characterization of impurity proles.

FUTURE TRENDS
Impurity is yardstick for comparative study that defines what constitutes as an impurity and identify potential source .such type impurity plays important role in change of synthesis , formulation and production procedures to get desirable profile purity of drug in finished product development role in the drug discovery process and Information of structures of degradation products can also help synthetic chemists to modify their novel compounds for prepare drug with improved stability.

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21.