Upload
amit-sharma
View
85
Download
3
Tags:
Embed Size (px)
Citation preview
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 identification 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]
Ma daily dose Rep Reporting threshold Ide Identiification thresholdQual Identfication threshold
Less Less or equal to 2g\day 0.05 0.05% 0.10 0.10% or 1.0 mg\day
(whi (whenever lower)
0.15 0.15% or 1.0 mg\day
>2g. > 2g\day 0.03 0.03% 0.05 0.05% 0.0 s 0.05%
According to ICH , Any unspecified impurity with an acceptance criterion of not more than (≤) in the
identification threshold in table 1.
ICH Guidelines for identification and qualification of impurity in Bulk drug formulation table 2.
Threshold for reporting degradation products in a new drug product table 3.
Dose Thre Threshold for identification (%)Qual Qualification (%)
< 1 <1mg 1.0d 1.0 1.0d 1.0
1-10 1-10mg 0.5 0.5 1.0h 1.0
10-1 10-100mg 0.2 h 0.2 0.5 c 0.5
1001 100mg-2g 0.1d 0.1 0.2d 0.2
>2g > 2g 0.1h 0.1 0.1d 0.1
Max. daily dose Threshold for identification
1 g 0.1%
>1g 0.05%
For force degradation study ICH Q1A suggests such following condition can be employed [5-6]
(i) 10 °C increments above the accelerated temperatures (e.g. 50 °C, 60 °C,etc.),
(ii) 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 LC–MS 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 30°C.[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 60°C 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 60°C for 6 h.. For oxidative degradation studies, 3% hydrogen peroxide solution is
added often temperature or heated at 60°C 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 significantly 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 LC-
MS\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 fluorescent 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 five 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 ml−1 in 3% H2 O2 and 20 mg ml−1 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 fluorescent light and 210 W h m−2 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
influence 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 (ramipril–diacid) 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 4-
amino-6-chloro-1,3-benzenedisulfonamide (DSA) as a degradation product. Both these impurities along
with an additional impurity HCTZ–DSA 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 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)
[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.
(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 (290–320 nm) and
UVA (320–400nm) 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 and major
photodegradation product is identified 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.
(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 UVA–UVB 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 UVA–UVB 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 UVB–UVA radiations gives similar I,II photodegradation photoproducts
respectively.[49]
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 beta-
adrenorecptor 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 profiles.
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.
REFERENCE:
1.United states federal register, vol. 65, no. 251
2. Sandor Gorog et al Drug safety, drug quality, drug analysis Journal of Pharmaceutical and Biomedical Analysis 48 (2008) 247–253
3.International Conference on the Harmonization of the Technical Requirements for Registration of Pharmaceuticals for Human Use 2006 .ICH harmonized tripartite guideline: impurity in new drug substances Q3A: International Conference on the Harmonization: Geneva, Switzerland
4.International Conference on the Harmonization of the Technical Requirements for Registration of Pharmaceuticals for Human Use 2006 .ICH harmonized tripartite guideline: impurity in new drug product Q3B: International Conference on the Harmonization: Geneva, Switzerland
5. International Conference on the Harmonization of the Technical Requirements for Registration of Pharmaceuticals for Human Use 2003 .ICH harmonized tripartite guideline: stability testing of New drug substance and products Q1A(R3) International Conference on the Harmonization: Geneva, Switzerland
6. Monika Bakshi et. al Development of validated stability-indicating assay methods—critical review Journal of Pharmaceutical and Biomedical Analysis 28 (2002) 1011–1040
7.ANDAs: Impurities in drug products, Guidance for Industry, US Food and Drug Administration, Center for Drug Evaluation and Research, Department of Health and Human Services, 1998.
8.Satinder Ahuja et.al Assuring quality of drugs by monitoring impurities Advanced Drug Delivery Reviews 59 (2007) 3–11
9.Joachim Ermer et.al. “Quality concept for impurities during drug development – use of the hyphenated LC–MS technique” reviews research focus ,PSTT Vol. 1
10. R. Nageswara Rao et. Al An overview of the recent trends in development of HPLC methods for determination of impurities in drugs Journal of Pharmaceutical and Biomedical Analysis33 (2003) 335_/377
11. Lili Zhou et. al Impurity profile tracking for active pharmaceutical ingredients:Case reports Journal of Pharmaceutical and Biomedical Analysis 44 (2007) 421–429
12. Min li ,Bin chen et al. Application of LC-MSn in conjuction with mechanism – based stress studies in the elucidation of drug Impurity \degradation product structures aand degradation pathways , global quality service –analytical science schering –plough coporation
13. L.R. Snyder, J.J. Kirkland, J. Glajch, Practical HPLC Method Development, 2nd ed., Wiley & Sons, New York, 1997, pp. 537–541
14. Edward M. Sheldon et. al “Development of a LC/LC/MS complete heart-cut approach for the characterization of pharmaceutical compounds using standard instrumentation” J. Pharmaceut. Biomed.Anal.31 (2003) 1153/1166
s15. S.D. McCrossen et. al Comparison of LC detection methods in the investigation of non-UV detectable organic impurities in a drug substance Journal of Pharmaceutical and Biomedical Analysis17 (1998) 455–471
16. Changkang Pan et. al drug degradation study The use of LC/MS, GC/MS, and LC/NMR hyphenated techniques to identify a drug degradation product in pharmaceutical development, Journal of Pharmaceutical and Biomedical Analysis 40 (2006) 581–590
17. dherashai Gandhi element of pharmacology
18.K.D tripathi essential of pharmacology 5th edition published by jaypee brothers medical publishers (p) Ltd. New delhi india.
19..Velinger et. al “preparation of reference standards substances for the evaluation of impurities and degradation products life saving drugs “ Indian drug , vol .46(11) nov. 2009, pg.no. 1844-1849
20. Mojtaba Shamsipur et. al A study of the photo-degradation kinetics of nifedipine by multivariate curve resolution analysis Journal of Pharmaceutical and Biomedical Analysis 31 (2003) 1013_/1019
21.Indian pharmacopoeia ,published by pharmacopoeia commission ,Ghaziabad 2007.
22. United states pharmacopoeia (NF) 31st revision 2008, united states pharmacopeial convention , Rockville ,MD,USA
23.Pharmeuropa 5th edition vol 24. British pharmacopeia
25. V. Marinkovic et. al Simultaneous HPLC determination of nitrendipine and impurities of the process of synthesis Journal of Pharmaceutical and Biomedical Analysis 24 (2001) 993–998
26.D.N. Tipre et. al Oxidative degradation study of nitrendipine using stability indicating, HPLC, HPTLC and spectrophotometric method Journal of Pharmaceutical and Biomedical Analysis 24 (2001) 705–714
27.Panagiotis Barmpalexis et. al Developing and optimizing a validated isocratic reversed-phase high-performance liquid chromatography separation of nimodipine and impurities in tablets using experimental design methodology Journal of Pharmaceutical and Biomedical Analysis 49 (2009) 1192–1202
28. P. Sudhakar et. al Identification and characterization of potential impuritiesof amlodipine maleate_ Journal of Pharmaceutical and Biomedical Analysis 40 (2006) 605–613
29.Rakesh S.U.et al antihypertensive and antianginal agent in form of besylate salt Indian drug vol 47(3) March 2010
30.P. De Filippis et. al Photodegradation studies on lacidipine in solution: basic experiments with a cis trans reversible photoequilibrium under UV-A radiation exposure Journal of Pharmaceutical and Biomedical Analysis 27 (2002) 803–812
31. G. Bartlett et. al Determination of degradation products from the calcium-channel blocker isradipine Journal of Pharmaceutical and Biomedical Analysis 18 (1998) 335–345
32.. M.G. Quagliaa et. al Analysis of diltiazem and its related substances by HPLC and HPLC/MS Journal of Pharmaceutical and Biomedical Analysis 37 (2005) 695–701
33.. L. Valvo et. al Development and validation of a liquid chromatographic method for the determination of related substances in verapamil hydrochloride journal of pharmaceutical and biomedical analysis15 (1997) 989 996
34..Zhongxi (Zack) Zhao et. al Identification of losartan degradates in stressed tablets by LC-MS and LC- MS:MS Journal of Pharmaceutical and Biomedical Analysis 20 (1999) 129–136
35. Randal A. Seburg et. al Photosensitized degradation of losartan potassium in an extemporaneous suspension formulation Journal of Pharmaceutical and Biomedical Analysis 42 (2006) 411–422
36. Surbhi Mehta et. al LC and LC–MS/TOF studies on stress degradation behaviour of candesartan Cilexetil Journal of Pharmaceutical and Biomedical Analysis 52 (2010) 345–354
37. A. Sampatha et. al Identification and characterization of potential impurities of valsartan, AT1 receptor antagonist Journal of Pharmaceutical and Biomedical Analysis 50 (2009) 405–412
38. Ch. Krishnaiah et. al Stability-indicating UPLC method for determination of Valsartan and their degradation products in active pharmaceutical ingredient and pharmaceutical dosage forms Journal of Pharmaceutical and Biomedical Analysis 53 (2010) 483–489
39.Cuirong Sun et. al Characterization of a novel impurity in bulk drug eprosartan by ESI/MSn and NMR journal of Pharmaceutical and Biomedical Analysis 51 (2010) 778–78
40. Ravi P. Shah et. al Identification and characterization of degradation products of irbesartan usin LC–MS/TOF, MSn, on-line H/D exchange and LC–NMR Journal of Pharmaceutical and Biomedical Analysis 51 (2010) 1037–1046
41. Tomonori Murakamia et. al Identification of a degradation product in stressed tablets of olmesartan medoxomil by the complementary use of HPLC hyphenated techniques Journal of Pharmaceutical and
Biomedical Analysis 47 (2008) 553–559
42. Ravi P. Shah et. al Identification and characterization of a photolytic degradation product of telmisartan using LC–MS/TOF, LC–MSn, LC–NMR and on-line H/D exchange mas studies Journal of Pharmaceutical and Biomedical Analysis 53 (2010) 755–761
43. Sunny Piyush Bhardwaj et. al Study of forced degradation behavior of enalapril maleate by LC and LC–MS and development of a validated stability-indicating assay method Journal of Pharmaceutical and Biomedical Analysis 46 (2008) 113–120
44..L. Hanysova et. al Stability of ramipril in the solvents of different PH Journal of Pharmaceutical and Biomedical Analysis 37 (2005) 1179–1183
45. Christopher A. Et. al Development and validation of a stability indicating HPLC method for determination of lisinopril, lisinopril degradation product and parabens in the lisinopril extemporaneous formulation Journal of Pharmaceutical and Biomedical Analysis 37 (2005) 559–567
46. John D. Franolic et. al Isolation of a 2:1 hydrochlorothiazide–formaldehyde adduc impurity in electrospray ionization LC–MS journal of Pharmaceutical and Biomedical Analysis26 (2001) 651–663
47. Hua Chen et. al Isolation and identification of novel impurities in spironolacton Journal of Pharmaceutical and Biomedical Analysis 40 (2006) 1263–1267
48..V. Andrisano et. al Photodegradation studies on Atenolol by liquid Chromatography Journal of Pharmaceutical and Biomedical Analysis 21 (1999) 851–857
49. Vincenza Andrisano et. al Studies on the photostability and in vitro phototoxicity of Labetalol European Journal of Pharmaceutical Sciences 12 (2001) 495–504
s50.Olga Galanopouloua et. al HPLC analysis, isolation and identification of a new degradation product in carvedilol tablets Journal of Pharmaceutical and Biomedical Analysis 48 (2008) 70–77
51 Monika Bakshi et. al Validated specific HPLC methods for determination of prazosin, terazosin and doxazosin in the presence of degradation products formed under ICH-recommended stress conditions , Journal of Pharmaceutical and Biomedical Analysis 34 (2004) 19–26
52. R. Nageswara Rao.et. al Enantiomeric resolution of doxazosin mesylate and its process-related substances on polysaccharide chiral stationary phases journal of Pharmaceutical and Biomedical
Analysis 41 (2006) 766–773
21.