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CHAPTER 2CHAPTER 2CHAPTER 2CHAPTER 2

Drug Profile and Literature

Review

Section Title Page No.

2.1 Drug Profile 33-43

2.1.1 Tapentadol hydrochloride 33

2.1.2 Febuxostat 36

2.1.3 Aspirin 38

2.1.4 Atorvastatin calcium 41

2.2 Literature review of drugs 44-54

2.2.1 Literature review for TAP 44

2.2.2 Literature review for FBX 47

2.2.3 Literature review for ASP and ATR 50

2.3 References 55

Chapter 2

33

2.1 Drug Profile

2.1.1 Tapentadol hydrochloride (TAP) (Drugs ; DrugInformation ; DrugBank ;

USFDA)

Structure:

OH

CHCH2

H3CCH

CH3

CH2 N

CH3

CH3

HCl

Figure 2.1 - Structure of TAP

Common Name: Tapentadol hydrochloride.

Approval Status: TAP was approved for marketing in India by CDSCO on April 2011.

Chemical Names:

1. 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochloride.

2. 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol.

CAS No: 175591-09-0; (Component: 175591-23-8)

Molecular Formula: Molecular formula is C14H23NO•HCl.

Molecular Mass: Molecular weight of tapentadol HCl is 257.80, molecular weight of

tapentadol base is 221.34.

Appearance: TAP is a white to off-white powder.

Melting point : 204 – 210 ºC

Solubility: TAP is freely soluble in water, 0.1 N HCl, and simulated intestinal fluid (SIF),

soluble in ethanol, sparingly soluble in methanol and slightly soluble in 2-propanol.

pKa Values: 9.34 and 10.45.

Log P value: 2.87 (n-octanol and water system)

Indications: TAP is indicated for the management of moderate to moderately severe pain in

adults who require continuous treatment for several days or more.

Drug Profile and Literature Review

34

Pharmacological Class: TAP is a centrally-acting synthetic analgesic. Although its exact

mechanism is unknown, analgesic efficacy is thought to be due to µ-opioid agonist activity

and the inhibition of norepinephrine reuptake.

Pharmacokinetics:

Absorption

Mean absolute bioavailability after single-dose administration (fasting) of TAP is

approximately 32% due to extensive first-pass metabolism.

Distribution

TAP is widely distributed throughout the body. Following intravenous administration, the

volume of distribution (Vz) for TAP is 540 +/- 98 L. The plasma protein binding is low and

amounts to approximately 20%.

Metabolism

In humans, the metabolism of TAP is extensive. About 97% of the parent compound is

metabolized. TAP is mainly metabolized via Phase 2 pathways, and only a small amount is

metabolized by Phase 1 oxidative pathways. The major pathway of TAP metabolism is

conjugation with glucuronic acid to produce glucuronides. None of the metabolites

contributes to the analgesic activity.

Elimination

TAP and its metabolites are excreted almost exclusively (99%) via the kidneys. The terminal

half life after oral administration is on average (± standard deviation) 5.9 (±2.0) hours and the

apparent clearance (CL/F) is on average 4449 (±1199) mL/min across all doses of TAP CR.

The total serum clearance of TAP after intravenous administration is 1530 +/- 177 ml/min.

Pharmacodynamics:

TAP is a novel synthetic opiate analgesic with a dual mechanism of action, mu-opioid agonist

and norepinephrine reuptake inhibitor. It is 18 times less potent than morphine in binding to

the human mu-opioid receptor and is 2-3 times less potent in producing analgesia in animal

models. TAP has been shown to inhibit norepinephrine reuptake in the brains of rats resulting

in increased norepinephrine concentrations. In preclinical models, the analgesic activity due to

the mu-opioid receptor agonist activity of TAP can be antagonized by selective mu-opioid

Chapter 2

35

antagonists (e.g., naloxone), whereas the norepinephrine reuptake inhibition is sensitive to

norepinephrine modulators. TAP exerts its analgesic effects without a pharmacologically

active metabolite.

Dose and Administration: TAP is administered orally and it is available as control release

tablets having strength of 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg.


36

2.1.2 Febuxostat (FBX)(Drugs ; MedlinePlus ; Neil 674; USFDA)

Structure:

S

N

OH

O

N

O

Figure 2.2 –Structure of FBX

Common Name: Febuxostat

Chemical Names: 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole 5-carboxylic

acid.

CAS No: 144060-53-7

Approval Status: FBX was approved in India by CDSCO on 14th November 2009.

Molecular Formula: Molecular formula is C16H16N2O3S.

Molecular Mass: Molecular weight of FBX is 316.38.

Appearance: FBX is a non-hygroscopic, white crystalline powder.

Melting point : 205 – 208 ºC

Solubility: FBX is freely soluble in dimethylformamide; soluble in dimethylsulfoxide;

sparingly soluble in ethanol; slightly soluble in methanol and acetonitrile; and practically

insoluble in water.

pKa Values: 3.42 (weak acid)

Log P value: 3.52

Indications: FBX is indicated to lower serum uric acid levels in patients with gout.

Pharmacological Class: FBX is a nonpurine selective inhibitor of xanthine oxidase inhibitor.

Pharmacokinetics:

Absorption

The absorption of radio labeled febuxostat following oral dose administration was estimated

to be at least 49% (based on total radioactivity recovered in urine). Maximum plasma

concentrations of febuxostat occurred between 1 to 1.5 hours post-dose. After multiple oral 80

Chapter 2

37

mg once daily doses, Cmax is approximately 2.9 ± 1.4 mcg/mL (N=226). Absolute

bioavailability of the febuxostat tablet has not been reported.

Distribution

The mean apparent steady state volume of distribution (Vss/F) of FBX was approximately 54

L (CV 49%). The plasma protein binding of febuxostat is approximately 99.2% (primarily to

albumin).

Metabolism

FBX is extensively metabolized by both conjugation via uridine diphosphate glucuronosyl

transferase (UGT) enzymes including UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and

oxidation via cytochrome P450 (CYP) enzymes including CYP1A2, 2C8and2C9 and non-

P450 enzymes. The relative contribution of each enzyme isoform in the metabolism of

febuxostat is not clear. The oxidation of the isobutyl side chain leads to the formation of four

pharmacologically active hydroxy metabolites, all of which occur in plasma of humans at a

much lower extent than febuxostat.

Elimination

FBX is eliminated by both hepatic and renal pathways. Approximately 49% of the dose was

recovered in the urine as unchanged FBX (3%), the acyl glucuronide of the drug (30%), its

known oxidative metabolites and their conjugates (13%), and other unknown metabolites

(3%). In addition to the urinary excretion, approximately 45% of the dose was recovered in

the feces as the unchanged FBX (12%), the acyl glucuronide of the drug (1%), its known

oxidative metabolites and their conjugates (25%), and other unknown metabolites (7%). The

mean terminal elimination half-life (t1/2) of febuxostat was approximately 5 to 8 hours.

Pharmacodynamics:

FBX is a 2-arylthiazole derivative. This compound is a potent, non-purine selective inhibitor

of xanthine oxidase (NP-SIXO). In vitro studies indicated that febuxostat inhibits xanthine

oxidase (XO) with Ki values in the range of 0.6-0.10 nM. The compound potently inhibits

both the oxidized and reduced forms of the enzyme. Febuxostat shows no effect on other

enzymes involved in purine or pyrimidine metabolism, namely guanine deaminase,

hypoxanthine guanine phosphoribosyl transferase, orotate phosphoribosyl transferase,

orotidine monophosphate decarboxylase and purine nucleoside phosphorylase. In vivo animal


38

studies using normal and hyperuricemic mice and rats, as well as chimpanzees, demonstrated

that febuxostat exhibits hypouricemic activity.

Dose and Administration: FBX is administered orally and it is available in tablet dosage

form. It is available in two strengths, 40 mg and 80 mg.

2.1.3 Aspirin (ASP) (Moffat, Osselton and Widdop 654-55; Neil 143-44; UnitedStatesPharmacopeia 2263-64; BritishPharmacopoeia 182-83; EuropeanPharmacopoeia 917-18; IndianPharmacopoeia 849-50)

Structure:

Figure 2.3 - Structure of ASP.

Common Name: Acetyl salicylic acid.

Chemical Names: 2-acetoxybenzoic acid.

CAS No: 50 – 78 – 2.

Molecular Formula: Molecular formula is C9H8O4.

Molecular Mass: Molecular weight of ASP is 180.2

Appearance: Colourless crystals or a white, crystalline powder; odourless or almost

odourless.

Melting point : 135 ºC

Solubility: ASP is soluble 1 in 300 of water, 1 in 5 of ethanol, 1 in 17 of chloroform, and 1 in

10 -15 of ether, soluble in solutions of acetates and citrates.

pKa Values: 3.5

Log P Value: 1.1 (octanol/ buffer at pH 7.4)

Indications: ASP is an analgesic, antipyretic, antirheumatic, and anti-inflammatory agent.

ASP is also used for temporary relief of various forms of pain, inflammation associated with

various conditions (including rheumatoid arthritis,juvenile rheumatoid arthritis, systemic

lupus erythematosus, osteoarthritis, and ankylosing spondylitis), and is also used to reduce the

Chapter 2

39

risk of death and /or nonfatal myocardial infarction in patients with a previous infarction or

unstable angina pectoris.

Pharmacological Class: ASP is the prototypical analgesic used in the treatment of mild to

moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of

cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins.

Acetylsalicylic acid also inhibits platelet aggregation and is used in the prevention of arterial

and venous thrombosis.

Pharmacokinetics:

Absorption

Aspirin and other salicylates are absorbed rapidly from the gastrointestinal tract when taken

orally but absorption after rectal doses is less reliable. Aspirin and other salicylates can also

be absorbed through the skin. After oral doses, absorption of non-ionised aspirin occurs in the

stomach and intestine. Some aspirin is hydrolysed to salicylate in the gut wall. Once absorbed,

aspirin is rapidly converted to salicylate, but during the first 20 minutes after an oral dose

aspirin is the main form of the drug in the plasma. Aspirin is 80 to 90% bound to plasma

proteins and is widely distributed; its volume of distribution is reported to be 170 mL/kg in

adults. As plasma-drug concentrations increase, the binding sites on the proteins become

saturated and the volume of distribution increases.

Distribution

Salicylic acid is widely distributed to all tissues and fluids in the body including the central

nervous system (CNS), breast milk and fetal tissues. The highest concentrations are found in

the plasma, liver, renal cortex, heart and lungs.The protein binding of salicylate is

concentration-dependent, i.e, non-linear. At low concentrations (< 100 micrograms/milliliter

(mcg/mL), approximately 90 percent of plasma salicylate is bound to albumin while at higher

concentrations (> 400 mcg/mL), only about 75 percent is bound. The early signs of salicylic

overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma concentrations

approximating 200 mcg/rnL. Severe toxic effects are associated with levels > 400 mcg/mL.

Metabolism

ASP is rapidly hydrolyzed in the plasma to salicylic acid such that plasma levels of ASP are

essentially undetectable 1-2 hours after dosing. Salicylic acid is primarily conjugated in the


40

liver to form sallcyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of

minor metabolites. Salicylic acid has a plasma half-life of approximately 6 hours. Salicylate

metabolism is saturable and total body clearance decreases at higher serum concentrations due

to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide.

Following toxic doses (10-20 grams (g)), the plasma half-life may be increased to over 20

hours.

Elimination

The elimination of salicylic acid follows zero order pharmacokinetics; (i.e., the rate of drug

elimination is constant in relation to plasma concentration). Renal excretion of unchanged

drug depends upon urine pH. As urinary pH rises above 6.5, the renal clearance of free

salicylate increases from < 5 percent to > 80 percent. Alkalinization of the urine is a key

concept in the management of salicylate overdose. Following therapeutic doses,

approximately 10 percent is found excreted in the urine as salicylic acid, 75 percent as

salicyluric acid, 10 percent and 5 percent as the phenolic and acyl glucuronides, respectively.

Pharmacodynamics:

Aspirin affects platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase.

This effect lasts for the life of the platelet and prevents the formation of the platelet

aggregating factor thromboxane A2. Non-acetylated salicylates do not inhibit this enzyme and

have no effect on platelet aggregation. At somewhat higher doses, aspirin reversibly inhibits

the formation of prostaglandin 12 (prostacyclin), which is an arterial vasodilator and inhibits

platelet aggregation. At higher doses aspirin is an effective anti-inflammatory agent, partially

due to inhibition of inflammatory mediators via cyclo-oxygenase inhibition in peripheral

tissues. In vitro studies suggest that other mediators of inflammation may also be suppressed

by aspirin administration, although the precise mechanism of action has not been elucidated.

It is this nonspecific suppression of cyclo-oxygenase activity in peripheral tissues following

large doses that leads to its primary side effect of gastric irritation.

Mechanism of action:

Aspirin is a more potent inhibitor of both prostaglandin synthesis and platelet aggregation

than other salicylic acid derivatives. The differences in activity between aspirin and salicylic

acid are thought to be due to the acetyl group on the aspirin molecule. This acetyl group is

responsible for inactivation of cyclo-oxygenase via acetylation.

Chapter 2

41

Dose and Administration: ASP is administered orally and it is available in strength of 75,

150, 300, and, 600 mg. Usually 1.2 to 4 gm daily given in acute rheumatic disorders.

ASP and ATR fixed dose combination was approved by CDSCO in India on 18th Jan 2008.

This combination is indicted for the treatment of dyslipidemia associated with atherosclerotic

arterial disease with risk of myocardial infarction, stroke or peripheral vascular disease.

2.1.4 Atorvastatin calcium (ATR) (IndianPharmacopoeia 849-50; Moffat,

Osselton and Widdop 654-55; Neil 143-44; UnitedStatesPharmacopeia 2263-64)

Structure:

3 H2O

Figure 2.4 – Structure of ATR.

Common Name: Atorvastatin

Chemical Names: ATR is a is calcium salt of (βR,8R)-2-(4-fluorophenyl)-α,δ-dihydroxy-5

(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid.

CAS No: 134523-00-5 (atorvastatin); 134523-03-8 (atorvastatin calcium).

Molecular Formula: Molecular formula is C66H68CaF2N4O10, 3H2O.

Molecular Mass: Molecular weight of ATR is 1209.4

Appearance: A white to off-white, crystalline powder.

Melting point: 159.2 – 160.7 ºC

Solubility: ATR is insoluble in aqueous solutions with pH less than 4; it is very slightly

soluble in distilled water, phosphate buffer, pH (7.4) and acetonitrile. Slightly soluble in

ethanol, freely soluble in methanol.

pKa Value: 4.46


42

Log P Value: 6.36 (octanol/water)

Indications: ATR is indicated to reduce the risk of MI, stroke, revascularization procedures,

and angina in patients without CHD, but with multiple risk factors. To reduce the risk of MI

and stroke in patients with type 2 diabetes without CHD, but with multiple risk factors. To

reduce elevated total-C, LDL-C, apo B, and TG levels and increase HDL-C in adult patients

with primary hyperlipidemia (heterozygousfamilial and nonfamilial) and mixed dyslipidemia.

Pharmacological Class: ATR is HMG-CoA reductase inhibitor.

Pharmacokinetics:

Absorption

ATR is rapidly absorbed after oral administration; maximum plasma concentrations occur

within 1 to 2 hours. Extent of absorption increases in proportion to LIPITOR dose. The

absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic

availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low

systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or

hepatic first-pass metabolism. Food also decreases the rate and extent of drug absorption by

approximately 25% and 9%, respectively.

Distribution

Mean volume of distribution of LIPITOR is approximately 381 liters. ATR is ≥98% bound to

plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration

into red blood cells.

Metabolism

ATR is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-

oxidation products. Invitro inhibition of HMG-CoA reductase by ortho- and para

hydroxylated metabolites is equivalent to that of ATR. Approximately 70% of circulating

inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies

suggest the importance of ATR metabolism by cytochrome P450 3A4, consistent with

increased plasma concentrations of ATR in humans following co-administration with

erythromycin, a known inhibitor of this isozyme.

Chapter 2

43

Elimination

ATR and its metabolites are eliminated primarily in bile following hepatic and/or extra-

hepatic metabolism; however, the drug does not appear to undergo enterohepatic

recirculation. Mean plasma elimination half-life of LIPITOR in humans is approximately 14

hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to

the contribution of active metabolites. Less than 2% of a dose of LIPITOR is recovered in

urine following oral administration.

Pharmacodynamics:

ATR as well as some of its metabolites are pharmacologically active in humans. The liver is

the primary site of action and the principal site of cholesterol synthesis and LDL clearance.

Drug dosage, rather than systemic drug concentration, correlates better with LDL-C

reduction. Individualization of drug dosage should be based on therapeutic response.

Mechanism of action:

ATR is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme

that converts 3-hydroxy-3- methylglutaryl-coenzyme A to mevalonate, a precursor of sterols,

including cholesterol. Cholesterol and triglycerides circulate in the blood stream as part of

lipoprotein complexes.

Dose and Administration:

ATR is administered orally and it is available as tablets in strengths 10, 20, 40 and 80 mg.

Initial dose of 10 mg is administered with maximum of 80 mg of daily dose.

ASP and ATR fixed dose combination was approved by CDSCO in India on 18th Jan 2008.

This combination is indicted for the treatment of dyslipidemia associated with atherosclerotic

arterial disease with risk of myocardial infarction, stroke or peripheral vascular disease.


44

2.2 Literature review of drugs

2.2.1 Literature review for TAP

TAP is not official in any of the official compendia. Different analytical methods have been

reported for estimation of TAP alone as well as in combination with other drugs. Various

analytical methods available in literature are summarized in following table 2.1.

Table 2.1- Summary of various reported analytical methods for estimation of TAP

Analytical methods for TAP alone UV-Spectrophotometric Method

Matrix Details of Method Reference Bulk and Tab

Solvent: water. Wavelength: 272 nm Linearity: 25-150 µg/ml

(ADITHYA, Mahesh and Vijayalakshmi 52-55)

Bulk and Laboratory

Sample

1st derivative method Solvent: water. Wavelength: 228 nm Linearity: 5-60 µg/ml 2nd derivative Solvent: water. Wavelength: 235 nm Linearity: 5-60 µg/ml

(Mobrouk et al. 122-25)

Bulk and Tablets

Difference Spectroscopy In 0.1 N HCl and 0.1 N NaOH at wavelength 269.5 nm and 290 respectively. Linearity: 3 -18 µg/ml

(Anandakumar and Buddi 1586-90)

Bulk and Tab

Solvent: Methanol Wavelength: 272 nm Linearity: 20-100 µg/ml Spectrophotometric method Derivatizing agent: Folin-Ciocalteu reagent Wavelength:750 nm Linearity: 5 - 35 µg/ml

(Sherikar and Mehta 4134-40)

Spectrofluorimetric Method. Bulk and Tab

Solvent: Water Excitation Wavelength: 273 nm Emission Wavelength:298 nm Linearity:1 -10 µg/ml


RP- HPLC. Bulk and Tab

Column: HiQ Sil C8 column, 250 x 4.6 mm i.d, 5µm

Mobile Phase: 50mM phosphate buffer pH 3.62 and acetonitrile in ratio of 70:30 (% v/v) with 0.1% triethylamine Wavelength: 285 nm. Retention Time: 5.40 min.


Chapter 2

45

Bulk and Tablets

Column: Symmetry C18 (4.6 x 150mm, 5µm) Mobile Phase: Acetonitrile : Potassium dihydrogen orthophosphate buffer 0.1 M, pH 3.6 (50: 50%v/v) Wavelength: 243 nm. Retention Time: 3.16 min.

(Rizwana, Prakash and Mohan 755-62)

Bulk and Tablets

Column: Thermo Hypersil C18 column (250 mm x 4.6 mm; 5µm) Mobile Phase: Acetonitrile: Potassium dihydrogen orthophosphate buffer pH 7 (50: 50%v/v) Wavelength: 217 nm. Retention Time: 3.58 min.

(Shaik, Deepa and Agarwal 178-80)

Bulk and Tablets

Column: C18 column (250 mm x 4.6 mm; 5µm) Mobile Phase: solvent A Methanol: Solvent B Acidic water (pH 3.8 adjusted by using triethylamine and o-phosphoric acid) in ratio of (58:42 % v/v) Wavelength: 271 nm. Retention Time: 4.13 min.

(Rizwana, Prakash and Mohan 755-62)

HPTLC Bulk and Tablets

Plate – Precoated Silica gel 60 F 254

Mobile Phase - butanol :water : glacial acetic acid (6:2:2) v/v/v Densitometric detection at – 254 nm Rf Value for TAP – 0.68.

(Kathirvel S and K 51-55)

Stability Indicating Assay by RP- HPLC Bulk and Tab

Column: Enable column C-18, 250 x 4.6mm i.d. 5µm

Mobile Phase: phosphate buffer pH 6 and acetonitrile in ratio of 80:20 (% v/v) Wavelength: 215 nm. Retention Time: 7.7 min.

(Kathirvel, Satyanarayana and Devalarao 1-8)

Bulk and Tablet

Stability indicating assay with PCM RP – HPLC method Column: C-18, Hypersil BDS, 150 x 4.6mm i.d.

Mobile Phase: phosphate buffer pH 6.8 and methanol in ratio of 70:30 (% v/v) Wavelength: 215 nm. Retention Time: 4.65 min. (TAP) and 2.39 min (PCM)

(Ramanaiah et al. 391-96)

Bulk and Tablets

Column: Princeton C 8 column (250 mm x 4.6 mm; 5µm) Mobile Phase: Buffer (mixture of 10mM aqueous potassium dihydrogen orthophosphate and 0.1% triethylamine), pH adjusted to 3.0: Acetonitrile (65:35 v/v). Wavelength: 217 nm. Retention Time: 3.86 min.

(Marathe et al. 34-41)


46

Methods other than SIAM Urine Sample

Bioanalytical Estimation UPLC-MS method Column: Waters Acquity UPLC BEH Shield RP18 (2.1 mm × 50 mm × 1.7 µm). Mobile Phase: 0.1% formic acid (Solvent A) and acetonitrile (Solvent B) in gradeint mode. Detection: By Mass.

(Bourland et al. 450-57)

Bulk and Tablet

Related substance method by RP-HPLC Column: Zodiac C18 column (250 mm x 4.6 mm; 5µ)

Mobile Phase: phosphate buffer pH 7, acetonitrile and methanol in gradient mode. Wavelength: 220 nm. Retention Time: 14.0 min.

(Reddy and Sekhar 1-10)

Bulk

Enantioseparation by normal Phase chromatography

Column: Chiralcel OD-H (tris-[3.5-dimethylphenyl] carbamoyl cellulose, 250 mm × 4.6 mm, 5 µm) Mobile Phase: heptane–propan-2-ol–diethylamine (980:20:1, v/v/v). Fluorescence Detection: Excitation Wavelength: 273 nm Emission Wavelength:295 nm

(Douša et al. 111– 16)

Chapter 2

47

2.2.2 Literature review for FBX

FBX is not official in any of the official compendia. Different analytical methods have been

reported for estimation of FBX. Various analytical methods available in literature are

summarized in following table 2.2.

Table 2.2 Summary of analytical methods available for estimation of FBX

Analytical methods for FBX alone UV-Spectrophotometric Method

Matrix Details of Method Reference

Tablets

Difference spectrophotometric method. In 0.1 N HCl and 0.1 N NaOH at wavelength 260 nm and 315 respectively. Linearity: 5-25 µg/ml

(Sheth, Joshi and Patel 1621-24)

Tablet

Solvent: Methanol Wavelength: 316 nm Linearity: 2-20 µg/ml

(Sameer and Bhalekar 3122-23)

Bulk and Tablet

Solvent: Methanol Wavelength: 315 nm Linearity: 0.2- 15 µg/ml

(Bagga et al. 2655-59)

RP-HPLC Method

Bulk and Tablet

Column: C18 column 250 x 4.6 mm i.d, 5µm

Mobile Phase: Methanol:OPA (90:10) v/v Wavelength: 316 nm. Retention Time: 5.28 min.

(Lakade, Bhalekar and Harde 46-49)

Bulk and Tablet

Column: Symmetry C18 column 250 x 4.6 mm i.d, 5µm

Mobile Phase: Methanol: Phosphate Buffer (80:20) v/v Wavelength: 315 nm. Retention Time: 3.61 min.

(Krishnareddy et al. 3900-03)

Tablets

Column: Phenomenex, Luna C18 column (250 mm x 4.6 mm; 5µ) Mobile Phase: Water: Acetonitrile (30:70 % v/v) Wavelength: 314 nm. Retention Time: 2.49 min.

(Nasare et al. 137-42)


48

Bulk and Tablet

Column: Symmetry YMC C8 column (150 x4.6 mm; 3.0 µm) Mobile Phase: ACN: Phosphate Buffer (60:40) v/v Wavelength: 320 nm. Retention Time: 3.145 min.

(Rao, Ganapaty and Rao 1104 – 08)

Bulk

Column: Nucleosil C18 (250x4.6mm, 5µm in particle size) Mobile Phase: Isocratic elution with 10 mM ammonium acetate buffer (buffer of pH adjusted to 4.0 with 0.2% triethyl amine): acetonitrile (15 : 85, v/v) Wavelength: 275 nm. Retention Time: 3.45 min.

(Muvvala, Nadh Ratnakaram and Rao Nadendla 1358-66)

Stability Indicating Assay Method

Bulk and Tablet


Mobile Phase: tetra butyl ammonium hydrogen sulphate: acetonitrile (30:70, v/v) Wavelength: 216 nm. Retention Time: 5.73 min.

(Annapurna et al. 677-88)

. Bulk and Tablet


Mobile Phase: sodium acetate buffer (pH 4.0): acetonitrile (40:60, v/v) Wavelength: 254 nm. Retention Time: 3.47min.

(Mukthinuthalapati et al. 1–8)

Tablet

Column: symmetry C8 (4.6×150 mm i.d, particle size 3µm ) Mobile Phase: acetonitrile and 20mM sodium dihydrogen phosphate in water (pH 2.5 adjusted with orthophosphoric acid) in the ratio of 50:50 v/v Wavelength: 315 nm. Retention Time: 2. 35 min.

(Rajyalakshmi.Ch, Benjamin.T and babu.C 138-44)

Bulk

Column: C18, Waters Acquity BEH 150 x 2.1 mm, 1.7 µm. Mobile Phase: acetonitrile and ammonium acetate buffer (pH4.5) in the ratio of 70:30 (v/v) Wavelength: 315 nm. Retention Time: 2.04 min.

(Sahu, Shaharyar and Siddiqui 1-7)

Chapter 2

49

Impurity Profiling

Bulk

Column: Kromasil C18, 150 mm × 4.6 mm, 5 µm Mobile Phase: Mobile phase A consists of 0.01 M aqueous ammonium acetate and pH adjusted to 3.5 with Trifluoroacetic acid. Acetonitrile was used as Mobile phase B. Gradient Mode. Wavelength: 315 nm. Retention Time: 24.17 min.

(Kadivar et al. 749-57)

Bulk and Tablet

Related substance by RP – HPLC method Column: Poroshell 120 E18C18 column (500 mm x 4.6 mm; 2.7µ) Mobile Phase: Phosphate buffer (pH 3.0): Methanol Gradient Mode. Wavelength: 318 nm. Retention Time: 3.6 min.

(Reddy and Sekhar 1-10)


50

2.2.3 Literature review for ASP and ATR

ASP and ATR both are official in IP and USP. Additionally, ASP is also official in BP and

EP, official method for assay of ASP is titrimetric method where as for ATR official method

is HPLC. Since this combination is not official in any pharmacopoeia no official HPLC

method is available for their simultaneous estimation. Literature survey revealed several

analytical methods have been reported for estimation of ASP and ATR alone as well as in

combination with each other or in combination with other drugs by various analytical

techniques. The main objective of present study was to carry out stability study of ASP and

ATR alone and in combination. Hence in present literature survey articles in relation with

stability studies, as well as articles which are most relevant to present work and recently

reported has been taken in to consideration. Analytical methods for estimation of ASP and

ATR alone as well in combination with each other and in combination with other drugs are

summarized in following table 2.3.

Table 2.3 – Summary of analytical methods available for estimation of ASP and ATR in

literature.

Analytical methods for ASP alone Matrix Method Details Reference

RP-HPLC Method Tablets

Column: Hypersil BDS C18 (100 x 4.6 mm, 5µm) Mobile phase: sodium perchlorate buffer (pH 2.5): acetonitrile: isopropyl alcohol (85:14:1 % v/v). Detection wavelength: 275 nm. Retention Time: 4.68 min

(Kumar et al. 389-99)

Aerosol

Column: Econosphere, C8 5 µm, 4.6 × 250 mm Mobile phase: water, methanol. Tetrahydrofuran, 1 M phosphoric acid and water (44:5:5 water qs to 100 ml) Detection wavelength: 275 nm. Retention Time: 5.609 min

(Blondino and Byron 111-19)

API Column: Luna, C18 5 µm, 4.6 × 150 mm Mobile phase: Acetonitrile and ammonium acetate pH 4.5 (75:25) v/v Detection wavelength: 245 nm. Retention Time: 2.25 min

(Jain, Deepak Kumar, Nilesh Jain, and Jitendra Verma 218-21)

API Column: Kromasil C18 5 µm, 4.6 × 180 mm Mobile phase:Acetonitrile : Methanol (60:40) v/v Detection wavelength: 277 nm. Retention Time: 4.303 min

(Ramjith et al. 1-5)

Chapter 2

51

Analytical methods for ASP along with other drugs Matrix Method Details Reference Tablets

Along with dipyridamole

ASP and dipyridamole stability indicating RP-HPLC Column: Adsorbosil, C8 5 µm, 4.6 × 250 mm Mobile phase: water-acetonitrile-ortho-phosphoric acid (65:35:2 v/v/v) Detection wavelength: 250 nm. Retention Time: 3.8 min (ASP), 2.2 min (Dipyridamole)

(Hammud et al. 19-28)

Tablets

ASP and clopidogrel bisulphate RP-HPLC Method Column: Phenomenex Luna C18 (250 x 4.6 mm, 5µm) Mobile phase: acetonitrile: 50 mM potassium dihydrogen phosphate buffer, methanol, solution pH adjusted to 3, in the ratio 50:30: 20; v/v Detection wavelength: 240 nm. Retention Time: Clopidogrel bisulphate 7.47 min and ASP 2.2 min.

(Shrivastava et al. 667-69)

Tablets

ASP and clopidogrel bisulphate stability indicating HPTLC Method Stationary phase: TLC aluminum plates precoated with silica gel 60 F254 Mobile phase: carbon tetrachloride-acetone (6: 2.4 v/v). Detection wavelength: 220 nm. Retardation factor: Clopidogrel bisulphate 0.78 and ASP 0.13.

(Damle, Sinha and Bothra 152-60)

Tablets

ASP and paracetamol degradation studies by HPLC Column: Bondapak C18, (250 x 4.6 mm, 5µm) Mobile phase: methanol: water (35:65; v/v) adjusted to pH 3.1 with 10% orthophosphoric acid. Detection wavelength: 235 nm. Retention Time: paracetamol 2.675 min and ASP 6.60 min.

(Akay et al. 167-73)

Analytical methods for ATR alone Matrix Method Details Reference

Bulk and Tablet

Column: Lichrospher C18 (BDS) (250 x 4.6 mm, 5µm) Mobile phase: Potassium dihydrogen phosphate buffer pH-3.2 and acetonitrile in the ratio of 50:50 v/v Detection wavelength: 246 nm. Retention Time: for ATR 11.93 min.

(Surekha, Swamy and

Kumar 91-93)


52

Stability Indicating Assay Method Bulk

Column: C-18 column, Mobile phase: Ammonium acetate buffer (0.01 M, pH 3.0) and acetonitrile in a gradient mode. Detection wavelength :246 nm,

(Shah, Kumar and Singh 613-

22)

Bulk and Pharmaceutical

dosage form

Column: XTerra C18 (250 x 4.6 mm, 5µm) Mobile phase: Methanol: Acetonitrile : Potassium dihydrogen phosphate buffer 0.02 M pH- 6,85 in the ratio of 45:45:10 v/v Detection wavelength: 246 nm. Retention Time: for ATR 6.98 min.

(Zaheer et al. 204-10)

Bulk and Tablet

Column: Hypersil BDS, C18 (250 x 4.6 mm, 5µm) Mobile phase: Water: Acetonitrile 48:52 v/v pH adjusted to 2 with OPA. Detection wavelength: 245 nm. Retention Time: for ATR 6.5 min.

(Stanisz and Kania 471-76)

Bulk

Column: XBridge Shield RP 18, (150 x 4.6 mm, 3.5µm) Mobile phase: Gradient elution using 5% acetonitrile (mobile phase A) and 75% acetonitrile (mobile phase B) in 20mM ammonium acetate pH4.0 adjusted with acetic acid. Detection wavelength: 248 nm. Retention Time: for ATR 15.82 min.

(Kračun et al. 729-36)

Matrix Method Details Reference Analytical methods for ATR with other drugs

Tablet dosage form

Stability Study by RP-HPLC Method for ATR and Amlodipine

Column: Lichrospher C18, (100 x 4.6 mm, 5µm) Mobile phase: Acetonitrile and 50mM potassium dihydrogen phosphate buffer pH 3 in ratio of 60:40 v/v Detection wavelength: 254 nm. Retention Time: ATR 5.03 min and amlodipine 2.79 min

(Chaudhari, Patel and Shah

241-46)

Method Details

Tablet

Stability Study by RP-HPLC Method for ATR and Amlodipine

Column: Phenomenex Gemini C18 (250 x 4.6 mm, 5µm) Mobile phase: Methanol: Acetonitrile : Potassium dihydrogen phosphate buffer 0.02 M pH- 4 in the ratio of 45:45:10 v/v Detection wavelength: 240 nm. Retention Time: for ATR 11.6 min and amlodipine 4.5 min.

(Shah et al. 754-60)

Chapter 2

53

Tablet

Stability indicating UPLC Method for ATR and Fenofibrate

Column: Acquity UPLC BEHC18 (100 x 2.1 mm, 1.7µm) Mobile phase: Acetonitrile: Ammonium acetate buffer 0.01 M pH- 4.7, in gradient mode. Detection wavelength: 247 nm. Retention Time: for ATR 0.982 min and fenofibrate 2.29 min.

(Kadav and Vora 120-26)

Tablet

Stability Study by RP-HPLC Method for ATR and Nicotinic Acid

Column: Phenomenex C18 (250 x 4.6 mm, 5µm) Mobile phase: Acetonitrile : Potassium dihydrogen phosphate buffer 0.05 M pH- 4.5, 68:32, v/v Detection wavelength: 247 nm. Retention Time: for ATR 5.310 min and nicotinic acid 2.877

min.

(Gupta, Askarkar and

Wadodkar 294-303)

Matrix Analytical methods for ASP and ATR in combination Reference Capsule dosage form

RP-HPLC estimation Column: SS Grace C18 (250 x 4.6 mm, 5µm) Mobile phase: Acetonitrile : Ammonium acetate buffer 0.02 M pH- 4.5, 68:32, v/v Detection wavelength: 245 nm. Retention Time: for ATR 4.59 min and for ASP 3.28 min.

(Suma et al. 1449-56)

Capsule dosage form

HPTLC estimation Stationary phase: TLC aluminum plates precoated with silica gel 60 GF254. Mobile phase: chloroform: toluene: methanol: glacial acetic acid (4.5:6: 0.4:0.5 v/v/v/v). Detection wavelength: 247 nm. Retardation factor: ATR 0.61 and for ASP 0.84.

(Suma et al. 92-95)

Capsule dosage form

UPLC estimation of ASP, ATR and degradation products Column: Acquity UPLC BEHC18 (50 mm x 2.1 mm, 1.7µm) Mobile phase: Acetonitrile: Phosphate buffer 0.01 M pH- 2.0, in gradient mode. Detection wavelength: 247 nm. Retention Time: for ATR 1.919 min and fenofibrate 0.479 min.

(Vora and Kadav 2821-

37)

Plasma

Simultaneous estimation by LC-MS/MS Column: Zorbax XDB Phenyl column, (75 mm x 4.6 mm, 3.5 µm) Mobile phase: mixture of 0.2% acetic acid buffer, methanol, and acetonitrile 20:16:64, v/v/v Detection: ESI - MS

(Gajula et al. 923-40)


54

Matrix Analytical methods for ASP and ATR from Polypill Reference

Capsule

RP-HPLC determination of ASP, ATR, and pioglitazone

Column: Zorbax SBCN (250 x 4.6 mm, 5µm) Mobile Phase: Acetonitrile: Phosphate buffer with pH 3.5, pH was adjusted by using phosphoric acid, in the ratio of 40:60 v/v Detection wavelength: 261 nm. Retention Time: for ASP 4.039 min, pioglitazone 6.063 min, and ATR 14.423 min

(Rajavel et al. 40-42)

Matrix Analytical methods for ASP and ATR from Polypill Reference

Capsule

RP-HPLC determination of ASP, ATR, and Ramipril Column: C18 column (250 x 4.6 mm, 5µm) Mobile Phase: Methanol and acetate buffer, pH 3.1 adjusted with dil. orthophosphoric acid, in the ratio, 70:30 v/v Detection wavelength: 210 nm for ramipril, 245 nm for ATR, and 254 nm for ASP. Retention Time: for ASP 3.04 min, ramipril 5.62 min, and ATR 8.38 min.

(Patole et al. 40-45)

Capsule

Stress behavior of ASP, ATR, Ramipril and Metoprolol Succinate by UPLC

Column: Acquity BEH C18 column (100 x 4.6 mm, 1.7µm) Mobile Phase: 0.1% Perchloric acid (pH adjusted to 2.5) used as solution A & Acetonitrile as solution B in gradient mode. Detection wavelength: 215 nm Retention Time: for metoprolol 1.12 min, ASP 1.16 min, ramipril 1.42 min and ATR 1.78 min.

(Shetty et al. 401-10)

Bulk Drug

Separation of degradation / interaction products of lisinopril, aspirin, atenolol, hydrochlorothiazide and

simvastatin/atorvastatin/ pravastatin Column: C-8 Supelco Discovery (250mm×4.6mm i.d., particle size 5 µm) Mobile Phase: acetonitrile: phosphate buffer (10 mM, potassium dihydrogen orthophosphate, pH 2.3) in gradient mode. Detection wavelength: 210 nm

(Kumar, Shah and Singh 508-15)

Bulk Drug

Separation of degradation / interaction products of lisinopril, atenolol and aspirin by LC-MS/TOF

Column: C-8 Supelco Discovery (250mm×4.6mm i.d., particle size 5 µm) Mobile Phase: acetonitrile: water pH was adjusted to 2.3 using formic acid in gradient mode. Detection: By ESI-MS

(Kumar, Malik and Singh 619-28)

Chapter 2

55

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