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Chapter 2 Literature Review

School of Pharmaceutical Sciences, Shobhit University 40

2. Literature Review

Biswas et al., (2010) developed high performance liquid chromatography method for

determination of paracetamol, chlorzaxozone and diclofenac potassium. The

chromatographic method was standardized using a reverse phase C-18 column with UV

detector at 254 nm. Mobile phase consisted of methanol and (0.01M) monobasic sodium

phosphate (70:30) (pH was adjusted to 2.5 ± 0.2 using 10% orthophosphoric acid) and

the flow rate was 1 ml/min. The recovery values were between 99.65% and 101.20%.

The method was validated in terms of accuracy, precision, linearity, limit of detection,

limit of quantitation, robustness and ruggedness as per ICH guidelines. The method was

successfully applied for the determination of paracetamol, chlorzaxozone and diclofenac

potassium in marketed formulations 1

.

Freddy et al., (2010) carried out a simple, specific, accurate and economical isocratic

reverse phase liquid chromatographic (RP-HPLC) method for the determination of

paracetamol, acetyl salicylic acid, mefenamic acid and cetirizine dihydrochloride.

Separation was achieved with a Nucleodur, C–18 column having 250 x 4.6 mm i.d. with

5 μm particle size. Disodium hydrogen phosphate (pH-6.5) and acetonitrile (60:40 v⁄v)

was used as eluent at a constant flow rate of 1.0 ml/min. UV detection was performed at

220 nm. The retention times of acetyl salicylic acid, paracetamol, mefenamic acid and

cetirizine dihydrochloride were found to be 2.01 min, 2.92 min, 4.91 min and 10.2 min

respectively. The proposed method was validated and successfully used for estimation of

paracetamol, acetyl salicylic acid, mefenamic acid and cetirizine dihydrochloride in the

pharmaceutical dosage forms2.

Kasawar et al., (2010) developed and validated stability indicating RP-HPLC method

for simultaneous estimation of related substances of albuterol sulfate and ipratropium

bromide in nasal solution. Heat, acid, base, UV radiation and oxidation stress conditions

were applied to check the stability of combined dosage form. The chromatographic

conditions were optimized using an inertsil C-8 column with dimensions 250 mm x 4.6

mm, 5 µm. Mobile phase was consisted of solvent A (solution containing 2.5 g of

potassium di hydrogen phosphate and 2.87 gm of heptane-1-sulfonic acid sodium salt

per liter of water, adjusted to pH 4.0 with ortho phosphoric acid) and solvent B



(acetonitrile). Flow rate was maintained 1.0 ml min−1

. The analytes were detected and

quantified at 210 nm using photodiode array (PDA) detector3.

Kumudhavalli et al., (2010) developed a rapid, sensitive and specific RP-HPLC method

using UV detection for determination and quantification of pseudoephedrine

hydrochloride, cetirizine dihydrochloride and paracetamol and validated the same.

Optimization of chromatographic conditions was carried out on a pre-packed Crosmosil

C-8 (250x4.6 mm) column using filtered and degassed mixture of buffer and acetonitrile

in the ratio of 85:15 as mobile phase at a flow rate of 1.0 ml/min. Effluent was

monitored at 215 nm. The method was validated in terms of linearity, precision,

accuracy, robustness, ruggedness and specificity4.

Nora et al., (2010) developed RP-HPLC method for the simultaneous determination of

phenylephrine hydrochloride and chlorpheniramine maleate using UV

spectrophotometry. A reversed-phase column and mobile phase of methanol : water :

acetonitrile (80:12:8 v/v/v/) at 0.9 ml/min flow rate was used to separate both drugs with

a UV detection at 270 nm. The limit of detection was found to be 0.142 and 0.342 μg/ml

for phenylephrine hydrochloride and chlorpheniramine maleate. The limit of

quantification was noted to be 0.550 and 0.715μg/ml for phenylephrine hydrochloride

and chlorpheniramine maleate, respectively. Recovery values were between 99.79-

101.49%. They concluded that the proposed method was precise, accurate, selective and

rapid for the simultaneous determination of phenylephrine hydrochloride and

chlorpheniramine maleate. The results obtained using the proposed methods were

statistically analyzed5.

Fegade et al., (2009) carried out simultaneous estimation of paracetamol and piroxicam

in tablets. Separation was achieved on Eurosphere 100 C-18 as stationary phase. Mobile

phase was methanol: water (70:30). Detection wavelength was 227nm. Recovery values

were between 99.44 and 100.01%. The method was validated in terms of accuracy,

precision, linearity, limit of detection, limit of quantitation, robustness and ruggedness as

per ICH and USP guidelines. The method was successfully applied for the determination

of paracetamol and piroxicam in marketed formulations6.



Godse et al., (2009) reported a reverse phase HPLC method for determination of

aceclofenac and paracetamol in tablet dosage form. An ODS C18 (Intersile 25 cm x 4.6

mm, 10μm) column was used as stationary phase. Mobile phase used was methanol:

water (70:30 v/v) at flow rate of 1mL/min. Linearity was observed in the concentration

range of 2-50μg/ml for aceclofenac and 5-50μg/ml for paracetamol. Recoveries values of

aceclofenac and paracetamol were 100.6% and 100.7% respectively. They concluded

that the proposed method was precise, accurate, selective and rapid for the simultaneous

determination of aceclofenac and paracetamol7.

Hadad et al., (2009) worked on development and validation of stability- indicating RP-

HPLC method for determination of paracetmol with dantrolene or/and cetirizine and

pseudoephidrine in pharmaceutical dosage forms. Stability indicating capability of the

method was demonstrated by adequate separation of these four analytes from all the

degradants peaks. A gradient mobile phase system consisting of acetonitrile and 50

mmol/lit sodium dihydrogen phosphate, 5 mmol/lit heptane sulfonic acid sodium salt

was used. Separation was achieved by HS C18 analytical column. Quantitation was

monitored on UV detector at 214 nm. The developed method was sensitive, accurate and

precise8.

Karthikeyan et al., (2009) developed HPLC method for the determination of

paracetamol, chlorzoxazone and aceclofenac in pharmaceutical formulation. Separation

was achieved by Phenomenex C18 column using a mixture of acetonitrile: 0.05 M

disodium hydrogen orthophosphate (65:35) (pH 3.0) as a mobile phase. UV detection

wavelength was 271 nm. The calibration curves were linear in the range of 20-100μg/ml

for paracetamol, chlorzoxazone and 4-20 μg/ml for aceclofenac. LOD was found to be

0.9μg/ml, 1.81μg/ml and 0.9μg/ml for paracetamol, chlorzoxazone and aceclofenac

respectively. The method was validated in terms of accuracy, precision, linearity, limit of

detection, limit of quantitation, robustness and ruggedness as per ICH guidelines9.

Louhaichi et al., (2009) determined pseudoephdrine, pheniramine, guaifenesin,

pyrilamine, chlorpheniramine and dextromethorphan in cough and cold medicines using

HPLC. The separation was achieved by Kromasil C18 column as a stationary phase.



Mobile phase was methanol: di-hydrogen phosphate buffer (pH 3.0) (45:55). The

analyses were performed at flow rate 1ml/min and detection wavelength was 220 nm.

Range was 5-60μg/ml for pseudoephdrine, pheniramine, chlorpheniramine and 50-

600μg/ml for pyrilamine, dextromethorphan. The recovery values were between 98.5

and 101.71%10

.

Raman et al., (2009) validated stability-indicating RP-HPLC method for famciclovir.

The method used Intersil ODS 3 V (250 x 4.6mm, 5μm) column as a stationary phase.

The mobile phase used was mixture of 0.01 M potassium dihydrogen orthophosphate

buffer (pH 3.0) and methanol (80:20). The degradation products were well resolved from

standard peak and its impurities. They concluded that famciclovir degraded significantly

in oxidative, acid and base conditions and mildly in hydrolytic conditions. The

developed method was validated in terms of accuracy, precision, linearity, limit of

detection, limit of quantitation, robustness and ruggedness as per ICH guidelines11

.

Bhatia et al., (2008) reported reverse phase high performance liquid chromatography

and spectrophotometric method for the estimation of ambroxol hydrochloride and

cetirizine hydrochloride in combined dosage form. The chromatographic methods were

optimized using a (HIQSIL) C-18 column with dimensions 250 X 4.6 mm, i.d. 10 µm

particle size, with UV detection at 229 nm. Mobile phase used was mixture of methanol,

acetonitrile and water at fixed ratio of 40:40:20 v/v. The linearity range was 5–55μg/ml

and 10–40μg/ml for ambroxol hydrochloride and cetirizine hydrochloride respectively.

The method was validated in terms of accuracy, precision, linearity, limit of detection,

limit of quantitation, robustness and ruggedness as per ICH guidelines 12

.

Crevar et al., (2008) carried out RP-HPLC analysis of caffeine, paracetamol and its

degradation product p-aminophenol. Mobile phase was consisted of methanol and

phosphate buffer (20:80 v/v). The flow rate was 1 mL/min at 230nm. Separation was

achieved using Zorbax Extend C-18 Column (150 mm × 4.6 mm, 5 µm). The proposed

method was simple, accurate, economical, rapid and reproducible. The method was

validated in terms of accuracy, precision, linearity, limit of detection, limit of

quantitation, robustness and ruggedness as per ICH guidelines. The results obtained in

this study were precise, rapid and sensitive13

.



Karakus et al., (2008) developed and validated a rapid reverse phase high performance

liquid chromatography method for the determination of cetirizine or fexofenadine with

pseudoephedrine in binary pharmaceutical dosage forms. Separation was achieved by C-

18 column with mobile phase acetonitrile and phosphate buffer (60:40 v/v). The

wavelength was 230 nm. The recovery was more than 99%. The method was simple,

precise, rapid and reliable. The proposed method gave a good resolution between

cetirizine, fexofenadine and pseudoephedrine14

.

Nagappan et al., (2008) developed an RP-HPLC method for simultaneous estimation of

ambroxol hydrochloride and loratidine in pharmaceutical formulation. The method was

carried out on a Phenomenex Gemini C18 (25 cm x 4.6 mm i.d., 5 µ) column with a

mobile phase consisting of acetonitrile: 50 mM ammonium acetate (50:50 v/v) at a flow

rate of 1.0 ml/min. Detection was done at wavelength 255 nm. The method was


quantitation, robustness and ruggedness as per ICH guidelines15

.

Sawsan et al., (2008) reported simultaneous determination of phenylephrine

hydrochloride, guaifenesin, and chlorpheniramine maleate in cough syrup by gradient

liquid chromatography. Separation was achieved by C-8 column using 0.005 M heptane

sulfonic acid sodium salt (pH 3.4) and acetonitrile as a mobile phase by gradient elution

at different flow rates. The separated drugs were detected using UV detector at

wavelength 210 nm. The responses were linear in the concentration range of 30-

180μg/ml, 120-1800μg/ml and 10-60μg/ml for phenylephrine hydrochloride,

guaifenesin, and chlorpheniramine maleate respectively16

.

Shirkhedkar et al., (2008) carried out simultaneous determination of paracetamol and

piroxicam in tablets by HPLC combined with densitometry forms using a mixture of

n-dichloroethane, methanol and triethylamine (30:20:50 v/v) as mobile phase. The

wavelength was 284 nm with flow rate 1 mL/min. The developed HPLC method was

simple, precise, accurate and reproducible and can be used for simultaneous

determination of paracetamol and piroxicam in tablets17

.



Shaikh et al., (2008) carried out HPLC analysis for simultaneous estimation of

ambroxol hydrochloride and azithromycin in tablet dosage form. Chromatographic

separation was achieved on Xterra RP- 18 (250mm×4.6mm, 5µm) analytical column. A

mixture of acetonitrile: di potassium phosphate (30mM pH 9.0) in ratio 50:50, v/v at a

flow rate of 1.7 ml/min was used as mobile phase. The detection wavelength was 215

nm. The method was validated in terms of accuracy, precision, linearity, limit of

detection, limit of quantitation, robustness and ruggedness as per ICH guidelines. The

method was successfully applied for simultaneous determination of ambroxol

hydrochloride and azithromycin in marketed formulations18

.

Palabıyık et al., (2007) carried out HPLC analysis of phenylephrine hydrochloride,

paracetamol, chlorpheniramine maleate and dextromethorphan hydrobromide in

pharmaceutical preparations. The separation was achieved by C18 column using a

gradient mobile phase of acetonitrile: sodium perchlorate (pH 3, 0.01 M) at a flow rate

of 1.4 ml/min. Detection wavelength was 204 nm. LOQ for phenylephrine

hydrochloride, paracetamol, chlorpheniramine maleate and dextromethorphan

hydrobromide were 0.08μg/ml, 0.29μg/ml, 0.24μg/ml and 0.03 respectively. LOD for the

phenylephrine hydrochloride, paracetamol, chlorpheniramine maleate and

dextromethorphan hydrobromide was 0.03 μg/ml, 0.10μg/ml, 0.08μg/ml and 0.13μg/ml

respectively. The method was suitable for the determination of the four compounds in

sugar-coated tablet19

.

Bhavsar et al., (2006) estimated paracetamol and valdecoxib in combined dosage form

by RP-HPLC. Separation was achieved by Luna C18 column and methanol: phosphate

buffer (pH 3.5) (60: 40) as eluent. Detection wavelength was 242 nm. Etoricoxib was

used as an internal standard. Concentration range for paracetamol and valdecoxib was

25-150μg/ml and 1-6μg/ml respectively. The average recovery of paracetamol and

valdecoxib was 101.1% and 101.7% respectively. The method was validated in terms of

accuracy, precision, linearity, limit of detection, limit of quantitation, robustness and

ruggedness as per ICH guidelines. The developed method was accurate, precise and

selective20

.



Grossa et al., (2006) developed a simultaneous stability indicating, HPLC-DAD method

for determination of guaifenesin, methyl and propyl-parabens in cough syrup. The

isocratic separation and quantitation were achieved within 17 min on 150 mm column

with an ether-linked phenyl stationary phase and a hydrophilic end capping. The mobile

phase was consisted of eluent A: 10 mM aqueous phosphate buffer (pH 3.0) and

acetonitrile in ratio 25:75 (v/v) and eluent B as methanol. The eluent A and B were kept

in ratio 85:15 (v/v) with a flow rate 1ml min-1

. The detection of analytes was carried out

at dual wavelength as 254 and 276 nm. Heat, acid, base, UV radiation and oxidation

stress conditions were performed for stability of combined dosage form21

.

Kambia et al., (2006) determined stability and compatibility of paracetamol injection

with ketoprofen using HPLC. The mobile phase used was methanol and phosphate

buffer (65:35v/v) at 230 nm wavelength. The paracetamol and ketoprofen were

physically compatible and chemically stable upto 48 hrs at room temperature. The

method was validated in terms of accuracy, precision, linearity, limit of detection, limit

of quantitation, robustness and ruggedness as per ICH guidelines 22

.

Schieffer et al., (2006) developed a method for simultaneous estimation of

phenylepherine hydrochloride, phenylpropanolamine hydrochloride and guaifenesin in

dosage forms by reverse phase paired-ion high performance liquid chromatography.

Heat, acid, base, UV radiation and oxidation stress conditions were applied to study the

stability of combined dosage form. The separation was carried out on a Waters

Bondapak C18 column (300 x 3.9 mm). The eluent was 5 mM hexanesulfonic acid

sodium salt in 1% glacial acetic acid and methanol in ratio of 80/20 (v/v). Wavelength

for detection of drugs was kept at 220 nm23

.

Selvan et al., (2006) reported simultaneous estimation of ambroxol,

phenylpropanolamine, levocetirizine and paracetamol in combined dosage forms by

reversed-phase high performance liquid chromatography. The separation was carried out

by Hichrom C18 column with mobile phase acetonitrile: buffer: triethylamine

(30:70:0.5). Detection was carried out at 238nm. Tadalafil was used as an internal

standard. The LOD values for levocetirizine, ambroxol, phenylpropanolamine and



paracetamol were 5ng/ml, 100ng/ml, 200ng/ml and 15ng/ml and LOQ were 15ng/ml,

100ng/ml, 200ng/ml and 15ng/ml respectively. The recovery values were between 99.58

and 100.00%24

.

Sun et al., (2006) reported simultaneous determination of acetaminophen, caffeine and

chlorpheniramine maleate in pharmaceutical dosage forms. Separation and quantitation

were achieved by C18 column. The mobile phase was methanol: phosphate buffer

(45:55), containing 0.1% triethylamine and pH was adjusted 3.6 with phosphoric acid.

All drugs were detected by UV detector at 260 nm. The recovery values were between

99.25% and 101.98%. The method was simple, sensitive and could be used in estimation

of commercially available formulation25

.

Tan et al., (2006) carried out simultaneous determination of pseudoephedrine and

cetirizine in human plasma using liquid-chromatography–ion trap spectrometry by

Hypersil C-18 column with methanol and 1mM ammonium acetate (65:35v/v) as mobile

phase at 230 nm by UV detector. Bio-analytical study was specific, sensitive, accurate

and precise. The method was robust and can be successfully applied to pharmacokinetics

study of pseudoephedrine and cetirizine in human plasma26

.

Olmo et al., (2005) developed new approaches with cyano columns for the separation of

acetaminophen, phenylephrine, chlorpheniramine and related compounds. Separation

was achieved by discovery cyanopropyl (SUPELCO) column. Mobile phase was

aqueous: organic solvent (95:5, v/v). The method was validated in terms of accuracy,

precision, linearity, limit of detection, limit of quantitation, robustness and ruggedness.

Recovery values were observed between 102% and 108%27

.

Barbas et al., (2004) developed a stability indicating HPLC method for determination of

dextromethorphan and guaifenesin in cough syrup. Forced degradation study was also

carried out to check the stability of the syrup. Mobile phase used was phosphate buffer

(25 mM, pH 2.8) with triethylamine (TEA): acetonitrile (75:25, v/v). Stress conditions

like heat, acid, base, UV radiation and oxidations were applied to study the stability of

combined dosage form28

.



Ferrayolli et al., (2004) carried out validation of a chiral HPLC assay for (R)-salbutamol

sulfate. The method was validated in terms of specificity, robustness, linearity, precision

and accuracy. Under the chromatographic conditions of the method, known impurities

were separated from the active principle. Separation was achieved by 250mm × 4.6 mm

Chirobiotic T column (amphoteric glycopeptide teicoplanin bonded to a 5 µm silica gel).

A mixture with fixed ratio of acetonitrile, methanol, acetic acid, triethylamine in the ratio

60:40:0.3:0.2 (v/v/v/v) was used as mobile phase. Flow rate was kept at 1.5 ml min−1.

The drugs were monitored at 276 nm wavelength29

.

Marin et al., (2004) carried out LC/MS analysis for the degradation profiling of cough-

cold product under forced conditions. Heat, acid, base, UV radiation and oxidation stress

conditions were applied to study the stability of cough–cold products. Liquid

chromatography coupled with mass spectrometry was used to analyze the degraded

samples and obtain molecular weights information. Chromatographic analysis was

performed on a 5 µm particle, Discovery HS PEG column Supelco 15 cm x 0.46 cm at

35°C. Mobile phase was phosphate buffer 20 mM (pH 7.0) : acetonitrile 90:10 v/v. Flow

rate was 1.0 ml/ min with UV detection at 215 and 254 nm30

.

Basavaraj et al., (2003) reported HPLC method for simultaneous estimation of

paracetamol and cetirizine hydrochloride in tablet dosage form by C-18 column with

mobile phase acetonitrile and water (40:60 v/v). The UV detection wavelength was 230

nm. The retention time was 2.29, 3.5 and 5.88 minutes for paracetamol, cetirizine

hydrochloride and nimesulide, respectively. The % recovery was between 99.68 and

100.13. The method was validated in terms of accuracy, precision, linearity, limit of

detection, limit of quantitation, robustness and ruggedness as per ICH guidelines. The

proposed method was simple, accurate, economical, rapid and reproducible31

.

Garcia et al., (2003) developed HPLC method for determination of paracetamol,

phenylephrine hydrochloride and chlorpheniramine maleate in capsule using HS PEG C-

18 column with mobile phase consisting of 20 mM phosphate buffer and acetonitrile

(65:35v/v). The UV detection was performed at 215 nm for all compounds. The method



was validated in terms of accuracy, precision, linearity, limit of detection, limit of

quantitation, robustness and ruggedness as per ICH guidelines. The recovery values were

between 99.25% and 101.98%. The method was simple, sensitive and could be used in

estimation of commercially available formulations32

.

Goger et al., (2003) reported UV spectrophotometric and high performance liquid

chromatographic method for quantitative determination of ambroxol in tablet dosage

form. A reversed-phase C-18 column with mobile phase consisting of aqueous phosphate

(0.01 M), acetonitrile, glacial acetic acid (59:40:1, v/v/v) (pH 3.12) was used. UV

detection was done at 252 nm. The limit of detection was noted to be 0.278 and limit of

quantification was 0.705 μg/ml. Recovery was noted to be between 99.08 and 101.26%.

The method was evaluated for specificity, robustness, linearity, precision and accuracy33

.

Hood et al., (2003) carried out simultaneous analysis of codeine phosphate, ephedrine

HCl and chlorpheniramine maleate in cough syrup formulation. They used Eurosphere

100 C18 column as stationary phase. Mobile phase was methanol: water (70:30).

Detection wavelength was 227 nm. The method was validated in terms of accuracy,


per ICH guidelines. The method was applied for the analysis of these analytes in

commercially available tablets34

.

Kim et al., (2003) developed a simple method for determination of ambroxol in human

plasma using LC-MS/MS. The stationary phase was C-18 X-Terra MS column (2.1cm X

30 mm) with 3.5 µm particle size. The mobile phase was composed of 20 mM

ammonium acetate in 90% acetonitrile (pH 8.8). The flow rate was 2.50 ml/min. The

recovery values were between 100.35% and 101.28%. The method was validated in

terms of accuracy, precision, linearity, limit of detection, limit of quantitation, robustness

and ruggedness as per ICH guidelines. The proposed method was simple, accurate,

economical, rapid and reproducible35

.

Nagaralli et al., (2003) worked on liquid chromatographic determination of cetirizine

hydrochloride and paracetamol in human plasma and pharmaceutical formulations.



Separation was achieved by CLC C18 (5μ × 25cm×4.6mm i.d) column as a stationary

phase. Detection wavelength was 230 nm. The mobile phase was acetonitrile: water

(55:45 v/v). The linearity range was 0.715–55μg/ml and 0.55–39μg/ml for cetirizine and

paracetamol, respectively. The limits of detection were 0.248 and 0.208μg/ml and limits

of quantification were 0.550 and 0.715μg/ml for cetirizine and paracetamol respectively.

Recovery values were between 99.28 and 100.19%. The method was applied for the

analysis of these analytes in commercially available formulations36

.

Qi et al., (2003) carried out HPLC analysis of paracetamol, caffeine, chlorpheniramine

maleate and guaiacol glycerile ether in syrup by Diamonsil C-18 column with mobile

phase consisting of methanol and acetic acid (55:45v/v) at 215 nm. The retention times

were noted to be 4.8, 6.3, 7.5 and 9.5 minutes respectively for chlorpheniramine maleate,

paracetamol, caffeine and guaiacol glycerile ether. The recovery values were between

99.97% and 100.95%. The method was validated in terms of accuracy, precision,

linearity, limit of detection, limit of quantitation, robustness and ruggedness as per ICH

guidelines.

The proposed method was simple, accurate, economical, rapid and

reproducible. The method was sensitive and could be used in estimation of commercially

available formulations37

.

Wang et al., (2003) developed HPLC method for analysis of paracetamol, caffeine and

chlorpheniramine maleate in tablet using C-18 column with mobile phase 5 mM aq.

solution of hexane sulfphonic acid, 10 mM tri ethyl amine and 1% acetic acid and

(20:30:30v/v) and detection at 223 nm. The proposed method was simple, accurate,

economical, rapid and reproducible. The limits of detection were 0.532, 0.765 and 0.534

μg/ml and limits of quantification were 0.987, 0.875 and 0.782 μg/ml for paracetamol,

caffeine and chlorpheniramine maleate, respectively. Recovery values were between

100.08 and 101.19%. The method was successfully applied for simultaneous

determination of paracetamol, caffeine and chlorpheniramine maleate in marketed

formulations38

.

Marın et al., (2002) developed a new HPLC method for quantification of

acetaminophen, phenylephrine and chlorpheniramine in pharmaceutical formulations,



capsules and sachets using C-18 column. The mobile phase was mixture of 40 mM

phosphate buffer and acetonitrile (75:25 v/v). The detection was monitored at 238 nm.

The method was precise and accurate for determining concentrations in the range 0.15 to

0.46 mg/ml for acetaminophen, 0.003 to 0.009 mg/ml for phenylephrine and 0.001 to

0.004 mg/ml for chlorpheniramine39

.

Panda et al., (2002) reported simultaneous analysis of phenylpropanolamine,

chlorpheniramine and bromhexine in syrup by derivative spectrophotometry. The

analysis was done on spherisord C8 (4.6 × 250MM, 5 µm) column. The mobile phase

was acetonitrile and sodium dihydrogen orthophosphate (75:25). The flow rate was 1.5

mL/min. The detection wavelength was 224 nm. The proposed method was simple,

accurate, economical, rapid and reproducible40

.

Qi et al., (2002) carried out simple HPLC method for simultaneous determination of

acetaminophen, caffeine and chlorpheniramine maleate in tablet formulations. The

mobile phase was composed of 20 mM ammonium acetate in 60% acetonitrile (pH 4.5)

at a flow rate 1.5 ml/min. The method was validated in terms of accuracy, precision,


guidelines. Linearity, accuracy and precision were found to be acceptable over the ranges

31.6-315.8μg/ml for acetaminophen, 9.5-94.6μg/ml for caffeine and 1.4- 13.8μg/ml for

chlorpheniramine maleate. Recovery values were between 98.3 and 101.5%41

.

Senyuva et al., (2002) developed and validated high-performance liquid

chromatographic method for determination of paracetamol, phenylephrine HCl, and

chlorpheniramine maleate in pharmaceutical dosage forms. Separation was achieved

using Bondapak CN RP analytical column (125 Å, 10 μm, 3.9 × 150 mm) as stationary

phase. The mobile phase was mixture of acetonitrile and phosphate buffer (pH 6.22,

78:22). LOD for phenylephrine and chlorpheniramine was 0.0325μg/ml, 0.0272μg/ml.

LOQ was 0.251μg/ml and 0.184 for phenylephrine and chlorpheniramine respectively.

The recovery values were between 98.0 and 99.73%. It was concluded that method was

reliable and reproducible for the determination of the active ingredients in pediatric

cough–cold syrups42

.



Takagaki et al., (2002) developed and validated simple and sensitive method for

determination of chlorpheniramine maleate in human plasma using liquid

chromatography–mass spectrometry. The mobile phase used was water and acetonitrile

(60:40v/v) and detection was done at 238 nm wavelength. The developed LC–MS–MS

method was convenient and sensitive. The method was validated in terms of accuracy,


per ICH guidelines. The method was applied for the analysis of these analytes in

commercially available formulations43

.

Heinanen et al., (2001) carried out HPLC analysis for quantification of ambroxol

hydrochloride and benzoic acid in syrup dosage form for stability evaluation.

Chromatographic conditions for the method included; stationary phase symmetry shield

RP C8, 5 mm, 250 mm X 4.6 mm, and mobile phase methanol : H3PO4 ( 8.5 mM pH 2.8

adjusted with triethyl amine) in ratio 40:60 (v/v) at 247 nm. The recovery values were



.

Kartal et al., (2001) carried out LC method for the analysis of paracetamol, caffeine and

codeine phosphate in pharmaceutical preparations. Separation was achieved using

Bondapack C8 column with flow rate 1.0 ml/min. The mobile phase composition was

phosphate buffer, methanol, acetonitrile, isopropyl alcohol in the ratio of 20/20/30/30

(v/v/v/v). Detection was carried out at 215 nm. Linearity ranges were 0.400-1500μg/ml,

0.075-0.90μg/ml and 0.300-30μg/ml for paracetamol, caffeine and codeine phosphate

respectively. While the limits of detection were 0.150, 0.023 and 0.10μg/ml. Limits of

quantification were 0.400, 0.075 and 0.300μg/ml for paracetamol, caffeine and codeine

phosphate, respectively. Recovery values were between 94.40 and 106.09%. Method

was validated in terms of linearity, reproducibility, specificity, sensitivity and

ruggedness45

.

Celma et al., (2000) carried out simultaneous determination of paracetamol and

chlorpheniramine in human plasma by liquid chromatography–tandem mass

spectrometry. The mobile phase was composed of water and acetonitrile at flow rate 1.2



ml/min. The limits of detection were 0.15, and 0.32 μg/ml and limits of quantification

were 0.76, and 0.98 μg/ml for paracetamol and chlorpheniramine, respectively. Recovery

values were between 99.40 and 101.09%. LC–MS–MS method was accurate, precise and

reliable for estimation of paracetamol and chlorpheniramine concentrations in human

plasma after oral administration46

.

Koundourellis et al., (2000) developed a high performance chromatographic method for

estimation of ambroxol in presence of different preservatives in pharmaceutical

preparations. The eluents were monitored by UV detector at 247 nm. The mobile phase

used was 0.05 M ammonium acetate buffer (pH 3.45) with glacial acid and methanol in

ratio 30:70 (v/v). The method was validated in terms of accuracy, precision, linearity,

limit of detection, limit of quantitation, robustness and ruggedness as per ICH

guidelines.

The developed method was simple, accurate, economical, rapid and

reproducible47

.

Muszalska et al., (2000) worked on HPLC analysis of paracetamol, caffeine, ascorbic

acid and phenylephrine hydrochloride in tablet formulations using C-18 column with

mobile phase 0.015 phosphate buffer and methanol (65:35v/v) at 254 nm. The flow rate

was maintained at 1.2 ml/min. The method was simple, selective, rapid, accurate and

precise for simultaneous determination of these drugs. The recovery values were



.

Sahu et al., (2000) carried out spectrophotometric analysis for simultaneous

determination of chlorpheniramine maleate, phenylpropanolamine HCI and

dextromethorphan hydrobromide in syrup dosage forms. The wavelength maxima of

phenylpropanolamine and chlorpheniramine maleate and bromhexine hydrochloride in

0.1 N hydrochloric acid were found to be 257, 265 and 278nm respectively. The method


quantitation, robustness and ruggedness as per ICH guidelines. The drugs obeyed Beer’s

law in the concentration ranges of 200-600μg/ml, 10-32μg/ml and 50-160μg/ml for



phenylpropanolamine, chlorpheniramine and dextromethorphan respectively. The

recovery values were between 98.69% and 100.80%49

.

Stewart et al., (2000) carried out HPLC analysis for determination of guaifenesin with

selected medications on underivatized silica with an aqueous- organic mobile phase. The

separation and quantitation was achieved on a 25 cm underivatized silica column using a

mobile phase of (60:40 v/v) 6.25 mM phosphate buffer (pH 3.0) and acetonitrile at a

flow rate of 1 ml /min. UV detection of all analytes were done at 216 nm. The method


quantitation, robustness and ruggedness as per ICH guidelines. The developed method

was simple, accurate, economical, rapid and reproducible.50

.

Vasudevan et al., (2000) developed a liquid chromatographic method for simultaneous

estimation of phenylpropanolamine HCl, guaifenesin and diphenylpyraline HCl in syrup

dosage form. The stationary phase used was Shimpak® C8 column with mobile phase

acetonitrile, triethylamine buffer (pH adjusted to 3.5 using orthophosphoric acid; 0.5%),

in ratio 35:65 (v/v). The flow rate was maintained at 1.2 ml /min. Detection was carried

out at wavelength 210 nm. Recovery values were between 99.50 and 101.09%. The

method was successfully applied for simultaneous determination of

phenylpropanolamine HCl, guaifenesin and diphenylpyraline HCl in marketed

formulations51

.

Suzen et al., (1999) reported high performance liquid chromatographic method for

simultaneous estimation of guaifenesin and codeine phosphate in tablets. The separation

achieved on a Kromasil C-18 column. Isocratic mobile phase containing affixed ratio of

methanol–di hydrogen phosphate buffer at pH 3.0 (45:55, v/v) was used. The analysis

was performed at a flow rate of 1.0 ml min-1

and detection wavelength was 220 nm. The

method was validated in terms of specificity, robustness, linearity, precision and

accuracy. The limits of detection were 0.33 and 0.41 μg/ml for guaifenesin and codeine

phosphate and limits of quantification were 0.550 and 0.715μg/ml for guaifenesin and

codeine phosphate, respectively. The recovery values were between 98.95% and

100.88%52

.



Erka et al., (1998) reported simultaneous high performance liquid chromatographic and

derivative ratio spectra spectrophotometry determination of chlorpheniramine maleate

and phenylephrine hydrochloride by Li-Chrosorb C-18 column with mobile phase

methanol and phosphate buffer (70:30 v/v). The flow rate was maintained at 1.0 ml /min.

Detection was carried out at wavelength 267nm. Recovery values were between 100.01

and 100.92%. The method was successfully applied for simultaneous determination of

chlorpheniramine maleate and phenylephrine hydrochloride in marketed formulations53

.

Basley et al., (1997) investigated degradation of salbutamol after gamma irradiation

using HPLC and ESR spectroscopy. The separation was carried out on a Waters -

Bondapak C-18 column (300 x 3.9 mm). The eluent was 5 mM hexane sulfonic acid

sodium salt in 1% glacial acetic acid (aqueous) and methanol in a ratio of 80/20 (v/v).

The UV detection wavelength was 220 nm and flow rate was 1 ml/min. The method was


quantitation, robustness and ruggedness as per ICH guidelines. The developed method

was simple, accurate, economical, rapid and reproducible 54

.

Barnal et al., (1996) compared a high performance liquid chromatography with

superficial fluid chromatography for determination of salbutamol sulphate and its

impurities in pharmaceutical formulations. For optimum separation of active

compounds, gradient elution using aqueous buffer pH 3.0 and acetonitrile was

undertaken. The method was validated in terms of accuracy, precision, linearity, limit of

detection, limit of quantitation, robustness and ruggedness. The method was simple,

sensitive and could be used in estimation of commercially available formulations55

.

Yamato et al., (1996) carried out simultaneous determination of chlorpheniramine

maleate by high-performance liquid chromatography using tetra-n-butyl ammonium

phosphate as an ion-pair reagent. Separation was achieved by Capcell Pak C-8 column.

Isocratic mobile phase consisting of 50 mM KH2PO4, tetra-n-butyl ammonium

phosphate as an ion-pair reagent and methanol in the ratio of 80:2:18 v/v was used. The

UV detection was done at wavelength of 245 nm. The limit of detection was noted to be



0.31 μg/ml for chlorpheniramine maleate while the limit of quantification was 0.71

μg/ml. The method was simple and sensitive 56

.

Indrayanto et al., (1995) performed simultaneous assay of phenylpropanolamine HCl,

caffeine, paracetamol, glyceralguaiacolate and chlorpheniramine maleate in silabat

tablets using HPLC coupled with diode array detector. Analysis was carried out by

LiChrospher 100CN as stationary phase. Mobile phase was acetonitrile: tetrahydrofuan:

ion pair solution (7:6:87 v/v) (pH was adjusted at 3.3) at flow rate 1 ml/min. Detection

wavelengths were 265nm, 260nm, 298nm, 284nm and 310nm for phenylpropanolamine

HCl, chlorpheniramine maleate, caffeine, glyceralguaiacolate and paracetamol

respectively. The method was validated in terms of accuracy, precision, linearity, limit of

detection, limit of quantitation, robustness and ruggedness. The recovery values were

between 98.5 and 101.5%57

.

Laine et al., (1995) carried out HPLC analysis to study decomposition of salbutamol in

aqueous solution. They attempted to demonstrate the effect of different buffer

concentration, buffer species, role of pH, and antioxidants on stability of formulation. A

Li-Chrosorb reverse phase C-18 column (125 × 4 mm i.d., particle size 5 µm) was used

as stationary phase. The mobile phase consisted of acetonitrile, sodium dihydrogen

phosphate (40 mM) and triethylamine (5.74 mM). The flow rate was 1.5 ml/min at

wavelength 220 nm. The method was validated in terms of accuracy, precision, linearity,

limit of detection, limit of quantitation, robustness and ruggedness. The developed

method could be used in estimation of commercially available formulations 58

.

Yamaguchi et al., (1994) carried out high-performance liquid chromatographic

determination of phenylephrine in human serum. Separation was achieved by Intersil

ODS C-18 column with fluorescence spectrometer. Mobile phase was potassium di-

hydrogen phosphate and methanol in the ratio of 60:40 (v/v). Linearity range was 5-

500ng/ml. The recovery values were between 88.0 and 95.5%. The method was applied

for the determination of phenylephrine in human serum after oral administration of

phenylephrine hydrochloride59

.



Shanawany et al., (1990) worked on HPLC analysis of paracetamol, caffeine, ascorbic

acid and phenylephrine hydrochloride in tablet formulation. Separation was achieved

using Eurosphere 100 C-18 column, in isocratic mode. Mobile phase was methanol:

water (70:30 v/v). The flow rate was maintained at 1.0 ml/min. The detection

wavelength was 227 nm. The method was validated in terms of accuracy, precision,


guidelines. The developed method was simple, selective, rapid, accurate and precise. The

recovery values were between 100.11% and 101.33%60

.

Gupta et al., (1984) worked on quantitation of acetaminophen, chlorpheniramine

maleate, dextomethorphan HBr and phenylpropanolamine HCl in combination using

HPLC. The column Bondapak phenyl (30cm X 4mm i.d.) with three different mobile

phases was used for adequate separation of drugs at flow rate of 1 ml/min. Detection

wavelength was 256nm. Recovery values were between 98.7- 101.4%. The method was


quantitation, robustness and ruggedness. The developed method was simple, accurate,

economical, rapid and reproducible. The method was successfully applied for

simultaneous determination of acetaminophen, chlorpheniramine maleate,

dextomethorphan HBr and phenylpropanolamine HCl in marketed formulations61

.



2.1. Research Envisaged

Pharmaceutical analysis plays a very significant role in quality control of pharmaceutical

products through a rigid check on raw materials, in process samples and finished

products. It is instrumental in ensuring the quality of pharmaceutical products and

requires development of methods with high degree of accuracy and precision. The

accuracy and precision depend upon the relative and absolute errors. Errors will be

minimized if the method is simple. Thus simplicity of the method can be indirectly

related to accuracy and precision. Therefore it is one of the prime considerations while

developing analytical method.

Literature survey revealed that as such no HPLC method has yet been reported

for simultaneous estimation of the drugs selected for the present study. The drugs

include Ambroxol hydrochloride, Cetirizine hydrochloride, Chlorpheniramine maleate,

Guaiphenesin, Paracetamol, Phenylephrine hydrochloride and Salbutamol sulphate.

The nonavailability of HPLC method for the analysis of the combination of

above mentioned drugs made it worth while to pursue the present research work. The

objective of the present work was to develop simple, accurate, precise and rapid stability

indicating analytical methods for simultaneous estimation of the selected drugs in

marketed dosage forms.

The developed method was also validated as per ICH guidelines. Assay

validation assures the accuracy and reliability of test results for drug identity,

strength, quality and purity. A validated analytical method is often employed for product

testing at various critical stages of a manufacturing to check and ensure whether the

manufacturing process does what it purports to do.



2.2. Plan of Work

The work was carried out on the following lines;

Exhaustive literature survey

Selection of drug candidates

Method development

Procurement of drugs sample, chemicals and solvents

Selection of solvent system

Wavelength selection

Chromatographic conditions

(Column, mobile phase, pH, temperature, concentration range, modifier etc.)

Method validation with respect to parameters such as:

Linearity

Range

Specificity

Accuracy

Precision

Limit of detection

Limit of quantitation

Statistical validation

Estimation of selected drugs in marketed formulations

Stability studies

Compilation and submission of the thesis



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