Analytical Methods of Ciprofloxacin and its Combinations Review

 

Ghoufran Kawas, Mohammad Marouf, Oussama Mansour*, Amir Alhaj Sakur

1Pharmaceutical Chemistry and Quality Control Dept, Faculty of Pharmacy, Al Andalus University, Syria

2Dept. of Chemistry Faculty of Science Tishreen University, Syria.

*Corresponding Author E-mail: mansouroussama@yahoo.fr

 

ABSTRACT:

Ciprofloxacin is a second generic and an antibiotic generic drug. It is a very popular fluoroquinolone that can treat a number of bacterial infections. The quinolones are family or a group that has activity against both - negative and positive –gram bacteria, when compared to Ciprofloxacin. The first aim of this review is to provide a comprehensive update of analytical methods for determining the Ciprofloxacin and its combinations, binary or triple mixture use of endodontic treatment of primary teeth using a combination of antibacterial drugs. The other aim of this review is to evaluate clinical and radiographic success of the endodontic treatment of infected primary teeth using a combination of ciprofloxacin, metronidazole, minocycline, and clindamycin. Several methods were used in the analytical determination of Ciprofloxacin and its metabolites in human biological fluids (plasma) and in pharmaceutical preparations. various techniques have been reported, such as UV, TLC, GC- Mass, HPLC and RP-HPLC methods, for the determination of Ciprofloxacin alone and in its combinations by high performance liquid chromatography and reversed phase-high performance liquid chromatography. This review provides details on separation conditions for Ciprofloxacin alone and its combinations.

 

KEYWORDS: Ciprofloxacin, separation techniques, Chromatography, HPLC, RP-HPLC, endodontic treatment.

 

 


INTRODUCTION:

Ciprofloxacin hydrochloride is a pale yellow, slightly hygroscopic, crystalline powder, soluble in water, very slightly soluble in dehydrated alcohol, practically soluble in acetone, in dichloromethane, and in ethyl acetate, as well as in methyl alcohol. A 2.5% solution in water has a pH of 3.5 to 4.5 stored in airtight containers. Protected from light [1] Ciprofloxacin hydrochloride,  (Figure1) is chemically (1-cyclopropyl- 6- Fluoro- 4- oxo-7-(piperozin-1-yl)–mono-hydrochloride- quinolone-3-Carboxyl acid,  is a second generation Fluoroquinolone.

 

 

Figure 1: Chemical structure of Ciprofloxacin Hydrochloride

monohydrate

 

Molecular weight: 367.82 g/ mol

Molecular Formula: C17H18FN3O3.HCl

Ciprofloxacin is one of the most widely used and the most successful compounds of the class[2]. It was patented in 1983 by Bayer A. Grass, and subsequently approved by the united States in 1987.

 

Ciprofloxacin may interact with a number of other drugs, same herbal and natural supplements, and certain thyroid medications[3].

 

During the past 30-35 years, antimicrobial agents have been introduced at a rate exceeding our ability to integrate then into clinical practice[4-5]. The Novel of this review, a triple antibiotic mixture of ciprofloxacin, metronidazole, and minocycline or clindamycin was used as an intracranial (intracanal) medicament in an attempt to disinfect the root canal system for revascularization of a tooth with a necrotic pulp. However, discoloration developed after applying the triple antibiotic mixture [6-16].

 

Since their introduction, Fluoroquinolones [17] have become a mainstay in the treatment of serious bacterial Infections[18-19].

 

Some brands of Ciprofloxacin are mentioned in (table1).

 


 

Table1: Major brands of Ciprofloxacin Some Countries[20-21]  and Syria[22]

Name of Country

Brand name of Ciprofloxacin

Australia

C-Flox, Ciloquin, Ciloxan, Ciprol, Ciproxin, Profloxin, Proquin

Canada

Ciloxan, Cipro

Iceland

Biofloxacin,Cifloxager, Ciproxin, Profloxin, Truoxin

Syria

Ciproflex, ciproz, cipromed, sestendo

New Zealand

South Africa

Ciloxan, Cipflox, Ciproxin, Topistin, Ufexil

Adco- Ciprin, Biocip, Cifloc,Cifran, Ciloxan, Ciploxx, Cipro-Hexal, Ciprobay, Ciprogen, Dynafloc, Orpic, Spec- Topistin

United Kingdom

Ciloxan, Ciproxin

United States

Ciloxan,Cipro

India

Ciloxan, Cipron, Cifran, Ciplox

 

Table 2: Summary of HPLC methods for determination of Ciprofloxacin in Official methods

Drug/Dosage

Form

Method

Column

Mobile Phase

Elution

Flow Rate

(ml/min)

Temp

(0C)

tR

(min)

λ

(nm)

Ref.

Ciprofloxacin API,

Ciprofloxacin HCl

API, i.v. injection and tablet

HPLC

Stainless steel column (250 mm× 4.6 mm, 5 µm particle size)

0.025 M Phosphoric acid

(pH  3.0±0.1) previously  adjusted  with TEA : Acetonitrile

(87:13, v/v)

Isocratic

1.5

25

 

278

[23]

Ciprofloxacin HCl

API, i.v. infusion

and tablet

HPLC

Stainless steel column (250 mm × 4 mm, 5 µm particle size)

0.025 M Phosphoric acid

(pH  3.0±0.1)  previously  adjusted  with

TEA : Acetonitrile

(87:13, v/v)

Isocratic

1.5

25

 

278

[24]

 

Ciprofloxacin

eye drop

HPLC

Stainless steel column (250 mm

× 4.6 mm, 5 µm particle size)

0.005  M  Tetra  butyl

ammonium   phosphate   (pH   2.0±0.1)

previously  adjusted  with  o-Phosphoric

acid : Methanol

(75:25, v/v)

Isocratic

1.5

25

 

280

[25]

Ciprofloxacin API,

Ciprofloxacin HCl

API, Ciprpfloxacin injection and tablet

HPLC

Stainless steel column (250 mm× 4 mm, 5 µm particle size)

0.025 M Phosphoric acid

(pH  3.0±0.1)  previously  adjusted  with TEA : Acetonitrile

(87:13, v/v)

Isocratic

1.5

25

 

278

[26]

 


Determination Of Ciprofloxacin By HPLC or RP-HPLC Official Methods For Ciprofloxacin:

It is also the official method (table 2) in the United States pharmacopoeia, British pharmacopoeia and Brazilian pharmacopoeia[23-26] .

 

 

REPORTED METHODS FOR CIPROFLOXACIN:

In recent years, there has been rapid progress in quinolone research and development, resulting in the production of many clinically important Fluoro quinolones, which have been subjected to diverse analytical or assay methods. Various physicochemical properties of analytical methods have been used for the determination of Ciprofloxacin in pharmaceutical dosage forms and biological fluids. HPLC can be used efficiently in the analysis of ciprofloxacin as it offers rapid results and is specific and sensitive[27].

 

Different types of detectors such as UV or fluorescence detectors can be coupled to HPLC. UV detectors are often preferred because they are cheaper and widely available  [28]. Chromatographic retention times of over 10 minutes for ciprofloxacin have been reported in previously published studies[29-30].

 

Many important analytical researches for determination of Ciprofloxacin using HPLC or RP-HPLC were reported and summarized in Table3. Accurate and precise measurement of plasma drug concentrations was required. We describe a rapid, selective and sensitive HPLC method coupled with fluorescence detection for determination of ciprofloxacin in human plasma. Internal standard (IS; sarafloxacin) was added to plasma aliquots (200µL) prior to protein precipitation with acetonitrile. Ciprofloxacin and IS were eluted on a Synergy Max-RP analytical column (150mm×4.6mm i.d., 5µm particle size) maintained at 40 ◦C. The mobile phase comprised a mixture of aqueous ortho-phosphoric acid (0.025 M)/methanol/acetonitrile (75/13/12%, v/v/v); the pH was adjusted to 3.0 with trimethylamine. A fluorescence detector (excitation/emission wavelength of 278/450 nm) was used. Retention times for ciprofloxacin and IS were approximately 3.6 and 7.0 minutes, respectively. Calibration curves of ciprofloxacin were linear over the concentration range of 0.02–4µg/mL, with correlation coefficients (r2)≥0.998. Intra and inter-assay relative standard deviations (SD) were <8.0% and accuracy values ranged from 93% to 105% for quality control samples (0.2, 1.8 and 3.6µg/mL). The mean (SD) extraction recoveries for ciprofloxacin from spiked plasma at 0.08, 1.8 and 3.6µg/mL were 72.8±12.5% (n=5), 83.5±5.2% and 77.7±2.0%, in both cases). The recovery for IS was 94.5±7.9% (n=15). The limits of detection and quantification were 10 ng/mL and 20 ng/mL, respectively. Ciprofloxacin was stable in plasma for at least one month when stored at −15 ◦C to −25 ◦C and −70 ◦C to −90 ◦C. This method was successfully applied to measure plasma ciprofloxacin concentrations in a population pharmacokinetics study of ciprofloxacin in malnourished children[31].

 

Another accurate and precise RP-HPLC method was developed for the determination of Ciprofloxacin in tablet a simple, sensitive and stability indicative method for assay determination of drug substances ciprofloxacin hydrochloride by (HPLC).

 

 

Separation of impurities from the main drug substances and accurate assay quantification with a simple method is difficult by Spectrophotometry. The separation of co-eluents and impurities from the ciprofloxacin drug substances was archived by HPLC with simple mobile phase 0.15% orthophosphoric acid adjusted pH to 3.0 with triethylamine and acetonitrile using a gradient program, column inertsil C18, 250 mm × 4.0 mm, 5 μm. Flow rate was 0.7 mL/min, the column temperature and injection volume were 35˚C and 10.0 μL. Chromatographic analysis was carried out at wavelength 278 nm. The developed method was validated according to the international conference on harmonization (ICH) guidelines regarding: Precision, specificity by degradation, linearity, accuracy, range and robustness. The proposed method showed good linearity (correlation coefficient and regression coefficient were not less than 0.999 and 0.998) in the range of 50% to 150% of working concentration. The recovery at 50%, 100% and 150% of working concentration level was within 98.0% to 102.0%. The range of the method is concluded that developed method is from 50% to 150% of target concentration for ciprofloxacin hydrochloride. The applicability of the proposed method was verified through the analysis of the samples and percentage recoveries in the range of 98% to 102% were obtained without any interference detected at the main peak in the chromatogram. The validated method is highly selective, simple, accurate, cost effective, and it is applicable for stability studies and routine quality control analysis in the pharmaceutical industries[32].

 

Another simple and rapid method to determine ciprofloxacin concentrations in serum is described. Methods: the method has been validated for linearity, precision, accuracy and stability, following the guidelines for industry bioanalytical method validation recommended by the Food and Drug Administration (FDA). Serum samples were precipitated with acetonitrile. An RP-HPLC method with fluorescence detection was used (excitation and emission wave lengths for ciprofloxacin were 278 and 440 nm, respectively). The calibration range was 0.5 to 10.0 mg/L. Three quality controls (0.8, 4 and 8 mg/L) were tested. Results: The intra- and inter-assay variability was within 7.5%. The lower limit of quantification (LLOQ) was determined at 0.2 mg/L. The freeze-and-thaw, the short term, long-term, the stock solution and post-preparation stability were all determined and adequate. The extraction recovery was 82%, 87% and 88% at respectively 0.8, 4 and 8 mg/L. Conclusion: this simple and fast method is suitable for TDM and pharmacokinetic studies[33].

 

Although, A rapid and sensitive HPLC–UV method for the determination of ciprofloxacin in human plasma is described, Protein precipitation with acetonitrile was used to separate the drug from plasma protein. An ACE® 5 C18 column (250 mm×4.6 mm, 5µ m) with an isocratic mobile phase consisting of phosphate buffer (pH 2.7) and acetonitrile (77:23, v/v) was used for separation. The UV detector was set at 277 nm. The method was validated in the linear range of 0.05–8 µg/ml with acceptable inter- and intra-assay precision, accuracy and stability. The method is simple and rapid and can be used to quantify this widely used antibiotic in the plasma of patients suffering from Peripheral Arterial Disease[34].

 

Other methods: A liquid chromatography with fluorescence detection method was developed and validated for determining ciprofloxacin concentrations in two different matrices: plasma and prostate micro dialysate. Ciprofloxacin was separated on a C18 column eluted with a mobile phase constituted of a mixture of 0.4% aqueous tri-ethylamine: methanol: acetonitrile (75:15:10, v/v/v) and 0.4%aqueous tri-ethylamine: acetonitrile (88:12, v/v) for micro dialysate and plasma samples, respectively. Linearity was obtained over a concentration range of 5–1000 ng/mL (micro dialysate) and 10–2000 ng/mL (plasma), with coefficients of determination ≥0.9956. Precision was determined from the analysis of six quality control samples and showed RSD values <11.1 and 7.4% for intra and inter-assay precision, respectively. The accuracy ranged from 85.6 to 114.3%. The method was applied to a preliminary pharmacokinetic study to investigate ciprofloxacin concentrations in prostate, sampled by micro dialysis, and plasma after a 7 mg/kg intravenous dose to Westar rats. The method showed high sensitivity using only protein precipitation as plasma sample clean-up and was successfully applied to investigate ciprofloxacin prostate penetration [35].

A simple, precise, and rapid high performance liquid chromatography (HPLC) method for the determination of ciprofloxacin level in human plasma using gatifloxacin as an internal standard (IS) was developed and validated. 0.5 ml Plasma samples containing ciprofloxacin were mixed with 200 μl of IS (50 μg/ ml in buffer) and filtered through a centrifugal filter device by centrifuging at 4000 rpm for 30 minutes. A 100 μl of ultra-filtrate clear solution was injected in the HPLC system.

 

The compounds of interest were efficiently separated on Xterra RP-18 (4.6 x 150 mm, 5-μm) steel column (25şC) proceeded by a universal sentry guard column (symmetry C18, 5-μm insert) and detected with a photodiode array detector set at 276 nm. The mobile phase consisted of a mixture of 0.025 M of sodium phosphate monobasic (pH=3.0, adjusted with phosphoric acid) and acetonitrile (85:15, v:v). The mobile phase was delivered at a flow rate of 1 ml/min and run for 10 min. No interference in blank plasma or by commonly used drugs was observed, and the detection limit of ciprofloxacin was 0.05 μg/ml. The relationship between ciprofloxacin concentration in plasma and peak area ratio of ciprofloxacin /IS was linear (R2 ≥ 0.9997) in the range of 0.1–12.0 μg/ml. Intra- and inter-day coefficient of variation and bias were ≤ 7.0% and ≤ 11.1%, respectively. Mean extraction recovery of ciprofloxacin and the IS from the plasma samples were ≥ 90%, and 85%, respectively. Using the method, ciprofloxacin in found to be stable in human plasma for 16 weeks at -20 ˚C. Further, the method was successfully employed to measure ciprofloxacin level in plasma samples from a healthy volunteer [36].

 

 


 

Table3: Summary of HPLC methods for determination of Ciprofloxacin in Reported method

Drug/Dosage

Form

Method

Column

Mobile Phase

Elution

Flow Rate

(ml/min)

Temp.

(°C)

tR

(min)

LOQ

μg/mL

λ

(nm)

Ref.

Ciprofloxacin in  plasma and urine

HPLC

Bondaback C-18 Column (150mm ×4mm, 10 µm Particle Size)

50 ml/lit Acetic acid: Acetonitrile

(9 : l,v/v)

Isocratic

2.0

 

 

 

280

[37]

Ciprofloxacin in human plasma

HPLC

Novapack  C-18 Column (150mm ×4.6mm, 10 µm Particle Size)

0.01 M Phosphate Buffer

(pH  2.6  ± 0.1) 

(82:18, v/v)

Isocratic

2.0

 

 

 

277

[38]

Ciprofloxacin HC tabletl

HPLC

Lichro CART® C-18 Column (125mm ×4.6 mm, 5 µm Particle Size)

0.025 M Phosphoric acid

(pH  3.0 ± 0.1)  l

(60:40,v/v

Isocratic

2.0

 

 

 

278

[39]

Ciprofloxacinl  tablet

HPLC

Phenomenex  C -18 Column (125mm ×4.6mm, 5 µm Particle Size)

Acetonitrile: 2%  Acetic acid  aqueous  solution

 

(16:84, v/v)

Isocratic

1.0

 

 

 

280

[40]

Ciprofloxacin HCl  API,

 

Stability

indicating

RP-HPLC

Phenomenex  C18  column ( 250 mm× 4.6 mm, 5 µm particle size)

Potassium  dihydrogen   o-phosphate  (pH  3.0 ± 0.1) 

(80:20 v/v)

1.0

 

 

 

278

[41]

Ciprofloxacin HCl  tablet

 

HPLC

Stainless steel C-18   column (125 mm× 4 mm, 5 µm particle size)

0.025 M Orthophosphoric acid + Triethylamine

(pH  3.0 ± 0.1) 

(40:60, v/v)

2.0

40

1.750-1.753

 

278

[42]

Ciprofloxacin HCl Bulck drug and from formulations

RP-HPLC

Stainless steel C-18   column (250 mm×4.6 mm, 5 µm particle size)

Water- acetonitrile- triethylamine

(pH 4.0 ± 0.1) 

(75:25:0.1

v/v/v)

1 .0

 

4.0

8.01

254

 

[43]

 

Ciprofloxacin

HCl  Film –

Coated

Tablets

HPLC

Inertsil ODS3 C8

Column

(250mm ×4.6 mm,5

µm Particle Size)

2.45g of phosphoric

Acid with water

(pH  3.0 ± 0.1)

 

 

1.5

60

 

15.632

278

[44]

Ciprofloxacin

Drug in Serun

And Urine

RP-HPLC

C18 Column

 

Phosphate buffer/

Acetonitrile/

Methanol

(81/5/14

By vol)

1.5

25

8.03

12.79

 

270

440

[45]

Ciprofloxacin

Pharmaceutical

and in

human plasma

RP-HPLC

C18 Column

(150mm ×4.6 mm,5

µm Particle Size)

Acetonitrile and

2% acetic acid

Aqueous solution

( 84/16 v/v)

1.0

25

6.5

 

280

[46]

Ciprofloxacin

Pharmaceutical

preparations

RP-HPLC

C18 Column

(250mm ×4.6 mm,5

µm Particle Size)

Acetonitrile –

Methanol- acetate

Buffer (pH 3.6 ;

0.05M)

(10:30:60

v/v/v)

0.8

45

9

 

300

458

[47]

Ciprofloxacin

Pharmaceutical

products

HPLC

C18 Column

(250mm ×4.6 mm,5

µm Particle Size)

Water: acetonitrile:

Phosphoric acid

(800:200:2  v/v/v)

1.5

25

 

 

 

278

[48]

Ciprofloxacin

In Jiaozhou

Seawater

HPLC

C18 Column (Hitachi;

Japan)

(250mm ×4.6 mm,5

µm Particle Size)

25mM

Orthophosphoric acid

(pH 2.4) With

Trietylamine :

Acetonitrile

( 82/18; v/v)

0.8

25

6.5

0.67

280

[49]

 

Ciprofloxacin

In human

plasma

RP-HPLC

Xterna RP-18 Steel

Column

(250mm ×4.6 mm,5

µm Particle Size)

0.025M Sodium

Phosphate(pH 3

 

85/15;v/v)

1.0

25

 

 

276

[50]

ciprofloxacin

In human

Plasma

HPLC

C18 Bondapack column (250 mm × 3.9 mm)

acetonitrile: potassium dihydrogen

 

(20:80, v/v,

1.5

40

9.064

0.025

276

[51]

 

 

Table4: Summary of HPLC methods for determination of Ciprofloxacin in Combination

Drug/Dosage

Form

Method

Column

Mobile Phase

Elution

Flow Rate

 

Temp.

(°C)

tR

(min)

LOQ

μg/mL

λ

(nm)

Ref.

Ciprofloxacin and Tinidazole in tablet

RP-HPLC

Inersil ODS C-18 Column (250mm ×4.6 mm, 5 µm)

Isocratic system of

Water: Methanol

(60 : 40

, v/v)

0.8

25

 

 

316

[52]

Ciprofloxacin and Tinidazole in tablet

Stability indicating

RP-UPLC

Purospher star    C-18 Column (100mm ×2.1mm, 2µm)

Potassium

dihydrogen   o-phosphate  Buffer

(pH  3  ± 0.1) : Acetonitrile

(8o:20, v/v)

Isocratic

0.3

70

1.71 (Cip)

2.22 (Tini)

0.193 (Cip)

0.030 (Tini)

278.5 (Cip)

317.5 (Tini)

[53]

Ciprofloxacin and Dexamethasone in eye/ear drop

RP-HPLC

Grace smart C-18 Column (250 mm ×4.6 mm, 5 µm Particle Size)

Methanol :Water:

Triethlamine

(pH  3.0 ± 0.1)

With O-Phosphoric acid

(59:45:0.6

v/v/v)

Isocratic

system

0.8

25

4.123 (Cip)

9.688 (Dex)

0.89 (Cip)

0.77 (Dex)

254

[54]

Ciprofloxacin HCl and Lomefloxacin in

presence of acid

degradation product

RP-HPLC

Bondapack C18

Column (250 mm ×4.6 mm, 5 µm Particle Size)

Water: acetonitrile:

Triethylamine

With O-Phosphoric acid

 

(80:20:0.6

v/v/v)

Isocratic

system

1.5

25

 

 

328

[55]

Ciprofloxacin HCl and Norfloxacin in pharmaceutical

formulation

HPLC

LiChrospher®100  C18  column ( 125 mm× 4.0 mm, 5 µm particle size)

Water: acetonitrile:

Triethylamine

With O-Phosphoric acid

 

(80:20:0.3

v/v/v)

Isocratic

system

1.0

24±2

5

 

279

[56]

Ciprofloxacin HCl and Metronidazole

in bulk drug and  suspension

RP-HPLC

LiChrospher®100C18  column        (125 mm×4.0 mm, 5 µm particle size)

Phosphate buffer :

Acetonitrile

 

(80: 20, v/v)

1.0

25

3.51 (Metro)

6.84 (Cip)

0.5 (Metro)

1.0 (Cip)

290

[57]

Ciprofloxacin HCl

Doxycycline and

Phenazopyridine

HCl in bulk and

tablet dosage form

RP-UPLC

 

BHE C18   column

(500 mm× 2.1 mm,

1.7 µm particle size)

0.05 M Ammonium acetate buffer pH

 

(50: 50, v/v)

1 .0

25

0.90 (Cip)

1.60 (Doxy)

4.17 (Phena)

 

278 (Cip)

350 (Doxy)

378 (Phena)

[58]

Ciprofloxacin HCl

Ofloxacin,,Tinidazole and Ornidazole in bulk

RP-HPLC

Phenomene C18

Column (250mm ×

4.6 mm, 5  µm

Particle Size)

Water:acetonitrile:

Triethylamine

With O-Phosphoric acid

(80:20:0.6

v/v/v)

Isocratic

system

1.0

25

 

 

300

[59]

Ciprofloxacin

Enrofloxacin

and

Balofloxacin in

broiler chicken

Muscle

RP-HPLC

 

Phenomene C18

Column (150mm ×

4.6 mm, 5  µm

Particle Size)

 

Water:acetonitrile:

Triethylamine

With O-Phosphoric acid

 

(80:19:1

v/v/v)

Isocratic

system

1.2

 

2.688 (Cip)

3.365 (EFX)

7.343 (BFX)

 

295

[60]

 

Ciprofloxacin

And Ornidazole

In tablet

RP-HPLC

Zorabax C18

Column (250mm ×

4.6 mm, 5  µm

Particle Size)

Acetonitrile: water

(pH 3 adjusted with

O-Phosphoric acid)

(45:55, v/v)

Isocratic

system

1.0

25

1.96 (CPF)

4.33 (ORD)

 

299

[61]

 

Ciprofloxacin

And

Tinidazole In bulk and

Pharmaceutical

Dosage

RP-HPLC

Zorabax  Rx-phase

C18Column

(150mm ×

4.6 mm, 5  µm

Particle Size)

O-Phosphoric acid

(pH 3):  Methanol

 

(70:30, v/v)

Isocratic

system

1.5

50

2.3 (CPF)

7.2 (TDZ)

5 (CPF)

3 (TDZ)

225

[62]

Ciprofloxacin

And Tinidazole

Forced

degradation

RP-HPLC

Revere phase-

C18 Column

(100mm ×2.1 mm, 2µm Particle Size)

Phosphate Buffer:

Acetonitrile

(pH 3 adjusted with

O-Phosphoric acid)

(80:20,v/v

 

0.3

60

 

1.71 (CH)

2.22 (TZ)

0.193 (CH)

0.0304 (TZ)

278.5 (CH)

317.5 (TZ)

[63]

 

Ciprofloxacin

And Norfloxacin

In

Pharmaceutical

Preparation

RP-HPLC

LiChrospher®

RP-18 Column

(125mm ×4 mm,5µm)

Water: acetonitrile:

Triethylamine

the pH of final mixture

 

(80:20:0.3

v/v/v)

1.0

24±2

2.45 (CIP)

2.30 (NOR)

 

 

279

[64]

Ciprofloxacin

And Tinidazole

RP-HPLC

Luna RP-C18 Column

(250mm ×4.6 mm, 5µm Particle Size)

Acetonitrile:water:

Trimethylamine

(30:67: 3

v/v/v)

1.0

25

8.43 (CP)

4.82 (TZ)

 

296

[65]

 

Ciprofloxacin

HCl and

Tinidazole in

Bulk and tablet

RP-HPLC

Inerstil- BDS C18

Column

(250mm ×4.6 mm, 5µm)

Methanol : O-

phosphoric acid

 

( 55:45; v/v)

1.0

27

3.539 (CP)

2.955 (TZ)

1.74 (CP)

1.69 (TZ)

245

[66]

 

Ciprfloxacin

and

Phenylephrine

In Pharmaceytical

Dosage form

HPLC

Zorbax Bonus RP C18Column

Water:acetonitrile:

Triethyleamine

pH 3

 

(85: 15:0.1,

v/v/v)

Isocratic

1.0

25

3.71 (CIP)

2.17 (PHE)

7.91 (CIP)

0.75 (PHE)

272

[67]

 

Ciprfloxacin and Phenazopyridine in combined tablet dosage form.

RP-UPLC

 

C18   column

(250 mm× 4.6 mm, 5 µm particle size)

 

Ammonium  Ortho –Phosphate (0.01N, pH 3.5 n

(50: 50, v/v)

1 .0

25

2.783 (CPX)

4.111 (PZD)

4.38 (CPX)

2.92 (PZD)

275

[68]

Ciprofloxacin HCl

,Tinidazole and Dicyclomine

In Bulk and

Tablet

RP-HPLC

 

Hiq Sil C18

Column (250mm ×4.6 mm, 5  µm

Particle Size)

Buffer pH 4.0:

Methanol

 

(60:40,v/v)

Isocratic

system

system

1.0

26

5.42 (TNZ)

6.96 (DIC )

8.04 (CPX )

0.00244 (CPX)

0.00996 (TNZ)

0.00478 (DIC)

218

[69]

 

 

Ciprofloxacin

HCl,and

Tinidazole in

Combined

Tablet

RP-HPLC

Inertsil C18

Column (250mm ×

4.6 mm, 5  µm

Particle Size)

Phosphate buffer

(pH 6.8):acetonitrile

(82:18, v/v)

Isocratic

system

1.0

25

5.6 (CIP)

9.82 (TNZ)

 

316

[70]

Ciprofloxacin

And

Levofloxacin in

Human sputum

MEPS–

HPLC–

PDA

 

C8 Column (250mm ×

4.6 mm, 5  µm)

 

Phosphoric acid

(buffer at pH 2.5)

1% triethylamine

(86:14, v/v)

Isocratic

system

1.0

25

12.989 (Levo)

9.661 (CF)

0.05

295 (Levo)

279  (CF)

[71]

 

Ciprofloxacin

HCl,and

Ofloxacin in

Dosage forms

RP-HPLC

Column Sil C18-RP

(125mm ×4.6 mm,

5 µm)

 

Phosphate buffer

(15mM):Methanol

Acetonitrile:

Trimethylamine

At pH 6.5

(66:24:10:1 %

v/v/v/v)

Isocratic

system

1.0

25

3.01 (CPL)

6.03 (OFX)

0.47 (CPL)

0.14 (OFX)

289

 

[72]

Ciprofloxacin

HCl And

Ornidazole in

Human plasma

RP-HPLC

Revere phase-

C18 Column

(250mm ×4.6mm, 5µm Particle Size)

Acetonitrile:

Methanol:water:

triethylamine

(40:20:40:

1% v/v/v/v)

Isocratic

system

1.0

28

2.13 (CIP)

4.91 (ODZ)

1.50 (CIP)

8.33 (ODZ)

300

[73]

Ciprofloxacin

And

Levofloxacin

In human

Prostate tissue

HPLC-ESI-

MS/MS

ES RP-18 Column

(2.1mm ×50 mm, 2.7 µm)

0.1% F0rmic acid aqueous:0.1% Formic acid methanol solution

(79:21, v/v)

0.5

40

2.9 (CPR)

1.9 (LVF)

0.13 (CPR)

0.2 (LVF)

 

[74]

 

Ciprofloxacin

HCl and

Tinidazole in

Bulk and tablet

RP-HPLC

Inerstil- BDS C18

Column

(250mm ×4.6 mm, 5 µm Particle Size)

Methanol : O-

phosphoric acid

 

( 55:45; v/v)

1.0

27

3.539 (CP)

2.955 (TZ)

1.74 (CP)

1.69 (TZ)

245

[75]

 

 

 


REPORTED METHODS FOR CIPROFLOXACIN IN COMBINATION:

Various analytical methods have been reported for the assay of Ciprofloxacin alone or in combination with other antibacterial agents pharmaceutical formulations (tables 4).

 

However many methods were reported. Thus far, no HPLC or RP- HPLC method has been reported for the simultaneous estimation of ciprofloxacin, metronidazole and minocycline or ciprofloxacin, metronidazole and clindamycin in combined dosage forms. In the present investigation, an attempt has been made to develop accurate and precise HPLC or RP-HPLC method for the simultaneous estimation of ciprofloxacin and another antibiotic  like metronidazole , clindamycin and another mixtures with ciprofloxacin like  metronidazole, minocycline with in combined dosage forms

CONCLUSION:

A few methods for determination of Ciprofloxacin or its metabolites have been reported. Many HPLC or RP-HPLC assay methods were also used to monitor Ciprofloxacin. Methods For the analysis of Ciprofloxacin and another antibiotic has also been reported. Some articles related to the determination of Ciprofloxacin alone or in its combination in pharmaceutical dosage forms has been mentioned.

A triple antibiotic mixture of ciprofloxacin, metronidazole, and minocycline was used as an intracranial medicament in attempt to disinfect the root canal system for revascularization of a tooth with a necrotic pulp, However, discoloration developed after applying the triple antibiotic mixture.

 

 

 

REFERENCE:

1        Martindale. The Complete Drug Reference. 33rd ed, Pharmaceutical Press. Taunton, Massachusetts, USA, 2009.

2        Appelbaum PC, Hunter PA. The fluoroquinolone antibacterial: past, present and future perspectives. Int J Antimicrob Agents. (16); 2000: 5-15.

3        Cooper IG, Harboe K, Frost SK, Skadberg O. Ciprofloxacin interacts with thyroid replacement therapy. BMJ. (330); 2005: 1002.

4        Dax Sl. Antibacterial Chemotherapeutic Agents. London: Blackie Academic& professional. 1997: 298-315.

5        Lee C, Ronald AR. Norfloxacin:its potential in clinical practice.Am J Med. (82); 1987: 27-34.

6        Takushing T, Cruz E.V, Asgor AM and Hoshino E. Endodontic treatment of primary teeth using a combination of antibacterial drugs. Inter Endodontic J. (37); 2004: 132-138.

7        Divya S, Retnakumari N. Lesion Sterilization and Tissue Repair in Primary Teeth with Periapical  Pathosis - A Case Series. (IOSR-JDMS). (13)3; 2014:7-11.

8        Dasari V, Maroli S, Chowdary L, Karukola R, Premakumar S.H, Vusurumarthi V. An in vivo  study   evaluating lesion sterilization and tissue repair 3 MIXMP noninstrumentation endodontic treatment as an alternative to conventional endodontic retreatment. CHRISMED Journal of Health and Research. (34)111; 2017: 284-287.

9        Kim J.H, Kim Y, Shin S.J, Park J.W and Jung Y, Tooth Discoloration of Immature Permanent  Incisor Associated with Triple Antibiotic Therapy: A Case Report. JOE. (36) 6; 2010: 1086-1091.

10      Z. Mohammadi1and P. V. Abbott, On the local applications of antibiotics and antibiotic-based  agents in endodontics and dental traumatology.Review. J of Inter Endodontic. (42); 2009: 555-567.

11      Khalil I, Mohidul IslamM .K, Hossain Z, Shah A.K, Badruddoza A and Moral A.A, Lesion Sterilization and Tissue Repair (LSTR)-3mix MP Therapy showed Reliable Efficacy against the Most Resistant Endodontic Bacteria Enterococcus faecalis. J. City Dental College. (9)2; 2012: 1-4.

12      Vijayaraghavan R, Mathian V.M,   Sundaram A, Karunakaran R and Vinodh S. Triple antibiotic paste in root canal therapy. J Pharm Bioall Sci. (4); 2012: 230-233.

13      Parasuraman V.R, Muljibhai B.S. 3Mix- MP in Endodontics – An overview. IOSR Dental and JDMS. (3)1; 2012: 36-45.

14      Nanda R, Koul M, Srivastava S, Upadhyay V and Dwivedi R. Clinical evaluation of 3 Mix and Other Mix in non-instrumental endodontic treatment of necrosed primary teeth. J. oral biology and craniofacial research. (4); 2014: 114-119.

15      Sumanthini M.V, Shenoy V.U, Deshmukh R, Kumar R. Successful nonsurgical retreatment of resected teeth associated with persistent periapical lesion by placing triple Antibiotic paste and mineral trioxide aggregate apical plug - A case report. J.Endodntology. (25)2; 2013: 81-88.

16      Taneja S and Kumari M. Use of triple antibiotic paste in the treatment of large periradicular lesions. J of Investigative and Clinical Dentistry. (3); 2012: 72-76.

17      Oliphant C.M, Pharm D, GARY M.G, permanente K. "Quinolones: A Comprehensive Review". Am FAM physician. (65)3; 2002: 455-465.

18      Patrick G.L. An Introduction to Medicinal Chemistry. Oxford: Oxford University Press. 2003:379-435.

19      Buck M.L. Ciprofloxacin use in children: a review of recent findings. Pediatr Pharm. (4);1998:  12-18.

20      Sharma C P, Jain A, Jain S, Pahwa R, and Yar S M. Ciprofloxacin: review on developments in synthetic, analytical, and medicinal aspects, J. of Enzyme Inhibition and Medicinal Chemistry, (4)25; 2010: 577–589.

21      Cipro. Bayer response 12 Feb 2009. http://www.fda.gov/cder/foi/label/2009/019537s69,19857s50,20780s271b1.pdf. Accessed 6 May 2009.

22      Syrian Drug Reference (SDR), Vol 5, 7th edition, Government of Syria, Ministry of Health, Syrian Pharmacists Syndicate , Published by the Controller of Publications: Damascus, 2016.

23      United States Pharmacopoeia (USP); 32th ed. United States Pharmacopoeia Convention Inc: Rockville, 2009; 1939-1945.

24      British Pharmacopoeia, Vol II, The Department of Health, Social Services and Public Safety: London, 2010; 2504-2505.

25      Farmacopéia Brasileira. 4.ed. Săo Paulo: Atheneu, 1988.

26      Indian Pharmacopoeia, Vol III, 6th edition, Government of India, Ministry of Health and Family Welfare, Published by the Controller of Publications: Delhi, 2010: 1090-1094.

27      Carlucci G. Analysis of fluoroquinolones in biological fluids by high-performance liquid chromatography, J. Chromatogr. A. (812); 1998: 343–367.

28      Venn R.F, Principles and Practice of Bioanalysis, second ed. Taylor and Francis, London, 2005.

29      Imre S, Dogaru M.T, Vari C.E, Muntean T, Kelemen L. Validation of an HPLC method for the determination of ciprofloxacin in human plasma, J. Pharm. Biomed. Anal. (33); 2003: 25–30.

30      Watabe S, Yokoyama Y, Nakazawa K, Shinozaki K, Hiraoka R, Takeshita K, Suzuki Y, Simultaneous measurement of pazufloxacin, ciprofloxacin, and lev-ofloxacin in human serum by high-performance liquid chromatography with fluorescence detection, J. Chromatogr. (19)878; 2010: 1555–1561.

31      Muchohi S.N,  Thuo N,  Karisa J,  Muturi A, Kokwaro G.O and  Maitland K. Determination of ciprofloxacin in human plasma using high-performance liquid chromatography coupled with fluorescence detection: Application to a population pharmacokinetics study in children with severe malnutrition. J. Chromatogr .B Analyt Technol Biomed Life Sci. 879(2); 2011: 146–152.

32      Shrinivas S, Revanasiddappa M. Analytical Stability Indicative Method Development and Validation by High Pressure Liquid Chromatography for Assay in Ciprofloxacin hydrochloride Drug Substances. American Journal of Analytical Chemistry. (6); 2015: 719-730.

33      Sneha J.K, Nirav P.B, Parag P.R, Nikita P.N, Hemant D.T. Development and validation of stability indicating method for simultaneous estimation of ciprofloxacin hcl and tinidazole using rp-uplc method. IOSR Journal of Pharmacy. (2)5; 2012: 12-19.

34      Vella J, Busuttil F, Bartolo N.S, Sammut C, Ferrito V, Inglott A.S, Azzopardi L.M, LaFerla G, A simple HPLC-UV method for the determination of ciprofloxacin in human plasma. Journal of Chromatography B. (989);  2015: 80-85

35      Zimmermann E.S, Torres B.G.S, Costa T.D. Validation of a sensitive HPLC/fluorescence method for assessment of ciprofloxacin levels in plasma and prostate microdialysate samples from rats, J. Biomedical Chromatography. (30); 2015: 330-336.

36      Alswayeh R, Hussein R.F, Alvi S.N and Hammami M.M. Rapid  Determination of Ciprofloxacin Concentration in human plasma by high performance liquid chromatography. W. J. of pharmacy and pharmaceutical sciences. (5)3; 2016: 1765-1774.

37      Kamberia M, Tsutsumi K, Kotegava T, Nakamura K and Nakano S. Determination of Ciprofloxacin in plasma and urine by HPLC with ultraviolet detection. Clin. Chem. (44)6; 1998: 1251-1255.

38      Amini M, Khanavi M and Ahafiee A. Simple HPLC method for determination of Ciprofloxacin in human plasma. Ind. J. Pharm. Res. (2); 2004: 99-101.

39      Sani A, Chijioke C, Rafat O, Sikirat S, Emmanuel T, Musa A and Mohammed I. HPLC method development and validation indicating assay for Ciprofloxacin Hydrochloride. J. Appl. Pharm. Sci. (8)1; 2011: 239-243.

40      Shihn S, Chih Y and Yen H. Analysis of Ciprofloxacin by a simple HPLC method. J. Chromatogr. Sci. (46); 2008: 490-495.

41      Umme M, Nazmul M, Mehedi M, Zakir M and Asma R. Study of forced degradation of Ciprofloxacin HCl indicating stability using RP-HPLC method. Der Pharm. Chem. (6)5; 2013: 132-137.

42      Ali A.S, Mmuo C.C, Abdulraheem O.R, Abdulkareem S.S, Alemika T.E, Sani A.M and Ilyas M. High Performance Liquid Chromatography ( HPLC) Method Development and Validation Indicating Assay for Ciprofloxacin Hydrochloride. J. of Applied Pharmceutical Science. (8)1; 2011: 239-243.

43      Jain P.S, Desai D.N, Shah P.S, Pirthipal S.P and Amin D.P. A Simple and Rapid Stability Indicating LC Determination of Ciprofloxacin Hydrochloride as a Bulk Drug and from Formulations. J. of Chromatographia Supplement. 2009.

44      Aksoy B, kucukguzel i and Rollas S. Development and Validation of a Stability-Indicating HPLC Method for Determination of Ciprofloxacin Hydrochloride and its Related Compounds in Film-Coated Tablets. J. of Chromatographia Supplement. (66); 2007: 57-63.

45      Nix D.E, De Vito J.M, and Schentag J.J. Liquid-Chromatographic Determination of Ciprofloxacin in Serum and Urine. J. of Clinical Chemistry.(31)5; 1985: 684-686.

46      Wu S.S, Chein Y.C, and Wen H.Y. Analysis of Ciprofloxacin by a Simple High-Performance Liquid Chromatography Method. J. of Chromatographic Science. (46); 2008: 490-495.

47      Zotou A and Miltiadou N. Sensitive LC determination of ciprofloxacin in pharmaceutical preparations and biological fluids with fluorescence detection. J. of Pharmaceutical and Biomedical Analysis. (28); 2002: 559–568.

48      Qureshi N.M, Rahman U.I and Marwat A.G. Comparative Analysis of Ciprofloxacin in Different Pharmaceutical Products By High Performance Liquid Chromatograph. J. of Sci. Tech. and Dev. 31 (1); 2012: 69-73.

49      Lian Z and Wang J. Determination of ciprofloxacin in Jiaozhou Bay using molecularly imprinted solid-phase extraction followed by high-performance liquid chromatography with fluorescence detection. J. of ScienceDirect. 2016: 1-7.

50      Alwayeh R, Hussein F.R, Alvi N.S and Hammami M.M. Rapid determination of Ciprofloxacin concentration in human plasma by high performance liquid chromatography. wjpps. 5(3); 2016: 1765-1774.

51      Emami J and Rezazadeh M, A simple and sensitive highperformance liquid chromatography method for determination of ciprofloxacin in bioavailability studies of conventional and gastroretentive prolongedrelease formulations. J. of Advanced Biomedical . (5);  2017: 163- 171.

52      Dhavani K, Karunapriyachitra V. RP-HPLC method development and validation for simultaneous estimation of Ciprofloxacin and Tinidazole in tablet dosage form. Pharmanest: Int. J. Adv. Pharm. Sci. (3-4)3; 2012: 196-203.

53      Yadav S, Patel N and Desai H. Development and validation of stability indicating method for simultaneous estimation of Ciprofloxacin HCl and Tinidazole using RP-UPLC method. Int, Org. Sci. Res. J. Pharm. (5)2; 2012: 12-19.

54      Suhagia B, Desai U, Patel M and Mehta J. RP-HPLC method for simultaneous estimation of Ciprofloxacin and Dexamethasone in eye/ear drops. Int. J. Pharm. Sci. Drug Res. (2)5; 2013: 62-66.

55      Sonia T, Ramzia I, Hanaa M and Maha M. Simultaneous determination of intact Lomefloxacin and Ciprofloxacin in the presence of their acid degradation products. Bull. Pharm. Sci. (30)2; 2007: 241-258.

56      Nájla M, Anil K, Erika K and Maria M. Quantitative determination of Ciprofloxacin and Norfloxacin in pharmaceutical preparations by HPLC. Brazilian J. Pharm. Sci. (41)4; 2005: 507-513.

57      Patel A, Shah N and Patel N. Simultaneous estimation of Metronidazole and Ciprofloxacin by RP-HPLC method in bulk drug and suspension. Int. J. Chem. Sci. (3)7; 2009: 2115-2121.

58      Chavan J, Charya S, Baris I, Patil S and Patil S. Development and validated RP-UPLC method for simultaneous estimation of Ciprofloxacin HCl, Doxycycline and Phenazopyridine HCl in bulk and tablet dosage form. Am. J. PharmTech Res. (3)3; 2013: 370-381.

59      Singha R, Maithani M, Saraf S and Gupta R. Simultaneous estimation of Ciprofloxacin Hydrochloride, Ofloxacin, Tinidazole and Ornidazole by RP-HPLC. Eurasian J. Anal. Chem. (4)2; 2009: 161-167.

60      Ovando H, Gorla M, Biol C, Weyers A and Ugnia L. Simultaneous quantification of Ciprofloxacin, Enrofloxacin and Balofloxacin in broiler chicken muscle. Archivos de Med. Vetrinaria. (36)1; 2004:  93-98.

61      Carolin I.N, Balan  P, Sathiya S.R, Ashok J.K and Rajasekar  S. Simultaneous RP-HPLC Estimation of Ciprofloxacin and Ornidazole in Tablet Dosage Form. Asian Journal of Research in Chemistry. (4)2; 2011: 227-230.

62      Kulsum S, Reddy R, Durga K.M, Padmalatha M. A Simple and validated RP-HPLC method for the simultaneous estimation of Tinidazole and Ciprofloxacin in bulk and pharmaceutical dosage forms. (ijrdplsci). (2)1; 2012: 238-243.

63      Sneha J.K, Nirav P.B, Parag P.R, Nikita P.N, Hemant D.T. Development and validation of stability indicating method for simultaneous estimation of ciprofloxacin hcl and tinidazole using rp-uplc method. IOSR Journal of Pharmacy. (2)5; 2012: 12-19.

64      Kassab M.N, Singh K.A, Kedor-Hackmam M.E, Santoro R.M. Quantitative determination of ciprofloxacin and norfloxacin in pharmaceutical preparations by high performance liquid chromatography. Brazilian Journal of Pharmaceutical Sciences (RBCF). (41)4; 2005: 507-513.

65      Sharma M, Pandey K.B, Yadav S.K, Patil S, Choudhary N and Mishra PG. Application of RP-HPLC for the simultaneous determination of ciprofloxacin hydrochloride and tinidazole in solid dosage form. Scholars Research Library (USA). 5(6); 2013: 41-46.

66      Murugan S, Sunil K.V, Vineela Ruth M.P, Niranjan B.M and Kathiravan M.K. Method development and validation of Tinidazole and Ciprofloxacin HCl in bulk and tablet dosage form by Rp-HPLC. International Journal of Novel Trends in pharmaceutical Sciences (ijntps).4(5); 2014: 130-139.

67      Khushbu B. Thula P.C and Maheshwari G.D. Stability indicating HPLC Method for simultaneous estimation of Ciprofloxacin and Phenylephrine in pharmaceutical dosage form. Pharmacophorejournal. (5)2;  2015: 262-272.

68      Pola M.L, Gowri S.D. Novel isocratic reverse phase high performance liquid chromatography method development and validation for simultaneous estimation of Ciprofloxacin and Phenazopyridine in solid dosage form. Int Journal Pharmacy and Pharmaceutical Sci. (7)4; 2015: 355-361.

69      Raghunath M and Dhamne A. RP-HPLC method for simultaneous estimation of Ciprofloxacin, Tinidazole and Dicyclominein bulk and tablet dosage form. Journal of Pharmaceutical Research. (14)3; 2015: 66-70.

70      Goyal A, Choudhary S, Singh D.G. A Validated Rp-Hplc Method for Estimation of Ciprofloxacin and Tinidazole in Tablet Dosage Form. Int journal of Pharmaceutical Chemistry and Analysis. (2)1; 2015: 22-27.

71      Locatelli, Ciavarella T.M, Paolino D, Fiscarelli C.C, Ricciotti G, Pompilio A, Grande B.G, Zengin G, Marzio D.L. Determination of ciprofloxacin and levofloxacin in human sputumcollected from cystic fibrosis patients using microextraction bypacked sorbent-high performance liquid chromatography photodiodearray detector. J. Chromatography.(1419); 2015: 58-66.

72      Sachan N, Chandra P, Saraf S.K and Gupta R.C. Novel method for simultaneous estimation of Ciprofloxacin Hydrochloride and Ofloxacin by Reverse phase – High performance Liquid chromatography (RP-HPLC). IJPSR. (1)7;  2010: 100-107.

73      Rote A.R, Saudagar R.B. High Performance Liquid Chromatographic Determination of Ciprofloxacin Hydrochloride and Ornidazole in Human Plasma. J.Pharmaceutical Analytical Chemistry. (1)1; 2015:3-4.

74      Szerkusa O, Jacynaa J, Gibasb A, Sieczkowskib M, Siluka D, Matuszewskib M, Kaliszana R, Markuszewski M.J. Robust HPLC–MS/MS method for levofloxacin and ciprofloxacindetermination in human prostate tissue. Journal of Pharmaceutical and Biomedical Analysis (jpba). (132); 2017: 173-183.

75      Murugan S, Sunil k.V, Vineela Ruth M.P, Niranjan B.M and Kathiravan M.K. Method development and validation of Tinidazole and Ciprofloxacin HCl in bulk and tablet dosage form by Rp-HPLC. Ijntps. (4)5; 2014: 130-139.

 

 

 

 

 

 

 

 

 

Received on 29.12.2017           Modified on 30.01.2018

Accepted on 14.03.2018          © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(5):2139-2148.

DOI: 10.5958/0974-360X.2018.00396.7