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Ciprofloxacin: Physical Profile

Mohammed A. Al-Omar
Department of Pharmaceutical Chemistry
College of Pharmacy, King Saud University
P.O. Box 2457, Riyadh-11451
Kingdom of Saudi Arabia

PROFILES OF DRUG SUBSTANCES, 163 Copyright ß 2004 Elsevier Inc.


EXCIPIENTS, AND RELATED All rights reserved
METHODOLOGY – VOLUME 31
DOI: 10.1016/S0000-0000(00)00000-0
164 M.A. AL-OMAR

CONTENTS

1. General Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164


1.1 Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
1.1.1 Systematic chemical names. . . . . . . . . . . . 164
1.1.2 Nonproprietary names . . . . . . . . . . . . . . . 165
1.1.3 Proprietary names . . . . . . . . . . . . . . . . . . 165
1.1.4 Synonyms. . . . . . . . . . . . . . . . . . . . . . . . 165
1.2 Formulae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
1.2.1 Empirical formula, molecular weight, CAS
number . . . . . . . . . . . . . . . . . . . . . . . . . 165
1.2.2 Structural formula. . . . . . . . . . . . . . . . . . 165
1.3 Elemental analysis. . . . . . . . . . . . . . . . . . . . . . . . 165
1.4 Appearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
2. Physical Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . 165
2.1 Solution pH . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
2.2 Solubility characteristics . . . . . . . . . . . . . . . . . . . 166
2.3 Optical activity . . . . . . . . . . . . . . . . . . . . . . . . . . 166
2.4 X-Ray powder diffraction pattern. . . . . . . . . . . . . 166
2.5 Thermal methods of analysis . . . . . . . . . . . . . . . . 170
2.5.1 Melting behavior. . . . . . . . . . . . . . . . . . . 170
2.5.2 Differential scanning calorimetry . . . . . . . 170
2.6 Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
2.6.1 Ultraviolet spectroscopy. . . . . . . . . . . . . . 170
2.6.2 Vibrational spectroscopy . . . . . . . . . . . . . 171
2.6.3 Nuclear magnetic resonance
spectrometry . . . . . . . . . . . . . . . . . . . . . . 172
2.7 Mass spectrometry . . . . . . . . . . . . . . . . . . . . . . . 174
3. Stability and Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
4. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

1. GENERAL INFORMATION
1.1 Nomenclature
1.1.1 Systematic chemical names [1, 2]
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-
quinolinecarboxylic acid.
CIPROFLOXACIN: PHYSICAL PROFILE 165

1.1.2 Nonproprietary names


Ciprofloxacin

1.1.3 Proprietary names [2, 3, 4]


Aceto, Baycip, Ciflox, Cifluran, Ciloxan, Ciplox, Ciprinol, Cipro,
Ciprobay, Ciproxan, Ciproxin, Flociprin, Septicide, Velmonit,
Xorpic.

1.1.4 Synonyms [3]


Bay-q-3939.

1.2 Formulae
1.2.1 Empirical formula, molecular weight, CAS number [3, 4]
C17H18FN3O3 331.35 [0085721-33-1].

1.2.2 Structural formula

HN

N N

F COOH

1.3 Elemental analysis


C ¼ 61.62% H ¼ 5.48% F ¼ 5.73% N ¼ 12.68% O ¼ 14.49%.

1.4 Appearance [1, 3]


Ciprofloxacin is obtained as a light yellow crystalline powder.

2. PHYSICAL CHARACTERISTICS
2.1 Solution pH
A 2.5% solution in water has a pH of 3.0–4.5 [3].
166 M.A. AL-OMAR

2.2 Solubility characteristics


Ciprofloxacin is practically insoluble in water, very slightly soluble in
dehydrated alcohol and in dichloromethane, and soluble in dilute acetic
acid [3].

2.3 Optical activity


Since ciprofloxacin has no centers of dissymmetry, it does not exhibit
optical activity.

2.4 X-Ray powder diffraction


The X-ray powder diffraction pattern of ciprofloxacin was obtained using
a Simons XRD-5000 diffractometer, which is shown in Figure 1. Table 1
contains a compilation of values for the observed scattering peaks (in
units of degrees 2-), the interplanar d-spacings (units of Å), and the
relative intensities associated with the powder pattern.

10 15 20 25 30 35 40 45 50 55
Scattering Angle
(degrees 2-θ)
Figure 1. X-ray powder diffraction pattern of ciprofloxacin.
Table 1

Crystallographic Data from the X-Ray Powder Diffraction Pattern


of Ciprofloxacin

CIPROFLOXACIN: PHYSICAL PROFILE


Scattering d-Spacing Relative Scattering d-Spacing Relative
angle (Å) intensity angle (Å) intensity
(degrees 2h) (%) (degrees 2) (%)

8.185 10.7928 5.94 9.065 9.7475 21.43

11.348 7.7913 4.75 12.843 6.8870 3.41

13.247 6.6780 5.91 13.700 6.4583 3.39

15.139 5.8474 9.95 15.390 5.7527 9.95

16.451 5.3840 5.90 18.144 4.8853 4.40

18.478 4.7976 11.76 18.913 4.6882 37.85

19.37 4.5864 43.48 19.810 4.4779 23.85

21.104 4.2063 4.03 21.820 4.0697 1.34

167
(continued)
168
Table 1 (continued)

Scattering d-Spacing Relative Scattering d-Spacing Relative


angle (Å) intensity angle (Å) intensity
(degrees 2) (%) (degrees 2) (%)

22.575 3.9354 5.10 23.192 3.8321 13.76

23.935 3.7148 1.94 24.372 3.6491 2.44

M.A. AL-OMAR
24.783 3.5895 11.12 25.094 3.5458 8.16

25.581 3.4793 4.50 26.112 3.4098 15.18

26.545 3.3551 100.00 26.978 3.3023 26.33

27.360 3.2570 9.73 28.015 3.1823 10.33

28.929 3.0838 7.98 29.304 3.0452 21.44

29.585 3.0169 14.82 30.458 2.9324 5.99

31.120 2.8715 2.89 31.747 2.8163 10.09


32.786 2.7293 4.01 33.614 2.6639 3.78

34.916 2.5675 4.14 35.893 2.4998 3.30

37.335 2.4065 5.42 38.237 2.3518 3.68

CIPROFLOXACIN: PHYSICAL PROFILE


38.919 2.3122 2.96 39.304 2.2904 4.99

40.576 2.2215 1.27 41.682 2.1651 3.71

44.047 2.0542 3.26 45.987 1.9719 2.13

46.324 1.9584 2.75 46.939 1.9341 3.38

51.353 1.7777 1.17 53.777 1.7032 2.44

55.569 1.6524 1.47 57.358 1.6051 1.64

57.924 1.5907 1.70

169
170 M.A. AL-OMAR

2.5 Thermal methods of analysis


2.5.1 Melting behavior
Ciprofloxacin is found to melt in the range of about 318–320 C [2].

2.5.2 Differential scanning calorimetry


The differential scanning calorimetry (DSC) thermogram of ciprofloxacin
was obtained using a DuPont TA-9900 thermal analyzer interfaced with a
DuPont Data Unit. The thermogram shown in Figure 2 was obtained at
a heating rate of 10 C/min, and was run from 40 to 400 C. The sole
observed thermal event was the melting endotherm which was observed
at 322 C.

2.6 Spectroscopy
2.6.1 Ultraviolet spectroscopy
The UV spectrum of ciprofloxacin dissolved in methanol was recorded
using a Shimadzu ultraviolet–visible Spectrophotometer 1601 PC, and is

100 200 300 400


Temperature (°C)
Figure 2. Differential scanning calorimetry thermogram of ciprofloxacin.
CIPROFLOXACIN: PHYSICAL PROFILE 171

220 240 260 280 300 320 340 360 380

Wavelength (nm)
Figure 3. The ultraviolet absorption spectrum of ciprofloxacin in methanol.

shown in Figure 3. The spectrum of ciprofloxacin was found to exhibit


the following characteristics at the three observed maxima:

Wavelength A[1%, 1 cm] Molar absorptivity


maximum (nm) (L mol1 cm1)
320.6 1.95 129
280 5.76 382
228 1.57 104
2.6.2 Vibrational spectroscopy
The infrared absorption spectrum of ciprofloxacin was obtained in a KBr
pellet using a Perkin Elmer infrared spectrophotometer. The infrared
spectrum is shown in Figure 4, and the principal peaks were noted at
3490, 3320, 2930, 2840, 1696, 1605, 1480, 1435 cm1. The assignments for
the major infrared absorption bands are summarized in Table 2.
172 M.A. AL-OMAR

880 960 1040 1120 1200 1280 1360 1440 1520 1600 1680 1760 1840 1920 2000 2080 2160 2240

Peak Energy (cm−1)


Figure 4. The infrared absorption spectrum of ciprofloxacin obtained in a
KBr pellet.

2.6.3 Nuclear magnetic resonance spectrometry


2.6.3.1 1H-NMR spectrum
The proton NMR spectrum of ciprofloxacin was obtained using a Bruker
Advance system, operating at 300, 400, and 500 MHz. The sample was
dissolved in D2O, and tetramethylsilane (TMS) was used as the internal
standard. The proton NMR spectrum is shown in Figure 5, and
assignments for the 1H-NMR resonance bands of ciprofloxacin are found
in Table 3.

2.6.3.2 13C-NMR spectrum


The carbon-13 NMR spectrum of ciprofloxacin was obtained using a
Bruker Advance system operating at 75, 100, and 125 MHz. Standard
Bruker Software was used to obtain DEPT spectra. The sample was
dissolved in D2O, and tetramethylsilane (TMS) was used as the internal
standard. Assignments for the various carbons of ciprofloxacin are
shown in Table 4.
CIPROFLOXACIN: PHYSICAL PROFILE 173

Table 2

Assignments for the Infrared Absorption Bands of


Ciprofloxacin
Frequency (cm1) Assignments

3490 O–H stretch

3320 N–H stretch of piperazinyl moiety

2930 Aliphatic C–H stretch

2840 N–C stretch

1696 C¼O stretch of carboxyl group

1605 C¼O stretch of quinoline

1480, 1435 C–N stretch

10 9 8 7 6
Chemical Shift (ppm)
1
Figure 5. The H-NMR spectrum of ciprofloxacin in D2O.
174 M.A. AL-OMAR

Table 3

Assignments for the observed Resonance Bands in the


1
H-NMR Spectrum of Ciprofloxacin
1a 1b

3'
HN 4' 2' 1c

5' 1'
6' N 8a N
8 1
7 2
6 3
5 4 3a
4a
F COOH

Proton Chemical shift Multiplicity Number of


atoms (ppm relative (s: singlet, proton
to TMS) d: doublets) atoms

H-2 8.63 s 1

H-5 7.46 d 1

H-8 7.52 d 1

H-20 ,60 or 30 ,50 3.66 d 2

H-20 ,60 or 30 ,50 3.56 d 2

H-1a 1.22 s 1

H-1b, 1c 1.47 d 2

2.7 Mass spectrometry


The electron impact (EI) spectrum of ciprofloxacin is presented in
Figure 6, and was recorded using a Shimadzu PQ-5000 GC-MS
spectrometer. The spectrum shows a mass peak (M.) at m/z 332, and a
base peak at m/z 288 resulting from the loss of the group. All these and
Table 4

13
Assignments for the Observed Resonance Bands in the C-NMR Spectrum of
Ciprofloxacin

CIPROFLOXACIN: PHYSICAL PROFILE


1a 1b

3'
HN 4' 2' 1c

5' 1'
6' N 8a N
8 1
7 2
6 3
5 4 3a
4a
F COOH

Carbon Chemical shift Assignment at Carbon Chemical Assignment


atoms (ppm relative carbon number atoms shift (ppm at carbon
to TMS) relative number
to TMS)

C-1a, C-1b 36.90 2 C-5 111.26 1

C-1c 43.96 1 C-6 107.14 1

C-2 139.48 1 C-7 145.40 1

175
(continued)
176
Table 4 (continued)

Carbon Chemical shift Assignment at Carbon Chemical Assignment


atoms (ppm relative carbon number atoms shift (ppm at carbon
to TMS) relative number
to TMS)

C-3 155.60 1 C-20 , C-60 43.96 2

M.A. AL-OMAR
C-3a 169.31 1 C-30 , C-50 47.05 2

C-4 176.12 1 C-8 119.04 1

C-4a 148.69 1 C-8a 152.26 1


CIPROFLOXACIN: PHYSICAL PROFILE 177

150 200 250 300 350 400 450


m/z
Figure 6. Mass spectrum of ciprofloxacin.

other proposed fragmentation patterns of the drug are presented in


Table 5.

3. STABILITY AND STORAGE [3, 5]


Solutions of ciprofloxacin are light sensitive and should be protected
from light and freezing [3]. When the concentrate formulated for
intravenous injection, or the 1.2 g pharmacy bulk package, is diluted
with 5% dextrose injection or 0.9% sodium chloride injection to a final
concentration of 0.5–2 mg/mL, the resultant solution is stable for upto 14
days when stored at room temperature or when refrigerated at 2–8 C [5].

The commercially available injection for intravenous infusion that


contains 2 mg/mL in 5% dextrose is provided in a plastic container
fabricated from a specially formulated polyvinyl chloride (PVC).
Tammilehto et al. used thin-layer chromatography to study the
degradation of ciprofloxacin hydrochloride solutions after these were
irradiated by a high pressure mercury lamp [6].
178 M.A. AL-OMAR

Table 5

Assignments for the Fragmentation Pattern Observed in


the Mass Spectrum of Ciprofloxacin
Mass number Relative Structural
(m/z) intensities assignment

332 45 C17H18FN3O3e þ þ mass peak (M.)

314 55 M–H2O

288 100 M–CO2

245 30 M–(CO2  C2H5N)

4. REFERENCES
1. Remington’s: Pharmaceutical Sciences, 20th edn., A.R. Gennaro,
ed., Mack Publishing Co., Pennsylvania, p. 1539 (2000).
2. The Merck Index, 12th edn., S. Budavari, ed., Merck and Co., NJ,
p. 2374 (1996).
3. Martindale, The Complete Drug Reference, 33rd edn., S.C.
Sweetman, ed., The Pharmaceutical Press, Chicago, p. 182
(2002).
4. Index Nominum 2000: International Drug Directory, 17th edn.,
Swiss Pharmaceutical Society, Medpharm Scientific Publishers,
Ontario, p. 239 (2000).
5. Drug Information, 95 edn., G.K. McEvoy, ed., American Society
of Health-System Pharmacists, p. 493 (1995).
6. S. Tammilehto, H. Salomies, and K. Torniainen, J. Planar.
Chromatogr. Mod. TLC, 7, 368 (1994).