CHAPTER 1

Buclizine
Gamal A.E. Mostafa and Abdullah A. Al-Badr

Contents 1. Description 2
1.1. Nomenclature 2
1.1.1. Systematical chemical names 2
1.1.2. Nonproprietary names 2
1.1.3. Proprietary names 2
1.2. Formulae 2
1.2.1. Empirical formula, molecular weight,
and CAS number 3
1.2.2. Structural formula 3
1.3. Elemental analysis 3
1.4. Appearance 3
2. Uses and Application 3
3. Methods of Preparation 4
4. Physical Characteristics 6
4.1. Solubility 6
4.2. Melting range 6
4.3. X-ray powder diffraction pattern 6
4.4. Spectral properties 7
4.4.1. UV/VIS spectroscopy 7
4.4.2. Infrared spectrum 7
4.4.3. Nuclear magnetic resonance
spectrometry 7
4.5. Mass spectrometry 11

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Kingdom of
Saudi Arabia

Profiles of Drug Substances, Excipients, and Related Methodology, Volume 36 # Elsevier Inc.
ISSN 1871-5125 All rights reserved.

1
2 Gamal A.E. Mostafa and Abdullah A. Al-Badr

5. Methods of Analysis 12
5.1. Compendial methods 12
5.1.1. British pharmacopoeia methods [11] 12
5.2. Spectrophotometric methods 16
5.3. Potentiometric methods 18
5.4. Chromatographic methods 20
5.4.1. Thin layer chromatography 20
5.4.2. Gas chromatography 28
5.4.3. High-performance liquid chromatography 28
6. Stability 32
Acknowledgment 32
References 32

1. DESCRIPTION
1.1. Nomenclature
1.1.1. Systematical chemical names
1-[(4-chorophenyl)phenylmethyl]-4-[(4-tert-butylphenyl)methyl]
piperazine;
1-(p-tert-butylbenzyl)-4-(p-chloro-a-phenylbenzyl)piperazine;
1-(p-chlorobenzhydryl)-4-(p-tert-butylbenzyl)diethylenediamine;
1-(p-tert-butylbenzyl)-4-(p-chlorodiphenylmethyl)piperazine;
(RS)-1-(4-tert-butylbenzyl)-4-(4-chlorobenzhydryl)piperazine
dihydrochloride;
Piperazine, 1[(4-chlorophenyl)phenylmethyl]-4-[[4-(1,1-dimethylethyl)
phenyl]methyl];
1-(p-chlorobenzhydryl)-4-(4-tert-butylbenzyl)-hexahydropyrazine;
1-[(4-chlorophenyl)phenylmethyl]-4-[(4-tert-butylphenyl)-methyl]
piperazidine [1–6].

1.1.2. Nonproprietary names

Buclizine; Histabutyzine; Histabutizine; NSC-25141; UCB 4445

1.1.3. Proprietary names

Aphilan, Bucladin-S, Buclifen, Buclina, Longifene, Posdel, Postadoxine,
Postafen Postafeno, Softran, Vibazine [1–6].
 Buclizine 3

1.2. Formulae
1.2.1. Empirical formula, molecular weight, and CAS number

Buclizine C28H33ClN2 433.0 82-95-1

Buclizine
2HCl C28H35Cl3N2 506.0 129-74-8

1.2.2. Structural formula

Cl

CH3
CH N N CH2 C CH3

CH3

1.3. Elemental analysis

 Buclizine: C 77.66%, H 7.68%, Cl 8.19%, N 6.47% [1].
 Buclizine HCl: C 66.47%, H 6.97%, Cl 21.02%, N 5.54% [1].

1.4. Appearance
A white or slightly yellowish, crystalline powder, odorless and
tasteless [5,6].

2. USES AND APPLICATION

Buclizine hydrochloride, a piperazine derivative, is a sedating antihista-

mine with antimuscarinic and moderate sedative action. The drug is used
mainly for its antiemetic action, particularly in the prevention of motion
sickness, and in the treatment of migraine in combination with analgesics.
In some countries, it is given in the management of allergic conditions and
in the pruritic skin disorders. Buclizine has also been used in the treat-
ment of vertigo associated with disorders of vestibular system, although
its value in these conditions remains to be established [2–6].
4 Gamal A.E. Mostafa and Abdullah A. Al-Badr

To prevent motion sickness, the drug is given at least 30 min before

travelling in a dose of 50 mg by mouth which may be repeated,
if necessary, after 4–6 h. The usual dose to alleviate nausea is 50 mg
given up to three times daily. In the treatment of migraine, the drug is
given in usual doses of 12.5 mg at the start of an attack or when one is
known to be imminent. In pruritic skin disorders, the usual dose of
buclizine hydrochloride is 25–50 mg daily [2–5]. The drug has an antihis-
taminic [2], antimycobactrium [3], anticonvulsant [4], and motion sick-
ness prevention activities [5].

3. METHODS OF PREPARATION

Morren and Strubbe [7] prepared buclizine by mixing hydrochloric acid

with 0.5 mol of 1-(p-tert-butylbenzyl)-piperazine 1, adding 0.5 mol
p-chlorobenzaldehyde 2, and adding dropwise aqueous 0.55 M potassium
cyanide, then heating on a water bath for 2 h, yields an addition product
which is separated in toluene and dried before reaction with phenylmag-
nesium bromide 3 to give buclizine 4.

O CH3
MgBr
Cl C HN N CH2 C CH3 HCl, KCN,
H + 3
CH3

2 1

Cl

CH3
CH N N CH2 C CH3
CH3

4
Lui et al. [8] prepared buclizine by reducing p-chlorophenyl phenyl
ketone 1 with potassium borohydride to p-chlorobenzhydryl alcohol 2,
which was converted into p-chlorobenzhydryl bromide 3. The latter com-
pound 3 was prepared by reaction of p-chlorophenylmagnesium bromide
4 with benzaldehyde 5. p-tert-Butylbenzyl chloride 6 was condensed
directly with piperazine 7 to give p-tert-butylbenzylpiperazine 8. Treat-
ment of p-chlorobenzhydryl bromide 3 with p-tert-butylbenzylpiperazine
8 in the presence of anhydrous sodium carbonate gave buclizine 9
hydrochloride.
 Buclizine 5

Cl Cl Cl

H H O
KBH4
C O C C Cl MgBr + C
OH Br H

4 5
1 2 3

CH3 CH3
ClH2C C CH3 + HN NH HN N CH2 C CH3
CH3 CH3

6 7 8

Cl

H CH3
C + HN N CH2 C CH3 Na2CO3
Br
CH3

3 8

Cl

CH3
CH N N CH2 C CH3
CH3

9
Cossement et al. [9] synthesized the enantiomers of 1-(p-chlorobenzhy-
dryl)-4-(p-methylphenyl)sulfonyl piperazine 3 and used it as an interme-
diate for the preparation of buclizine 6 and other histamines. The
enantiomers of (þ)- and ()-1-(p-chlorobenzhydryl)-4-(p-toluene sulfo-
nyl)piperazine 3 were prepared and converted by hydrolysis to the enan-
tiomers of (þ)- or ()- of p-chlorobenzhydryl piperazine 4. Compound 3
was prepared by refluxing p-chlorobenzhydrylamine 1 with N-bis-2-
chloroethyl-p-toluene sulfonamide 2 with ethyl diisopropylamine. Reac-
tion of p-tert-butylbenzyl chloride 5 with p-chlorobenzhydryl piperazine 4
gives buclizine 6.
6 Gamal A.E. Mostafa and Abdullah A. Al-Badr

Cl

Cl CH2 CH2 O
CH NH2 N S CH3
+ Ethyl diisopropylamine
Cl CH2 CH2 O

1 2

Cl Cl

O
CH N N S CH3 Hydrolysis CH N NH
O

3 4

Cl
CH3
ClCH2 C CH3
CH3 CH3
CH N N CH2 C CH3
5 CH3

4. PHYSICAL CHARACTERISTICS
4.1. Solubility
Practically insoluble in water; sparingly soluble in chloroform and in
propane-1, 2-diol; very slightly soluble in ethanol (96%) [5].

4.2. Melting range

230–240  C.

4.3. X-ray powder diffraction pattern

X-ray powder diffraction pattern (Fig. 1.1) has been obtained on D
8-Advanced Bruker AXE Germany, diffractometer equipped with
scintillation detector using copper Ka (¼ 1.5406 Å) radiation with
scanning range between 2y and 50y at scanning speed of 2 min 1.
A full data summary is compiled in Table 1.1.
 Buclizine 7

800

600

4.691
6.062
12.100

400

3.966
4.414
12.800

3.736

3.087
4.149
7.369

200

3.464
6.652

5.035

2.847
3.300

2.928
3.229

2.650
3.386

2.996

2.704

2.210
2.354

2.106
2.247

1.971
1.894

1.826
1.875
2.291

2.047
3.573

2.527
2.447

1.625
5.640

1.748

1.685

1.596
0
10,0000 20,0000 30,0000 40,0000 50,0000 60,0000
2q (°)

FIGURE 1.1 X-ray powder diffraction pattern of buclizine hydrochloride.

4.4. Spectral properties

4.4.1. UV/VIS spectroscopy
The ultraviolet absorption spectrum of buclizine in methanol was
scanned from 200 to 400 nm, using UV/VIS spectrometer (Shimadzu
Ultraviolet-visible spectrophotometer 1601 PC) and is shown in Fig. 1.2.
The compound exhibited two maxima at 230 and 209 nm. Clarke [10]
reported the following: methanol 255, 260 nm.

4.4.2. Infrared spectrum

The infrared absorption spectrum of buclizine (Fig. 1.3) was obtained in
KBr pellet using a Perkin-Elmer infrared spectrophotometer. The princi-
ple peaks were observed at 3051, 2961, 1093, 1604, 1312, and 1071 cm 1.
Assignments for the major infrared absorption band are provided in
Table 1.2. Clarke [10] reported principal peaks at 1002, 1131, 754, 800,
1075, and 694 cm 1.

4.4.3. Nuclear magnetic resonance spectrometry

1
H and 13C NMR spectra of buclizine were recorded with a Varian Gemini
200 spectrometer (200 MHz). Chemical shifts were expressed in parts per
million with respect to the tetramethysilane (TMS) signal for 1H and
13
C NMR.

4.4.3.1. 1H NMR spectrum The one-dimensional proton 1H NMR spec-

trum of buclizine base dissolved in CDCl3 is shown in Figs. 1.4 and 1.5.
The corresponding spectral assignments 1H NMR for buclizine are
provided in Table 1.3.
8 Gamal A.E. Mostafa and Abdullah A. Al-Badr

TABLE 1.1 Data deduced from X-ray powder diffraction pattern of buclizine

Peak no. Diffraction angel (2y) Flex width d-value Intensity I/Io

1 6.9 0.353 12.8002 273 53

2 7.300 0.353 12.0996 321 62
3 12.0 0.353 7.3691 139 27
4 13.3 0.706 6.6516 118 23
5 14.6 0.471 6.0621 447 87
6 15.7 0.471 5.6398 13 3
7 17.6 0.353 5.0350 108 21
8 18.9 0.353 4.6915 518 100
9 20.1 0.471 4.4140 295 57
10 21.4 0.706 4.1487 159 31
11 22.4 0.471 3.9657 320 62
12 23.8 0.353 3.7355 267 52
13 24.9 0.353 3.5729 23 5
14 25.7 0.471 3.4635 131 26
15 26.3 0.353 3.3858 60 12
16 27.0 0.353 0.353 105 21
17 27.6 0.471 0.471 86 17
18 28.9 0.706 0.706 216 42
19 29.8 0.353 0.353 57 12
20 30.5 0.353 0.353 97 19
21 31.4 0.588 2.8466 109 22
22 33.1 0.471 2.7041 45 9
23 33.8 0.35 2.6497 81 16
24 35.5 0.471 2.5266 22 5
25 36.7 0.471 2.4467 19 4
26 38.2 0.471 2.3540 42 9
27 39.3 0.588 2.2906 24 5
28 40.1 0.588 2.2468 28 6
29 40.8 0.353 2.2098 51 10
30 42.9 0.588 2.1064 41 8
31 44.2 0.471 2.0474 18 4
32 46.0 0.588 1.9714 28 6
33 48.0 0.588 1.8938 26 5
34 48.5 0.353 1.8754 23 5
35 49.9 0.471 1.8261 25 5
36 52.3 0.353 1.7478 14 3
37 54.4 0.588 1.6852 13 3
38 56.6 0.471 1.6248 18 4
39 57.7 0.588 1.5964 10 3
40 60.6 0.353 1.5267 11 3
41 62.5 0.471 1.4848 11 3
42 65.0 0.353 1.4336 11 3
 Buclizine 9

3.000

2.000

A
b
s
.

1.000

0.000
200.0 220.0 240.0 260.0 280.0 300.0
Wavelength (nm)

FIGURE 1.2 Ultraviolet spectrum of buclizine hydrochloride.

49.4
45

40
Percentage temperature

740.25
35
578.82
877.39 494.22
30 440.75
1654.06 507.49
1724.64 1031.78
25 1700.30 1202.13 614.07
1604.40 1294.45 1108.84 866.93 705.69
1238.07
1019.85 624.89
20 312.62 1078.60
1517.09 845.95 650.29
1397.661270.21
1378.22 539.96
15 2625.26 1093.83 723.57
3430.50 3051.80 1362.84
10 942.39
922.38
2502.11 1496.21 809.60
1473.08 763.82
5 2343.79
1436.78
2961.50
1.0
4400.0 4000 3000 2000 1500 1000 400.0
cm-1

FIGURE 1.3 The IR spectrum of buclizine hydrochloride.

10 Gamal A.E. Mostafa and Abdullah A. Al-Badr

TABLE 1.2 Vibrational assignments for buclizine infrared

absorption bands

Frequency (cm 1) Assignment

3051 Aromatic CH
2961 Aliphatic CH
1093 C–C
1604 C¼C
1312 C–N
1111 C–Cl

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 ppm
1.00
1.12

4.61
2.40
8.00
0.91

1.12
4.65
2.37
4.66

0.98
12.10
0.55

1
FIGURE 1.4 H NMR spectrum of buclizine in CDCl3.

4.4.3.2. 13C NMR spectrum The one-dimensional 13C NMR spectrum of

buclizine dissolved in CDCl3, which was recorded at 24  C and internally
referenced to TMS. The 13C NMR assignments are presented in
 Buclizine 11

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 ppm
4.61

2.40
8.00
0.91

1.12

4.65

2.37

4.66

FIGURE 1.5 Expanded 1H NMR spectrum of buclizine in CDCl3.

Figs. 1.6–1.8. The assignments for the observed resonance bands asso-
ciated with the various carbons are listed in Table 1.4. Figures 1.9–1.15
show the HSQC, HMBC, DEPT 90 and DEPT 135 NMR spectra,
respectively.

4.5. Mass spectrometry

Mass spectra of buclizine, carried out with electron impact method, were
registered using Varian 320-GC/MS spectrometer. Figure 1.16 shows the
detailed mass fragmentation pattern and Table 1.5 shows the mass
fragmentation pattern of the drug substance. Clarke [10] reported the
presence of the following principle peaks at m/z ¼ 231, 147, 285, 232,
201, 132, 165, and 166.
12 Gamal A.E. Mostafa and Abdullah A. Al-Badr

TABLE 1.3 Assignment of the resonance bands in the 1H NMR spectrum of buclizine
30
29
H3C
25 27 CH3
26
24
CH3
21 28
23
20
22
1N
6 2

5 3
N4
13 19
14
12
8 7 18

9 15 17
Cl 11 10 16

Chemical shift (ppm, Number of Assignment (proton

relative to TMS) protons Multiplicity at carbon atom)

1.17, 1.21, 1.30 9 3s 28, 29, 30

2.12–2.47 8 m 2, 3, 5, 6
3.64 2 d 20
7.20–8.06 13 m 9,10, 12, 13, 15, 16, 17,
18, 19, 22, 23, 25, 26

s, singlet; d, doublet; m, multiplet.

5. METHODS OF ANALYSIS

5.1. Compendial methods

5.1.1. British pharmacopoeia methods [11]
Buclizine hydrochloride is (RS)-1-(4-tert-butylbenzyl)-4-(4-chlorobenzhy-
dryl)piperazine dihydrochloride. It contains not less than 99% and not
more than 100.5% of C28H33ClN2
2HCl, calculated with reference to the
dried substance. It is a histamine H-receptor antagonist and antiemetic.

5.1.1.1. Characteristics A white or slightly yellowish, crystalline powder.

Practically insoluble in water, sparingly soluble in chloroform and in
propan-1,2-diol, very slightly soluble in ethanol (96%).

5.1.1.2. Identification
Test A: The infrared absorption spectrum, Appendix IIA, is concordant
with the reference spectrum of buclizine hydrochloride (RS O32).
 Buclizine 13

154.13

136.25
132.91
131.77
130.95
130.23
130.14
129.92
128.32
126.58
123.90

77.50
77.30
77.05
76.79

60.60

48.49
47.45
47.36

34.85
31.12
200 180 160 140 120 100 80 60 40 20 ppm
13
FIGURE 1.6 C NMR spectrum of buclizine in CDCl3.

Test B: A 0.25% (w/v) solution in ethanol (50%) yields solution A charac-

teristic of chlorides, Appendix VI.

5.1.1.3. Tests
 Related substances

Carry out the method for liquid chromatography, Appendix IIID, using
four solutions in the initial mobile phase containing (1) 0.001% (w/v) of
buclizine hydrochloride; (2) 0.50% (w/v) of buclizine hydrochloride;
(3) 0.001% (w/v) of 1,4-biz(4-chlorobenzhydryl)piperazine BPCRS; and
(4) 0.50% (w/v) of buclizine hydrochloride impurity standard BPCRS.
The chromatographic procedure may be carried out using a stainless
steel column (20 cm  4 cm) packed with octadecylsilyl silica gel for chro-
matography (10 mm) (Nucleosil, C18 is suitable). Use as the initial mobile
phase 0.01 M sodium heptane sulfonate in a mixture of 55 volumes of water
and 45 volumes of acetonitrile and as the final mobile phase 0.01 M sodium
14 Gamal A.E. Mostafa and Abdullah A. Al-Badr

130.952

130.231
130.149
129.920

128.320

126.579

132.0 131.5 131.0 130.5 130.0 129.5 129.0 128.5 128.0 127.5 127.0 126.5 126.0 ppm
12.37

50.22

14.64

12.97

FIGURE 1.7 Expanded 13C NMR spectrum of buclizine in CDCl3.

heptanesulfonate in a mixture of 20 volumes of water and 80 volumes of

acetonitrile. Before use, adjust the pH of both the initial and final mobile
phases to 4 with 1 M orthophosphoric acid. Carry out a linear gradient
elution with a flow rate of 2 ml/min for 30 min and maintain the final
mobile phase for 10 min with the same flow rate. Use a detection
wavelength of 230 nm.
The test is not valid unless the chromatogram obtained with solution
(4) closely resembles the chromatogram supplied with buclizine
hydrochloride impurity standard BPCRS.
In the chromatogram obtained with solution (2) the area of any peak
corresponding to 1,4-bis-(4-chlorobenzylhydryl)piperazine is not greater
than the area of the peak obtained in the chromatogram with solution (3)
and the area of any other secondary is not greater than the area of the peak
in the chromatogram obtained with solution (1).
 Buclizine 15

136.25

132.91

131.77
130.95
130.23
130.14
129.92

128.32

126.58

123.90

140 138 136 134 132 130 128 126 124 122 ppm

FIGURE 1.8 Expanded 13C NMR spectrum of buclizine in CDCl3.

 Loss on drying

When dried to constant weight at 100–105  C, loses not more than 1%

of its weight. Use 1 g.
 Sulfate ash

Not more than 0.1, Appendix IXA.

5.1.1.4. Assay Carry out Method 1 for nonaqueous titration, Appendix

VIIIA, using 0.4 g and determining the end-point potentiometrically.
Each milliliter of 0.1 M perchloric acid VS is equivalent to 25.3 mg of
C28H33ClN2
2HCl.
16 Gamal A.E. Mostafa and Abdullah A. Al-Badr

TABLE 1.4 Assignment for the resonance bands in the 13C NMR spectrum of buclizine
30
29
H3C
25 27 CH3
26
24
CH3
21 28
23
20
22
1N
6 2

5 3
N4
13 19
14
12
8 7 18

9 15 17
Cl 11 10 16

Chemical shift (ppm) Carbon number

31.0 28, 29, 30

34.85 27
47.36 3,5
47.45 2,6
48.49 20
60.6 7
123.90 23, 25
126.58 17
129.92 22, 26
128.32 15, 19
130.14 16,18
130.23 9, 13, 10, 12
130.95 11
131.77 21
132.91 8
136.25 14
154.13 24

5.1.1.5. Impurities
A. 1,4-bis-(4-chlorobenzyhydryl)piperazine.
B. 4-chlorobenhydrol, 1-(4-chlorobenzyhydryl)piperazine, 4-chlorobenzo-
phenone.

5.2. Spectrophotometric methods

Pregmollato and Pissalto [12] presented methods for the determination of
buclizine dihydrochloride by titration with perchloric acid, using a crystal
violet indicator; by thin-layer chromatography with subsequent
 Buclizine 17

ppm
0

20

40

60

80

100

120

140

15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

FIGURE 1.9 The HSQC NMR spectrum of buclizine in CDCl3.

spectrophotometric determination at 239 nm (in chloroform) or 274 nm

(in benzene); and by infrared spectrophotometric determination of
buclizine dihydrochloride formulations. Spectral absorption data for the
drugs are also given.
Annapurna et al. [13] established simple, accurate, and reproducible
UV spectrophotometric methods for the assay of buclizine based on the
formation of precipitation, charge transfer, and redox products. Precipi-
tation/charge transfer complex formation of the buclizine with I2/p-nitro
methyl amino phenol sulfate-sulfanilic acid by method A, the precipita-
tion/complex formation with ammonium molybdate/potassium thiocy-
anate by method B and precipitation/redox reaction of buclizine with
phosphomolybdic acid/Co2þ/EDTA by method C were proposed. Deter-
mination of buclizine in bulk form and in pharmaceutical formulations
was also incorporated.
El-Walily et al. [14] described a simple and sensitive spectrophotomet-
ric method for the determination of buclizine in bulk and tablets was based
on the formation of charge-transfer complex between buclizine as n-donor
and iodine as s-acceptor measurement of the absorbance at 295 and
355 nm. A Job’s plot indicated a 1:1 complex between the drug and iodine,
18 Gamal A.E. Mostafa and Abdullah A. Al-Badr

ppm

30

35

40

45

50

55

60

65

70

75

80
7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm

FIGURE 1.10 The expanded HSQC NMR spectrum of buclizine in CDCl3.

and Beer’s law was obeyed in the concentration range of 4–30 mg/ml.
To validate the method, the results obtained were compared statistically
with a newly developed UV-derivative spectrophotometric method.
The charge-transfer method was favored due to its higher sensitivity.

5.3. Potentiometric methods

Zakkari et al. [15] described a potentiometric nonaqueous titration of
buclizine and other halides of nitrogen bases using bismuth oxyacetate
and perchloric acid or trifluoromethylsulfonic acid. Samples of buclizine
and the other bases were dissolved in anhydrous acetic acid with heating
if necessary and treated with a 2% solution of bismuth oxyacetate
in anhydrous acetic acid. The mixture was stirred until any
precipitation formed re-dissolved, then titrated potentiometrically with
 Buclizine 19

ppm
0

20

40

60

80

100

120

140

160

180

200

15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

FIGURE 1.11 The HMBC NMR spectrum of buclizine in CDCl3.

130.952
130.231
130.149
129.920
128.320
126.579

77.505
77.256

31.114

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

FIGURE 1.12 DEPT 90 NMR of buclizine in CDCl3.

20 Gamal A.E. Mostafa and Abdullah A. Al-Badr

130.95
130.23
130.15
129.92
128.32
126.58

77.50
77.26
70.59

60.60

48.49
47.45
47.36

31.12

200 180 160 140 120 100 80 60 40 20 0 ppm

13
FIGURE 1.13 The DEPT 135 C NMR of buclizine in CDCl3.

0.1 N-trifluoromethyl sulfonic acid. The end-point was detected with use
of glass Ag/AgCl combination electrode. Results compared well with
those obtained using perchloric acid as titrant. The coefficient of variation
were  0.42% and recoveries were > 99%.

5.4. Chromatographic methods

5.4.1. Thin layer chromatography
Tang [16] described an improved method for thin layer chromatographic
identification of compound buclizine. Compound buclizine contains
mainly buclizine hydrochloride, bromhexine hydrochloride, and pro-
methazine hydrochloride. A 20 ml portion of sample solution was made
alkaline with 0.05 M sodium hydroxide (2.5 ml) and extracted with
chloroform (5 ml). Standard solution of buclizine hydrochloride, brom-
hexine, hydrochloride, and promethazine together or separately were
similarly prepared. The chloroform solution were spotted on to Silica
gel G plates (previously treated with 0.5% sodium hydroxymethylcellu-
lose solution and activated at 100  C for 1 h) with chloroform:methanol:
 Buclizine 21

77.50
77.26

70.59

60.60

48.49
47.45
47.36

31.12
80 75 70 65 60 55 50 45 40 35 ppm

FIGURE 1.14 The expanded DEPT 135 13C NMR of buclizine in CDCl3.

dimethylformamide (20:2:1) as mobile phase. Visualization was

performed in iodine vapor. Results were satisfactory. The method is
simple and has good reproducibility.
Clarke [10] reported the following thin layer chromatography systems.
Plates: Silica gel G, 250 mm thick, dipped in or sprayed with 0.1 M
potassium hydroxide in methanol, and dried.
Mobile phase: Methanol:strong ammonia solution (100:1.5).
Reference compounds: Atropine Rf 18, Codeine Rf 33, Chlorprothexaine
Rf 56, Diazepam Rf 75.
Rf ¼ 75 [17,18].

Plates: Silica gel G, 250 mm thick, dipped in or sprayed with 0.1 M

potassium hydroxide in methanol, and dried.
Mobile phase: Cyclohexane:toluene:diethylamine (75:15:10).
22 Gamal A.E. Mostafa and Abdullah A. Al-Badr

130.95

130.23
130.15
129.92

128.32

126.58

132 131 130 129 128 127 126 ppm

FIGURE 1.15 The expanded DEPT 135 13C NMR of buclizine in CDCl3.

Reference compounds: Codeine Rf 06, Desipramine Rf 20, Prazepam Rf 36,

and Trimipramine Rf 62.
Rf ¼ 61 [17,18].

Plates: Silica gel G, 250 mm thick, dipped in or sprayed with 0.1 M

potassium hydroxide in methanol, and dried.
Mobile phase: Chloroform: methanol (90:10).
Reference compounds: Desipramine Rf 11, Physostigmine Rf 36,
Trimipramine Rf 54, and Lidocaine Rf 71.
Rf ¼ 83 [18,19].
 Buclizine 23

100 73

185 241
55
56

57

207 221

125

% 147
143
281
97
98
283

84

121

357
166
101 222 355

284
91 242
111
341
431
223
54 358 415
369 433
296 327
51 372401 434 489 503 549 565 579
461
0 m/z
73 123 173 223 273 323 373 423 473 523 573

FIGURE 1.16 Mass spectrum of buclizine hydrochloride.

Plates: Silica gel G, 25 mm thick, dipped in or sprayed with 0.1 M

potassium hydroxide in methanol, and dried.
Mobile phase: Acetone.
Reference compounds: Amitriptyline Rf 15, Procaine Rf 30, Papaverine Rf 47,
and Cinnarizine Rf 65.
Rf ¼ 72 (acidified iodoplatinated solution: positive) [17,18].
TABLE 1.5 Mass spectral fragmentation pattern of buclizine

Fragment
m/z Relative intensity (%) Formula Structure

433 5 C28H33N2Cl
Cl
CH3
CH N N CH2 C CH3
CH3

355 18 C22H28N2Cl Cl
CH3
CH N N CH2 C CH3
CH3

341 13 C21H26N2Cl Cl
CH3
CH N N CH2 CH
CH3

285 5 C17H18N2Cl
Cl

CH N N
284 15 C17H17N2Cl
Cl

CH N N

283 38 C17H16N2Cl
Cl

CH N N

221 58 C12H14N2Cl
Cl

CH N N CH

207 59 C11H12N2Cl
Cl

CH N N

(continued)
TABLE 1.5 (continued)

Fragment

m/z Relative intensity (%) Formula Structure

185 85 C12H13N2
CH N N CH2

147 49 C11H15 CH3

CH2 C CH3
CH3

125 55 C7H6Cl Cl

CH2

111 15 C6H4Cl
Cl

98 38 C5H10N2
N N CH2
97 40 C5H9N2
N N CH2

91 14 C7H7
CH2

73 100 C3H9N2 H
N

N
H H

71 38 C3H7N2 H
N

N
H

57 72 C4H9 CH3
C CH3
CH3

56 76 C4H8 CH2
C CH3
CH3
28 Gamal A.E. Mostafa and Abdullah A. Al-Badr

5.4.2. Gas chromatography

Clarke [10] reported the following gas chromatographic systems:
Packed column: 3% SE-30 or OV-1 on 80–100 mesh Chromosorb G HP (acid
washed and dimethyldichlorosilane treated) 2 m  2 mm i.d. glass
column: it is essential that the support be fully deactivated.
Column temperature: Normally between 100 and 300  C; for isothermal
conditions, an approximate guide to temperature is to use the RI  10.
Carrier gas: Nitrogen at 45 ml/min.
Capillary column: 10–15 m  0.32 or 0.53 mm i.d., 100% dimethyl-PSX (X-I)
with a 1.5–3 mm film thickness.
Carrier gas: Helium.
Temperature program: 4 min at 135  C, 13  C min 1 to 200  C, 6  C min 1 to
312  C, 6 min final hold.
RI ¼ 3360 [19].

Capillary column: 20–30 m  0.2 or 0.25 mm i.d., 5% phenyl-95%-

dimethyl-PSX (X-5) with a 0.5–1 mm film thickness.
Carrier gas: Helium, constant flow 1 ml/min.
Temperature program: 0.7 min at 90  C, 35  C min 1 to 240  C, 8  C min 1 to
290  C, 25  C min 1 to 325  C, 6 min final hold.
Reference compounds: n-Alkanes with an even number of carbon atoms or a
reference drug mix that contains amphetamine (1125), ephedrine
(1365), benocaine (1545), methyl phenidate (1725), diphenylhydramine
(1870), tripelennamine (1976), methaqualone (2135), trimepramine
(2215), codeine (2375), nordazepam (2490), prazepam (2648), papaver-
ine (2825), haloperidol (2930), and strychnine (3116).
RI ¼ 3461 [10].

5.4.3. High-performance liquid chromatography

Gaillard and Pepin [20] screened and identified buclizine and other drugs
in human hair by high-performance liquid chromatography-photodiode-
array ultraviolet detection and gas chromatography-mass spectrometry
after solid-phase extraction. Powdered hair (75 mg) is incubated for 12 h
at 56  C in 2 ml of distilled water (acidic compounds) or 0.1 M hydro-
chloric acid (neutral and basic compounds). A twin solid-phase extraction
on C18 cartridge is used for sample clean-up procedure. Acidic drugs are
fixed at pH 2 and eluted with 1% ammonical methanol while natural and
basic drugs are retained on the column at pH 8.5 and eluted with metha-
nol containing 0.5% acetic acid. The internal standard for acidic extraction
was bupivacaine and for basic extraction was prazepam. The separation
of the drugs was performed using both the liquid and the gas chromatog-
raphy, whereas identification was achieved using photodiode array and
 Buclizine 29

mass spectrometric detection, respectively. The liquid chromatography

system gives an elution of the drugs following a multi step gradient from
a symmetry C8 5 mm column (25 cm  4.6 mm) at 30  C with acetonitrile–
phosphate buffer (pH 3.8). Identification is achieved using the reference
data (retention times and spectra) of buclizine and many other pharma-
ceuticals, toxicants and drugs of abuse.
Wheals [21] described an isocratic multicolumn high-performance
liquid chromatography for qualitative analysis and characterization of
buclizine and several basic drugs using an aqueous methanol solvent.
A variety of high-performance liquid chromatography packing materials
were prepared and their chromatographic properties compared for separ-
ating buclizine and several basic drugs using a single solvent system.
Massart and Detaevernier [22] selected the preferred systems for the
high-performance liquid chromatography of buclizine and other basic
drugs and applied them to the separation of the antihistamine drugs.
Two preferred systems (combination of a stationary phase and a mobile
phase) for the high-performance liquid chromatography analysis of bucli-
zine and the other basic drugs are selected. The same nitrile stationary
phases are combined with a polar and a non polar eluent. The preferred
systems were applied to the separation of the drugs with excellent results.
Jane et al. [23] used high-performance liquid chromatographic method
for the analysis of buclizine and numerous basic drugs on silica columns
using nonaqueous ionic eluents. Low wavelength ultraviolet and fluores-
cence detection were used, and fluorescence was optimized by a post-
column pH change or derivatization of primary aliphatic amines with
o-phthlaladehyde. Retention and relative response data, UV, 254 nm and
electrochemical, þ 1.2 V, have been generated for buclizine and the other
basic compounds using a 125 mm Spherisorb S5W silica column and
methanolic ammonium perchlorate (10 mM, pH 6.7) as eluent. This
system was used isocratically in qualitative analyses and also for quanti-
tative work, when either the wavelength or the applied potential is
adjusted to optimize the response.
Wahbi et al. [24] used a high-performance liquid chromatographic
method for the determination of buclizine dihydrochloride in the pres-
ence of acid-induced degradation products. The kinetic of the drug deg-
radation at different temperatures was studied. The assay was carried out
using a 300  3.9 mm (i.d.) stainless steel column; packed with Waters
Bondapak C18 (10 mm) at ambient temperature, a mobile phase consisting
of acetonitrile–water (85:15) containing 0.5% triethanolamine at pH 6.6;
filtered through 0.45-mm membrane filter; and degassed by vacuum, a
flow rate of 2 ml/min and detection at 260 nm. Laboratory-made tablets
containing buclizine dehydrochloride, 50 mg and nicotinic acid, 25 mg
per tablet were analyzed by the method and the mean percentage
recovery was found to be 100 0.17 (n ¼ 6).
30 Gamal A.E. Mostafa and Abdullah A. Al-Badr

Aryne et al. [25] developed an isocratic reversed-phase high-perfor-

mance liquid chromatographic method with UV detection at 230 nm for
the determination of buclizine hydrochloride in human serum and dos-
age formulation. Methylparaben was used as an internal standard. Good
chromatographic separation between buclizine and internal standard
peaks was achieved by using a stainless steel analytical column Nucleosil,
C18 (10 mm, 25 cm  0.46 cm). The system was operated at room temper-
ature using a mobile phase consisting of acetonitrile–water (1:1) (pH 2.6)
with phosphoric acid 85% at a flow rate of 2 ml/min. The calibration
curve for buclizine hydrochloride in human serum was linear over the
tested concentration range of 10, 3, 1.5, 0.5, 0.15, 0.05, and 0.025 mg/ml
with a correlation coefficient of 0.9999. The intra- and inter-run precision
and accuracy results were 98.07–100.34. The method was validated for
selectivity, linearity, accuracy, and precision. The method was found to be
suitable for the quality control of buclizine hydrochloride in bulk drug as
well as in human serum.
Aryne et al. [26] presented rapid liquid chromatographic procedures
for quality control of pharmaceuticals and human serum containing anti-
histamines, meclizine, and buclizine alone or in combination with pyri-
doxine using acetonitrile:water (80:20) as a mobile phase (pH adjusted to
2.6), methylparaben as internal standard deviation and UV detection was
made at 230 nm. The results obtained showed a good agreement with the
declared content. The method had good linearity in the range of
0.03–10 mg/ml for pyridoxine and (0.025–10 mg/ml) for meclizine and
buclizine serum concentration with a correlation coefficient of 0.9999.
Dhakane and Ubale [27] developed and validated an isocratic
reversed-phase stability indicating high-performance liquid chro-
matographic assay method for the quantitative determination of buclizine
hydrochloride in the bulk drugs and the degradation products generated
from forced decomposition. The method uses a Grace Alpha C18
(250 mm  4.6 mm) (5 mm) column and the mobile phase containing the
mixture of triethylamine–phosphoric acid buffer (pH 3) by orthopho-
sphoric acid–acetonitrile (20:80). The detection was carried out at
wavelength 230 nm. The method was validated with respect to linearity,
accuracy, precision, system suitability, selectivity, robustness, and
the forced degradation studies prove the stability indicating ability of
the method.
Siddiqui et al. [28] developed and validated an analytical spectral
calibration method to quantify buclizine hydrochloride, which is a piper-
azine derivative and used a single active principle in pharmaceutical
forms were done. The quantification of buclizine hydrochloride was
performed in the wavelength range of 218–226 nm at N ¼ 6. The linear
regression equation has been constructed using relationship between
concentration and absorbance at 218, 220, 222, 224, and 226 nm.
 Buclizine 31

The method was applied directly and easily to the analysis of the pharma-
ceutical tablet preparations. Mean percent relative standard deviation was
found to be 0.6231% (LongifeneÒ tablet 25 mg). The method was
completely validated and proven to be rugged. This validated UV spec-
trophotometric method is potentially useful for a routine laboratory anal-
ysis because of its simplicity, rapidity, sensitivity, precision, and accuracy.
Arayne et al. [29] developed and validated a reversed-phase high-
performance liquid chromatographic method for the estimation of bucli-
zine hydrochloride and other H1-receptor antagonists in the presence of
gliquidone. A good chromatographic separation between these drugs was
achieved using a mobile phase containing methanol–water (80:20) at pH
3.5 with a flow rate of 1 ml/min; and detection was performed at 230 nm
with a UV detector. Validation of the method was performed in terms
linearity, accuracy, precision, and limit of detection and quantification.
The linearity of the calibration curve of buclizine hydrochloride was
0.325–50 mg/ml (r ¼ 0.9967). There was no significant difference between
the amount of drug spiked in serum and the amount recovered, and
serum did not interfere in the simultaneous estimation. The method is
suitable for the simultaneous analysis of the active ingredients in tablet
dosage forms and human serum.
Arun et al. [30] developed and validated a rapid high-performance
liquid chromatographic method for the estimation of buclizine hydro-
chloride in tablet dosage form. The stationary phase used was precoated
silica gel 60 F254. The mobile phase used was a mixture of methanol:
chloroform:ammonia (8:1:1). The detection of spots was carried out at
234 nm. The method was validated in terms of linearity, accuracy, preci-
sion, and specificity. The calibration curve was linear between 100 and
700 ng/spot. The limit of detection and the limit of quantification were
20 and 100 ng/spot, respectively. The method can be used to determine
the drug content of tablet dosage formulation.
Clarke [10] reported the following HPLC systems:
Column: Silica Spherisorb S5W (125  4.9 mm, 5 mm).
Mobile phase: Solution containing 1.175 g (0.01 M) of ammonium perchlo-
rate in 1 l methanol; adjust to pH 6.7 by the addition of 1 ml 0.1 M
sodium hydroxide in methanol.
K values 0.7 [23].
Column: C18 symmetry (250  4.6 mm, 5 mm).
Column temperature: 40  C.
Mobile phase: (A:B) Sulfuric acid (0.5 ml of 2.5 M) in water (500 ml); sulfuric
acid (0.5 ml of 2.5 M) in acetonitrile (500 ml).
Elution program: (98:2) for 3 min to (2.88) over 23 min, hold for 10 min back
to initial conditions over 2 min with equilibration of 8 min before next
injection.
32 Gamal A.E. Mostafa and Abdullah A. Al-Badr

Detection: UV diode-array.
Standards: Nitro-n-alkanes (C1 to C16) 10 ml in 10 ml acetonitrile.
RI ¼ 454 [31].

6. STABILITY

Buclizine should be stored in highly closed containers at temperatures

less than 40  C, preferably between 15 and 30  C [32].

ACKNOWLEDGMENT
The authors wish to thank Mr. Tanvir A. Butt, Pharmaceutical Chemistry Department,
College of Pharmacy, King Saud University for his secretarial assistance in preparing this
profile.

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