CHIRALITY 23:955–960 (2011)
Chromatographic Separation and Spectroscopic Characterization
of the E/Z Isomers of Acrivastine
1
2
3
4
PRAKASH M. DAVADRA,1 BATUK DABHI, MANOJ K. SINGH, MUKUL R. JAIN, HITENDRA S. JOSHI, AND ATUL H. BAPODRA5
*
1Department of Biopharmaceutics, Zydus Research Centre, Ahmedabad, Gujarat, India
2Department of Strategic Technology Development, Zydus Research Centre, Ahmedabad, Gujarat, India
3Department of Pharmacology and Toxicology, Zydus Research Centre, Ahmedabad, Gujarat, India
4Department of Chemistry, Saurashtra University, Rajkot, Gujarat, India
5Department of Chemistry, M. D. Science College, Porbandar, Gujarat, India
ABSTRACT
A reverse phase high performance liquid chromatography (HPLC) method has
been developed for the separation of two geometric isomers of Acrivastine using crude reaction
mixture. The resolution between two isomers was found more than 2.9. The geometric isomers
have been isolated by preparative HPLC and characterized by spectroscopic techniques, such
as NMR, infrared, and MS. The developed method has been validated for the determination of
Z-isomer in Acrivastine. The limit of detection and limit of quantification of the Z-isomer were
0.05 and 0.2 lg/ml, respectively. The developed method is precise, linear, accurate, rugged and
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robust for its intended use. Chirality 23:955–960, 2011.
2011 Wiley-Liss, Inc.
KEY WORDS: Acrivastine; geometric isomers; E/Z isomers; HPLC; validation
INTRODUCTION
mechanism for the formation of both the isomers are pre-
sented in Figure 2.
Acrivastine, (E,E)-3-{6-[1-(4-methyl-phenyl)-3-(1-pyrrolidinyl)-
1-propenyl]-2-pyridinyl}-2-propenoic acid (Fig. 1a), is a potent
histamine H1-receptor antagonist derived from triprolidine.1
It has rapid onset of action and has a low potential to pene-
trate the central nervous system.1 Acrivastine has shown to
be an effective and a well-tolerated antihistamine in the treat-
ment of chronic urticaria and allergic rhinitis.2
The isomer (E, E) is desired isomer (Acrivastine) as a
drug, while (E, Z) isomer is undesired. Therefore, it is nec-
essary to monitor the amount of undesired isomer present in
Acrivastine, for which suitable, precise and accurate chro-
matographic method is needed. Now onward, we refer unde-
sired (E, Z) isomer, as a ‘‘Z-isomer’’ of Acrivastine. The struc-
ture of the ‘‘Z-isomer’’ is shown in Figure 1b.
A literature review revealed that Acrivastine has been
determined and studied by several procedures; gas chroma-
tography mass-spectrometric analysis,3 a sensitive radioimu-
noassay to measure plasma levels,4 nondirect spectrofluori-
metric method5 and several spectrophotometric procedures
to measure acrivastine in urine and pharmaceuticals.5–8 The
high performance liquid chromatography (HPLC) methods
have also been reported for the determination of acrivastine
in capsules using ultraviolet detection.8,9 There are reports
for the determination of the Acrivastine in human urine and
pharmaceutical by spectroflourimetric method10 and by elec-
trochemical method.11
Acrivastine (Fig. 1a) has two unsaturated bonds, one at
the 2-position of propenoic acid and second at 1-position of
the propene attached to 6-position of pyridine ring. All the
four substituents at both double bonds are different, there-
fore four geometric isomers are possible, i. e., (E, E), (E, Z),
(Z, E), and (Z, Z). Since, during the synthesis of Acrivastine
the unsaturated bond at 2-position of propanoic acid is con-
structed by ‘‘Heck reaction’’ and the Heck reaction is known
for the generation of trans geometry predominantly. There-
fore, configuration of the unsaturated bond at 2-position of
propenoic acid is ‘‘E’’, while the configuration of the unsatu-
rated bond at 1-position of propene attached to 6-position of
pyridine ring may ‘‘E’’ or ‘‘Z.’’ The geometry of one of the
double bond is fixed, because of extensive precedences and
mechanism of the Heck reaction and the second double
bond was formed in propane moiety due to dehydration
(elimination reaction). Therefore, two geometric isomers (E,
E) and (E, Z) are possible during synthesis, the scheme and
As, we can see in the preceding literature review, there is
no HPLC method reported for the separation of isomeric im-
purity, i.e., Z-isomer of Acrivastine from the Acrivastine. The
aim of this work was to devise a suitable separation method
and subsequently validate it. This work deals with the sys-
tematic method development, isolation and characterization
of the Z-isomer and Acrivastine, determination of relative
response factor (RRF) of Z-isomer and method validation.
MATERIALS AND METHODS
Chemicals
Crude reaction mixture containing Acrivastine and its Z-isomer was
supplied by Department of Strategic Technology Development of Cadila
Healthcare, Ahmedabad, India. HPLC grade acetonitrile and methanol
were purchased from S.D.Fine, India. AR grade Di-sodium hydrogen
phosphate, Phosphoric acid and Potassium bromide were purchased
from Merck, India. Triflouro acetic acid and Deuteriated methanol were
purchased from Sigma Aldrich, Germany.
Analytical HPLC Method
Analytical HPLC method was developed using Agilent 1100 series
(Germany) HPLC system equipped with degasser auto sampler, auto in-
jector, thermostatic compartment, and photo diode array (PDA) detector.
*Correspondence to: Prakash Madhavjibhai Davadra, Department of Biophar-
maceutics, Zydus Research Centre, Sarkhej-Bavla N. H. No. 8A, Moraiya,
Ahmedabad 382 213, Gujarat, India.
E-mail: prakashdavadra@zyduscadila.com or prakashdavadra@yahoo.co.in
Received for publication 11 July 2010; Accepted 29 June 2011
DOI: 10.1002/chir.21022
Published online 26 September 2011 in Wiley Online Library
(wileyonlinelibrary.com).
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2011 Wiley-Liss, Inc.