Impurity profile study of venlafaxine hydrochloride, an antipsychotic drug substance

Article abstract of DOI:10.1080/00397910903162767

Venlafaxine hydrochloride is a phenyl ethylamine derivative, used for the treatment of depression. During the process development of venlafaxine hydrochloride, six process-related potential impurities were detected in high-performance liquid chromatograph

Full text of DOI:10.1080/00397910903162767

Synthetic Communications1, 40: 1880–1886, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903162767
IMPURITY PROFILE STUDY OF VENLAFAXINE
HYDROCHLORIDE, AN ANTIPSYCHOTIC
DRUG SUBSTANCE
Mohanarangam Saravanan,1,2 Karra Suresh Kumar,1
Padi Pratap Reddy,1 and Bollikonda Satyanarayana1
1Research and Development, Integrated Product Development, Dr. Reddy’s
Laboratories Limited, Bachupalli, Andhra Pradesh, India
2Institute of Science and Technology, Jawaharlal Nehru Technological
University, Hyderabad, Andhra Pradesh, India
Venlafaxine hydrochloride is a phenyl ethylamine derivative, used for the treatment of
depression. During the process development of venlafaxine hydrochloride, six process-
related potential impurities were detected in high-performance liquid chromatography.
All these impurities were identified, synthesized, and subsequently characterized by their
1
respective spectral data (IR, mass, H NMR, and 13C NMR) as described in this article.
Keywords: Antipsychotic; depression; potential impurities; venlafaxine
INTRODUCTION
Venlafaxine hydrochloride (1)[1–3] is a potent serotonin–norepinephrine
reuptake inhibitor (SNRI) used for the treatment of depression, a common type
of psychiatric disorder. This product was developed by Wyeth Laboratories
and is currently being marketed under the trade name of Effexor. It is chemi-
cally known as RS-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol
hydrochloride.
The presence of related compounds or impurities in an active pharmaceutical
ingredient (API) can have significant impact on the quality and safety of the drug
product. As per the guidelines recommended by ICH,[4] it is a mandatory require-
ment to identify and characterize all the unknown impurities that are present in
an API with a level of >0.10%. Hence, a comprehensive study was undertaken to
identify and characterize all the impurities that are present in the API. In this
context, the present work describes the impurity profile study of venlafaxine hydro-
chloride (1), which includes identification, synthesis, and spectral characterization.
Received March 26, 2009.
IPDO-IPM Communication No. 00096.
Address correspondence to Bollikonda Satyanarayana, Research and Development, Integrated
Product Development, Dr. Reddy’s Laboratories Limited, Bachupalli, Qutubullapur, Rangareddy
District 72, Andhra Pradesh, India. E-mail: bsn2626@yahoo.com; satyanarayanab@drreddys.com
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IMPURITY PROFILE STUDY OF VENLAFAXINE
1881
RESULTS AND DISCUSSION
During the process development of venlafaxine hydrochloride (Scheme 1), six
process-related potential impurities were detected in high-performance liquid chro-
matography (HPLC). To identify the molecular weight of the respective impurities,
liquid chromatographic–mass spectrometry (LC-MS) was performed.
From the molecular weight information, extensive study was undertaken to syn-
thesize the six impurities. Finally, all these impurities were synthesized and subsequently
subjected for spectral analysis [mass, 1H NMR, 13C NMR, and infrared (IR)]. Based on
the spectral data, these impurities were characterized as (2RS)-2-(cyclohex-1-enyl)-2-(4-
methoxyphenyl)-N,N-dimethyl ethanamine (2), (2RS)-2-cyclohexyl-2-(4-methoxyphenyl)-
N,N-dimethyl ethanamine (3), 1-[(1RS)-1-(4-methoxyphenyl)-2-(methylamino)ethyl]
cyclohexanol (5), (5RS)-5-(4-methoxyphenyl)-3-methyl-1-oxa-3-azaspiro[5.5]unde-
cane (6), (RS)-5-(4-methoxyphenyl)-3-aza-1-oxaspiro[5,5]undecane (7),[5] and 2-(4-
methoxyphenyl)-N,N-dimethylethanamine (8).
The related compound (impurity) 2 was synthesized by acid-catalyzed dehy-
dration of 1 with sulfuric acid (Scheme 2). The mass spectrum of 2 displayed a
protonated molecular ion peak at m=z 259.8, which is 18 amu lesser than 1. In the
IR spectrum, a broad band between 3500 and 3300 cmꢀ1 corresponding to OH
absorption disappeared, which suggests that a water molecule was lost from 1. In
the 1H NMR spectrum, a triplet signal at d 5.6 ppm corresponding to alkene proton
with one proton integration was observed, and it was confirmed because the
13C NMR displayed alkene carbon signals at d 121.4 and 139.2 ppm. Based on these
spectral data, the structure of 2 was confirmed as (2RS)-2-(cyclohex-1-enyl)-2-(4-
methoxyphenyl)-N,N-dimethylethanamine. Compound 3 was synthesized by cata-
lytic hydrogenation of 2 using Pd=C (Scheme 2) in methanol as solvent. The mass
spectrum of 3 displayed a protonated molecular ion peak at m=z 262.3, which is
2 amu greater than 2. In the 1H NMR spectrum, a signal at d 5.6 ppm corresponding
to alkene proton disappeared, and signals at 0.9–1.5 ppm corresponding to cyclohexyl
group were observed. In the 13C NMR spectrum, signals at d 121.4 and 139.2 ppm
corresponding to alkene carbons disappeared. Based on the spectral data, the
structure of 3 was confirmed as (2RS)-2-cyclohexyl-2-(4-methoxyphenyl)-N,
N-dimethylethanamine.
Scheme 1. Synthesis of venlafaxine hydrochloride.

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M. SARAVANAN ET AL.
Scheme 2. Synthesis of impurities 2 and 3.
Formylation of 4 using formic acid afforded 5a, confirmed in mass spectra by a
protonated molecular ion peak at m=z 278.2. Compound 5a was further reacted with
BH3 ꢁ Me2S (Scheme 3) in the presence of tetrahydrofuran (THF) at reflux tempera-
ture to yield 5. The mass spectrum of 5 displayed a protonated molecular ion peak at
m=z 264.3, which is 14 amu greater than 4. In the IR spectrum, a week band at
1
3306 cmꢀ1 corresponding to secondary NH absorption was observed. In H NMR
spectrum, all signals are similar to that of 4; in addition to that, a singlet signal at
d 2.7 ppm corresponding to N-CH3 with three proton integration was observed,
which was further confirmed in 13C NMR by a signal at d 30.8 ppm. Based on these
spectral data, the structure of 5 was confirmed as 1-[(1RS)-1-(4-methoxyphenyl)-2-
(methylamino)ethyl]cyclohexanol.
The related compound 6 was synthesized from intermediate 4 by reaction with
formaldehyde and formic acid in the presence of water as solvent (Scheme 4) at
reflux temperature. The mass spectrum of 6 displayed a protonated molecular ion
peak at m=z 276. In the IR spectrum, a broad band between 3500 and 3300 cmꢀ1 cor-
1
responding to OH absorption disappeared. In the H NMR spectrum, a methylene
group attached between NH and oxygen was observed as a quartet at d 4.4 ppm with
two-proton integration, a methyl group attached to nitrogen was observed as singlet
at d 2.4 ppm with three-proton integration, and it was further confirmed in 13C NMR
by a signal at d 39.9 ppm. Based on the spectral data, the structure of 6 was
confirmed as (5RS)-5-(4-methoxyphenyl)-3-methyl-1-oxa-3-azaspiro[5.5]undecane.
Reaction of 4 with formaldehyde in the presence of water as solvent (Scheme 4)
yielded impurity 7. The mass spectrum of 7 displayed a protonated molecular ion
peak at m=z 262.1, which is 12 amu greater than 4. In the IR spectrum, a broad band
between 3500 and 3300 cmꢀ1 corresponding to OH absorption disappeared, and a
weak band at 3308 cmꢀ1 corresponding to secondary NH absorption was observed.
1
In the H NMR spectrum, a methylene group attached between NH and oxygen
was observed as a quartet at d 4.4 ppm with two-proton integration. Based on the
spectral data, the structure of 7 was confirmed as (RS)-5-(4-methoxyphenyl)-3-
aza-1-oxaspiro[5,5]undecane.
Scheme 3. Synthesis of impurity 5.

IMPURITY PROFILE STUDY OF VENLAFAXINE
1883
Scheme 4. Synthesis of impurities 6 and 7.
Scheme 5. Synthesis of impurity 8.
2-(4-Methoxyphenyl)ethanamine (9) was reacted with formaldehyde and
formic acid in the presence of water as a solvent (Scheme 5) to yield impurity 8.
The mass spectrum of 8 displayed a protonated molecular ion peak at m=z 180.9.
In the 1H NMR spectrum, the methyl group attached to nitrogen appeared as
a singlet at d 2.8 ppm with six-proton integration and further confirmed in
13C NMR by a signal at d 42.97 ppm. Based on the spectral data, the structure of
8 was confirmed as 2-(4-methoxyphenyl)-N,N-dimethylethanamine.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian Mercury Plus 400-MHz
Fourier transform (FT)–NMR spectrometer, and chemical shift values were reported
on d ppm relative to tetramethylsilane (TMS). The 13C NMR spectra were recorded
on a Varian Mercury Plus 400-MHz FT-NMR spectrometer, and the chemical shift
values were reported on d ppm relative to CDCl3 and dimethylsulfoxide (DMSO-d6).
The IR spectra were recorded in the solid state as KBr dispersion using a Perkin-
Elmer FT-IR spectrophotometer. The mass spectra were recorded on a Shimadzu
LCMS-QP8000 instrument. Elemental analysis for CHN was performed on a
Perkin-Elmer model 2400 CHNS=O analyzer.
(2RS)-2-(Cyclohex-1-enyl)-2-(4-methoxyphenyl)-N,N-
dimethylethanamine (2)
Sulfuric acid (1.0 mL, 0.02 mol) was added slowly to a solution of (RS)-1-[2-
dimethyl-amino)-1-(4-methoxyphenyl)ethyl]cyclohexanol (1, 5.0 g, 0.02 mol) and
dichloromethane (DCM; 30 mL) at 0–5 ꢂC and stirred for 3 h. The pH of the reaction
mass was adjusted to 7.5 with saturated aqueous bicarbonate solution (50 mL), and
layers were separated. The organic layer was washed with water (25 mL) and concen-
trated under reduced pressure at less than 45 ꢂC to afford the title compound 2

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M. SARAVANAN ET AL.
1
(4.1 g, 88.0%). Mass: 259.8 (Mþ1); IR (cmꢀ1): 3099 (Ar-H), 1611 (C C); H NMR
=
=
(CDCl3, d ppm): 7.1 (d, 2H, Ar-H), 6.8 (d, 2H, Ar-H), 5.6 (t, 1H, C CH), 3.8 (s,
3H, OCH3), 3.3 (t, 1H, Ph-CH-CH2), 2.6 (dd, 2H, CH2), 2.2 [s, 6H, N(CH3)2], 2.1
(t, 2H, cyclohexene), 1.8 (m, 2H, cyclohexene), 1.5 (m, 4H, cyclohexene); 13C
NMR (CDCl3, d ppm): 157.80, 139.27, 135.34, 128.70, 121.45, 113.53, 62.93,
55.16, 50.08, 45.98, 26.94, 25.35, 22.99, 22.52. CHN analysis calcd. for C17H25NO:
C, 78.72; H, 9.71; N, 5.40. Found. C, 78.65; H, 9.76; N, 5.47.
(2RS)-2-Cyclohexyl-2-(4-methoxyphenyl)-N,N-
dimethylethanamine (3)
To a mixture of 2 (5 g, 0.02 mol) and methanol (50 mL) in an autoclave
equipped with hydrogen gas inlet and gas induction stirring system, 5% wet Pd=C
(0.5 g) was charged. Temperature was maintained at 40–45 ꢂC for 3 h under
2–3 kg=cm2 hydrogen gas pressure and then cooled to 25–35 ꢂC. The catalyst was
filtered off, and the filtrate was concentrated under reduced pressure at less than
60 ꢂC to afford the title compound 3 (4.6 g, 92.0%). Mass: 262.3 (Mþ1); IR (cmꢀ1):
1
3164 (Ar-H) 1245 & 1041 (C-O-C); H NMR (CDCl3, d ppm): 7.1 (d, 2H, Ar-H),
6.9 (d, 2H, Ar-H), 3.8 (s, 3H, OCH3), 3.6 (m, 1H, Ph-CH-CH2), 3.3 (dd, 1H,
CH2), 3.0 (dd, 1H, CH2), 2.2 (s, 6H, N(CH3)2), 0.9–1.7 (m, 11H, cyclohexyl);
13C NMR (CDCl3, d ppm): 158.89, 130.99, 129.37, 114.37, 61.22, 55.21, 46.61,
44.65, 43.53, 42.46, 39.13, 31.23, 29.71, 26.14, 26.08, 26.01. CHN analysis calcd.
for C17H27NO: C, 78.11; H, 10.41; N, 5.36. Found: C, 78.16; H, 10.50; N, 5.32.
1-[(1RS)-1-(4-Methoxyphenyl)-2-(methylamino)ethyl]-
cyclohexanol (5)
Formic acid (2.2 g, 0.048 mol) was added to a solution of 1-[(RS)-2-amino-
1-(4-methoxyphenyl)ethyl]cyclohexanol (free base of 4, 10 g, 0.04 mol) in toluene
(60 mL), and the mixture was heated to reflux for 5 h. The reaction mass was cooled
to 25–35 ꢂC and washed with saturated aqueous sodium bicarbonate solution
(150 mL). The toluene layer was washed with water (2 ꢃ 25 mL) and distilled off
completely under reduced pressure at less than 70 ꢂC to afford N-[2RS-(1-
hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl]formamide 5a (11 g, 99%). To a
solution of 5a (11 g, 0.04 mol) in THF (30 mL), 10 mol solution of boranedimethyl
sulfide (9.1 g, 0.12 mol) was slowly added and heated to reflux for 5 h. The reaction
mass was cooled to 0–5 ꢂC, quenched with methanol (50 mL), and concentrated under
reduced pressure at less than 60 ꢂC. The residual product was dissolved in DCM
(50 mL) and washed with water (30 mL). The DCM layer was distilled off completely
under reduced pressure to afford the title compound 5 (7.7 g, 73%). Mass: 264.3
1
(Mþ1); IR (cmꢀ1): 3500–3200 (OH), 3306 (N-H) 1243 & 1039 (C-O-C); H NMR
(CDCl3, d ppm): 7.1 (d, 2H, Ar-H), 6.9 (d, 2H, Ar-H), 3.9 (s, 3H, OCH3), 3.8
(m, 1H, Ph-CH-CH2), 3.3 (dd, 1H, CH2), 3.1 (dd, 1H, CH2), 2.7 (s, 3H, NCH3),
0.9–1.7 (m, 11H, cyclohexyl); 13C NMR (CDCl3, d ppm): 158.86, 130.49, 130.17,
113.88, 74.58, 55.24, 52.57, 50.83, 36.87, 33.91, 30.86, 25.36, 21.30, 21.16. CHN analy-
sis calcd. for C16H25NO2: C, 72.96; H, 9.57; N, 5.32. Found C, 72.91; H, 9.53; N, 5.36.

IMPURITY PROFILE STUDY OF VENLAFAXINE
1885
(5RS)-5-(4-Methoxyphenyl)-3-methyl-1-oxa-3-azaspiro[5.5]-
undecane (6)
To a solution of 4 (5 g, 0.02mol), a free base, in water (50 mL), 36% formaldehyde
(4.7 mL, 0.047 mol) and formic acid (3.7 mL, 0.08 mol) were added and heated to
90–95 ꢂC for 60min. The resultant reaction mass was cooled to 0–5 ꢂC, the pH adjusted
to 9.0 with 10% sodium hydroxide solution (30 mL), and the product was extracted
with DCM (2 ꢃ 100 mL). The DCM layer was washed with water (25 mL) and distilled
off completely to afford the compound 6 (3.9 g, 88.0%). Mass: 276 (Mþ1); IR (cmꢀ1):
1
3164 (Ar-H) 1250 & 1055 (C-O-C); H NMR (CDCl3, d ppm): 7.1 (d, 2H, Ar-H),
6.9 (d, 2H, Ar-H), 4.4 (q, 2H, O-CH2-NCH3), 3.8 (s, 3H, OCH3), 3.1 (dd, 1H, CH2),
2.8 (dd, 1H, CH2), 3.2 (m, 1H, Ph-CH-CH2), 2.4 (s, 3H, NCH3), 0.9–1.7 (m, 10H, cyclo-
hexyl); 13C NMR (CDCl3, d ppm): 158.34, 132.11, 130.32, 113.28, 78.97, 75.48, 55.21,
53.14, 47.22, 39.92, 36.82, 25.82, 24.37, 20.99, 20.41. CHN analysis calcd. for
C17H25NO2: C, 74.14; H, 9.15; N, 5.09. Found C, 74.19; H, 9.11; N, 5.14.
(RS)-5-(4-Methoxyphenyl)-3-aza-1-oxaspiro[5,5]undecane (7)
To a solution of a free base of 4 (5 g, 0.02 mol) in water (30 mL), 36% formal-
dehyde (5 mL, 0.06 mol) was added, and the mixture was stirred at 25–35 ꢂC for 4 h.
The separated solid was filtered, washed with water (15 mL), and dried at 40–50 ꢂC
to afford the title compound 7 (4.9 g, 93%). Mass: 262.1 (Mþ1); IR (cmꢀ1): 3308
1
(N-H), 1242 & 1022 (C-O-C); H NMR (CDCl3, d ppm): 7.1 (d, 2H, Ar-H), 6.9
(d, 2H, Ar-H), 4.4 (q, 2H, O-CH2-NCH3) 3.8 (s, 3H, OCH3), 3.6 (dd, 1H, CH2),
3.4 (dd, 1H, CH2), 2.9 (m, 1H, Ph-CH-CH2), 0.9–1.7 (m, 11H, cyclohexyl);
13C NMR (CDCl3, d ppm): 158.3, 132.1, 130.3, 113.2, 78.9, 75.4, 55.2, 53.1, 47.2,
39.9, 36.8, 25.8, 24.3, 20.9, 20.4. C H N analysis calcd. for C16H23NO2: C, 73.53;
H, 8.87; N, 5.36. Found: C,73.55; H, 8.83; N, 5.33.
2-(4-Methoxyphenyl)-N,N-dimethylethanamine (8)
To a solution of 9 (5 g, 0.033 mol) in water (50 mL), 36% formaldehyde
(8.3 mL, 0.10 mol) and formic acid (7.6 mL, 0.16 mol) were added, and the mixture
was heated to 90–95 ꢂC for 12 h. The resultant reaction mass was cooled to
0–5 ꢂC, pH was adjusted to 9.0 with 10% sodium hydroxide solution (30 mL), and
the product was extracted with DCM (2 ꢃ 100 mL). The DCM layer was washed
with water (25 mL) and distilled off completely to afford the compound 8
(4.8 g, 82%). Mass: 180.9 (Mþ1); IR (cmꢀ1): 3011 (Ar-H), 1251 & 1025 (C-O-C);
1H NMR (CDCl3, d ppm): 7.2 (d, 2H, Ar-H), 6.9 (d, 2H, Ar-H), 3.8 (s, 3H,
OCH3), 2.8 (s, 4H, Ar-CH2-CH2-N), 3.2 [s, 6H, N(CH3)2]; 13C NMR (CDCl3,
d ppm): 158.78, 129.62, 127.48, 114.37, 59.26, 55.24, 42.97, 29.91. CHN analysis
calcd. for C11H17NO: C, 73.70; H, 9.56; N, 7.81. Found: C, 73.76; H, 9.50; N, 7.78.
ACKNOWLEDGMENTS
The authors are thankful to the management of Dr. Reddy’s Laboratories
Limited and the colleagues in the Research and Development division for their
constant encouragement and excellent cooperation.

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