PSEUDOEPHEDRINE Latest Revision: June 22, 2005

OH
C CH 3
H H
C

HN
CH 3

1. SYNONYMS

CFR: Pseudoephedrine

NIST #: Base: 245957

Hydrochloride: 116820

Other Names: (αS)-α-[(1S)-1-

(Methylamino)ethyl]benzenemethanol

(1S,2S)-2-Methylamino-1-phenylpropan-1-ol
d--Ephedrine
d-Isoephedrine

2. CHEMICAL AND PHYSICAL DATA

2.1. CHEMICAL DATA

Form Chemical Formula Molecular Weight Melting Range (°C)

Base C10 H15NO 165.23 118-118.7

Hydrochloride C10H15NO·HCl 201.70 182.5-183.5

2.2. SOLUBILITY

Form A C E H M W

Base *** FS FS *** FS PS

Hydrochloride *** PS VSS *** FS FS

A=acetone, C=chloroform, E=ether, H=hexane, M=methanol, W=water, VS=very soluble, FS=freely soluble,
S= soluble, PS=sparingly soluble, SS=slightly soluble, VSS=very slightly soluble, I=insoluble
3. SCREENING TECHNIQUES

3.1. COLOR TESTS

REAGENT COLOR PRODUCED PREPARATION

Chen’s Purple Reagents:

1) 1% acetic acid solution
2) 1% copper sulfate solution
3) 2.0 N NaOH

3.2. CRYSTAL TESTS

REAGENT TEST DESCRIPTION OF CRYSTALS

Gold chloride in diluted H3PO4 Direct High birefringence, thin branching

sticks, blades, spearheads
Hanging drop, volatility High birefringence, thin branching
sticks, combs

Bismuth iodide in diluted H2SO4 Hanging drop, volatility Orange-red rhomboids, sticks,
forms readily

3.3. THIN-LAYER CHROMATOGRAPHY

Visualization

Acidified potassium permanganate solution

COMPOUND System TLC5

adrenaline 0.0

ephedrine 0.8

methamphetamine 0.9

pseudoephedrine 1.0

amphetamine 1.2

cathine 1.2

phenylpropanolamine 1.3

caffeine 1.5
3.4. GAS CHROMATOGRAPHY/MASS SPECTROMETRY (GC/MS)

Method PSE-GCMS1

Instrument: Gas chromatograph operated in split mode/mass selective detector

Column: 5% phenyl/95% methylsiloxane, 30 m x 0.25 mm i.d. x 0.25 µm film

thickness

Carrier gas: Nitrogen at 1.1 mL/min

Temperatures: Injector: 280°C

Detector: 280°C
Oven Program:
1) initial temperature 60°C (hold 2 min)
2) ramp at 20°C/min to 280°C
3) hold final temperature for 6 min

Injection Parameters: Split Ratio = 80:1, 1 µL injected

Samples are dissolved in an appropriate solvent (i.e. methanol, chloroform/base extract) and filtered prior to
injection.

COMPOUND RRT COMPOUND RRT

dimethylsulfone 0.49 guaifenesin 1.22

amphetamine 0.59 acetaminophen 1.26

P2P 0.76 pheniramine 1.36

methamphetamine 0.81 caffeine 1.37

ephedrine 0.99 ketamine 1.38

pseudoephedrine) 1.00 (7.66 min) lidocaine 1.40

nicotinamide 1.02 chlorpheniramine 1.48

MDA 1.09 procaine 1.50

MD-P2P 1.09 naproxen 1.53

MDMA 1.13 cocaine 1.61

MDEA 1.16 triprolidine 1.64

3.5. GAS CHROMATOGRAPHY/VAPOR PHASE INFRARED SPECTROSCOPY (GC-IRD)

Method PSE-IRDS1

Instrument: Gas chromatograph operated in splitless mode/infrared detector

Column: 100% methylpolysiloxane, 15 m x 0.32mm i.d. x 0.25µm film thickness

Carrier gas: Helium at 1.0 mL/min

Temperatures: Injector: 275°C

Oven Program:
1) initial temperature 70°C (hold 1 min)
2) ramp at 15°C/min to 280°C
3) hold final temperature for 3 min

Injection Parameters: Splitless, 1 µL injected

Samples are dissolved in an appropriate solvent (i.e. methanol, chloroform) and filtered prior to injection.

Note: Reference the RRT from GC section 3.4 as listed above as this parameter is column dependent.

4. SEPARATION TECHNIQUES

Pseudoephedrine hydrochloride can be isolated from several adulterants and diluents as well as several
controlled substances by the use of solvent extractions. For example, pseudoephedrine hydrochloride can be
separated from common tablet excipients by performing a chloroform extraction of the mixture.
Pseudoephedrine will dissolve in the chloroform extract, leaving behind the tableting material.

Additionally, pseudoephedrine hydrochloride can occasionally be separated from a mixture containing

methamphetamine hydrochloride via solvent extraction (depending on concentration of each analyte in the
mixture.) Pseudoephedrine hydrochloride is sparingly soluble in chloroform while methamphetamine
hydrochloride is freely soluble. To isolate pseudoephedrine hydrochloride, a small amount of the mixture is
placed into a cotton-plugged pipette or other appropriate filtering device and a small volume of chloroform is
rapidly washed through the mixture. The methamphetamine hydrochloride will dissolve in the chloroform
extract, leaving behind the pseudoephedrine hydrochloride in the cotton-plugged pipette. If the
methamphetamine hydrochloride was removed completely by the chloroform extraction and the mixture was
comprised of only these two components, the remaining powder will be pseudoephedrine hydrochloride, which
can be subsequently analyzed. If additional components are present in the mixture, use of a different solvent
may be required to isolate the pseudoephedrine hydrochloride. Since pseudoephedrine hydrochloride is very
slightly soluble in ether, it may be possible to subsequently isolate the pseudoephedrine hydrochloride from the
remaining solid mixture (if the remaining mixture contains only diluents) by washing with ether; however, this
step is concentration dependent.

5. QUANTITATIVE PROCEDURES

5.1. GAS CHROMATOGRAPHY

Method PSE-GCQ1

Internal Standard Stock Solution:

4.0 mg/mL tridecane in chloroform.

Standard Solution Preparation:

In a volumetric flask, accurately weigh and prepare a standard solution of pseudoephedrine hydrochloride at a
target concentration of 1.6 mg/mL in 1 part methanol, 1 part internal standard stock solution, and 3 parts
chloroform. In order to preserve the standard stock solution, a 1-2 mL aliquot of the solution may be
transferred to a 13mm x 100mm test tube and base extracted with 5 N NaOH, ensuring a pH ~14. Remove the
bottom layer and filter through a cotton-plugged pipette or other appropriate filtering device. Additionally, the
entire standard solution may be extracted by adding 5 N NaOH directly into the flask, ensuring a pH ~14.
Remove the bottom layer and filter through a cotton-plugged pipette or other appropriate filtering device.

Sample Preparation:
In a volumetric flask, accurately weigh and prepare a sample solution of pseudoephedrine hydrochloride at a
target concentration of 1.6 mg/mL in 1 part methanol, 1 part internal standard stock solution, and 3 parts
chloroform. Add an appropriate amount of 5 N NaOH directly into the flask and shake vigorously to ensure
that all pseudoephedrine hydrochloride is dissolved. Check pH to ensure a pH ~14. Vortex and centrifuge if
necessary. Remove the bottom layer and filter through a cotton-plugged pipette or other appropriate filtering
device into an autosampler vial.

Instrument: Gas chromatograph operated in split mode

with FID

Column: 100% methylpolysiloxane, 15 m x 0.32 mm

i.d. x 0.25 µm film thickness

Carrier gas: Helium at 2.2 mL/min

Temperatures: Injector: 275°C

Detector: 280°C
Oven Program: 130°C isothermal for 7.0 min

Injection Parameters: Split Ratio = 35:1, 1 µL injected

Typical Retention Time: Pseudoephedrine: 2.07
Tridecane: 1.74

Linear Range: 0.2-4.0 mg/mL

Repeatability: RSD < 1.0%

Correlation Coefficient: 0.9999

Note 1: Although pseudoephedrine readily dissolves in methanol, its solubility in chloroform is limited; and in
many instances, matrix effects can be problematic. Therefore, the entire sample solution must be base extracted
with 5 N NaOH.
Note 2: The pKa of pseudoephedrine hydrochloride is 9.22. Use of a concentrated sodium hydroxide solution
(pH ~14) is necessary to ensure complete conversion of the pseudoephedrine hydrochloride into the base, with
subsequent extraction into the organic chloroform layer. Running pseudoephedrine (and other
phenethylamines) as the base strongly recommended. Failure to do so will result in poor chromatographic peak
shape due to the interaction of the amine salts with the stationary phase of the column. DO NOT USE sodium
carbonate or sodium bicarbonate solutions to extract the pseudoephedrine as the pH of these solutions is not
sufficiently high to fully convert the hydrochloride to the base form and extract the base into the chloroform
layer. In cases of strongly acidic liquids, a higher normality of NaOH may be required to obtain a pH of 14.
Note 3: Triprolidine and chlorpheniramine are common adulterants in tablets. These compounds will not elute
under the isothermal conditions before the 7 minute time elapses. If these compounds are present in a sample,
the temperature should be ramped after 7 minutes and held until these compounds elute.

COMPOUND RRT COMPOUND RRT

tridecane 1.00 (1.74) MDP2P 1.68

dimethylsulfone 0.40 MDA 1.76

P2P 0.57 MD-P2P-ol 1.78

amphetamine 0.59 BZP 1.87

methamphetamine 0.68 MDMA 2.24

safrole 0.91 pentadecane 2.26

phenylpropanolamine (note co- 1.00 MDEA 2.79

elution with tridecane)

piperonal (note co-elution with 1.00 MDP2P oxime 3.84

tridecane)

isosafrole #1 1.06 caffeine 4.50

ephedrine 1.19 N-acetyl MDA 4.63

pseudoephedrine 1.20 (2.07 min) ketamine 4.65

isosafrole #2 1.22 PCP 4.81

PMA 1.22 N-acetyl N-acetoxy MDA 5.08

PMMA 1.53
5.2. HIGH PERFORMANCE LIQUID CHROMATOGRAPHY

Method PSE-LCQ1

Standard Solution Preparation:

In a volumetric flask, accurately weigh and prepare a standard solution of pseudoephedrine hydrochloride at a
target concentration of 0.3 mg/mL in 0.1 N HCl.
Sample Preparation:
In a volumetric flask, accurately weigh and prepare a sample solution of pseudoephedrine hydrochloride at a
target concentration of 0.3 mg/mL in 0.1 N HCl. Sonicate 20-30 minutes or until all pseudoephedrine
hydrochloride dissolves. Completely invert the flask and shake to obtain a uniform concentration of analyte in
solution. Filter solution through a 0.45μm filter.

Instrument: High performance liquid

chromatograph equipped with a
UV-diode array

Column: Phenomenex LUNA C18(2), 150

mm x 3.0 mm i.d. x 5 μm particle
size
Guard column: Phenomenex
security guard column, 4 mm x
2.0 mm i.d., C18 cartridge

Detector: UV-DAD, 200 nm and/or 210 nm

Flow: 1.5 mL/min

Injection Volume: 2.5 µL

Buffer: 4000 mL HPLC grade water,

10.0 g NaOH, 30 mL phosphoric
acid, 8.0 mL hexylamine, 10 mg
sodium azide; pH = 2.0
(measured)

Mobile Phase: Buffer: acetonitrile (98:2)

Note 1: Although pseudoephedrine readily dissolves in the 0.1 N HCl solution, sugars, inorganic salts, and
some of the more common tablet excipients are insoluble. This may require additional sonication time in order
to release all of the pseudoephedrine from the excipient matrix.
Note 2: Resolution between pseudoephedrine and ephedrine is less than the 1.5 critical value necessary for
accurate quantitation if both compounds are present. Do NOT use this method for quantitation if both
ephedrine and pseudoephedrine are present.
Note 3: Triprolidine does not elute under these conditions. A gradient ramp to buffer:ACN (50:50) must be
added to the end of the method in order to elute triprolidine.

COMPOUND RRT COMPOUND RRT

phenylpropanolamine 0.67 amphetamine 1.26

ephedrine 0.92 methamphetamine 1.61

pseudoephedrine 1.00 (1.84 min) chlorpheniramine 2.19

6. QUALITATIVE DATA

See spectra on the following pages for FT-IR, Raman, ATR, Mass Spectrometry, Nuclear Magnetic Resonance,
Vapor Phase IR, GC/MS-TPC, and CD-ORD results.

7. REFERENCES

Budavari, S., The Merck Index, 13th Edition, Merck and Co., Inc., 2001, pgs. 1416-1417.

Fulton C. C., Modern Microcrystal Tests for Drugs, Wiley-Interscience, New York, 1969, pgs. 204-205.

Moffat A. C., Sr. Ed., Clarke's Isolation and Identification of Drugs, The Pharmaceutical Press, London,
Second Edition, 1996, pgs. 944-945.

8. ADDITIONAL RESOURCES

Forendex

Wikipedia
 FTIR (ATR): Pseudoephedrine hydrochloride
16 scans, 2 cm-1 resolution, range 4000-600
100

95

90

85
%R eflectance

80

75

70

65

60

3000 2000 1500 1000

Wavenumbers (cm-1)

FTIR (ATR): Pseudoephedrine base

16 scans, 2 cm-1 resolution, range 4000-600

95

90

85

80

75
%R eflectance

70

65

60

55

50

45

40

35

3000 2000 1500 1000

Wavenumbers (cm-1)
 FTIR: Pseudoephedrine Hydrochloride, direct in KBr
2 scans, 4 cm-1 resolution Range: 4000-400
100.0

90

80

70

60

%T 50

40

30

20

8.0
4000.0 3000 2000 1500 1000 400.0
cm-1

FTIR: Pseudoephedrine Base, direct in KBr

2 scans, 4 cm-1 resolution, range: 4000-400 cm-1
100.0

90

80

70

60

%T 50

40

30

20

8.0
4000.0 3000 2000 1500 1000 400.0
cm-1
 FT RAMAN: Pseudoephedrine hydrochloride
64 scans, 8 cm-1 resolution range 3700-410

6.0

5.5

5.0

4.5

4.0
R aman intensity

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.0
3000 2000 1500 1000 500
Raman shift (cm-1)

FT-RAMAN: Pseudoephedrine base

64 scans, 8 cm-1 resolution Range 3700-410
6.0

5.5

5.0

4.5

4.0
R aman intensity

3.5

3.0

2.5

2.0

1.5

1.0

0.5

3000 2000 1500 1000 500

Raman shift (cm-1)
 IR (Vapor Phase): Pseudoephedrine base, 1 mg/mL
1.5 scans/S., 8 cm-1 resolution, range 4000-550

MS (EI): Pseudoephedrine
Abundance

Scan 959 (7.660 min): 061605D.D

4000000 58

3500000

3000000

2500000

2000000

1500000

1000000

500000
77
42 51
65 71 85 91 98 105 117 132 146 166
0
40 50 60 70 80 90 100 110 120 130 140 150 160 170
m/z-->
 GC/MS-TPC: d,l-Pseudoephedrine
chloroform, base extracted with 5 N NaOH, C-4 (time reference), TPC reagent
Abundance

TIC: DLPSDT.D
3000000

2800000

2600000

2400000

2200000

2000000

1800000

1600000

1400000

1200000

1000000

800000

600000

400000

200000

1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00 5.50 6.00 6.50 7.00 7.50
Time-->

Abundance

Scan 1049 (6.276 min): DLPSDT.D

58 166

8000 l-Pseudoephedrine
6000

4000

2000 251
42 77 96 148
117 133 194
179 207 224 273 289 340
0
40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340
m/z-->
Abundance

Scan 1061 (6.333 min): DLPSDT.D

58 166

8000 d-Pseudoephedrine
6000

4000

2000 252
42 77 96
117 133148 194
207 224 273 289 341
0
40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340
m/z-->
 1.0 No. (ppm)
1 1.08
FT-NMR 100 MHz Proton (TMS)
0.9 2 1.10
3 2.73
Pseudoephedrine Hydrochloride
4 3.34 in CD3OD (20 mg/mL)
0.8 5 3.36
6 3.37
0.7 7 3.38
8 4.57
Normalized Intensity

9 4.59
0.6 10 4.89
11 7.34
0.5 12 7.35
13 7.36
14 7.38
0.4
15 7.40
16 7.42
0.3 17 7.44

0.2

0.1

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
Chemical Shift (ppm)

1.0 No. (ppm)

1 11.51
FT-NMR 100 MHz Carbon (TMS) 2 29.41
3 47.25
0.9 Pseudoephedrine Hydrochloride
4 47.46
in CD3OD (110 mg/mL) 5 47.68
0.8 6 47.89
7 48.10
8 48.32
0.7 9 48.53
10 60.59
Normalized Intensity

11 74.35
0.6 12 127.08
13 128.58
14 128.66
0.5
15 140.73

0.4

0.3

0.2

0.1

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

Chemical Shift (ppm)
 1.0
No. (ppm)
1 0.77 FT-NMR 100 MHz Proton (TMS)
0.9 2 0.78 Pseudoephedrine Base
3 2.40
4 2.69
in CD3OD (20 mg/mL)
0.8 5 2.71
6 2.72
0.7 7 2.73
8 4.27
Normalized Intensity

9 4.29
0.6 10 4.91
11 4.91
0.5 12 7.26
13 7.27
14 7.28
0.4 15 7.29
16 7.33
0.3 17 7.34

0.2

0.1

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0
Chemical Shift (ppm)

No. (ppm)
1.0 1 13.89
FT-NMR 100 MHz Carbon (TMS) 2 32.17
0.9 Pseudoephedrine Base 3 47.21
4 47.42
in CD3OD (110 mg/mL) 5 47.63
0.8 6 47.85
7 48.06
0.7 8 48.27
9 48.49
10 60.78
Normalized Intensity

0.6 11 77.60
12 127.07
0.5 13 127.65
14 128.19
15 142.79
0.4

0.3

0.2

0.1

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

Chemical Shift (ppm)
 ORD: d-Pseudoephedrine base (methanol)
cell length: 1 cm concentration: 0.100304 (w/v)%

CD: d-Pseudoephedrine base (methanol)

cell length: 1 cm concentration: 0.100304 (w/v)%
 ORD: l-Pseudoephedrine base (methanol)
cell length: 0.5 cm concentration: 0.100504 (w/v)%

CD: l-Pseudoephedrine base (methanol)

cell length: 0.5 cm concentration: 0.100504 (w/v)%
 ORD: d-Pseudoephedrine hydrochloride (water)
cell length: 0.5 cm concentration: 0.10189 (w/v)%

CD: d-Pseudoephedrine hydrochloride (water)

cell length: 0.5 cm concentration: 0.10189 (w/v)%