Phân tích tạp chất - Kiểm nghiệm thuốc - Esomeprazole

PHARMACEUTICAL IMPURITIES
TESTING

ESOMEPRAZOLE
GROU
P1


» Brand name: Nexium® -AstraZeneca and
Nexium® OTC- Pfizer
» Ranking 18th (Nexium®) in top 50 pharmaceutical
products by global sales (2014)

1


GENER
IC


content
1.
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BACKGROUND
IMPURITIES OF ESOMEPRAZOLE
IMPURITY ORIGIN
TOXICITY

QUALIFICATION & IMPURITY TEST

Let’s go with the second set of slides


“

the important
thing is to never
stop questioning”
-Albert Einstein-


IMPURITIE
S
Esomeprazole impurities include A, B, C, D, E, F
and S-binol


ESOMEPRAZOLE
IMPURITIES
Impurity A
5-Methoxy-1Hbenzimidazole-2thiol
Impurity B
2-[(RS)-[(3,5-Dimethylpyridin-2yl)methyl]
sulphinyl]-5-methoxy-1H-benzimidazole
Impurity C
5-Methoxy-2-[[(4-methoxy3,5-dimethyl
pyridin-2-yl)methyl]sulphanyl]
-1H-benzimidazole

ESOMEPRAZOLE
IMPURITIES
Impurity D
5-Methoxy-2-{[(4-methoxy-3,5dimethyl-2pyridinyl)methyl]sulfonyl}-1Hbenzimidazole
Impurity E
4-Methoxy-2-[[(RS)-(5-methoxy-1Hbenzimidazol
-2-yl)sulfinyl]methyl]-3,5dimethylpyridine-1-oxide
Impurity F
6-methoxy-2-[(4-(R)-methoxy-3,5dimethylpyridin
-2-yl)methylsulfinyl]-1H-benzimidazole


ESOMEPRAZOLE
IMPURITIES

Impurity S-binol
1-(2-Hydroxynaphthalen-1yl)naphthalene-2-ol


IMPURITY
ORIGIN
Imp-E is degradent. Imp-D and Imp-C are process
impurities as well as degradents. Imp-A, Imp-B and S-binol
are process impurities.


SOURCES OF ESOMEPRAZOLE
IMPURITIES

Impurity
Impurity
Impurity
Impurity

A
B
F
S-binol

Impurity C
Impurity D

PROCESS
Journal of Pharmaceutical and
Biomedical Analysis 57 (2012), 109-114

Impurity E

DEGRADE
NTS


PROCESS IMPURITIES

Heterocyclic Communications
22(1), 2016, 17-19
Process for the preparation of
esomeprazole magnesium

dihydrate,
Patent WO2008102145A2


PROCESS IMPURITIES
Omeprazole
(Racemic)

optical
resolution
agent or

ENANTIOMER
PURITY

asymmetrica
lly oxidizing

Esomeprazol
e (S)
Patent WO2008102145A2
Patent WO 2007/013743 A1

Impurity F


PROCESS IMPURITIES

Method of preparing Esomeprazole and salts thereof,
Patent WO 2007/013743 A1

Omeprazole
(Racemic)
(S)-binol

Inclusion
complex (S)omeprazole
and (S)-binol

(S)-binol

optical
resolution
agent  

Chromatography
or filtration or
extraction
Esomeprazol
e (98%)

is

Impurity
S-binol

an


DEGRADENTS

Esomeprazole

Oxid
atio
n

Impurity

n
atio
d
i
Ox

D

Impurity

E

C

Impurity
Ufiprazole

Heterocyclic Communications 22(1), 2016, 17-19
Iranian Journal of Pharmaceutical Sciences 12 (2), 2016, 43-60

TOXICITY
GHS classification, toxicity in humans,
damage to patients


GHS CLASSIFICATION
Globally Harmonized System

Impurities A B C D E F S GHS hazard statements
H301
H302

X
X

Harmful if swallowed
X

H315

X X X X X X

H317

X X X X

H319

X X X X X X X

H335

X X X X X X

May be harmful if swallowed
Health hazards

Causes serious eye irritation
May cause respiratory irritation
Harmful to aquatic life

X

H411

X
X X

Causes skin irritation
May cause an allergic skin reaction

X

H410
H412

Toxic if swallowed

X

H303

H402

EXPLAIN

Environmental hazards

Very toxic to aquatic life with long-lasting effects
Toxic to aquatic life with long-lasting effects
Harmful to aquatic life with long-lasting effects


UALIFICATION
IMPURITY
TEST
British Pharmacopoeia 2016, European Pharmacopoeia
8.0,
United States Pharmacopoeia 40, Vietnamese
Pharmacopoeia IV qualification


MONOGRAPHS

MATERIAL
Esomeprazole Magnesium
Dihydrate, Trihydrate and
Anhydrous
Esomeprazole Strontium
Tetrahydrate and Anhydrous

PRODUCT
Esomeprazole Magnesium
Delayed-release Capsule

MATERIAL
Esomeprazole Magnesium
Dihydrate
Esomeprazole Magnesium
Trihydrate


MONOGRAPHS

MATERIAL
Esomeprazole Magnesium
Trihydrate


MATERIAL IMPURITY CRITERION
MATERIAL

Esomeprazole
Magnesium
Dihydrate

IMPURITY

USP 40

BP 2016

EP 8.0

unspecified impurity
Impurity D
Impurity E

0.1%
0.2%
0.1%

0.1%
0.15%
0.15%

-

Total NMT

Total maximum

0.3%

-

Impurity F

0.2%

0.6%

-

unspecified impurity
Impurity D
Impurity E

0.1%
0.2%
0.1%

0.1%
0.15%
0.15%

0.1%
0.2%
0.1%

Total NMT

Total maximum

Total maximum

0.2%

0.2%

0.2%

0.5%

Esomeprazole
Magnesium
Trihydrate

0.5%

Impurity F

0.3%

0.5%


MATERIAL IMPURITY
CRITERION
MATERIAL

Esomeprazole
Magnesium
Anhydrous

Esomeprazole
Strotium
Tetrahydrate
and Anhydrous

IMPURITY

USP 40

BP 2016

EP 8.0

unspecified impurity
Impurity D
Impurity E

0.1%
0.2%
0.1%

-

-

0.5%

-

-

Impurity F

0.2%

-

-

unspecified impurity
Impurity D
Impurity S-binol

0.1%
0.1%
0.05%

-

-

0.3%

-

-

0.1%

-

-

Total NMT

Total NMT

Impurity F


IMPURITIES CRITERION IN
PRODUCTS

PRODUCT
Esomeprazole
Magnesium
Delayed-release
Capsule

IMPURITY

USP 40

BP 2016

EP 8.0

Impurity D

0.5%

-

-

Any other individual impurity

0.2%

-

-

-

-

Total NMT

2%


RELATED IMPURITY TESTING
METHOD
Pharmacop
oeia
Monograph
s

USP 40
Esomeprazol
e Strontium

BP 2016

Esomeprazol
e Magnesium

Esomeprazole
Magnesium
Delayed- Release
Capsules

Esomeprazole
Magnesium

Method

LC

LC

LC

LC

Stationary
phase

Packing L7
(Octyl silane)
5 μm.

Packing L7
(Octyl silane)
5 μm.

Packing L1
(Octadecyl
silane) 3 μm.

Octylsilyl silica
gel for
chromatography R
5 μm

Mobile
phase

Acetonitrile +
phosphate
buffer pH7.6

Acetonitrile +
phosphate
buffer pH 7.6

Acetonitrile +
phosphate buffer
pH7.6

UV at 280 nm

UV at 280 nm

UV at 302 nm

Detection
Run
time/distan
ce

4.5 times the
retention time
of

Acetonitrile
R+phosphate buffer
pH 7.6
UV at 280 nm
4 times the
retention time of
esomeprazole


RELATED IMPURITY TESTING
METHOD
Pharmacop
oeia

USP 40

BP 2016

Esomeprazol
e Magnesium

Esomeprazole
Magnesium
Delayed- Release
Capsules

Column

4.6-mm × 15cm; 5-µm

4.0-mm ×
12.5-cm or 4.6mm × 15-cm;
5-µm

4.6-mm × 10-cm;
3-µm

Flow rate

1 mL/min

0.8-1 mL/min

1 mL/min

50µL

20 μl

Monograph
s

Injection
Column
temperatur
e

Esomeprazol
e Strontium

5µL
300

Esomeprazole
Magnesium

4.6-mm × 12.5-cm
1 mL/min
40 μl