Atorvastatin-Ca

Transcription

Atorvastatin-Ca

****Small but Strong Corporation****
MEDICHEM KOREA. CO., LTD
www.medichemkorea.com
“Beyond the dream, above the vision”
MEDICHEM KOREA always goes with you
until our dreams and visions come true.
ATORVASTATIN-Ca
111-7, Kuun-dong, Kwonsun-gu, Suwon-ci, Gyeonggi-do, KOREA, 441-814
TEL. : +82-31-225-7613
FAX. : +82-31-225-7614
1
LIPITOR® (atorvastatin calcium) is a synthetic lipid-lowe
ring agent. Atorvastatin is an inhibitor of 3-hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) reductase. This
enzyme catalyzes the conversion of HMG-CoA to meval
onate, an early and rate-limiting step in cholesterol bio
synthesis.
Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-β,
δ -dihydroxy-5- (1-methylethyl)-3-phenyl-4-[(phenylami
no) carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt
(2:1) trihydrate. The empirical formula of atorvastatin cal
cium is (C33H34 FN2O5)2Ca•3H2O and its molecular weigh
t is 1209.42. Its structural formula is:
I. Structure
OH OH
NH
Ca2+
N
O
O
O2
F
II. Molecular formular : C66H68CaF2N4O10
III. Cas No. : 344423-98-9
IV. Molecular weight : 1209.41
V. Assay : 99.9%
Patent Number
Contesnts
Date of Pat.
Assignee
1. KR10-0763770
Intermediate of ATORVASTATIN
05-29-2009
MEDICHEMKOREA CO., LTD.
2. KR10-0850558
Preparation Process of ATORVASTATIN
01-02-2008
3. KR10-0856133
01-11-2008
4. PCT/KR2008/001902
04-04-2008
5. KR10-2010-006461
Preparation Process of Novel crystal ATORVASTATIN
01.16.2010
2
KR10-1199919, KR10-0850558, KR10-0856133, PCT/KR2008/001902
OR
OR
O
O
CO2H
O
O
O
O
N
H2N
O
O
F
O
RO
HO
O
O-
O
H
N
O
N
Ca 2+
HO
O
O
F
H
N
O
N
O
F
2
3
MEDICHEMKOREA
PFIZER-Ⅰ
MCK-Ⅰ,Ⅱ
MCK-Ⅲ-2
MCK-Ⅲ-4
ANHYDROUS
XRD
Crystal
Crystal
Crystal
amorphous
Crystal
FT-IR
ⅰ) Similar to Ⅰ-from
ⅱ) No Find hydrate peak
ⅱ) Find hydrate peak
(3667cm-1)
No Hydrate peak
(3667cm-1)
Patent / actual
ⅰ) Hydrate peak
MOISTURE (%)
(3.5 ~ 5.5 %)
1.7 ~ 2.2 %
4.1 ~4.8 %
4.1 ~ 4.7 %
Anhydrous
3.5 ~ 5.5 %
STAGE
Lab / Pilot
(MCK-Ⅰ)
Lab / Pilot
/ Commercial (Taiwan)
Lab / Pilot
/ Commercial (Japan)
Lab
COMMENTS
New Crystal form
New Crystal form
New Crystal form
-
ⅱ) Find hydrate peak
(3667cm-1)
-
4
ITEM
REQUIREMENT
RESULTS
WHITE OR PALE YELLOWISH WHITE CRYSTALLINE POWDER
WHITE CRYSTALLINE POWDER
(III-2/III-4)
IR : MEET THE REQUIREMENT
CONFORM
-7 ° ~ -10 °
- 7.4 °
NOT MORE THAN 20ppm
CONFORM
3.5 ~ 5.5 %
4.2 %
A*Des fluoro (A)
NOT MORE THAN 0.3 %
0.06 %
A*3S,5R (B)
NOT MORE THAN 0.3 %
NOT DETECTED
A*Difluoro (C)
NOT MORE THAN 0.3 %
NOT DETECTED
A*Epoxide (D)
NOT MORE THAN 0.2 %
NOT DETECTED
ANY OTHER INDIVIDUAL IMPURITY
NOT MORE THAN 0.1 %
0.04%
TOTAL IMPURITIES
NOT MORE THAN 1.0 %
0.13 %
NOT MORE THAN 0.3 % OF ATORVASTATIN RELATED
DOMPOUND E
NOT DETECTED
98.0 ~ 102. 0 % (ANHYDROUS BASIS)
99.9 %
APPEARANCE
IDENTIFICATION
OPTICAL ROTATION
HEAVY METALS
WATER CONTENT
RELATED SUBSTANCES ( A*: ATORVASTATIN)
ENANTIOMERIC PURITY
ASSAY (BY HPLC)
5
OH OH
O
O
OH
O-
N
O
2+
NH
Ca
OH O
OH OH
N
O
2+
NH
Ca
F
2
2+
NH
Ca
2
3S,5S-ATV
N
DES-ATV
OH
OH OH O
-
O
O
F
O
O-
N
2+
NH
Ca
O-
N
2+
Ca
Ca
F
F
2
2
2
3R,5S-ATV
3S,5R-ATV
DIF-ATV
O
O
O
-
N
O
O
2+
NH
Ca
F
OH
O
OH
O
O-
N
2+
NH
Ca
F
2
3-Methoxy ATV
OH O
NH
2+
NH
F
OH
O-
N
2
OH OH O
O
O
F
ATV
O
O
-
OH
O
N
OH
OH O
N
H
OH
NH
F
2
5-Methoxy ATV
Diamino ATV
6
15000
14000
13000
d=32.91457
III-2
11000
d=2.35590
d=2.46250
1000
d=2.42248
d=2.92265
d=3.01191
d=3.25822
d=3.18014
d=3.11826
d=3.46473
d=3.94293
d=3.79363
d=3.70004
d=4.06482
d=4.55792
d=4.25524
d=4.38331
d=4.96033
d=4.82621
d=5.16310
d=5.39327
d=5.61344
d=5.92231
d=7.03306
d=6.36998
d=8.07608
2000
d=11.42708
d=10.73195
d=16.27146
3000
d=12.87901
d=11.98993
d=3.27085
d=3.47513
4000
d=3.38740
d=3.67020
5000
d=8.61082
d=32.26320
7000
d=10.15884
8000
d=24.04234
d=4.12427
d=3.94654
d=4.06992
d=3.82477
d=3.79750
d=4.26190
d=5.24359
d=4.96802
d=6.37419
100
9000
6000
d=5.89107
d=7.54947
d=7.34419
d=7.05679
d=9.44692
d=11.52001
d=10.87151
d=16.38975
200
d=8.63099
d=9.90108
d=10.28898
d=29.62410
d=24.32489
Lin (Counts)
300
Lin (Counts)
d=4.57039
10000
500
400
III-4
12000
0
0
2
10
20
30
40
2-Theta - Scale
File: 2.raw - Type: 2Th/Th locked - Start: 2.000 ? - End: 40.000 ? - Step: 0.020 ? - Step time: 0.4 s - Temp.: 25 캜 (Room) - Time Started: 2 s - 2-Theta: 2.000 ? - Theta: 1.000 ? - Chi: 0.00 ? - Phi: 180.00 ? - X: 0.0 mm Operations: Smooth 0.090 | Import
2
10
20
30
2-Theta - Scale
File: 36-3.raw - Type: 2Th/Th locked - Start: 2.000 ° - End: 40.005 ° - Step: 0.020 ° - Step time: 11.8 s - Temp.: 25 °C (Room) - Time Started: 15 s - 2-Theta: 2.000 ° - Theta: 1.000 ° - Chi: 0.00 ° - Phi: 0.00 ° - X: 0.0 m
Operations: Fourier 20.000 x 1 | Fourier 20.000 x 1 | Import
Pfizer-I
7
MCK- III-2
MCK- III-4
Pfizer-I
8
Pfizer- I
MCK- III-4
9

Atorvastatin-Ca

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