sugammadex manufacturing technology related process intermediate … · 2017-11-07 · technology...
TRANSCRIPT
1
Sugammadex manufacturing technology
related process intermediate standards,
process impurities
and analysis
2
Sugammadex is one of the greatest success in the history of
cyclodextrins. There is an increasing interest for this product
and for the development of Sugammadex since the recent
approval by the FDA is estimated to have a 3-4-fold increase
in the global sales of the product.
CycloLab has vast experience in the production of Per-6-
halogen-gamma-CD intermediates and have performed
developed Sugammadex via various process routes and
related compounds, supported by sensitive analytical tools to
characterize the products.
Sugammadex
3
• Supplying the key intermediates (Per-6-halogen-gamma-
CDs) for the synthesis of the API (on commercial scale)
• Assisting in the optimization of the API production
• Comparing samples (both API and final formulations) using
our proprietary sensitive analytical methods (capable of
separating 20-30 potential impurities in the API)
• Providing high purity standards (intermediates,
Sugammadex, key process impurities) to quantify the true
and accurate purity of the compounds
What does CycloLab offer?
Out-licensing: CycloLab has developed a novel, economic and
versatile purification process that allows to obtain
Sugammadex with the originator’s purity without the need of
chromatography.
4
Technology and analysis
Using Cyclolab’s proprietary technology,
a product quality outperforming the
originator’s in all aspects can be
achieved with an economical production.
min6 8 10 12 14 16 18 20 22
mAU
150
200
250
300
350
400
*DAD1 A, Sig=210,4 Ref=360,100 (SGM 2017-05-12\V_4_1.D)*DAD1 A, Sig=210,4 Ref=360,100 (SGM 2017-05-31 1\bridion_L045_16_1.D)
Commercial Bridion sample
CycloLab’s product
5min12 13 14 15 16 17 18 19
mAU
0
20
40
60
80
100
120
140
DAD1 A, Sig=210,4 Ref=360,100 (SGM 2017-05-31 1\bridion_L045_14 SzH_1.D)
(OH
)2-S
GM
(OH
)1-S
GM
(Me)
1-SG
M
(SH
)1-S
GM
or (
Cl)1
-SG
M
SGM
-(m
ono-
sulfo
xide
)
12.
391
13.
458
14.
496
15.
595
15.9
81
16.
395
17.
617
17.
972
18.
274
SGM
-(m
ono-
disu
lfide
)
SGM
-(m
onoa
nhyd
ro)
SGM
Technology and analysis
Bridion itself is claimed to potentially contain 14 cyclodextrin
related impurities (public regulatory information), while other
synthetic approaches generate just as many different ones.
The accurate analysis of such an API is not possible without
proper methods and standard materials.
Commercial Bridion sample
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Raw material and product standards
γCD
γCD
8
S ONa
O
Gamma-cyclodextrin Working Standard:
• Declaration by CycloLab
Sugammadex Primary reference
standard:
• >99.5% purity (on dry substance)
• Identification by NMR, IR, HPLC and
HPLC-MS
7
Process intermediate standards
γCD
8Br
γCD
8Cl
γCD
8I
Per-6-halogen-gamma-cyclodextrin primary standards:
• available for any chosen synthetic route (chloro-, bromo- or
iodo derivative)
• >90% content
• Identification by NMR, IRMain impurities (as monoOH-perhalogeno-GCDs) are also available
8
Major process impurities
Mono-OH-, Di-OH- and
Tri-OH-Sugammadex:
• >95% (Area %) with proprietary HPLC method, DAD detection,
peak purity proven by LC-MS
• Identification by NMR, IR, HPLC-MS
• Residual solvents by TGM-MS and residual salts by CE
γCD
17
OHSNaO
O
γCD
26
OHSNaO
O
γCD
35
OHSNaO
O
9
Major process impurities
Mono-halogen-Sugammadex:
• available for any chosen synthetic route (chloro-, bromo- or
iodo derivative)
• >90% (Area %) with proprietary HPLC method, DAD
detection, peak purity proven by LC-MS
• Identification by NMR, IR, HPLC-MS
• Residual solvents by TGM-MS and residual salts by CE
10
Minor process impurities
Typical analysis:
• >90% (Area %) with
proprietary HPLC method, DAD
detection, peak purity proven by LC-MS
• Identification by NMR, HPLC-MS
• Residual solvents by TGM-MS and residual salts by CE
Contact us for any other impurities
you identified in your generic
Sugammadex!
Mono-ester-Sugammadex
γCD
17
SHSNaO
O
Mono-thio-mono-OH-
Sugammadex
Mono-thio-Sugammadex
γCD
61
SHSNaO
O 1OH
γCD
1
S OCH3
O
7
SNaO
O
Mono-sulfoxide-Sugammadex
γCD
17
SNaO
O
S ONa
OO
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Minor process impurities
Typical analysis:
• >90% (Area %) with
proprietary HPLC method, DAD
detection, peak purity proven by LC-MS
• Identification by NMR, HPLC-MS
• Residual solvents by TGM-MS and residual salts by CE
Contact us for any other impurities
you identified in your generic
Sugammadex!
Mono-ester-Sugammadex
Mono-methylthio-Sugammadex
Mono-disulfide-Sugammadex
γCD
17
SNaO
O
S-S ONa
O
γCD
17
SCH3SNaO
O
γCD
17
SNaO
O
S OC2H5
O
12
Company contacts:
CycloLab Cyclodextrin Research & Development Laboratory Ltd.
Budapest, P.O. Box 435, H-1525 Hungary
Location: Illatos út 7., Budapest, H-1097 Hungary
Tel: (+36) 1-347-60-60 or -70; Fax: (+36) 1-347-60-68
E-mail: [email protected]
Homepage: http://www.cyclolab.hu
Contact person: Zita Vincze
Sales Executive
E-mail: [email protected]
Tel: (+36) 1-347-60-62