Excipients make the difference!

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Excipients make the difference!
Excipients make the difference!
Dr. Felicitas Guth
Global Technical Service Excipients
Pharma Ingredients & Services
BASF SE
Paradigm shift in pharmaceutical development
Traditional
medicinal products
Drug delivery
systems
Trial & error
Quality by Design
Increased functionality and understanding of excipients.
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Excipients make the difference
F.Guth PharmSciFair 2009 2
Innovation in excipients
„ Standard excipients used in combination with innovative
technologies
„ Co-processed excipients
(a combination of two or more excipients designed to physically
modify their properties in a manner not achievable by simple
physical mixing, and without significant chemical change)
„ Novel excipients
(new chemical entities, mostly polymers with a specific functionality)
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Excipients make the difference
F.Guth PharmSciFair 2009 3
Standard excipients & innovative technologies
Copovidone in pharmaceutical
melt extrusion
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Excipients make the difference
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The solubility challenge
∆HTrans, ∆STrans
∆HSolv, ∆SSolv
∆HSub,SSub
∆HS, ∆SS
Zimmermann, I.: Pharmazeutische Technologie. Springer Verlag Berlin, Heidelberg, 1998
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Excipients make the difference
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Relevant types of solid dispersions
Drug
crystalline
amorphous
dissolved
Polymer
amorphous
amorphous
amorphous
Thermoynamic
stability
almost stable
unstable
(kin. Controlled)
stable (below
satur. solubility)
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Excipients make the difference
F.Guth PharmSciFair 2009 6
Polymers in pharmaceutical melt extrusion
Instant release
Copovidone*
PEG**
Povidone
PVA-PEG
HPMC
HPC
Poloxamers
Enteric
Methacrylic acid
copolymer
HPMCAP
HPMCAS
Sustained release
PVAc
PVP/ PVAc
EC
Ammonio methacrylate
copolymer
Amino methacrylate
copolymer
* Kaletra® (Actives: Ritornavir & Lopinavir; copovidone matrix)
** Gris-PEG®, Novartis (Active: Griseofulvin, PEG matrix)
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Excipients make the difference
F.Guth PharmSciFair 2009 7
Principle of pharmaceutical melt extrusion
Screw
Tempering
Powder
Cylinder
Extrudate
Die
Engine
Shaping
Mixing
Melting
according to Reitz (2007)
Temperature:
Residence time:
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above Tg of polymer (80 – 180°C)
variable (0.5 – 5 min)
Excipients make the difference
F.Guth PharmSciFair 2009 8
Performance characteristics
Long term
stability
Hygroscopicity
Physicochemical
properties
of active
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Targeted
release
profile
Drug +
Polymer
Thermostability of
drug &
polymer
Glass
transition
temperature
Melt
viscosity
Solution &
solubilizing
capability
Excipients make the difference
Not all relevant parameters
may be covered by the
standard specification of the
excipient!
F.Guth PharmSciFair 2009 9
Copovidone
ƒ Copovidone is a copolymer consisting of 6 parts of N-vinylpyrrolidone
ƒ
ƒ
and 4 parts of vinyl acetate.
Pharmacopeia monographs in JPE, Ph.Eur and USP/NF
Traditional use: Wet binder and film forming agent
CH
CH CH2
N
O
O
n
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Excipients make the difference
CH 2
O
C
CH3
m
F.Guth PharmSciFair 2009 10
Copovidone in melt extrusion processes
Requirements
Copovidone
9
Thermoplastic behavior
Suitable Tg and melt viscosity
Tg: 101°C
Good thermal stability between 50 &
180°C
Low water content and hygroscopicity to
prevent re-crystallization
9
Water content: max. 5%
Safety
Self affirmed GRAS
High [or no] solubilization capacity
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Excipients make the difference
9
F.Guth PharmSciFair 2009 11
Melt viscosity as a function of temperature
1000000
KollicoatKollicoat
MAE 100MAE
P
Shear stress controlled rotational
rheometer (Rheometrics SR5)
Plate plate geometry
Angular frequency: 1.6 rad/s
Kollidon 30
Viscosity [Pa · s]
100000
Kollidon 12 PF
Kollidon 30
Kollidon SR
Kollidon VA 64
10000
1000
Kollidon 12 PF
Kollidon SR
100
120
140
160
180
Kollidon VA 64
200
220
240
Temperature [°C]
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Excipients make the difference
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Melt viscosity as a function of shear rate
10000000
Shear stress controlled rotational
rheometer (Rheometrics SR5)
Plate plate geometry
Temperature: 170°C
Viscosity [Pa*s]
1000000
100000
10000
Kollidon SR
Kollicoat MAE 100 P
Kollidon VA64
1000
Kollidon 12
100
0.01
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0.1
1
10
Angular Frequency [rad/s]
Excipients make the difference
100
10
F.Guth PharmSciFair 2009 13
Processes run at high temperatures
Hot melt extrusion
Steam sterilization
z 80 – 150°C/ 0.5 - 5 min
z Non aqueous environment
z Potential reactions:
Hydrolysis, oxidation,
elimination of water
z Relatively new process;
few approved drug products
z 121°C/ 2 bar/ 15 min
z Aqueous environment
z Potential reactions:
Hydrolysis
z Process well known by
excipient users and
health authorities
Low Probability of significant
degradation due to short
process times!
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Thermal stability of copovidone
Test parameter
Requirements
Results
Powder
Results
Extrudates
Vinyl acetate
max. 10mg/kg
<10mg/kg
< 10mg/kg
Vinyl pyrrolidone
max. 10mg/kg
<2mg/kg
< 2mg/kg
Acetaldehyde
max. 500mg/kg
<10mg/kg
<10mg/kg
Peroxide
max. 400mg/kg
<20mg/kg
<20mg/kg
2-Pyrrolidone
max. 0.5g/100g
0.06g/100g
0.06g/100g
Saponification value
[mg KOH/g]
230-270
246
237
pH-value
(10% in Solution)
min. 3.0
max. 7.0
4.1
4.1
K-value
(1% aqueous solution)
min. 25.2
max. 30.8
27.0
26.6
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Excipients make the difference
Polymers for pharmaceutical F.Guth
melt extrusion.ppt/15
PharmSciFair 2009 15
Thermal stability of copovidone
0.90
0.80
Kollidon VA 64 LOT 76964875L0
extruded 160°C
0.70
Kollidon VA 64 LOT 76964875L0
w(log(M))
0.60
0.50
0.40
0.30
0.20
0.10
0.00
1,000
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10,000
100,000
M/Da
Excipients make the difference
1,000,000
10,000,000
F.Guth PharmSciFair 2009 16
Innovation potential & challenges
„ Pharmaceutical melt extrusion with selected thermo-stable polymers
proved to be a potent technology to overcome limitations in bioavailability.
„ But:
The technology usually involves exposure to higher temperatures and
requires excipient doses which significantly exceed the amount in
previously approved medicinal products
Users and suppliers have to jointly define relevant performance
characteristics and evaluate the safety of the excipient.
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Excipients make the difference
F.Guth PharmSciFair 2009 17
Novel excipients
PEG-PVA Copolymer
(Kollicoat® IR)
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Excipients make the difference
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Desired functionality
Target:
Requirements
Excipient
properties
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Cost efficient
coating process
Good stability and
rapid dissolution
of the active ingredient
Processing of coating
suspensions with a
high solid content
Flexible and elastic film
that dissolves quickly
Low viscosity &
low surface tension of the
polymer solution
High solubility &
high flexibility
of the polymer
Excipients make the difference
F.Guth PharmSciFair 2009 19
Kollicoat® IR - Polymer structure & properties
~ 25 %PEG & ~75% PVA units
Mw: ~ 45 000
„ The polyvinyl alcohol moiety provides good film-forming properties
„ The polyethylene glycol part acts as an internal plasticizer
„ The polymer quickly dissolves in water, weak acids and bases as
well as in diluted ethanol. It is practically insoluble in organic
solvents
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Excipients make the difference
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Viscosity of aqueous polymer solutions
60
Dynamic viscosity [mPas]
50
40
Kollicoat IR: 17%
PVA:
11%
HPMC 603: 10%
HPMC 606: 6%
30
20
10
0
25
35
45
55
65
75
85
Temperature [°C]
Kollicoat IR
PVA 5-88
HPMC type 603
HPMC type 606
Equipment: ThermoFisher Scientific, Haake RheoWin 322
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Viscosity of aqueous polymer solution
3000
Temperature: 25°C
Dynamic viscosity [mPas]
2500
Kollicoat IR
PVA
HPMC 3 type 603
HPMC 6 type 606
2000
1500
1000
500
0
0
5
Equipment: Haake Rotovisko RV1
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10
15
20
25
30
Polymer concentration [%]
Excipients make the difference
F.Guth PharmSciFair 2009 22
Dissolution of polymer films
Modified dissolution tester
Orifice
(35x23 mm)
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Film
Excipients make the difference
F.Guth PharmSciFair 2009 23
Solubility and dissolution of polymer films
240
Time [s/100µm]
180
120
60
0
HPMC type 603
HPMC type 606
Beginning dissolution of the film
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PVA
Kollicoat IR
Complete dissolution of the film
Excipients make the difference
F.Guth PharmSciFair 2009 24
Elongation at break
Texture Analyzer
TA-XT2i HR
Stable Micro Systems
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Excipients make the difference
F.Guth PharmSciFair 2009 25
Elongation at break
70
60
Strain [N/mm²]
50
40
30
20
10
0
0
50
100
150
200
250
Elongation at break [%]
Kollicoat IR
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PVA
HPMC 3 cP
Excipients make the difference
HPMC 6 cP
F.Guth PharmSciFair 2009 26
Applications
Application
Functionality
Instant release coating
Protects against unpleasant taste or odor
Improves appearance
Makes tablets easier to swallow
Protects sensitive active ingredients
Binder
For very rapidly dispersible/ soluble granules or
tablets
Pore former in sustained
release applications
Highly flexible and hydrophilic pore former
allows to adjust release rates
API loaded films
Polymer carrier
Film former in sprays
Extremely flexible texture
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Excipients make the difference
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Novel excipients – the regulatory challenge
Novel excipients are very welcome at R&D departments,...
Precedence
of use
Pharmacopoeia
monograph
...., but who wants to be the first to file a drug application?
Generic companies in less regulated markets use novel products first
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Excipients make the difference
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Kollicoat IR – a commitment to innovation
2003
2004
2005
2006
2007
2008
2009
2010
Product
launch
1st Approved drug
product EU (Ger)
Japan
USA
Draft Ph.Eur. Monograph
PE 20/ 3
Draft NF. Monograph
PF 35 (2)
Today, Kollicoat IR is also approved and used in several other countries all over the world!
Since 1998 BASF has sucessfully introduced 13 new
excipients. Two of them were new chemical entities.
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F.Guth PharmSciFair 2009 29
Conclusion
„ We believe that the challenges in drug delivery can only be
overcome with new technologies and new excipients.
„ New and highly functional excipients can help to reduce drug
dosages, minimize side effects and therefore make medicines better
and safer.
„ New excipients can contribute to a cost effective and efficient
manufacture of drug products and offer the possibility to
differentiate.
Excipients make the difference!
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Excipients make the difference
F.Guth PharmSciFair 2009 30
Thank you for your attention!
Data: Dr. Karl Kolter, Nils Rottmann, Thorsten Cech
Dr. Felicitas Guth
Global Technical Service Excipients
BASF SE
G-EMP/ME
Pharma Ingredients & Services
Care Chemicals
Phone:
+ 49 (0) 621 / 60 – 28707
Fax:
+ 49 (0) 621 / 60 – 66 28707
Mail:
Internet:
29.04.2009
[email protected]
www.pharma-solutions.basf.com
Excipients make the difference
F.Guth PharmSciFair 2009 31

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