Excipients make the difference!
Dr. Felicitas Guth
Global Technical Service Excipients
Pharma Ingredients & Services
BASF SE
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Paradigm shift in pharmaceutical development
Traditionalmedicinal products Trial & error
Drug delivery systems Quality by Design
Increased functionality and understanding of excipients.
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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)
29.04.2009 Excipients make the difference F.Guth PharmSciFair 2009 4
Standard excipients & innovative technologies
Copovidone in pharmaceuticalmelt extrusion
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The solubility challenge
∆HS, ∆SS
∆HSub,SSub
∆HTrans, ∆STrans
∆HSolv, ∆SSolv
Zimmermann, I.: Pharmazeutische Technologie. Springer Verlag Berlin, Heidelberg, 1998
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Relevant types of solid dispersions
crystalline amorphous dissolvedDrug
amorphous amorphousamorphousPolymer
almost stable unstable(kin. Controlled)
stable (below satur. solubility)
Thermoynamicstability
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Polymers in pharmaceutical melt extrusion
Instant release Enteric Sustained release
Copovidone*PEG**PovidonePVA-PEGHPMCHPCPoloxamersAmino methacrylatecopolymer
Methacrylic acid copolymer HPMCAPHPMCAS
PVAcPVP/ PVAcECAmmonio methacrylatecopolymer
* Kaletra® (Actives: Ritornavir & Lopinavir; copovidone matrix)** Gris-PEG®, Novartis (Active: Griseofulvin, PEG matrix)
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Principle of pharmaceutical melt extrusion
Engine
DieTempering
CylinderScrew
Powder
Extr
udat
e
according to Reitz (2007)MeltingMixingShaping
Temperature: above Tg of polymer (80 – 180°C)Residence time: variable (0.5 – 5 min)
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Performance characteristics
TargetedreleaseprofileLong term
stability
Hygros-copicity
Physico-chemical
propertiesof active
Thermo-stability of
drug & polymer
Solution &solubilizingcapability
Meltviscosity
Drug + Polymer
Glass transition tempera-
ture
Not all relevant parametersmay be covered by the standard specification of theexcipient!
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Copovidone
Copovidone is a copolymer consisting of 6 parts of N-vinylpyrrolidoneand 4 parts of vinyl acetate. Pharmacopeia monographs in JPE, Ph.Eur and USP/NFTraditional use: Wet binder and film forming agent
O
CH CH2
n
CHO
C O
CH3
CH 2
m
N
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Copovidone in melt extrusion processes
Requirements Copovidone
Thermoplastic behavior
Suitable Tg and melt viscosity Tg: 101°C
Good thermal stability between 50 & 180°CLow water content and hygroscopicity to prevent re-crystallization Water content: max. 5%
Safety Self affirmed GRAS
High [or no] solubilization capacity
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Melt viscosity as a function of temperature
Kollidon 12 PF
Kollidon VA 64
Kollidon SR
Kollicoat MAE
Kollidon 30
100
1000
10000
100000
1000000
120 140 160 180 200 220 240
Temperature [°C]
Visc
osity
[Pa
· s] Kollidon 12 PF
Kollidon SR
Kollicoat MAE 100 P
Kollidon VA 64
Kollidon 30
Shear stress controlled rotational rheometer (Rheometrics SR5)Plate plate geometry Angular frequency: 1.6 rad/s
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Melt viscosity as a function of shear rate
100
1000
10000
100000
1000000
10000000
0.01 0.1 1 10 100 10
Angular Frequency [rad/s]
Viscosity [P
a*s]
Kollidon 12
Kollidon SR
Kollicoat MAE 100 PKollidon VA64
Shear stress controlled rotational rheometer (Rheometrics SR5)Plate plate geometryTemperature: 170°C
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Processes run at high temperatures
Hot melt extrusion Steam sterilization
80 – 150°C/ 0.5 - 5 minNon aqueous environmentPotential reactions: Hydrolysis, oxidation,elimination of waterRelatively new process;few approved drug products
121°C/ 2 bar/ 15 minAqueous environmentPotential reactions: HydrolysisProcess well known by excipient users andhealth authorities
Low Probability of significant degradation due to shortprocess times!
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Thermal stability of copovidone
Test parameter Requirements ResultsPowder
ResultsExtrudates
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. 3.0max. 7.0 4.1 4.1
K-value(1% aqueous solution)
min. 25.2 max. 30.8 27.0 26.6
Polymers for pharmaceutical melt extrusion.ppt/15
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Thermal stability of copovidone
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1,000 10,000 100,000 1,000,000 10,000,000
M/Da
w(lo
g(M
))
Kollidon VA 64 LOT 76964875L0extruded 160°C
Kollidon VA 64 LOT 76964875L0
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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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Novel excipients
PEG-PVA Copolymer(Kollicoat® IR)
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Desired functionality
Cost efficient coating process
Good stability and rapid dissolution
of the active ingredientTarget:
Processing of coating suspensions with a high solid content
Flexible and elastic film that dissolves quickly
Requirements
Low viscosity &low surface tension of the
polymer solution
High solubility &high flexibility of the polymer
Excipientproperties
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Kollicoat® IR - Polymer structure & properties
~ 25 %PEG & ~75% PVA unitsMw: ~ 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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Viscosity of aqueous polymer solutions
0
10
20
30
40
50
60
25 35 45 55 65 75 85
Temperature [°C]
Dyn
amic
vis
cosi
ty [m
Pas]
Kollicoat IR PVA 5-88 HPMC type 603 HPMC type 606
Equipment: ThermoFisher Scientific, Haake RheoWin 322
Kollicoat IR: 17%PVA: 11%HPMC 603: 10%HPMC 606: 6%
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Viscosity of aqueous polymer solution
Temperature: 25°C
Equipment: Haake Rotovisko RV1
0
500
1000
1500
2000
2500
3000
0 5 10 15 20 25 30
Polymer concentration [%]
Dyn
amic
vis
cosi
ty [m
Pas] Kollicoat IR
PVAHPMC 3 type 603HPMC 6 type 606
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Dissolution of polymer films
Modified dissolution tester
Orifice(35x23 mm)
Film
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Solubility and dissolution of polymer films
0
60
120
180
240
HPMC type 603 HPMC type 606 PVA Kollicoat IR
Tim
e [s
/100
µm]
Beginning dissolution of the film Complete dissolution of the film
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Elongation at break
Texture AnalyzerTA-XT2i HR
Stable Micro Systems
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Elongation at break
0
10
20
30
40
50
60
70
0 50 100 150 200 250
Elongation at break [%]
Stra
in [N
/mm
²]
Kollicoat IR PVA HPMC 3 cP HPMC 6 cP
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Applications
Application Functionality
Instant release coating
Protects against unpleasant taste or odorImproves appearanceMakes tablets easier to swallowProtects 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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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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Kollicoat IR – a commitment to innovation
2003 2004 2005 2006 2007 2008 2009 2010
Product launch
Japan1st Approved drugproduct EU (Ger)
USA
Draft NF. MonographPF 35 (2)
Draft Ph.Eur. MonographPE 20/ 3
Today, Kollicoat IR is also approved and used in several other countries all over the world!
Since 1998 BASF has sucessfully introduced 13 newexcipients. Two of them were new chemical entities.
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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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Thank you for your attention!
Data: Dr. Karl Kolter, Nils Rottmann, Thorsten Cech
Dr. Felicitas GuthGlobal Technical Service ExcipientsBASF SEG-EMP/MEPharma Ingredients & ServicesCare ChemicalsPhone: + 49 (0) 621 / 60 – 28707Fax: + 49 (0) 621 / 60 – 66 28707
Mail: [email protected]: www.pharma-solutions.basf.com