Excipients make the difference! - IPEC...

Excipients make the difference!

Dr. Felicitas Guth

Global Technical Service Excipients

Pharma Ingredients & Services

BASF SE

29.04.2009 Excipients make the difference F.Guth PharmSciFair 2009 2

Paradigm shift in pharmaceutical development

Traditionalmedicinal products Trial & error

Drug delivery systems Quality by Design

Increased functionality and understanding of excipients.


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)


Standard excipients & innovative technologies

Copovidone in pharmaceuticalmelt extrusion


The solubility challenge

∆HS, ∆SS

∆HSub,SSub

∆HTrans, ∆STrans

∆HSolv, ∆SSolv

Zimmermann, I.: Pharmazeutische Technologie. Springer Verlag Berlin, Heidelberg, 1998


Relevant types of solid dispersions

crystalline amorphous dissolvedDrug

amorphous amorphousamorphousPolymer

almost stable unstable(kin. Controlled)

stable (below satur. solubility)

Thermoynamicstability


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)


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)


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!


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


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


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


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


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!


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


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


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.


Novel excipients

PEG-PVA Copolymer(Kollicoat® IR)


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


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


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%


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


Dissolution of polymer films

Modified dissolution tester

Orifice(35x23 mm)

Film


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


Elongation at break

Texture AnalyzerTA-XT2i HR

Stable Micro Systems


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


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


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


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.


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!


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

Excipients make the difference! - IPEC...

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