Excipients make the difference! Dr. Felicitas Guth Global Technical Service Excipients Pharma Ingredients & Services BASF SE

Transcription

1 Excipients make the difference! Dr. Felicitas Guth Global Technical Service Excipients Pharma Ingredients & Services BASF SE

2 Paradigm shift in pharmaceutical development Traditional medicinal products Trial & error Drug delivery systems Quality by Design Increased functionality and understanding of excipients Excipients make the difference F.Guth PharmSciFair

3 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) Excipients make the difference F.Guth PharmSciFair

4 Standard excipients & innovative technologies Copovidone in pharmaceutical melt extrusion Excipients make the difference F.Guth PharmSciFair

5 The solubility challenge H Trans, S Trans H Sub,S Sub H Solv, S Solv H S, S S Zimmermann, I.: Pharmazeutische Technologie. Springer Verlag Berlin, Heidelberg, Excipients make the difference F.Guth PharmSciFair

6 Relevant types of solid dispersions Drug crystalline amorphous dissolved Polymer amorphous amorphous amorphous Thermoynamic stability almost stable unstable (kin. Controlled) stable (below satur. solubility) Excipients make the difference F.Guth PharmSciFair

7 Polymers in pharmaceutical melt extrusion Instant release Enteric Sustained release Copovidone* PEG** Povidone PVA-PEG HPMC HPC Poloxamers Amino methacrylate copolymer Methacrylic acid copolymer HPMCAP HPMCAS PVAc PVP/ PVAc EC Ammonio methacrylate copolymer * Kaletra (Actives: Ritornavir & Lopinavir; copovidone matrix) ** Gris-PEG, Novartis (Active: Griseofulvin, PEG matrix) Excipients make the difference F.Guth PharmSciFair

8 Principle of pharmaceutical melt extrusion Die Tempering Cylinder Screw Powder Extrudate Engine Shaping Mixing Melting according to Reitz (2007) Temperature: above T g of polymer ( C) Residence time: variable (0.5 5 min) Excipients make the difference F.Guth PharmSciFair

9 Performance characteristics Long term stability Targeted release profile Glass transition temperature Hygroscopicity Drug + Polymer Melt viscosity Physicochemical properties of active Thermostability of drug & polymer Solution & solubilizing capability Not all relevant parameters may be covered by the standard specification of the excipient! Excipients make the difference F.Guth PharmSciFair

10 Copovidone Copovidone is a copolymer consisting of 6 parts of N-vinylpyrrolidone 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 2 N O CH O C CH 2 O n CH 3 m Excipients make the difference F.Guth PharmSciFair

11 Copovidone in melt extrusion processes Requirements Thermoplastic behavior Copovidone Suitable Tg and melt viscosity Tg: 101 C Good thermal stability between 50 & 180 C Low water content and hygroscopicity to prevent re-crystallization Safety High [or no] solubilization capacity Water content: max. 5% Self affirmed GRAS Excipients make the difference F.Guth PharmSciFair

12 Melt viscosity as a function of temperature Viscosity [Pa s] Kollicoat Kollicoat MAE 100 MAE P Kollidon 30 Kollidon 12 PF Kollidon SR Kollidon VA 64 Kollidon 12 PF Kollidon 30 Kollidon SR Shear stress controlled rotational rheometer (Rheometrics SR5) Plate plate geometry Angular frequency: 1.6 rad/s 100 Kollidon VA Temperature [ C] Excipients make the difference F.Guth PharmSciFair

13 Melt viscosity as a function of shear rate Shear stress controlled rotational rheometer (Rheometrics SR5) Plate plate geometry Temperature: 170 C Viscosity [Pa*s] Kollidon SR Kollicoat MAE 100 P Kollidon VA Kollidon Angular Frequency [rad/s] Excipients make the difference F.Guth PharmSciFair

14 Processes run at high temperatures Hot melt extrusion Steam sterilization C/ min Non aqueous environment Potential reactions: Hydrolysis, oxidation, elimination of water Relatively new process; few approved drug products 121 C/ 2 bar/ 15 min Aqueous environment Potential reactions: Hydrolysis Process well known by excipient users and health authorities Low Probability of significant degradation due to short process times! Excipients make the difference F.Guth PharmSciFair

15 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] ph-value (10% in Solution) K-value (1% aqueous solution) min. 3.0 max. 7.0 min max Polymers for pharmaceutical melt extrusion.ppt/ Excipients make the difference F.Guth PharmSciFair

16 Thermal stability of copovidone Kollidon VA 64 LOT L0 extruded 160 C Kollidon VA 64 LOT L0 w(log(m)) ,000 10, ,000 1,000,000 10,000,000 M/Da Excipients make the difference F.Guth PharmSciFair

17 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 Excipients make the difference F.Guth PharmSciFair

18 Novel excipients PEG-PVA Copolymer (Kollicoat IR) Excipients make the difference F.Guth PharmSciFair

19 Desired functionality Target: Cost efficient coating process Good stability and rapid dissolution of the active ingredient Requirements Processing of coating suspensions with a high solid content Flexible and elastic film that dissolves quickly Excipient properties Low viscosity & low surface tension of the polymer solution High solubility & high flexibility of the polymer Excipients make the difference F.Guth PharmSciFair

20 Kollicoat IR - Polymer structure & properties ~ 25 %PEG & ~75% PVA units Mw: ~ 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 Excipients make the difference F.Guth PharmSciFair

21 Viscosity of aqueous polymer solutions Dynamic viscosity [mpas] Kollicoat IR: 17% PVA: 11% HPMC 603: 10% HPMC 606: 6% Temperature [ C] Equipment: ThermoFisher Scientific, Haake RheoWin 322 Kollicoat IR PVA 5-88 HPMC type 603 HPMC type Excipients make the difference F.Guth PharmSciFair

22 Viscosity of aqueous polymer solution 3000 Temperature: 25 C 2500 Dynamic viscosity [mpas] Kollicoat IR PVA HPMC 3 type 603 HPMC 6 type Equipment: Haake Rotovisko RV1 Polymer concentration [%] Excipients make the difference F.Guth PharmSciFair

23 Dissolution of polymer films Modified dissolution tester Orifice (35x23 mm) Film Excipients make the difference F.Guth PharmSciFair

24 Solubility and dissolution of polymer films Time [s/100µm] HPMC type 603 HPMC type 606 PVA Kollicoat IR Beginning dissolution of the film Complete dissolution of the film Excipients make the difference F.Guth PharmSciFair

25 Elongation at break Texture Analyzer TA-XT2i HR Stable Micro Systems Excipients make the difference F.Guth PharmSciFair

26 Elongation at break Strain [N/mm²] Elongation at break [%] Kollicoat IR PVA HPMC 3 cp HPMC 6 cp Excipients make the difference F.Guth PharmSciFair

27 Applications Application Instant release coating Binder Pore former in sustained release applications API loaded films Film former in sprays Functionality Protects against unpleasant taste or odor Improves appearance Makes tablets easier to swallow Protects sensitive active ingredients For very rapidly dispersible/ soluble granules or tablets Highly flexible and hydrophilic pore former allows to adjust release rates Polymer carrier Extremely flexible texture Excipients make the difference F.Guth PharmSciFair

28 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 Excipients make the difference F.Guth PharmSciFair

29 Kollicoat IR a commitment to innovation Product launch 1 st 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 Excipients make the difference F.Guth PharmSciFair

30 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! Excipients make the difference F.Guth PharmSciFair

31 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 / Fax: + 49 (0) 621 / Mail: Internet: felicitas.guth@basf.com Excipients make the difference F.Guth PharmSciFair