Insight into solid state properties during processing

Transcription

1 Insight into solid state properties during processing Jukka Rantanen Outline * Background role of process analysis * Solid state analysis, special emphasis on interfacing and data analysis during: 1. crystallization polymorph screen 2. milling amorphous material 3. wet granulation 4. dissolution testing * Future challenges 1

2 Perspective to manufacturing Synthetic activities/ search for new candidates Identification of target protein/receptor structure Perspective to manufacturing * innovative formulations * new unit operations, new ways of processing 2

3 Background Where is the focus of analysis of drug products? Process analysis is aiming to combine the process and material information -> use it to increase process understanding -> ensure product quality Quality by Design (QbD) Process analysis SYNTHESIS CRYSTALLIZATION GRANULATION MIXING TABLETING COATING Process analytical solutions: - Spectroscopy (IR, NIR, Raman, THz ) -Image analysis -Laser diffraction -X-ray diffraction - Mechanical properties - Thermal properties -Acoustic information - Electrostatics

4 Process analysis M 4 M 5 OUT 1 What do we do with all this? IN 2 M n M 3 M 1 M 2 IN 1 t [M 1 M 2 M 3 M 4 M 5 M n ] [M 1 M 2 M 3 M 4 M 5 M n ] [M 1 M 2 M 3 M 4 M 5 M n ] [M 1 M 2 M 3 M 4 M 5 M n ] [M 1 M 2 M 3 M 4 M 5 M n ] Process analysis - experimental Effective use of: * design of experiments * multivariate data analysis Design Space 4

5 Process analysis - modeling Effective use of: * process modeling First principles Outline * Background role of process analysis * Solid state analysis, special emphasis on interfacing and data analysis during: 1. crystallization polymorph screen 2. milling amorphous material 3. wet granulation 4. dissolution testing * Future challenges 5

6 Solid state properties Solid dosage forms; crystalline - amorphous material -> performance of a dosage form 1 Å scale Å scale Process analysis SYNTHESIS CRYSTALLIZATION GRANULATION MIXING TABLETING COATING Process analytical solutions: - Spectroscopy (IR, NIR, Raman, THz ) -Image analysis -Laser diffraction -X-ray diffraction - Mechanical properties - Thermal properties -Acoustic information - Electrostatics

7 Raman measurement fiber optics fluorescence? SPECTROMETER Laser Target; tablet etc. also aqueous OK Interfacing with spectroscopy Effective sampling volume TABLET The amount of energy 7

8 Polymorph screening Polymorph screening model system: nitrofurantoin 8

9 Polymorph screening Aaltonen et al, JPBA Polymorph screening Clustering of the Raman spectra of different polymorphs of nitrofurantoin (CCDC refcodes indicated). 9

10 Crystallization SYNTHESIS CRYSTALLIZATION Final purification phase prior to secondary manufacturing GRANULATION MIXING TABLETING COATING Crystallization 10

11 Crystallization PVM = image analysis ATR-FTIR = solution conc. FBRM-Raman = solution/particle properties (polymorphism) Crystallization 11

12 Crystallization model system: nitrofurantoin Crystallization Two crystal structures of nitrofurantoin monohydrate monohydrate I (HAXBUD01) plate habit monohydrate II (HAXBUD) needle habit 12

13 Crystallization S S metastable hydrate - plate morphology stable hydrate - needle morphology Fang, T. unpublished data Amorphous system SYNTHESIS CRYSTALLIZATION GRANULATION MIXING A risk for solid state transitions Equilibrium between amorphous crystalline state of matter Use of NIR TABLETING COATING STABILITY 13

14 Process-induced amorphization NIR as a tool for at-line quantitation of amorphous content during milling. Process-induced amorphization NIR as a tool for quantitation of amorphous content with model sugars. Savolainen M. et al, 2007 JPP

15 Processing of amorphous Solid dosage form SYNTHESIS CRYSTALLIZATION GRANULATION MIXING TABLETING A risk for solid state transitions Transitions between hydrate - anhydrate form of API - wet granulation -drying Use of Raman COATING STABILITY 15

16 Active compound in aq. slurry 100 μm 100 μm Anhydrous API After 20 min in water Spectroscopic approaches model system: quantification of anhydrate/hydrate systems nitrofurantoin 16

17 Spectroscopic approaches Crystal structures nitrofurantoin anhydrate (LABJON02) monohydrate (HAXBUD) Spectroscopic approaches Raman 17

18 Wet granulation 100 Amount transformed (mole%) 50 0 Theophylline Caffeine Carbamazepine Nitrofurantoin Time (min) In-line monitoring of anhydrate/ hydrate phase transition (granulation). Drying small scale fluid bed device probe Real-time monitoring of hydrate/ anhydrate phase transition during drying. Aaltonen J. et al, Chem Eng Sci

19 Real-time monitoring of hydrate/ anhydrate phase transition (drying). Dehydration Real-time monitoring of hydrate/ anhydrate phase transition during drying. Kogermann K. et al, J. Pharm. Sci (in press) 19

20 Dissolution testing Tablet surface during dissolution test. Dissolution testing exp. Dissolution testing Modified dissolution device for real-time monitoring of solid state properties. Aaltonen J. et al, J. Pharm. Sci

21 Dissolution testing Simultaneous measurement of solution concentration and solid state properties. Future challenges SYNTHESIS CRYSTALLIZATION GRANULATION MIXING TABLETING COATING New ways to look into formulation understanding at a molecular level Track the particle from nucleation to final dissolution Effective use of experimental data vs. process modeling Are we ready to analyze phenomena during processing of macromolecular systems? 21

22 Acknowledgements Pharmaceutical technology group Prof. Jukka Rantanen Assoc. prof. Jørn Møller Sonnergaard Assoc. prof. Claus Cornett, Anette Müllertz Post doc Fang Tian Assist. prof. Anna Jørgensen, Stefania Baldursdottir, Holger Grohngaz PhD students Anne Zimmermann, Kaisa Naelapää, Morten Allesø, Vishal Koradia Lab techn. Dorthe Kyed Ørbæk Prof. emer. Henning Kristensen Prof. Jouko Yliruusi Prof. Thomas Rades ACKNOWLEDGEMENTS Lundbeck Ferring Nycomed LEO Pharma AstraZeneca Hexal - Sandoz Novo Nordisk Orion Pharma 22