STUDY AND OPTIMISATION OF PHARMACEUTICAL PRODUCTS FREEZE-DRYING PROCESS

Transcription

1 STUDY AND OPTIMISATION OF PHARMACEUTICAL PRODUCTS FREEZE-DRYING PROCESS UNIVERSITE CLAUDE BERNARD LYON1: LAGEP: Pr. J. ANDRIEU (scientific responsable); S. VESSOT (Pr Assistant); P. CHOUVENC, A. HOTTOT (Ph. D. students) Collaborations with Aventis Pasteur and Biomérieux

2 LAGEP EQUIPMENTS General equipments : Cold room equipped with :.Axial episcopic photonic microscope coupled with camera video and image analysis treatment Modulated DSC (T.A.) Activitymeter at low temperature (GbX) Cryomicroscopic cell (Linkam) T collapse Implementations to freeze-drier : Rapid closing valve (MTM method) Water vapor and total pressure sensors Torino LYO PRO Meeting of 27 September 2002

3 FREEZE-DRYER: Vacuum Scheme of a pilot freeze-dryer unit minilyo type (USIFROID) Freeze-drying model of pharmaceutical materials in vials

4 FREEZE DRYER INSTRUMENTATION 3 shelves 0.45 m 2 Cold trap temperature: up to 65 C 2 independent refrigeration loops (frigo-pump) Sampling system without breaking vacuum 7 thermocouples for the product (K type) Hygrometer measuring dew point (Panametrics) from 110 C to +20 C Chamber pressure sensor (capacitance type:mks) Integrated control system by P.C. Torino LYO PRO Meeting of 27 September 2002

5 FREEZE-DRYING (LYOPHILISATION): Advanced vacuum and low temperature drying 3 steps: Freezing Sublimation (Primary desiccation) Desorption (Secondary desiccation ) Pressure S L Freezing 4.58 mmhg Vacu -um SUBLIMATION V O C Temperature

6 ELEMENTARY PHENOMENA DURING FREEZE-DRYING: Formulation Freezing: Cooling Supercooling Seeding Nucleation Crystal growth, eutectic phase separation Glass transition Morphology.Size distribution Ostwald ripening Drying: Ice sublimation Desorption

7 PROJECT OBJECTIVES : OPTIMIZE THE FREEZE-DRYING CONDITIONS Formulation parameters (cryoprotectants, excipients, etc.) Freezing operating parameters (freezing rate, supercooling degree, etc.) Sublimation and desorption parameters (T, P, etc.) STABILITY AND REHYDRATION OF THE DRY FREEZE-DRYED MATERIAL EXTRAPOLATION, CONTROL AND COMMAND OF INDUSTRIAL UNITS. FUNDAMENTAL INVESTIGATION Phase diagrams (Tcollapse, Tg, Tf ) Heat and mass transfer coefficients and parameters.

8 WORKING TASKS PROGRAMME: DISPERSION CHARACTERIZATION S.E.M, Optic microscopy Image analysis Thermophysical properties: Cp, a, l, etc. FREEZING : EXPERIMENTAL STUDY- MODELING Temperature profiles T(x,t) Frozen material texture: morphology, ice crystals size distribution, mean sizes, etc.. Water type (N.M.R): ice, adsorbed water, vitreous water, SUBLIMATION/DESORPTION :EXPERIMENTAL STUDY- MODELING Total pressure Plate temperature and condensor temperature Heat flux PILOT PLANT INDUSTRIAL RUNS

9 FREEZING CELLS Keithley multimeter 2 freezing cell types: Plexiglass cylinder Insulating plug PVC tube Thermocouples T Copper sheet (0.5mm) Cylindrical freezing cells: - Fint= 80mm - F int= 20mm Thermocouples T spherical cell : Fint=12mm

10 Measure of the mean ice crystals size (Direct method) Principle : reflexion of the light ice air bubble h Coaxial optical microscopy. Observation of the freezing product in a cold room. surface at T I

11 Images analysis ice initial image image builds up again by the skeleton Frequence distribution and mean size frequence distribution cumulative distribution The mean size noted L* is the value at 50% of the cumulative distribution.

12 Reproducibility Cumulative distribution 1,0 0,8 0,6 0,4 0,2 0,0 CG62 CG58 CG73 T I = -20 C T II = 3 C h = 25 mm Size (µm) L* = 9,9 +/- 0,7 µm

13 Influence of the freezing temperature T I Cumulative distribution 1,0 0,8 0,6 0,4 0,2 0,0 CG 55 / nitrogen CG 56 / -40 C CG 58 / -20 C CG 74 / -10 C T II = 3 C h = 25 mm Size (µm) The size L* decreases when the temperature T I decreases.

14 liquid nitrogen -40 C -20 C -10 C

15 DIRECT OBSERVATION METHOD OF ICE CRYSTALS: OPTICAL MICROSCOPY WITH A COLD CHAMBER Observation of sucrose solution (10% by mass) after unidirectional freezing at 40 C. Vertical cut Observation of sucrose solution (10% by mass) after unidirectional freezing at 40 C and immersion in liquified nitrogen. Vertical cut

16 Method advantages: - dendrites mean size direct measurement; - matrix texture characterization (porosity, permeability, etc.) Problems to work out: - image contrast, sample surface uniformity; - sample melting: collapse temperature Ts lower than 25 C; - set up of a starter for the acquisition data chain from the cold chamber

17 FORMULATION STATE DIAGRAMME OF THE STUDIED MATRICE Température (K) Mass fraction of dried mater (%)