Particle Design using Spray Drying

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1 Particle Design using Spray Drying Reinhard Vehring MedImmune Inc., 319 North Bernardo Ave, Mountain View, CA 94043

2 Outline Study of Particle Formation Mechanism Experimental Methods Droplet Chain Monodisperse Spray Dryer Theoretical Approach Results Particle Design Examples Summary and Outlook

3 Droplet Chain Technique Laminar gas flow, T,v,RH Droplet Generator z Laser SEM Sampler Sensor Droplets do not influence gas phase Allows measurement of evaporation rates Vehring, et al., AAAR Annual Conf., Atlanta, GA, 2004

4 Monodisperse, Monomorph Particles Production Lot Model Particles Geometric diameter and density can be correlated with drying rate Only small quantities can be produced (< 1mg/h)

5 Monodisperse Spray Dryer 1000 x higher production rates Gas phase conditions not constant No direct observation of evaporation process Online measurement of aerodynamic dry particle diameter APS

6 Particles from Monodisperse Spray Dryer Consistent morphology Density of main population can be determined

7 Analytical Description Analytical model provides dimensionless numbers Diffusion equation for normalized radial coordinate, R=r/r s, 2 c D c c = t r + 2 s R R R + 2 R c rs r R t 2 2, d ( t) d κ t s = 2 0 D: Diffusion coefficient, c: concentration, r s : droplet radius, d: droplet diameter, κ: evaporationon rate.. Solution c = c m R exp 2 exp 2 ( 0.5PeR ) 2 ( 0.5PeR ) dr, Pe = rs rs D t = κ 8D where the concentration is expressed as a function of the average concentration in the droplet, c m. Pe is the Peclet number. After: Leong, K. H., J. Aerosol Sci 18, 511, (1987)

8 Case 1: Large Molecules Pe = 2.7 Pe = 5.6 Pe = 12.5 T G = 25 o C T G = 50 o C T G = 125 o C Morphology and density change with drying rate Glycoprotein, MW: 51 kda, D: m 2 /s (estimate)

9 Density Decreases with Increasing Pe-Number 6 Peclet Number Geometric Diameter in μm d g ρ Density in g/cm Gas Temperature in o C 0.0

10 Theory Predicts Surface Enrichment of Protein Dry particle formation coincides with predicted high surface concentration of the protein.

11 Diffusion Controlled Particle Formation Surface Enrichment Shell / Skin Formation Crumpling Buckling

12 Large Peclet Number Examples 5 µm 500 nm Polystyrene nanoparticle (170 nm) suspension Peptide formulation Salmon Calcitonin N. Tsapis et al. PNAS 99, (2002); H.-K. Chan et al, AAPS annual meeting, 2002; Vehring, R. IBC 4th Annual Conference, Delivery Strategies for Proteins and Peptides, Boston, MA, 2004

Case 2: Small Molecules 1.6 1.5 Density in g/cm 3 1.4 1.3 1.2 1.

0 50 60 70 80 90 100 Inlet Gas Temperature in C Low Peclet

13 Case 2: Small Molecules Density in g/cm Trehalose Inlet Gas Temperature in C Low Peclet Number (<2) and high solubility leads to solid particles with a density close to the pycnometer density (1.53 g/cm 3 )

number range: 2-5 Saccharides can form hollow particles at

14 Small Molecules at High Peclet Numbers Lactose particles, dried at high drying gas temperatures (200 C inlet) Peclet number range: 2-5 Saccharides can form hollow particles at high Peclet numbers Elversson, J., et al. J. Pharm Sci, 92, 900 (2003)

Small Molecules Low Solubility High Surface Activity Solubility: 8 mg/ml (25 C, ph7) Surface Activity: 42 mn/m (sat, 25 C) MW: 357.5 Da Density in g/cm 3 0.5 0.4 0.3 0.2 0.1 0.0 Pe 0 0.

15 Small Molecules Low Solubility High Surface Activity Solubility: 8 mg/ml (25 C, ph7) Surface Activity: 42 mn/m (sat, 25 C) MW: Da Density in g/cm Pe Trileucine Geometric Diameter Range: µm µm µm Gas Temperature in C Particles with very low density can be formed from small molecules es

Pe ~ 0.9 Small Molecules Low Solubility Low Surface Activity 0.5 Pe 0 0.6 0.9 1.3 1.7 2.1 0.4 Density in g/cm 3 0.

16 Pe ~ 0.9 Small Molecules Low Solubility Low Surface Activity 0.5 Pe Density in g/cm Tyr-Ile Gas Temperature in C Surface activity is not necessary for low particle density

17 Particle Formation Coincides with Supersaturation d 2 (µm 2 ) Drying droplet diameter, 500 Region of Shell Formation 400 and Collapse Surface Concentration Time (ms) Trileucine supersaturation, C/S Precipitation leads to sharp increase in Pe - number

18 Particle Formation with Early Phase Separation Bulk Precipitation Shell Formation Supersaturation Surface Precipitation

Designing Structured Particles - Applications Encapsulation Structural layers Improving physical stability Improving biological / chemical

19 Designing Structured Particles - Applications Encapsulation Structural layers Improving physical stability Improving biological / chemical stability Improving powder / aerosol properties Flowability Dispersibility Density / Aerodynamic diameter Improving delivery Solubility Bioadhesion Release

20 Encapsulation of a Model Molecule 100 % PVP K17 90 % PVP, 10 % Amino Acid Amino acid solubility intentionally reduced by a co-solvent to achieve encapsulation Vehring, et al., US , WO/2005/000267

21 Surface Modification of an Antibody Therapeutic IgG1 - Antibody Encapsulated with 37.5 % amino acid Encapsulation improves dispersibility

Encapsulation Improves Physical Stability 56 % encapsulation excipient, 20 % saccharide, 20 % low Tg API, 4 % organic salt 8 7 6 measured predicted g H 2 O / 100 g 5 4 3 2 1 Moisture

22 Encapsulation Improves Physical Stability 56 % encapsulation excipient, 20 % saccharide, 20 % low Tg API, 4 % organic salt measured predicted g H 2 O / 100 g Moisture Sorption % RH 80 Tg in C Plasticization g H 2 0 / 100 g Vehring, R. IBC 4 th Annual Conf., Deliv. Strat. Proteins & Peptides, Boston, 2004

23 Structured Particle with Excellent Environmental Robustness Lot LPM Data 60 LPM Data ~ 20 C above Tg! % FPD < 3.3 μm Time Zero 25C/60RH. 72hr 25C/60RH. 7 day 65/11RH,"72hr Low Tg core protected by a high Tg shell

24 Summary and Outlook Particle formation can be understood in the context of component saturation and Peclet number Surface activity and other material properties may influence particle morphology Analysis of particle formation enables rational particle design of structured particles through formulation and process design Particle engineering achieves much improved particle properties, enabling new products and improving product performance More work is necessary to understand and control nanostructures and multiple functional layers Process technology and formulation science must work together

25 Acknowledgements Willard R. Foss Amgen Inc., Thousand Oaks, CA Christopher I. Grainger Kings College, London David Lechuga-Ballesteros Ballesteros, Mei Chang Kuo, Danforth P. Miller Nektar Therapeutics, San Carlos, CA Solid State Formulation Group MedImmune Inc., Mountain View, CA James Ivey, Lisa Williams, Sandhya Buchanan, Yi Ao, Luisa Yee, Emilie Pan, Rekha Rao

Spray Drying of Protein Particles for Pulmonary Delivery Reinhard Vehring Willard R. Foss, John W.Y. Lee, Nazli Egilmez

Spray Drying of Protein Particles for Pulmonary Delivery Reinhard Vehring Willard R. Foss, John W.Y. Lee, Nazli Egilmez Advanced Technology Development Inhale Therapeutic Systems, Inc. 150 Industrial Road,