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

Transcription

1 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, San Carlos, CA 94070

2 Outline Introduction: Pulmonary delivery of pharmaceutical particles. The spray drying process and how to control it. CFD model and characterization of the atomization step CFD model of the drying chamber Numerical and experimental studies on particle formation Raman spectroscopy as a particle design tool

3 Goal: Pulmonary Delivery Non-invasive delivery of macromolecules to the deep lung via inhalation of aerosolized drug in addition to the classic application of treating locally. Asthma COPD, CF Infections

4 Biology: How does it work? a tight contact with vasculature A branching structure leading to and a huge transport surface. Deep lung deposition leads to effective transport into the bloodstream

5 Lung Deposition for Polydispersed Aerosols Inhaled volume 4 l Inhaled flow rate 30 l/min Breath hold 10secs GSD 2.2 location [%] Oropharynx Tracheobroncial Peripheral Lung Mass median aerodynamic diameter [um] After Clark & Egan (1994) J Aerosol Sci., Vol25, #1,

6 What s the Ideal Particle Consistent properties independent of drug chemistry Size and morphology optimized for lung delivery Physical chemistry ensuring long shelf-life Chemical stability of active Non-toxic Manufacturable In low and high quantities Economical With good yields

7 Methods to Produce a Fine Dry Powder Molecule Spray Drying SCF Lyophilization Crystallization Hammer / Jet Milling Pulmosphere TM Pulmosol TM Fine Powder (MMAD ~ 1-3 µm)

8 Functional Elements of the Spray Drying Process Formulation Excipients for particle design Atomization Particle Creation Particle Collection Air- assist atomizer Drying chamber Cyclone/bagfilter

9 Atomizers: From Laboratory to Production Laboratory scale (<0.6 kg/hr) ~6 in. Air-assisted atomization. Level 1 production scale (< 6 kg/hr) Center liquid jet enshrouded by high speed gas annulus. Repeatable performance. Drug contact material compliant. Level 2 production scale (< 60 kg/hr)

10 Atomizer Exit Gas Flow- Single Phase CFD Mach # contours Temperature contours Standing shock structure Low Temperature Regions Nozzle Exit Gas Flow Atomizer design / scale-up supported by CFD

11 Atomizer Test Facility Phase Doppler Measurements Atomizer operating conditions controlled and performance verified

12 Cross-sectional droplet size distribution Small droplet size from custom atomizers leads to a commercially attractive process 1 Normalized Number Freq Droplet Diameter, microns

13 Drying Chamber and Cyclone Preclinical Commercial Clinical

14 Internal Spray Dryer Gas Flow Field Process Gas Spray Plume CFD models help maintain similar gas phase conditions throughout different scales

15 Studying the Droplet Drying Process Two phase flow in the spray dryer is complex. It is more effective to perform particle formation research on model systems. Approach: Isolate relevant subprocesses and study them in idealized environments Numerical model of droplet evaporation on single droplets in stagnant gas phase Experimental studies on monodisperse droplets in a laminar flow field

16 Numerical Model of Droplet Evaporation r Tgas 0 a(t) r Transient evaporation of a radially symmetric droplet Finite difference mesh moves with interface Concentration and temperature profiles in liquid and gas Temperature and concentration dependent material properties Multiple solutes and solvents Accounts for surface activity

17 Internal Distribution of Components During the Drying Process WEIGHT FRACTION EXCIPIENT PROTEIN RADIUS, µm The model can be used to predict the influence of processing conditions and formulation on the structure of the dry particle

18 Experimental studies on monodisperse model particles Laminar gas flow, T,v,RH Droplet Generator z Laser SEM Sampler Sensor

19 Droplet size measurements using elastic light scattering 50k 40k Time: 0 ms, Diameter: micron Intensity in a.u. 30k 20k 6k 5k Time: 460 ms, Diameter: 3.3 micron 10k Scattering Angle in deg. Intensity in a.u. 4k 3k 2k 1k Scattering Angle in deg.

20 Evaporation Rate and Droplet Lifetime DIAMETER 2, micron TIME, ms EVAPORATION RATE, sq. micron/ms THEORY TEMPERATURE, C H 2 O EXPERIMENT Method applicable to co-solvent systems and concentrated solutions

21 Model Particles: Perfect Control of Size and Morphology

22 Particle design: Controlling the Particle Density Cold/dense Hot/light

23 Particle Design: Controlling the Particle Morphology 100 % Large molecule With excipient Desirable properties can be designed into powders through control of processing conditions in combination with special excipients

24 Model Particles Analyzing and Optimizing Powder from Spray Drier

25 Particle Analysis by Raman Spectroscopy Goals: Quantitative analysis of solid state properties, e.g. amorphous fraction and polymorphism. Analysis of protein conformation. Challenges: Multicomponent systems, Model particles - sample mass too low for XRD, Environmental control of sample (RH, T). Solution: Custom-built Raman system

26 Dispersive Raman with Red Excitation Laser Beam 670 nm Sample Chamber Collection Optic CCD-Sensor Spectrograph Filter Stage

27 Inhale s Research Raman System

28 High Sensitivity Low Sample Mass Sample mass: 10 µg

29 Measuring the Amorphous Content Example: Citrate Clear differences allow easy identification 8.0x10 4 δ(ch 2 ) ν a (COO), δ(c OH) 6.0x10 4 ν s (COO), ν(c C ), ω(ch 2 ) Signal 4.0x x10 4 crystalline amorphous Raman shift in cm -1

30 Unique Spectral Fingerprints of Mannitol Polymorphs 150k 100k alpha Raman Signal in Counts 50k 0 150k 100k 50k 0 200k 150k 100k 50k beta delta Raman Shift in cm -1

31 Quantitative Measurements by Raman Spectroscopy The Raman signal is linearly proportional to concentration The proportionality constant is generally unknown Solution: Measurement relative to an internal standard Raman signal, Φ A, of a substance A Φ A = φ c A N a V σ A φ Radiant flux density in the laser focus Molar concentration of substance A c A N a Avogadros Number V Sample volume σ A Scattering cross section

32 Solid State Analysis in Multicomponent Systems Mass Fraction in % amorphous Mannitol Salmon Calcitonin δ α β Mannitol Mass Fraction in %

33 Summary Inhale has developed advanced research and development tools and methods to understand and control the spray drying process. Increased understanding and control lead to shorter development times, saving material and cost, decreased scale-up risk and optimized product performance.

34 Acknowledgements Andy Clark David Lechuga Yi Liang Jim Nasiatka John Patton Mark Postich Robert Schearrer Carlos Schuler Herm Snyder Vathana Tep