MECHANICAL ENGINEERING

Mechanistic Understanding of Microparticle Formation in

Respiratory Applications

Reinhard Vehring

Outline

Experimental model systems

Single droplet

Droplet chain

Monodisperse spray dryer

Research spray dryers with process model

Theoretical models

Analytical

Numerical

Particle Formation

Evaporation and condensation

Liquid phase diffusion

Precipitation

Particle Zoo

1

Single Particle Levitation

Electrodynamic Balance

Davies, J.F. Haddrell, A.E., Reid, J.P.: Time-resolved measurements of the evaporation of volatile components from single aerosol droplets. Aerosol Sci Technol, 46, 666-77, 2012

Highest level of idealization

Excellent control of parameters

Many analytical options

Difficult for fast processes and high temperatures

Dried particle not collected

2

Droplet Chain Technique

Gomez, M., Ordoubadi, M., McAllister, R. A., Melhem, O., Barona, D., Gracin, S., Ajmera, A., Lechuga-Ballesteros, D., Finlay, W. H., Vehring, R.: Monodisperse Droplet

Chain Technique to Support Development of Co-solvent Based Inhalation Products. Respiratory Drug Delivery 2018, Vol 2, pp 563–568, 2018.

Laminar gas flow,T,v,RH

Droplet Generator

SEM Sampler

Sensor

Laserz

3

Droplet Chain Model Particles

Vehring, R.: Expert Review: Pharmaceutical Particle Engineering via Spray Drying. Pharmaceutical Research, 25, 999-1022, 2008.

Production of monodisperse, monomorph particles

Good control of parameters

Allows sampling of dried particles

Realistic conditions for spray drying

Comprehensive analysis difficult for small particles

Small sample sizes (A few million particles)

Model ParticlesProduction Lot

4

Monodisperse Spray Drying

Azhdarzadeh, M., Shemirani, F. M., Ruzycki, C. A., Baldelli, A., Ivey, J., Barona, D., Church, T., Lewis, D., Olfert, J. S., Finlay, W. H.,

Vehring, R.: An Atomizer to Generate Monodisperse Droplets from High Vapor Pressure Liquids. Atomization & Sprays, 26, 121-134, 2016.

Replaces twin fluid atomizer with vibrating orifice droplet generator

in a spray dryer.

Most particles are monodisperse. Produces milligram quantities.

Works with propellants.

Not as well controlled as droplet chain

8 Orifice Plate

9 Spring Contact

10 Piezoceramic

11 Orifice Cup

12 Dispersion Cup Body

13 Dispersion Cup Top

5

Monodisperse Spray Drying Examples

Ivey, J.W., Bhambri, P., Church, T.K., Lewis, D.A., Vehring, R.: Experimental Investigations of Particle Formation from Propellant and Solvent Droplets Using a Monodisperse Spray

Dryer. Aerosol Science and Technology, 52 (6), 702-716, 2018.

BDP and Caffein particles from

HFA 134a + ethanol

Can function as a test bed for

pMDI aerosols

6

Research Spray Dryers

Ly, A., Carrigy, N.B., Wang, H., Harrison, M., Sauvageau, D., Martin, A. R., Vehring, R., Finlay, W. H.: Atmospheric Spray Freeze Drying of Sugar Solution with Phage D29.

Frontiers in Microbiology, submitted.

Atmospheric Spray Freeze DryingModular

Dryer

7

Model Based Particle Engineering

Vehring, R.: Theoretical Tools for Particle Engineers: Spray Drying Complex Formulations for Inhalation. Respiratory Drug Delivery Europe 2015, Vol 1, pp 187-196, 2015.8

Outline

Experimental model systems

Single droplet

Droplet chain

Monodisperse spray dryer

Research spray dryers with process model

Theoretical models

Analytical

Numerical

Particle Formation

Evaporation and condensation

Liquid phase diffusion

Precipitation

Particle Zoo

9

What part of particle formation can be modeled?

Just atomized:

Well mixed

solution

Saturated on

the surfaceNucleation

Crystal

growth

Shell

formation

Dry

particle

Example: Formation of a hollow crystalline particle from an evaporating solution droplet

Need to know the internal distribution of components at the onset of shell formation!

(Later stages of particle formation are very complex and material properties are missing)

10

Model Scope

Droplet: Gas Phase:

Isothermal, no convection No convection other than Stefan flow

Well mixed for solvents Spatially averaged material properties

Radial distribution of components Evaporation (condensation) rates

Time resolved

r

r0 a(t)

Tgas

11

Internal Distribution of Components

Based on Fick’s 2nd law: cDt

c

D: Diffusion coefficient, : evaporation rate,

: normalized time, c: normalized concentration,

R: normalized droplet radius

R

cR

R

c

RR

c

Pe

c

)1(2

2

)1(2

12

2

Fully normalized version for radial symmetry:

DPe

8

Boraey, M. A., Vehring, R.: Diffusion Controlled Formation of Microparticles. J. Aerosol Science, 67, 131-143, 2014.

is controlled by the Peclet number, Pe:

Analytical solution possible (VFL model)

- for constant evaporation rate and constant diffusion coefficient

Numerical model

- necessary for co-solvent systems, propellants, or variable material properties

12

Outline

Experimental model systems

Single droplet

Droplet chain

Monodisperse spray dryer

Research spray dryers with process model

Theoretical models

Analytical

Numerical

Particle Formation

Evaporation and condensation

Liquid phase diffusion

Precipitation

Particle Zoo

13

Single Solvent - Single Solute Constant Rate Evaporation

2

0d

Aqueous Solution Droplet

2

0D

d

tdtd 2

0

2

Measurement

Numerical model

Analytical model

14

Ethanol – Water Co-solvent System

Symbols: EDB data.

Solid line: Stefan-Fuchs model.

0 200 400 600 800 1000

0.0

0.5

1.0

20 °C

8 °C

0 °C

d2/d

2 0

t/d20 (s/mm2)

30 % water / 70 % ethanol

Different temperatures

0 200 400

0.0

0.5

1.0 0.4:0.6 w/w water/ethanol, EDB

0.4:0.6 w/w water/ethanol, Stefan-Fuchs

0.3:0.7 w/w water/ethanol, EDB

0.3:0.7 w/w water/ethanol, Stefan-Fuchs

0.2:0.8 w/w water/ethanol, EDB

0.2:0.8 w/w water/ethanol, Stefan-Fuchs

d2/d

2 0

t/d20 (s/mm2)

20 °C

Different co-solvent ratios

15

Solvent Composition Changes Over Time

0 200 400

0.0

0.5

1.0W

ater

Mas

s F

ract

ion

t/d20 (s/mm2)

0.4:0.6 w/w water/ethanol

0.3:0.7 w/w water/ethanol

0.2:0.8 w/w water/ethanol

20 °C

Different co-solvent ratios

co-solvent

water

ethanol

16

Impact on Particle Formation in Multi-Solvent Systems

In multi-solvent systems, the solubility of active or excipients can change with time due to the change in

solvent composition

17

Evaporation in Humid Air

100 % Ethanol, 20 °C, 91 % RH

Why does the evaporation rate

change?

Ordoubadi, M., Gregson, F., Finlay, W. H., Vehring, R., Reid, J. P.: Interaction of Evaporating Multicomponent Microdroplets with Humid Environments. Respiratory Drug

Delivery 2018, Vol 2, pp 569–572, 2018.18

Water Condensation Effect

100 % Ethanol, 20 °C, 91 % RH

Why does this matter?

Ordoubadi, M., Gregson, F., Finlay, W. H., Vehring, R., Reid, J. P.: Interaction of Evaporating Multicomponent Microdroplets with Humid Environments. Respiratory Drug

Delivery 2018, Vol 2, pp 569–572, 2018.

Ethanol droplet cools

Water condenses on

Ethanol evaporates

Water evaporates

19

Water or Ice Templated Porous Particles

Ivey, J. W., Bhambri, P., Church, T. K., Lewis, D. A., McDermott, M. T., Elbayomy, S., Finlay, W. H., Vehring, R.: Humidity Affects the Morphology of Particles Emitted from

Beclomethasone Dipropionate Pressurized Metered Dose Inhalers. International Journal of Pharmaceutics, 520 (1-2), 207-215, 2017.

Dry

Humid

20

Beclomethasone dipropionate

pMDI

Diffusion Controlled Particle Formation

Peclet Number:

Describes balance betweenvelocity of surface recession and diffusion

Predicts internal distribution of components

Example: Pe >> 1

Polystyrene nanoparticle suspension

500 nm5 µm

N. Tsapis et al. PNAS 99, 12001 (2002)

21

Low Peclet Number Particle Formation (Pe ~ 1)

100 % trehalose in water. Drying temperature 80 °C. Droplet chain (SEM and FIB-SEM)

Small molecule

excipients and

actives with high

solubility and low

propensity to

crystallize form solid

amorphous particles

22

Particle Density Changes with Peclet Number (non-crystallizing)

Pe = 2.7, 5.6, 12.5 Pe = 77

Glycoprotein

P = 0.5, 0.35, 0.15 kg/L

Cellulose acetate butyrate

P = 0.7 kg/L

Baldelli, A., Boraey, M. A., Nobes, D., Vehring, R.: Analysis of the Particle Formation Process of Structured Microparticles. Molecular Pharmaceutics, 12 (8),

2562-2573, 2015 23

Application Example: Stabilize Phage in a Flowable Powder

Campylobacter

Phage CP30A

Needs glass stabilization for

room temperature storage

add trehalose

Trehalose alone does not work, because

the phage (nanoparticle) enriches on the

surface where it is not protected

Approach: Add a high Pe number amorphous

shell former to replace the phage on the surface

while still allowing mixing with trehalose

Pullulan

24

Solid Phase Modeling to Achieve Storage Stability

Carrigy NB, Vehring R. Engineering stable spray dried biologic powder for inhalation. (Released February 2019). Chapter 12 in Pharmaceutical Inhalation Aerosol Technology, 3rd edition,

ed. Hickey AJ. New York: Marcel Dekker, Inc. 25

Particle Formation Model Predicts Radial Distributions

Carrigy NB, Ordoubadi M, Liu Y, Melhem O, Barona D, Wang H, Milburn L, Vehring R. Spray dried pullulan trehalose microparticle platform for pulmonary delivery of biologics.

In preparation.

0.00

0.25

0.50

0.75

1.00

0.7 0.8 0.9 1.0

Mass

Fra

ctio

n

r/R

40%P 60%T

10%P 90%T

Trehalose

Pullulan

120

150

180

210

0.7 0.8 0.9 1.0

Tg

,PT

,dry

(°C

)

r/R

40%P 60%T

10%P 90%T

Full numerical model simulation indicates

that pullulan enriches on the surface

Coupled with Fox equation:

Glass transition temperature increases

near the surface due to the high glass

transition temperature of pullulan

26

Use Droplet Chain to Study Shell Folding

5% pullulan, 95% trehalose

Carrigy NB, Liang L, Wang H, Kariuki S, Nagel TE, Connerton IF, Vehring R. Amorphous shell formers improve the biological stability of spray dried Campylobacter bacteriophage.

Frontiers in Microbiology. Submitted Oct 11, 2018.

Preliminary results:

Good dispersibility from DPI

100 fold better process loss and short term stability compared to trehalose alone

Perhaps a new platform for biologics

27

20% pullulan, 80% trehalose 40% pullulan, 60% trehalose

Outline

Experimental model systems

Single droplet

Droplet chain

Monodisperse spray dryer

Research spray dryers with process model

Theoretical models

Analytical

Numerical

Particle Formation

Evaporation and condensation

Liquid phase diffusion

Precipitation

Particle Zoo

28

Particle Formation in Crystallizing Systems

��,� =��

�

1 −

��,� �

����,�

��

Time to saturation:

j: component in multicomponent system

d0: Initial droplet diameter

C0: Initial solution concentration

: Evaporation rate

Csol : Solubility

E : Surface enrichment

Key parameters are related to kinetics not to formulation composition

Predicts which component, i, crystallizes first

29

Crystallization Window

Time available for crystal growth

��� =��

�

��

����

��

d0: Initial droplet diameter

: Evaporation rate

C0: Initial solution concentration

Csol: Solubility

E: Surface enrichment

Predicts crystal size and whether components may be amorphous

30

Particle Density Decreases With Increasing Crystallization Window

NaNO3Different T

Different feed

concentration

(Using critical supersaturation)

Baldelli, A., Power, R., Miles, R., Reid, J. P., Vehring, R.: Effect of Crystallization Kinetics on the Properties of Spray Dried

Microparticles. Aerosol Science and Technology, 50 (7), 693-704, 2016.

Low density is caused by shell

formation

Shell formation requires time for

nucleation and crystal growth

The earlier the shell formation

starts the more void space can be

created

31

Particle Density in Multicomponent Systems

Binary system:

NaNO3/KNO3

(For component that saturates first)

Baldelli, A. Vehring, R.: Control of the Radial Distribution of Chemical Components in Spray Dried Crystalline Microparticles. Aerosol Science and Technology, 50 (10),

1130-1142, 201632

How can we control crystal size?

5 mg/ml

75ºC

5 10-1 mg/ml

100ºC

5 10-2 mg/ml

75ºC5 10-3 mg/ml

75ºC

5 10-5 mg/ml

125ºC

�ts (ms): 221 6 119 18 117 2 101 3 18 2

Mostly

amorphous

NaNO3

Baldelli, A.: Experimental and Theoretical Studies on the Particle Formation Process of Particles for the Improvement of Pulmonary Drug

Delivery. PhD Thesis, University of Alberta, 2016.

The size of the crystals that form the shell decreases when less time is available for crystal growth (decreasing �ts)

The solid phase of the particles becomes increasingly disordered with decreasing �ts

Microcrystals nanocrystals amorphous

33

Crystal Size Determines Surface Roughness

Baldelli, A., Vehring, R.: Analysis of Cohesion Forces between Monodisperse Microparticles with Rough Surfaces. Coll. Surf. A, 506, 179, 2016

34

Colloidal Probe Microscopy on Monodisperse Particles

Baldelli, A., Vehring, R.: Analysis of Cohesion Forces between Monodisperse Microparticles with Rough Surfaces. Coll. Surf. A, 506, 179, 2016.

35

Effect of Different Rugosity on Cohesion

Baldelli, A., Vehring, R.: Analysis of Cohesion Forces between Monodisperse Microparticles with Rough Surfaces. Coll. Surf. A, 506, 179, 2016.

Cohesion measured by Colloidal Probe Microscopy

90 nN

Changes in crystal size cause large changes in roughness and cohesion.

Affected product parameters: Dispersibility, colloidal stability, MMAD.

45 nN 3 nN 10 nN 125 nN

9 nN

36

Surface Composition in Multi-components Particles Depends on Crystallization Sequence

Dilute,

Homogeneous,

binary

Radial profiles

develop

First component

crystallizesComposite

shell forms

Surface is enriched by the component which first reaches saturation (smallest ts)

j: component (NaNO3 or KNO3)

d0: Initial droplet diameter

C0: Initial solution concentration

(t) : Evaporation rate (function of gas temperature)

Csol (t) : Solubility

E (t) : Surface enrichment

Na K

��,� =��

�

1 −

��,� �

����,�

��

Boraey, M. A., Vehring, R.: Diffusion Controlled Formation of Microparticles. Journal of Aerosol Science, 67, 131-143, 2014.

37

Surface is enriched by the component which first reaches saturation

Baldelli, A. Vehring, R.: Control of the Radial Distribution of Chemical Components in Spray Dried Crystalline Microparticles. Aerosol Science and Technology, 50 (10), 1130-1142,

2016.

Time

to saturation

39

Shell Composition by STEM + X-ray Spectroscopy

Baldelli, A. Vehring, R.: Control of the Radial Distribution of Chemical Components in Spray Dried Crystalline Microparticles. Aerosol Science and Technology, 50 (10), 1130-1142, 2016.

40

Particle Zoo

unpublished

41

Multi-component nano-emulsion Low-density, nano-composite gel particles

Particle Zoo

unpublished

42

Multi-phase particles: Amorphous + nano-crystalline + oil nanodroplets

Particle Zoo

unpublished

43

Nano-crystal scaffolds

FIB -

HIM

HIM

Particle Zoo

unpublished

44

Ultralow-density particles via Atmospheric Spray Freeze Drying

Atomized solution droplet

Freeze

concentrate

Ice

Freezing

Freeze concentrate

desiccation

Ice sublimation

Summary and Conclusions

The morphology of spray dried, amorphous microparticles is determined by Peclet number and

shell buckling mechanisms.

The shell deformation (buckling) phase remains largely unexplored.

The morphology of spray dried, crystalline microparticles is strongly influenced by evaporation and

crystallization kinetics.

Material properties for many substances of interest are missing.

Experimental tools in combination with theoretical particle formation models are necessary for

advanced particle design.