The use of Inverse Gas Chromatography in formulation ... · The use of Inverse Gas Chromatography in formulation development and manufacturing of dry powder inhalation products. Overview

Dr Frank Thielmann Inolytix IGC Symposium, June 2015

The use of Inverse Gas Chromatography in formulation development and manufacturing of dry powder

inhalation products

Overview2

Introduction – Respiratory diseases and inhalation devices

Study I – Understanding of granulation behaviour

Study II – Morphology changes upon micronisation

Study III – Interaction of drug substance and propellant

Conclusions

Respiratory Diseases

COPD (Chronic Obstructive Pulmonary Disease) COPD is a general expression for various diseases

characteristics (phenotypes) There are predominately two phenotypes:

COPD is mainly caused by smoking (western world) and air pollution (developing world)

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• Chronic Bronchitis (lung damage and inflammation in the large airways).

• Emphysema (lung damage and inflammation of the air sacs/ alveoli).

Source: Wikipedia

Inhaler device types Nebuliser (p)MDI DPI Reservoir Powder in Blister Capsule-based Active devices

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Source: Wikipedia

Dry Powder Aerosol Delivery Systems

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Expert System

Drug substance & formulation development/ manufacturing

Aerosol generation and delivery by inhalation device

Deposition in the lungs

Source: Wikipedia

Amorph. content

Flowability

Roughness

Shape Density

Electrostatics

Particle sizeBlend uniformity

Bulk Powder

‘Structural’

ParticleSize

ShapeDensity

HardnessSurf. Area

FlowabilityCompressibilityBulk Density(Blend uniformity)

PolymorphismTrue Density

Surface Energy

Moisture Content

Classification of physico-chemical properties

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ElectricalProp.

For further reading: Zeng, X.M. et al, Particulate Interactions in Dry Powder Formulations for Inhalation, Taylor & Francis, London 2001.

How to measure surface energetics?

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Techniques available:

Atomic Force Microscopy Difficult to perform

Low reproducibility

Wettability (Contact Angle) Poor reproducibility on powders

Limited sensitivity

Vapour Sorption IGC

Gravimetric Vapour Sorption (DVS)

Slide adapted with permission of Surface Measurement Systems, UK

Overview8





Conclusions

Case Study: Granulation of glass beads9

Materials Model “Active”: Hydrophilic and hydrophobic glass

beads of two different particle sizes

Binders: Hydroxypropylcellulose (HPC)

Granule Properties Fluidized bed granulation

Particle size distribution measurements and Imaging

Goal Use IGC to measure surface energetics of individual

components (drugs and binders) and correlate to granulation behaviour


Source: Stepanek, F. and Thielmann, F., Powder Techn. (2008), 181 (2), 160-168

Case Study: Granulation of glass beads10

Hydrophilic glass beads show higher disp. surface energies than hydrophobic

20

25

30

35

40

AF AF225 HPC

Dis

pers

ive

Sur

face

Ene

rgy

[mJ/

m2]


Case Study: Granulation of glass beads

0

5

10

15

20

25

AF primary AF-225 primary HPC

Fre

e en

ergy

of d

esor

ptio

n [k

J/m

ol]

DichloromethaneAcetonitrileAcetoneEthyl acetateEthanol

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Specific free energies show “fingerprint” of beads and binder


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Granules from hydrophilic beads

Contact angle of binder solution: 0’ (complete wetting)




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Granules from hydrophobic beads

Contact angle of binder solution: 114+/-6’



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Particle size distribution

0

5

10

15

20

25

30

35

40

500

425

355

300

250

180

150

1069075

Sieve cut [µm]

Fra

ctio

n re

tain

ed [

%] AF225

AF

hydrophilic hydrophobic



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Hydrophilic granules show finger print of HPCHydrophobic granules a mixture of HPC and beads

0

5

10

15

20

25

AF granules AF-225granules

HPC

Fre

e en

ergy

of d

esor

ptio

n [k

J/m

ol] Dichloromethane

AcetonitrileAcetoneEthyl acetateEthanol


Case Study: Granulation of glass beads - Results

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Binder appears to “spread” on hydrophilic glass beads which results in “coating”.

Hydrophobic glass beads show “islands” of binder and solid bridges can be formed.

Due to spreading of binder little granulation occurs with hydrophilic glass beads and mean particle size is rather small.

Hydrophobic glass beads show bigger granules as solid bridges can be formed although size distribution is wide due to non-optimised granulation conditions.

Source: Stepanek, F. and Thielmann, F., Powder Techn. (2007), in press


iGC – Concentration Ranges

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Am

ount

Ads

orbe

d

Elutant (Probe Molecule) Concentration

Infinite Dilution

Henry Region

BET Region

Finite Dilution

Usually pulse IGC is carried out at Infinite Dilutioni.e in the Henry Region


Determination of Surface Energy Distributions

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Energy Distribution of Aspirin19

Disp. Surface Energy Profile

333435363738

0 0.2 0.4 0.6 0.8 1

n/nm [-]

gam

ma

d [

mJ/

m²]


J. Heng, A. Bismarck, A. Lee, K. Wilson and D. Williams, J. Pharm. Sci., 96, 2134-2144 (2007)

A. E. Jefferson, George D. Wang, D. J. Burnett, F. Thielmann, and J. Y. Y. Heng, Proceedings of Annual AAPS Meeting (2011)

Overview20





Conclusions

Drug Product Manufacturing21

Air jet milling of API/ Dry blending

Spray-drying

(Spray) freeze-drying

SCF technology

Controlled crystallisation (e.g. ultrasonic)

Ultrasound assisted

Precipitation

Milling and Micronization Reduction of particle size by

mechanical force (stress) Advantage: universal, easy and

cheap Disadvantage: Process conditions need to be

carefully controlled Impact on morphology and

generation of amorphous material

Potential stabililty issues Mechanical properties of

materials as well as particle roughness and shape affected

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Case Study: Impact of milling on β D-mannitol properties

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Material Milled and unmilled β-D-mannitol

Investigation Ball-milled, different size fractions collected

Sieving of unmilled material to obtain similar sizefractions (elimination particle size effects)

Goal Correlation of aspect ratios and surface energetics

(determined by contact angle with single crystals) with IGC results obtained on powder in different particle size

Understanding of fractioning/ breakage mechanism duringmilling


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Impact of milling on β D-mannitol properties

Molecular structure of D-mannitol Crystal habit of D-mannitol


Milling reduces particle aspect ratio (shorter crystals). The bounding rectangular width is used here as a particle size parameter for sieved particles.

Milling increases BET specific surface area. However, the surface area within one group hardly changes, this is attributed to the inefficiency of sieving for needle-shaped particles.

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For needle-shaped crystals like D-mannitol, the weakest attachment energy crystal plane (010) is notpreferentially exposed.

Due to geometric effect, crystals fracture along the shortest axis (011) upon milling, resulting in a decrease in dispersive surface energy.

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Disp. Surface Energy (mJ/m2) Sieve fraction (µm) Aspect ratio

47.4 355-250 2.50747.2 250-180 2.48445.4 180-125 2.33744.8 125-63 2.092

Disp. surface energy shows small change with particle size and aspect ratio.

Disp. surface energy distribution confirms trends and shows that change is small due to small differences in energy of the crystal facets.

‘Infinite dilution’ ~ high energy sites

D.J. Burnett, M. Naderi, Raimundo Ho, J. Heng, F.Thielmann, A. Keith and G. Thiele, Proceedings of Annual AAPS Meeting (2011)

Overview28





Conclusions

Drug-propellant interactions in MDI’s

• Materials• Drug substance: Salbutamol sulphate (SS),

salmeterol xinafoate (SX) and budesonide (BD)

• Propellants: HFA134a and HFA227

• Goal• Use IGC to measure surface energetics of

individual drug substances to estimate drug-drug interactions

• Measure specific interactions between drug substance and propellant directly

• Look at the impact of different background RH

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Dispersive surface energies (mJ/m2) for budesonide (BD), salbutamol sulphate (SS) and salmeterol xinafoate (SX) as well as specific free energies (kJ/Mol) of interaction with HFA 134a and 227.

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Change in the dispersive contribution of the surface energy (mJ/m2) of salbutamol sulphate with increasing humidity.

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Change in the specific free energy (kJ/Mol) of HFA 134a and 227 with increasing humidity for salbutamol sulphate.

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Drug-propellant interactions in MDI’s Cohesion force decreases in the sequence:

BD>SS>SX. All three components show a stronger

interaction with the slightly more polar HFA 134a.

An increase in humidity reduces the drug-propellant interaction for salbutamol sulphatemore significantly than it affects the drug-drug interaction causing a potential reduction of suspension stability.

It is important to keep the moisture content of the drug substance as well as the moisture sorption during the formulation process low.

F. Thielmann M. Naderi, P. Jannick, Proceedings of Drug Delivery to the Lungs Symposium (2006)

Conclusions34

IGC is a useful tool to complement physico-chemical characterisation of pharmaceutical raw materials and products as well as to gain increased process understanding.

Surface energy measurements can be used to understand changes in morphology as shown in the case of Mannitol fracturing upon milling.

Adhesion/ cohesion balances derived from surface energy measurements can help to understand the suspension stability in MDI formulations

Surface energies are related to wetting properties and are therefore a good indicator for coating/ granulation behavior.

Inolytix IGC Symposium, June 2015

Acknowledgements

• My colleagues at Novartis, Switzerland• Dr Daniel Burnett, Surface Measurement

Systems Ltd. USA• Dr Jerry Heng, Imperial College, London,

UK• Peter Jannick, Solvay Fluor, Germany

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The use of Inverse Gas Chromatography in formulation ... · The use of Inverse Gas Chromatography in formulation development and manufacturing of dry powder inhalation products. Overview