Finnish Society of Physical Pharmacy, 9Finnish Society of Physical Pharmacy, 9thth Feb 2012Feb 2012

Particle interactions in dry and suspension based formulations

Pharmaceutical Surface Science Research Group,

Department of Pharmacy and Pharmacology,

University of Bath

Prof. Robert Price

E-mail: r.price@bath.ac.uk

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WhatWhat are my research interests?are my research interests?

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Bioavailability of inhaled particles in the lungBioavailability of inhaled particles in the lung

There is limited knowledge of the permeability of drugs within the respiratory tract.

Majority of in vitro techniques (both cell culture and dissolution apparatus) do not reflect the circumstances an aerosol particle will experience within the lung.

Current approaches investigate extremely high doses per unit area.

In vitro – in vivo correlations significantly limited

There is an additional need to model deposition characteristics within the lung

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Targeting by depositionTargeting by deposition

Trachea18 mm

Lobar Bronchus8.3 mm

Alveolarduct

0.43 mm

Terminal Bronchiole

0.6 mm

Airway diameter

7 - 10 µm

2 - 7 µm

0.5 - 2 µm

Deposition particle diameter

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Available surface area is highly variable Available surface area is highly variable

Total surface areaca. 80,000 cm2

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Scaling EffectScaling Effect

The change in the dominant force between different scales is called the scaling effect

Gravitational and inertia forces weakenA composite of physical forces dominate

Behaviour of Macroscopic objects dominated by force of Gravity

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Particle interactions are dependent upon:

van der Waals

Capillary Forces

Tribo induced electrostatic forces

Environmental conditions directly influence these interactions

The interfacial energy and contact area between interacting surfaces is critically important

Particle interactions are dependent upon:

van der Waals

Double layer electrostatic forces

DLVO theory not established for non-aqueous solutions

XDLVO theory – sensitive to polar vDW interactions

Double layer forces limited influence on particle interactions in propellants

Surface energetics of the API is key

pMDI DPI

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5 sec 15 sec 30 sec 60 sec 120 sec 300 sec

Dispersion Dispersion stability stability a function of Colloidal forcesa function of Colloidal forces

Micronised Budesonide

Controlled Crystallisation Budesonide

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For pMDIs surface energy is the driving force for dispersion stability

Surf

ace

Ener

gy (

mJ/

m2 )

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vvan Oss an Oss -- Extended DLVO (XDLVO)Extended DLVO (XDLVO)

DLVO GTot = GLW + GELxXDLVO GTot = GLW + GAB + GEL

LW = apolar Lifshitz-van der WaalsEL = Electrostatic double layerAB = polar Acid/Base interaction

van Oss Approach

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Theoretical XDLVO ModelTheoretical XDLVO Model

Wad = - Gad

11LW1 ,, 11

LW1 ,,

)0(, 33LW3

LW attraction between particles and solution

G131

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LW

3

LW2

41 1

Polar adhesion between particles

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n = 3 Surface energy

measurements by contact angle

Work of Adhesion (Wa)

(mJm-2)Material s

LW

(mJm-2)

S+

(mJm-2)

S-

(mJm-2)

sTot

(mJm-2) DLVO XDLVO

BA 46.49 8.25 18.48 71.12 19.62 69.02

STER 49.07 0.34 22.47 53.66 22.04 33.14

LABA 48.51 0.11 35.04 51.69 21.15 29.24

DLVO rank order : STER LABA BAXDLVO rank order : BA > STER LABA

Surface Energy of APIsSurface Energy of APIs

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Flocculation Flocculation Profiles Profiles

Similar sedimentation times

Suggested strong agglomeration of BA particles

In agreement with XDLVO approach via contact angle data

BABA STERSTER LABALABA

T= 24 h

DLVODLVO

WWBABA--BABA = 19.62 mJm= 19.62 mJm--22

XDLVOXDLVO

WWBABA--BABA = 69.02 mJm= 69.02 mJm--22

DLVODLVO

WWSTERSTER--STERSTER = 22.04 mJm= 22.04 mJm--22

XDLVOXDLVO

WWSTERSTER--STERSTER = 33.14 mJm= 33.14 mJm--22

DLVODLVO

WWLABALABA--LABALABA = 21.15 mJm= 21.15 mJm--22

XDLVOXDLVO

WWBABA--BABA = 29.24 mJm= 29.24 mJm--22

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FluidisationFluidisation of of dry powder inhaler (DPI) formulationsdry powder inhaler (DPI) formulations(Drug and Carrier)(Drug and Carrier)

Dilated Powder Bed AerosolGeneration

Dispersion of Drug Particles

Static Powder Bed

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Interfacial forces is highly sensitive to a physico-chemical change of the API

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SurfaceSurface properties dominateproperties dominate

The balance of forces is dependant on subtle and complex interactions between drug substance(s), the carrier and device.

Interactions are highly sensitive to the physical and chemical properties of the drug

A change in the surface properties of the drug may directly affect this force balance.

The success or failure of a formulation is therefore highly dependant on the nature of these surfaces.

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Crystals

Processing history of the drug particlesProcessing history of the drug particles

Goal:

To understand the effect of processing of API’s on formulation performance

Mechanical

Particles

Powders

Interactiveforces

Physicochemical/Interfacial forces

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Presence of different crystal habits

A change in polymorphic form

Presence of amorphous material

What influences theWhat influences the surface surface properties ofproperties ofmicronisedmicronised powderspowders??

Traditional perspective

Current perspective

Physical Geometry - Particle Roughness and surface morphology

Interfacial chemistry - Process induced affects on interfacial forces

between API and Excipient

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Which one dominates?Which one dominates?

Physical Chemical

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What influences interfacial properties of an API

Mainly related to the processing history of the API

Degree of mechanical activation upon processing

Post-activation, the relaxation behaviour ofdisordered/deformed regions influences product properties

Relaxation processes dependent on initial degree of disorder and storage (temperature and %RH) conditions

Conditioning of the surface upon processing may expedite relaxation

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Surf

ace

Free

Ene

rgy

()

Time

crystalline state

Milling Mechanical relaxation

Relaxation energy

Relaxation induced by conditioning

deformation

Mechanically activated surface

energy change

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CohesiveCohesive--Adhesive Balance (CABAdhesive Balance (CAB™)™) MeasurementsMeasurements

drug excipient

Fcohesion(drug-drug)

Fadhesion(drug-excipient)

drug drug

Atomically smooth substrate surfaces Uniform contact area

Constant load force to minimize plastic deformation Drug Excipient

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Fadhesion = Fcohesion

Fadhesion

Probe 1

Probe 3

Probe 2

Probe 1

Probe 2

Probe 3

Batch A

Batch B

Probe 4

Probe ….

Probe 4

CohesionCohesion--Adhesion Balance (CAB) Adhesion Balance (CAB)

Representative of the interfacial properties of the bulk API powder

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Interfacial forces relate to performance

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INFLUENCE OF MECHANICAL RELAXATION ON INFLUENCE OF MECHANICAL RELAXATION ON SURFACE AND INTERFACIAL PROPERTIES OF AN APISURFACE AND INTERFACIAL PROPERTIES OF AN API

Case Study I

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Surf

ace

Free

Ene

rgy

()

Time

Mechanically Relaxed

Conditioned

C1

C2C3

Case Study I Case Study I –– 3 batches3 batches((C1, C2 and C3) C1, C2 and C3)

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1.5%

0.5%

15%

Influence on product functionalityInfluence on product functionality

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High shear blending of two different suppliers of High shear blending of two different suppliers of micronisedmicronised Fluticasone PropionateFluticasone Propionate

Case Study II

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General General physicophysico--chemical chemical characterisationcharacterisation

FP Batch AFP Batch A FP Batch BFP Batch B

FP Batches d10 m) d50 m) d90 m)Surface Area

(m2/g)

FP Batch A 0.76 1.88 4.00 7.2

FP Batch B 0.97 2.19 4.04 6.3

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CohesiveCohesive--Adhesive Balance of FP BatchesAdhesive Balance of FP Batches

FP Batches CAB

FP Batch A 0.750.75

FP Batch B 1.821.82

110nN 267nN

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Blending DynamicsBlending Dynamics

Segregation issues with the cohesive led FP (batch B)

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Variability in micronised FP samplesVariability in micronised FP samples

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ConclusionsConclusions

The API requires greater degree of characterisation to ensure consistency in stability, performance and the distribution of the drug within the lung.

There is a need therefore to understand the critical impact of material attributes and processing history on the functionality of solid dosage forms.

Development of model in vitro dissolution and permeability techniques remain of limited use in understanding its correlation with in vivo data.

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AcknowledgementsAcknowledgements

Dr Harshal Kubavat

Dr Sebastian Kaerger

Dr Jag Shur

Roberto Depasquale

EPSRCEPSRC

NanopharmNanopharm

ProsonixProsonix

Novartis Novartis PharmaPharma AGAG