Post on 15-Jun-2019
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