Particle interactions in dry and suspension based formulations

Transcription

1 Finnish Society of Physical Pharmacy, 9 th Feb 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 r.price@bath.ac.uk

2 What are my research interests? 2

3 Bioavailability 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 3

4 Targeting by deposition Airway diameter Trachea 18 mm Lobar Bronchus 8.3 mm Terminal Bronchiole 0.6 mm Alveolar duct 0.43 mm Deposition particle diameter 7-10 µm 2-7 µm µm 4

5 Available surface area is highly variable Total surface area ca. 80,000 cm 2 5

6 Scaling Effect Behaviour of Macroscopic objects dominated by force of Gravity The change in the dominant force between different scales is called the scaling effect Gravitational and inertia forces weaken A composite of physical forces dominate 6

7 pmdi DPI Particle interactions are dependent upon: van der Waals Double layer electrostatic forces DLVO theory not established for nonaqueous 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 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 7

8 Dispersion stability a function of Colloidal forces 5 sec 15 sec 30 sec 60 sec 120 sec 300 sec Micronised Budesonide 8 Controlled Crystallisation Budesonide

9 For pmdis surface energy is the driving force for dispersion stability Surface Energy (mj/m 2 ) 9

10 van Oss - Extended DLVO (XDLVO) DLVO x G Tot = G LW + G EL XDLVO G Tot = G LW + G AB + G EL van Oss Approach LW = apolar Lifshitz-van der Waals EL = Electrostatic double layer AB = polar Acid/Base interaction 10

11 Theoretical XDLVO Model W ad = - G ad LW,( ) LW,, LW 1, 1, 1 G LW 3 LW LW attraction between particles and solution Polar adhesion between particles 11

12 Surface Energy of APIs n = 3 Material Surface energy measurements by contact angle LW s + S - S Tot s (mjm -2 ) (mjm -2 ) (mjm -2 ) (mjm -2 ) Work of Adhesion (Wa) (mjm -2 ) DLVO XDLVO BA STER LABA DLVO rank order : STER LABA BA XDLVO rank order : BA > STER LABA 12

13 Flocculation Profiles T= 24 h BA STER LABA DLVO W BA-BA = mjm - 2 XDLVO W BA-BA = mjm - 2 W STER-STER W STER-STER DLVO STER = mjm - 2 XDLVO STER = mjm - 2 DLVO W LABA-LABA = mjm - 2 XDLVO W BA-BA = mjm - 2 Similar sedimentation times Suggested strong agglomeration of BA particles In agreement with XDLVO 13 approach via contact angle data

14 Fluidisation of dry powder inhaler (DPI) formulations (Drug and Carrier) Static Powder Bed Dilated Powder Bed Aerosol Generation Dispersion of Drug Particles 14

15 Interfacial forces is highly sensitive to a physicochemical change of the API 15

16 Surface properties 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. 16

17 Processing history of the drug particles Crystals Particles Mechanical Powders Goal: Physicochemical/I nterfacial forces To understand the effect of processing of API s on formulation performance Interactive forces 17

18 What influences the surface properties of micronised powders? Traditional perspective Presence of different crystal habits A change in polymorphic form Presence of amorphous material Current perspective Physical Geometry - Particle Roughness and surface morphology Interfacial chemistry - Process induced affects on interfacial forces between API and Excipient 18

19 Which one dominates? Physical Chemical 19

20 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 of disordered/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 20

21 Milling Mechanical relaxation Surface Free Energy ( ) deformation Mechanically activated surface energy change Relaxation energy Relaxation induced by conditioning crystalline state Time 21

22 Cohesive-Adhesive Balance (CAB ) Measurements F cohesion (drug-drug) F adhesion (drug-excipient) drug drug drug excipient Atomically smooth substrate surfaces Uniform contact area Constant load force to minimize plastic deformation Drug Excipient 22

23 Cohesion-Adhesion Balance (CAB) Batch A Batch B F adhesion = F cohesion Probe 4 Probe 3 Probe. Probe 4 Probe 2 Probe 3 Probe 1 Probe 1 Probe 2 Representative of the interfacial properties of the bulk API powder 23 F adhesion

24 Interfacial forces relate to performance 24

25 Case Study I INFLUENCE OF MECHANICAL RELAXATION ON SURFACE AND INTERFACIAL PROPERTIES OF AN API 25

26 Case Study I 3 batches (C1, C2 and C3) Surface Free Energy ( ) C1 C2 Mechanically Relaxed Conditioned C3 Time 26

27 Influence on product functionality 0.5% 15% 1.5% 27

28 Case Study II High shear blending of two different suppliers of micronised Fluticasone Propionate 28

29 General physico-chemical chemical characterisation FP Batch A FP Batch B FP Batches d 10 m) d 50 m) d 90 m) Surface Area (m 2 /g) FP Batch A FP Batch B

30 Cohesive-Adhesive Balance of FP Batches FP Batches CAB FP Batch A 0.75 FP Batch B nN 267nN 30

31 Blending Dynamics Segregation issues with the cohesive led FP (batch B) 31

32 Variability in micronised FP samples 32

33 Conclusions 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. 33

34 Acknowledgements Dr Harshal Kubavat Dr Sebastian Kaerger Dr Jag Shur EPSRC Nanopharm Prosonix Novartis Pharma AG Roberto Depasquale 34