modeling and characterization of powder dispersion in dpis
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Modeling and Characterization of Powder Dispersion in DPIs
May 31st, 2019
Analytical TechnologyBoris Shekunov
Takeda Pharmaceutical Company Limited
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Reference
CRC Press
March 25, 2019
ISBN 9781138064799 - CAT# K33394
Chapter 1:
Physicochemical Properties of Respiratory Particles and FormulationsBoris Shekunov
(Mechanisms of dispersion for solid and liquid aerosols,
different formulation approaches, optimization strategies
and regulatory considerations)
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“Misconceptions” and Challenges with DPI formulations
• Air-flow independent therapy and variability in total lung delivery• Device resistance and application of high resistance devices by patients with reduced lung
function• Development of new integrated device-formulation systems• Development of high-dose DPIs• Understanding of powder dispersion mechanisms• Interparticle interactions and powder agglomeration • Effects of coarse and fine lactose on powder mixing and aerosolization• Properties of engineered particles• Particle dissolution and uptake• Stability of amorphous formulations
Formulation-Flow-Device Paradigm: Relate the material characteristics of the formulation (e.g. particle adhesion/cohesion and aggregate strength) with the flow rate, pressure drop and inhaler resistance to the inhaler performance in terms of the FPF
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Deposition profiles
Nasopharyngeal -impaction-sedimentation-electrostatic
Tracheobronchial -impaction-sedimentation-diffusion
Pulmonary -sedimentation-diffusion
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Physical inhaler- patient interface: flow rate and pressure drop
(a) Influence of the inertial impaction parameter, dA2Q, on mouth-throat deposition and (b) variability of total lung deposition for porous engineered particles vs. pressure drop across DPIs (from: Weers J., Clark A. The impact of inspiratory flow rate on drug delivery to the lungs with dry powder inhalers. Pharm Res. 2017)
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Generalized model of dispersion
B
A
• Flow, Q, through a device with the pressure differential, ΔP, and volume of the active dispersing zone, V, define the rate of turbulent energy dissipation, ε.
• The input-output parameters: initial fine particle fraction, FPF0, the resulting fine particle fraction, FPF, and the maximum achievable fine particle fraction, FPFmax
• Two most important functions: breakage frequency (Γ) and turbulent stress (σ)
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In vitro delivered fine particle doses (FPD) vs. label claim
From: A. H. de Boer et al. Dry powder inhalation: past, present, and future. Expert Opinion on Drug Delivery, 14:4, 501 (2017). Tested at 4 kPa (high resistance devices) or 2 kPa (low resistance devices); range of flow rates 40–75 L/min using a NGI.
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Effect of device resistance (RD) and flow rate (Q) on energy of dispersion
• ρ is air density
• For most commercial DPIs, RD typically in the range 0.01-0.07 kPa1/2 min/L
• Device parameter, Z = 2 × 103 – 5 × 103 depends only weakly on the inhaler type
∆"#.%= '()* = +,-../,-.0.123..43
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Mechanism of dispersion in DPIs
σ erosion
σ rapture
σ compression
σ collision
Γ
σa (10-3) << σb (10-1) ≈ σc (10-1) < σ’b,c (100) << σe (101) <σf (102) <σd (102)
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Dependence of FPF on airflow
• Γ ~ εx: the power x ≈ 1/3 – 1/2 (within the same dispersion mechanism) is the exponent of the turbulent energy dissipation rate
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
0 0.5 1 1.5 2 2.5
log(-ln
(1-FPF))
log(Q, L/min)
Insert I
Insert II
Insert III
Experimental data from: Gac J, Sosnowski TR, Gradon L. Turbulent flow energy for aerosolization of powder particles. Aerosol Sci. 2008
!"#(− ln 1 − )*) ) = - + 30 − 1 !"#1
x ≈ 0.47
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Dependence of FPF for Micronized and Engineered Particles
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.4 0.6 0.8 1 1.2 1.4
log(-ln
(1-FPF))
logQ
micronized
engineered
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Types of flow dependencies
“ideal” inhaler and formulation
FPF = 0
FPF = 1
inhaler design issues
variable dispersion mechanism
Q
formulation issues
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Aggregate strength: key to determination of powder performance
!" = $( &''()*
+ ,-.+
, = −0123-4
Tensile strength:
Interparticle force defined by the Johnson-Kendall-Roberts (JKR) relationship:
K - dependent on aggregate size and W is the work of adhesion
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Conclusions from the aggregate model
(a) The aggregate strength is inversely proportional to dp
(b) Surface asperities can significantly decrease both the interparticle bond and aggregate strength (by a factor ~2qy/dp where y is the diameter of asperity and q number of contacts. The same applies for binary mixtures consisting nanoparticles resulting in a minimum strength at a certain surface coverage
(c) For binary mixtures consisting large carrier particles, the carrier-drug bond increases at least by a factor of 2, given the same W and contact cross-section, compared to the bond between drug particles themselves. However the balance of strength for such aggregate depends on the drug-carrier surface coverage and packing order of drug particles
(d) Both parameters, K and σT, become dependent on the aggregate (or cross-section) size when they are comparable to the size of primary particles. In particular, K has a smaller value for the fracture cross-sections close to the aggregate surface
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Formulation design: dilemma with lactose carriers and adhesive blends
Functions of carriers:
(a) “Dilution” of formulation: ordered mixtures (b) Enhance dispersion(c) Fixed dose combinations
σp ≈ 2.4 kPa
σpc (max) ≈ 29 kPaTheoretical drug loading:
!"!#
≃ % &'()*+#'#(#)*+
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Ternary blends with lactose
Moderating effects of fine lactose particles:
(a) “Energetic” sites (b) Small lactose-drug aggregates (c) Disruption of ordered layer
σp ≈ 1.5 kPa
σpc ≈ 5-10 kPa
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Control of dispersion using particle engineering• Reduced density - smaller aerodynamic
diameter
• Large volume diameter - reduced strength of agglomeration
• Larger surface asperity / rugosity – reduced interparticle interactions
• Smaller specific work of adhesion / cohesion -reduced interparticle interactions
• Increased shape factor – reduced interparticle interactions
• Larger specific surface area – improved dose uniformity
• Smaller number of particles in aggregate –faster dispersion Spray-dried large (c)- and small (d) - porous particles
(G J Weers and DP Miller, J Pharm Sci. 2015)
Spray-Freezing(B. Shekunov data)
Spray-Drying with FCA(NYK Chew, B Shekunov, HHYTong, et al., J Pharm Sci, 2005)
1 µm 1 µma b
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In: A. H. L. Chow, H. H. Y. Tong, P. Chattopadhyay, B. Shekunov. Particle Engineering for Pulmonary Drug Delivery. Pharm Res, 24 (2007)
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Aerosolization Performance of Different Engineered Materials
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Analytical aspects for assessing formulation performance
• Predictions of aggregate strength using physicochemical measurements (e.g. AFM, microscopy, BET, IGC)
• More detailed data analysis from cascade impactors
• Use of particle size methods
• Utilization of Standardized Entrainment Tubes (SET)
• Flexible DPIs design (inserts, mold modifications)
• In combination with theoretical quantitative models and CFD
| Title | DD/MM/YY
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Regulatory considerations
• Solid-State: Physicochemical characterization of API(s) and excipients relevant to their functionality in drug product; compatibility with diluents c; effects of environmental moisture a,b, low temperature b; temperature cycling b,d; moisture content a,b; sameness / therapeutic equivalence of API (generics).
• Particulate and Surface: PSD (for APIs and carriers); ASPD; single actuation FPD a,b,d; (delivered) dose content uniformity (DCU) a,b,d (containers intra-and inter-batch) or uniformity of dosage units a,c,d; DCU and FPD at various flow rates a and at various lifestages (i.e. beginning, middle, end) a,b,d; FPD with spacer b; actuator / mouthpiece deposition a,b,d; shaking requirements; drug delivery rate and total drug delivered c; foreign particulate matter.
• Formulation: Assay, mean delivered dose vs. label claim a,b,d; DCU a,b,d; dose proportionality (for different strengths and/or APIs); formulation / inhaler robustness; drug product stability; qualitative (Q1) sameness and quantitative (Q2) equivalence of excipients and media physicochemical similarity c (generics). aDPIs; bpMDIs; cnebulizers; dnon-pressurized metered dose inhalers
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Design of efficient and robust inhalation products
• Inhaler designed for formulation
• More efficient use of quantitative aerodynamic dispersion models and CFD
• Wider applications of in vitro analytical technology in R&D
• Optimization of ternary mixtures
• Engineered particles for new drugs including biological molecules and
amorphous formulations
• Particle designed for complete performance: aerosolization within inhaler -
deposition / distribution in the airways - drug release / uptake / clearance at
the site of action
• Assessment of manufacturing feasibility and GMP implications
| Title | DD/MM/YY