Transcript Young Innovators 2009
I
NNOVATORS
2010
Novel Performance Evaluation of Dry Powder Aerosols
Graduate Student Symposium Award in Manufacturing Science and Engineering Zhen Xu and Anthony J Hickey University of North Carolina, Eshelman School of Pharmacy, Chapel Hill, NC 27599
A BSTRACT
•
Purpose: Performance evaluation of carrier surface modified formulation using powder aerosol deaggregation equation (PADE).
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A BSTRACT
• • • • • • Methods: Lactose monohydrate (sieved (SV) and milled (ML)) were coated with stearic acid (SA) using adsorption-coacervation method. The amount of surface coating was quantified by gas chromatography. The formulation blends were prepared at 2%(w/w). Particle size distribution, morphology, and thermal properties of drug carriers, and mixtures were examined. Experimentally designed in vitro aerosolization was performed using standardized entrainment tubes (SETs) with well-defined airflow parameters. Formulations that pneumatically entrained were characterized by twin-stage liquid impinger (TSLI) at a flow rate of 60 L/min. The particle deaggregation exemplified by fine particle fraction (
FPF
) was correlated with SET shear stress ( t
s
) by applying PADE (non-linear and linear regression). Formulation reproducibility across increasing shear stress can be determined when the hyperbolic curve approaches a plateau. (1-4) Young Innovators 2009
I NTRODUCTION
• • • • • The surfaces of pharmaceutical dry powder aerosols are heterogeneous. In principle, the heterogeneity manifests on the particle surfaces should be similar to that described in the surface adsorption theory, since the fundamental forces and surface energies are described and characterized similarly. The practical approach to describing energy heterogeneity (e.g. adsorption or protein binding) is to average local thermodynamic quantities and treat them statistically.
PADE is an analogy to the surface adsorption theory. It led to a novel way of interpreting particle interactions. (1-4) PADE model:
FPF FPF
max
k d
1
k d
t
s
t
s
(
Eq
.
1 ) t
s FPF
t
s FPF
max 1
k d
(
FPF
max ) (
Eq
.
2 ) Young Innovators 2009
I NTRODUCTION
• As a shear force applies to the surface of carrier particles, drug particles are removed with increasing difficulty because of the sites that they occupy until a saturation is reach, when no drug particle can be removed at increasing shear.
• PADE is mechanistically different form adsorption theory because it involves rapid system volume expansion and changing boundary condition. (4) Young Innovators 2009
M ATERIALS
• • • •
Respirable drug:
micronized albuterol sulfate (AS).
Carrier:
lactose monohydrate (Respitose TM ), surface-modified sieved (SV) and ML (ML) batches
Surface active agent
: stearic acid.
Other chemicals
: anhydrous dichloromethane, anhydrous chloroform, petroleum ether, boro trifuoride (14%) in methanol, deionized water.
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M ETHODS
• • • • • • • • The theoretical estimation for monolayer surface coating was performed based on the surface area of lactose batches determined by nitrogen adsorption method. Adsorption-coacervation for stearic acid (SA) coating. (5) Interactive physical mixtures of AS and lactose batches (SV, ML, SV-0SA, ML-0SA, SV lowSA, ML-lowSA, SV-highSA, and ML-highSA) were prepared at drug concentration 2%(w/w).
Particle volume size distribution of drug and carriers was characterized by laser diffraction Particle size and morphology was assessed by SEM at different magnification.
Thermal properties of drug, carriers, and mixtures were examined by DSC at scanning rate of 5 o C/min.
Experimentally designed in vitro aerosolization was performed using SETs.
Formulations that pneumatically entrained were characterized by TSLI at 60 L/min. PADE was applied. Statistical analysis was carried out suing SigmaPlot software.
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R ESULTS
• • • • • Jet-milled drug particles were in the respirable size range (D 50 similar D 50 = 3.59). SV and ML had (59.7, 54.6 um), but significantly different span (1.10
vs.
3.13).
Non-spherical drug particles formed aggregates due to strong interfacial interactions at solid solid interface. The primary particle size similar, but SV blend had much less fine particle/agglomerates associated with the primary particles than ML.
Surface monolayer coverage were estimated to be 0.7 and 2.1 mg/g, respectively.
The adsorption-association isotherms obtained were similar for SV and ML. The surface coating at two equilibrium concentrations were selected for performance studies.
DSC thermograms show reduced enthalpy for both endothermic peaks. The characteristic exothermic peak at ~173 o C disappeared. No enhancement of the exothermic peak after blending.
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R ESULTS
x5,000
X3,000 DSCG
x600
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R ESULTS
Figure 2B Figure 2A
25 50 SV SV-0SA SV-lowSA SV-highSA 75 100 125 150 Temperature ( o C) 175 200 225 250 25 50 ML ML-0SA ML-lowSA ML-highSA 75 100 125 150 Temperature ( o C) 175 200 225 250 Young Innovators 2009
R ESULTS
• The correlation plots using PADE non-linear and linear regression analyses showed excellent correlation. – – Non-linear regression: Adjusted R 2 = 0.8497-0.9957
Linear regression: R 2 = 0.9526-0.9993
• Solvent treatment (SV-0SA, ML-0SA) resulted in negative influence on the aerosolization performance (smaller
FPF max
). For SV formulations, the performance was dependent upon the amount of SA coated. Conversely, the performance of ML formulations were less susceptible to the amount of SA coated.
• ML formulations gave higher performance efficiency.
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Figure 3A
25 20 SV+AS SV-0SA+AS SV-lowSA+AS SV-highSA+AS 15 10 5 0 40 0 2 4 6 8 Shear stress ( t s ) (N/m 2 ) 10
Figure 3C
60 50 ML+AS ML-0SA+AS ML-lowSA+AS ML-highSA+AS 30 20 10 0 0 2 4 6 8 10 Shear stress ( t s ) (N/m 2 ) 12
Figure 3B
120 100
R ESULTS
SV+AS SV-0SA+AS SV-lowSA+AS SV-highSA+AS 80 14 60 40 20 0 0 2 4 6 8 Shear stress ( t s ) (N/m 2 ) 10
Figure 3D
50 40 ML+AS ML-0SA+AS ML-lowSA+AS ML-highSA+AS 30 12 20 10 0 2 4 6 8 Shear stress ( t s ) (N/m 2 ) 10 12 12 14 14
C ONCLUSION
Significant differences were characterized between SV and ML on size distribution, morphology, and surface energetics. SA was quantitatively coated on the surfaces of SV and ML particles.
Physicochemical characterization indicated strong influence of solvent during coating.
The application of robust PADE, based on fundamental Langmuir theory, gave excellent performance prediction (model well-tolerated), which allow rational design of dry powder formulation instead of trial and error.
The reduced aerosolization could be explained by stripping of natural surface coating on lactose monohydrate, whereas the artificial coating with SA could reduce surface heterogeneity and improve aerosolization.
ML formulations performed better than SV formulations.
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A CKNOWLEDGMENTS
•
This research was funded by DMV-Fonterra Excipients and Pfizer.
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R EFERENCES
1. Xu Z, Mansour, HM, Mulder T, McLean R, Langridge, J, Hickey, AJ, J Pharm Sci 2010, 99(8): 3398-3414.
2. Xu Z, Mansour HM, Mulder T, McLean R. Langridge J, Hickey AJ, J Pharm Sci 2010, 99(8): 3415-3429.
3. Mansour HM, Xu Z, Hickey AJ, J Pharm Sci, 2010, 99(8): 3430-3441.
4. Xu Z, Mansour HM, Mulder T, McLean R, Langridge J, Hickey AJ, J Pharm Sci 2010, 99(8): 3442-3461.
5. Hickey AJ, Jackson GV, Fildes FJ, J Pharm Sci, 1988, 77, 804-809.
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BIOS/C ONTACT INFO
• • • • • • Zhen Xu PhD in Pharmaceutical Sciences, University of North Carolina at Chapel Hill. Area: formulation and preformulation; aerosol drug delivery. Graduated in August, 2010.
Master of Sciences in Chemistry, Michigan State University, carbohydrate chemistry. Graduated in August, 2004.
(919)-809-4174 6808 Blenheim Rd Apt D, Baltimore, MD 21212 Young Innovators 2009