eBook: Formulation of Dry Powder Inhaler - 7

sealed in aluminum pans, vented, and scanned in
ADSC mode (a single-frequency temperature-modulated
DSC technique) from 0 to 170°C at 2.5°C/min
with a modulation of 1.5°C every 60 s. The Tg
was
analyzed using STARe software (Mettler Toledo), reporting
the onset and midpoint temperatures of the
transition. To measure the unfolding (melting) temperature
of the as-received bevacizumab in solution,
10 μL of solution was pipetted into a 40-μL aluminum
pan and hermetically sealed. Then 10 μL of pH
6.3 phosphate buffer was pipetted into the reference
pan to subtract the contribution of the liquid to the
thermal trace. The sample was scanned from 30 to
110°C at 5°C/min.
Karl Fischer (KF) Titration
The water content of the spray-dried powder was
measured using a coulometric Metrohm® 851
Titrando KF oven titrator (Metrohm USA Inc., Tampa,
FL, USA), with the generator electrode operated in
diaphragm-less mode. A 10- to 30-mg sample was
sealed into a crimped KF vial and analyzed at 105°C.
Scanning Electron Microscopy (SEM)
To assess morphology, SEM images of bevacizumab
spray-dried powders were obtained using a Hitachi
SU3500 (Hitachi High Technologies America Inc.,
Schaumburg, IL, USA). A trace amount of sample was
applied to double-sided carbon tape mounted on an
aluminum stub. The sample was then sputter-coated
with gold/palladium for 10 min at 15 to 20 mV
using a Hummer® 6.2 Sputter System (Anatech Ltd.,
Battle Creek, MI, USA).
Size-Exclusion Chromatography with MultipleAngle
Laser Light Scattering (SEC-MALLS)
Bevacizumab spray-dried powder and control solution
was analyzed by SEC-MALLS to determine the
presence of high molecular weight species (e.g.,
dimers and trimers of the mAb). Materials were diluted
to 5 mg/mL with pH 6.3 phosphate buffer. An
Agilent 1100 high-performance liquid chromatography
(HPLC) instrument (Agilent Technologies, Santa
Clara, CA, USA) was used with a TSKgel GMPWXL column
(7.8 mm ID, 30-cm length, 13-μm particle size,
10- to 100-nm pore size)(Tosoh Bioscience, Tokyo,
Japan). The mobile phase was pH 7.4 phosphate
buffered saline. Samples were run isocratically at a
flow rate of 0.8 mL/min for 50 min with an injection
volume of 20 μL.
Geometric Particle Size Distribution
The geometric particle size distribution of the
spray-dried powder was measured with a Malvern
Mastersizer 3000 using an Aero S dry powder disperser.
Mastersizer software was used to analyze
the results using the Fraunhofer approximation.
Samples were run in triplicate with obscuration levels
between 0.1 and 8%, disperser pressure of 2 to 3
bar, and feed rate of 30 to 70%.
Aerodynamic Particle Size Distribution
The aerodynamic particle size distribution of spraydried
powder was measured using a TSI Aerodynamic
Particle Sizer® 3321 spectrometer with a Model 3433
small-scale powder disperser and Model 3302A diluter
(TSI, Shoreview, MN, USA). The air flow rate was
18.5 L/min in the powder disperser, and the sheath
flow rate was 4 L/min. The diluter used a 100:1 capillary
at pressure of 0.32 in. of water. Samples were
measured in triplicate for 30 s each.
Next Generation Impactor (NGI)
The aerosolization properties of the spray-dried powder
were analyzed using an MSP NGI Model 170,
MSP Corp., Shoreview, MN, USA) with a high-resistance
4-kPa Plastiape dry powder inhaler (Plastiape
S.p.a., Osnago, Italy). Spray-dried powder (10 mg) was
7

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