ABBREVIATIONS

Albuterol sulphate, AS; Carr’s index, CI; charge–to–mass ratio, CMR; coefficient of variation, CV; d10%, particle sizes at 10%volume distribution;d50%, median diameter; d90%, particle sizes at 90% volume distribution; differential scanning calorimetry, DSC; dispersibility, DS; effective inhalation index, EI; emitted fraction, EF; energy dispersive X–ray, EDX; equation, Eq; equivalent diameter, Dequi; fine particle fraction, FPF; fourier transform infrared,FT–IR; geometric standard deviation, GSD; impaction loss, IL; induction port, IP; inhaler with mouthpiece adaptor, I+M; mass median aerodynamic diameter, MMAD; mean diameter, MD; Multi–Stage liquid impinger, MSLI; negative charge–to–mass ratio, N–CMR; overall desirability function, DF; particle size distribution, PSD; positive charge–to–mass ratio, P–CMR; powder X–ray diffraction, PXRD; relative humidity, RH; scanning electron microscopy, SEM; spray dried mannitol, SDM; Yi, actual observedvalue; Ymax,the maximum acceptablevalue; Ymin, the minimum acceptablevalue.

SM1.Maximum (Ymax) and minimum (Ymin) values for DPI formulation parameters used for formulation optimization using overall desirability function

DPI formulation parameter / Ymin / Ymax
Fine particle fraction (FPF, %) / 1 / 100
Coefficient of variation (CV, %) / 1 / 50
Carr’s index (CI, %) / 1 / 50
Deposition on inhaler with mouthpiece adaptor + induction port (I+M+IP, %) / 1 / 100

SM2. Particle size distribution (% undersize and density distributions) and scanning electron photographs for spray dried mannitol (SDM) particles with different size fractions: 90–125 µm (SDM–A), 63–90 µm (SDM–B), 45–63 µm (SDM–C) and 20–45 µm (SDM–D) (mean±SD, n=10). MD: mean diameter based on volume. SDM particles demonstrated considerably different size distributions.

SM3. SEM images for spray dried mannitol (SDM) particles sieved in different size fractions: 90–125 µm (SDM–A), 63–90 µm (SDM–B), 45–63 µm (SDM–C)and 20–45 µm (SDM–D).

SM4.Differential scanning calorimeter (DSC) tracesand melting enthalpies for spray dried mannitol (SDM) particles with different size fractions: 90–125 µm (SDM–A), 63–90 µm (SDM–B), 45–63 µm (SDM–C) and 20–45 µm (SDM–D), acetone crystallized mannitol (ACM, α–mannitol), commercial mannitol A (CM–A, β–mannitol) and commercial mannitol B (CM–B, δ–mannitol)heated from -20 °C to 250 ºC at a heating rate of 10 K/min.

SM5. Structural Rietveld refined lattice parameters for different mannitol products, i.e.,spray dried mannitol (SDM) particles sieved in different size fractions: 90–125 µm (SDM–A), 63–90 µm (SDM–B), 45–63 µm (SDM–C),20–45 µm (SDM–D), acetone crystallized mannitol (ACM, α–mannitol), commercial mannitol A (CM–A, β–mannitol) and commercial mannitol B (CM–B, δ–mannitol).

Phase name / Mean crystallite size
Cry. size Lorentzian
(nm) / k: 1 LVol–IB
(nm) / k: 0.89 LVol–FWHM
(nm)
SDM–A / α–D–mannitol / 1160 / 739 / 1034
β–D–mannitol / 1470 / 930 / 1310
SDM–B / α–D–mannitol / 841 / 535 / 748
β–D–mannitol / 1010 / 646 / 900
SDM–C / α–D–mannitol / 1054 / 671 / 938
β–D–mannitol / 1110 / 708 / 990
SDM–D / α–D–mannitol / 920 / 583 / 815
β–D–mannitol / 810 / 517 / 723
ACM / α–D–mannitol / 732 / 466 / 652
CM–A / β–D–mannitol / 881 / 561 / 784
CM–B / δ–D–mannitol / 1000 / 652 / 894

SM6. True density (mean±SD, n=6); bulk density and tap density (mean±SD, n=5); Carr’s index (CI), and porosity (mean±SD, n=5) for spray dried mannitol (SDM) particles with different size fractions: 90–125 µm (SDM–A), 63–90 µm (SDM–B), 45–63 µm (SDM–C) and 20–45 µm (SDM–D). SDM particles demonstrated a similar true density, however, different bulk and tap densities and different flow properties. ‘S’ indicates statistically similar (P0.05).

SM7.SEM photographs of micronized albuterol sulphate (AS) alone (a);and formulation blends consisting of albuterol sulphate blended separately with spray dried mannitol (SDM) particles sieved in different size fractions: 90–125 µm (SDM–A)(b), 63–90 µm (SDM–B) (c), 45–63 µm (SDM–C)(d)and 20–45 µm (SDM–D) (e). Circles refer to AS particles.

SM8.Scanning electron microscopy/energy–dispersive X–ray spot analysis on formulation blends consisting of albuterol sulphate blended separately with spray dried mannitol particles with different size fractions: 90–125 µm (A), 63–90 µm (B), 45–63 µm (C) and 20–45 µm (D).