Design, characterization, and aerosolization of organic solution advanced spray-dried moxifloxacin and ofloxacin dipalmitoylphosphatidylcholine (DPPC) microparticulate/nanoparticulate powders for pulmonary inhalation aerosol delivery

Figures & data

Figure 1 The chemical structures of moxifloxacin hydrochloride, ofloxacin, and dipalmitoylphosphatidylcholine.

Notes: (A) Moxifloxacin hydrochloride; (B) ofloxacin; (C) dipalmitoylphosphatidylcholine.

Table 1 Spray drying conditions for organic solution advanced spray drying in closed-mode under ultra-high purity nitrogen gas for MOXI:DPPC and OFlX:DPPC spray-dried and cospray-dried systems

Formulations	Solvent	Aspiration gas: ultra-high purity nitrogen gas (L/hour)	Inlet temperature (°C)	Outlet temperature (°C)	Pump rate (%)	Aspirator (%)
MOXI:DPPC = 100:0	Methanol	670	150	75	50	100
MOXI:DPPC = 75:25	Methanol	670	150	72	50	100
MOXI:DPPC = 50:50	Methanol	670	150	70	50	100
MOXI:DPPC = 25:75	Methanol	670	150	68	50	100
OFLX:DPPC = 100:0	Methanol	670	150	73	50	100
OFLX:DPPC = 75:25	Methanol	670	150	69	50	100
OFLX:DPPC = 50:50	Methanol	670	150	76	50	100
OFLX:DPPC = 25:75	Methanol	670	150	73	50	100
MOXI/OFLX:DPPC = 0:100	Methanol	670	150	64	50	100

Abbreviations: MOXI, moxifloxacin; DPPC, dipalmitoylphosphatidylcholine; OFLX, ofloxacin.

Table 2 Particle size parameters of spray-dried and cospray-dried MOXI:DPPC powders (mean ± standard deviation; n = 3)

Formulations	Diameter (μm)	Range (μm)
MOXI:DPPC = 100:0	0.67 ± 0.19	0.379–1.363
MOXI:DPPC = 75:25	0.70 ± 0.21	0.354–1.406
MOXI:DPPC = 50:50	0.69 ± 0.21	0.403–1.533
MOXI:DPPC = 25:75	0.69 ± 0.22	0.325–1.655
MOXI:DPPC = 0:100	0.64 ± 0.18	0.236–1.166

Abbreviations: MOXI, moxifloxacin; DPPC, dipalmitoylphosphatidylcholine; n, number.

Figure 2 SEM micrographs of (A) moxifloxacin hydrochloride (magnification: 1,000×), (B) ofloxacin (magnification: 1,000×), and (C) DPPC (magnification 1,000×) as supplied by the manufacturer.

Abbreviations: SEM, scanning electron microscope; DPPC, dipalmitoylphosphatidylcholine.

Figure 3 SEM micrographs of SD and co-SD powders.

Notes: (A) SD MOXI (magnification: 10,000×); (B) co-SD MOXI:DPPC = 75:25 (magnification: 10,000×); (C) co-SD MOXI:DPPC = 50:50 (magnification: 10,000×); (D) co-SD MOXI:DPPC = 25:75 (magnification 10,000×); and (E) SD DPPC (magnification 10,000×).

Abbreviations: SEM, scanning electron microscope; SD, spray-dried; co-SD, cospray-dried; MOXI, moxifloxacin; DPPC, dipalmitoylphosphatidylcholine.

Figure 4 SEM micrographs of SD and co-SD powders.

Notes: (A) SD OFLX (magnification: 10,000×); (B) co-SD OFlX:DPPC = 75:25 (magnification: 10,000×); (C) co-SD OFlX:DPPC = 50:50 (magnification: 10,000×); (D) co-SD OFlX:DPPC = 25:75 (magnification 10,000×); and (E) SD DPPC (magnification: 10,000×).

Abbreviations: SEM, scanning electron microscope; SD, spray-dried; co-SD, cospray-dried; OFLX, ofloxacin; DPPC, dipalmitoylphosphatidylcholine.

Table 3 Particle size parameters of spray-dried and cospray-dried OFLX:DPPC powders (mean ± standard deviation; n = 3)

Formulations	Diameter (μm)	Range (μm)
OFLX:DPPC = 100:0	0.69 ± 0.15	0.399–1.293
OFLX:DPPC = 75:25	0.59 ± 0.15	0.326–1.317
OFLX:DPPC = 50:50	0.60 ± 0.18	0.277–1.190
OFLX:DPPC = 25:75	0.57 ± 0.18	0.277–1.178
OFLX:DPPC = 0:100	0.64 ± 0.18	0.236–1.166

Abbreviations: OFLX, ofloxacin; DPPC, dipalmitoylphosphatidylcholine; n, number.

Figure 5 XRPD diffractograms of MOXI hydrochloride, OFLX, and DPPC (supplied by the manufacturer) spray-dried and cospray-dried powders at various molar ratios.

Notes: (A) MOXI:DPPC; (B) OFLX:DPPC.

Abbreviations: MOXI, moxifloxacin; DPPC, dipalmitoylphosphatidylcholine; OFLX, ofloxacin; XRPD, X-ray powder diffraction.

Figure 6 DSC thermograms of MOXI hydrochloride, OFLX, and DPPC (supplied by the manufacturer) spray-dried and cospray-dried powders at various molar ratios.

Notes: (A) MOXI:DPPC; (B) OFLX:DPPC.

Abbreviations: MOXI, moxifloxacin; DPPC, dipalmitoylphosphatidylcholine; OFLX, ofloxacin; DSC, differential scanning calorimetry.

Figure 7 ATR-FTIR spectra of MOXI hydrochloride, OFLX, and DPPC (supplied by the manufacturer) spray-dried and cospray-dried powders at various molar ratios.

Notes: (A and B) MOXI:DPPC; (C) OFLX:DPPC; and (D) MOXI hydrochloride and OFLX supplied by the manufacturer.

Abbreviations: MOXI, moxifloxacin; DPPC, dipalmitoylphosphatidylcholine; OFLX, ofloxacin; ATR-FTIR, attenuated total reflectance infrared–Fourier transform infrared spectroscopy.

Figure 8 Representative HSM micrographs for DPPC supplied by the manufacturer versus SD DPPC powders.

Notes: (A) Raw DPPC; (B) SD DPPC powders.

Abbreviations: DPPC, dipalmitoylphosphatidylcholine; SD, spray-dried; HSM, hot-stage microscopy.

Figure 9 Representative HSM micrographs for MOXI hydrochloride supplied by the manufacturer versus SD MOXI powders.

Notes: (A) Raw MOXI; (B) SD MOXI.

Abbreviations: MOXI, moxifloxacin; SD, spray-dried; HSM, hot-stage microscopy.

Figure 10 Representative HSM micrographs for OFLX supplied by the manufacturer versus SD OFLX powders.

Notes: (A) Raw OFLX; (B) SD OFLX.

Abbreviations: OFLX, ofloxacin; SD, spray-dried; HSM, hot-stage microscopy.

Figure 11 Representative HSM micrographs for co-SD MOXI:DPPC 75:25 versus co-SD OFLX:DPPC 75:25 powders.

Abbreviations: co-SD, cospray-dried; MOXI, moxifloxacin; DPPC, dipalmitoylphosphatidylcholine; HSM, hot-stage microscopy; OFLX, ofloxacin.

Figure 12 Raman spectra obtained via confocal microscopy of OFLX, MOXI, and DPPC (supplied by the manufacturer) shown in comparison to representative spectra obtained from SD MOXI:DPPC (100:0) and OFLX:DPPC (100:0) particles.

Abbreviations: OFLX, ofloxacin; SD, spray-dried; DPPC, dipalmitoylphosphatidylcholine; MOXI, moxifloxacin.

Figure 13 Raman band area ratio map of the MOXI to DPPC ratio in agglomerated spray-dried particles and extracted spectra from three points that illustrate the homogeneous distribution of MOXI and DPPC across the mapped region.

Notes: (A) Raman band area ratio map of the MOXI to DPPC ratio in agglomerated spray-dried particles (MOXI:DPPC 50:50) superimposed on a brightfield optical image. Increasing blue–green color is associated with greater concentration of MOXI relative to DPPC. The map sampled a 10 × 30 rectangle using 10 μm stage increments, and a full spectrum was acquired at each point. (B) Extracted spectra from three points (denoted by red, purple, and green-bordered rectangles in [A]) that illustrate the homogeneous distribution of MOXI and DPPC across the mapped region.

Abbreviations: MOXI, moxifloxacin; DPPC, dipalmitoylphosphatidylcholine.

Figure 14 Raman band area ratio map of the OFLX to DPPC ratio in agglomerated spray-dried particles and extracted spectra from three points that illustrate the homogeneous distribution of OFLX and DPPCacross the mapped region.

Notes: (A) Raman band area ratio map of the OFLX to DPPC ratio in agglomerated spray-dried particles (OFLX:DPPC 50:50) superimposed on a brightfield optical image. Increasing blue–green color is associated with greater concentration of OFLX relative to DPPC. The map sampled a 24 × 24 region using 10 μm stage increments, and a full spectrum was acquired at each point. (B) Extracted spectra from three points (denoted by red, purple, and green-bordered rectangles in [A]) that illustrate the homogeneous distribution of OFLX and DPPC across the mapped region.

Abbreviations: OFLX, ofloxacin; DPPC, dipalmitoylphosphatidylcholine.

Figure 15 Fluorescence microscopy images showing the overall homogeneity of drug distribution in agglomerated particles.

Notes: (A) MOXI:DPPC (25:75); (B) OFLX:DPPC (25:75). Images were obtained using a 20× objective.

Abbreviations: MOXI, moxifloxacin; DPPC, dipalmitoylphosphatidylcholine; OFLX, ofloxacin.

Table 4 Aerosol dispersion performance parameters as aerosolized dry powders of SD and co-SD for MOXI:DPPC including ED, FPF, RF, MMAD, and GSD

SD and co-SD powders	ED (%)	FPF (%)	RF (%)	MMAD (μm)	GSD
MOXI:DPPC = 100:0	92.85 ± 1.76	57.17 ± 1.94	37.48 ± 5.55	5.61 ± 2.15	3.42 ± 0.57
MOXI:DPPC = 75:25	86.35 ± 2.11	66.66 ± 0.79	85.68 ± 1.24	1.76 ± 0.04	1.76 ± 0.02
MOXI:DPPC = 50:50	96.71 ± 0.56	56.64 ± 0.72	46.04 ± 2.11	5.24 ± 0.23	2.61 ± 0.16
MOXI:DPPC = 25:75	94.08 ± 2.88	48.08 ± 2.97	73.36 ± 2.07	3.13 ± 0.35	1.93 ± 0.06
MOXI:DPPC = 0:100	95.85 ± 1.78	57.45 ± 1.26	17.62 ± 0.75	22.55 ± 1.15	4.83 ± 0.08

Notes: Mean ± standard deviation; n = 3.

Abbreviations: SD, spray-dried; co-SD, cospray-dried; MOXI, moxifloxacin; DPPC, dipalmitoylphosphatidylcholine; ED, emitted dose; FPF, fine particle fraction; RF, respirable fraction; MMAD, mass median aerodynamic diameter; GSD, geometric standard deviation; n, number.

Table 5 Aerosol dispersion performance parameters as aerosolized dry powders of SD and co-SD for OFLX:DPPC including ED, FPF, RF, MMAD, and GSD

SD and co-SD powders	ED (%)	FPF (%)	RF (%)	MMAD (μm)	GSD
OFLX:DPPC = 100:0	90.51 ± 8.43	62.59 ± 3.70	39.75 ± 4.38	5.30 ± 1.03	2.85 ± 0.19
OFLX:DPPC = 75:25	96.96 ± 0.76	67.77 ± 0.92	25.25 ± 5.02	13.23 ± 4.97	4.42 ± 0.60
OFLX:DPPC = 50:50	96.52 ± 2.33	59.52 ± 3.89	34.92 ± 6.53	8.52 ± 2.64	3.22 ± 0.35
OFLX:DPPC = 25:75	97.40 ± 0.82	63.35 ± 0.81	17.80 ± 2.44	23.27 ± 5.32	5.14 ± 2.67
OFLX:DPPC = 0:100	95.85 ± 1.78	57.45 ± 1.26	17.62 ± 0.75	22.55 ± 1.58	4.83 ± 0.08

Notes: Mean ± standard deviation; n = 3.

Abbreviations: SD, spray-dried; co-SD, cospray-dried; OFLX, ofloxacin; DPPC, dipalmitoylphosphatidylcholine; ED, emitted dose; FPF, fine particle fraction; RF, respirable fraction; MMAD, mass median aerodynamic diameter; GSD, geometric standard deviation; n, number.

Figure 16 In vitro aerosol dispersion performance as the percent of deposition at each stage of the Next generation Impactor™ at Q = 60 L/minute with the Handihaler® DPI device for dry powder inhalation aerosols.

Notes: (A) SD and co-SD MOXI:DPPC; (B) SD and co-SD OFLX:DPPC.

Abbreviations: MOXI, moxifloxacin; DPPC, dipalmitoylphosphatidylcholine; OFLX, ofloxacin; Q, airflow rate; DPI, dry powder inhaler; SD, spray-dried; co-SD, cospray-dried.