Rifampicin-Carbohydrate Spray-Dried Nanocomposite: A Futuristic Multiparticulate Platform For Pulmonary Delivery

Figures & data

Table 1 Composition, Yield, And Drug Content Of Spray-Dried Rifampicin Nanocomposites

Formula	Carrier/Nanosuspension (w/w) Ratio			Yield* % w/w	Drug Content* % w/w
	Mannitol	Maltodextrin	Leucine
F1	4	–	–	44.80±3.13	90.4±1.71
F2	3	–	1	61.24±2.67	96.3±3.24
F3	2	–	2	66.65±3.35	92.6±2.06
F4	–	4	–	71.40±1.51	89.3±4.04
F5	–	3	1	79.84±2.84	91.3±4.03
F6	2	1	1	73.05±3.34	98.3±0.75
F7	1	2	1	86.67±2.08	99.2±3.32

Note: *Mean±SD (n=3).

Figure 1 Scanning electron microscope (SEM) micrograph of raw rifampicin (A), spray-dried nanosuspension (B) and selected spray-dried rifampicin nanocomposites powders F₁ (C), F₄ (D), F₂ (E), F₅ (F), F₇ (G) and F₇ at higher magnification (H).

Table 2 Particle Size Distribution And Surface Area Of Spray-Dried Rifampicin Nanocomposites

Formula	Dv(10%) (µm)	Dv(50%) (µm)	Dv(90%) (µm)	Span Index	Surface Area (m^2/g)
NS	11.3±2.95	22.9±3.20	41.12±2.09	1.30±0.201	–
F1	1.22±0.12	5.12±0.13	10.53±1.42	1.81±0.230	2.169
F2	1.83±0.12	3.47±0.42	09.73±1.56	2.28±0.209	3.105
F3	2.35±0.17	6.80±0.71	13.00±0.79	1.57±0.071	3.997
F4	1.51±0.11	6.25±0.31	13.68±1.02	1.95±0.104	1.343
F5	1.21±0.07	4.35±0.52	11.61±1.44	2.39±0.058	2.942
F6	1.95±0.35	4.77±1.03	10.42±1.18	1.80±0.206	3.089
F7	1.58±0.23	3.85±0.77	09.06±0.47	1.94±0.512	3.065

Note: Data are presented as mean±SD (n=3).

Table 3 Physiochemical Characteristics Of Reconstituted Spray-Dried Rifampicin Nanocomposites

Formula	Particle Size* (d-nm)	Particle Distribution Index*	Redispersibility Index*	Zeta Potential* (mV)
NS	473.5±15.8	0.598±0.03	4.7±0.16	−8.77±1.66
F1	111.2±2.97	0.483±0.04	1.1±0.03	−21.4±2.19
F2	123.9±3.95	0.552±0.05	1.2±0.04	−20.2±1.77
F3	208.1±2.72	0.532±0.06	2.0±0.04	−18.8±1.06
F4	221.0±3.46	0.319±0.01	2.2±0.03	−20.0±1.41
F5	277.7±3.21	0.440±0.07	2.7±0.03	−19.4±0.85
F6	147.5±4.16	0.462±0.05	1.5±0.04	−19.6±1.08
F7	177.6±2.72	0.479±0.03	1.7±0.04	−21.4±2.05

Note: *Mean±SD (n=3).

Table 4 Flow Features Of Spray-Dried Rifampicin Nanocomposites

Formula	Angle Of Repose*	Bulk Density* (g/cm^3)	Tapped Density* (g/cm^3)	Carr’s Index* (%)	Hausner Ratio*
NS	60.17±4.05	0.089±0.005	0.160±0.008	44.38±5.39	1.79±0.16
F1	41.80±1.09	0.129±0.003	0.178±0.007	27.53±2.09	1.38±0.04
F2	32.63±2.03	0.145±0.004	0.177±0.003	18.08±1.03	1.22±0.02
F3	36.24±2.18	0.149±0.008	0.194±0.003	23.19±3.87	1.30±0.07
F4	48.10±3.15	0.103±0.006	0.154±0.007	33.12±3.18	1.49±0.13
F5	37.58±1.19	0.172±0.004	0.227±0.009	24.23±4.04	1.32±0.07
F6	34.06±1.63	0.161±0.008	0.199±0.004	19.09±3.14	1.23±0.05
F7	31.83±2.93	0.151±0.008	0.183±0.005	17.49±3.87	1.21±0.04

Note: *Mean ± SD (n=3).

Figure 2 In-vitro dissolution profiles of different spray-dried rifampicin nanocomposites powders and crude rifampicin in PBS pH 7.4 at 37±2°C (mean±SD n=3).

Figure 3 In-vitro dissolution parameters; dissolution efficiency, %DE at 10 min and mean dissolution time, MDT of spray-dried rifampicin nanocomposites prepared with different matrix formers and raw rifampicin powder (mean±SD n=3).

Table 5 Aerosol Dispersion Performance Parameters Of Spray-Dried Rifampicin Nanocomposites

Formula	Aerosol Dispersion Performance Parameters
	Calculated dae* µm	EF* % w/w	RF* % w/w	EI* % w/w
NS	9.17±1.45	60.70±3.04	19.03± 4.33	25.72±3.29
F1	2.16±0.09	81.14±2.43	49.91± 2.49	57.39±3.44
F2	1.46±0.18	90.46±1.05	59.90±4.98	70.04±4.20
F3	2.99±0.29	85.20±4.26	53.01±3.71	60.53±3.03
F4	2.45±0.08	78.42±2.35	40.12±3.61	49.70±3.97
F5	2.07±0.21	82.69±1.65	57.19±4.57	62.54±2.50
F6	2.13±0.44	89.01±3.56	58.52±2.34	68.10±4.41
F7	1.65±0.32	95.22±1.90	65.41±2.62	77.93±3.17

Notes: *D_ae, aerodynamic diameter. Mean±SD (n =3).

Abbreviations: EF, emitted fraction; RF, respirable fraction; EI, effective inhalation index.

Figure 4 Effect of the flow properties on the inhalation indices of spray-dried rifampicin nanocomposites, namely emitted fraction (%EF) and respirable fraction (%RF), mean±SD (n=3).

Figure 5 In-vitro deposition data of rifampicin-loaded spray-dried nanocomposites powders determined using a twin stage impinger. Aerolizer^® (DPI) was used to deliver the dose into the various parts of the TSI operated at a flow rate of 60 L/min, mean±SD (n=3).

Figure 6 DSC thermograms of rifampicin-loaded spray-dried nanocomposites powder with its individual components, rifampicin (A), maltodextrin (B), leucine (C), mannitol (D), physical mixture (E) and formula F₇ (F).

Figure 7 FTIR spectra of rifampicin-loaded spray-dried nanocomposites powder (F₇) with its individual components, rifampicin (A), physical mixture (B), mannitol (C), maltodextrin (D), leucine (E) and formula F₇ (F).

Figure 8 X-ray powder diffraction patterns of rifampicin (A), leucine (B), mannitol (C), maltodextrin (D), spray-dried rifampicin nanosuspensions (NS) (E), physical mixture (F) and spray-dried RIF nanocomposites (F₇) (G).

Figure 9 Percentage of viability of A549 cells measured by the MTT cytotoxicity assay after exposure for 24 hrs to various concentrations of free rifampicin, rifampicin nanosuspensions and spray-dried rifampicin nanocomposites (F₂, F₅, F₆, F₇) at 37±0.5°C, mean±SD (n=3).

Table 6 Stability Study Of Spray-Dried Rifampicin Nanocomposites (F₇) Stored At Room Temperature (25±2°C) For 6 Months

Time (Month)	DC (%)	z-Average (d-nm)	PdI	ZP (mV)	tap (g/cm^3)	Dv(50%) (µm)	dae (µm)
0	99.2±3.32	177.6±2.723	0.479±0.030	− 21.4±2.05	0.183±0.005	3.85±0.77	1.65±0.32
6	97.4±0.54	177.9±4.711	0.474±0.027	− 20.1±0.42	0.185±0.009	3.81±0.73	1.64±0.30

Note: Data are presented as mean± SD (n=3).

Abbreviations: DC, drug content; PdI, particle distribution index; ZP, Zeta potential; _tap,tapped density; d_ae, aerodynamic diameter.