Physicochemical compatibility of fluticasone-17-propionate nebulizer suspension with ipratropium and albuterol nebulizer solutions

Figures & data

Table

Drug	Stationary phase	aMobile phase	Detector setting (nm)	Retention time (min)	Flow rate (mL/min)	rel. SD (%)
						bIntraday	cInterday
Flluticasone-17-propionate	dSpherisorb ODS	Methanol: acetonitrile: ephosphate buffer (50:15:35)	239	9.5	1.0	2.3	1.8
Ipratropium and albuterol	fSTIP Lichrocart	gphosphate buffer: acetonitrile (87.5:12.5)	205 (ipratropium) 280 (albuterol)	10 (ipratropium) 1.4 and 1.8 (albuterol)	1.2	1.5 (ipratropium) 1.7 (albuterol)	1.3 (ipratropium) 3.2 (albuterol)

Notes: ^aEach mobile phase was degassed in an ultrasonic bath.

^b n = 6.

^c For fluticasone-17-propionate n = 7; for ipratropium bromide n = 8; for albuterol sulfate n = 8.

^d Spherisorb ODS column with precolumn, 1.5 μm particle size, 250 mm × 4.6 mm inner diameter, MZ Analysentechnik GmbH, Mainz, Germany.

^e The phosphate buffer was prepared by dissolving 1.15 g monobasic ammonium phosphate in 1000 mL water. pH value was adjusted to 3.5 with 85% H₃PO₄. The buffer was passed through a 0.45-μm filter (millipore, catalogue number FHLC04700, lot: H3SN59888).

^f STIP Lichrocart column with precolumn, 5μm particle size, 125 mm × 4 mm inner diameter, MZ Analysentechnik GmbH, Mainz, Germany.

^g The phosphate buffer was prepared by mixing 875 mL water, 241 μL triethylamine and 660 μL 85% H₃PO₄. pH value was adjusted to 3.35 with KOH 10 mol/L.

Table

		Fluticasone-17-propionate concentration
		% of initial concentration ± rel. SD (%)**		μg/ml (mean)± rel. SD (%)*
		After 5 h	After 25 h	Nominal***	Initially	After 5 h	After 25 h
Control samples	Flutide^® forte in glass containers	99.33 ± 1.47	101.00 ± 1.24	20	20.14 ± 0.59	20.01 ± 0.88	20.35 ± 0.83
	Flutide^® forte in polystyrene containers	n.d.	90.83 ± 1.46	20	17.94 ± 4.74	n.d.	16.30 ± 5.29
Test suspension	Flutide^® forte + Atrovent^® LS + Sultanol^®	100.60 ± 0.10	n.d.	20	20.16 ± 1.21	20.28 ± 1.11	n.d.

Notes: *Concentrations expressed as mean (n = 9) ± relative SD (%) of triplicate determinations of three control samples or test suspensions.

** Drug concentrations in samples taken at time 0 were designated as 100%.

*** Nominal in the injected solution, corresponding to 444 μg/mL in the test suspension.

Table

		Ipratropium bromide concentration
		% of initial concentration ± rel. SD (%)**		μg/ml (mean) ± rel. SD (%)*
		after 5 h	after 25 h	nominal***	initially	after 5 h	after 25 h
Control samples	Atrovent^® LS + Sultanol^® in glass containers	100.06 ± 0.29	100.42 ± 1.22	11.11	11.16 ± 0.21	11.16 ± 0.49	11.20 ± 1.20
	Atrovent^® LS + Sultanol^® in polystyrene containers	n.d.	99.61 ± 0.42	11.11	11.12 ± 0.86	n.d.	11.07 ± 0.60
Test suspension	Flutide^® forte + Atrovent^® LS + Sultanol^®	99.15 ± 0.8	n.d.	11.11	11.11 ± 0.80	11.02 ± 1.29	n.d.

Notes: *Concentrations expressed as mean (n = 9) + relative SD (%) of triplicate determinations of three control samples or test suspensions.

** Drug concentrations in samples taken at time 0 were designated as 100%.

*** Nominal in the injected solution, corresponding to 55.55 μg/mL in the test suspension.

Figure 1 Example of a chromatogram of the HPLC-determination of fluticasone-17-propionate in a diluted sample of the admixture of Flutide^® forte Fertiginhalat “ready to use” 2,0 mg/2 ml with 2,0 ml Atrovent^® LS and 0,5 ml Sultanol^® after 5 h storage at room temperature.

Figure 2 Example of a chromatogram of the simultaneous HPLC-determination of ipratopium and albuterol in a 1:10 diluted sample of the admixture of Flutide^® forte “ready to use” 2.0 mg/2 ml with 2.0 ml Atrovent^® LS and 0.5 ml Sultanol^® after 5 h storage at room temperature.

The peak at retention time ~ 1 minute is designated to excipients in the nebulizable drugs.

Table

		Albuterol sulfate concentration
		% of initial concentration ± rel. SD (%)**		μg/ml (mean) ± rel. SD (%)*
		After 5 h	After 25 h	Nominal***	Initially	After 5 h	After 25 h
Control samples	Atrovent^® LS + Sultanol^® in glass containers	100.14 ± 0.24	100.52 ± 0.84	55.56	55.78 ± 0.37	55.86 ± 0.13	56.07 ± 1.17
	Atrovent^® LS + Sultanol^® in polystyrene containers	n.d.	99.97 ± 0.13	55.56	55.99 ± 1.46	n.d.	55.97 ± 1.37
Test suspension	Flutide^® forte + Atrovent^® LS + Sultanol^®	100.59 ± 0.30	n.d.	55.56	54.63 ± 1.30	54.59 ± 1.08	n.d.

Notes: *Concentrations expressed as mean (n =9) + relative SD (%) of triplicate determinations of three control samples or test suspensions.

** Drug concentrations in samples taken at time 0 were designated as 100%.

*** Nominal in the injected solution, corresponding to 1111 μg/mL in the test suspension.

Table 4 Osmolality and pH values of the pure nebulizer suspension/solutions Flutide^® forte “ready to use”, Atrovent^® LS and Sultanol^® Inhalationslösung (Inhalation solution) and mixtures of these 3 nebulizable drugs, stored under ambient light conditions at room temperature

Nebulizer suspension/solutions	pH	1.5 h after mixing	6 h after mixing	Osmolality (osmol/kg) + rel. SD (%)	1.5 h after mixing	6 h after mixing
Flutide^® forte	6.1	n.a.	n.a.	0.284 ± 0.44 (n = 8)	n.a.	n.a.
Atrovent^® LS	4.0	n.a.	n.a.	0.282 ± 0.47 (n = 6)	n.a.	n.a.
Sultanol^®	4.5	n.a.	n.a.	0.029 ± 0.00 (n = 8)	n.a.	n.a.
Flutide^® forte +
Atrovent^® LS +	n.a.	5.8	5.8	n.a.	0.260 ± 1.95	0.253 ± 1.72
Sultanol^®					(n = 5)	(n = 5)

Abbreviation: na, not available.