A new strategy for taste masking of azithromycin antibiotic: development, characterization, and evaluation of azithromycin titanium nanohybrid for masking of bitter taste using physisorption and panel testing studies

Figures & data

Figure 1 Chemical structure of azithromycin.

Table 1 Sequential method for the selection of trainee volunteers

Test no	Taste code	G-1					G-2					G-3					G-4					G-5
		1	2	3	4	5	1	2	3	4	5	1	2	3	4	5	1	2	3	4	5	1	2	3	4	5
1	0	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓
	1	✗	✓	✗	✓	✓	✓	✗	✓	✓	✗	✓	✗	✓	✓	✓	✓	✗	✓	✓	✓	✓	✓	✗	✓	✓
	2	✓	✗	✗	✓	✗	✓	✓	✗	✗	✓	✗	✓	✓	✓	✓	✓	✓	✓	✓	✗	✗	✓	✗	✗	✓
	3	✓	✗	✗	✓	✓	✓	✗	✓	✓	✗	✗	✗	✓	✓	✗	✓	✗	✓	✗	✓	✗	✓	✗	✓	✓
	4	✓	✓	✗	✓	✓	✓	✗	✓	✓	✗	✓	✓	✓	✓	✓	✓	✗	✓	✓	✗	✗	✓	✓	✓	✗
2	0	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓
	1	✓	✓	✗	✓	✓	✓	✗	✓	✓	✓	✓	✓	✓	✗	✓	✓	✓	✓	✓	✗	✓	✓	✓	✓	✓
	2	✓	✗	✓	✓	✓	✗	✓	✓	✓	✗	✓	✗	✗	✓	✗	✓	✗	✓	✓	✓	✗	✓	✗	✓	✗
	3	✗	✗	✗	✓	✗	✓	✗	✓	✗	✗	✓	✗	✓	✓	✓	✗	✗	✓	✓	✗	✗	✓	✗	✓	✓
	4	✓	✓	✓	✗	✓	✓	✓	✓	✓	✓	✓	✗	✓	✓	✓	✓	✓	✓	✓	✗	✓	✓	✓	✓	✓
3	0	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓
	1	✓	✓	✗	✓	✓	✓	✗	✓	✓	✓	✓	✗	✓	✓	✓	✓	✓	✓	✓	✗	✗	✓	✗	✓	✓
	2	✗	✗	✓	✓	✗	✓	✗	✓	✓	✗	✓	✗	✓	✗	✓	✓	✗	✗	✓	✗	✗	✓	✗	✓	✓
	3	✓	✓	✗	✓	✓	✓	✓	✓	✓	✗	✓	✗	✓	✓	✓	✓	✗	✓	✓	✗	✓	✓	✓	✗	✓
	4	✓	✗	✓	✓	✓	✓	✗	✓	✓	✗	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓
Score out of 15		12	9	7	14	12	14	7	14	13	7	13	7	14	13	13	14	8	14	14	7	8	15	8	13		13
A/R		A	R	R	A	A	A	R	A	A	R	R	R	A	A	A	A	R	A	A	R	R	A	R	A		A

Notes: 0, tasteless; 1, very slightly bitter; 2, bitter; 3, very bitter; 4, intense bitter.

Abbreviations: A, approved; R, rejected.

Table 2 Preparation of AZNs

Formulation code	Quantity of AZ (2% w/v)	Titanium dioxide nanosuspension (0.25% w/v)	Theoretical wt of AZ+TNP (mg)	Theoretical drug loading (%)	Experimental drug loading (%)	Adsorption efficiency (%)
AZN-1	10 mL (200 mg)	1 mL (2.5 mg)	202.50	98.76	85.3±1.2	86.37±2.2
AZN-2	10 mL (200 mg)	1.5 mL (3.75 mg)	203.75	98.15	85.7±1.6	87.31±1.5
AZN-3	10 mL (200 mg)	2 mL (5 mg)	205.00	97.56	86.2±1.3	88.35±2.0
AZN-4	10 mL (200 mg)	2.5 mL (6.25 mg)	206.25	96.96	87.5±1.2	90.24±1.6
AZN-5	10 mL (200 mg)	3 mL (7.5 mg)	207.50	96.38	88.6±1.7	91.92±1.8
AZN-6	10 mL (200 mg)	3.5 mL (8.75 mg)	208.75	95.80	89.7±1.4	93.63±2.2
AZN-7	10 mL (200 mg)	4 mL (10 mg)	210.00	95.23	93.6±1.3	98.28±1.3
AZN-8	10 mL (200 mg)	4.5 mL (11.25 mg)	211.25	94.67	91.8±1.3	96.96±2.3
AZN-9	10 mL (200 mg)	5 mL (12.5 mg)	212.5	94.11	88.5±1.5	94.03±2.5
AZN-10	10 mL (200 mg)	5.5 mL (13.75 mg)	213.75	93.56	88.0±1.3	94.05±2.4

Abbreviations: AZ, azithromycin; AZNs, azithromycin nanohybrids; TNP, Titanium dioxide nanoparticle.

Figure 2 (A) Scanning electron micrographs of unprocessed azithromycin, (B) titanium dioxide nanoparticles, and (C) azithromycin nanohybrid.

Figure 3 Langmuir adsorption isotherm of AZ and TNP equilibrium.

Abbreviations: AZ, azithromycin; TNP, titanium dioxide nanoparticles.

Figure 4 (A) Fourier-transformed infrared spectrum of unprocessed azithromycin, (B) azithromycin nanohybrid, and (C) titanium dioxide nanoparticles.

Abbreviations: AZN, azithromycin nanohybrids; TNP, titanium dioxide nanoparticle.

Figure 5 EDX of azithromycin nanohybrid.

Abbreviation: EDX, energy-dispersive X-ray.

Figure 6 (A) X-ray powder diffraction pattern of TNP, (B) AZ unprocessed, (C) AZN.

Abbreviations: AZ, azithromycin; AZN, azithromycin nanohybrids; TNPs, titanium dioxide nanoparticles.

Figure 7 (A) Dissolution rate of formulations (F1–F5) and AZN at pH 7.4. (B) Dissolution rate of formulations (F6–F10) and AZN. (C) Comparative dissolution rate of optimized formulation (F6), marketed drug, AZN, and unprocessed AZ at pH 7.4. (D) Comparative dissolution rate of unprocessed AZ, AZN, standard (marketed) AZN, and optimized formulation (F6) at saliva pH.

Abbreviations: AZ, azithromycin; AZN, azithromycin nanohybrids.

Table 3 Formulation of AZN

Ingredient	Dry suspension final formulation codes and strength (g/15 mL)
	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10
(AZN-7)≅AZ	0.6	0.6	0.6	0.6	0.6	0.6	0.6	0.6	0.6	0.60
Tribasic sodium phosphate	0.03	0.03	0.03	0.03	0.045	0.045	0.045	0.060	0.060	0.060
Sodium benzoate	0.03	0.03	0.04	0.04	0.055	0.055	0.055	0.060	0.065	0.070
Colloidal silicon dioxide	0.03	0.04	0.05	0.06	0.070	0.080	0.09	0.10	0.11	0.12
Xanthan gum	0.0025	0.0035	0.0045	0.0055	0.0065	0.0075	0.0085	0.0095	0.010	0.015
Methyl paraben	0.002	0.002	0.002	0.002	0.002	0.002	0.002	0.002	0.002	0.002
Propyl paraben	0.001	0.001	0.001	0.001	0.001	0.001	0.001	0.001	0.001	0.001
HPMC	0.0005	0.0005	0.0006	0.0006	0.0007	0.0007	0.0008	0.0008	0.0009	0.0009

Abbreviations: AZ, azithromycin; AZN, azithromycin nanohybrids; HPMC, hydroxy propyl methyl cellulose.

Table 4 Physicochemical stability of azithromycin as dry suspension (F6)

	Day 0	Day 2	Day 4	Day 6	Day 8	Day 10	Day 12	Day 14
% active content	99.68	98.94	97.98	97.42	96.77	95.98	95.14	94.18
Viscosity (mPa s)	310.6	310.6	310.6	310.5	310.5	310.4	310.4	310.2
pH	8.0	8.0	8.0	8.0	8.0	8.0	7.9	7.9
Redispersion	Good	Good	Good	Good	Good	Good	Good	Good
Taste	Palatable	Palatable	Palatable	Palatable	Palatable	Palatable	Palatable	Palatable

Table 5 Panel testing for taste evaluation of various formulations

Formulation code	Group 1			Group 2			Group 3			Group 4			Group 5
F1	0	1	2	1	0	1	1	1	1	1	2	0	1	1	1
F2	1	0	1	2	1	0		1	0	1	1	1	2	1	0
F3	0	1	1	0	1	1	0	1	2	1	0	1	1	0	0
F4	1	0	1	0	1	1	0	0	2	1	1	0	1	0	1
F5	0	0	1	2	0	1	1	0	1	1	0	1	0	1	0
F6	0	0	0	1	0	0	0	0	0	0	0	0	0	1	0
F7	0	0	0	1	0	0	0	0	0	1	1	0	0	1	0
F8	1	0	0	0	2	0	1	0	1	1	0	1	0	1	0
F9	0	1	0	1	0	1	0	0	1	0	1	0	1	0	0
F10	1	0	0	1	0	1	0	1	1	0	1	0	2	1	0

Note: Taste code: 0, palatable; 1, very slightly bitter; 2, bitter after taste; 3, bitter.

Table 6 Stability study of optimized formulation (F6) after reconstitution kept at 8°C–15°C

Tests	Time period
	Day 0	Day 30	Day 60	Day 90
Assay (active content)	99.67±1.25	99.63±1.50	99.58±0.68	99.56±0.82
Viscosity (mPa s)	310.6	310.6	310.4	310.5
pH	8.0	8.0	8.0	7.9
Powder flow	Good	Good	Good	Good
Dispersion	Good	Good	Good	Good

Note: Values of active contents are expressed as %±SD; n=3.