Effect of particle size on solubility, dissolution rate, and oral bioavailability: evaluation using coenzyme Q₁₀ as naked nanocrystals

Figures & data

Figure 1 Suspensions of bulk drugs and naked coenzyme Q₁₀ nanocrystals of different sizes after storage for 2 days at room temperature.

Notes: From left to right: bulk drugs, nanocrystals of 80 nm, 120 nm, 400 nm, and 700 nm, respectively. The drug content of all five formulations was about 1 mg/mL.

Table 1 Particle size, polydispersity index, and zeta potential of coenzyme Q₁₀ nanocrystals (n = 4)

Formulation	Particle size (nm)	PI	Zeta potential (mV)
A	80.6 ± 4.3	0.042 ± 0.023	−32.20 ± 0.36
B	122.2 ± 10.5	0.156 ± 0.005	−31.29 ± 0.24
C	391.6 ± 14.3	0.238 ± 0.085	−16.98 ± 0.27
D	680.1 ± 63.1	0.181 ± 0.069	−5.58 ± 1.46

Abbreviation: PI, polydispersity index.

Figure 2 Physical stability of the suspensions of naked coenzyme Q₁₀ nanocrystals at room temperature (n = 3).

Figure 3 Transmission electron micrographs of coenzyme Q₁₀ nanocrystals with particle sizes of (A) 80 nm, (B) 120 nm, (C) 400 nm, and (D) 700 nm.

Note: Bar = 500 nm.

Figure 4 Differential scanning calorimetry patterns of suspensions of coenzyme Q₁₀ nanocrystals of different sizes and coarse suspensions.

Notes: (A) Coarse suspensions; (B) 80 nm, (C) 120 nm, (D) 400 nm, (E) 700 nm; (F) coarse suspensions after storage for 4 hours; (G) 50-fold concentrated 120 nm nanocrystal suspensions.

Figure 5 Differential scanning calorimetry patterns of dried suspensions of coenzyme Q₁₀ nanocrystals of different sizes and coarse suspensions.

Notes: (A) Coarse suspensions; (B) 80 nm, (C) 120 nm, (D) 400 nm, (E) 700 nm; (F) 50-fold concentrated 120 nm nanocrystal suspensions.

Figure 6 Kinetic solubility of coenzyme Q₁₀ at different drug contents ranging from about 0.03 mg/mL to 0.33 mg/mL.

Notes: Results are expressed as the mean ± standard deviation of three replicates. ● = 0.03 mg/mL; ♦ = 0.10 mg/mL; ▲ = 0.17 mg/mL; ♦ = 0.33 mg/mL. Solid line: placed horizontally; dotted line: placed vertically.

Figure 7 Kinetic solubility of coenzyme Q₁₀ nanocrystals and bulk drugs from the suspensions in three types of dissolution medium. Experiments were performed at 100 rpm and 25°C, and samples were placed horizontally for agitation. The drug content was about 0.33 mg/mL in every case. The results are expressed as the mean ± standard deviation of three replicates. (A) Distilled water containing 1.3% w/v Tween 20, (B) distilled water containing 1.3% w/v Tween 20 and 5.0% v/v isopropanol, and (C) distilled water containing 1.3% w/v Tween 20 and 10.0% v/v isopropanol.

Notes: Solid bar: passed through a three-layer membrane filter (the pore size from the top to bottom layer being 0.1 μm, 0.05 μm, and 0.1 μm); dashed bar: passed through a one-layer 0.05 μm Millipore filter.

Figure 8 Solubilization model of nanocrystals and bulk drugs. (A) Solubilization process; (B) solubilization curves.

Table 2 Size and size distribution of different coenzyme Q₁₀ nanocrystals after dissolution in three types of dissolution medium for different predetermined times*

Medium	Day	80 nm		120 nm		400 nm		700 nm
		Size (nm)	PI	Size (nm)	PI	Size (nm)	PI	Size (nm)	PI
	0	78.8 ± 0.8	0.05 ± 0.02	134.2 ± 0.9	0.08 ± 0.00	376.9 ± 2.0	0.15 ± 0.00	698.7 ± 2.4	0.23 ± 0.01
A	1	81.1 ± 3.7	0.07 ± 0.00	144.9 ± 4.8	0.06 ± 0.00	322.9 ± 4.4	0.18 ± 0.00	667.2 ± 5.1	0.23 ± 0.00
	3	146.7 ± 22.8	0.08 ± 0.01	139.7 ± 9.3	0.05 ± 0.01	330.4 ± 17.0	0.16 ± 0.00	657.8 ± 22.9	0.24 ± 0.01
	30	x	x	x	x	506.8 ± 87.0	0.43 ± 0.06	648.8 ± 66.3	0.26 ± 0.03
B	1	104.4 ± 18.5	0.27 ± 0.09	189.6 ± 13.0	0.21 ± 0.04	385.4 ± 1.2	0.07 ± 0.01	688.4 ± 17.3	0.10 ± 0.01
	3	312.8 ± 74.4	0.39 ± 0.05	198.0 ± 43.0	0.30 ± 0.04	384.4 ± 39.2	0.18 ± 0.01	706.1 ± 79.8	0.24 ± 0.02
	30	x	x	x	x	x	x	763.7 ± 131.1	0.40 ± 0.10
C	1	x	x	x	x	459.7 ± 38.2	0.08 ± 0.01	745.5 ± 83.2	0.22 ± 0.04
	3	x	x	x	x	620.1 ± 127.3	0.46 ± 0.08	924.4 ± 139.7	0.49 ± 0.19
	30	x	x	x	x	x	x	x	x

Notes:

* All data were obtained from three experiments and expressed as the mean ± standard deviation. x represents large visible particles which aggregated into very large bundles and subsequently sedimented.

Abbreviation: PI, polydispersity index.

Figure 9 Dissolution profiles of coenzyme Q₁₀ nanocrystals and bulk drugs from the suspensions in three types of dissolution medium. (A) Distilled water containing 1.3% w/v Tween 20, (B) distilled water containing 1.3% w/v Tween 20 and 5.0% v/v isopropanol, and (C) distilled water containing 1.3% w/v Tween 20 and 10.0% v/v isopropanol.

Notes: The dissolution study was performed at 100 rpm and 25°C. About 0.6 mg of coenzyme Q₁₀ was used in 900 mL of dissolution medium. The results are expressed as the mean ± standard deviation of three replicates. ● = 80 nm; ○ = 120 nm; ▲ = 400 nm; △ = 700 nm; ■ = bulk drugs.

Table 3 Pharmacokinetic parameters obtained after oral administration of different coenzyme Q₁₀ nanocrystal suspensions, coarse suspensions, and capsules (n ≥ 4)a

Formulation	Tmax (hours)	Cmax (μg/mL)	AUC0–48 (μg h/mL)
80 nm	3.25 ± 0.50*	1.19 ± 0.18**	17.52 ± 1.55***
120 nm	4.86 ± 3.34*	0.64 ± 0.24**	12.18 ± 5.47**
400 nm	5.60 ± 1.67*	0.55 ± 0.09***	11.25 ± 1.16***
700 nm	6.00 ± 3.58	0.50 ± 0.06***	10.53 ± 1.79***
Coarse suspension	19.50 ± 9.00	0.11 ± 0.01	2.40 ± 0.74
Capsules	19.60 ± 12.52	0.13 ± 0.03	2.56 ± 0.63

Notes:

a Results are expressed as the mean ± standard deviation.

* P < 0.05,

** P < 0.01, and

*** P < 0.001 compared with the corresponding parameters of coarse suspensions.

Abbreviations: T_max, time taken to reach peak plasma concentration; C_max, peak plasma concentration; AUC, area under the concentration-time curve.

Figure 10 Serum concentration–time profiles of coenzyme Q₁₀ after oral administration of different suspensions and capsules at doses of 60 mg/body in beagle dogs.

Notes: Results are expressed as the mean, with the bars showing the standard deviation values. ● = 80 nm nanocrystal suspensions; ○ = 120 nm nanocrystal suspensions; ▲ = 400 nm nanocrystal suspensions; △ = 700 nm nanocrystal suspensions; ■ = capsules; □ = coarse suspensions (n ≥ 4).