Dexibuprofen nanocrystals with improved therapeutic performance: fabrication, characterization, in silico modeling, and in vivo evaluation

Figures & data

Figure 1 Chemical structure of dexibuprofen.

Figure 2 Graphical abstract showing nanocrystals formation and their interaction with polymers.

Note: ***Outstanding significant.

Abbreviation: MD, molecular dynamics.

Table 1 Particle sizes and PDI values for Dexi nanocrystals produced using different polymer combinations

S No	Polymer–Dexi complexes	Particle size (nm) ± SD	PDI ± SD
1	PVP–Dexi	280.0±3.5	0.31±0.03
2	PVA–Dexi	450.0±2.5	0.42±0.04
3	HPMC–Dexi	350.0±3.0	0.40±0.03
4	EUD–Dexi	330.0±4.0	0.28±0.05
5	PVP–PVA–Dexi	150.0±2.0	0.21±0.03
6	HPMC–PVP–Dexi	85.0±2.5	0.17±0.01
7	HPMC–PVA–Dexi	310.0±4.5	0.45±0.02
8	HPMC–EUD–Dexi	90.0±3.0	0.18±0.02
9	PVP–EUD–Dexi	165.0±5.0	0.30±0.04
10	PVA–EUD–Dexi	320.0±6.0	0.23±0.05

Abbreviations: Dexi, dexibuprofen; EUD, Eudragit; HPMC, hydroxypropyl methyl cellulose; PDI, polydispersity index; PVP, polyvinyl pyrrolidone; PVA, polyvinyl alcohol.

Figure 3 Particle size measurements of Dexi–HPMC–polyvinyl pyrrolidone (A) and Dexi–HPMC–Eudragit (B) nanocrystals.

Abbreviations: Dexi, dexibuprofen; HPMC, hydroxypropyl methyl cellulose.

Figure 4 Scanning electron microscopy micrographs for unprocessed Dexi (A) and transmission electron microscopy images of Dexi nanocrystals (B).

Abbreviation: Dexi, dexibuprofen.

Figure 5 Differential scanning calorimetry thermograms of polyvinyl pyrrolidone K-30 (A), unprocessed Dexi (B), Dexi nanocrystals (C), Eudragit RS100 (D), and hydroxypropyl methyl cellulose (E).

Abbreviation: Dexi, dexibuprofen.

Figure 6 Powder X-ray diffraction diffractograms of Dexi nanocrystals, unprocessed Dexi, and chosen polymers.

Abbreviations: Dexi, dexibuprofen; EUD, Eudragit; HPMC, hydroxypropyl methyl cellulose.

Figure 7 Fourier transform infrared spectra of hydroxypropyl methyl cellulose (A), unprocessed Dexi (B), Dexi nanocrystals (C), polyvinyl pyrrolidone K-30 (D), and Eudragit RS100 (E).

Abbreviation: Dexi, dexibuprofen.

Figure 8 Solubility studies of Dexi nanocrystals, unprocessed Dexi in pure water and stabilizer solutions.

Abbreviations: Dexi, dexibuprofen; EUD, Eudragit; HPMC, hydroxypropyl methyl cellulose; PVP, polyvinyl pyrrolidone.

Table 2 The binding energies for Dexi–polymer complexes obtained from docking calculations

S No	Polymer	ΔGbinding (kcal/mol)
1	PVP	−3.9
2	PVA	−2.3
3	HPMC	−3.1
4	EUD	−3.2
5	PVP–PVA	−4.3
6	HPMC–PVP	−4.7
7	HPMC–PVA	−3.4
8	HPMC–EUD	−4.6
9	EUD–PVP	−4.1
10	EUD–PVA	−3.5

Abbreviations: Dexi, dexibuprofen; EUD, Eudragit; HPMC, hydroxypropyl methyl cellulose; PVP, polyvinyl pyrrolidone; PVA, polyvinyl alcohol.

Figure 9 Interactions of HPMC–Dexi (top) and HPMC–PVP–Dexi (bottom) complexes showing hydrogen bonding as black lines.

Note: (A) Hydrophobic interactions between the drug and the PVP side chains may have contributed to the enhanced binding, (B) molecular surface of the polymers is displayed according to polarity.

Abbreviations: Dexi, dexibuprofen; HPMC, hydroxypropyl methyl cellulose; PVP, polyvinyl pyrrolidone.

Figure 10 Interactions of EUD–Dexi (top) and HPMC–EUD–Dexi (bottom) complexes showing hydrogen bonding as black lines.

Note: (A) Enhanced binding might be due to hydrogen bonding formation with both polymeric units, (B) molecular surface of the polymers is displayed according to polarity.

Abbreviations: Dexi, dexibuprofen; EUD, Eudragit; HPMC, hydroxypropyl methyl cellulose.

Figure 11 Comparative dissolution studies of Dexi nanocrystals and its counterparts including tablets, microsuspension, and raw Dexi.

Abbreviations: Dexi, dexibuprofen; EUD, Eudragit; HPMC, hydroxypropyl methyl cellulose.

Table 3 Monitoring of particle size measurements of Dexi nanocrystals for 90 days at 25°C

Dexi–polymer complexes	Average particle sizes of Dexi nanocrystals ± SD
	Day 0	Day 15	Day 30	Day 45	Day 60	Day 75	Day 90
PVP–Dexi	280.0±2.0	291±3.5	300±4.5	312±3.0	321±4.5	330±3.8	343±3.7
PVA–Dexi	450.0±2.5	468±2.0	485±3.5	502±4.0	512±4.2	530±3.5	565±3.8
HPMC–Dexi	350.0±3.0	362±4.0	372±3.0	383±3.0	392±4.0	410±3.7	422±3.0
EUD–Dexi	330.0±4.0	340±3.0	348±2.7	356±3.2	367±2.4	380±3.5	392±2.8
PVP–PVA–Dexi	150.0±2.0	160±3.7	170±3.5	176±3.7	182±2.5	187±2.0	192±3.0
HPMC–PVP–Dexi	85.0±2.5	87.0±2.0	90±2.7	92±2.0	93±3.0	95±3.5	96±2.5
HPMC–PVA–Dexi	310.0±4.5	318±2.4	326±3.5	335±3.0	347±2.4	355±3.6	364±3.0
HPMC–EUD–Dexi	90.0±3.0	93±2.0	96±2.5	99±3.0	102±2.0	105±2.5	106±2.3
PVP–EUD–Dexi	165.0±2.8	176±2.5	188±2.0	196±2.4	205±3.0	212±2.7	220±2.5
PVA–EUD–Dexi	320.0±2.0	328±2.8	337±3.5	350±3.0	358±3.7	367±3.0	374±3.2

Abbreviations: Dexi, dexibuprofen; EUD, Eudragit; HPMC, hydroxypropyl methyl cellulose; PVP, polyvinyl pyrrolidone; PVA, polyvinyl alcohol.

Figure 12 Comparative physical stability studies of Dexi nanocrystals as a function of time while monitoring the particle sizes and PDI values at 2°C–8°C (A), 25°C (B), and 40°C (C).

Abbreviation: Dexi, dexibuprofen.

Figure 13 Comparative antinociceptive effect of Dexi nanocrystals and unprocessed counterpart at graded doses of 5–15 mg/kg in the acetic acid-induced abdominal constriction assay.

Notes: Data presented as mean ± standard error of the mean. ***P<0.001 as compared to saline-treated group. No significant difference was observed between Dexi (40 mg/kg)-treated group and groups treated with Dexi-nano (5, 10, and 15 mg/kg). One-way analysis of variance followed by Tukey’s post hoc multiple comparison test. n=6 mice per group.

Abbreviation: Dexi, dexibuprofen.