Integrating the Quality-by-Design (QbD) Approach in the Development of Febuxostat-loaded Proniosomal Gel for Topical Delivery

Rajeshwar V. Kshirsagar^¹, Sujata R. Rajewar^¹, Shreya S. Kokil^¹, Matte Kasi Viswanadh^², Ramling G. Patrakar^³, Datta Maroti Pawde^⁴()

1School of Pharmacy, Swami Ramanand Teerth Marathwada University, Nanded, Maharashtra, India

2KL College of Pharmacy, Koneru Lakshmaiah Education Foundation Deemed to be University (KLEF), Green Fields, Vaddeswaram, Guntur, India

3Shree Santkrupa College of Pharmacy, Ghogaon, Tal. Karad, Satara, Maharashtra, India

4Department of Pharmaceutical Sciences, Dr. Vishwanath Karad MIT World Peace University, Pune

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Abstract

Febuxostat (FXT) is useful in treating hyperuricemia and chronic gout. However, it has limited bioavailability orally due to its low solubility and short half-life. This results in the need for more frequent and larger doses, increasing the likelihood of adverse effects. Against this background, the current study was established to prepare and optimize an FXT-loaded proniosomal gel using the coacervation-phase separation method. A Quality-by-Design (QbD) methodology was used to ensure the quality of the finished product by assessing how critical process parameters and critical material attributes (CMAs) affected the proniosomal gel’s critical quality attributes. Box–Behnken design was employed to explore the effect of CMAs such as the amount of cholesterol, Span 40, and Span 60 on particle size and entrapment efficiency. The optimized proniosomes had a particle size and percentage entrapment efficiency of 193.7 ± 2.26 nm and 85.3% ± 0.89%, respectively. Scanning electron microscopy was used to examine the surface morphology of the optimized formulation. The developed formulation was also subjected to in vitro drug release and ex vivo permeation studies, which established the efficiency of the prepared proniosomal gel. Stability studies also established the fact that the prepared formulation is stable to variations in temperature for up to 6 months.

Keywords

febuxostat proniosomal gel Quality-by-Design (QbD)drug delivery

References

[1]

B.A. Habib, A.S. Abd El-Samiae, B.M. El-Houssieny, et al. Formulation, characterization, optimization, and in-vivo performance of febuxostat self-nano-emulsifying system loaded sublingual films. Drug Delivery, 2021, 28(1): 1321−1333. https://doi.org/10.1080/10717544.2021.1927247

QTPP Elements		Target	Justification
Dosage form		Proniosomal gel	Elevates permeation into the skin, avoids first-pass metabolism, and also improves bioavailability
Route of administration		Topical	Better patient compliance and reduced systemic side effects
Stability		24 months	The product should have sufficient shelf life
Drug product quality attributes	Particle size	<400 nm	A smaller particle size enhances permeation into the stratum corneum
	PDI	Minimize	Monodisperse particle size distribution
	Zeta potential	>± 30	Decide the stability of the formulation and prevent agglomeration
	Drug content	Maximum (85%–95%)	Impacts safety and efficacy, to fulfill therapeutic requirements
	Entrapment efficiency	Maximum without affecting the required size range	Maximum entrapment of drug supports in enhanced permeation
Critical Quality Attributes		Justification
Particle size		A smaller particle size increases drug penetration into the skin
Particle size distribution		For uniform drug release and distribution of the drug
Entrapment efficiency		Entrapment efficiency affects drug loading; the capture efficiency should be maximal to increase drug loading
Stability		The shelf life of the product depends on its stability; an increase in the stability of the formulation/product increases the product’s shelf life

Critical quality attributes(CQAs)	Material attributes and process parameters
Critical quality attributes(CQAs)	Conc. of cholesterol	Conc. of soya lecithin	Conc. of SPAN 40	Conc. of SPAN 60	Temperature	Organic solvents for dissolution of lipophilic excipients
Particle size	High	Medium	High	High	Medium	Low
PDI	High	Low	High	High	Low	Low
Entrapment efficiency	High	Medium	High	High	Medium	High
Drug release	High	Low	High	High	Low	High

MAs and PPs	Severity (S)	Detectability (D)	Occurrence (O)	RPN score
Concentration of the cholesterol	6	5	6	180
Concentration of soya lecithin	7	5	7	245
Concentration of Span 40	8	7	6	336
Concentration of Span 60	8	7	6	336
Temperature	2	1	2	4
Organic solvents for the dissolution of lipophilic excipients	2	1	1	2

Independent variables (factors)	Levels
Independent variables (factors)	+1.0	0.0	−1.0
X₁: Amount of cholesterol (mg)	150	175	200
X₂: Amount of Span 40 (mg)	300	350	400
X₃: Amount of Span 60 (mg)	300	350	400
Dependent variables (responses)	Target
Y₁: Mean particle size (nm)	Minimize
Y₂: Drug entrapment efficiency (%)	Maximize

Run	Coded values			Real values (mg)
Run	X₁	X₂	X₃	Amount of cholesterol	Amount of Span 40	Amount of Span 60
1	−1.0	−1.0	0.0	150	300	350
2	1.0	1.0	0.0	200	400	350
3	0.0	0.0	0.0	175	350	350
4	0.0	0.0	0.0	175	350	350
5	0.0	−1.0	−1.0	175	300	300
6	−1.0	0.0	1.0	150	350	400
7	0.0	0.0	0.0	175	350	350
8	1.0	−1.0	0.0	200	300	350
9	−1.0	0.0	−1.0	150	350	300
10	−1.0	1.0	0.0	150	400	350
11	0.0	1.0	−1.0	175	400	300
12	0.0	1.0	1.0	175	400	400
13	1.0	0.0	1.0	200	350	400
14	0.0	−1.0	1.0	175	300	400
15	1.0	0.0	−1.0	200	350	300

Run	Coded values			Response values
Run	X₁	X₂	X₃	Mean particle size (nm)	Drug entrapment efficiency
1	−1.0	−1.0	0.0	176	83%
2	1.0	1.0	0.0	397.8	75%
3	0.0	0.0	0.0	275.4	79%
4	0.0	0.0	0.0	221	77%
5	0.0	−1.0	−1.0	235.8	84%
6	−1.0	0.0	1.0	339.8	79%
7	0.0	0.0	0.0	246.9	80%
8	1.0	−1.0	0.0	292.5	82%
9	−1.0	0.0	−1.0	326	81%
10	−1.0	1.0	0.0	421.2	75%
11	0.0	1.0	−1.0	398.2	81%
12	0.0	1.0	1.0	348.1	78%
13	1.0	0.0	1.0	419.9	73%
14	0.0	−1.0	1.0	293.9	77%
15	1.0	0.0	−1.0	314.8	80%
Responses	R²	Adjusted R²	Predicted R²	Standard deviation	Coefficient of variation (%)
Mean particle size	0.505 9	0.467 9	0.372 1	54.95	17.51
DEE	0.593 4	0.525 6	0.305 7	2.15	2.73

Mean particle size
Source	Sum of squares	df	Mean square	F-value	p-value	Significance
Model	40 200.30	1	40 200.30	13.31	0.002 9	Significant
B-Span 40	40 200.30	1	40 200.30	13.31	0.002 9	Significant
Residual	39 257.90	13	3 019.84
Lack of Fit	37 777.10	11	3 434.28	4.64	0.1906	Not significant
Pure Error	1 480.81	2	740.40
Cor Total	79 458.20	14
Drug entrapment efficiency
Source	Sum of squares	df	Mean square	F-value	p-value	Significance
Model	81.25	2	40.62	8.75	0.004 5	Significant
B-Span 40	36.13	1	36.13	7.79	0.016 3	Significant
C-Span 60	45.12	1	45.12	9.72	0.008 9	Significant
Residual	55.68	12	4.64
Lack of Fit	51.02	10	5.10	2.19	0.354 4	Not significant
Pure Error	4.67	2	2.33
Cor Total	136.93	14

Formulation	Storage condition (°C)	Particle size (nm)			Zeta potential (mV)			Physical stability at the end
		0 days	3 months	6 months	0 days	3 months	6 months
Febuxostat-loaded proniosomal gel	25 ± 2	164 ± 29.3	170 ± 6.2	188 ± 20.5	−16±1.21	−13.24 ± 3.13	−11.45 ± 1.13	The formulation remains stable
	40 ± 2	165±18.7	177.31 ± 9.41	193.45 ± 29.2	−15±3.28	−10.77 ± 2.15	−7.06 ± 2.14	The formulation remains stable
	2 –8	164±21.4	173.32 ± 12.19	178.67 ± 8.22	−16± 2.74	−11.68 ± 1.47	−9.70 ± 3.17	The formulation remains stable