Risperidone mucoadhesive buccal tablets: formulation design, optimization and evaluation

Figures & data

Table 1 Experimental design matrix and corresponding responses

Run	Variables		Responses
	A (CP)	B (SA)	R1 (TH)	R2 (RT)	R3 (DF)
1	20	20	65.2	10	2.15
2	25	15	71.4	11	1.93
3	20	20	64.7	9.5	2.09
4	10	40	48.3	7	2.28
5	20	10	68.6	8.5	0.95
6	30	20	74.1	17	2.29
7	20	30	62.4	11	2.51
8	25	15	72.5	12	1.86
9	13.3	16.7	57.9	5.5	1.54
10	30	10	77.2	14	1.33
11	10	26.7	53.1	6	2.16
12	40	10	81.4	22	1.62
13	10	26.7	52.9	6	2.07
14	10	26.7	52.1	6.5	2.11
15	25	25	67.0	14	2.55
16	30	10	76.5	15	1.37
*	16.4	20.3	46.2	8	1.99

Note:

* Optimized formulation with predicted responses.

Abbreviations: CP, carbopol (%); DF, peak detachment force; RT, ex vivo residence time; SA, sodium alginate (%); TH, tablet hardness.

Table 2 Physical properties of powder mixtures and buccal tablets with different polymer types

Polymer type	CI (%)	HR	AR (°)	FC	WV (mg)	TH (N)	TS (MPa)	FB (%)	RT (h)	DF (N)
CP	19.56	1.23	36.12±1.38	F	100.39±2.32	81.68±3.12	3.71	0.11	18	1.52±0.16
HPMC	20.29	1.25	40.83±1.46	P	100.88±2.90	63.75±4.70	2.89	0.22	10	1.16±0.14
HEC	15.85	1.18	36.90±1.09	F	99.53±2.57	75.86±4.96	3.45	0.36	<0.5	NA
XG	14.86	1.17	35.61±1.12	G	101.21±1.80	32.57±3.54	1.48	0.74	4	0.76±0.06
GG	13.80	1.16	34.68±1.14	G	99.94±1.51	27.94±2.55	1.27	1.15	<0.5	NA
AG	22.82	1.30	40.69±1.75	P	100.34±2.57	60.75±3.50	2.76	0.23	2.5	0.61±0.07
SA	22.81	1.30	41.20±2.10	P	99.71±1.94	34.22±2.58	1.56	0.51	4.5	2.05±0.16
CH	18.28	1.22	38.99±1.18	F	100.55±1.70	37.48±3.06	1.70	0.47	1.5	1.05±0.12
PVP	14.42	1.17	35.55±1.04	F	100.91±1.12	50.51±3.19	2.30	0.18	1	0.98±0.11
*	18.09	1.22	37.15±1.24	F	99.67±2.13	45.52±3.85	2.07	0.14	7.67	2.13±0.17

Note:

* Experimental parameters for optimized formulation.

Abbreviations: AG, acacia gum; AR, angle of repose; CH, chitosan; CI, Carr’s index; CP, carbopol; DF, peak detachment force; F, fair; FB, friability; FC, flow character; G, good; GG, guar gum; HEC, hydroxyethyl cellulose; HPMC, hydroxypropyl methylcellulose; HR, Hausner ratio; NA, not applicable; P, passable; PVP, polyvinylpyrrolidone; RT, ex vivo residence time; SA, sodium alginate; TH, tablet hardness; TS, tensile strength; WV, tablet weight variation; XG, xanthan gum.

Table 3 ANOVA results for response R1

Source	Sum of squares	df	Mean square	F value	p-value
Model	869.30	5	173.86	536.00	<0.0001
A-A	21.81	1	21.81	67.24	<0.0001
B-B	8.89	1	8.89	27.40	0.0004
AB	0.87	1	0.87	2.67	0.1332
A2	5.88	1	5.88	18.14	0.0017
B2	0.44	1	0.44	1.36	0.2703
Residual	3.24	10	0.32
Lack of fit	2.37	5	0.47	2.73	0.1474
Pure error	0.87	5	0.17
Total correlation	872.54	15

Note: R² =0.9963, adjusted R² =0.9944, predicted R² =0.9875.

Abbreviation: ANOVA, analysis of variance.

Table 4 ANOVA results for response R2

Source	Sum of squares	df	Mean square	F value	p-value
Model	314.85	5	62.97	203.93	<0.0001
A-A	36.88	1	36.88	119.43	<0.0001
B-B	2.50	1	2.50	8.11	0.0173
AB	0.12	1	0.12	0.38	0.5500
A2	2.19	1	2.19	7.08	0.0239
B2	0.056	1	0.056	0.18	0.6795
Residual	3.09	10	0.31
Lack of fit	1.80	5	0.36	1.39	0.3632
Pure error	1.29	5	0.26
Total correlation	317.94	15

Note: R² =0.9903, adjusted R² =0.9854, predicted R² =0.9594.

Abbreviation: ANOVA, analysis of variance.

Table 5 ANOVA results for response R3

Source	Sum of squares	df	Mean square	F value	p-value
Model	3.00	5	0.60	146.77	<0.0001
A-A	0.018	1	0.018	4.32	0.0644
B-B	0.12	1	0.12	28.84	0.0003
AB	0.023	1	0.023	5.65	0.0388
A2	0.031	1	0.031	7.58	0.0204
B2	0.30	1	0.30	72.81	<0.0001
Residual	0.041	10	0.0040
Lack of fit	0.032	5	0.0063	3.48	0.0986
Pure error	0.0091	5	0.0018
Total correlation	3.04	15

Note: R² =0.9866, adjusted R² =0.9798, predicted R² =0.9140.

Abbreviation: ANOVA, analysis of variance.

Figure 1 3D response surface plots for (A) R1 (TH), (B) R2 (RT), and (C) R3 (DF) as a function of SA and CP weight ratios (%).

Abbreviations: 3D, three-dimensional; CP, Carbopol; DF, peak detachment force (N); RT, ex vivo residence time (h); SA, sodium alginate; TH, tablet hardness (N).

Figure 2 FT-IR spectra of RIS, CP, SA, LM, and buccal tablet.

Abbreviations: CP, carbopol; FT-IR, Fourier transform infrared; LM, lactose monohydrate; RIS, risperidone; SA, sodium alginate.

Figure 3 DSC thermograms of RIS, CP, SA, LM, and buccal tablet.

Abbreviations: CP, carbopol; DSC, differential scanning calorimetry; LM, lactose monohydrate; RIS, risperidone; SA, sodium alginate.

Figure 4 (A) In vitro release profile of RIS from buccal tablets. (B) Swelling index profile of buccal tablets. (C) Images of buccal tablets during swelling studies.

Note: All data represent the mean ± SD (n=3).

Table 6 In vitro release kinetics of RIS from optimized buccal tablets

Model	Kinetic constant	R^2
Zero-order	11.33 (k0)	0.9937
First-order	0.303 (k1)	0.9503
Higuchi	37.80 (kH)	0.9839
Hixson–Crowell	0.322 (kHC)	0.9865
Korsmeyer–Peppas	0.77 (n)	0.9970
Release-order	Anomalous (non-Fickian)

Abbreviations: k₀, zero-order release constant (mg%/h); k₁, first-order release constant (h⁻¹); k_H, Higuchi release constant (mg%/h^1/2); k_HC, Hixson–Crowell release constant (mg%/h^1/2); n, release exponent; R², determination coefficient; RIS, risperidone.