Controlled-release carbamazepine matrix granules and tablets comprising lipophilic and hydrophilic components

Figures & data

Table 1.  Composition of CBZ wet granulations comprising lipophilic–hydrophilic matrix components.

Formula code^$	Matrix component’s ratio	Components
		CBZ*	Compritol^®	HPMC**	Avicel^® PH-102
A1	7:2:1	200	280	80	40
A2	6:3:1	200	240	120	40
A3	4:5:1	200	160	200	40
A4	2:7:1	200	80	280	40
A5	1:8:1	200	40	320	40
Control	9:0:1	200	360	—	40

^$ All the formulations prepared into granules and tablet.

* CBZ:matrix ratio was kept constant at 1:2.

** Hydroxypropyl methylcellulose K15M.

Figure 1.  DSC thermograms of pure CBZ, Compritol^®, HPMC, and Avicel^® and of physical and granulated mixture at 7:2:1 Compritol^®:HPMC:Avicel^® weight ratio.

Figure 2.  Infrared spectra of pure CBZ, Compritol^®, HPMC, and Avicel^® and of physical and granulated mixture at 7:2:1 Compritol^®:HPMC:Avicel^® weight ratio.

Figure 3.  % Carbamazepine released from Compritol:HPMC matrix granules (size fraction 710–500 μm).

Table 2.  Fitting of release kinetic models to CBZ release data for wet granulations (size fraction 710–500 μm).

Release model	Formula code
		A1	A2	A3	A4	A5	control^c	Tegretol^®
Zero-order	r**	0.765	0.938	0.767	0.842	0.713	0.665	0.939
	k0	6.531	7.493	8.482	8.472	45.590	5.272	11.88
First-order	r	0.856	0.989	0.843	0.923	0.848	0.889	0.995
	k1	0.146	0.112	0.163	0.144	1.728	0.326	0.427
Higuchi diffusion	r	0.860	0.992	0.859	0.949	0.855	0.815	0.998
	kH	23.69	22.55	24.63	25.72	32.67	19.24	36.6
Korsmeyer-Peppasn^#	r	—	—	—	0.905	0.845	—	0.999
	k^−n	—	—	—	80.31	47.83	—	44.46
		—	—	—	0.447	0.342	—	0.433

* Analyzed by the regression coefficient method.

** Correlation coefficient.

# Release exponent evaluated for < 70% released drug.

^c Matrix composed of Compritol^®:Avicel (9:1).

Best fit in bold.

— Too rapid release to allow calculation for < 70% release.

Table 3.  Mean dissolution time (MDT), dissolution efficiency (%DE) and difference factor (f₁) of release behavior between experimental wet granulations and matrix tablets and reference CBZ.

Formula code	Granules			Tablet
	MDT^# (h)	%DE*	f1**	MDT (h)	%DE	f1
A1	0.6	85.4	34.9	3.10	7.4	89.8
A2	0.8	80.7	26.4	3.34	13.8	81.9
A3	0.63	79.6	26.9	2.70	26.3	65.9
A4	0.6	72.5	13.1	2.60	43.5	44.8
A5	1.0	63.3	4.3	2.44	50.1	34.7
Tegretol				1.91	71.32

# Mean dissolution time (MDT-80%) calculated from equation (5).

* Dissolution efficiency over 7 hr calculated according to equation (6).

** Difference factor calculated according to equation (7).

Figure 4.  % Carbamazepine released from prepared matrix tablets and commercial product Tegretol^®.

Table 4.  Fitting of release kinetic models to Tetretol release data for matrix-tablets.

Formula code	Zero Order		First Order		Higuchi model		Peppas-Sahlin model			n#
	r	k0 (%h^−1)	r	k1 (h^−1)	r	kH (%h^−1/2)	r	kd (%h^−m)	kr (%h^−2m)
A1	0.991	1.63	0.997	0.02	0.989	5.19	0.979	4.78	1.63	0.624
A2	0.995	3.72	0.992	0.04	0.976	11.7	0.997	8.76	2.91	0.846
A3	0.997	6.26	0.994	0.08	0.996	20.3	0.996	7.84	11.87	0.884
A4	0.998	10.9	0.992	0.19	0.992	35.4	0.999	7.71	27.72	1.010
A5	0.996	11.18	0.994	0.22	0.988	36.6	0.987	7.83	28.71	0.938
Experimental control ^C	0.664	5.272	0.889	0.33	0.815	19.24				0.668
Tegretol^®	0.9393	11.88	0.995	0.427	0.998	36.6				0.433

* Analyzed by the regression coefficient method.

# Release exponent evaluated for < 70% released.

^c Matrix composed of Compritol^® 888ATO:Avicel (9:1). k_d and k_r calculated according to equation (4). Best fit in bold.

Figure 5.  Water uptake (swelling %) of compacted matrix-forming components.

Figure 6.  % Carbamazepine released from matrix tablets of increased CBZ loading.