EFFECT OF THREE DIFFERENT DIRECT COMPRESSION FILLERS ON THE
RELEASE KINETICS OF DILTIAZEM HYDROCHLORIDE FROM
HYDROPHILIC SWELLABLE MATRICES CONTAINING XANTHAN GUM
Zaw Min Soe1,*, Satit Puttipipatkhachorn2, Somboon Jateleela2, #
1
Master of Science in Pharmacy Program, Department of Manufacturing Pharmacy, Faculty
of Pharmacy, Mahidol University, 447Sri-Ayudhya Road, Bangkok 10400, Thailand
2
Department of Manufacturing Pharmacy, Faculty of Pharmacy, Mahidol University, 447SriAyudhya Road, Bangkok 10400, Thailand
*e-mail: zawminsoe01@gmail.com, #e-mail: somboon.jat@mahidol.ac.th
Abstract
One of the most interesting drug delivery systems is hydrophilic swellable matrix system
which is controlled by polymer swelling, polymer erosion, drug dissolution and/or drug
diffusion. In this study, the effect of three different direct compression fillers on the release
kinetics of diltiazem hydrochloride (DAH) in pH 6.8 phosphate buffer from hydrophilic
matrices containing various mass fractions (mf) of xanthan gum (XG) was investigated using
USP dissolution apparatus 2. Each formulation of 360 mg matrix tablet contained 120 mg
DAH at MF of 0.33; a natural polymer namely XG was used at the mf of 0.15, 0.30, 0.45 or
0.6; and an insoluble filler namely microcrystalline cellulose (MCC) or dibasic calcium
phosphate dihydrate (DCPD or soluble filler namely spray dried lactose (SDL) was used for
the left mf. From analysis of variance (ANOVA, p < 0.01) and multiple comparison test using
least significant difference procedure (LSD, p < 0.01, 2-tailed) for comparing release rates of
DAH from matrices containing each filler, the release rates might be ranked as (1) MCC:
0.15 XG > 0.30 XG ≈ 0.45 XG ≈ 0.60 XG, (2) DCPD: 0.15 XG > 0.30 XG > 0.45 XG > 0.60
XG, and (3) SDL: 0.15 XG ≈ 0.30 XG > 0.45 XG > 0.60 XG whereas the sustaining efficacy
of fillers for drug release might be ranked as MCC > DCPD > SDL at XG mf of 0.15 – 0.45.
Various drug release models were applied to drug release data in order to explain release
mechanisms and kinetics.
Keywords: dibasic calcium phosphate dihydrate, diltiazem hydrochloride, microcrystalline
cellulose, spray dried lactose, hydrophilic swellable matrix
Introduction
DAH is a calcium channel blocker widely used for the treatment of angina pectoris
and the management of hypertension. Its short biological half-life of 3.5 h, high aqueous
solubility, and frequent administration make it a potential candidate for sustained release
preparations. To control the release of the drugs, which are having different solubility
properties, the drug is dispersed in hydrophilic swellable matrix or hydrophobic nonswellable
matrix (1-3).
Matrix is the release system which prolongs and controls the release of the drug.
Various factors such as the type of polymer, drug: polymer ratio, solubility of drug and
fillers, and compression force relate to the release of drug from hydrophilic swellable
matrices. Husen et al. investigated influence of fillers and natural gums on the controlled
release of metochlopramide hydrochloride from direct compressible tablets. Fastest release
from tablet with 45% guar gum was observed in the case of MCC, followed by lactose and
DCPD. The difference in the filler solubility explains the slower drug release from matrix
with DCPD as compared to lactose (4-7).
The objective of this study was to investigate the effect of MCC, DCPD and SDL on
the release rates and kinetics of DAH from matrices containing xanthan gum. Because of its
very high solubility in water and short elimination half-life of 3.5 h, DAH is a suitable model
candidate selected to study the release kinetics(10).
Methodology
Twelve formulations were prepared with batch size of 20 tablets. Each formulation of
360 mg matrix tablet contained 120 mg DAH (B.T. Gen S.A, Lugano Branch, Switzerland) at
MF of 0.33, XG (Pernofen/Wulzeshofen, Austria) was used as a natural polymer at MF of
0.15, 0.30, 0.45 or 0.6 while MCC (Avicel® PH-101) or DCPD (Emcompress®) was used as
an insoluble filler or SDL (FlowLac®) was used as a soluble filler. Blending of the mixture is
performed in pestle and motar for 15 min. Each matrix were manually made by direct
compaction of the 360 mg mixture at a force of 1000 kg in a hydraulic press (model C, Fred
S. Carver, USA) equipped with a 12.5-mm round flat-face tooling. The release of DAH from
the matrices was measured in a 900 ml of pH 6.8 phosphate buffer at 37ºC ± 0.5ºC using
basket apparatus (model VK 7000, Vankel, USA) at a speed of 100 rpm. Filtered samples
were withdrawn and assayed at 1, 2, 3, 4, 5, 6, 12 and 24 h using the UV spectrophotometer
(Shimadzu, model UV-1601, Japan) at 236.4 nm. Six replicates were tested and their mean
% released and SD was calculated.
Table 1. DAH Formulation prepared with insoluble and soluble fillers containing Xanthan Gum
Formulation
DAH
XG
MCC
DCPD
SDL
I
120
54
186
-
II
120
108
132
-
III
120
162
78
-
IV
120
216
24
-
V
120
54
186
-
VI
120
108
132
-
VII
120
162
78
-
VIII
120
216
24
-
IX
120
54
-
X
120
108
-
XI
120
162
-
XII
120 mg
216 mg
-
186
132
78
24 mg
Theoretical Consideration (8-10)
The release of a water-soluble-drug drug by diffusion through the gel layer is
approximately dependent on the square root of time and can be expressed in the following
formula which conforms Higuchi’s model of drug diffusion.
Q = k’√𝐷𝑎 𝑡 = k √𝑡
(1)
Where Q is the amount of drug released in time, t; Da is the apparent diffusivity of
drug through the rubbery region; k’ and k are kinetic constants.
For Soluble Filler
To predict drug release from a matrix system with various concentration of polymers,
several assumptions were made (i) drug release can be approximately modeled using Eq (1),
(ii) apparent diffusivity of drug in the rubbery region is related to the porosity, ε and the
tortuosity, τ of the swelling layer Eq (2), (iii) for soluble filler, the porosity is directly
proportional to the volume fraction of soluble solutes (drug and filler) in matrix, which are
related to (1- polymer concentration) / apparent density of mixed solute compact (ρa) as in Eq
(3), and (iv) Shah et al demonstrated that the tortuosity depends upon the degree of polymer
hydration, which is directly proportional to the polymer concentration as in Eq (4).
Da = ε/τ
ε = δ (1–Cp)/ρa
τ = ψCp
Da = γ (1-Cp)/Cp
Q=
𝜎√(1−𝐶𝑝 )𝑡
√𝐶𝑝
(2)
(3)
(4)
(5)
(6)
where δ, ψ, γ and σ are kinetic constants.
From Eq (6) Q is the function of Cp and can be expressed as
Q = α+β √(1 − 𝐶𝑝 )/𝐶𝑝
(7)
where α and β are kinetic constants.
The regression equations for the amount of drug released at 1, 2, 3, ….i h (Q1, Q2, Q3,
…Qi) in relation of polymer concentration are as follows:
Qi = ai+bi√(1 − 𝐶𝑝 )/𝐶𝑝
(8)
A plot of the amount, Q versus √(1 − 𝐶𝑝 )/𝐶𝑝 will give ai and bi. It is possible that
both ai and bi are a function of the square root of time if is constant, therefore,
ai = c + Ka √𝑡
(9)
bi = d + Kb√𝑡
(10)
where c, d, Ka, and Kb are the regression constants.
Equation (8) is further derived to obtain the working equation for prediction drug
release from a hydrophilic swellable matrix.
Qi = (c+Ka√𝑡) + (d+Kb√𝑡) √(1 − 𝐶𝑝 )/𝐶𝑝
(11)
Qi = (c+d√(1 − 𝐶𝑝 )/𝐶𝑝 ) + (Ka+Kb√(1 − 𝐶𝑝 )/𝐶𝑝 )√𝑡
(12)
For Insoluble filler
For insoluble filler, the porosity is only directly proportional to the volume fraction of
soluble drug in matrix, which depends upon the mass fraction of drug divided by the density
of solid compact and is assumed to be constant, f as in Eq (13), and (iv) Shah et al
demonstrated that the tortuosity depends upon the degree of polymer hydration, which is
directly proportional to the polymer concentration as in Eq (14).
ε = δf/ρa
(13)
τ = ψC
(14)
Da = γ/Cp
(15)
Q=
𝜎 √𝑡
√𝐶𝑝
(16)
where δ, ψ, γ and σ are kinetic constants.
From Eq (16) Q is the function of Cp and can be expressed as
Q = α+β√1/(𝐶𝑝
(17)
where α and β are kinetic constants.
The regression equations for the amount of drug released at1, 2, 3, ….i h (Q1, Q2, Q3,
…Qi) in relation of polymer concentration are as follows:
Qi = ai+bi√(1/𝐶𝑝
(18)
A plot of the amount, Qi versus √(1/𝐶𝑝 will give ai and bi. It is possible that both ai
and bi are a function of the square root of time, therefore
ai = c+Ka√𝑡
(19)
bi = d+Kb√𝑡
(20)
where c, d, Ka and Kb are the regression constants.
Equation (18) is further derived to obtain the working equation for prediction drug
release from a hydrophilic swellable matrix:
Qi = (c+Ka√𝑡) + (d +Kb√𝑡)√(1/𝐶𝑝 )
(21)
Qi = (c+d√(1/𝐶𝑝 )+ (Ka+Kb√(1/𝐶𝑝 )√𝑡
(22)
Results and Discussions
High regression coefficients (R2) from linear regression analysis between % DAH
released and √𝑡 indicated that the release of DAH by diffusion across swelling matrix was
dependent on √𝑡 and various kinetic rate constants k were received as shown in Table 2-3.
Using equation 22, the working equation to predict drug release from xanthan gum
matrices containing insoluble fillers and equation 12, the working equation to predict drug
release from xanthan gum matrices containing soluble filler are as follows:
For insoluble fillers,
Q = (-11.91+5.37x) + (14.74+1.28) √𝑡 for MCC
(23)
Q = (-10.27+4.52x) + (8.41+6.31x) √𝑡 for DCPD
(24)
where x = √(1/𝐶𝑝 )
For soluble filler,
Q = (-12.50+6.40x) + (15.21+4.09x) √𝑡 for SDL
(25)
where x = √(1 − 𝐶𝑝 )/𝐶𝑝 )
Figure 1-3 show the theoretical DAH release profiles versus experimental data for
xanthan gum matrices using MCC, DCPD and SDL, respectively. The experimental data
from release testing are closely matched the theoretical release profiles. This implies that the
release profiles of DAH from various matrices can be predicted mainly by the diffusion
model of Shah et al for insoluble MCC or DCPD and that of Jateleela et al for soluble SDL.
Table 2. Kinetic constants k, y-intercepts and R2 for formulations containing insoluble fillers.
Formulation
k, % h-1/2
SD of k
y-intercept, %
R2
I
18.97
0.75
0.02
0.9979
II
16.64
1.37
-0.58
0.9978
III
16.83
0.48
-4.50
0.9968
IV
17.51
0.92
-5.91
0.9958
V
24.69
0.43
1.77
0.9976
VI
19.71
0.37
-2.70
0.9967
VII
18.42
0.20
-4.04
0.9972
VIII
16.15
0.53
-3.60
0.9959
Table 3. Kinetic constants k, y-intercepts and R2 for formulations containing SDL.
Formulation
k, % h-1/2
SD of k
y-intercept, %
R2
IX
24.20
1.03
3.68
0.9942
X
23.55
1.23
-4.53
0.9967
XI
20.91
0.25
-7.44
0.9960
XII
16.97
0.78
-4.95
0.9900
100
% Drug Rleleased
80
60
40
20
0
0
-20
4
8
12
16
20
24
Time, h
Figure 1. Theoretical predicted release profiles versus experimental data for matrices using MCC at various mf
of XG. Key: Theoretical: ˗˗˗, 0.15; - - -, 0.30; ˗ ∙ ˗ ∙ ˗, 0.45; and ........., 0.60. Experimental: ●, 0.15; ■, 0.30; ▲,
0.45; and ♦, 0.60.
% Drug Released
100
80
60
40
20
0
0
4
8
-20
12
16
20
24
Time, h
Figure 2. Theoretical predicted release profiles versus experimental data for matrices using DCPD at various mf
of XG. Key: Theoretical: ˗˗˗, 0.15; - - -, 0.30; ˗ ∙ ˗ ∙ ˗, 0.45; and ........., 0.60. Experimental: ●, 0.15; ■,
0.30; ▲, 0.45; and ♦, 0.60.
% Drug Released
100
80
60
40
20
0
0
4
8
12
Time, h
16
20
24
Figure 3. Theoretical predicted release profiles versus experimental data for matrices using SDL at various mf
of XG. Key: Theoretical: ˗˗˗, 0.15; - - -, 0.30; ˗ ∙ ˗ ∙ ˗, 0.45; and …., 0.60. Experimental: ●, 0.15; ■,
0.30; ▲, 0.45; and ♦, 0.60.
From analysis of variance (ANOVA, p < 0.01) and multiple comparison test using
least significant difference procedure (LSD, p < 0.01, 2-tailed) for comparing release rates of
DAH from matrices containing each filler, the release rate of DAH was significantly affected
by the mf of XG and might be ranked as (1) MCC: 0.15 XG > 0.30 XG ≈ 0.45 XG ≈ 0.60
XG, (2) DCPD: 0.15 XG > 0.30 XG > 0.45 XG > 0.60 XG, (3) SDL: 0.15 XG ≈ 0.30 XG >
0.45 XG > 0.60 XG The sustaining efficacy of fillers for DAH release rate might be ranked
as MCC > DCPD > SDL at XG mf of 0.15 – 0.45, but at 0.60 XG, the sustaining efficacy of
these fillers was not significantly different. MCC or DCPD cannot be dissolved in phosphate
buffer whereas SDL can be dissolved and released very rapidly, subsequently smaller pores
are produced in the insoluble matrix and DAH is then released with slower rate than from
matrix using SDL. However, MCC provided slower drug release than DCPD did at 0.15 –
0.45 mf XG. This may be caused by some swelling property of MCC which result in smaller
pores in matrix. From fig 2, the matrix using DCPD showed that the real % DAH release data
is higher theoretical prediction. This indicated that matrix using DCPD at lowest mf of XG
possessed lower structural strength and easily caused eroded particles from the surface which
provide higher release rate of DAH.
Conclusion
The release rate of DAH was significantly affected by the mf of XG in matrix
containing each direct compression filler and might be ranked as (1) MCC: 0.15 XG > 0.30
XG ≈ 0.45 XG ≈ 0.60 XG, (2) DCPD: 0.15 XG > 0.30 XG > 0.45 XG > 0.60 XG, (3) SDL:
0.15 XG ≈ 0.30 XG > 0.45 XG > 0.60 XG. MCC provided highest retarding efficacy of for
DAH release from matrices containing XG mf of 0.15 – 0.45.
The release profiles of DHA from XG matrices using insoluble MCC or DCPD or
soluble SDL could be predicted by the three operating equations developed according to
Higuchi’s diffusion model along with Shah et al equations for insoluble fillers, and Jateleela
et al equations for soluble filler. This investigation showed that the drug release from
matrices could be optimized to prepare an once-daily dose of DAH using a minimum of
experiments.
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