Pharmaceutical Development and Technology
ISSN: 1083-7450 (Print) 1097-9867 (Online) Journal homepage: http://www.tandfonline.com/loi/iphd20
Divisability of Diltiazem Matrix Sustained-Release
Tablets
P. Costa & J. M. Sousa Lobo
To cite this article: P. Costa & J. M. Sousa Lobo (2001) Divisability of Diltiazem Matrix SustainedRelease Tablets, Pharmaceutical Development and Technology, 6:3, 343-351
To link to this article: http://dx.doi.org/10.1081/PDT-100002616
Published online: 31 Jul 2001.
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Pharmaceutical Development and Technology, 6(3), 343–351 (2001)
RESEARCH ARTICLE
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Divisability of Diltiazem Matrix
Sustained-Release Tablets
P. Costa and J. M. Sousa Lobo
Serviço de Tecnologia Farmacêutica, Faculdade de Farmácia da
Universidade do Porto Rua Anı́bal Cunha, 164, 4050-047 Porto, Portugal
ABSTRACT
The objective of this work was to study the possibility of a solid sustained-release
dosage form, like a tablet, be divided without changing its release characteristics.
Diltiazem hydrochloride Sustained-Release (SR) tablets with a standard groove on
one face, were tested and the following dissolution parameters were evaluated: t10% ,
t25% , and t50% dissolution time, and dissolution efficiency at t120 , and at t360 . To analyze the release mechanism, several release models were tested such as Higuchi,
zero order, first order, Baker-Lonsdale, Hixson-Crowell, Weibull, and KorsmeyerPeppas. The similarities between two in vitro dissolution profiles were assessed by
the difference factor (f 1 ), the similarity factor (f 2 ) and the Rescigno index (ξi ). The
in vitro release kinetics of diltiazem hydrochloride tablets were evaluated using USP
apparatus 4. Using a one-way ANOVA (α = 0.05), statistically significant differences
were found for t10% , t25% , and t50% dissolution times with a constant and with a
variable pH dissolution fluid. The variation coefficient for the divisibility assay
(Portuguese Pharmacopoeia VI) was lower than the limit value of 10%. The diltiazem
release rate from this pharmaceutical system was not constant, and diminished with
the square root of time (Higuchi model) showing that the phenomenon controlling
drug release was the diffusion occurring inside the swelled polymeric matrix. Diltiazem release rate was a function of the area in direct contact with the dissolution
fluid and not of the pharmaceutical matrix volume. The results obtained permit us to
conclude that the division, in this case, affects the drug release characteristics.
∗
Corresponding author. Fax: 351 222003977; E-mail: pccosta@mail.ff.up.pt
343
C 2001 by Marcel Dekker, Inc.
Copyright www.dekker.com
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Costa and Sousa Lobo
KEY WORDS: Diltiazem; Divisibility assay; Drug release; Drug release models;
Tablets division.
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INTRODUCTION
The main advantage of a SR dosage form is the maintenance of the drug blood concentration at therapeutic levels
by means of controlled-release of the drug, during a long
period of time using only one administration. Sometimes,
when the doses contained in each of the commercially
available forms are only a few, it is advantageous to divide a dosage form in order to obtain lower plasma concentrations, according to a therapeutic prescription. The
possibility of division of a SR dosage form depends on
the maintenance of its physical and drug release characteristics. A SR tablet, in order to be divisible, should keep
its controlled release characteristics, its halves should be
well defined and the overall weight variation and powder
loss should be small. The extent to which the division affects dissolution is in most cases unknown and may pose a
serious risk in SR formulations where structural integrity
generally plays a fundamental role in controlling drug release (1–5).
Frequently, the release control is achieved at the surface of the pharmaceutical dosage form by coating, which
limits the passage of the drug. This is one of the most
common methods for tablets. In this case, division is not
possible, as it would compromise the integrity of the coating layer and the drug could freely diffuse from its interior
in the fractured zone.
Polymeric matrixes are used as another type of SR
dosage forms. In this case, the drug is dissolved or dispersed in a matrix and drug release occurs by diffusion or by erosion of the matrix itself. The SR dosage
forms studied were polymeric matrix tablets containing
180 mg of diltiazem hydrochloride and the division of
this SR dosage forms should not compromise the drug
release control. Other SR diltiazem hydrochloride preparations have been recently studied by Sood et al. (5). The
SR tablet (T1 formula) and the SR half tablet (T2 formula) were compared in order to verify if the release profiles were identical. The following dissolution parameters:
t10% , t25% , and t50% dissolution time, dissolution efficiency
(6,7) at t120 and at t360 in different pH conditions were also
compared.
Dissolution profiles may be considered similar through
the overall profile or at each dissolution sample time point.
The dissolution profile comparison may be carried out
using model independent or model dependent methods.
In order to analyze the release mechanism, several release
models were tested such as:
√
Higuchi (8–10) : Q t = K H t
where Q t is the amount of drug released at time t and
K H is the Higuchi release rate; this is the most widely
used model to describe drug release from pharmaceutical
matrices.
Zero Order : Q t = Q 0 + K 0 t
where Q t is the amount of drug released at time t, K 0 is
the apparent dissolution rate constant or zero order release
constant, and Q 0 is the initial concentration of the drug in
the solution resulting from a burst effect; in this case the
drug release runs at a constant rate.
First Order (11,12) : lnQ t = lnQ 0 + K 1 t
where K 1 is the first order release constant; in this case the
drug released at each time is proportional to the residual
drug inside the dosage form.
Baker–Lonsdale (13) :
(3/2)1 − (1 − (Q t /Q ∞ )2/3 − (Q t /Q ∞ ) = K t
where Q ∞ is the maximal amount of drug released at
infinite time; this model was developed by Baker and
Lonsdale from Higuchi model and describes the drug
controlled-release from a spherical matrix.
1/3
1/3
Hixson–Crowell (14) : Q 0 − Q t
= Kst
where Q 0 is the initial amount of drug in the pharmaceutical dosage form, Q t is the drug amount remaining in the
pharmaceutical dosage form at time t, and K s is a constant
incorporating the surface/volume relation.
Weibull (15–18) :
log[−ln(1 − (Q t /Q ∞ )] = β × log(t − Ti ) − log a
where a is the scale parameter that defines the time scale
of the process, Ti is the lag time of the onset of the
dissolution or release process that, in most cases, will
be equal to zero, and β is the shape parameter of the
dissolution curve. The parameter a can be replaced by
the more informative dissolution time, Td representing
the time interval necessary to dissolve or to be released
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Diltiazem Sustained-Release Tablets
63.2% of the drug contained in the pharmaceutical dosage
form.
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Korsmeyer–Peppas (19–21) : Q t /Q ∞ = K k t n
where K k is a constant incorporating structural and geometric characteristics of the drug dosage form and n
is the release exponent, indicative of the drug release
mechanism.
The differences for t10% , t25% , and t50% dissolution times
were statistically examined by a one-way analysis of variance (ANOVA). In order to compare the differences for the
release profiles between the tablets and their halves a simple model independent approach using a difference factor
( f 1 ), a similarity factor ( f 2 ), and the Rescigno index (ξi )
with i = 1 and 2 were used (22,23). The similarity factor
has been adopted by Center for Drug Evaluation and Research (FDA) and by Human Medicines Evaluation Unit
of The European Agency for the Evaluation of Medicinal Products (EMEA), as a criterion for the assessment
of the similarity between two in vitro dissolution profiles
(24,25):
−0,5
n
2
f 2 = 50 × log 1 + (1/n)
|Rj − Tj |
× 100
j=1
This similarity factor is a logarithmic reciprocal square
root transformation of one plus the average mean squared
differences in percent dissolved between the test (Tj )
and reference (Rj ) products over all time points (n).
The FDA and EMEA suggest that two dissolution profiles are declared similar if f 2 is between 50 and 100
(24).
Diltiazem (hydrochloride) is a calcium channelblocking drug used as a coronary vasodilator and an
antihypertensive agent. Its classical oral, adult, dose is
initially 30 mg 4 times a day before meals and at bedtime,
which can be increased to 360 mg/day, when necessary (26). Its short biological half-life and thus frequent administration makes it a good candidate for SR
preparations.
The choice of the dissolution media has become a very
important matter. Water is one of the most common dissolution media found in USP dissolution monographs. A
recent publication (27) proposed the replacement of water as a dissolution medium by media that better simulated
the physiological environment of the gastrointestinal tract.
The authors stated that when physiological relevance is being considered, water may not be adequate due to its lack
of buffering capacity as well as it is not representative of
gastrointestinal environment. This opinion has not been
well accepted and has been much criticized (28). So the
345
analysis of diltiazem release from tablets and halves in
different dissolution media (with different pH conditions)
was made to evaluate its influence.
MATERIALS AND METHODS
The studied diltiazem hydrochloride SR formulation
(taken once daily) was commercially available in Portugal. The tablets presented one score in one of the faces
(Fig. 1). All chemicals used were analytical reagent grade.
In HPLC procedure, HPLC grade acetonitrile and double
distilled water were used.
The tablets weight was determined using a Mettler AG
245. Twenty tablets were weighed and the mean value
was determined (29). The halves were also weighted and
the same limits were applied. The tablets hardness was
determined using an Erweka TBH 28. The tablets (n =
10) were orientated always in the same way in relation
to the direction of the strength application. The hardness
of the halves was also determined (n = 20). The tablets
friability was determined using an Erweka TAP. Twenty
SR tablets were used.
The variation coefficient/divisibility test (30) was determined as follows: 20 halves were separated, from the
left and the right hand alternatively, and then each half
was weighed. The standard deviation and the mean weight
were calculated using these 20 halves. The variation coefficient (VC) is expressed in percentage and the VC value
should not be higher than 10%. The influence of the operator was determined comparing the results obtained with
2 persons knowing the division process (Portuguese Pharmacopoeia VI). The weight of the halves, resulting from
the left and the right hands, were tested for significant
differences with one-way ANOVA (α = 0.05).
In vitro release kinetics of diltiazem hydrochloride SR
tablets were evaluated using USP apparatus 4 (n = 3).
Figure 1. Diltiazem tablets dimensions.
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346
Costa and Sousa Lobo
Although there is a monograph of diltiazem hydrochloride extended release capsules in the USP 23 (31), it does
not make reference to the release assay. The tablet (T1 formula), or the half tablet (T2 formula), was put inside the
cell with the dissolution fluid (water) with a flow rate of
10 mL/min. The used dissolution fluid was the one indicated in the USP monograph “Diltiazem hydrochloride
tablets” at 37 ± 0.5◦ C (32). With this apparatus the influence of the dissolution fluid pH was determined using a
pH 1.5 buffer solution. After the first, the second, and the
third hour of the assay, the dissolution fluid was changed
to a solution with pH 3.0, 5.0, and 6.5, respectively, and
the results were compared with the ones obtained with
water as dissolution fluid. At predetermined time intervals (10, 20, 30, 60, 120, 180, 240, 300, and 360 min), the
dissolution fluid was collected for analysis.
The HPLC system (33) consisted of a pump (Varian
model 9012), a 20-µl loop, a variable wavelength detector
(Varian model 9050) at 235 nm, and a C8 column (LiChrospher 100 RP8 5 µm 100 × 4 mm) maintained at ambient
temperature. The mobile phase was acetonitrile/dissodium
phosphate 0.01 M solution (Na2 HPO4 ) (50:50) containing 0.01% of triethanolamine. The flow rate was
2.0 mL/min.
RESULTS
A change in the physical characteristics of the tablets
was noticed resulting from the division process. The hardness of the intact tablets (Kp) was 10.4 ± 6.2 (mean ±
sd) but decreased by division to only 6.2 ± 2.4. The friability of the tablets was 0.23%, and increased to 0.69%
after division. So, division did not critically change these
characteristics. The variation coefficient for the divisibility assay was 3.0% and 5.5%, respectively for operator
1 and operator 2. A significant difference was found, between the halves obtained from the left and the right hand
on one of the operators (Table 1) and this reflected a great
Figure 2. Diltiazem tablets dimensions after hydration.
influence of the different strengths applied by both hands,
in the moment of division. The mean weight loss resulting
from the sustained release tablets division was 0.09% to
operator 1 and 0.13% to operator 2.
The diltiazem matrix tablets contacting the dissolution
fluids swelled forming a jelly mass that practically didn’t
change in volume for more than 4–6 h. The diltiazem
tablets dimensions increased after hydration (Fig. 2): the
tablet length changed from 1.82 to 2.05 cm (increase of
13%), the width changed from 0.77 to 1.03 cm (35%),
and the height changed from 0.56 to 0.71 cm (28%). After
division, the sum of the halves length was 2.32 cm (an
increase of 27% in relation to the dry tablet and 15% in
relation to the hydrated tablet).
The diltiazem release profiles (mg) for the tablets
and their halves, can be seen in Figure 3. The best fitting of the diltiazem release profiles was obtained with
Higuchi, Weibull, and Korsmeyer–Peppas (n ≈ 0.5) models (Table 2), with determination coefficients (R 2 ) higher
than 0.996. The Weibull shape parameter (10), β, characterizes the dissolution profile as exponential (β = 1), as
sigmoid, S-shaped, with upward curvature followed by a
turning point (β > 1) or as parabolic, with a higher initial slope and after that consistent with the exponential
(β < 1). This shape parameter was always β < 1, indicating that the dissolution profile was parabolic, and showed
Table 1
Effect of the Operator in the Tablets Division
Half
Operator
1
2
a Signif.
DA (%)
Left
Right
Signif. Dif.a
p-value
3.0
5.5
0.3201
0.3112
0.3215
0.3299
0.2168
0.0005
Deviation
Losses
(%)
>5%
>10%
0.09
0.13
4
8
0
5
dif—Significant differences for the halves resulting from left and right hands.
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347
Figure 3. Comparison of diltiazem release profiles (%) with constant pH (left) and with variable pH (right).
little variation from the T1 and T2 formulas but larger
differences to pH variation. There was a great influence
of the dissolution fluid pH value on the entire tablets and
their halves release profiles and this can be explained by
the lower diltiazem solubility at lower pH values. Td parameter almost doubled for the variable pH dissolution
medium showing that the release rate in this condition was
smaller as can also be seen by the other release parameter
evaluated. Using Higuchi model it is possible to calcuTable 2
Model Fitting of the Diltiazem Release Profiles (Q expressed in
mg)
Constant pH
Models
Tablet
1/2 Tablet
Variable pH
Tablet
1/2 Tablet
Higuchi
KH
R2
7.4296
0.9987
4.0038
0.9991
4.1718
0.9967
2.1675
0.9987
Zero order
K0
R2
0.3310
0.9785
0.1917
0.9707
0.1865
0.9835
0.1042
0.9779
First order
K1
R2
0.0065
0.8203
0.0074
0.8168
0.0068
0.8268
0.0075
0.8281
Baker-Lonsdale K
R2
0.0004
0.9779
0.0004
0.9900
0.0001
0.9849
0.0001
0.9919
Hixson-Crowell K s
R2
0.0077
0.8928
0.0071
0.8862
0.0065
0.9007
0.0058
0.8969
Weibull
β
0.8536
0.8574
0.8105
0.7787
0.9993
0.9998
0.9995
0.9991
R2
Td 299.6979 248.2813 572.4898 508.1790
KorsmeyerPeppas
Kk
n
R2
0.2790
0.560
0.9999
0.3448
0.514
0.9997
0.1378
0.615
0.9995
0.1782
0.527
0.9992
late the drug release rate (mg min−0.5 ) for the complete
tablet and the half tablets of 7.43 and 4.00, using constant
pH conditions, and 4.17 and 2.17, using variable pH
conditions.
Using a one-way analysis of variance (α = 0.05), statistically significant differences were found for t10% , t25% ,
and t50% dissolution times with a constant pH dissolution fluid ( p-value of 0.0043, 0.0009, and 0.0014, respectively) and with a variable pH dissolution fluid ( p-value
of 0.0071 and 0.0103), values showing that the tablets and
the halves exhibit different release profiles. The half tablet
does not release half of the tablet drug dose at the same
rate. It should be borne in mind that a significant difference
( p-value < 0.05) indicates that the release of whole and
half tablets truly differ, but it says nothing about the magnitude of that difference or its clinical significance.
In order to verify if the contact area of the pharmaceutical formula with the dissolution fluid was the main responsible mechanism for this difference, the surface areas
of the tablets and halves were calculated. As the diltiazem
tablets and halves acquire a rod shape after hydration,
a simple model (Fig. 4) was used to calculate the surface
area, as it would be equal to a sphere area plus a cylinder
lateral area. The diameter value (d) obtained was 0.87 cm
(mean value between the width and the height of the hydrated tablet) and the cylinder length (h) was 1.18 cm
for tablets and 0.29 cm for halves. Using this model, the
total area value obtained was 5.60 cm2 for tablets and
3.17 cm2 for their halves (57% tablet area value). The total volume, also calculated with this model, was 1.05 cm3
for tablets and 0.52 cm3 for their halves. This value represents approximately half (49%) of the tablets volume
value. It was then possible to calculate the release profile
by unit of area of contact with the dissolution fluid (Fig. 5).
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Costa and Sousa Lobo
Table 3
Comparison of Diltiazem Release Parameters
Constant pH
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t10%
t25%
t50%
Efficiency t120
Efficiency t360
Figure 4. Model used to calculate the diltiazem tablets surface
area (sphere area plus cylinder lateral area); d = 0.87 cm; h =
1.18 cm (T1) and h = 0.29 cm (T2).
As can be seen, the release profiles expressed in percentage of released drug by unit of area (%/cm2 ) were
practically the same, mainly in the first four hours of the
assay. After this period of time, the release profiles became
a little different and that fact could be explained by the failure of the used model on the calculus of the contact area
with the dissolution fluid. By that time, the dimensions
of the pharmaceutical formula became different from the
theorized one.
Comparing the differences for the release profiles between the tablets (T1) and their halves (T2) the difference
factor ( f 1 ) was lower than 15, the similarity factor ( f 2 )
Variable pH
Tablet
Half
Tablet
Half
22.1
77.7
215.2
39.6
41.6
18.6
62.2
172.8
45.9
46.5
53.5
190.1
–
20.5
22.5
44.7
168.1
–
23.3
23.9
higher than 50, and the Rescigno index ξ1 and ξ2 lower
than 0.06 (Table 3). Although the release profiles of both
T1 and T2 were not identical, differences were small
and, using as reference the model independent approach,
especially the similarity factor, they could be considered
similar. Unfortunately, these parameters are insensitive to
the shape of the dissolution profiles, are sensitive to the
number of sampling time points and don’t take into account the information of unequal spacing between them.
They are sample statistic that cannot be used to formulate
a statistical hypothesis for assessment of dissolution similarity. It is, therefore, impossible to evaluate false positive and false negative rates of decisions for approval of
drug products based on them. Simulation results also indicated that the similarity factor is too liberal in concluding similarity between dissolution profiles (34,35). The,
adimensional, Rescigno index is 0 when the two release
profiles are identical and 1 when the drug from either the
test or the reference formulation is not released at all. The
Rescigno index method does not indicate how close the indices should be to zero in order to conclude for similarity.
Figure 5. Comparison of diltiazem released amounts (%/cm2 ) with constant pH (left) and with variable pH (right).
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Diltiazem Sustained-Release Tablets
349
In general, no statistical inference can be made,
by direct implementation of the criterion based on
these model-independent factors, about dissolution
dissimilarity. However, recently the criterion for average similarity on a confidence interval basis of the
dissolution profiles using the similarity factor has been
formulated as an interval procedure (36). Although the
model-independent methods are easy to apply, they lack
scientific justification and no information is obtained to
the knowledge of the release mechanism (34–37). Besides
the above limitations, these model-independent methods
can be used as a very important tool in the area of Quality
Control. Because of that, the comparison of dissolution
profiles was mainly based in the model-dependent method.
CONCLUSIONS
In a previous work a great influence of the stirring speed
(USP apparatus 2) and a large effect of the type of dissolution apparatus used on the tablets and halves release profiles (33,38) was found. The analysis of tablets and halves
in different pH conditions allows to conclude that this factor also affected diltiazem release. The choice of the type
of dissolution apparatus and the stirring speed should then
be very carefully chosen, in order to allow the determination of the correct release profile from the pharmaceutical
systems. The results obtained with complete tablets and
half tablets, permit to conclude that the division, in this
case, does affect the dissolution characteristics, as can be
seen by the dissolution parameters used: t10% , t25% , and
t50% dissolution time, dissolution efficiency at t120 and t360
(Table 4). The release profile of both T1 and T2 are not
identical, but differences are not great and consequently
the division should be carefully planned and executed.
The variations found for the halves obtained from the
division, were high, reaching values of almost 15% for the
halves, with low powder losses. The halves (in the case of
one of the operators), were not in accordance with the rules
of mass uniformity (13% of the tablet halves presented
Table 4
a weight difference value higher than the double of the
limit).
The divisibility assay (DA) results, quite similar for
both operators, were lower than the limit value of 10%,
showing that this pharmaceutical dosage form might be
divided taking only in consideration the tablets physical
characteristics. The diltiazem release rate from this pharmaceutical system was not constant, and diminished with
the square root of time (as stated by the Higuchi model).
It is possible to conclude that the phenomenon controlling
drug release was the diffusion occurring inside the swelled
polymeric matrix.
Some results obtained with complete tablets and half
tablets of SR theophylline (1,2), acetylsalicylic acid (3),
and diltiazem (5) formulations showed that the division did
affect the dissolution characteristics although in a small
scale. In general splitting of the tablets originated faster
drug release. Other results (3,4) obtained with tablets of
SR acetylsalicylic acid (ASA) formulations showed that
the division did not affect the dissolution characteristics.
In those cases, the studied SR dosage forms were tablets
obtained from SR microencapsulated particles and the division of these SR forms did not compromise with the
release control, as it resulted from the coating of the granules, which was not affected by the division process. The
release profiles of both intact and split tablets were identical, and consequently the division was possible in order
to obtain lower doses of ASA. The ASA release rate from
these pharmaceutical systems was constant (zero order
model). This kind of SR dosage forms is ideal whenever
the division is considered as an option to obtain lower
drug doses. The matrix SR dosage forms, as they suffer a
change in drug release surface after division, have different release profiles for the complete and the half tablets
and consequently this possibility should be carefully studied. The similarity between dissolution of intact and split
tablets should be proved in a one-to-one basis.
As a general conclusion we can say that diltiazem release was a function of the area in direct contact with
the dissolution fluid and not of the pharmaceutical matrix
volume. The dose released from halved tablets was higher
than from whole tablets and that was due to the increased
surface area exposed by breaking the tablet.
Comparison of the Release Profiles Differences Between
the Tablets and Their Halves Using a Difference Factor
( f 1 ), a Similarity Factor ( f 2 ), and the Rescigno Index (ξi )
f1
f2
ξ1
ξ2
Constant pH
Variable pH
12.20
65.36
0.057
0.055
8.01
85.71
0.039
0.035
ACKNOWLEDGMENTS
The authors thank Junta Nacional de Investigação
Cientı́fica (JNICT) for financial support through project
Prodep 5.2/264/1/94.
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