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Formulation and evaluation of Ranolazine sustained release matrix tablets

using Eudragit and HPMC

Article in International Journal of Research in Pharmaceutical and Biomedical Sciences · January 2011

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 Available online at
International Journal of
www.pharmscidirect.com PHARMACEUTICAL
AND BIOMEDICAL
Int J Pharm Biomed Res 2011, 1(5), 172-177 RESEARCH

ISSN No: 0976-0350

Research article

Formulation and evaluation of Ranolazine sustained release matrix tablets

using Eudragit and HPMC
Md. Mofizur Rahman1*, Sayeed Hasan2, Md. Ashiqul Alam2, Sumon Roy3, Mithilesh Kumar Jha1,
Md. Qamrul Ahsan4, Md. Habibur Rahman1
1
Department of Pharmacy, Bangladesh University, Mohammadpur, Dhaka-1207, Bangladesh
2
Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Dhaka, Dhaka-1000, Bangladesh
3
Department of Pharmacy, Southeast University, Banani, Dhaka-1213, Bangladesh
4
Department of Pharmacy, Southern University, Bangladesh

Received: 06 Jan 2011 / Revised: 11 Jan 2011 / Accepted: 18 Jan 2011 / Online publication: 03 Feb 2011

ABSTRACT
In the present work, an attempt was made to formulate sustained release matrix tablets for Ranolazine using Eudragit L
100-55 and different viscosity grades of HPMC (Methocel E50 and Methocel K15M CR). The matrix tablets were prepared
by direct compression process. The prepared tablets were evaluated for various physico chemical parameters. In vitro drug
release study was carried out in simulated gastric fluid (0.1 N HCl) for the first 2 h and in phosphate buffer (pH 6.8) for the
next 6 h following USP 25 paddle method. Increase in Eudragit L 100-55 and HPMC concentrations or increase in viscosity
grades of HPMC polymers (Methocel E50 and Methocel K15M CR) resulted in a significant decrease in Ranolazine release.
For instance, the matrix tablets containing 15% of polymers shows delayed and extended drug release when compared to
10% polymers irrespective of viscosity grades of HPMC in the tablet. Further, the drug release from Eudragit L 100-55 and
higher HPMC viscosity grades (Methocel K15M) was slower as compared to lower viscosity grades (Methocel E50). The in
vitro data is fitted in to different kinetic models and the best-fit was achieved with the Higuchi model followed by the zero-
order plot, Korsmeyer and Hixson Crowell equations. The release of Ranolazine from matrix tablets containing high Eudragit
L 100-55 and HPMC (Methocel K15M CR) content was prolonged as a result; an oral sustained release dosage form to
circumvent the frequency of administration has been achieved.
Key words: Ranolazine, Sustained release dosage forms, Eudragit L100-55, HPMC, Methocel E50, Methocel K15 CR.

1. INTRODUCTION disorders [2]. Ranolazine, initially, 500 mg twice daily; may

Ranolazine sustained-release tablets were recently
approved in the EU for chronic stable angina as add-on
therapy when symptoms are not controlled with first-line
agents [1]. Chronic Angina resistant to medical treatment
with hemodynamically acting agents is a major problem in
clinical setup. For such patients, large numbers of clinical
trials have documented the beneficial effect of Ranolazine. It
acts as an anti-anginal agent that controls myocardial
ischemia through intracellular metabolic changes, hence
beneficial in chronic angina and other cardio metabolic
*Corresponding Author. Tel: +8801911605139, Fax: 880 2 9892914
Email: rmfi02@yahoo.com
©2011 PharmSciDirect Publications. All rights reserved.
increase to maximum of 1 g twice daily [3-6]. Peak plasma
concentrations occur between 2–5 h and the terminal half-life
is approximately 7 h [3].
The matrix tablet by direct compression has attracted
much attention due to its technological simplicity in
comparison with other controlled release systems. It required
fewer unit operations, less machinery, reduced number of
personnel and processing time, increased product stability
and production rate [7]. HPMC, a semisynthetic derivative of
cellulose, is a swellable and hydrophilic polymer. Some
research groups have worked on the usage of swellable
HPMC as the retarding polymer to sustain the release of
different drugs [8-10]. It is very suitable to use as a retardant
material in controlled release matrix tablets, as it is nontoxic
and easy to handle [11]. Matrix tablets prepared using HPMC
 Md. Mofizur Rahman et al., Int J Pharm Biomed Res 2011, 1(5), 172-177
on contact with aqueous fluids gets hydrated to form a
viscous gel layer through which drug will be released by
diffusion and/or by erosion of the matrix [12]. Previous
studies developed by Williams et al. [13] led to the
conclusion that the type and level of excipient influenced the
rate and extension of drug release. Recently, Samani et al.
[14] investigated the effect of polymer blends on release
profiles of sodium Ranolazine from matrices and the results
showed that the drug release depends on the kind of polymer,
its proportion in the formulation and its viscosity grade.
HPMC is used to control drug release from several
pharmaceutical systems because of its non-toxic nature, easy
compression, swelling properties and accommodation to high
levels of drug. This cellulose derivative excipient has been
widely investigated in our laboratory [15-17]. Despite the
high number of papers on this subject, few of them discuss
the drug-release processes from both methylcellulose [18,19]
and HPMC [20,21]. The use of hydrophilic matrix alone for
extending drug release for highly water soluble drugs is
restricted due to rapid diffusion of the dissolved drug through
the hydrophilic matrix. For such drugs it becomes essential to
include hydrophobic polymers in the matrix system, for
instance, Eudragit L 100. Among the several polymers
available, methacrylic resins (Eudragit) are particularly
attractive [14], because of their high chemical stability, good
compatibility properties and large variety of products with
different physicochemical characteristics present on the
market.
In the present work, Ranolazine sustained release matrix
tablets have been developed using Eudragit L 100-55 and
HPMC (E50, K15M CR).
2. MATERIALS AND METHODS
2.1 Materials
Ranolazine was obtained as gift sample from Skyef
Pharmaceuticals Ltd. Dhaka, Bangladesh. HPMC (E50,
K15M CR) was a gift sample received from Colorcon Asia
Pvt.Limited. Avicel PH 102 was purchased from Ming Tai
Chemical Co.Ltd., (Taiwan). Eudrgit L 100-55 was procured
from Rhom pharma, Germany. Magnesium stearate was
procured from Hanua Chemicals Limited, (Japan). Aerosil
was procured from CABOT, India.
2.2 Preparation of matrix tablets
Tablets were prepared by direct compression process.
Different batches of tablets, F1 to F6 were prepared by
varying the concentration of Eudragit L 100-55 and HPMC
(methocel E50, K15M CR) polymers from 10 to 15%. The
polymer ratios, Eudragit L 100-55:HPMC (methocel E50)
and Eudragit L 100-55:HPMC (K15M CR) were maintained
as 1:1 in all the batches (Table 1). The drug, Eudragit L 100-
55, Methocel E50/Methocel K15M CR and Talc were mixed
for 10 min. Dried granules were sieved through #20, to get
173
compressible granules. Lubricants were added during
blending. During blending total mass was taken in a
laboratory designed small drum blender machine for about 30
min. Particular attention was given to ensure thorough
mixing and phase homogenization. The appropriate amounts
of the mixture were accurately weighed in an electronic
balance for the preparation of each tablet and finally
compressed using Pressima D type 4-station compression
machine, Germany, with a 19 mm punch. All the preparations
were stored in airtight containers at room temperature for
further study.
2.3 Physical characterization of matrix tablets
The tablets of the proposed formulations (F1 to F6) were
evaluated for hardness, weight variation, thickness, friability
and drug content. Hardness of 10 matrix tablets from each
formulation was measured using Hardness tester (Erweka
GMBH, 300H model, Germany). Friability of the tablets was
determined using 10 tablets in a Roche friabilator (Campbell
Electronics, Mumbai) for 4 min at 25 rpm performed in
triplicate. A slide calipers was used to measure the thickness
for 5 tablets. Weight variation test was performed by taking
10 tablets using an electronic balance (OHAUS LS 200,
Switzerland).
2.4 Drug content assay
Twenty tablets were weighed and finely powdered. An
amount of tablet powder equivalent to 500 mg of Ranolazine
was accurately weighed and transferred in a 100 mL
volumetric flask and 50 mL of pH 6.8 phosphate buffer was
added. The solution was subjected to sonication for 10 min
for complete extraction of drugs and the solution was made
up to the mark with the same buffer to obtain a concentration
of 5 mg/mL. The above solution was diluted using the same
buffer solution to get a concentration of 100µg/mL and
absorbance was measured at 271 nm using Shimadzu 1240
UV visible spectrophotometer. The actual concentration of
the sample was determined from the calibration curve of
Ranolazine prepared using pH 6.8 phosphate buffer.
2.5 In vitro release studies
The in vitro release of Ranolazine from the formulated
tablets was carried out in USP 25 dissolution test apparatus II
using 900 mL of dissolution medium maintained at
37.0±0.5°C and a stirring rate of 100 rpm. Six tablets from
each formulation were tested individually in 900 mL 0.1 N
HCl for the first 2 h and in phosphate buffer (pH 6.8) for the
following 6 h. At every 1 h interval, samples of 5 mL were
withdrawn from the dissolution medium and replaced with
fresh medium to maintain the volume constant. After
filtration and appropriate dilution, the amount of Ranolazine
present in each sample was determined
spectrophotometrically at 271 nm.
 Md. Mofizur Rahman et al., Int J Pharm Biomed Res 2011, 1(5), 172-177 174

Table 1
Formulation of Eudragit L 100-55 and HPMC (E50, K15M) based Ranolazine sustained release matrix tablets
Formulation Code Ingredients per tablet (mg)
Ranolazine Eudragit L 100-55 Methocel E50 Methocel K15M CR Lactose Avicel PH 102 Aerosil
F1 500 100 100 -- 80 205 5
F2 500 125 125 -- 30 205 5
F3 500 150 150 -- 0 185 5
F4 500 100 -- 100 80 205 5
F5 500 125 -- 125 30 205 5
F6 500 150 -- 150 0 185 5
Each formulation also contains 10 mg magnesium stearate. Compression weight of each formulation was 1000 mg

2.6 Release kinetics

Different kinetic models (zero-order, first-order,
Higuchi’s, Korsmeyer’s and Hixson Crowell) were applied to
interpret the release profile (the order and mechanism of
Ranolazine release) from matrix system. To study the
mechanism of drug release from the matrix tablets, the
release data were fitted to zero-order, first-order, and Higuchi
equation. However, two factors diminish the applicability of
Higuchi’s equation to matrix systems. This model fails to
allow the influence of swelling of the matrix (upon
hydration) and gradual erosion of the matrix. Therefore, the
dissolution data were also fitted according to the well-known
exponential equation (Korsmeyer equation), Eq. (1), which is
often used to describe the drug release behavior from
polymeric systems.
Log (Mt /Mf) = Log k + n Log t -------------- (1)
where, Mt is the amount of drug release at time t; Mf is the
amount of drug release after infinite time; k is a release rate
constant incorporating structural and geometric
characteristics of the tablet; and n is the diffusional exponent
indicative of the mechanism of drug release. Talukder et al.
[22] applied this equation to evaluate the drug release
mechanism from xanthan gum matrix tablets. To clarify the
release exponent for different batches of matrix tablets, the
log value of percentage drug dissolved was plotted against
log time for each batch according to the equation 1. A value
of n = 0.45 indicates Fickian (case I) release; >0.45 but <0.89
for non-Fickian (anomalous) release; and >0.89 indicates
super case II type of release. Case II generally refers to the
erosion of the polymeric chain and anomalous transport (non-
Fickian) refers to a combination of both diffusion and erosion
controlled-drug release [23].
The Hixson - Crowell cube root equation is:
M1/3 = Mo1/3 – Kct ------------------ (2)
where, Kc is the cube root dissolution rate constant. Cube
roots of percent releases (Cube root of initial drug load minus
cube root of % drug remaining) are plotted against time
(hour) to demonstrate the Hixson Crowell plot. Mean
dissolution time (MDT) was calculated from dissolution data
using the following equation [24].
MDT = (n / n+1) K -1/n -------------------- (3)
2.7 Statistical analysis
A one way analysis of variance (ANOVA) was used to
analyze the dissolution data obtained for each batch of
formulation to compare the drug release rate and comparison
of mean dissolution time (MDT) of all formulations. A
confidence limit of P<0.05 was fixed and the theoretical
calculated values of F (Fcrit and Fcal) were compared for
the interpretation of results. ANOVA was determined using
SPSS software (Version 12, SPSS Inc., USA).
3. RESULTS AND DISCUSSION
3.1 Physical characterisation of matrix tablets
The tablets of the proposed formulations (F1 to F6) were
evaluated for hardness, weight variation, thickness, friability
and drug content. The mean thickness (n=5) of the tablets
were ranged from 4.12 to 4.85 mm. The mean hardness
(n=10) and percentage friability (<1%) of the tablets of all
batches ranged from 8.50 to 8.90 kg/cm2 and 0.54% to
0.63%, respectively. The average percentage weight
deviation of 10 tablets of each formula was less than ± 5%.
Mean drug content of different batches ranged from 498.05
mg to 502.25 mg.
3.2 Effect of polymer concentration or viscosity grades on
drug release
The concentration of polymers, Eudragit L 100-55 and
HPMC (Methocel E50) in F1, F2 and F3 were 10, 12.5 and
15% w/w, respectively. Similarly, in the case of formulations
F3, F4 and F5, the concentration of polymers, Eudragit L
100-55 and HPMC (K15M CR) in were 10, 12.5 and 15%
w/w, respectively. This polymer has been well known to
retard the drug release by swelling in aqueous media. A
polymer’s ability to retard the drug release rate is related to
its viscosity. Processing factors including particle size,
hardness, porosity and compressibility index etc. also can
affect the release rate of drug from tablets [25]. The
hydration rate of HPMC depends on the nature of the
substituents like hydroxypropyl group content. Hence,
Methocel K15M CR was used because it forms a strong
viscous gel in contact with aqueous media, which may be
useful in controlled delivery of drug [26].
 Md. Mofizur Rahman et al., Int J Pharm Biomed Res 2011, 1(5), 172-177 175

Table 2
Release kinetics of formulated Ranolazine from different proportion of Eudragit L 100-55 and HPMC (E50, K15M CR) based matrices
Zero order First order Higuchi Korsmeyer Hixson Crowell
Code
R2 K0 (% h-1) R2 K1 (% h-1) R2 Kh (% h-0.5) R2 n R2 Kc (% h-1)
F1 0.835 9.322 0.986 -0.107 0.985 30.860 0.994 0.400 0.940 0.267
F2 0.907 8.100 0.972 -0.069 0.995 25.850 0.991 0.452 0.965 0.194
F3 0.923 7.485 0.962 -0.058 0.986 23.560 0.977 0.474 0.960 0.169
F4 0.857 9.181 0.985 -0.096 0.990 30.067 0.988 0.443 0.957 0.248
F5 0.906 7.908 0.980 -0.064 0.997 25.290 0.991 0.495 0.965 0.183
F6 0.926 7.142 0.976 -0.052 0.992 22.530 0.982 0.520 0.967 0.155
R2-Correlation coefficients, K0, K1, Kh, Kc Release rate constant for zero order, first order, Higuchi, and Hixson Crowell release equation, respectively, n,
diffusional exponent, indicative of release mechanism in Korsmeyer equation. All formulations except F1 and F4, (Fickian release) followed Non-Fickian
(Anomalous) release

100
The effect of polymer concentrations on drug release
from matrix tablets is shown in Fig.1. It can be seen that by
increasing the polymer concentration from 10% to 15%, the
rate of drug release from the matrix tablet decreases
80
Cumulative percentage drug release

dramatically. The formulations containing relatively higher

polymer content shows less initial drug release due to the
unavailability of drug molecules at the surface of matrix
60
tablets. Further, by increasing the concentration of polymer in
the microsphere formulation, a point will be reached where
the pores or channels formed by the drug particles within the
40
F1 polymer matrix were diminished. i.e., the diffusion of drug
F2
molecules from the channels of the matrix was disturbed by
F3
F4 the increased concentration of polymer. In addition, lactose
20
F5 causes a decreased tortuosity of the path of the drug due to its
F6
preferential solubility than Methocel K15 M CR, by its
swelling effect, additionally weakened the integrity of the
0
matrix [24]. In other words, increased polymer concentration
0 2 4 6 8
affects the drug leaching and diffusion process from the
Time (h)
matrix, by making it less porous and slower drug release rate
Fig.1. Zero order plot of Ranolazine release from matrix tablets occurs.
Further, the drug release from higher HPMC viscosity
grade (Methocel K15M) was slower and extended as
compared to lower viscosity grade (Methocel E50). i.e. the
2.50
drug release increased with lower viscosity grade and
polymer proportion in the matrix tablet. The release rate was
significantly dependent on the viscosity grade proportion of
2.00 the polymer. A statistically significant decrease (P<0.05,
Fcrit (2, 15) = 3.68 and Fcal = 912.2) at the end of 1st hour,
Log percentage drug retained

(P<.05, Fcrit (2, 15) = 3.68 and Fcal = 3107.57) at the end
1.50 of 4th hour, (P<0.05, Fcrit (2, 15) = 3.68 and Fcal = 773.54)
and at the end of 8th hour was observed in the formulation F1
to F3. For the formulations F4 to F6, (P <0.05, Fcrit (2, 15)
1.00 = 3.68 and Fcal = 413.79) at the end of 1st hour, (P <0.05,
F1
Fcrit (2, 15) = 3.68 and Fcal = 1153.28) at the end four
F2 hours, (P<0.05, Fcrit (2, 15) = 3.68 and Fcal = 971.43) at
F3 the end of 8th hour, as the polymeric proportion increased
0.50 F4
F5
from 10% to 15% and viscosity grades of HPMC increase
F6 from Methocel E50 to K15M.

0.00 3.3 Release kinetic studies

0 2 4 6 8
Time (h) The in vitro drug release data obtained were fitted to
Fig.2. First order plot of Ranolazine release from matrix tablets kinetic models viz., Zero order (Fig.1), First order (Fig.2),
 Md. Mofizur Rahman et al., Int J Pharm Biomed Res 2011, 1(5), 172-177 176

Higuchi (Fig.3), Korsmeyer-Peppas (Fig.4) and Hixson-

100
Crowell equations (Fig.5) to know the pattern of drug release
and mechanism of drug release from the matrix tablets. In
this experiment, the in vitro release profiles of drug from all
Cumulative percentage drug release

80
formulations could be best expressed by Higuchi as the plots
showed highest linearity (R2 = 0.985 to 0.997) (Table 2). It
60
confers that drugs are released by diffusion. To confirm the
release mechanism, the data were fitted into Korsmeyer-
40 Peppas equation. All the formulations showed good linearity
F1
F2
(0.97 to 0.99) with slope (n) values ranging from 0.46 to 0.57
F3 (except F1 and F4, showed Fickian or burst release)
20 F4
indicating that diffusion was the predominant mechanism of
F5
F6 drug release from these formulations indicating that the
0
release mechanism was non-Fickian or anomalous release
0 1 2 3 (0.45 < n <0.89). It can be inferred that the release was
Square root of time (h) dependent on both drug diffusion and polymer relaxation,
which appears to indicate a coupling of diffusion and erosion
Fig.3. Higuchi’s plot of Ranolazine release from matrix tablets mechanisms-so called anomalous diffusion [23]. The good
correlation coefficients (R2 values nearly to unity) observed
for the kinetic parameters based on the first order model
Log time (h)
equation were mainly due to the drug release mechanism.
0.00 0.20 0.40 0.60 0.80 1.00
0.00
First order plot for all formulation showed good linearity.
This indicates that the amount of drug released is dependent
-0.10 on the matrix drug load. The release profile of Ranolazine
from all these formulations displayed very fairly good fitting
Log percentage drug release

-0.20
with Hixson-Crowell cube root model of drug release confers
-0.30
that the drug releases by dissolution and with the changes in
surface area and diameter of the particles or tablets [27].
-0.40 MDT value is used to characterize the drug release rate
F1
F2 from the dosage form and the retarding efficacy of the
-0.50 F3 polymer. A higher value of MDT indicates a higher drug
F4
F5 retarding ability and vice-versa. The MDT value was found
-0.60
F6
to be low for formulation F1 and F4, medium for F2 and F5,
-0.70 and high for F3 and F6 (Table 3). In other words, the
formulations containing higher percentage of Eudragit L 100-
Fig.4. Korsmeyer’s plot of Ranolazine release from matrix tablets 55 and HPMC (E50, K15M CR 1:1, 30%) exhibited a higher
value of MDT and a low value of Higuchi release rate than
that of batch F1 and F2 indicating the higher drug-retarding
2.5
ability of these formulations. An inverse relationship was
found between viscosity grade of HPMC in the formulations
and the MDT values of the dosage form. The MDT value was
Cube root percentage drug release

2.0 found to decrease viscosity of HPMC and Eudragit L 100-55

was increased in the formulations.
1.5

Table 3
1.0 Mean dissolution time of various formulations (F1-F6)
F1
F2
Formulation Dissolution time (h) MDT
F3 T25% T50% T80%
0.5 F4
F1 0.325 1.841 5.961 2.975
F5
F2 0.752 3.484 9.856 5.027
F6
F3 1.054 4.551 12.267 6.316
0.0 F4 0.476 2.272 6.560 3.333
F5 0.946 3.836 9.915 5.153
0 2 4 6 8
F6 1.339 5.077 12.537 6.587
Time (h)

Fig.5. Hixson Crowell plot of Ranolazine release from matrix tablets

 Md. Mofizur Rahman et al., Int J Pharm Biomed Res 2011, 1(5), 172-177
4. CONCLUSIONS
From the study, it is possible to conclude that the
proposed tablet formulations were suitable for direct
compression method. According to the release studies, the
decrease in the release rate was observed with an increase in
the viscosity of the polymeric system. Polymer with higher
viscosity and higher proportion of Eudragit L 100-55 and
HPMC (K15M) was shown to be beneficial than lower
viscosity of HPMC (methocel E50) as well as polymeric
level in controlling drug release. The results of in vitro
release studies indicated the possibility of achieving
sustained release matrix tablets for Ranolazine by the use of
Eudragit L 100-55 and HPMC (methocel E50, K15M CR)
combinations.
ACKNOWLEDGEMENTS
The authors are thankful to Colorcon Asia Pvt. Ltd.,
Bangladesh for their generous donation of various grades of
HPMC. The authors are also thankful to Bangladesh
University, Primeasia University and the University of Dhaka
for their supports and co-operations for the successful
completion of this project.
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