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MECHANISM OF DRUG RELEASE FROM MATRIX
TABLETS INVOLVING MOVING BOUNDARIES
by
BALA JI VENKATARAMANAPPA KADRI
A thesis submitteù in conformity with the requirements for the degree of Master of Science, Graduate Department of Phannaceutical Sciences,
University of Toronto
O Copyright by Balaji Venkatammappa Kadri November ZOO1
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MECHANISM OF DRUG RELEASE FROM MATRIX TABLETS INVOLVING MOVING BOUNDARIES
Master of Science, 2001
Balaji Venkataramanappa Kadri Department of ~harmaceutical Sciences
University of Toronto
ABSTRACT
Dmg release kinetics in relation to surface properties. liquid uptake behavior, and
swelling and erosion of matrix tablets containing dmgs of different solubility has been
studied. Contact angle, liquid uptake and swelling kinetics were studied by goniometry,
gravimetry and microscopy respectively
The contact angle and liquid uptake depended on HPMCnactose ratio and solubility of
the h g . Drug release became sustained with increasing HPMC concentration, because
of poorer wettability, slower hydration and formation of gelatinous layer. During
hydration of the tablets, the movement of three distinct moving fronts narnely swelling,
diffbsion and erosion fronts were obsewed, In the case of indomethacin tablets, the
diffbsion front moved outwards with the erosion front due to the presence of un-dissolved
drug. The correlation between release rate and different characteristics of matrix tablets
has been established based on the solubility of the dmg and the ratio of HPMC to lactose.
1 wish to acknowledge a number of people who contributed to the completion of this
thesis. First, 1 would like to extend my deepest gratitude and appreciation to my
supervisor, Professor X.Y.Wu for her constant encouragement, advice and guidance. 1
would also like to thank the members of my supervisory cornmittee, Professor Piquette
Miller and Professor Chalilcian Tigran for their valuable comments and suggestions. 1
wish to thank my parents, wife and my family for their support, both financially and
emotionally. 1 would also like to thank al1 my colleagues in the laboratory, especially Dr.
Talukdar and Dr. Huang, for their helps in so many ways; Mr. Andras Nagy for making
the dissolution apparatus. Finally 1 wish to acknowledge A p e x Inc. for financial support
of my tuition fee and NSERC for sponsoring the project.
iii
Balaji, V.K. and Wu, X.Y. Mechanism of dnig release from matrix tablets involving
moving boundaries. SYNERGY 2000 at Apotex Inc.
Balaji, V.K. and Wu. X.Y. Mechanism of drug release from HPMCLACTOSE matrix
tablets. AAPS annual meeting, Pharm Sci. vol. 2 (2000) 3146.
Wu, X.Y., Zhou, Y. and Balaji, K.V. Modeling of in vitro and in vivo release kinetics of
matrix tablets with rnoving boundaries of matrix and solid dmg. AAPS annual meeting,
Pharm Sci. vol. 1 (1999) 3321.
Balaji, KY. and Wu, X.Y. Effect of interfacial energy on drug release from rnatrix tablets
involving moving boundaries. Manuscnpt in preparation.
Table of contents
Abstract
Acknow ledgements
i i
iii
Publications ffom this thesis iv
Table of contents v
List of figures
List of tables
Chapter One Introduction
1.1 S tatement of problem
1.2 Scope of the thesis
1.3 Objective
vii
ix
1.4 Literahire review
1.4.1 Matrix tablets 4
1 .4.2 Mechanism of drug release from swellable matrix tablets 5
1.4.3 Polymers and disintegrants 10
1.4.4 Drug solubility
1.4.5 Swelling and diffusion fronts in mabix tablets
1.4.6 Methods used to snidy swelling kinetics 15
Re ferences
Chapter Two Dependence of release kinetics on moving boundaries of
erodible tablets
2.1 Introduction 25
2.2 Materials and methods
2.2.1 Tablets 27
2.2.2 Determination of changes in weight and dimension of
tablets 27
2.2.3 Release kinetics
2.3 Results and discussion
2.3.1 Erosion and release kinetics of ~ r a d o s o l ~ tablets 28
2.3.2 Erosion and release kinetics of ASA tablets 30
2.4 Conclusion 31
Re ferences
Chapter Three Influence of different characteristics on matrix tablets
containing drugs of different solubility
3.1 In trduction 35
3.2 Materials and method
3.2.1 Active dmg 38
3.2.2 Polymer 39
3.2.3 Diluent 39
3.2.4 Media used in this study 39
3.2.5 Manufacture of tablets 40
3.2.6 Surface properties 40
3.2.7 Release kinetics 41
3.2.8 Liquid uptake 41
3.2.9 Swelling kinetics 42
3.3 Results and discussion
3.3.1 Effect of HPMC content on surface properties 43
3.3.2 Effect of drug properties on surface properties 46
3.3.3 Effect of HPMC content and dnig solubility on release kinetics 48
3.3.4 Effect of HPMC content and dnig solubility on liquid uptake study 49
3.3.5 Swelling kinetics
3.3.5.1 Effect of HPMC content and drug solubility on erosion front 5 1
3.3.5.2 Effect of HPMC content and dnig solubility on diffusion front 53
3.3.5.3 Effect of HPMC content and h g solubility on swelling front 55
3.4 Discussion 59
3.5 Conclusion 67
References
Chapter Four 74 Summary and funire research
vi
Lisi of figures
Figure 1.1
Figure 2.1
Figure 2.2
Figure 2.3
Figure 3.1
Figure 3.2
Figure 3.3
Figure 3.5
Figure 3.6
Figure 3.7
Figure 3.8
Figure 3.9
Figure 3.10
Figure 3.1 1
Figure 3.12
Figure 3.13
Variation in solids content within a matrix tablet undergoing dissolution
Weight loss and release studies of Bradosol" tablets
Photographs of Bradosol' tablets in water at different time intervals
Weight loss and release studies of ASA tablets
Different fronts of a swellable matrix tablet
Contact angle studies 0' and 180'
Contact angle studies of tramadol hydrochloride matrix tablets with
different HPMC/LACTOSE ratio of 20:30,30:20 and 40: 10
Contact angle studies of indomethacin matrix tablets with different
HPMC/LACTOSE ratio of 20:30,30:20 and 40: 10
Contact angle of matrix tablets containing different dmgs
Contact angle of matrix tablets containing different drugs
Contact angle of matrix tablets containing different drugs
Dmg release profile of trarnadol hydrochloride matrix tablets with various
HPMCLATOSE ratio of 20:30,30:20 and 40: 10
Dnig release profile of indomethacin matnx tablets with various
HPMCLACTOSE ratio of 20:30, 30:20 and 40: 10
Liquid uptake studies of tramadol hydrochloride matrix tablets with
various HPMULACTOSE ratio of 20: 3O,3O: 20 and 40: 10
Liquid uptake studies of indomethacin matrix tablets with various
HPMCLACTOSE ratio of 20:30,30:20 and 40: 10
Kinetics of the erosion front of tiamadol hydrochloride matrix tablets with
various HPMC/LACATOSE ratio of 20:30,30:20 and 40: 10
Kinetics of the erosion front of indomethacin matrix tablets with various
HPMCLACATOSE ratio of 20:30,30:20 and 40: 10
vii
Figue 3.14 Kinetics of the di fision front of tramadol hydrochlonde matrix tablets
with various HPMC/LACTOSE ratio of 20:30,30:20 and 40: 10
Figure 3.15 Kinetics of the diffusion front of indomethacin matrix tablets with various
HPMC/LACTOSE ratio of 20:30,30:20 and 40: 10
Figure 3.16 Kinetics of the swelling front of tramadol hydrochlonde matrix tablets
with various HPMC/LACTOSE ratio of 2O:3O, 30:20 and 40: 10
Figure 3.17 Kinetics of the swelling front of indomethacin matrix tablets with various
HPMC/LACTOSE ratio of 20:30,30:20 and 40: 10
viii
Ust of Tables
Table 1.1 Summary of methods used for studying swelling kinetics of matnx tablets
Table 3.1 Summary of formulations of the tablets
Table 3.2 Contact angle vs. time intercept plot in degrees, initial work of adhesion
and standard deviation
Table 3.3 Summary of al1 expenrnents of our study
Chapter one
1.1 Statement of problem
The use of controlled-release technology in the formulation of pharrnaceutical product
is becoming increasingly important. Controlled dnig delivery involves the application of
physical and polymer chemistry to produce well characterired and reproducible dosage
forms, which control dnig entry into the body within the specifications of the required
drug delivery profile [l]. In this type of dosage forms, the rate of h g releose is mainly
controlled by the delivery system itself, though it may be infîuenced by extemal
conditions, such as pH, enzymes, ions, motility and physiological conditions [2].
The performance of matrix tablets is strongly dependent on the matrix materials used,
which are normally synthetic or serni-synthetic polymer 131. Synthetic polyrners which
are relatively well known for this purpose are poly(hydroxyalky1 methacrylate),
poly(viny1 alcohol) and their copolymers, poly(ethy1ene oxide). Semi-synthetic polymers
are cellulose ethers such as hydroxypropyl cellulose (HPC), methylcellulose (MC),
hydroxypropyl methylcellulose (HPMC) and sodium carboxy methylcellulose (Na CMC)
141. Depending on the properties of the polymer used, drug release fiom the tablets may
be swelling-controlled, erosion-controlled, multiple mechanism controlled.
Moreover, drug release from matrix tablet depends on other factors such as pore
permeability, shape and size of matrix, h g solubility, polyrner molecular weight, dntg
loading, compression force and hyâroâynamic conditions [5,6]. The compression force
has major control over the porosity, which directly influences the release charactenstics
of the tablet [7].
Drug solubility. hydrophilicity of the polymer. and tablet porosity detemines the rate
of liquid penetration into the tablet [8], and thus influences drug release rate. It has been
found that pore size distribution of the matrix and the permeation pressure of the release
media is defined by its surface tension and contact angle (91.
Swelling of matrix tablet is influenced by the initial wetting of the surface of matrix
tablet, hydrophobicity of the dmg and the arnount and type of polymer in the matrix
tablet [IO]. The property of the gel layer formed by swellable polyrners is the key factor
for prediction of the kinetics of matrix swelling [I l , 121.
The above factors are important in designing of controlled-release matrix tablet.
Therefore they desewe in-depth studies.
I.2 Scope of the thesis
This thesis comprises of a series of studies leading to the developrnent of a
relationship between dnig release kinetics and characteristics like surface properties.
liquid uptake behavior, kinetics of swelling and erosion of matrix tablets and drug
solubility. The rest of this chapter is devoted to the discussion of background information
from existing literature related to this thesis. Chapter 2 presents the study of release
kinetics of cornmercially available erodible tablets in relation to their erosion kinetics.
Chapter 3 focuses on an investigation of the relationship among nlease kinetics, swelling
kinetics, surface energy, and tablet composition such as HPMC content and the type of
dnig. Chapter 3 also includes a discussion of our results with the results of other groups.
The thesis concludes with a summary and recommendation for future work.
13 Objective
The main goal of this study is to correlate dnig release kinetics with surface
properties, liquid uptalce behavior, kinetics of swelling and erosion of matrix tablets
containing drugs of different solubility. The research carried out attempted to answer the
following questions:
1. How is release kinetics dependent on moving boundaries of erodible tablets?
2. What is the effect of composition of tablets and property of dmgs on surface energy of
swellable matrix tablets?
3. What is the effect of composition of tablets and property of dmgs on swelling kinetics
of the matrix tablets?
4. How is release kinetics dependent on the composition of tablêts and property of dnigs?
1.4 &tatute review
l.4.l M* tablets
Tablets are the most extensively used solid dosage forms. They are prepared by
molding or usually compressing a powder coniûining a dmg or dmgs with excipients on
machines called presses.
Conventionai tablets normally comprise the following components:
(1) Active ingredient - for therapeutic considerations
(2) Non-active ingredients - (a) for compressional characteristics of the tablet include
DILUENTS
BINDERS & ADHESIVES
LUBRICANTS, ANTIADHERENTS & GLIDANTS
and (b) those that affect the bio-pharmaceutics, chemical/physicai stability and marketing
considerations of the tablet such as
DISINTEGRANTS
COLORS
FLAVOURS & SWEETENERS
MISCELLANEOUS COMPONENTS - Buffers, adsorbents [13]
Some matrix tablets do not contain disintegrants, so they release their pay-load by
surface erosion. Lozenges such as ~radosol' are erodible tablets.
The goal of controlled delivery systems are to reduce the frequency and 1 or to
increase the effectiveness of the h g by localization at the target site, thereby reducing
the dose required to provide uniform drug delivery. The comrnonly used polymen for
controlled release are HPMC, HPC, HEC, EC, methylcellulose (MC), carboxy
methylcellulose (CMC), polyvinyl pyrrolidone (PVP) and polyethylene glycol (PEG).
These polymers, which swell in aqueous medium, are often used for the preparation of
controlled-release dosage foms. These are highlighted with the presence of a solvent
front, the potential for unlirnited swelling, and the combined controlling mechanism of
diffusion and erosion as king the distinguishing feature of HM devices.
Advantages perceived for some hydrophilic matrix systems are:
1. Simplicity of formulation
2. High dnig loading
3. Reduction in drug blood level fluctuations
4. Reduction in dosing frequency
5. Reduction in adverse side effects and
6. Rcduction in health care costs i.e., economy [14].
1.4.2 Mechanh of drug releasefrom swelbble mriirix tablets
Controlled dmg release is based on diffusion through polymers, erosion of polyrners
and special polymer characteristics such as osmotic and ion exchange properties.
When a glassy (or dry) polymer cornes into contact with water or any other medium with
which ii is thennodynarnically compatible, the solvent penetrates into the free spaces on
the surface between the macromolecular chahs. When enough solvent has entered into
the maaix, the glass transition temperature (Tg) of the polymer drops to the level of the
experimental temperature (which is usually 37OC) except for poly(ethy1ene oxide) whose
Tg is approxirnately -60°C. Therefore polymers with a Tg pa t e r than 37OC in their dry
(glassy) state can be used to prepare swelling controlled-release dosage foms. The
presence of solvent ia the glassy polymer causes stresses. which are then accommodated
by an increase in the radius of gyration and end-to-end distance of the polymer
molecules, i.e., the polymer chahs get solvated. The increase in the radius of gyration of
the polymer molecules is seen macroscopically as "swelling of the matrix". The solvent
molecules move into the glassy polymer matrix with a well-defined front at a particular
velocity and simultaneously, the thickness of the swollen or rubbery region increases
with time in the opposite direction. The time taken for the increase in radius of gyration
of the polymer molecules, which is a relational phenomenon, is a characteristic for that
particular polymer/solvent systern [4].
A matrix tablet dunng swelling is an aggregate mass of water-swollen polymer, drug,
and excipients experiencing various degrees of hydration or solution as illustrated in
Figure 1.1. The tablet contains regions with solid content varying from O to 100%. In the
ana near 100% solids, the gel is a wetted mass of powders. As water content of the
wetted powder mass increases, the polymer becomes hydrated and develops into a gel. At
the outer most layers, the polyrner is diluted to the point where it no longer has structurai
integrity and dissolves or wears away. This cornplex gelatinous layer controls the release
of dnigs by two mechanisms.
1. Water-soluble dmgs released by diffusion out of the gel layer.
2. Drugs released by erosion of the gel regardless of dnig solubility in the dissolution
media. A water insoluble dnig is exposed through erosion.
Dry tablet
Expnsim af the gel layer takes piacewith die fOtlllSLtim of
cmèmlt fîmts
Figure 1.1 Vaiiotion in s d i d r cmtent wahh a AicrhLt &blet undergoing dissoluth
- When dmg released from a matrix is controlled by diffusion ihrough the polymeric
matrix, its release kinetics obey Fick's 1" and 2" daws [15]:
Where J represents the diffusional flux of the dmg; D i s the diffusion coefficient of the
h g ; C is the concentration of the h g ; and x the distance of diffusion.
For a planar rnatrix, whose shape is close to a flat thin tablet, with dmg loading lower
than or equal to dnig solubility (C&Cs), the fraction of dmg released from the matrix into
a perfect sink by time t is described by Crank [15]:
where a is the thickness of the matrix and D is the diffusion coefficient. A simplified
equation cm be used for early tirne, e.g. M' 1.0.6, M,
Equation 1.4 suggest a square-rwt relaticn,
- When drug release is dominated by surface erosion, Hopfenberg's equation provides
good prediction for sphencal, cylindrical, and planar geometries (see details in Chapter
two). When dnig loading is much higher than dnig solubility ( C d S 3 , Higuchi's mode1
provides good approximation for planar matrix in a perfect sink. though it was initially
developed for drug release from ointment bases containing drugs in suspension [16].
Later Korsmeyer and Peppas developed a general mode1 for drug release fiom a planar
matrix containing dissolved drug, i.e., ( C M , ) :
M log- = logk + nlogt
M"
M Where 2 is the fractional release of the drug, t denotes the release time, K represents a
M,
constant incorporating structural and geometric characteristics of the release device, and
n is the time exponent indicative of the release mechanism for a slab. This equation
includes two cûug transport mechanisms, which are only valid for slab geometry: Fickian
diffusion (n=0.5 for square root of time kinetics) and case II transport (n=1 for zero-order
release kinetics) which means that dnig release rate is independent of time.
The dnig release kinetics and its exhibition of Fickian or case II dmg transport can
also ôe mechanistically analyzed using a novel dirnensionless analysis. Peppas and
Franson 1171 who introduced the swelling interface number, Sw, studied the physical
conditions that determine the kinetics of dmg release from swellable matrix. This number
compares the mobility of the solvent front relative to dmg mobility in the presence of
polymer relaxation and is detined as:
Where u is the velocity of the penetrating swelling front, d ( f ) represents the tirne-
dependent gel thickness and D is the h g diffusion coefficient in the swollen phase.
Values of S, near unity indicate anomalous transport, whereas values much greater
than 1 indicates Fickian diffusion, and values much lower than 1 indicate case II transport
[W*
To analyze the experimental results about dmg release from moving fronts of limited
swelling hydrophilic matrices, the following equation can be used:
dMJSdt=n COW" ( 1 .9)
Which represents the release velocity per unit area. Ractically Equation 1.9 was used for
the determination of n. and this value can be determined by a graphic representation of
dmg percentage (MiIM-) versus time 151.
Since, swellable matrix tablets normally contain a high dmg content (CX,), and the
polymer matrix experiences swelling and erosion none of the above mentioned models
can be applied.
1.4.3 Polymers and disintegrants
S yn thetic pol p e r s li ke pol y(h ydrox yeth y lmet hacrylate) (HEMA), poly(viny1 alco hol)
(PVA), poly(ethy1ene oxide) (PEO) and cellulose ethers like HPMC, HPC, MC and Na
CMC have been widely studied for controlled release [4, 18, 19,201. Cellulose ethers are
found to accommodate a large percentage of drugs and are easy to use in tablets. They are
also very stable over a wide range of conditions. In the presence of strong acid, water and
heat a cellulose ether polymer will àegrade by chain scission causing a loss of average
molecular weight or viscosity. HPMC is often used to prepare matrix of SR tablets
because the polymer is non-toxic, easy to handle and do not require any special
manufachuing technology [2 1-24].
Many factors affecting the release of drugs from cellulose matrices have ken
investigated. Alderman [l] studied various polymers and formulation variables such as
polymer molecular weight, chemical substitution, particle sizes and hydration rate.
Significant formulation variables such as polymer content, dosage form, dosage size and
manufacturing process were also dealt. From a cornparison of various polymers, it was
found that one important polymer property should be that the polymer must hydrate
quickly to fonn a gel layer before the contents of the tablet can dissolve prematurely. It
was evident that HPMC 2208 (methocel K4M premium) and carboxy vinyl polymers c m
release dmgs for longer time by quickly foming a gel layer. The particle size of polymer
is a key parameter becauss it affects hydration rate and thus the rate of gel formation and
dnig release.
Another important factor is viscosity of the polpers, which is higher as the molecular
weight increases. If the viscosity of the polymer increases, the gel layer viscosity also
increases, so that the gel layer becomes resistant to dilution and erosion. The dmg release
rate is then slower.
Like viscosity of the polyrner, the concentration of polyrner can also affect the
strength of the gel. The increase in polyrner concentration can result in stronger
difisional layet that is resistant to difhision or erosion. Ultimately this will slow drug
release. Aiderman [1] concluded: 1. Dnig release becarne more sustained with increasing
poiymer concentration or viscosity grade; 2. Different levels of rnethyl and
hydroxypropoxy substitution resulted in intrinsically àifferent hydration rates, which
&- affected the performance of the polyrner in the initiai stages of tablet hydration; and
3.Different substitution levels gave nse to different dnig release profiles, principally as a
result of differences in gel strength and susceptibility to erosion.
Size and shape (e.g. tablet or capsule) of matrix are other factors. For instance smaller
tablets will generally require higher polymer content. An increase in tablet size can result
in slower h g release due to a smaller surface to volume ratio and a smaller amount of
initial gel formation.
Swellable insoluble polymers and non-swellable insoluble fillers are used to modify
the release of drug in the early stages of dissolution. These fillers tend to expand the gel
layer and cause more dmgs to be released in the early stages, and thus function as
disintegrants. These include swellable insoluble fillea, e.g. MCC, cross-linked CMC, and
non-swellable insoluble tillers e.g. dicalcium phosphate. With non-swelling insoluble
polymea the gel layer is unable to swell uniformly. It causes intemal stress and results in
cracks, so that the tablet disintegrates prematurely.
Carmella et al. [25] studied the role of disintegrants in the swelling process, which
was carried out by studying a number of disintegrants available in the market. They used
various methods like X-ray analysis, rnicroscopic observation, particle volume increases
and hydration or solvation capacity. It was suggested that swelling could happen in ways
like capillary swelling and molecular swelling. So capillary and pore wetability are
important in the development of the sweiling force. The whole process involved the steps
of disintegration in the sequence of water penetration, particle swelling of the
disintegrant, force development and bond disruption. Nevertheless, swelling is the
--- - . goveming factor regarding the kinetics of the whole process. since it is linked to both
water penetration and force development.
1.4.4 Dtug solubiliry
In order to identify the different factors like solubility or the molecular size of the
solute influencing the release through cellulose matrices. Ranga Rao et al. [26] studied
the release rate of 27 dmgs with various solubilities and molecular weights through
HPMC and HPMC + Na CMC. Several less soluble drugs were released at a neariy zero
order rate through HPMC matrices, which indicates that the solubility of the drug plays
an important role in release behavior.
Ford et ai. [27] reported similar observations by studying the release of 7 soluble and
insoluble dmgs through HPMC matrices. The drugs of low aqueous solubility showed a
considerable lag time, before 4 5 kinetics (see equation 1.4) is obeyed. The lag times
are probably due to poor wetting of these dmgs with low aqueous solubility.
The swelling controlled release systems consist of a drug molecularly dissolved or
dispersed at high concentration in a polymer matrix. If the drug has a limited solubility in
the swollen polymer matrix, it is probable that an undissolved dnig front will be observed
within the continuously swelling polymer gel layer. Lee [28] using theoretical moàels for
the case of bio-erodible systems first made this observation. In addition, Peppas and
collaborators 129) indicated that in swellable matrix tablets, cirug dissolution might be
responsible for an observed zero-order release mechanism. Later Lee [30] observed a
h g dissolution front due to a limited solubility phenomenon.
L4.5 Sweüing and d&sbn fionts in nicinu tablets
Peppas [17.31] et al. studied the swelling and release process of matrix tablets and
observed swelling, dnig diffision and erosion fkonts. These fronts are sharp boundaries
separating various thermodynamic states of the polymer or various phases of the matrix,
which may be correlated with drug release kinetics. In their work, Peppas et al. studied
the influence of polymer molecular weight, matrix porosity, pH and ionic strength of the
dissolution medium. Matrix tablets were compressed by a wet granulation method.
Release kinetics was determined using USP II dissolution apparatus. The dnig used was
yellcw in color, which when dissolved in water gave a bright orange solution. This
helped in identifying clearly not only the boundaries between the glassy and rubbery
states of the polymer but also the boundary between the un-dissolved and the dissolved
dmg in the polymer gel state. It was noted that the dnig release was influenced by
polyrner molecular weight, probably because at high molecular weights, the polymer was
entangled and the effective molecular difision area was nduced. It was found that the
arnount of drug released increased with the increase of porosity because tablets with
higher porosity had a larger lateral ma . It was also shown that the amount of drug
released was significantly higher at pH 1.2 than at pH 7.4, and the dnig diffision front
movement was the main parameter affecting dmg release rate [16]. The role of polymer
relaxation stress on drug transport in swellable matrices was very evident in the case of
insoluble h g s where the undissolved / dissolved dnig boundary outward movement
indicated dnig particle displacement in the gel layer [32].
Belen Pirez-Marcos et al. [33] studied the effect of carbomer of different molecular
weights on the release rate of furosemide. Carbomers are a group of acrylic acid
A b derivatives, commercially hown as ~arbopol? As aforrmentioned, the solubility of the
dnig played an important role in the release behavior, which was also pointed out by
Aldeman [1] and confirmed by Ford et al. [27] and Ranga Rao et al. [4]. From the
crushing strength test of tablets, it was clear that dl three carbomers had similar surface
behavior. The friability and release profiles did not have any difference. The compression
force was major control over the scope of porosity parameter. They concluded that the
release mechanism was matrix erosion.
1.4.6 Methds used to study swelüng kinetics
Many methods have been applied to study swelling kinetics of matrix tablets, as
summarized in Table 1.1. Talukdar, M.M. and Kinget, R. [IO] studied high molecular
weight xanthan gum, which is prodwed by fermentation. They studied the swelling of
xanthan matrix tablet by measuring the radial and axial expansion of the tablet. The other
methods like weight gain, photographie technique and image analysis have not ken
studied here. The axial swelling showed that xanthan gum retarded drug release for a
long time. From radial swelling, the swelling and erosion was observed. The swelling
kinetics followed square mot of time profile. It was concluded that soluble dnigs were
released via. diffusion mechanism, whereas insoluble drugs by mechanism of erosion.
In order to look into the reasons for the previously observed difference in retarding
ability of dnig release, Talukdar, M.M. et al. [34] studied difision of three mode1 dmgs
by using two hydrophilic polymers, xanthan p m and HPMC. Again higher ability of
xanthan gum than HPMC to retard the release of h g was observed. The release rate and
diffisivity of soluble drugs increased with increasing salt concentration, while with the
insoluble drugs, the release rate decreased and the diffisivity increased with increasing
*-.A salt concentration. The final conclusion was that, other than diffusion, erosion also
contributed to the release of insoluble dnig from xanthan gum matrix tablets.
Other significant factors such as dmg solubility, polymer molecular weight, drug
loading dose, compression force and hydrodynamic conditions of dnig release from a
swellable hydrophilic delivery system have also been studied by another group [26].
Nishihata et al. 1351 studied sustained release tablet matrices prepared using HPMC
2910 of different viscosity and three different drugs of different solubility: methylpanben
(MP), propylparaben (PP) and U-78875. The tablets were prepared by granulating the
active compound with cornstarch and purified water, and blending the granulated
material with HPMC and lactose. The weight change of the tablets during release was
monitored. Solubility results indicated that MP was soluble, PP was reasonably soluble
and U-78875 was poorly soluble in the test medium. The wet weight of the tablet
prepared with HPMC 2910 4000 cps. increased with time indicating infiltration of
medium into intersperse of the tablet matrix. This was followed by swelling and erosion
of the matrix tablet. Surface erosion of the tablet was also observed. The drug release also
depended on the amount of dmg loaded and the solubility of dnig in the matrix.
The swelling of matrix tablets were studied, by Gao et al. using optical imaging (361.
The matrix tablets were prepared using different ratios of HPMCAactose and different
grades of HPMC. It was shown that the dmg release rate decreased with increasing
HPMC content and the dnig release rate decreased with increasinp molecular weight
[W.
Many approaches have been undertaken to study the swelling process and characterize
moving fronts (see Table 1.1). Some of the approaches used in the past are NMR imaging
techniques to study dimensional changes, a modified Enslin apparatus to study water
uptake and swelling. Other spectrometry techniques such as Rutherford back-scattering
spectrometry, electron spin resonance have also been applied to study liquid transport in
polymers. But the rnost used method is optical image analysis due to its accuracy and low
cost.
Moussa et al. [1 il studied moving fronts in cross-linked amylase [CLAI tablets.
Analysis of the swelling profile of CLA tablets was conducted for both radial and axial
direction. The degree of cross-linking had a significant influence on the swelling
properties of the matrix. In fact, equilibnum swelling degree of the tablets in the axial
direction increased with an increase in the degree of cross-linking of the polper. The
swelling rate was higher in the axial direction than in the radiai direction, probably due to
a greater contact surface area of the axial sides of the tablet with the solvent medium.
Also the percentage swelling at equilibrium was more prounced in the axial direction
compared to the radial direction probably linked to the influence of compression force
exerted mainly on the axial side of the tablet. Theu result also showed that reducing the
degree of cross-linking led to a significant decrease in the degree of swelling of the
matrix and drug release rate. The values obtained from image analysis were compared
with the data by gravimetry. Both showed excellent agreement. suggesting that image
analysis is an effective tool for studying swelling and solvent transport in large matrices.
Hat et al. [38) developed a mode1 to describe drug release from erodible tablets, based
on Hopfenberg's equation (see equation 2.1). Amoxicillin trihydrate tablets containing
polyrner were prepared and dissolution studies were also canied out. The erosion studies
were done using USP 1 basket method. At the end of the release experiments the matrix
- - A -- - was completely dissolved suggesting that the dnigrelease be controlled by tablet erosion.
Al1 of the formulations exarnined had a low degree swelling. The erosion rate constant
obtained from the axial direction was higher than in the radial direction. implying that the
different gel properties exist in the axial and radial directions. Results of the erosion
studies demonstrated that an erosion mechanism contmlled the dmg release.
19
- A v - . Tuble 1.1 Surnmaty of Methods Usedfor Studying SweUiRg Kinelies of M m Tablets
Author's Name Carmella, et al. [25]
peppw et al. [17]
Talu kdar, et al. [IO]
Gao, et al. 1361
Moussa, et al. [ I l ]
Pwpose of study The role of disintegran t in swelling process
Swelling and release process
To measure the radial and axial expansion of the tablet Characteriz ation of swelling
To snidy radial and axial swelling profile
Methods Used X-ray analysis, rnicroscop y, particle size hydration or solvation capacity
--- - -
Photographie technique
Graphic paper
Optical imaging
Image analysis, scanning electron microscop y
Observation
1. Swelling could happen in capillary swelling and moleculai swelling 2. Steps of disintegration in sequence are water penetration, particle swelling of disintegrant, force development and bond disruption 1. Clearly identi fied boundaries between the glassy and rubbery state 2. Observed front between undissolved and the dissolved drug in the polymer gel state 1. The axial swelling showed that xanthan gum retards dmg release for a long time. 2. From radial swelling, the swelling and erosion was observed
1. Swelling is isotropic with a preferential expansion in the axial direction. 2. Swelling is isotropic with respect to the gel layer thickness and composition in both axial and radial directions. 3. The gel layer develops in 3 stages. 4. Water penetration is Ficlcian in nature. 1. Swelling kinetics was faster in the axial direction than in the radial direction due to p a t e r contact of surface area of the axial sides of the tablet with the solvent medium, and also due to compression force exerted mainly on the axial sides of the tablet.
References Aldeman, D.A.9 A review of cellulose ethers in hydrophilic matrices for oral
controlled release dosage fom. Int. J. Pharm. Tech. Prod. Manuf., 5 (1984) 1-9.
Shah, A. C. Design of oral sustained release dmg delivery systems: in vitro / in vivo
considerations. In: oral sustained release formulations design and evaluation. Yacobi,
A. and Halperin-Walega, E. Pergamon press, New York (1988) 35-36.
Melia, D. C. Hydrophilic matrix sustained release systems based on polysaccharide
carriers. Critical Reviews in Therapeutic Dnig Carrier Systems. 8 (1991) 395-42 1.
Rao, K.V.R. and Devi. K.P. Swelling controlled release systems: recent developments
and applications. Int. J. Pharm. 48 (1988) 1- 13.
Veiga, F., Salsa, T and Pina, M.E. Oral controlled-release dosage forms II glassy
polyrners in hydrophilic matrices. Drug Dev. Ind. Pharm. 24 (1998) 1-9.
Kim, H. and Fassihi, R. Application of binary polymer system in dnig release rate
modulation 2. influence of formulation variables and hydrodynamic conditions on
release kinetics. J. Pharrn. Sci. 86 (1997) 323-328.
Mitchell, K., Ford, J.L., Armstron, D.J., Elliott, P.N.C., Rostron, C. and Hogan. J.E.
The influence of concentration on the release of dmgs from gels and matrices
containing eth hoc el^ 1nt. J. Pharm. 1 0 (1993) 155-163.
Mehta, KA., Kislalioglu, M.S., Phuapradit, W., Waseem Marlick, A. W. and Shah,
No H. Effect of formulation and process variables on porosity parameters and release
rates h m a rnulti unit erosion matrix of a p r l y soluble dmg. J. Contr. Rel. 63
(2000) 201-21 1.
9. Singh, P.. Desai, J.S., Simonelli, P.A. and Higuchi, LW. Role of wetting on the rate of
dmg release from inert matrices J. P h m . Sci. 57 (1968) 2 17-226.
10. Talukdar, M.M. and Kinget, R., Swelling and drug release behavior of xanthan p m
matrix tablets. Inter. J. Phann. 120 (1995) 63-72.
Il. Moussa, I.S. and Cartilier, L.H. Characierkation of moving fronts in cross-linked
amylase matrices by image analysis. J. Contr. Rel. 42 (1996) 47-55.
12. RajabiSiahbwmi, R., Bowtell, R.W., Mansfield, P., Davies, M.C. and Melia, C.D.
Stnicture and behavior in hydrophilic matrix sustained release dosage forms: 4.
Studies of water mobility and diffusion coefficients in the gel layer of HPMC tablets
using NMR imaging. P h m . Res. 13 (1996) 376-380.
13. Libermann, Pharmaceutical Dosage Forms: Tablets part 1. Marcel Dekker Inc. New
York (1990).
14. Agis kydonieus, Treatise on Controlled Dnig Delivery. Marcel Dekker Inc. New
York (1991) 15-21.
15. Crank, J. The mathematics of Difision, Oxford University Press, London (1975).
16. Colombo, P., Bettini, R., Massirno, O., Catellani, P.L., Santi, P. and Peppas, N.A.,
Drug diffusion front movement is important in drug release control from swellable
maüix tablets. J. P h a m Sci. 84 (1995) 991-997.
17. Colombo, P., Bettini. R. and Peppas, NA., Observation of swelling process and
diffusion front position during swelling in hydroxypropyl methyl cellulose (HPMC)
matrices containing a soluble drug. J. Contr. Rel. 61 (1999) 83-91.
18. Salsa, T., Veiga, F and Pina, M.E. Oral controlled-release dosage forms 1 cellulose
ether polymers in hydrophilic matrices. Drug Dev. and Ind. Pharm. 23 (1997) 929-
938.
19. Langer, R.S. and Peppas, N.A. Fresent and future applications of biomaterials in
controlled dnig delivery. Biomaterials 2 (1 987) 20 1-2 14.
20. Hogan, J.E. Hydroxypropyl methylcellulose sustained release technology. Dmg Dev.
and Ind. Pharm. 15 (1989) 975-1000.
21. Shah, A.C., Britten, N.J., Olanoff, L.S. and Basalamenti, N.J. Gel-matrix systems
exhibiting bimodal controlled release of oral drug delivery. J. Contr. Rel. 9 (1989)
169- 174.
22. Tahara, K., Mikawa, M., Yokohoma, S. and Nishihata, T., Characteristics of intestinal
absorption of adinazolam and in vivo evaluation of oral sustained release tablets of
adinazolam in beagle dogs. Int. J. Phami. 99 ( 1993) 3 1 1-320.
23. Skoug, J.W., Borin, M.T., Fleishaker. J.C. and Cwjxr, A.M., In vitro and in vivo
evaluation of whole and half tablets of sustained release adinazolam mesylate. Pharm.
Res. 8 (1991) 1482-1488.
24. Brazel. C. S., and Peppas, N. A. Modeling of dmg release from swellable polymen.
Eur. J. Pharm and Biopham. 49 (2000) 4758.
25. Caramella, C., Colombo, P., Conte, U., Gazzaniga A., and La Manna, A. The role of
swelling in the disintegration piocess. ht. J. Pham. Tech. & M. Mfr. 5 (1984) 1-5.
26. Rao, K.V.R., Devi K.P. and Buri, P. Influence of molecular size and water solubility
of the solute on its release f'rom swelling and erosion controlled polyrneric matrices.
J. Contr. Rel. 12 (1990) 133-141.
-- %.
27. Ford, J.L., Rubinstein, M.H., McCaul, F., Hogan, J.E. and Edgar, P.J. Importance of
dnig type, tablet shape and added diluents on ârug release kinetics from
hydroxypropyl methyl cellulose matrix tablets. ht. J. Pharm. 40 (1987) 223-234.
28. Lee, P.I., Diffusional release of a solute from a polymeric matrix approximate
anal ytical solution. J. Membr. Sci. 7(l98O) 225-275.
29. Gumy, R., Doelker, E. and Peppas, N.A. Modeling of sustained release of water-
soluble dmgs from porous, hydrophobic polymers. Biomaterials 3 (1982) 27-32.
30. Lee, P.I., J. Contr. Rel. 2 (1985) 227.288.
31. W n i , R., Peppas, N.A. and Colombo, P., Polyrner relaxation in swellable matrices
contributes to dnig release. Procee. Int'l. Symp. Control. Rel. Bioact. Mater. 25
(1998) 125.
32. Perez-Marcos, B., Gutierrez, C., Gomez-Amoza, J.L., Mutinez-Pacheco, R., Souto,
C. and Conchiero, A. Usef'ulness of certain varieties of carborner in the formulation of
hydrophilic furosemide matrices. Int. J. Pharm. 67 (199 1) 1 13-12 1.
33. Gao, P., Nixon, P. R. and Skoug, J. W. Diffusion in HPMC gels II. Rediction of drug
release rates from hydrophilic matrix extended release dosage forms. Pharm. Res. 12
(1995) 965-971.
34. Taiukdar, M.M. and Kinget, R., Comparative study of xanthan gum and
hydroxypropyl methylcellulose matrices for controlled-release dmg delivery II. Drug
difision in hydrated matrices. Inter. J. Pharm. 15 1 (1997) 99-107.
35. Tahara, K., Yamamoto, K. and Nishihata, T., Overat1 mechanism behind matrix
sustained release (SR) tablets prepared with h ydrox yprop y1 meth ylcellulose 29 10. J.
Contr. Rel. 35 (1995) 59-66.
36. Gao, P. and Meury, R.H. Swelling of hydroxypropyl methylcellulose matrix tablets.
1. Charactenzation of swelling, using a novel optical imaging methoà. J. Pharm. Sci
85 (1996) 725-73 1.
37. Gao, P., Skoug, J.W., Nixon, P.R., Ju, T.R., Stemm, N.L. and Sung, K. Swelling of
hydroxypropyl methylcellulose matrix tablets 2. Mechanistic study of the influence of
formulation variables on matrix performance and dnig release. J. Pharm. Sci. 85
(1996) 732-740.
38. Katzhendler, L, Hoffman, A., Goldberber, A. and Friedman, M. Modeling of drug
release from erodible tablets. J. Pharm. Sci. 86 (1997) 1 10-1 15.
39. Talukdar, M.M. and Rombaut, P. and Kinget, R. The release mechanism of an oral
controlled-release delivery system for indomethacin. Pharm. Dev. and Tech. 3 (1998)
1-6.
40. Wu, X. Y. and Zhou, Y. Finite element analysis of difisional drug releases from
complex matrix systems. J. Contr. Rel. 5 1 (1998) 57-7 1.
41. Colombo, P., Catellani, P.L., Peppas, N.A.9 Maggi, L. and Conte, U. Swelling
characteristics of hydrophilic matrices for controlled release new dimensionless
number to describe the swelling and release behavior. Int. J* Pharm. 88 (1992) 99-
109.
42. Ferrero, C., Munoz-Ruiz, A. and Jimenez-Castellanos, M.R. Fronts movement as a
usehl twl, for hydrophilic matrix release mechanism elucidation. Int. J. Pharm. 202
(2000) 2 1-28.
Chqpter Two Dependence of Release Enetics un Moving BoundMes
of Erodible Tables
2.1 Introduction
In erosion controlled monolithic systems. the dnig is distributed uniformly throughout
the polymer matrix and the difhision rate of the drug in the matrix is very slow compared
to polymer dissolution. The difference between erodible systems and nonerodible
systems is that the polymer phase in non-erodible system rernains unchanged with time
and drug is released by diffusion, while the polymer phase in erodible system decreases
with time [4].
Drug release from surface-eroding devices with various geometries, was analyzed by
Hopfenberg et al. [20]. They developed dissolution models describing the instantaneous
drug release from spheres, tablets, cylinders, and other shapes undergoing surface
erosion. Hopfenberg proposed a general mathematical equation describing dnig release
fiom slabs. spheres, and infinite long cylinders controlled by heterogeneous, i.e., surface
erosion:
MJM- = 1 - [1 - kot/&ln (2.1)
Whmc Mt is the amount of h g rcteascd frwi the device in time t, Mm is the total
amount of drug released when the device is exhausted, and 4 is the erosion rate constant.
Co is the uniform initial concentration of drug in the matrix, and is the initial radius for
a sphen or cylinder or the half-thickness, n=l for a slab, n=2 for a cylinder, and n=3 for a
sphem.
Equation 2.1 suggests a linear relationship between MtIM- and t for a slab if surface
erosion is a dominant mechanism of h g release. RecentIy, Mockel and Lippold [1] have
shown that the zerwrder release behavior is due to the erosion front movement, which
controls the drug release rate.
Heller [2,3] considered erodible systems in terms of k e e dissolution mechanisms:
(1) water-soluble polymers insolubilized by degradable cross-links; (2) water insoluble
polymers solubilized by hydrolysis, ionization. or protonation of pendant side groups and
(3) water insoluble polymers solubilized by backbone-chah cleavage to small water-
soluble molecules. These mechanisms represent extreme cases. and erosion by
combination of mechanism is possible.
The erosion mode of the delivery system is one of the factors controlling drug release.
There are two different modes of erosion: surface (heterogeneous) and bulk
(homogeneous) erosion. In bulk-degrading devices. degradation occurs homogeneously
throughout the bulk of the device. In surface-degrading devices, however, degradation is
confined to the outer surface of the device [12]. The rate of dmg release fkom a surface-
eroding device is determined by the relative contribution of the dmg diffusion and the
degradation of the matrix.
In order to undeatand the release kinetics of erodible tablets in relation to their weight
change, some commercially available products were used in this study. Both erosion rate
and release rate were detennined and correlated.
2.2 McrterCaIs and methods
2.2.1 Tablets
Commercially available lozenge, ~radosol@, erodible tablets containing 5 mg of
hexylresorcinol (Ciba-geigy Canada) and USP non-disintegrating tablets of acetyl
salicylic acid containing 300 mg of pure dnig (U.S.P.C. hc.) and weighing lgram and
0.2 grams respectively, were used in this study.
2.2*2 Detemination of changes in weighf and dimension of tablets
Above mentioned tablets were placed on a metal mesh in such a way that the medium
could penetrate the tablet fkom dl sides of the tablet and its dimensional change could
occur freely. The mesh and the tablet were placed in a water-jacketed container
containing 50ml distilled water for ~radosol" or 0.05M pH 7.4 phosphate buffer for
ASA tablet. The metal mesh was hanged to a balance and the weight was recorded versus
time. The weight change was calculated as a hinction of time. The dimensional change of
~radosol' tablet was also studied by photographing at different time intervals.
2.2.3 Releose kinetics
The release studies were carried out using a Cary 50 probe UV-Visible
spectrophotometer. The tablet was placed on a USP dissolution basket and immersed in
distiiled water for ~radosol' and in 0.05M pH 7.4 phosphate buffer for ASA tablet
respectively, in a 500-1111 water-jacketed beaker. A fiber optic probe was located in the
medium above the tablet and absorbance of the solution was measured at different times
at a wavelength of 280 nm for ~ radoso l~ and 294 nm for ASA tablets, respectively. The
calibration curves were obtained by making dilutions according to the amount of active
mentioned on the label.
2.3 Results and discussion
2.3.1 Erusion and release kinerin qf BIWIÙSOP rablets
The weight loss and the mount of dmg released from ~radosol" are plotted in Figure
2.1 as a function of time. It is shown that the erosion rate of the matrix is near constant
and the release rate is steady up to 90% of dnig released. This near zeroorder release
suggests that the release is erosion-controlled. However a significant difference between
the two curves is noticed: the release curve is faster and less linear than the weight loss
curve. This phenornenon may be ascribed to water uptake by the tablets, which adds more
weight to the tablets. Furthermore, drug diffusion plus erosion rnay also contribute to a
faster release than erosion only. In fact, a fast initial hydration of the tablets was observed
in water uptake, supporting this interpretation.
O 10 20 30
Time (minute)
Figure 2.1 Weight loss Md telease studios of ~mdosot@ tablets (nd) contaifiing 5 müligrams of hexylresorcinoi. Stananl devicilion LF srnalier than the symbols
The photographs shown in Figure 2.2 were taken at different time intervals during
the erosion studies. It is clearly visible that the tablet is undergoing surface erosion, with
the corners eioding faster. This agrees with the previous prediction by Wu and Zhou that
water penetration at the corners of a cylindrical matrix is faster [2 11.
Figure2.2 Photogrcr;phs of B ~ O S O P tablets in water a& different time intetvals
2.3.2 Erosion and release kànetics MASA tablets
Figure 2.3 depicts that both erosion and drug release rates of ASA tablets are constant
and both sets of data drop on the same line. This result implies that drug release from
ASA tablets may be described as a process that is controlled solely by surface erosion of
the tablet, because, according to Equation 2.1, drug release from a planar geometry
should be zero-order if it is controlled by surface erosion.
W e i g h t loss
O 50 1 00 150
Time (minute)
Figure 2.3 Weight loss and reiease studics of ASA tablets ( n a containing 300 müligrruns of ace@l salkylk acid. Stanhd deviotion i s smaller than the symbols
Our data has shown that the surface erosion of the commercial lozenge tablet,
13radosole, is not uniform in al1 the dimensions witb the corners king eroded faster. In
contrast, the erosion of ASA tablets is more uniform, mainly taking place on the axial
direction. The release profiles appear to follow near zeroorder kinetics as predicted by
theory of drug release ftom an eroâible tablei maintaining constant surface area with time
[ I l . The theoretical mode1 is more applicable to ASA tablets than ~radosol".
Finally the above experimental results of eroàible tablets have demonstrated an
erosion mechanism, which controls the dnig release. At the end of the release
expenments, the matrix was completely dissolved together with the completion of drug
release. suggesting that the dnig release was controlled by tablet erosion [4].
The determination of dnig release by gravimetry and release kinetics can provide
insight into the release mechanism of erodible tablets.
References
Mockel, J.E. and Lippold, B.C. Zero order dmg release from hydrocolloid matrices.
Pharm. Res. 10 (1993) 1066-1070.
Heller, J. Biomaterials 1 (1980) 5 1-57.
Tess, W.T. and Gary W.P. Appl. P o l p . Sci. 22 (1985) 1191-2009.
Katzhendler, I., Hoffman, A., Goldberber, A. and Friedman, M. Modeling of dnig
release from erodible tablets. J. Pharm. Sci. 86 (1997) 110-1 15.
Colombo, P., Bettini, R., Massimo, G., Catellani, P.L., Santi, P. and Peppas, N.A.
Drug diffision front movement is important in drug release control from swellable
matrix tablets. J. Pharm. Sci. 84 (1995) 991-997.
Colin, D. Melia. Hydrophilic matrix sustained release systems based on
polysaccharide carriers. Critical Reviews in Therapeutic Drug Carrier Systems, 8
(199 1) 395-42 1.
Talukdar, M.M. and Kinget, R., Swelling and drug release behavior of xanthan gum
matrix tablets. Inter. J. Pharm. 120 (1995) 63-72.
Talukdar, M.M. and Kinget, R., Comparative study of xanthan gum and
hydroxypropyl methylcellulose as matrices for controlled release drug delivery II.
Drug diffision in hydrated matrices. Inter. J. Pharm., 15 1 (1997) 99-107.
Kim, H. and Fassihi, R. Application of binary polymer system in drug release rates
modulation 2. influence of formulation variables and hydrodynamic conditions on
release kinetics. J. Pharm. Sci. 86 (1997) 323-328.
IO. Hogan, J.E. Hydroxypropyl methylcellulose stustained release technology. Drug Dev.
Ind. Pharm. 15 (1989) 975-1000.
1 1. Shah, A.C., Britten, N.J., Olanoff, L.S. and Basalamenti, N.J. Gel-matrix systems
exhibiting bimodal controlled release of oral dmg delivery. J. Contr. Rel. 9 (1989)
169- 174.
12. Tahara, K., Yamamoto, K. and Nishihata, T., Overall mechanism behind matrix
sustained release (SR) tablets prepared with hydroxypropyl methylcellulose 2910. J.
Contr. Rel. 35 (1995) 59-66.
13. Gao, P. and Meury, R.H. Swelling of hydroxypropyl methylcellulose matrix tablets.
1. Characterization of swelling, using a novel optical imaging method. J. Pharm. Sci
85 ( 1996) 725-73 1.
14. Moussa, I.S. and Cartilier, L.H. Characterization of moving fronts in cross-linked
amylose matrices by image analysis. J. Contr. Rel. 42 (1996) 47-55.
15. Katzhendler, L, Hoffman, A., Goldberber, A. and Friedman, M. Modeling of drug
release from erodible tablets. J. Pharm. Sci. 86 (1997) 1 lû- 1 15.
16. Hogan, J.E. Hydroxypropyl methylcellulose sustained release. Drug Dev. Ind. P h m .
15 (1989) 975-999.
17. Rao, K.V.R., Devi, K.P. and Buri, P. Influence of molecular size and water solubility
of the solute on its release from swelling and erosion controlled polymeric matrices.
J. Contr. Rel. 12 (1990) 133-141.
18 Singh, P., Desai, J.S., Simonelli, P.A. and Higuchi, LW. Role of wetting on the rate of
dmg release h m inert matrices. J. P h m . Sci. 57 (1968) 217-226.
19 Lee, P. 1. Diffisionai release of a solute from a polymeric matrix, approximate
analytical solution. J. Membr. Sci. 7 (1980) 255-275.
20 Hopfenberg. H.B. In Controlled release polymeric formulations; Paul, D. R.. Haris.
F. W.. Eds. ACS Symposium Senes 33; American Chernical Society: Washington,
DC (1976) 26-3 1.
21 Wu. X.Y. and Zhou, Y. Finite element analysis of diffusional drug release from
complex matrix systems. II. Factors influencing release kinetics. J. Contr. Rel. 51
(1998) 57-7 1.
Chapter Three IMuence of Material Properh'es on Swellable
Mahix Tablet Containing B u g s of Dufetent
Solubiliry
3.1 Introduction
Hydrophilic matrix (HM) continues to be a popular and widely used choice for
sustained drug release. A HM tablet is a compressed powder mixture of drug with a
swellable polyrner. In such a swelling controlled release system, the release of a drug is
controlled by one or more of the following processes: the transport of the solvent into the
polymer matrix, swelling of the associated polymer, diffision of the solute through the
swollen polymer, and erosion of the swollen polyrner.
When a HM tablet is placed in water, the medium starts to penetrate the matrix
creating sharp boundaries (fronts) that separate various thermodynamic States of the
polymer or various phases of the matrix. As illustrated in Figure 3.1, depending on the
solubility of the drug, thm fronts can be observed, (1) a swelling front, identifying the
boundary between the glassy polymer (A) and its nibbery gel state (B); (2) a diffision
front, indicating the boundary between the still un-dissolved (solid) dnig (B) and the
dissolved dnxg in the gel layer; and (3) an erosion front, identiîjmg the boundary
between the matrix (C) and the dissolution medium (water or buffer). The polymer
dissolves because of chah dis-entanglement. Thus, there is slow diminution of the
thickness, until finally the tablet disappears. The relative importance of these steps is
dictated by the characteristics of the polyrner and the dnig solubility.
Figure 3.1 Different fronts of a swellable mat& tablet
The movement of these fronts can be used to calculate three important parameters of
the swellingldissolution process: (1) the rate of water uptake, broadly associated with the
position of the swelling front, (2) the rate of dnig dissolution depending on the position of
the diffusion front, and (3) the rate of matrix erosion indicated by the erosion front
position.
The important role that the solubility of the dmg plays in its release behavior was
pointed out by Alderman [ I l ] and confirmed by Ford et al. 1471. In order to identify
whether the solubility or the molecular size of the solute is a primary factor influencing
dmg release from cellulose matrices, the release of 27 dmgs with various solubilities and
molecular weights h m matrices of HPMC and HPMC + Na CMC was studied by Ranga
Rao et al. [29]. Several less soluble drugs were released at a nearly zero-order rate
through matrices of HPMC indicating that the solubility of the drug plays an important
role in the release behavior.
The effect of polymer and diluent ratio has also widely been studied. Gao et al. studied
the effect of HPMCnactose ratio on drug release fiom matrix tablets. It was found that
HPMCAactose ratio modulates drug release rate by altering dmg difisivity [23].
The surface property of hydrophilic matrix tablet cm be studied by measunng the
contact angle of a liquid droplet on the surface of the solid. As shown in Figure 3.2, the
contact angle between a liquid and a solid may be 0'. signifying complete wetting, or
may approach 180' at which wetting is impossible. Since wetting is the first step of
hyâration of HM, the contact angle is a good measun of the easiness of hydration.
Contact angle may change with the size of the droplet. A larger droplet would result in
a greater contact angle for a given liquid-solid interface. For a given initial droplet size,
the contact angle may decrease with time depending on the matrix permeability and the
rate of liquid penetration through the matrix. The latter is deterrnined by pore size,
hydrophilicity and swellability of the matrix. On a surface of HM, an aqueous medium
can penetrate into the matrix readily, leading to a reduction in droplet size. When a gel
layer is fomed by polymer swelling, the rate of liquid penetration decreases. In this
work, the contact angle has been measured as a function of time and the dynamic contact
angle was used to describe the behavior of initial hydration of the matrix tablets.
Figure 3.2 Contact angle studics ff and 180'
The solubility of the drug plays an important role in its release kinetics. On this bais,
matrix tablets containing the water-soluble drug tramadol hydrochloride or the water
insoluble drug indomethacin were used for our study. The tablets of different
HPMCAactose ratios were used in order to get a better understanding of the effect of
polymer / diluent ratio on release mechanism and kinetics. The relationship amongst
release kinetics, surface properties. liquid uptake and kinetics of swelling and erosion of
matrix tablet was studied.
3.2 Mrtterials and merlrod
3.2.1 Dtugs
To investigate the infîuence of dmg propeiries on the release mechanism and kinetics,
two dmgs were chosen, one was k l y soluble in water and the other was insoluble in
water.
Tramadol hydrochloride (Sigma Chernical Co.), a narcotic analgesic, was used. It is
white crystalline, readily soluble in water and its melting point is 180 -181'C. The name
-- - of pmprietary solid dosage form in USA is Ultram.
hdomethacin (Sigma Chemical Co.). which was first introduced in 1962, is an
effective non-steroidal anti-inflammatory (NSAID) agent and a potent inhibitor of
prostaglandin synthesis. Practically insoluble in water; soluble in 1 in 50 of ethanol, 1 in
30 of chloroform, 1 in about 40 of ether; soluble in acetone. It is a white to yellow-tan,
crystalline powder and its melting point is 158 - 162'C.
3.2.2 Polymer
Methocel K4M Premium, HPMC 2208, a commercial product of hydroxypropyl
methylcellulose obtained hom the Dow Chemical Co. was used in the tablets as a
swellable polymer. According to the manufacturer's specification, the nominal viscosity
of a 2% W N aqueous solution of the K4M grade is 4 0 0 cps. It has no ionic charge. and
will not complex with rneta.Uk salts and ionic organics to form insoluble precipitates.
Solutions of HPMC are stable over a wide range of pH between pH 3.0 and 11 .O. A basic
structure of hydroxypropyl methylcellulose is shown below, where R is H, CH3 or
[CH3CH(OH)CH2].
on
OR -09 acpr : 3.2.3 Diluent
Anhydrous lactose from Wisconsin Dairie was used as a diluent. It is primarily beta
Iactose or a mixture of alpha and beta lactose. Lactose is a sugar obtained from milk and
is white to off-white, crystalline particle or powder. It is odorless and slightly sweet
tasting.
3.2.4 Mediai m d in this study
(a) MQ wufer: Distilled deionized water was obtained from a M U Q water purification
system. Hence it is called MQ water h m now on.
(b) R e m o n of pH 7.2 phosphate buffer: To 50 ml of 0.2 M potassium phosphate
monobasic (27.2 gram in 1 0 ml) in a 200 ml volumetric flask, 34.7 ml of 0.2 M (8
grams in 100 ml) sodium hydroxide solution was added, and then a necessary amount of
water was used to make up the volume to 200 ml. This buffer was diluted four times with
MQ water resulting in a pH 7.2 phosphate buffer solution, as per the dissolution
procedure mentioned in a pharmacopoeia [3]
3.2.5 Manufacture of tablets
Matrix tabtets were manufactured using the following compositions:
Table 3.1 Summuty of fornuMons of the tablets
Indomethocin/ Tt~madol Hel*
(Sigma chern. CO.)
Formulation 1 1 50%
Formulation 2
Methocel K4M premium (Dow chem.co.)
Lmctose Anhydrous
(Wisconsin daine)
Powders with the above compositions were mixed and compressed using a CARVER'
hydraulic press at 2000 lbs. with a 6.25mm flat-faced die and punches. These tablets were
Formulation 3
used to study surface properties, release kinetics, liquid uptake and swelling kinetics.
3.26 Surface propertr'es
The contact angle of MQ water or pH 7.2 phosphate buffer on the matnx tablet was
measured with a goniorneter (OLYMPUS PGHM mode1 115). A tablet was placed in the
50% 40% 10%
chamber where the temperature was maintained at 37OC by a thermal stat. A &op of
water or pH 7.2 buffer was placed on the surface of the tablet with a syringe. The contact
angle was read every minute, until constant reading was obtained. The experiment was
repeated for three tablets of each formulation. The average of three readings was then
plotted against square root of tirne.
3.2.7 Releme kinetics
Drug release kinetics was studied in MQ water for tramadol hydrochloride or pH 7.2
phosphate buffer for indomethacin matrix tablets. A USP dissolution apparatus Il was
used with one liter of dissolution medium in the vesse1 for al1 experiments. The paddle
speed was maintained at 50 RPM and the medium temperature was 37OC. The medium
was pumped through connections to the UV cells in order to collect the data
automatically. The absorbance of the dissolution medium was read at 280 nm for
trarnadol hydrochloride and 320 nm for indomethacin respectively using a UV
spectrophotometer (HP8452A).
3.2.8 Liquid uptake
The liquid uptake of the matrix tablet was studied by gravimehic method. A hanging
mesh was placed in a jacketed beaker containing MQ water or pH 7.2 phosphate buffer
for tramadol hydrochloride or indomethacin matrix tablets respectively. The temperature
of the medium was maintained at 37OC. The weight of the tablet was measured using an
analytical balance at predetermined time intervals. The tablet dong with mesh was
removed from the liquid and transfed back to the balance after weighing. During the
weighing time the stop - watch was paused. nie percent weight gain was cakulated by
using the following formula:
% Weight gain = (W2-Wl)X100 Wl
WI = Weight of the dry tablet
W2 = Weight of wet mesh and tabiet - Weight of wet mesh
3.2.9 Swelhg Rinetics
The initial movement of different fronts was studied by measunng the diameter of the
fronts. A hanging mesh with a tablet was placed in a jacketed beaker containing MQ
water for trarnadol hydrochloride or pH 7.2 phosphate buffer for indomethacin matrix
tablets, respectively. The temperature of the medium was maintained at 37OC. The
diarneter of different fronts (see Figure 3.1) was measured at different time intervals by a
microscope (Wild makroskop M420). equipped with a Wild MMS 235 digital optical
accessory. Dunng this time the stop - watch was paused. The diarneter was plotted
against time for each front.
3.3 Rus& and disctlssions
3.3.1 Eflect of HPMC content on surface propertes
Figure 3.3 shows the contact angle of tramadol hydrochloride matrix tablets of
different HPMCAactose ratios as a function of square - root of tirne. The contact angle
was found to increase with an increase in the polymer proportion. In other words,
wettability decreases with an increase in the polymer proportion. The figure also shows
thiit it took longer for the contact angle to reach the equilibrium for tablets with higher
polymer proportion because of initial gel formation. Furthemore, owing to a stronger gel
layer, the liquid àroplet stayed on the surface of the tablets containing 40% HPMC,
whereas, the droplet disappeared quickly for tablets with 20% HPMC.
1 2 3
SQRT Time (min")
Figure 3.3 Contact angle stirdies of tramado1 hydmch20ride matrit tablets w$h different HPMC/LCTOSE mtii of 2O:3O, 30:20 and 40:lO (nd) . The standatd
deviolion LF indicated by emr bat.
Figure 3.4 shows the dynamic contact angle of indomethacin matrix tablets for
different HPMCnactose ratios. Like the previous case the contact angle was found to
increase with increasing polymer proportions. In other words. wettability decreases with
increasing polymer proportions.
O 1 2 3 4
SQRT Time (minIn)
Figute 3.4 Contact angie studies of Indomethucin matrije tablets with d o r e n t HPMC/LA CTOSE ratio 0f20:30,30:20 and 4O:l O (nd j rn The standard deviation Zr
indicated by emw bar. increasing the polymer Ied to more surface free energy at the interface which also
meant that a larger 0 means lower surface energy. Interestingly, the effect of polymer
content on the contact angle and its dynarnics was less significant for indomethacin
tablets than tramadol hydrochloride tablets. This is probably due to the dominating effect
of hydrophobicity or solubility of the dnig.
Generally the plot of contact angle 0 against t "' was linear. But some curves, e.g. that
for tramadol hydrochloride tablets with a 40: 10 HPMCnactose ratio, were non-linear. So
in order to evaluate the initial contact angle, O,, a portion of the curve was used using the
following equation:
The estimated values of 0, were obtained by calculation of the work of adhesion, WA,
using an alternative f o m of Young's equation WA= y~ (l+cos go) (3.2)
where y~ is the surface tension of the medium. We used YL = dynekm 72.8 for water at
2 0 ' ~ to complete the work of adhesion. The readings of initial contact angle and work of
adhesion along with standard deviations are shown in Table 3.2.
Table 3.2 Contact angle vs. time intercepf plot in degrees, iniiicl work of udhesion and standard deviarion
Tablet lactose ratio angle, 0, adhesion deviation 1 1 (Degrees) 1 (Dpe/cm) 1 of
Standard
-
Table 3.2 shows that the initial contact angle increased From 19' to 36' for tramadol
hydrochloride tablets and 28' to 37' for indornethacin tablets with increasing
HPMCllactose ratio. This result indicates poocer wetability for tablets with higher
HPMCIlactose ratios. Moreover, the contact angles on indomethacin tablets were
generally larger than tramdaol tablets, which means that the hydrophobicity of the dmg
contribute to surface energy and wettability of the tablets. Interestingly, the effect of
polymer content on the contact angle and its dynamics was less signifiant for
indomethacin tablets than tnunadol hydrochloride tablets. This was probably due to the
dominating effect of hydrophobicity or solubility of the drug. WA decreased with increase
Matrix
Tramadol Hydrochloride
Indomethacin
Initial contact HPMCI
Initial work of
20:30 30:20 40: 10 20:30 30:ZO 40: 10
19 24 36 28 35 37
142 139 132 137 132 131
0.58 0.58 2.00 0.58 1.15 3.79
of polymer proportion in the ma& tablet and was also more in the case of tramadol
hydrochloride matrix tablet than indomethacin because of its solubility. This depended on
the hydrophobicity of the dmg and also the formation of gel in the matrix.
3.3.2 Effect of dtug propem on surfae propedies
As shown in Table 3.2 and Figures 3.5, 3.6 and 3.7, the contact angle was generally
larger on indomethacin tablets than that on tramadol hydrochloride matrix tablets. In
addition, the change of contact angle with time for indomethacin tablets is slower than
tramadol hydrochloride tablets. This is because indomethacin is much more hydrophobic
and less water soluble than trarnadol hydrochlonde, which hindered liquid penetration. It
is also due to the presence of insoluble dnig at the surface and the time taken by polyrner
to change to gelatinous state immediately.
HPMCAac tose (20:30)
O 1 2 3 4
SQRT ~ime(min'~)
+ Tramadol h ydroc hloride
+ Indomethacin
Figura 3SContact a~gle of mat& tablets conralning different dtugs ( n a The standard devitation is indicated by error bar.
HPUCAac tose (30:20)
+ Tramadol hydroc hloride
+ indomethacin
Figure 3.6 Contact angle qfmaîrir tablets containing different drugs ( n a The standard deviah'on is indjcated by error bar.
I + Tramadol h ydrochloride I indomethacin
Figure 3.7 Contact angle of matràx tablets containhg different drugs (nd) . The standord devùation is intltcaîed by error bar.
49
3.3.3 Effect of HPMC content and drug solubil@ on telease Ainetics
Drug dissolution profiles from tramadol hydrochloride and indomethacin matrix
tablets of three different HPMCnactose ratios (20:30, 30:20, and 40: 10) with 50% dmg
are depicted, respectively in Figure 3.8 and Figure 3.9. It is evident that the dmg release
rate time increased with increasing HPMC content suggesting that the gel layer became
stronger and more resistant to difhision with an increase in HPMC content.
O 100 200 300 400
Time (minute)
Figun 3.8 Dtug relèase profile of î t d 1 hy&ochlorUlc matrix tablets with v M o v s HPMC/LACTOSE tatio of 2O:3O (SD=f LJ), 30:20 (SD= f1.6) and 40:lO (SD=S.J)(nd). The standard deviaih'on was srnalier than the symbols.
Molecular size and water solubility of drugs are important determinants in the release
of a drug from swelling and erosion controlled polymenc matrices [26]. As nported
previously [22-251 and from this study, it is seen that increasing the polper content led
to a corresponding decrease in the rate of h g release, and the dnig release was
sustained. This also indicated that lactose variation with HPMC altered the drug release
rate, mainly by altering the dnig difisivity in the gel layer. Inspection of release profile
fiirther indicates that there was surface erosion in indomethacin matrix tablets for 20%
polyrner proportion, whereas, in case of 30% and 40% polyrner proportion the release is
sustained. The release is faster due to the much higher solubility of tramadol
hydrochloride than indomethacin, a sparingly soluble dnig.
O 200 400 600 800 1OOO 1200 Time (minute)
Figun 3.9 Drug retease profle of indmethacin matrix tablets with vadous HPMCILACTOSE rorio of 2O:3O (SD=it2.4), 30:20 (SDtB.5) and 40:10 (SD=arn 7)(n4)rn The standard deviotion war smaller thun the symbols.
3.3.4 Effect of HPMC content and dmg solubil& on tiqua uptake studies
The effect of polyrner proportion on weight change of Trarnadol hydrochloride and
indomethacin matrix tablets studied is illustrated in F i p n 3.10 and Figure 3.11
respectively. In bah cases, the percent of weight gain increased with an increase of
polyrner proportion. The liquid uptake was slower as polymer proportion increased. This
is because the presence of polymer enhanced gel formation and inhibited water
5 1
penetration. Moreover, because lactose is very water-soluble, its solution would generate
more liquid-filled pores on channels for water to diffuse in.
O 10 20 30 40 50 60 70
Time (minute)
Figure 3.10 Uquùà uptake studies of ttamadol hydrochlodde mat& tablets WM various HPMC/UCTOSE d o of 2O:JO (SD=ff lS), 30:20 (SD-9.5) and 40:10
(SD=Hm9)(n=J). The stan&vd deviation was smalter than the symbolï.
The % weight gain changing with time for matnx tablets containing indomethacin was
slower than the tramadol hydrochloride matrix tablets because of the presence of
undissolved drug in the hybated region. which prevented water penetration. It is seen
that indomethacin matrix tablets containing 20% polyrner underwent an initial fast
hydration, followed by a steady state, and then a rapid decrease in the weight. This
phenomenon may be a result of lactose dissolution and matrix erosion, a further
investigation on this is recommended. Thenfore a polynomial trendline has been plotted
in Figure 3.11 in order to explain this better.
O 10 20 30 40 50 60 70
Time (minute)
Figure 3.11 Liquid uptcukr studks of indomethacin mat& tabtets with various HPMC/LACTOSE &O of 2O:JO (SLkfPS), 30:20 (SDd9mO) and 40:lO (ShfiBa5)
(n =3). The standotd devialion war smaller than the syrnbols.
3.3.5 Swelling kinerics
3.3S.1 Effect of HPMC content and dmg solubility on crusion front
As shown in Fipre 3.12 and Figure 3.13 the diarneter of the erosion front of tramadol
hydrochloride and indomethacin matrix tablets of diffennt HPMCnactose ratios
decreased with increase in the polymer proportion. or weight gain (Figure 3.10).
Robably, the presence of HPMC slowed down the liquid uptake by the tablets and
swelling of the matnx.
Figure 3.12 Kinetics of the erosion fiont of tramadol Irydrochiotùie mat& tablets WU various HPMC/LCTOSE mtio of 2O:3O, 30:20 and 40:lO ( n d ) . The stanhrd
devirriion was smaller (SD=H.I) than the symbols.
The results have also shown that the presence of more polymer at the surface resulted
in instant formation of a gel layer upon contact wi th medium, which prevented initial
burst of drug release. This supports Lee's [8] observation that for relatively water
insoluble dmgs and /or lower viscosity grades of HPMC, polyrner dissolution plays an
important role in regulating dmg release.
v m 1 m m m I
O 10 20 30 40 50 60 70
Time (minute)
Figure 3.13 Kinetics of the etosion fiont of indomethacin rnatrîx tublets with various HPMC/UCTûSE tath of IO:M, 30:20 and 4O:lU ( n a The standard devwon was
srnulter (SD=dû.I) than the symbols.
The diameier of the erosion front in the tramadol hydrochloride matrix tablet was
smaller than in the indomethacin matrix tablet, because of a fast dissolution of the dmg
present on the surface of the matrix tablet. In addition, a slower increase in the erosion
fiont of indomethacin tablet after 10 hours was indicative of erosion
3.3.5.2 Effect of HPMC content and drug sdubilirp on diffusion pont
The movement of direction of the diffusion front of mamado1 hydrochloride and
indomethacin matrix tablets respectively is shown in Fipre 3.14 and 3.15. In the
indomethacin matrix tablet, the diffision front was clearly visible because of the presence
of un-dissolved dnig. which moved outwards with the erosion front. Hence, the diffusion
fiont of the indomethacin tablets increased with time, unlike tramadol hydrochloride
O 10 20 30 40 50 60 70
Tirne (minute)
Figure 3.14 Kittetics of the diffusion fmnt of honad02 hydrochloridr mat& tablets wàth various HPMULACTOSE ratio of 2O:3O, 30:20 and 40:10 (n=3). The stanàard
deviarion was smaller (SD=iM) than the symbolî.
The diameter of diffusion front increased with an increase of polyrner proportion,
which suggested that the diffusion front becarne stronger and resistant to diffusion with
the presence of more polymers in the matrîx. This supports kinetic studies where a
sustained drug release was observed with increase of polymer proportion. The distance
between the diffusion front and the erosion front represented the thickness of the
dissolved h g gel layer. That is the difisive layer played a role in controlling the dmg's
release process. The diffusive layer was smaIIer with smailer amounts of polymer thereby
showing less amounts of un-dissolved dmg in the difision front.
O 10 20 30 40 50 60 70
Time (minute)
F m 3.15 Kinetics of the d@sion front of indomethacin niath tablets wUh diffcent HPMC/LACTOSE d o of 2O:JO, 3O:2O and 40:10 (nd).The standard
deviotion was smaller (SD=IO.I) than the symbols.
3a3aS.3 Effect of HPMC content and drug solubilirp on swelling front
The swelling front diameter of tramadol hydrochloride and indomethacin math
tablets with various HPMCnactose ratios at different tirnes is shown in Figure 3.16 and
3.17 respectively. The swelling front moved in the inward direction faster in tablets with
low polyrner proportion than in tablets with higher polymer proportion because of
formation gelatinous layer. The diameter of swelling front increased with an increase of
polymer proportion due to gel formation which showed that the low amount of polymer
in the matrix rendered the matrix more sensitive to water penetration. The penetration of
the medium was faster in hydrophilic drug and slower in hydrophobie dmg. The
formation of gel layer was therefore slower. This may be due to hydrophobicity of the
dmg*
Figure 1 1 6 Kineffcs of the swelllng front of b a n d o f hydrochlorido rnahix tablets willr varbus HPMCUCTOSE mi0 of 2O:JO, 30:20 and 4O:I O ( n d ) . The stanhrd
devùztion wtas smaIIer (SD=Hel) than the symbokk.
Figure 3.1 7 Kinetics ofthe swelüngfnonf of indomethacin maîrix tablets wifh differeni HPMC/UCIOSE rcirlo of 2O:JO, 30:20 and 4 M 0 ( r d ) * The standad deviotion was
smaller ( S M 0 . l ) than the symbols.
Finally, the results of swelling lainetic studies of tramadol hydrochloride mauix tablets
showed the movement of erosion front outwards due to the swelling of matrix, whereas
the movement of diffision and swelling front was inwards towards the matrix core. But
in the case of indomethacin matrix tablets the movement of diffûsion front was outwards
dong with crosion fmnt. This was due to the hydrophobicity of the drug where the
undissolved drug remained in the gel layer and was c d e d outwards by the movement of
the gel.
The results of al1 the experiments of this study are summarized in Table 3.4. It is seen
that the type of dmg and the HPMCnactose ratio have significant effects on surface
energy, hydration rate, swelling rate and dmg release rate. The direction of the movement
of the diffision front dong with swelling front or erosion front depends solely on the
properties of the drug in the matrix.
Table 3.3 Summaty of al1 the experiments of our study
r
Serial
Number
1 1 diffision front 1 1
1.
2.
3.
4.
5.
6.
Indomethacin
matrix tablets
Tablets
property/performance
Slower
Tramadol
hydrochloride
matrix tablets
Change in contact
angle
Surface energy
Release rate
Weight gain
Swelling rate
Movement of
Lower
Lower
Lower
Faster
Higher
Higher
Higher
Higher
Inw ards
Lower
Ou twards
HPMCAac tose I ratio increases
in the following sections, the influence of dmg properties and HPMCllactose ratio on
the properties and performance of the matrix tablets will be discussed in detail.
3.4.1. Effect of drug pmperti*es
The properties of h g in the matrix are very important for understanding the
mechanism of cimg nlease fiom matrix tablets. The important drug properties include the
form of the h g i.e., a salt or a free baselacid, ionization degree, molecular weight,
solubility and hydrophobicity of the h g . Since the polymer, HPMC. is nonionic, and it
does not complex with any salts, the influence of complexation between the ionized dmgs
and HPMC will not be considered.
(i) loni&ioon degree of the drugs: The ionization degree of weak base and weak acid can
be cdculated using the following Henderson Hasselbatch equations:
[salt ] For weak acid pH = pKa + log- [acid]
[basel For weak base pH = pKw - pKb + log- [salt ]
Indomethacin is a weakly acidic dmg. Its ionization degree c m be found as follows:
[salt] 7.2 = 4.5 + log- [acid]
[salt ] log - = 7.2 - 4.5 = 2.7
[acid]
[salt 3 - = anti log 2.7 [acid]
501*2 x 100 = 99.8% % [salt] = - 502.2
The above calculation shows that the ratio of ionized indomethacin to free acid is
501.2, which means that 99.8% of the drug is ionized at pH 7.2. Since tramadol
hydrochlonde is a salt f o m that is readily ionized in water, the difference in ionization
degree between tramadol hydrochloride and indomethacin could not solely contribute to
the release rate in the studied pH range.
(ü) Moleculor weight of the drugs: The molecular weight (MW) of a dmg would affect
its diffusion coefficient and thus its release rate. The dependence of difision coefficient
on MW is described by Stokes-Einstein equation:
Where R is the gas law constant, r) is the viscosity of the solvent. No is Avogadro's
number, T is the absolute temperature and r is the radius of the spherical solute molecule.
This equation was initiated by Einstein who applied Stokes law to describe large,
spherical solute molecules moving through a continuum of small molecules. Thus, for
solute molecules that are sphencal and large compared to solvent moIecules, the solvent
perfonns as a continuum to the diffushg solute molecules. Assuming that r a M,"~, Di
and 4 are the diffusion coefficients of tramadol hydrochloride and indomethacin,
respectively, one can obtain
The above calculation shows that the difference in molecular weight only contributes
to 20% difference in the diffision coefficient of the two dmgs. This difference is much
smaller than that seen in the release rate, which was up to 80 % of uamadol
hydrochloride in 2 hours and while 80 % of indomethacin was in 8 hours (Figures 3.8 and
3.9). nienfore, it is believed that the molecular weight of the dmgs could not solely
contribute to the release rate in this snidy.
(iii) Drug solubil@ and drug hydrophobicàty: As the above analyses suggest, the
ionization degree and molecular weight of the two dnigs are not significantly different.
a- -- . Therefon, one may infer that dnig solubility and dnig hydrophobicity would play an
important role in drug release kinetics. As presented in section 3.2.1 trarnadol
hydrochloride is readily soluble in water and indomethacin is practically insoluble in
water. Moreover, surface energy of indomethacin tablets is lower than that of tramadol
tablets, as reflected by larger contact angle (Figure 3.4) and slower liquid penetration.
Figures 3.5, 3.6 and 3.7 have shown that the presence of indomethacin in the matrix
tablet lowered the initial and equilibrium contact angle of the liquid and slowed the
penetration of the droplet into the matrix. These results indicate that, for a given
HPMCAactose ratio, indomethacin tablets have poorer wettability and slower liquid
penetration, owing to higher hydrophobicity of indomethacin. Our results of the % weight
p i n of the tablets also showed slower liquid penetration into the indomethacin tablets.
Comparing the observations that the matrix tablet with higher contact angle and slower
liquid penetration showed slower dmg release, we can conclude that dmg solubility and
hydrophobicity are two major determinants of dnig release kinetics.
Several groups have studied the dependence of release kinetics on dnig solubility.
Kim et al. [15] studied various drugs in matrix tablet and the release showed a slight burst
effect for the highly soluble drug and a small lag time with the insoluble dmg. Ranga Rao
et al. 1381 studied the release of 27 dmgs of various solubility and found that several less
soluble dmgs were released at a nearly zero order rate through HPMC matrices. Ford et
al. 145) obtained similar results with 7 drugs of different solubility. These results support
Our findings that solubility is an important factor in determining release kinetics.
However, these gmups did not investigate on drug hydrophobicity and its influence on
the properties like wettability and performance of tablet.
As demonstrated by this study, h g solubility and hydrophobicity have shown
significant effect on the movement of the fronts in the matrix. The movement of the
erosion front was outwards and the swelling front was inwards, while the movement of
the diffision front depended on the solubility of the dnig in the matrix. In tramadol
hydrochloride matrix tablets, the diffusion front moved inwards along with the swelling
front, whereas, in indomethacin matrix tablets, the undissolved drug remained in the gel
layer, so the difision front moved outwards together with the growth of the gel layer.
This is because of low solubility of indomethacin, which repels solvent. Over dl , this
lead to a slower release of indomethacin.
Colombo et al. [37] studied the movement of diffusion front in matrix tablets by using
a color drug (Buflomedil pyridoxalphosphate). The dmg diffusion front was readily
determined due to the yellow color of the h g . They showed that the dnig diffusion front
best described the overall release behavior of the system. Later the same group [46]
studied the diffusion front position with a soluble and the colond drug, which was used
in the previous study. It was found that the diffusion front was visible in tablets with
more than 30% h g , due to the presence of an undissolved drug layer. Al1 of these
results with different dmgs have shown that the movement of the diffusion front is
dependent on the solubility and concentration of the h g in the rnatrix. Lower dnig
solubility and or higher dnig concentration in the matrix would delay the exhaustion of
undissolved dnig in the p l layer. As a result, the diffusion front moves outwards as the
gel layer grows. This is another piece of evidence that dnig solubility is an important
factor of drug release mechanism and kinetics.
3.4.2 Wect qfHPMC/krctose tatiio
The proportion of excipients like HPMCnactose ratio greatly influences the drug
release from the matrix tablet. In this section the effects of HPMCnactose ratio on surface
properties, release kinetics, liquid uptake and swelling kinetics of tramadol hydrochloride
or indomethacin matrix tablets will be discussed.
(i) Effect on surface properfirs: This work showed that the increase in polymer
proportion caused a slower penetration of medium into the matrix and a decrease in
wettability, i.e., lower surface energy. This was evident by the larger contact angle
(Figure 3.4), slower change of 0 with time (Figures 3.5, 3.6 and 3.7) and slower weight
gain for the tablets containing more HPMC. The main reason is that the matrix with more
polyrner can form a stronger gel at the surface and make the penetration of medium into
the matrix difficult. In tum the release of drug h m the matrix becomes slower. Singh et
al. [l] studied the effect of wetting on the rate of h g release from matrices by
measuring the contact angle using a Gaertner telemicroscope. They observed that matrix
permeability and the penneation rate of the solvent could individually limit drug release
rates. However, they did not observe the dynamic contact angle.
(ii) Effect on releare kinetics und làquid uptake: The drug release rate decreased with the
increase in polymer proportion. This is because, on one hand, lactose dissolves quickly,
leaving liquid filled pores and channels that allow quicker medium penetration and drug
release; On the other hand, the polyrner swells and the resultant gel blocks the pathway of
the medium and the drug, thus slows down medium penetration and drug release. The
effect of polymer concentration on medium penetration is evidenced by the change rate
of 0 and weight of the tablets, as discussed above.
The slower dnig release at a higher polymer concentration is attributable to a stronger
or more viscous gel layer of HPMC and lactose that reduces the difision rate of the drug
and water concentrations. Gao et al. [23] measured the diffusion coefficient of the drug in
an aqueous solution of HPMC and lactose. They obsewed that the drug diffusivity
decnased with increasing HPMCAactose ratio. Their work explains why drug release rate
decnases as the HPMCnactose ratio increases. In addition to retardation of h g
difision, the increase in the polyrner concentration also prolongs the time of water
uptake, as indicated by a slower 8 weight gain.
(iii) Effect on swelling kinetics: The growth of erosion front, diffusion front, and
swelling front decreased with the incnase in polyrner proportion because of the
formation of a stronger gel layer, which made the entry of medium into the matrix
difficult. These results are consistent with those of dmg release and liquid uptake, which
were also slowed by the formation of a stronger gel layer. A similar observation was
reported by Talukdar et al. [ZI] on xantham pm/lactose matrix tablets. Similar type of
front movements was obsewed by Ferrero et al. [6] on matrix tablets containing two
different pol p e r s .
Unlike the movement of diffision front, whose direction depends on the
hydrophobicity of the dmg in the matrix, the HPMCnactose ratio did not show any
impact on the direction of rnovement of the diffusion front. In other words, the direction
of the diffision front was altered by the type of drug, instead of the HPMCnactose ratio.
This particular work involved similar type of measurement of fronts and the results were
similar to our work.
The above results reveal a close relationship between the release kinetics and the
surface properties, liquid uptake and swelling kinetics of the matrix tablets. The solubility
and hydrophobicity of the drug are more significant factors that influence dmg release
kinetics than the ionization degree and molecular weight of the drug. In conclusion, the
release of a drug from matrix tablets depends on the drug properties and the composition
of the matrix tablets.
3.5 Conclusion
The relationship between contact angle, liquid uptake, release rate and kinetics of
swelling and erosion of matrix tablets was studied using matrix tablets containing drugs
of different hydrophobicity and various HPMCAactose proportion.
It is shown that drug hydrophobicity and HPMCAactose ratio play important roles in
the properties of the tablets. and thus the release kinetics. An increase in dmg
hydrophobicity or in HPMCllactose ratio caused a decrease in surface energy, hydration
rate, swelling rate and dnig release. The presence of undissolved hydrophobic dmg in the
diffusion front changed the direction of movement of the front.
This work has demonstrated that release kinetics for swellable matrix tablets can be
correlated with the physicochemical properties, kinetics of hydration and swelling, and
composition of the tablets.
References
1. Singh, P., Desai, J.S., Simonelli, P.A. and Highchi, I.W. Role of wetting on the rate of
drug release from inert matrices. J. Pharm. Sci. 57 (1968) 217-226.
2. Wade. A. and Weller, J.P. Handbok of Pharmaceutical Excipients. II Edition (1994)
229-232,252-256.
3. United States Pharmacopeia. 23 (1995) 774,223 1.
4. USP-NF XVU Ninth Supplement. (1994) 362.2
5. Streubel, A.. Sieprnann, J. and Bodmeier, R. Biomodal drug release achieved with
multi layer matrix tablets. Pmceed. Int'l. S p p . Conwl. Rel. Bioact. Mater. 27
(2000) 62 10.
6. Ferrer, C., Munoz-Ruiz, A., Jimenez-Castellanos, R.M. Fronts movement as a useful
tool for hydrophilic matrix release rnechanism elucidation. int. J. Pharm. 202 (2000)
21-28.
7. Martin, A., Swarbnck, J. and Cammarata, A. Physical Pharmacy, III Edition k a and
Febiger. Philadelphia (1983) 405.
8. Pharm, A.T. and Lee, P.I. Probing the mechanism of dmg release from
hydroxypropyl methylcellulose matrices. Pharm. Res. 1 1 (1994) 1379-1 384.
9. Libermann. Pharmaceutical Dosage Forms: Tablets part 1. Marcel Dekker Inc. New
York (1990).
10. Kydonieus, A. Treatis on Controlled Drug Delivery. Marcel Dekker hc. New York
(1991) 15-21.
11. Alderman, D.A., A nview of cellulose ethers in hydrophilic matrices for Oral
Controlled Release Dosage Form. Int. J. Pham. Tech. Prod. Manuf. 5 (1984) 1-9.
12. Colombo, P.. Peppas, N.A and Colombo, P. Polymer relaxation in swellable matrices
contributes to h g release, Rocee. Int'l. Symp. Control. Rel. Bioact. Mater. 25
(1998).
13 Talukdar, M.M. and Kinget, R. Swelling and dnig release behavior of xanthan gum
matrix tablets. Inter. J. Phartn. 120 (1995) 63-72.
14 Talukdar, M.M. and Kinget, R., Comparative study of xanthan gum and
hydroxypropyl methylcellulose as matrices for controlled-release drugs delivery II.
Drug diffusion in hydrated matrices. Inter. I. Pharm. 15 1 (1997) 99-107.
15 Kim, H. and Fassihi, R. Application of binary polyrner system in dmg release rate
modulation 2. Influence of formulation variables and hydrodynamic conditions on
release kinetics. J. Pharm. Sci. 86 (1997) 323-328.
16 Langer, R.S. and Peppas, N.A. Present and future applications of biomaterials in
controlled h g delivery. Biomaterials 2 (1987) 20 1-2 14.
17 Hogan, LE. Hydroxypropyl methylcellulose sustained release technology. Dmg Dev.
and Ind. Pham. 15 (1989) 975- 1000.
18 Shah, A.C., Britten, N.J., Olanoff, L.S. and Basalamenti, N.J. Gel-matrix systems
exhibiting bimodal controlled release of oral dnig delivery. J. Contr. Rel. 9 (1989)
169- 174,
19 Tahara, K., Mikawa, M., Yokohoma, S. and Nishihata, T. Characteristics of intestinal
absorption of adinazolam and in vivo evaluation of oral sustained release tablets of
adinazolam in beagle dogs. Int. J. Pharm. 99 (1993) 3 11-320.
-- - 20 Skoug, J.W., Bonn, M.T., Fleishaker, J.C. and Cooper, A.M., In vitro and in vivo
evaluation of whole and half tablets of sustained release adinazolam mesylate. Pharm.
Res. 8 (1991) 148201488.
21 Tahara, K., Yamamoto, K. and Nishihata, T. Overall mechanism behind matrix
sustained release (SR) tablets prepared with hydroxypropyl methylcellulose 2910. J.
Contr. Rel. 35 (1995) 59-66.
22 Gao, P. and Meury, R.H. Swelling of hydroxypropyl methylcellulose matrix tablets.
1. Characterization of swelling, using a novel optical imaging method. J. Pharm. Sci
85 (1996) 725-73 1.
23 Gao, P., Skoug, J.W., Nixon, P.R., Ju, T.R., Stemm, N.L. and Sung, K. Swelling of
hydroxypropyl methylcellulose matrix tablets 2. Mechanistic study of the influence of
formulation variables on matrix pe~onnance and drug release. J. Pharm. Sci. 85
(1996) 732-740.
24 Moussa, I.S. and Cartilier, L.H. Characterization of moving fronts in cross-linked
amylose matrices by image analysis. J. Contr. Rel. 42 (1996) 47-55.
25 Katzhendler, I., Hoffman, A., Goldberber, A. and Friedman, M. Modeling of h g
release from erodible tablets. J. Pharm. Sci. 86 (1997) 1 10- 1 15.
26 Hogan, LE. Hydroxypropyl methylcellulose sustained release technology. Drug Dev.
Ind. P h m . 15 (1989) 975-999.
27 Mitchell, K., Ford, J.L., Armstron, D.J., Elîiott, P.N.C., Rostron, C. and Hogan, J.E.
The influence of concentration on the release of ârugs from gels and matrices
containing Methocel ? ht. J. P h m . 100 (1993) 155-163.
28 Shah. C.N., Zhang, G., Apelian, V., Zeng, F., Infeld, M.H. and Malick, A.W.
Miction of h g release from hydroxypropyl methylcellulose (HPMC) matrices:
Effect of polyrner concentration. Phann. Res. 10 (1993) 1693- 1695.
29 Rao, K.V.R., Devi, K.P. and Buri, P. Influence of molecular size and water solubility
of the solute on its release from swelling and erosion controlled polymeric matrices.
J. Contr. Rel. 12 (1990) 133-141.
30 Richter, W. Clinical investigation on the development of dependence during oral
therapy with tramadol. Anneimittel for Schung 35 (1985) 1742-4
31 Committee on safety of medicineslmedicines control agency. Tramadol - (Zydol,
Trama1 and Zarnadol) Current problems 22 (1996) 1 1.
32 Anonymous Tramadol - a new analgesic. Drug ther. Bull. 32 (1994) 96.
33 Radbruch, L. A risk benefit assessment of tramadol in the management of Pain Drug
safeîy 15 (1996) 8-29.
34 William, HL Tramadol Hydrochloride: Something new in oral analgesic therapy.
Curr. Ther. Res. 58 (1997) 215-26.
35 Lee, C.R. Tramadol: a preliminary review of its pharmacodynamie and
pharmacokinetic properties, and therapeutic potential in acute and chronic pain States.
Dmgs 46 (1993) 13-40.
36 Proceedings of a symposium Tramadol analgesia: Synergy in research and therapy.
h g s 47 (1 994) 1-46.
37 Colombo, P., Bettini, R., Massirno, G., Catellani, G.L., Santi, P. and Peppas, NA.
Dnig diffusion front movement is important in drug release control fiom swellable
matrix tablets. J.Pharm. Sci. 84 (1995) 991-997.
38 Baveja, S.K., Rao, K.V.R. and Devi, K.P. Zeroorder releases hydrophilic rnatrix
tablets of B-adrenergic blockers. Int. J. Pharm. 39 (1987) 39-45
39 Baveja, S.K., Rao, K.V.R., Singh, A. and Gombar, V.K. Release characteristics of
some bronchodilators from compressed hydrophilic polyrnerk matrices and their
correlation with moleculiu geometry. Int. J. Pharm. 41 (1988a) 55-62.
40 Melia, D.C. Hydrophilic matrix sustained release systems based on polysaccharide
carriers. Critical Reviews in Therapeutic Drug C h e r S ystems. 8 (199 1) 395-42 1.
41 Rao, K.V.R. & Devi, K.P. Swelling controlled release systems: recent developments
and applications. Int. J. Pharm. 48 (1988) 1-13.
42 Salsa, T., Veiga, F and Pina, M.E. Oral controlled-release dosage froms 1 cellulose
ether polymers in hydrophilic matrices. Drug Dev. and Ind. Pham. 23 (1997) 929-
938.
43 Veiga, F., Salsa. T. and Pina, M.E. Oral controlled-release dosage forms II glassy
polymers in hydrophilic matrices. Drug Dev. and Ind. Pharm. 24 (1998) 1-9.
44 Caramella, C., Colombo, P., Conte, U., Gazzaniga A. and La Manna, A. The role of
swelling in the disintegration processes. Int. J. Pharm. Tech. & Prod. Mfr. 5 (1984) 1-
5.
45 Ford, J.L., Rubinstein, M.H., McCaul, F., Hogan, LE. and Edgar, P.J. Importance of
dmg type, tablet shape and added diluents on drug release kinetics from
hydroxypropyl methylcellulose matrix table&. Int. J. P h m . 40 (1987) 223-234.
46 Colombo, P., Bettini, R. and Peppas, N.A. Observation of swelling process and
diffusion front position during swelling in hydroxypropyl methylcellulose (HPMC)
matrices containing a soluble h g . J. Contr. Rel. 61 (1999) 83-9 1.
47 Perez-Marcos, B., Gutiercez, C., Gomez-Amoza, J.L., Martinez-Pacheco, R., Souto,
C. and Conchiero, A. Usefulness of certain varieties of carborner in the formulation of
hydrophilic furosemide matrices. kt. J. Pharm. 67 (1991) 1 13- 121
48 Moussa, I.S., Lenaerts, V., Cartilier, L.H. Effect of some physical parameters on the
swelling properties of cross-linked amylase matrices. Int. J. Pharm. 173 (1998) 35-41.
49 Talukdar, M.M., Mooter, G.V., Augustijins, P., Tjandra-Maga, T., Verbeke, N. and
Kinget, R. In vivo evaluation of xanthan gum as a potential excipient for oral
controlled-release matrix tablet formulation. Inter. J. Pharm. 169 (1998) 105- 1 13.
50 Peh, K.K. and Wong, C.F. Application of similarity factor in development of
controlled-release diltiazen tablet. Drug Dev. and Ind. Pharm. 26 ( 2 0 0 ) 723-730.
51 Talukdar, M.M., Rombaut, P. and Kinget, R. The release mechanism of an oral
controlled-release delivery system for indomethacin. Pharm. Dev. and Tech. 3 (1998)
1-6.
- -- - Chapter F o w Summaiy and Future Direction
This study has correlated h g release kinetics with surface properties. liquid uptake
behavior, kinetics of swelling and erosion of matrix tablets containing drugs of different
hydrophobicity. Initially from the studies of erosion and release kinetics of commercial
erodible tablets, the mechanism of erosion-controlled release was understood. The
influence of different characteristics on the performance of swellable matrix tablets
containing various HPMCllactose ratios with dmgs of different hydrophobicity was
studied. The surface energy of the tablets depended on the proportion of polymer and the
type of drug in the matrix of the tablets. The release rate and weight gain increased with
an increase in the polymer proportion. The hydrophobicity of the drug also influenced
swelling kinetics where movement of the diffusion front was in different directions and
showed un-dissolved drug in the gelatinous layer.
The present study was limited to two different àrugs, one type of polymer and one
type of diluent. However, investigation of tablets made of dnigs of various
hydrophobicity and different types of polymers or different grades of one polyrner will
provide additional information. In addition, further studies using different methodologies
to study charactenstics of matrix tablets are desirable. We anticipate that hure studies
will lead to a better understanding of the mechanisms of drug release fiom matrix tablets.