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Am J Drug Deliv 2004; 2 (1): 43-57 1175-9038/04/0001-0043/$31.00/0

HEALTHCARE TECHNOLOGY REVIEW

 2004 Adis Data Information BV. All rights reserved.

Factors Affecting Mechanism and Kinetics of Drug Release from Matrix-Based Oral Controlled Drug Delivery Systems Manthena V.S. Varma,1 Aditya M. Kaushal,1 Alka Garg2 and Sanjay Garg2 1 2

National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 1. Mechanism of Drug Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 1.1 Modeling of Drug Release from Matrix Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 2. Factors Influencing Drug Release from Matrix Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 2.1 Drug-Related Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 2.1.1 Drug Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 2.1.2 Dose/Drug Content . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 2.1.3 Molecular Weight and Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 2.1.4 Particle Size and Shape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 2.2 Polymer-Related Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 2.2.1 Polymer Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 2.2.2 Polymer Viscosity Grade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 2.2.3 Polymer Proportion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 2.2.4 Polymer Particle Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 2.2.5 Polymer Combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 2.3 Formulation Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 2.3.1 Formulation Geometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 2.3.2 Processing Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 2.3.3 Formulation Excipients/Additives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

Abstract

Matrix technologies have often proven popular among the oral controlled drug delivery technologies because of their simplicity, ease in manufacturing, high level of reproducibility, stability of the raw materials and dosage form, and ease of scale-up and process validation. Technological advancements in the area of matrix formulation have made controlled-release product development much easier than before, and improved upon the feasibility of delivering a wide variety of drugs with different physicochemical and biopharmaceutical properties. This is reflected by the large number of patents filed each year and by the commercial success of a number of novel drug delivery systems based on matrix technologies. Matrix-based delivery technologies have steadily matured from delivering drugs by first-order or square-root-of-time release kinetics to much more complex and customized release patterns. In order to achieve linear or zero-order release, various strategies that seek to manipulate tablet geometry, polymer variables, and formulation aspects have been applied. Various drug, polymer, and formulation-related factors, which influence the in situ formation of a polymeric gel layer/drug depletion zone and its characteristics as a function of time, determine the drug release from matrix systems.

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Various mathematical models, ranging from simple empirical or semi-empirical (Higuchi equation, Power law) to more complex mechanistic theories that consider diffusion, swelling, and dissolution processes simultaneously, have been developed to describe the mass transport processes involved in matrix-based drug release. Careful selection of an appropriate model for drug release provides insight to the underlying mass transport mechanisms and helps in predicting the effect of the device design parameters on the resulting drug-release rate. Thus, a basic understanding of release kinetics and appropriate mechanisms of drug release from matrix system and their inter-relationships may minimize the number of trials in final optimization, thereby improving formulation development processes.

The controlled-release drug delivery market is expanding rapidly, paralleled with an active and aggressive research in the field. There has been a significant increase in approvals of novel drug delivery systems (DDS) in the last few years, and this is expected to continue at an impressive rate in the near future. Conceptually, an ideal drug delivery system should fulfill two prerequisites: the first is to deliver the drug at a rate dictated by the needs of the body over the period of treatment, and the second is spatial targeting to specific site(s).[1] These prerequisites provide a need for controlled-release technologies that can improve the therapeutic efficacy and safety of a drug by precise temporal and spatial placement in the body, thereby reducing both the size and number of doses required. Furthermore, the possibility of repatenting successful drugs, coupled with the increasing expense in bringing new drug entities to market, has been instrumental in generating interest in controlled-release drug delivery systems (CRDDS). A number of technologic advancements with regard to regulating the rate of drug delivery, sustaining the duration of therapeutic action, and/or targeting the drug to a specific site or tissue have been made over recent years. Today, excellent control of drug release is possible by employing fairly sophisticated systems. Self-regulated insulin delivery systems using lectins[2] and Glucowatch[3] are illustrative examples. Based on their technologic sophistication, CRDDS can be classified as diffusion/dissolution, activation-modulated, feedback-regulated, stimuli-sensitive, or site-targeted DDS.[1,4] Despite significant interest and numerous reports about the design of CRDDS for various drugs, only a few have made it to the marketplace. Diffusion/dissolution-based delivery systems are the most common mode of controlled release. Even though certain stimuli-sensitive and site-targeted DDS are commercialized, the other classes still require a considerable amount of research. The major limitation of feedback-regulated and activation-modulated systems is that they are not useful for all types of drugs, and oral administration of many such systems is difficult. Among the wide spectrum of CRDD technologies, diffusion devices are the simplest to adapt for large-scale manufacturing.  2004 Adis Data Information BV. All rights reserved.

Diffusion controlled-release systems can be classified further as reservoir and matrix devices. In matrix devices, the drug is homogeneously dispersed in either a lipophilic or hydrophilic polymer matrix. The release rate from matrix systems remains unaffected by thin spots, pinholes, and other similar defects, which can be a serious problem with reservoir systems.[5,6] These advantages, along with the low fabrication cost, outweigh the less desirable feature of declining release rates with time, which is a characteristic of matrix systems. Such devices can be conveniently prepared by using a simple polymer fabrication technique involving a physical blending of the active agent with matrix formers, followed by compaction, extrusion, or solvent casting. Based on the nature of the matrix forming material, five major types of matrix systems can be differentiated, i.e. hydrophilic, plastic, lipidic, resin, and biodegradable matrices.[7] A large number of simple monolithic and sophisticated matrix systems are available commercially. Table I presents a summarized view of some of the commercialized matrix systems. Selection of a matrix type depends on the dose size, desired release rate, and the physiochemical properties of the drug of interest. The present manuscript gives a brief outline of the mechanisms of drug release from a matrix-based CRDDS, and describes in detail, with examples, the various factors affecting drug release from these systems. It is anticipated that knowledge of the kinetics and mechanism involved shall serve to shorten the development time by use of proper methodologic approaches. Emphasis is made on hydrophilic matrices as they are suitable for a wide range of drugs and offer many advantages over the hydrophobic matrices. 1. Mechanism of Drug Release On exposure to aqueous fluid, hydrophilic matrices take up water, and the polymer starts hydrating to form a gel layer.[8] Drug release is controlled by a gel diffusional barrier and/or by surface erosion. An initial burst of soluble drug may occur due to the surface leaching. When a matrix containing a swellable glassy polymer comes in contact with an aqueous medium, there is an abrupt change from a glassy to a rubbery state, which is associated with the swelling process.[9,10] The individual polymer chains, Am J Drug Deliv 2004; 2 (1)

Factors Affecting Release from Matrix Systems

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Table I. Commercial matrix-based controlled-release technologiesa Technology

Description

Developer

Source

TIMERx

Uses locust bean gum and xanthan gum. Allows for rapid formulation development with desired release profiles

Penwest Pharmaceuticals Co., Danbury, CT, USA

www.penw.com

MICROTROL

Coated/uncoated beadlets filled into capsules/ compressed into tablets

Shire Laboratories, Inc., Rockville, MD, USA

www.shirelabs.com

NUTRACEUTIX CDT

Uses a variety of ionic and non-ionic additives to modulate swelling and erosion kinetics

Nutraceutix, Inc., Redmond, WA, USA

www.nutraceutix.com

DUREDAS

Bilayer tableting technology specifically developed to provide for two different release rates

Elan Corporation, Dublin, Ireland

www.elan.com

GEOMATRIX

Multi-layered tablets with drug core sandwiched between polymer matrix

SkyePharma Plc., London, UK

www.skyepharma.com

GEMINEX

Bi-layered dual-release tablet technology incorporating both an immediate release and controlled-release component or two different controlled-release components

Penwest Pharmaceuticals Co., Danbury, CT, USA

www.penw.com

SOLUTROL

Once daily matrix tablets with extended release

Shire Laboratories, Inc., Rockville, MD, USA

www.shirelabs.com

PRODAS

Programmable Oral Drug Absorption System drug delivery technology based on the encapsulation of controlled-release mini tablets

Elan Corporation, Dublin, Ireland

http://elan.com

CONTRAMID

Use of specially modified starch-conventional tableting process to form matrix tablets

Labopharm, Inc., Laval, QC, Canada

www.labopharm.com

CONSURF

Releases drug by concurrent swelling and erosion of matrix tablets

Biovail Pharmaceuticals, Inc., NJ, www.biovailpharm.com USA

SMARTRIX

Contains a core matrix with an upper and lower compressed coating layer that erodes at a specific rate

Lohmann Therapy Systems, West Caldwell, NJ, USA

a

www.ltslohmann.de

Mechanism of drug release from the above technologies is diffusion/dissolution; however, the kinetics of release is manipulatable. Thus, based on the therapeutic requirement, desired release may be attained by fulfilling the prerequisites of precise and temporal placement in the body.

DUREDAS = Drug Release Drug Absorption System; PRODAS = Programmable Oral Drug Absorption System.

originally in an unperturbed state, absorb water so that their endto-end distance and radius of gyration expand to a new solvated state. This is due to the lowering of the polymer transition temperature, which is controlled by the characteristic concentration of the swelling agent and, in turn, depends on temperature and thermodynamic interactions of the polymer-water system. A sharp distinction between glassy and rubbery regions is observed and the matrix increases in volume because of swelling. On a molecular basis, this phenomenon can activate a convective drug transport, thus increasing the reproducibility of the drug release (compared with release based on erosion). With time, water infiltrates deep into the core, increasing the thickness of the gel layer. Concomitantly the outer layers become fully hydrated and start dissolving or eroding.[11] When water reaches the center of the system, and the concentration of the drug  2004 Adis Data Information BV. All rights reserved.

falls below the solubility value, the release rate of the drug begins to reduce. At the same time, an increase in the thickness of the barrier layer with time increases the diffusion path length, reducing the rate of drug release. Drug-release kinetics associated with these gel-layer dynamics, range initially from Fickian to anomalous (non-Fickian), and subsequently from quasi-constant (near zero-order) to constant. Matrices of high molecular weight polymers rarely show all three regimens (Fickian, non-Fickian and quasi-constant) of drug release because of a low chain disentanglement rate and insufficient external polymeric mass transfer.[12,13] In the case of inert matrix systems, the eluting medium dissolves or erodes the polymer from a surface-forming porous network in the core. Soluble drug diffuses through this aqueousfilled porous network. On the other hand, poorly soluble drugs dispersed in inert polymer systems are released primarily by Am J Drug Deliv 2004; 2 (1)

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Eroding surface

a

Drug release

Drug dispersed in polymer matrix

Gel layer b

Diffusion front

Erosion front Drug release

Drug dispersed in polymer matrix

Fig. 1. Schematic of drug release form matrix diffusion controlled-release drug delivery systems with the drug homogenously dispersed in: (a) an erodible polymer matrix; and (b) a hydrophilic, swellable polymer matrix. In erodible matrices, polymer erosion from the surface of the matrix determines the drug release, whilst in hydrophilic matrices, formation of the gel layer and its dynamics as a function of time determines the drug release. Gel layer thickness, which determines the diffusional path length of the drug, corresponds to the distance between the diffusion and erosion fronts. As the swelling process proceeds, the gel layer gradually becomes thicker, resulting in progressively slower drug-release rates; however, due to continuous hydration, polymer disentanglement occurs from the surface of the matrix, resulting in a gradually decreasing depletion zone and an increased dissolution rate.

erosion.[14] Schematic representation of the mechanism of drug release from hydrophilic and erodible polymer matrix systems is given in figure 1. In general, two major factors control drug release from swelling controlled matrix systems.[9,15] These include: (i) the rate of aqueous medium infiltration into the matrix, followed by a relaxation process (hydration, gelation, or swelling); and (ii) the rate of matrix erosion. As a result of these simultaneous processes, two fronts are evident – a swelling front, where the polymer gets hydrated, and an eroding front. The distance between the two fronts, i.e. diffusion layer thickness, depends on the relative rates at which the swelling and eroding fronts move in relation to each other.[16] If the polymer gels slowly, solvent can penetrate deep into the glassy matrix, thus dissolving the drug; therefore, gel layer thickness and its stability are crucial in controlling drug release. Bettini et al.[17,18] and Colombo et al.,[19-22] in a series of studies, concluded that the gel layer as a function of time is exposed to continuous changes in its structure and thickness. The profile of the gel layer thickness versus time consists of three stages: (i) initial increase due to polymer swelling; (ii) maintenance of constant gel layer thickness (often referred to as front synchronization); and (iii) reduction of gel layer thickness as the glassy core depletes. The growth of the hydrophilic polymer gel depends on the swelling rate at the water penetration front and erosion rate at  2004 Adis Data Information BV. All rights reserved.

the outer surface of the gel; however, gel erosion often lags behind since the polymer concentration should reach a threshold value known as the polymer disentanglement concentration (the concentration of the polymer in a fully hydrated state at which there are no polymer-polymer interactions).[23-25] Continuous growth of the polymer gel layer will result when water penetration is more rapid than polymer disentanglement. In contrast, when water penetration is retarded by the gel layer and polymer chain disentanglement proceeds steadily, little or no change in the gel layer thickness may occur.[26] Several techniques have been used to study the swelling of matrix tablets and to characterize the gel layer and front movements. Optical imaging has been widely used to detect the movement of the water-advancing front, which is based on the change in the refractive index at the interface of the polymer gel and glassy core.[27] Other sophisticated techniques reported to study gel movement include 1Hydrogen nuclear magnetic resonance (NMR),[28,29] pulsed-field gradient spin-echo NMR,[30] confocal laser scanning microscopy, cryogenic scanning electron microscopy, and texture analysis.[31] The gel layer thickness is determined by the relative position of the swelling and erosion fronts. A diffusion front located between the swelling and erosion fronts, which separates solid from dissolved drug, has been identified by imaging analysis. This diffusion front is related to the drug dissoAm J Drug Deliv 2004; 2 (1)


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lution rate in gel and is dependent on drug solubility and loading. The front conditions express that the rate of drug release is always equal to the rate at which the drug is brought to the diffusion front. A more comprehensive review on front movements has been reported by Colombo et al.[11] 1.1 Modeling of Drug Release from Matrix Systems

Drug diffusion and polymer relaxation/dissolution are the basic drug transport mechanisms from a matrix system. Fick’s first and second laws define diffusion of a solute across a particular medium. These laws form the basis for several mathematical models proposed for drug diffusion from matrix systems. Higuchi[32] related the release rate of a drug dispersed in ointment bases to the pertinent physical constants. This model was modified to correlate factors governing the rate of drug release from homogenous matrices.[32] Assuming that the matrix does not dissolve and that the drug is uniformly distributed in it, the square root of time-dependent drug release was derived for planner and spherical matrices. Experimental data demonstrating the validity of the Higuchi equation are reported;[33-36] however, this equation was derived under pseudo steady-state assumptions in which the concentration profile from the dispersed agent front to outer surface is assumed to be linear, therefore cautious interpretation is necessary when applied to matrix systems, which in most cases undergo surface alterations and erosion. A simple semi-empirical equation, which relates the drug fractional release with time, was introduced by Korsmeyer et al.:[37] Mt/M∝ = Ktn

where Mt/M∝ is the fractional release of the drug, ‘t’ denotes the time, ‘K’ represents a constant incorporating structural and geometric characteristics of the release device, and ‘n’ is the time exponent indicative of the release mechanism. This equation has been used to analyze drug release profiles of several systems.[38,39] Two competing release mechanisms (Fickian diffusional release and Case II relaxational release) are the limits of this phenomenon. Fickian diffusional release occurs by molecular diffusion of the drug because of the chemical potential gradient. Case II relaxational release is the drug transport mechanism associated with stresses and state transition in hydrophilic glassy polymers. These two mechanisms controlling the drug release are considered additive and can be resolved to get the contribution of either in ultimate drug release.[40] A thorough understanding of drug release mechanism and kinetics gives a fairly good idea about the variables that can be manipulated in achieving a desired release profile. An extensive review by Siepmann and Peppas[41] on the modeling of drug release from hydroxypropyl methylcellulose (HPMC) matrices deserves a special mention. Drug release mechanisms and kinetics are the two important characteristics of a delivery system in describing the drug dissolution profile. A number of mathematical models have been developed in the last few decades to analyze drug release from different types of CRDDS.[42] An extensive summary of various kinetic models explaining the drug release from various controlled-release solid dosage forms can be found elsewhere.[43] Some of the basic mathematical models are summarized in table II.

Table II. Mathematical modelsa used to describe drug release kinetics from various matrices Kinetic model

Relation

Systems following the model

References

First order

ln Qt = ln Qo + Kt (release is proportional to amount of drug remaining)

Water-soluble drugs in porous matrix

44

Zero order

ft = Kot (independent of drug concentration)

Transdermal systems Osmotic systems

43,45

Higuchi

ft = KHt1/2 (proportional to square root of time)

Matrix formulations

32

Weibull

m = 1 – e[– (t – Ti)b/a]

Erodible formulations

46

Hixson-Crowell

Wo1/3

Erodible isometric matrices

47

Korsmeyer-Peppas

Mt/M∝ = Ktn

Swellable polymeric devices

37

Peppas-Sahlin

Mt/M∝ = Ktm + Kt2m

Swellable polymeric devices

40

Baker-Lonsdale

3/2[1 – (1 – Mt/M∝)2/3] – Mt/M∝ = Kt

Microcapsules or microspheres

6

a

–

Wt1/3

= Kst

Refer to the respective original articles for a complete understanding of the terms, conditions, and features of the models.

a = scale parameter; b = surface parameter; f t = fraction of dose release at time ‘t’; k, K, KH, Ko, and Ks = release rate constants characteristic to respective models; m and n = the release exponents; Mt = amount released at time ‘t’; M∝ = amount released at infinite time; Qo = the drug amounts remaining to be released at zero hour; Qt = the drug amounts remaining to be released at time ‘t’; Ti = lag time before the onset of dissolution; Wo = initial amount of drug present in the matrix; Wt = amount of drug released at time ‘t’.  2004 Adis Data Information BV. All rights reserved.

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2. Factors Influencing Drug Release from Matrix Systems The feasibility of formulating a drug into a CRDDS is dictated by the biopharmaceutical and pharmacokinetic aspects of drug absorption and disposition, which is a composite of processes, described by the LADMER (Liberation, Absorption, Distribution, Metabolism, Elimination, and Response) system.[48] Liberation of the drug from the dosage form, describing systemic bioavailability,[49] is the very first step in this system and is, in most cases, flexible and can be manipulated by optimizing various formulation and polymer variables. According to the Higuchi equation, drug release from a matrix system can be controlled by optimizing: the initial concentration of drug in the matrix; drug solubility; porosity and tortuosity of the matrix; polymer system; matrix shape; and size.[32] Polymer-, drug-, and formulation-related variables that affect release kinetics, and therefore can be manipulated to achieve the desirable release kinetics, are illustrated in figure 2. 2.1 Drug-Related Factors

Drug dose, its solubility, and diffusivity in polymer and eluting medium are important drug-related factors that determine the drug release mechanism and kinetics from matrix-based systems 2.1.1 Drug Solubility

Aqueous solubility of a drug depends on its chemical structure, physicochemical nature of the functional groups, and the variations in its stereo-chemical configuration and the polymorphic form. Diffusivity of a solute depends upon the chemical gradient across the medium, which is a function of solubility; thus, a drug with high solubility shows faster release, while poorly watersoluble drugs (500mg) are difficult to design into a matrix-based CRDDS because of the requirement of high amounts of polymers or other matrix formers, along with general excipients. An increase in drug content at a constant polymer content increases the rate of release due to higher drug concentration and, thus, higher chemical gradient at the diffusion front. When matrix swelling and erosion attain equilibrium, i.e. the processes are in a dynamic state, volume fraction gradients of water, polymer, and the drug exist between the erosion and swelling fronts. The local volume fraction of a drug (γds) in the gel layer is a function of drug solubility and loading and can be calculated by the following equation:[21] γds = Cs γw/εd (cm3drug/cm3gel) where Cs is the solubility of drug in water, γw is the volume fraction of water at that point, and εd is the density of drug. The volume fraction of water will be high towards the erosion front and the polymer volume fraction will be high towards the swelling front. The effects of drug solubility and drug loading on the kinetics and mechanism of drug release from hydrophilic matrices were discussed by Tahara et al.[9] They reported that when solubility is not high enough, erosion of the polymer plays an important role and release rate is proportional to the ratio of drug solubility to drug loading. Rao et al.[51] supported this principle by studying the release of a poorly water-soluble drug from HPMC matrices; however, contradictory results were reported by Beom-Jin et al.[59] They observed a decrease in the percentage release rate when the melatonin loading was increased to five times, and concluded that melatonin stabilizes HPMC gel structure. 2.1.3 Molecular Weight and Size

The diffusion coefficient of a drug in a gel layer or drugdepletion zone is one of the most important factors that govern the release kinetics. The diffusion coefficient of a drug in a matrix system gradually changes from near zero in a dry matrix, to a maximum when the matrix is completely hydrated. According to the classical Higuchi’s model, the release rate from a matrix-based CRDDS is proportional to the square root of the diffusion coefficient, which, in turn, depends on molecular weight and diameter of the solute molecule and the viscosity of the diffusion medium. Drugs with a molecular weight of >500Da are thought to  2004 Adis Data Information BV. All rights reserved.

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have poor diffusivity in hydrophilic matrices due to the constrain imposed by the aqueous gel structure.[60] Fyfe and Blazek-Welsh[28] used a quantitative NMR imaging study to probe the mechanism of drug release from HPMC matrices. Out of the two model drugs, triflupromazine hydrochloride and fluorouracil, the rate of drug release was higher for the latter. This was attributed to the molecular weight and size difference between the two drugs. The diffusion of triflupromazine hydrochloride would have been hindered significantly by interactions with the gel network. Baveja et al.[61] studied the release characteristics of some structurally related water-soluble bronchodilators, namely ephedrine hydrochloride, salbutamol sulphate, terbutaline sulphate, aminophylline, and reproterol hydrochloride from HPMC matrices and their correlation with molecular geometry. The release rates from HPMC matrices of different viscosity grades were found to correlate to the accessible surface area of the drugs, indicating the importance of molecular shape and size in the release rates from matrix systems. 2.1.4 Particle Size and Shape

Other factors, such as the particle size and shape of soluble drugs, also influence drug release, mainly because of the difference in effective surface area and, thus, the intrinsic dissolution rate. Tros de llarduya et al.[62] found decreased oxazepam dissolution rates with an increase in drug particle size, at a constant drug : HPMC K100M ratio. These findings were in accordance with the results reported by Ford et al.[33] for HPMC K15M matrices containing indomethacin. 2.2 Polymer-Related Factors

Drug release from matrix-based CRDDS depends on drug diffusion through polymers and/or erosion of polymers. Drug diffusivity increases as the free volume of polymer increases relative to its dimensions, and also depends on the thermodynamic interactions between the polymer and solute. Diffusion of the drug occurs both through the aqueous-filled pores and the swollen polymer; thus, the effective diffusion coefficient of a drug in the gel layer or drug depletion zone of an erodible matrix, depends on the diffusivity of the drug in the corresponding medium. The internal structure of a polymer, which governs the release rate, is dependent on its chemical nature, type and degree of substitution, cross-linking, and molecular weight. 2.2.1 Polymer Type

Silicon derivatives have been used in the past for fabrication of controlled-release matrix systems; however, the trend has shifted towards the use of water-soluble or bio-erodible polymers. Polymers, by definition, are high molecular weight molecules made up of monomer units with unique properties attributed to Am J Drug Deliv 2004; 2 (1)

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their size and three-dimensional arrangement. On a broad basis, polymers can be classified as water-soluble and water-insoluble polymers. Polymers that are sufficiently polar can interact with an aqueous medium and generate sufficient energy to disperse polymer chains from the glassy state. Although many polymers have been widely used in drug delivery, hydro-polymers such as cellulose ethers are perhaps the most often used.[63] Water-insoluble polymers such as ethyl cellulose, and pH-dependent soluble polymers such as eudragits and HPMC acetate succinate, have also been reported to have utility in controlled-release matrix systems. Rafiee-Tehrani and Sadegh-Shobeiri[64] studied drug-release behavior of ibuprofen from matrices containing ethyl cellulose, Eudragit RS100 1, Eudragit S100, and a combination of ethyl cellulose and Eudragit RS100. The amount of drug released in acidic pH (1.2) was substantially less from eudragits because of their pH-dependent solubility. As discussed in section 1, drug is released from a hydrophobic matrix through aqueous pores formed in the drug depletion zone, while drug diffuses across the hydrated gel layer in the case of hydrophilic matrix. This explains the differences in release kinetics with different polymer type. Furthermore, the ionic nature and chemical interactions of some polymers with different classes of drugs complicate the release mechanism and kinetics. Physicochemical properties of a drug are reported to influence the gel layer formation and stability in carbopol matrices.[65] The rate of growth of the gel layer in carbopol matrices with basic drugs was found to be more than that for acidic drugs, which may be because of the pH-dependent gelation of carbopol. A similar type of pH-dependent release was also reported for other ionic polymers, such as sodium carboxymethylcellulose (NaCMC) and chitosan.[61,66] Chitosan (poliglusam), a cationic polymer, has been found to interact with anionic drugs and excipients in the matrix formulation, thereby affecting the release rate.[67] Matrix formers such as HPMC, substituted amylose, egg albumin, and other cellulose derivatives may show stereo-selective dissolution from a formulation containing racemates. Stereo-selective interaction between spatially oriented functional groups of the drug and polymer can be responsible for such differences in release rate within enantiomers.[68,69] Some important parameters, which need consideration during the selection of a polymer include viscosity, gel point, hydration rate, and glass transition temperature. Polymers reported for controlling the drug release from oral matrix systems, along with their relevant characteristics, are summarized in table III. 1

2.2.2 Polymer Viscosity Grade

For a given polymer at a fixed polymer fraction, the viscosity of the polymer selected governs performance of the matrix by affecting the diffusional and mechanical characteristics of the gel layer or drug-depleted layers.[71] Higher viscosity grades are fast hydrating and form a mechanically stable gel layer. Faster hydrating polymers show rapid gel development, limiting the amount of the drug initially released from a matrix (also referred to as burst effect) and extending the period of release;[72,73] however, the presence of the drug and other excipients in a matrix system alters the hydration rate of polymers.[18] Studies directed towards elucidation of the mechanism of drug release from matrix systems report three polymer-related factors: (i) the apparent infiltration rate of aqueous medium and erosion rate of the matrix tablet depends on the type of polymer; (ii) different degrees of polymer substitution result in different hydration rates and viscosity grades; and (iii) an increase in polymer content results in increased viscosity of the gel, leading to a decrease in the effective diffusion coefficient of the drug.[74] A mechanically stable gel layer provides a more tortuous and resistant barrier to diffusion, resulting in a slower release.[75] There are a number of other polymer-related factors, such as polymer swelling, chain relaxation, hydration, wetting, and enthalpy changes associated with these; however, all these are in some way related to the above three considerations. Chebli and Cartilier[71] and Chebli et al.[76] used the mathematical model proposed by Peppas and Sahlin[40] for analyzing the contribution of diffusion and erosion mechanisms on drug release from substituted amylose matrices. At different degrees of substitution, amylose demonstrated different hydration rates and showed a change in release mechanism. The water uptake is dictated by the degrees of substitution, which, in turn, decides the gel structure. Relaxation and stresses of a substituted amylose chain due to water uptake will then predominately control drug transport. The study of rheologic properties of matrices provides mechanistic-based relationships and helps in understanding the release mechanism and kinetics. Delargy et al.[77] proposed a quantitative relationship between polymer viscosity and time for 50% release (t50%) of verapamil hydrochloride. A similar type of correlation was also reported between furosemide release rate and both viscosity and concentration of HPMC. Drugs such as nicotinamide increase the viscosity of HPMC in solution form.[78] Nicotinamide exhibits a salting-in effect on the HPMC solutions, resulting in an increase in gelation temperature and cloud point. Hydrogen bonding between nicotinamide and hydrophilic groups of HPMC expands the polymer coil, increasing viscosity. These types of interactions with a high molecular weight

The use of trade names is for product identification purposes only and does not imply endorsement.



Polymer

Types/grades

Molecular weight (Da)

Glass transition temperature (°C)

Hydroxypropyl-

Methocel K

10 000–150 0000

170–180

methylcellulose

Methocel E Methocel A

Hydroxyethyl-

Natrosol HHR,

cellulose

H4R, h, MHR, JR,

ND

135–140

Viscosity (mPa × s)

Solubility

Regulatory status

2–120 000 for 2% w/v

Soluble in cold water, in mixture

Approved in Japan,

aqueous solution at

of methanol and ethanol, and in

US, Europe, and

20°C

dichloromethane

other countries

2–20 000 for 2% w/v

Soluble in hot and cold water

a,b

1500–3000 for 1% w/v

Soluble in methanol, ethanol,

a,b,c,d

aqueous solution in

and dichloromethane

aqueous solutions

LR Hydroxypropyl-

Klucel GF, JF, LF,

cellulose

EF, HF

80 000–1 150 000

130



Table III. Polymers used in matrix-based controlled-release drug delivery systems and their physicochemical properties[70]

Klucel HF Carbomer

Carbopol 934

1–4 × 106

100–105

Carbopol 934P

a,b

10 000–100 000 for 1%

Soluble in water and ethanol

w/v in 7.4pH buffer

after neutralization

1200–1600 for 1% w/v

Soluble in old and warm water

a,b,c,d

4–110 for 5% w/v

Insoluble in water, glycerol, and

a,c

solution

glycols

Carbopol 971P Carbopol 1342 Xanthan gum

Xantural 75

2 × 106

82–85

solution at 25°C Ethylcellulose

Ethocel Std 4 to

ND

129–133

100 Premium Carageenan

k-Carageenan

ND

ND

5 at 75°C

Soluble in water at 80°C

a,c,d

≥100 000

ND

≤15

Insoluble in water; soluble in

a,b

λ-Carageenan Polymethacrylates

Eudragit RS, RL, NE

Poly-(ethylene

Polyox WSR

oxides)

-N60K

alcohols and acetone 100 000–7 000 000 60

30–10 000 (depending

Soluble in water, acetonitrile,

upon grades) at 25°C

chloroform, methylchloride

a

-303NF Included in the US FDA Inactive Ingredients Guide. GRAS listed.

b

Included in the nonparenteral medicines licensed in the UK.

c

GRAS listed.

d

Accepted as a food additive in Europe.

GRAS = Generally Regarded As Safe; mPa = millipascal; ND = no data; s = second; w/v = weight/volume. 51


a

52

Varma et al.

polymer lead to a reduction in molecular mobility of the drug, which is a function of diffusivity. Furthermore, such interactions will also increase glass transition temperature of the polymer, which may contribute to a reduction in release rates. 2.2.3 Polymer Proportion

In addition to the use of different polymer grades discussed in section 2.2.2, polymers at different proportions can vary the release profile from a matrix device. An increase in polymer proportion increases the viscosity of the gel and, thus, increases the diffusional path length. This could decrease the effective diffusional coefficient of a solute, leading to a reduction in drug-release rate. The effect of polymer viscosity and polymer proportion on drug release has been reported.[15] Changing the Methocel K4M level from 10 to 40% showed a slowing down of dissolution rate. In another study, two HPMC viscosity grades were evaluated as gelling agents for atenolol matrix tablets.[79] Varying the Methocel K4M proportion of both the grades showed a reduction in the release rate with an increase in Methocel K4M proportion. Doubling the total polymer proportion reduced the release rates significantly. An analysis of dissolution profiles, based on the Higuchi and Korsenmeyer models showed that the release mechanism in all the cases was diffusion. 2.2.4 Polymer Particle Properties

Polymer particle size, size distribution, and the number of particles directly influences the availability of particle contact points, porosity, viscosity, and tortuosity of matrices. The penetration rate of an aqueous medium increases exponentially with increasing bulk density of the matrix.[44] This implies increased resistance for water infiltration, with an increase in bulk density or a decrease in porosity. At a low polymer proportion, a significant change in release rates was observed with different particle size fractions.[80,81] Coarse fractions of HPMC hydrate too slowly to allow sustained release.[82] Mitchell et al.[83] reported that when the HPMC content in a formulation is higher, the effect of HPMC particle size on propranolol hydrochloride release is less significant than when the polymer proportion is lower. They justified these results by stating that a lack of HPMC particles in certain areas of matrices leads to a burst effect. HPMC particle size also significantly affects lag time and release mechanisms.[80] A larger particle size HPMC fraction showed less lag period, suggesting that burst release occurred during the initial stages prior to formation of the gel layer. Heng et al.[84] showed three different release characteristics with HPMC matrices prepared from different particle size levels. Matrices prepared from larger particles, within a size range, showed disinte 2004 Adis Data Information BV. All rights reserved.

gration, medium size level showed diffusion, while fine particles showed a combination of both diffusion and erosion mechanisms. A good linear relationship was demonstrated within each size fraction, between the first-order release constant (K1) and particle properties. The effect of polymer particle size (Ppolymer) and relative particle number (Npolymer) on the drug release rate (K1) was expressed in terms of the following equation: K1 = D/(Npolymer × Ppolymer)1/3 + A where D is the constant indicating sensitivity of the matrix system to changes in particle size and polymer quantity, and A is a release retarding constant. 2.2.5 Polymer Combinations

A combination of polymers may show additive or synergistic release retardation. Several investigators[85-87] have suggested that the consistency of the gel layer, which is related to the rheological characteristics of the gelling agent, may have important effects on the drug release profile and on dissolution rate. Synergism in gelling ability of a combination of polymers may be due to molecular interactions between the individual polymers.[88] Rheologic synergism in the gel layer is demonstrated when ionic cellulose derivatives are combined with some of the non-ionic cellulose derivatives, such as HPMC and methylcellulose.[89] Nonionic cellulose molecules may either cross-link with an NaCMC molecule or with a molecule of similar structure. If this crosslinking occurs via the carboxyl group, on NaCMC a greater extent of hydrogen-bonding results, leading to observed synergistic viscosity in the hydrated matrix; however, Vazquez et al.[90] reported higher dissolution efficiency when the ratio of HPMC K100LV to NaCMC was decreased, and concluded that the high aqueous solubility of NaCMC and its consequent inability to form an adequate gel layer may be responsible for such effect. A combination of NaCMC with xanthan gum reduces the apparent viscosity of NaCMC due to enzymatic breakdown.[89] Chitosan has been investigated as a matrix former with a unique gel-forming ability.[91] The addition of sodium alginate to chitosan results in extended release characteristics of the delivery system. Matsumoto et al.[92] studied the rheologic properties and fractal structure of the poly-ion complex between chitosan and sodium alginate, and observed that complexation occurs between the carboxyl anion of alginate and the amino group of chitosan. An interaction between the amino groups of chitosan and carboxyl groups of sodium hyaluronate causing increased viscosity of the gel layer has also been reported.[93] 2.3 Formulation Variables

Numerous publications showing the effect of various formulation variables on the release rate from matrix systems exist in the Am J Drug Deliv 2004; 2 (1)


literature. Major variables include system geometry (shape and size), processing techniques, physical characteristics of the dosage form (crushing strength), and the nature of excipients/additives (fillers, binders, surfactants, and buffering agents).

53

Small tablet

Large tablet r

h H

2.3.1 Formulation Geometry

Geometric factors play an important role in regulating the drug dissolution from matrices for a fixed formulation composition. An eluting medium penetrates at the same rate to a certain depth of tablet, regardless of tablet size, where hydration, polymer relaxation, and molecular rearrangement occur, allowing the formation of gel. This hinders infiltration of the aqueous medium to deeper layers of the tablet and limits diffusion and subsequent release of the dissolved drug. Thus, thickness of the rubbery gel layer will almost be the same for different geometries, but the glassy core will not be equivalent and should be hydrated for complete release of the drug; however, with increased tablet size, the amount of drug available for diffusion increases. This effect overcompensates the effect of decreased relative surface area (which decreases release rate), resulting in an overall increased absolute drug release rate. Figure 3 represents an example of how differences in tablet size can affect drug release; thus, modulation of shape alters the effective surface area and gives a scope to achieve the desired release rates.[67,68] The fraction of drug release from a matrix with a planar surface is proportional to the square root of time, and an initial portion of a similar plot for a cylindrical matrix will be similar to that of a planar one. Using numerical models and data obtained from in vitro experiments, the dimensions of diffusion-controlled-release dosage forms to achieve desired in vivo levels can be predicted. Siepmann et al.[68] developed a mathematical model for diffusional drug release from HPMC matrices, and examined the effect of aspect ratio (the ratio of width to height) and size of cylindrical matrices on drug release. Recently, this group proposed a mathematical model (‘sequential layer’ model), and applied it to understand and predict the effect of various factors, including initial tablet radius, height, and size on drug-release kinetics.[94,95] This model considers water and drug diffusion with nonconstant diffusivity and moving boundary conditions, nonhomogeneous polymer swelling, drug dissolution, and polymer dissolution, while predicting the drug-release kinetics. Ford et al.[34] demonstrated the influence of tablet shape and size on the release rates of promethazine hydrochloride tablets compressed to the same weight and having the same formula. Cobby et al.[96] found that the drug release could be described by a nonlinear expression for both cylindrical and biconvex tablets, even though the rate of drug release varied distinctly with tablet shape; however, Amaral et al.[97] showed that release of naproxen  2004 Adis Data Information BV. All rights reserved.

R r/h = R/H Hydration Hydration

Gel layer r1

h1 H1

R1 r1/h1 > R1/H1

Fig. 3. Schematic diagram showing the effect of tablet size on drug release from a hydrophilic matrix. Before hydration, the aspect ratio (the ratio of width to height) of the two tablets of different size is the same. After hydration, the gel layer thickness for both the tablets is the same; however, the aspect ratio of the glassy core is different for the two tablet sizes. Consequently, the drug available for release is greater in the case of the smaller tablet. h and H = the thickness of the small and large tablet, respectively, before hydration; h1 and H1 = the thickness of the glassy core of the small and large tablets after hydration; r and R = diameters of the small and the big tablets, respectively, before hydration. r1 and R1, refer to the diameter of the glassy core of the small and large tablets after hydration (see text for discussion).

from HPMC matrices was independent of contact surface. Zeroorder release kinetics from a matrix system is usually not observed, but various approaches, such as altering the geometry of the matrix,[12] non-uniform distribution of the drug in the matrix,[98,99] physical restriction of matrix swelling,[19] press coating, dual drugloaded matrices,[59] use of ion-exchange resins,[100] and the concept of multi-layered diffusional matrices,[101] have been proposed in the literature to achieve zero-order release. 2.3.2 Processing Technique

Nellore et al.[15] reported faster release of metoprolol tartrate from the direct compression formulations than the fluid-bed and high-shear granulation techniques. The authors postulated that the initial wetting of the polymer in the granulation stage might result in a much more rapidly hydrating gel layer, which might be responsible for prolonging the release. In contrast, Mandal,[102] using a factorial design, showed more sustained indomethacin release from directly compressed HPMC matrices than with matriAm J Drug Deliv 2004; 2 (1)

54

Varma et al.

ces prepared by wet granulation, and postulated that the observation may be due to a difference in the dissolution mechanism; however, granulation techniques used in both cases were different and, additionally, the physicochemical properties, such as solubility of the drug, should be considered before concluding the influence of such factors. Railkar and Schwartz[103] conducted feasibility studies on the use of moist granulation techniques to develop controlled-release dosage forms of acetaminophen (paracetamol), and concluded that the moist granulation technique is as efficient as the wet granulation technique, with both providing a more sustained release than those prepared by the direct compression process. Binding solvents can significantly influence the drug release from hydrophilic matrices.[103] The degree of swelling and gel forming ability of a polymer changes in the presence of a solvent; however, these changes in the characteristics of a polymer depend on the type of solvent used during the wet granulation process. The use of a higher amount of water in the wet granulation process will increase the dissolution rate, especially in the presence of watersoluble excipients.[104] Compression force applied during tablet preparation affects tablet hardness and thickness, thereby influencing tablet porosity, tortuosity, surface area, and surface characteristics; however, minimal effects of the compression force on drug release from HPMC tablets have been observed.[105,106] Kabanda et al.[107] reported that the crushing strength of tablets could influence the initial drugrelease phase. Tablets formulated with Methocel K4M at the lowest crushing strength showed an initial burst effect due to partial disintegration at the surface of the tablet. These reports suggest that crushing strength influences the drug-release phase before matrix hydration, but once the matrix takes up aqueous medium and swells to form a gel layer, the initial porosity and tablet hardness do not play a significant role in altering release kinetics. 2.3.3 Formulation Excipients/Additives

The physicochemical characteristics of excipients used in controlled-release products should be well controlled to provide reproducible performance. Studies of possible interaction between excipients in the solid dosage forms are necessary because these interactions can affect the drug release and bioavailability. The presence of hydrophobic diluents can result in a more resistant gel layer, which reduces the infiltration of aqueous mediums and drug diffusion. The addition of soluble fillers enhances the dissolution of soluble drugs by decreasing the tortuosity and, thus, the diffusional path length, while insoluble fillers affect the diffusion rate by blocking the surface pores of the tablet.[34] Alderman[82] reported that as little as 10% nonswelling insoluble filler may destroy the  2004 Adis Data Information BV. All rights reserved.

integrity of the gel layer and cause premature disintegration of a matrix tablet containing 10% Methocel K4M. A contradictory observation was reported by Nellore et al.[15] They concluded that at a polymer level of 20% filler solubility has a limited effect on metoprolol release from hydrophilic matrix tablets. This could be due to the formation of a more stable gel layer at a polymer level of 20%, where the presence of insoluble fillers did not affect its integrity. It is generally accepted that the diffusion mechanism of drug release involves three main processing steps. The first is surface wetting and medium ingression into the tablet; the second step is the dissolution of the drug in the hydrated matrix; and finally the diffusion of the soluble drug across the hydrated matrix into the dissolution medium. The water uptake into the tablet depends not only on the porosity of the tablet, but also on the wetability of these pores.[108] Incorporating a surfactant may result in an increase in drugrelease rate through improved wetting or solubilization. Nokhodchi et al.[109] studied the effect of surfactant type, its concentration, and the different ratios of surfactant combinations on the release rate of propranolol hydrochloride. The release rate of propranolol was found to decrease as the concentration of sodium laurilsulfate (SLS) increased, which may be due to complexation between SLS and propranolol; however, the incorporation of cationic surfactant cetrimonium bromide to the matrix containing SLS increased the release rate, which indicated that centrimonium bromide decreased the ability of anionic surfactant molecules to interact with the cationic drug. The presence of a relatively concentrated surfactant solution in the wetted tablet would have reduced inter-particle adhesion, thereby accelerating drug release as a result of increased disintegration;[50] however, interactions in the surfactant-matrix system may be much more complex and can adopt a wide variety of physical states depending on the relative concentrations of the components present. Anionic surfactants can prolong the release of drugs from HPMC matrices. It is believed to be due to the ability of anionic surfactants to bind to non-ionic polymers acting to increase the viscosity.[110] Such results were reported by Ford et al.,[34] where propranolol hydrochloride and SLS formed lyotropic liquid crystals when coming in contact with water, which retarded propranolol release. Binding agents used during the granulation process coat drug particles and also change the rheology of the gel layer, leading to retardation in release rates; however, the degree of retardation is determined by the swelling and hydrating capacities of the binding agent, amount of binder added and the method of addition. Other excipients, such as plasticizers, may enhance drug-release rates, which may be due to the increased dissolution rate of the plastiAm J Drug Deliv 2004; 2 (1)


cized polymer, while generally used lubricants will retard drugrelease rates because of their hydrophobic nature.[111] 3. Conclusions Drug release and mass transfer processes from matrix-based DDS depend on the physicochemical properties of the drug, matrix polymer type, geometry, and the composition. A literature review indicates that a good control over drug release from matrix systems can be achieved by designing the device, based on mechanistic principles manipulating the polymer and formulation variables. Various mathematical models are available for elucidating the mechanisms of drug release and their relative contribution to overall drug-release kinetics. Use of such mathematical modeling during formulation of the development stage will, thus, help in easier optimization with a minimum number of formulation trials. One of the major limitations of matrix-based delivery systems is time-dependent drug release, where release rate declines as a function of time. In general, diffusion and erosion process determines the diffusional path length. This diffusional path length of drug release shifts the release mechanism from a diffusion-controlled process to a process controlled by relaxation, erosion, and dissolution of the polymeric matrix. Desired zero-order release kinetics could be obtained by adjusting the release mechanism from a diffusion-controlled drug release toward a relaxation/erosion controlled process. Studying of release kinetics and their correlation to the dynamic behavior of the drug-release process may, thus, help in selecting the variables that provide better formulation optimization, with ease. As supported with examples, most of these factors are not simple and straightforward, but are often case-dependent. Nonobservance to the general rules is often observed; thus, a careful interpretation of the results helps in visualizing the underlying factors that are playing a significant role. Finally, a thorough understanding of relevant factors gives flexibility in tuning the systems so as to achieve a ‘defined’ drug-release profile. Acknowledgements Financial support from Unichem Laboratories Ltd, Mumbai, India, for related research activities is gratefully acknowledged. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

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Correspondence and offprints: Dr Sanjay Garg, School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Building 504, LGF, 85 Park Road, Grafton, Auckland, New Zealand. E-mail: [email protected]
