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Chapter 1 Introduction

SPP School of Pharmacy and Technology Management, SVKM‟s NMIMS, Mumbai

Chapter 1

Introduction


SPP School of Pharmacy and Technology Management, SVKM‟s NMIMS, Mumbai 2

1.0 Extended release dosage form

In the past few decades, significant advances have been made in the area of drug delivery with

the development of novel dosage forms. The area of extended drug delivery has graduated

from being merely a research item to result in full-fledged commercial reality products. An

appropriately designed extended release drug delivery system can be a major advance towards

solving problems concerning the targeting of a drug to a specific organ or tissue and

controlling the rate of drug delivery to the target sites. On the other hand, there is a growing

need for the controlled and or continuous delivery of such therapeutic agents due to several

biopharmaceutical, safety and patient compliance issues associated with these therapies.

Extended release systems provide drug release in an amount sufficient to maintain the

therapeutic drug level over an extended period of time, with the release profiles

predominantly controlled by the special technological construction and design of the system

itself. Development of oral extended release systems has been a challenge to formulation

scientists due to their inability to restrain and localize the system at targeted areas of the

gastrointestinal tract. There are numerous products in the market formulated for both oral and

parenteral routes of administration that claim extended or controlled drug delivery. Matrix

type drug delivery systems are one of the interesting and promising options in developing an

oral extended release system. In particular, the interest awakened by matrix type delivery is

completely justified in view of its biopharmaceutical and pharmacokinetic advantages over

the conventional dosage forms1.

The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper

site in the body to achieve promptly, and then maintain the desired drug concentration. This

idealized objective of delivering drug at a rate dictated by the needs of the body over the

period of treatment, points to the two aspects most important to drug delivery, namely, spatial

placement and temporal delivery of a drug. Spatial placement relates to targeting a drug

delivery to the target tissue, while temporal delivery refers to controlling the rate of drug

delivery to the target tissue. Despite significant interest and numerous reports about the

design of extended delivery systems for various types of drugs, very few have been

successful2.

For non-immediate release dosage forms, Kr <<<< Ka, that is release of drug from the dosage

form is the rate limiting step and not absorption as is the case with immediate release dosage

forms. Therefore the kinetic scheme is reduced as:



Drug (*) Release Elimination

(*) indicate rate limiting step

Fig.1.1: Kinetic scheme of release and elimination of the drug

from non- immediate release dosage forms.

Essentially the absorptive phase of the kinetic scheme becomes insignificant compared to the

drug release phase. Thus, the effort to develop a modified release delivery system must be

directed primarily at altering the release rate by affecting the value of Kr.

1.1 Comparison of immediate release dosage form with extended release dosage form

Over the past decades the treatment of acute and chronic illness has been accomplished

by many conventional drug delivery systems such as tablets, capsules, pills, creams,

ointments, liquids, aerosols, injectables and suppositories. These conventional drug

delivery systems are still the primary pharmaceutical products commonly seen today in

prescription. Oral route is the most commonly employed route of drug administration.

Although different routes of drug administration are used for the delivery of drugs, oral

route remains the preferred route. Even for extended release systems the oral route of

administration has been investigated the most, because of flexibility in dosage form

design that the oral route offers3.

Conventional drug therapy requires periodic doses of therapeutic agents . These agents

are formulated to produce maximum stability, activity and bioavailability. For most

drugs, conventional method of drug administration is effective, but some drugs are

unstable or toxic and have narrow therapeutic ranges3-5

. In these types of systems,

frequent dosing is required for achieving and maintaining concentration of drug within

the therapeutic range, which result into see-saw pattern of the drug levels, in such cases,

a method of continuous administration of therapeutic agent is desirable to maintain fixed

plasma level as shown in figure 1.2.

To overcome these problems extended release systems were introduced three decades ago.

Extended release, extended action, prolonged release, controlled release, extended action,

timed release, depot and redepository dosage forms are the terms used to identify drug

delivery systems that are designed to achieve a prolonged therapeutic effect by continuously

releasing medication over an extended period of time after administration of single dose.

Dosage form Target area



Term “controlled release” has become associated with those systems from which therapeutic

agents may be automatically delivered at predefined rate over long period of time.

Figure 1.2: Drug blood level versus time profile showing the relationship

between conventional release and controlled delivery system

The basic goal of drug therapy is to achieve a steady-state blood level or tissue level that will

be therapeutically effective and non-toxic for an extended period of time4. To achieve better

therapeutic action various types of drug delivery systems are available, out of which extended

release systems are gaining much importance because of their wide advantages over other like

ease of administration, convenience and non-invasiveness. The vast majority of traditional

dosage forms can be described as dump systems which deliver their active substances in first

order kinetics i.e., release occurs at rates that are highest initially and then decline steadily

thereafter. Clinically this peak and valley pattern results in a time dependant mix therapy.

Drug side effects tend to predominate at the high peak concentration in blood, whereas an

inadequate therapeutic effect may prevail at the valley level. Use of controlled release

systems provide an excellent tool to achieve precise control of rate (and also) at a particular

site. Besides, from the biological benefits incurred from the prolonged and predictable drug

levels extended release systems can allow for significant reduction in frequency of drug

administration and improved patient compliance, more predominantly for chronic ailments

such as high blood pressure, arthritis, asthma and diabetes. There are also good commercial

reasons for strong trend towards extended release system.



1.1.2 Terminology3, 6, 7

Different terminologies used for extended drug delivery system are as follows

Modified Release (MR): Modified Release dosage forms are defined by USP as those

whose drug release characteristics of time course and/or location are chosen to

accomplish therapeutic or convenience objectives not offered by conventional forms,

whereas an extended release dosage form allows a two-fold reduction in dosing

frequency or increase in patient compliance or therapeutic performance.

Sustained Release (SR): It indicates an initial release of the drug sufficient to provide a

therapeutic dose soon after administration, and then a gradual release over an extended period.

Extended Release (ER): Extended release dosage forms release drug slowly, so that

plasma concentration are maintained at therapeutic level for prolonged period of time.

Clear or well defined distinction cannot be made in the above terminology. Sometimes

it is conveniently referred in a particular place or group.

1.2 Fundamental release theories

Based on different drug release mechanisms, quite a few drug release theories have been

developed. For all different types of controlled release systems except osmosis – based

systems, the drug concentration difference between formulation and dissolution medium plays

a very important role in drug release rate. The drug concentration can be affected by its

solubility, drug loading, and / or excipients used. Besides drug concentration difference, the

dissolution rate of polymer carriers can affect drug release rate in dissolution controlled

systems, and the diffusion rate of both drug and dissolution medium inside polymer(s) can

affect drug release rate in diffusion controlled systems. Overall, for most CR formulations,

drug release can be affected by more than one mechanism.

Fick‟s first law of diffusion is used, in which the concentration with the diffusion volume

does not change with time. The drug release rate is determined by drug release surface area

(s) thickness (h) of transport barrier (such as polymer membrane or stagnant water layer) and

the concentration difference (∆C) between drug donor (Cd) and receptor (Cr) that is , between

drug dosage surface and bulk medium.

Figure 1.3 Fick‟s Law

Cd

∆C

h

Cr



dM

S.dt J =

Fick‟s first law states that

Where J is flux, M is the total amount of solute crossing surface area S in time t.

Fick‟s first law did not take into account the drug concentration changes with time in each

diffusion volume, which have been taken into consideration by Fick‟s second law of

diffusion. Based on Fick‟s second law, drug accumulation speed (dc/dt) is determined by

drug diffusivity (D) and the curvature of drug concentration

Most commonly seen drug release rate for oral controlled release formulation is first order

release and / or zero order release. Most oral controlled release formulations based on matrix

and coating approaches are close to first order release. There are mainly five types of release

profiles, zero order release (constant release rate), first order release (decreasing release rate),

bimodal release (two release modes rate) which can be either two separate immediate release

modes or one immediate release mode followed by one extended release mode8-10

, pulsatile

release (multiple release modes and multiple peaks of release rate11

and delayed release (e.g.

enteric coated tablets)12-14

.

The two important phenomena in controlled release formulations are the lag time effect and

the burst effect. In diffusion control system, if fresh membrane is used, it takes time for drug

molecules on the donor side to appear on the receptor side. Under sink condition, drug

molecules will be released at constant rate into the receptor side and steady state is reached.

The time to reach steady state is known as “lag time” however, if the membrane saturated

with drug is used, a “burst effect” will be observed at the beginning of drug release, gradually,

the drug concentration inside the polymer membrane will decrease until the steady state is

reached. Actually, for matrix approach controlled release formulation, because it takes time

for polymer molecules to form Hydrogel, “burst effect‟ is also a common phenomenon.

1.2.1 Limiting factors for oral extended release formulations

There are a few unique properties of the gastrointestinal (GI) tract that make development of

oral ER formulation rather difficult. Figure 1.1 shows schematic description of GI tract.

Based on histology and function, small intestine is divided into duodenum, jejunum, and

ileum, and large intestine is divided into the cecum, colon, rectum, and anal canal. W. A.

= D d

2 C

dx2

dC

dt



Ritschel reported the average length, diameter, and absorbing surface area of different

segments of the GI tract, and the data clearly show that jejunum and ileum (small intestine)

have similar surface absorbing area that are significantly larger than those of other

segments15

. For most drugs, there is better drug absorption in the upper GI tract, which is also

consistent with the significant higher surface absorbing area in the upper GI tract.

Table 1.1: pH values and the transit time at different segments

of the human GI tract16 – 20

Fasting condition Fed condition

Parts of intestine-

Anatomical site pH Transit

Time (h)

pH Transit

Time (h)

Stomach 1-3.5 0.25 4.3 – 5.4 1

Duodenum 5-7 0.26 5.4 0.26

Jejunum 6-7 1.7 5.4 – 6 1.7

Ileum 6.6 – 7.4 1.3 6.6 – 7.4 1.3

Cecum 6.4 4.5 6.4 4.5

Colon 6.8 13.5 6.8 13.5

1.2.2 Relatively short gastric empty and intestinal transit time and varying pH values

As oral dosage forms will be removed from the GI tract after a day or so, most oral ER

formulations are designed to release all drugs within 12-18 hrs. The values in table 1.1 show

the approximate transit time in different GI segments. The presence of food in the stomach

tends to delay gastric emptying. Among different foods, carbohydrates and proteins tend to

be emptied from stomach in less than 1h, while lipids can stay in the stomach for more than

1h16-20

. As a convenient resource, Gastroplus TM

can provide rough estimation on the transit

times and pH values of the GI tract under different situations and help to determine

corresponding drug PK profiles.

Table 1.1 shows that the small intestinal transit time is more reproducible and is typically

about 3–4 hrs. Thus, transit time from mouth to cecum (the first part of large intestine) range

from 3-7 hrs. Colonic transit is highly variable and is typically 10-20 hrs.21 – 23

. Since most

drugs are absorbed from small intestine, the time interval from mouth to cecum for oral

controlled release dosage forms is too short, unless the drug can be equally absorbed from

large intestine, thus the release profiles of most oral controlled release dosage forms can be

effective for only about 8 hrs., if the drug can be delivered for 24 hrs. with a single

administration of an oral controlled release dosage form. But many drugs require more than

one administration if they have the upper GI tract absorption window and short half life,

unless the release of those drugs can be controlled at the upper GI tract with special design.



The study on the GI transit time of once a day OROS ® tablets of both oxprenolol and

metoprolol showed that the median total transit time was 27.4 hrs. with a range of 5.1–58.324, 25

Nonuniform absorption abilities of different segments of GI tract drug transport across the

intestinal epithelium in each segment are not uniform, and in general, it tends to decrease as

the drug moves along the GI tract. Drug absorption from different regions of the GI tract is

different; the residence time of drug within each segment of that GI tract can profoundly

affect the performance of the oral controlled dosage form, that is, the absorption of drug.

If a drug is absorbed only from the upper segment of the GI tract, it is known to have a

“window for absorption”26

. For the drugs with window for absorption; adjusting drug release

rate on different segments of the GI tract may be needed to compensate decreased absorption,

in order to maintain relatively constant blood concentration. For example, to achieve a

plateau – shaped profile to plasma concentration at steady state throughout the 24 hrs. dosing

interval, Nisoldipine coat core controlled release formulation releases drug slowly in the

upper GI tract that has fast absorption and quickly in the colon that has decreased absorption

rate28

. Besides adjusting drug release rate, increasing the residence of drug formulations at or

above the absorption window can also enhance the absorption for those drugs. Currently, two

main approaches have been explored; bioadhesive micro spheres that have a slow intestinal

transit and the gastro retentive dosage system27,

28

.

1.2.3 Presystemic clearance for drugs

Presystemic clearance may occur at some sites of the GI tract and affect drug absorption.

Degradation of orally administered drugs can occur by hydrolysis in the stomach, enzymatic

digestion in the gastric and small intestinal fluids, metabolism in the brush border of the gut

wall, metabolism by microorganisms in the colon, and or metabolism in the liver prior to

entering the systemic circulation (i.e. first pass effect). Such degradation may lead to highly

variable or poor drug absorption into the systemic circulation. For example, digoxin

undergoes microbial metabolism before absorption29, 30

. For this type of drugs, for which

presystemic clearance is determined by the site of absorption, drug bioavailability can be

enhanced by restricting drug delivery to the upper segment of the gut, or to the stomach. For

example, the same amount of metoprolol was administered at the same rate using a

continuous 13.5 h intragastric infusion or an OROS® tablet at 6-15 hrs. After dosing, the

intra gastric infusion had higher plasma concentration than OROS® tablet31, 32

.



1.3 Criteria for selection of drug candidates for formulation of oral extended release

dosage form33

The design of extended release systems depends upon various factors such as the route of

administration, the type of delivery system, the disease being treated and the properties of

drug. These are either physicochemical or biological properties of the drugs.

1.3.1 Physicochemical properties

1.3.1.1 Aqueous solubility

Absorption of poorly soluble drugs is often dissolution rate limited. Such drugs do not

require any further control over their dissolution rate and thus may not seem to be good

candidates for extended release systems. Drugs with good aqueous solubility make good

candidates for oral extended release formulation.

1.3.1.2 Partition coefficient

Drugs that are very lipid soluble or very water soluble i.e., extremes in partition

coefficient will demonstrate either low flux into the tissue or rapid flux followed by

accumulation in tissue. Both cases are undesirable for extended release formulation.

1.3.1.3 Drug stability

As most oral extended release systems are designed to release their content over much of

the length of GI tract, drugs which are unstable in the environment of intestine are

difficult to formulate into prolonged release systems. Interestingly, placement of such

drugs in extended release system also improves the bioavailability picture.

1.3.1.4 Protein binding

Protein binding characteristics of drug can play significant role in the therapeutic effect,

regardless of type of dosage form. Extensive protein binding can be evident by long half life

elimination for the drug, and such drugs do not require extended release dosage form.

However, drugs that exhibit high degree of binding to plasma protein also might bind to

biopolymer in the GI tract, which could have influence on extended drug delivery.

1.3.1.5 Molecular size and difficulty

Drugs in many extended release systems must diffuse through a rate controlling membrane or

matrix, in addition to diffusion through various biological membranes. The ability of drug to

pass through membrane is called as diffusivity. It is function of its molecular weight. An

important influence upon the value of diffusivity (D) in polymers is the molecular size of



diffusing species. The value of diffusivity is related to the size and shape of cavities as well

as the size and shape of diffusing species.

1.3.1.6 Biological half-life

The usual goal of extended release product is to maintain therapeutic blood level over an

extended period of time. For this, rate at which the drug enters the circulation must be

approximately equivalent to the rate of its elimination which is quantitatively described by its

half-life. Drugs with shorter half-life 2-4 hrs make excellent candidates for extended release

preparation since this can reduce dosing frequency. Drugs with half-life shorter than 2 hrs

will require excessive amount of drug in each dosage form to maintain extended effect i.e., if

the dose of drug is high.

1.4 Biological properties

1.4.1 Absorption

To maintain a constant blood or tissue level of drug it must be uniformly released from the

extended release system and then uniformly absorbed. Usually, the rate limiting step in drug

delivery from extended release product is release from the dosage form, rather than inherent

absorption control. The fraction of drug absorbed from a single non-sustained dose of drug

can be quite low due to drug degradation, binding to proteins or dose dependent absorption.

Even if the drug is uniformly absorbed but incompletely, a successful release product can be

made. Dicoumarol and the amino glycosides, gentamicin and kanamycin are examples of

drugs erratically absorbed after oral administration, making the design of extended release

product e.g. riboflavin.

1.4.2 Distribution

Distribution of drugs into tissues is a major factor in the overall drug elimination kinetics.

Drugs with high apparent volume of distribution, which in turn influences the rate of

elimination for the drugs, are poor candidates. It influences the concentration and amount of

drug either in the blood or in the tissues. While designing extended release systems the

apparent volume of distribution can be used to obtain information concerning drug dosing.

1.4.3 Metabolism

Metabolism leads to either inactivation of an active drug moiety or activation of an inactive

drug molecule. Metabolic alteration of a drug mostly occurs in the liver. Metabolism is

reflected in the elimination constant of a drug or by the appearance of metabolite provided the

rate and extent of metabolism are predictable. This property can be incorporated into the



product design, although complex metabolic patterns make design more difficult, particularly

when biological activity is due to a metabolite. If the drug on administration induces or

inhibits enzyme synthesis, it will make a poor candidate for extended release product because

of the difficulty of maintaining uniform blood level.

1.4.4. Duration of action

The biological half life and hence the duration of action of a drug is influenced by its

distribution, metabolism and elimination patterns and plays a key role in determining the

candidature of the drug for preparation as extended release product. Drugs with short half-

lives require frequent dosing to minimize the fluctuation in blood levels accompanying

conventional oral dosage regimen and controlled release dosage form would appear highly

desirable for such drugs. However, for drug with a very short half-life, the desired rate of

release will be quite large which will in turn lead to a prohibitively large dose, unsuitable for

incorporation into an extended release unit. Similarly, there is little justification to prepare

extended release formulation for drugs with long biological half-lives. If there is no

significant difference in effectiveness when a drug is given as single large dose per day or in

several smaller doses throughout the day, the need for prolonged action dosage form is

doubtful, e.g. phenylbutazone and phenothiazines. Drugs with biological half-life of about 4

hrs. make good candidates for extended release products.

1.4.5 Side effects

Extended release formulation can minimize the incidence of side effects by controlling the

plasma concentration of the drug, e.g., controlled release levodopa has lowered the incidence

of side effects and increased patient tolerance to a large total daily dose. The technique of

controlled release has been more popularly used to lower the incidence of gastro-intestinal

side effects than that of systematic side effects. Thus, drugs that are prone to cause gastric

irritation are better tolerated in extended release dosage form, i.e., ferrous sulphate and

potassium chloride.

1.4.6 Margin of safety

Margin of safety of drug is commonly indicated by its therapeutic index. Drug is considered

to be relatively safe if its therapeutic index exceeds 10.

Therapeutic Index: Median toxic dose

Median effective dose



In designing extended release systems for drugs with relatively narrow therapeutic indices, it

is essential that the drug release pattern is precise to maintain the plasma concentration within

a safe and effective therapeutic range.

1.5 Development of extended release solid oral products

A pharmaceutical dosage form development program generally includes preformulation

studies, analytical method development and validation, design development, scale up,

optimization of formulation, manufacturing process, and stability studies.

Because of the complexity of solid dosage forms and the challenges in applying the principles

of basic and applied sciences in the pharmaceutical industry, the strategies and approaches

that have been and continue to be utilized in solid product development vary

significantly from company to company, and even across project teams within the same

organization.

Generally, modified release solid oral product can be developed by different approaches

like trial and error, semi empirical and rationale as given in table 1.2.

Table 1.2: Comparison of approaches to solid product development

Approach Characteristics Likely outcome

Trial and

error

Trying out various experiment or

hypotheses in different directions

until a desired outcome is obtained

with some degree of reliability

Lack of a consistent approach

Disconnect between data and

underlying mechanism

Can often be overwhelmed or

mislead by data generated

from uncontrolled experiments

with compounding variables,

thus exacerbating problems,

and inhibiting innovation

Inconsistent or non-robust

product and process that can

often lead to failures during

development or post approval

product recalls

Considerable waste of time,

and resources, resulting in

poor development efficiency



Approach Characteristics Likely outcome

Semi

empirical

Combining experience with

analysis of abundant data (often

retrospectively) to identify trends

or build empirical or semi

empirical relationships

Using best guessed “trial and

error” approach based on prior

knowledge

Results can be practically useful, but

may not be reliable or could be

misleading in certain cases, due to

improper design and limitation of

experiments and /or lack of

comprehensive scrutiny of pooled

data, and formulation / process

variables involved.

Lack of fundamental

understanding of underlying

Mechanism Lower development

Efficiency due to time and

extensive resources required.

Rationale

Applying proactively

comprehensive knowledge and

techniques of multiple scientific

disciplines and experience to the

understanding of the characteristics

of raw materials, delivery system,

process, and in vivo performance

Integrating formulation / process

design and development by

applying systematic approach,

and utilizing interdisciplinary

scientific and engineering

principles

Using the “best guessed”

approach appropriately by

combining prior knowledge

with theoretical analysis in

experimental designs

Enhanced understanding of how

material properties, process

variables, and product attributes

relate to product performance, as

well as the interplays between

biological system, and the drug

substance or dosage form

Greater product and process

understanding for consistent product

quality, improved control, and risk

management

Increased efficiency, decreased cost

and product rejects

Streamlined post-approval changes,

and enhanced opportunities for

continual improvement

Confirm to quality by design

principle under

cGMP of the twenty first century



1.6 Types of oral extended release systems

These days many types of commercial extended release preparations are available, none

works by single drug release mechanism. Most extended action products release drug by

a combination of processes involving dissolution, permeation, and diffusion . The single

most important factor is water permeation, without which none of the products generally

can control the rate at which the drug dissolves. Once the drug is dissolved, the rate of

drug diffusion may be further controlled to a desirable rate34

. Following are the major

extended release systems for oral use.

Matrix technology

Table 1.3: Controlled drug release mechanisms and related formulation

Mechanism Related formulation approach

Dissolution

Encapsulated dissolution system

(Reservoir system)

Matrix dissolution system

Diffusion

Reservoir system

1. Nonporous membrane reservoir

2. Microporous membrane reservoir

Monolithic device

1. Nonporous matrix

. a) Monolithic solution

b) Monolithic dispersion

2. Micro porous Matrix

a) Monolithic solution

b) Monolithic dispersion

Osmotic Ion exchange

1.6.1 Monolithic matrix

These systems are considered in two groups

Those with drug particles dispersed in a soluble matrix, with drug becoming

available as the matrix dissolves or swells and dissolves (hydrophilic matrices).

Those with drug particles dispersed in an insoluble matrix, with drug becoming

available as a solvent enters the matrix and dissolves the particles (lipid matrices

and insoluble polymer matrices).



Advantages of matrix systems35

Excipient are generally cheap and usually GRAS (generally regarded as safe)

Certified.

Capable of sustaining high drug load and high molecular weight compound.

Reproducible release profile.

Uses readily available pharmaceutical manufacturing equipment.

Possible to obtain different types of release profile: zero order or first order.

Since the drug is dispersed in the matrix system, accidental leakage of the total

drug component is less likely to occur, although occasionally, cracking of the

matrix material can cause unwanted release.

Disadvantages of the matrix systems

The remaining matrix must be removed after the drug is released.

The drug release rates vary with the square root of time. Release rate

continuously diminishes due to an increase in diffusion resistance and / or

a decrease in effective area at the diffusion front. However, a substantial

extended effect can be produced through the use of very slow release rate,

which in many applications are indistinguishable from zero order.

1.6.1.1 Lipid matrix systems

Wax matrices are a simple concept. They are easy to manufacture using standard methods

that is direct compression, roller compaction or hot melt granulation.

The matrix compacts are prepared form blends of powdered components. The active

component is contained in hydrophobic matrix that remains intact during drug release .

Release depends on an aqueous medium dissolving the channeling agent, which leaches

out of the compact, so forming a porous matrix of tortuous capillaries .

The active agent dissolves in aqueous medium and, by way of water filled capillaries,

diffuses out of the matrix. Wax matrices are simple unsophisticated delivery systems with

a good control of rate and extent of drug release.

1.6.1.2 Insoluble polymer matrix system

An inert matrix is one in which drug is embedded in an inert polymer which is not soluble

in gastrointestinal fluid. Drug release from inert matrices has been compared to the

leaching from sponge. The release rate depends upon drug molecules in aqueous solution

diffusing through a network of capillaries formed between compacted polymer particles .



The matrices remain intact during gastrointestinal transit. There have also been concerns

that impaction may occur in large intestine and that patient may be concerned to see the

matrix „ghost‟ in stool. More recently there has been renewed interest in this type of

matrix, and polymers such as ethylcellulose are finding favor. The release rate of drug

from inert matrix can be modified by changing the porosity and tortuosity of matrix, i.e.

its pore structure. The addition of core forming hydrophilic salts or solutes will have a

major influence, as can be manipulation of processing variables. Compression force

controls the porosity of matrix and will release the drug more slowly than less

consolidated matrix. The presence of excipient is likely to influence drug release. It may

be anticipated that water soluble excipient will enhance the wetting of matrix, or increase

its porosity on dissolution. Insoluble excipient will tend to decrease the wetability of

matrix and reduce the penetration of dissolving medium. An increase in drug loading

tends to enhance release rate, but the relationship between the two is not clearly defined.

One possible explanation may be a decrease in the porosity of the matrix. As may be

expected, release rate can be related to drug solubility.

1.6.1.3 Hydrophilic colloid matrix systems

These delivery systems are also called swellable – soluble matrices. In general they

comprise a compressed mixture of drug and water swellable hydrophilic polymer. The

system is capable of swelling, followed by gel formation corrosion and dissolution in

aqueous media. Their behavior is in contrast to a true hydrogel, which swell on hydration

but does not dissolve. On contact with water the hydrophilic colloid components swell to

form a hydrated matrix layer. This then controls further diffusion of water into the matrix.

Diffusion of drug through the hydrated matrix layer controls its rate of release. The outer

hydrated matrix layer will erode as it becomes more dilute; the rate of erosion depends on

the nature of the colloid. Hydrophilic colloid gels can be regarded as a network of

polymer fibrils that interlink in some way. There is also a continuous phase in the

interstices between the fibrils through which the drug diffuses.

1.6.1.4 Mechanisms of drug release from matrix systems

Now days many types of commercial extended release preparations are available. None

work by a single drug release mechanism. The release of drug from controlled devices is

via dissolution or diffusion or a combination of the two mechanisms.



1.6.1.4.1 Diffusion – controlled systems

In diffusion controlled extended release system the transport by diffusion of dissolved

drug in pores filled with gastric or intestinal juice or in a solid (normally polymer) phase

is the release controlling process. Depending on the part of the release unit in which the

drug diffusion takes place, diffusion controlled release system are divided into matrix

system (also referred to as monolithic system) and reservoir system. The release unit

can be a tablet or a nearly spherical particle of about 1mm in diameter (a granule or a

millisphere). In both cases the release unit should stay more or less intact during the

course of the release process. In matrix system diffusion occurs in pores located within

the bulk of the release unit as shown in figure 1.4.

1) The liquid that surrounds the dosage form penetrates, release units and dissolves

the drug. A concentration gradient of dissolved drug is thus established

between the interior and the exterior of the release unit.

2) The dissolved drug will diffuse from the pores of the released unit or the

surrounding membrane and thus be released

A dissolution step is thus normally involved in the release process, but the diffusion step

is the rate controlling step.

Figure 1.4: Release mechanism of matrix system

In a matrix system the drug is dispersed as solid particles within a porous matrix formed

of water–insoluble polymer, such as polyvinyl chloride figure 1.4. Initially, drug particles

located at the surface of the release unit will be dissolved and the drug is released rapidly.

Thereafter, drug particles at successively increasing distances from the surface of the

release unit will be dissolved and released by diffusion in the pores to the exterior of the

release unit. This process continues with the interface between the bathing solution and

the solid drug moving towards the interior.



Fig 1.5: Schematic illustration of the mechanism of drug release from

diffusion based on the matrix tablet (time)

If this system is to be diffusion controlled, the rate of dissolution of drug particles within

the matrix must be faster than the diffusion rate of dissolved drug leaving the matrix36

.

Derivation of the mathematical model to describe this system involves the following

assumption37, 38, 39

(Based on Fig 1.5).

1) a pseudo steady state is maintained during drug release;

2) the diameter of the drug particles is less than the average distance of drug

diffusion through the matrix; the diffusion coefficient of drug in the matrix

remains constant (no change occurs in the characteristics of the polymer

matrix)

3) the bathing solution provides sink condition at all times;

4) no interaction occurs between the drug and the matrix;

5) the total amount of drug present per unit volume in the matrix is substantially

greater than the saturation solubility of the drug per unit volume in the

matrix (excess solute is present)

6) only diffusion process occurs Depleted matrix zone

Drug

Solid drug Cs

dn

Ghost matrix x=0 x=n

Figure 1.6: Schematic representation of a matrix release system

The release behavior can be described by the following equation



dm / dn = C0. dh - Cs /2 (1)

Where,

dm - change in the amount of drug released per unit area

dn - change in the thickness of the zone of matrix that has been depleted of drug

C0 - total amount of drug in a unit volume of matrix

Cs – saturated concentration of drug within the matrix

From diffusion theory

dm = Dm Cs /h.dt (2)

By combining equation (1) and (2);

M = [ Cs .Dm (2 C0 - Cs ). T)] 1/2

(3)

When the amount of drug is in excess of saturation concentration, (C0 >>Cs)

M = [ 2Cs .Dm CD . T] 1/2

(4)

This indicates that the amount of drug released is a function of square root of time.

Drug release form a porous monolithic matrix involves the simultaneous

penetration of surrounding liquid, dissolution of drug and leaching out to the drug

through tortuous interstitial channels and pores. The volume and length of the

opening must be accounted for in the drug release from a porous or granular matrix

M = [DS Ca P / T ( 2C0 – p. Ca). t] 1/2

(5)

Where,

P = porosity of the matrix

T = tortuosity

Ca = solubility of the drug in the release medium

Ds = diffusion coefficient in the release medium

Porosity is the fraction of matrix that exists as pores or channel into which the

surrounding liquid can penetrate. It is the total porosity of the matrix after the drug

has been extracted; it consist of initial porosity due to the presence of air or void

space in the matrix before the leaching process begins as well as the porosity

created by extracting the drug and the water – soluble excipeints.

P = Pa + C0 / p + Cex /pex (6)

Where, p is the drug density and Cex are the density and the concentration of water-

soluble excipient respectively. In case where no water soluble excipient is used in

the formulation and initial porosity is much smaller tan porosity created by drug

extraction, total porosity becomes.

P = C0 /p (7)



Hence the release equation can be written as;

M = [Ds Ca P/T (2C0 – p. Ca).t] 1/2

(8)

M = [2 DS. Ca. C0. P/T. t] ½

(9)

For purpose of data treatment, equation (5) can be reduced to

M = k.t 1/2

Where, k is a constant, so that the amount of drug released versus the square root

of time will be linear, if the release of drug form matrix is diffusion–controlled. If

this is the case, one may control release of drug from a homogeneous matrix

system by varying the following parameters40, 41, 42

Initial concentration of drug in the matrix

Porosity

Tourtuosity

Polymer systems forming the matrix

Solubility of drug

1.6.1.4.2 Dissolution controlled systems

A drug with slow dissolution rate will demonstrate sustaining properties, since the release

of the drug will be limited by the rate of dissolution. In principle, it would seem possible

to prepare extended release products by decreasing the dissolution rate of drug that is

highly water-soluble. This can be achieved by

preparing an appropriate salt or derivative

coating the drug with a slowly dissolving material – encapsulation with

dissolution control

incorporating the drug into a tablet with a slowly dissolving carrier- matrix

dissolution control (a major disadvantages is that the drug release rate

continuously decreases with time)

The dissolution process can be considered diffusion layer controlled, where the rate of

diffusion from the solid surface to the bulk solution through unstirred liquid films is the

determining step. The dissolution process at steady state is described by Noyes -Whitney

equation

Dc /dt = kD .A (CS –C) = D /h.A. (CS – C)

Where, Dc/dt = dissolution rate

KD = the dissolution rate constant (equivalent to the diffusion coefficient divided

by the thickness of the diffusion layer D/h)



D = diffusion coefficient

CS = saturation solubility of the solid

C = concentration of solute in the bulk solution

Equation (1) predicts that the rate of release can be constant only if the following

parameters are held constant;

Surface area

Diffusion coefficient

Diffusion layer thickness

Concentration difference

1.6.1.4.3 Erosion – controlled system

In erosion–controlled extended–release systems the rate of drug release is controlled by the

erosion of matrix in which the drug is dispersed. The matrix is normally a tablet, i.e., the

matrix is formed by tableting operation, and the system can thus be described as a continuous

liberation of matrix material (both drug and excipient) from the surface of the tablet, i.e.

surface erosion. The consequence will be a continuous reduction in tablet weight during

course of the release process (figure 1.6). Drug release from an erosion system can thus be

described in two steps

1) Matrix material, in which the drug is dissolved or dispersed, is liberated from the

surface of the tablet.

2) The drug is subsequently exposed to the gastrointestinal fluids and mixed with (if

the drug is dissolved in the matrix) or dissolved in (if the drug is suspended in the

matrix) the fluid.

This release scheme is in practice a simplification, as erosion systems may combine different

mechanisms for drug release. For example, the drug may be released both by erosion and by

diffusion within the matrix. Thus, a mathematical description of drug release from an erosion

system is complex. However, drug release can often approximate zero-order for a significant

part of the total release time. The eroding matrix can be formed from different substances.

One example is lipids or waxes, in which the drug is dispersed. Another example is polymers

that gel in contact with water (e.g. hydroxy ethyl cellulose). The gel will subsequently erode

and release the drug dissolved or dispersed in the gel. Diffusion of the drug in the gel may

occur in parallel as shown in figure 1.7.



Figure 1.7: Schematic illustration of the mechanism of

drug release by erosion from tablet

1.7 Factors affecting drug release43

The study on the drug release from the hydrophilic matrices requires knowledge of properties

and interaction of the polymers used as the binder.

1.7.1 Polymer hydration

Polymer dissolution includes absorption/adsorption of water in more accessible place, rupture

of polymer–polymer linking with the simultaneous formation of water–polymer linkage,

separation of polymeric chain, swelling, and finally, dispersion of polymeric chain in the

dissolution medium. Methocel K polymer, because of low content of methoxy groups,

hydrates quickly, which justifies its application in controlled release matrices. Larger size

fraction of HPMC hydrates more rapidly than smaller fraction. The first few minutes of

hydration are the most important because they correspond to the time when the protective gel

coat is formed around matrices containing HPMC.

1.7.2 Polymer composition

The complex composition of polymer cellulose ether precedes several reactions, as hydroxyl

groups, that can be reacting covalently with many species both mono and poly-functional in

order to stabilize and insolubilize their structure44

.

1.7.3 Polymer viscosity

With cellulose ether, polymer viscosity is used as an indication of the matrix weight.

Increasing the molecular weight or viscosity of the polymers in the matrix formulation

increases the gel layer viscosity and thus slows the drug dissolution 45

.

Viscosity of the gelling agent slows down or speeds up the initial process of hydration

(without altering the release rate) Rekhi G.V et al46

studied the effect on release of metoprolol

tartarate from extended release formulation by using HPMC polymers of different viscosity.

Vazquez M J47

demonstrated that decreasing the matrix viscosity makes the drug diffusion



easier. Temperature affects HPMC hydration. With increase of gel temperature, the HPMC

looses hydration property followed by decrease in relative viscosity.

1.7.4 Drug solubility

Absorption of poorly soluble drugs is often dissolution rate limited. Such drugs do not

require any further control over their dissolution rate. During the preformulation phase it is

necessary to determine drug solubility not only in water but also at various pH. The aqueous

and pH dependent solubility is important for drug release. The aqueous solubility of drug

plays an important role in drug release mechanism, as soluble drugs are generally released by

diffusion mechanism while insoluble drugs are released by erosion.

1.7.5. Polymer drug proportion

Studies by Salomen, E Docker48

demonstrated that the release rate increases for lower amount

of HPMC with slightly soluble drug, the permeation depends on gel consistency.

1.7.6 Polymer drug interaction

The evaluation of water concentration profile was calculated from HPMC matrices with

different molecular weights. The thermal analysis of cellulose ether polymer demonstrated

that the drug polymer interaction occurs at hydrated gel layer around the matrix tablet and is

partially responsible for the drug release modulation. Ford et at49

studied water soluble drug

(promethazine hydrochloride) to evaluate the temperature effect on the drug release from

matrices with several degrees of viscosity and found drug release decreases with increase of

HPMC content and increase in temperature leads to increase in drug release rate.

1.7.7 Polymer swelling50, 51

Thermoplastic polymers, which are sufficiently hydrophilic, are water soluble. A sharp

advancing front divides the unpenetrated core form a swollen and dissolving shell. Under

stationary conditions, a constant thick surface layer is formed by the swollen polymer and by

a high concentration polymer solution. If the dissolution occurs normally, the steady-state

surface layer consists of four different sub layers as liquid sub layer (adjacent to the pure

solvent) gel sub layer, solid swollen sub layer and infiltration sub layer (adjacent to the

polymer), gel sub layer, solid swollen sub layer and filtration sub- layer (adjacent to the

polymer base into which the solvent has not yet migrated). The dissolution rate strongly

depends on hydrodynamic conditions, temperature, polymer molecular weight and crystalline

level52

. Although outwardly simple, drug release from hydrophilic matrices is a complex

phenomenon resulting from the interplay of many different physical processes. In short, drug



release from these systems is the consequence of controlled matrix hydration, followed by gel

formation, textural/ rheological behavior, matrix erosion, and/ or drug dissolution and

diffusion, the significance of which depends on drug solubility and concentration and changes

in matrix characteristics as illustrated in figure 1.753, 54

.

At the molecular level, drug release is determined by water penetration, polymer swelling,

drug dissolution, drug diffusion and matrix erosion. These phenomena depend upon the

interaction among water, polymer, matrix content and the drug. Water has to penetrate the

polymer matrix, leading to polymer swelling and drug dissolution, before the drug can diffuse

out of the system. In effect, water decreases the glass transition temperature of the polymer to

the experimental temperature resulting in a transformation of the glassy polymer into a

rubbery phase. The enhanced mobility of the polymeric chains favors the transport of water

and consequently of the dissolved drug55

.

.

Figure 1.8: water concentration gradient, textural behavior and polymer drug

concentration gradient in swelling polymer matrix

1.7.8 Tablet hardness and density

Valasco MV et al56

evaluated effect of compression force on drug release from HPMC

matrices and reported independence of drug release with compression force on drug release

from HPMC matrices.



1.7.9 Effect of diluents

Addition of water soluble diluent like lactose and water insoluble diluent like tri basic calcium

phosphate, showed difference in the release profile, This is because of the difference in the

solubility of the diluents and their subsequent effect on the tortuosity factor. As water soluble

diluents dissolve, they diffuse outward and decrease the tortuosity of the diffusion path of the

drug. Tri calcium phosphate does not diffuse outward, but rather become entrapped within

the matrix and affect an increase in the release of the drug by the fact that its presence

necessarily decreases the gum concentration. S. Kazuhiro et al57

investigated the effect of

water soluble fillers in gel forming matrix on in vitro and in vivo drug release and observed

marked difference in drug release.

1.8 Stability studies58, 59, 60

Adequate stability data of the drug and its dosage form is essential to ensure the strength,

safety, identity, quality, purity, in vitro and in vivo release rates that they claim to have at the

time of use. A controlled release product should release a predetermined amount of the drug

at specified time interval, which should not change on storage. Any considerable deviation

from the appropriate release would render the controlled release product useless. The in vitro

and in vivo release rate of controlled release product may be altered by atmospheric or

accelerated conditions such as temperature and humidity.

1.9 Polymers for controlled release formulation design

Even though there are a lot of different synthetic polymers, not many have been used in

pharmaceutical industry especially in oral CR formulation. Most common synthetic polymers

used in oral extended release/ controlled release formulation are polyvinyl alcohol (PVA),

polyacrylic acid and polymethacrylate. Polyacrylic acid and its derivatives are commonly

used in enteric coating due to their insolubility at low pH. Carbopol is high molecular weight

cross linked poly (acrylic acid) polymer. Polymethacrylate and derivatives, mainly

Eduragit®. Polymers are commonly used for extended release coating61

.

In pharmaceutical industry, more natural polymers or their derivatives than synthetic

polymers have been used in oral CR formulations. Among the three subclasses of natural

polymers, proteins, polysaccharides, and nucleotides, only polysaccharides are widely used in

oral extended release/ controlled release formulations.

Cellulose derivatives such as hydroxypropylmethyl cellulose (HPMC), hydroxyl-

propylcellulose (HPC), hydroxyethylcellulose (HEC), ethyl cellulose (EC) are the most



commonly used polymers in oral CR formulations62, 63

. For each cellulose derivative,

different grades can also have significantly different properties in terms of molecular weight,

viscosity, solubility, hydration etc. Different grades can be used for different purposes.

Besides cellulose derivatives, many polysaccharides especially dietary fibers have been used

in drug development. table 1.5 lists the commonly used natural polymers or their derivatives

in oral ER formulations. Polymers used in dissolution controlled release systems are different

than the polymers used in diffusion controlled systems. The polymers in diffusion controlled

systems are generally water insoluble. Some commonly used polymers for diffusion -

controlled systems (reservoir and monolithic systems) are cellulose (e.g., ethylcellulose),

collagen, nylon, poly (alkyl cyanoacrylate) polyethylene, poly (ethylene co vinyl acetate),

poly (hydroxyethyl methacrylate), poly (hydroxypropylethyl methacrylate) poly

(methylmethacrylate) polyurethane, and silicon rubber.

Table 1.4: Common natural polymers and derivatives used in oral ER formulation

Polymer Comment

Hydroxypropyl cellulose Used in matrix extended release formulation

Hydroxypropylmethyl

cellulose

Widely Used in matrix extended release

formulations

Ethyl cellulose Insoluble in water. Is widely used in coating for

extended release applications. Also used in matrix

tablets for diffusion – controlled CR formulation,

that is, lipophillic matrix64, 65.

Methyl cellulose Not as efficient as HPMC and HPC in slowing

down drug release rate

Carboxymethyl cellulose

Sodium

Sometimes used in matrix tablets together with

HPMC and HPC in slowing down drug release rate

Sodium alginate Besides thickening , gel – forming , and stabilizing

properties , it can also easily gel in the presence of

a divalent cation such as Ca2+

Chitosan pH dependent hydrogelation of chitosan matrixes

Xanthan gum Good alternative for cellulose polymer



1.9.1 Polymer properties

For polymers used in oral ER formulations, there are several important properties that can

influence formulation design especially drug release rate, as shown in table 1.6. Besides drug

release kinetics, polymer properties can also affect process development. Other polymer

properties such as flowability, compatibility, and so on are also very important in process

development.

Table 1.5 Polymer properties versus drug release mechanism

Mechanism Polymer property

Dissolution Polymers such as HPMC, soluble in water molecular weight,

viscosity, hydration speed and so on

Diffusion Lipophilic polymers, such as ethyl cellulose,

poly(methylmethacrylate) ploy (hydroxyethyl methacrylate),

insoluble in water molecular

weight viscosity, lipophilicity, and so on that can affect drug

diffusion through them

Osmosis Semi permeable membranes such as cellulose acetate

water permeability through them

Ion Exchange Cross linked resins

1.10 Hot melt granulation technology

Melt granulation/extrusion technology represents an efficient pathway for manufacture of

drug delivery systems. Industrial application of the extrusion process dates back to 193066

.

Mostly it has been used in the plastic, rubber and food industry67

. Recently melt granulation

has found its place in pharmaceutical manufacturing operations68

.

The potential of the technology is reflected in the wide scope of different dosage forms

including oral dosage forms, implants, bioadhesive ophthalmic inserts, topical films, and

effervescent tablets. In addition, the physical state of the drug in a granulate/extrudate can be

modified with the help of process engineering and the use of various polymers. Melt

granulation is now widely used in pharmaceutical research for the enhancement of dissolution

of poorly soluble drugs and for modifying the release of the drug. Melt granulation is a

process by which pharmaceutical powders get converted to granule form by the use of a

binder which can be a molten liquid, a solid or a solid that melts during the process. The drug

can be present in crystalline form for sustain release applications or dissolved in a polymer to



improve dissolution of poorly water-soluble drugs69

. The possible use of a broad selection of

polymers starting from high molecular weight polymers to low molecular weight polymers

and various plasticizers has opened a wide field of avenues for formulation research.

Melt granulation process is currently applied in the pharmaceuticals for the manufacture of

variety of dosage forms and formulation such as immediate release and extended release

pellets, granules and tablets. This process can be used for the preparation of extended release

dosage forms by using lipophillic binders such as glyceryl monostearate70

, a combination of

hydroxypropyl methylcellulose and hydrophobic polymers.

Advantages

Solvents are not used in this process.

Processing steps are few and time consuming drying step is eliminated.

Good stability at varying pH and moisture levels.

Process is relatively simple, continuous and efficient.

Limitations

Process requires high-energy input.

Process requires heating therefore best suited for thermostable drugs.

Low melting point binders are generally used in melt granulation technique,

they are at times difficult to handle as they may soften during storage.

High melting point binders, if used, require high temperature for melting

this causes instability problem for heat labile materials.

1.10.1 Main applications in Pharmaceutical Industry

For improving the dissolution rate and bioavailability of the drugs by forming a solid

dispersion e.g., Polyethylene glycol is used as the dissolution enhancer in griseofulvin tablets

and in turn that improvises the bioavailability. Controlling or modifying the release of the

drug e.g., spirapril hydrochloride tablets or metformin hydrochloride tablets with

hydrogenated vegetable oil and stearic acid71, 72, 73

. To mask the bitter taste of the active drug

e.g., Antibiotics such as cefpodoxime proxetil74

with stearic acid coating.

1.10.2 Materials used in the system

Two types of meltable binders are used frequently in melt granulation systems, hydrophilic

and hydrophobic. The temperature range in which they should melt is very critical from the

processing viewpoint. Hydrophilic meltable binders normally melt between 40-70°C.

Polyethylene glycol has been widely used in melt granulation because of its favorable solution



properties, low melting point, rapid solidification rate, low toxicity and low cost75

.

Poloxamers like copolymers of ethylene oxide and propylene oxide which are low melting

solids, can be used for melt granulation technology. Gelucire is a mixture of glycerides and

fatty acid esters of PEGs. It increases the dissolution rate of poorly water soluble drugs which

is attributed to surface active and self emulsifying properties76

and hydrophobic meltable

binders usually melt between 40-85°C and listed in table 1.7.

Table 1.6: List of Meltable binders

Meltable binders Melting range (°C )

Hydrophilic meltable binders

Polyethylene glycols 2000 – 20000 40-70

Poloxamer 188, 237, 338 or 407 49-57

Gellucire 44-50

Hydrophobic meltable binders

Stearic acid 46-69

Stearic alcohol 56-60

Hydrogenated castor oil 60-70

Glyceryl stearate 54-63

Glyceryl behenate 65-77

Glyceryl palmitostearate 52-55

Hydrogenated vegetable oils 61-66

Glyceryl monosterate 55-60

Beeswax 56-60

Carnauba wax 75-83

Paraffin wax 47-65

1.10.3 Techniques for melt granulation

Melt granulation technique involves agitation, kneading and layering the active in the

presence of a molten binding liquid. Dry granules are obtained as the molten binding liquid

solidifies on cooling. The equipments for the melt granulation include rotating pans, fluid bed

processer, low or high shear jacketed mixer etc.

During the melt granulation process, the meltable binder may be added as molten liquid or as

the dry flakes. In the later, the binder can be heated by hot air or by a heating jacket to above



the melting point of the binder. Alternatively, the melt granulation process involves an

extremely high shear input where due to the high shear heat of friction alone raises the

temperature of the binder and effects binding. Typically, the melting points of the meltable

binders range from 40-70°C.

There are various technologies available for the melt granulation.

1.10.3.1 Melt agglomeration

Melt agglomeration is a process by which the fine solid particles are bound together into

agglomerates by agitation, kneading and layering, in the presence of a molten binding liquid

which solidifies on cooling. Typical examples of melt agglomeration processes are melt

pelletization and melt granulation. During the agglomeration process, a gradual change in the

size and shape of the agglomerates would take place. It is usually not possible to clearly

distinguish between granulation and pelletization. Thus granulation is considered a

pelletization process when highly spherical agglomerates of narrow size distribution are

produced. The equipment for melt agglomeration include rotating drums or pans, fluid bed

granulators, low-shear mixers such as Z-blade and planetary mixers, high shear mixers.

1.10.3.2 Agglomeration by distribution

In agglomeration by distribution mode, distribution of molten binding liquid on the surface of

the particles will occur and agglomerates are formed via coalescence between the wetted

nuclei.

Agglomeration by immersion

In agglomeration by immersion mode, nuclei are formed by immersion of the primary

particles onto the surface of the droplet of the molten binding liquid. Primarily, the

distribution of molten binding liquid to surfaces of nuclei has to be effected by densification

prior to coalescence between the nuclei. Depending on the relative size between the solid

particles and the molten binding liquid droplets, the distribution will be a dominant mode

when the molten binding liquid droplets are smaller than the solid particles or of a similar

size. On the other hand, the immersion mode will dominate when the molten binding liquid

droplets are larger than the solid particles.

A molten binding liquid of low viscosity promotes the distribution mode of agglomeration. In

the case of immersion, it is more favorable for molten binding liquid of high viscosity, which

could resist breaking by dispersive forces.



Spray congealing

Spray congealing is a melt technique of high versatility. In addition to manufacture

multiparticulate delivery system, it can be applied to process the low meltable materials into

particles of defined size and viscosity values for the melt agglomeration process.

Processing of meltable materials by spray congealing involves spraying a hot melt of wax,

fatty acid, or glyceride into an air chamber below the melting point of the meltable materials

or at cryogenic temperature. Spray-congealed particles (10–3000 µm in diameter) are

obtained upon cooling. The congealed particles are strong and nonporous as the solvent is

evaporated. Ideally, the meltable materials should have defined melting points or narrow

melting ranges. Viscosity modifier, either meltable or non-meltable at the processing

temperature, may be incorporated into the meltable matrix to change the consistency of the

molten droplets.

Tumbling melt granulation

A newer melt agglomeration technique, i.e., tumbling melt granulation, for preparing

spherical beads has been reported. A powdered mixture of meltable and non-meltable

materials is fed onto the seeds in a fluid-bed granulator. The mixture adheres onto the seeds

with the binding forces of a melting solid to form the spherical beads. In preparing the

spherical beads, both viscosity and particle size of the meltable materials should be kept at an

optimum value. The particle size of a meltable material should be 1/6 or lower than the

diameter of the seeds. High-viscosity meltable materials should not be employed to avoid

agglomeration of seeds and producing beads of lower size.

Melt extrusion technology represents an efficient pathway for manufacture of drug delivery

systems. Resulting products are mainly found among semi-solid and solid preparations. The

potential of the technology is reflected in the wide scope of different dosage forms including

oral dosage forms, implants, bioadhesive ophthalmic inserts, topical films, and effervescent

tablets. In addition, the physical state of the drug in an extrudate can be modified with help of

process engineering and the use of various polymers. The drug can be present in crystalline

form for extended release applications or dissolved in a polymer to improve dissolution of

poorly water-soluble drugs. The possible use of a broad selection of polymers starting from

high molecular weight polymers to low molecular weight polymers and various plasticizers

has opened a wide field of numerous combinations for formulation research.



1.11 Multiparticulate unit dosage forms

Oral controlled release drug delivery systems can be classified into two broad groups. Single

unit dosage forms (e.g., tablets or capsules) and multiple unit dosage forms (e.g. pellets,

granules or microparticles). Although similar drug release profiles can be obtained with both

dosage forms, multiple unit dosage forms offer several advantages. The multiparticulates

spread uniformly throughout the gastrointestinal tract. High local drug concentrations and the

risk of toxicity due to locally restricted tablets can be avoided. Premature drug release for

enterically coated dosage forms in the stomach, potentially resulting in the degradation of the

drug or irritation of the gastric mucosa, can be reduced with coated pellets because of a more

rapid transit time when compared to enterically coated tablets. Better distribution of

multiparticulates along the GI-tract could improve the bioavailability, which potentially could

result in a reduction in drug dose and side effect. Inter and intra-individual variations in

bioavailability-caused, for example, by food effect are reduced. With coated single dose

dosage forms, the coating must remain intact during the drug release phase; damage to the

coating would result in a loss of the extended release properties and dose dumping. If not

compressed, the mechanical strength of the coating of pellets is not as critical as with tablets

since unwanted dose dumping from pellets is practically nonexistent. Various drug release

profiles can be obtained by simply mixing pellets with different release characteristics. In

addition, a more rapid onset of action can be achieved easier with pellets than with tablets as

shown in figure 1.9.

Figure 1.9: Drug release profile of matrix and multiparticulate dosage form

With regard to the final dosage form, the multiparticulates can be filled in hard gelatin

capsules or be compressed in to tablets.



The advantage of tableting multiparticulates includes a reduced risk of tampering and fewer

difficulties in esophageal transport when compared with capsules. Large volume tablets

generally have a higher patient compliance than capsules; higher dose strength could be

administered with tablets. Tablets from pellets can be prepared at lower cost when compared

to pellet filled capsules because of the higher production rate of tablet presses. The expensive

control of capsule integrity after filling is also eliminated. In addition, tablets containing

multiparticulates could be scored without losing the controlled release properties. Scored

tablets allow a more flexible dosing regimen.

Compaction of coated multiparticulates into tablets could either result in disintegrating tablets

providing a multiparticulate system during GI-transit or in intact tablets due to the fusion of

the multiparticulates in a larger compact. Ideally, the compacted pellets should disintegrate

rapidly in individual pellets in gastrointestinal fluids. The pellets should not fuse into a non-

disintegrating matrix during compaction. The drug release should not be affected by the

compaction process. The challenges of formulating pellets into tablets are evident. With

reservoir-type coated pellet dosage forms, the polymeric coating must be able to withstand the

compression force; it can deform, but should not rupture.

Without sufficient elasticity of the film, the coating could rupture during compression and the

extended release properties would be lost. In addition the bead core should also have some

degree of plasticity which can accommodate changes in shape and deformation during

tableting. The aim of compaction of pellets is to convert a multiple unit dosage form into a

single unit dosage form containing the multiparticulates, with this single unit dosage form

having the same properties, in particular drug release properties, as the individual

multiparticulates.

Extended release and delayed release dosage forms comprising multiple units such as pellets

offer various advantages over single unit dosage forms such as coated tablets and capsules81

.

The major advantages are reduced risk of local irritation and toxicity, less variations in

bioavailability caused by food effects, reduced premature drug release from enteric coated

dosage forms in the stomach because of a more rapid transit time of coated pellets when

compared to enteric coated tablets. Various drug release profiles can be obtained by simply

mixing pellets with different release characteristics. Most of these advantages are associated

with the uniform distribution of multiparticulates throughout the gastrointestinal tract. The



drawback of multiple unit modified release dosage forms are that their manufacture is

technically more complicated, time consuming and expensive.

With respect to the final dosage forms, the coated pellets can either be filled into hard gelatin

capsules or can be compressed into tablets. However, there are some disadvantage with

capsules such as feasibility of tampering, difficulties in esophageal transport, and higher

production costs, Therefore, tablet formulation is the preferred final dosage form. Only a few

multiple unit containing tablet products are available such as Beloc ® ZOK77, 78, 79

and Antra

MUPS. This is due to the inherent challenges involved in the compression of coated pellets.

Ideally, the compacted pellets should disintegrate rapidly into individual pellets in gastro

intestinal fluids and the drug release pattern of the coated pellets should not be affected by

compression. Certain formulation and process parameters play an important role in successful

production and functioning of the multiple unit – containing tablets.

1.11.1 Pellet core

Properties of pellets such as composition, porosity, size, and density have been reported to

affect the functioning of the multiple unit containing tablets. An understanding of the

compression behavior of uncoated pellets can provide a basis for the formulation of multiple

unit tablets.

Composition of the Pellets

Pellets have been shown to behave differently on compaction and consolidation than powder

of the same material, Wang et al80

found that the compatibility of lactose rich pellets was

better than that of MCC- rich pellets and the poor compatibility of the later was ascribed to

the loss of plasticity of MCC during the wet granulation process81

. The desirable mechanical

properties of the core are that they should be strong, should not be brittle and have a low

elastic resilience.

Beckert and Co–workers82

studied the behavior of the enteric coated bisacodyl pellets of two

different crushing strengths with different excipient, and concluded that the harder pellets

were able to withstand compression forces as they deformed to a lesser degree. The core

should have some degree of plasticity, which can accommodate changes in shape and

deformation during compression83

. It should deform and recover after compression without

any damage to the coating. Therefore, the core should preferably contain a material that

undergoes plastic deformation during compression. Microcrystalline cellulose is such an

excipient. The compression behavior of granulated microcrystalline cellulose has been



thoroughly studied by Johansson84

. Maganti and Celilk85

compared the compaction behavior

of pellet formulations, mainly consisting of MCC, to that of the powders from which they

were formed and found significant differences between the two. The powders were found to

compact by plastic deformation and produced strong compacts, while the pellets exhibited

elastic deformation and brittle fragmentation, resulting in compacts of lower strength. This

was ascribed to the low surface to volume ratio of the granules, which might result in a

decreased area of contact between the particles as they consolidate.

Porosity of the pellets

Porosity of the pellets is another key factor that affects the compaction pattern and thereby

affects the polymer coat integrity during compression. Tuton and co workers86

studied the

compaction behavior of pellets of three different porosities, containing microcrystalline

cellulose and salicylic acid that were prepared by extrusion – spheronization and coated with

ethyl cellulose. They found that the coating did not significantly interfere with the

compression behavior of the pellets. The effect of intragranular porosity on the compression

behavior and drug release from the reservoir pellets was high in the compacted pellets of high

porosity which were highly densified and deformed, while drug release was unaffected87

.

The compression behavior and compatibility of nearly spherical microcrystalline cellulose

pellets of different porosities and mechanical properties was investigated by Johansson et al87

.

The pellet porosity was found to control the degree of deformation of the pellets, caused by a

reposition of primary particles within the pellet, seemed to be controlled by the total volume

of air that surrounds the primary particles in the pellets. An increase in pellet porosity

increased the degree of deformation of the pellets during compression and the tensile strength

of the tablets because of the formation of stronger intragranular bonds.

Nicklasson et al88

studied the compaction behavior of pellets prepared form 4:1 mixture of

dicalcium phosphate and microcrystalline cellulose with porosities in the range of 26-55%.

The pellet porosity was found to significantly affect the tableting behavior of the DCP/ MCC

pellets. The relationship between pellet porosity and the compaction behavior was further

confirmed through a study of drying rate effects on porosity and tabletting behavior of

microcrystalline pellets89

. An increased drying rate gave more porous pellets, due to

decreased pellet densification during the drying process which were more deformable and

which formed tablets of a higher tensile strength.



Size of pellets

The size of the pellets also affects the compaction properties and the drug release from the

compacted pellets. At the same coating level, smaller pellets were more fragile than larger

pellets. This was attributed to the reduced film thickness of the smaller pellets because of the

larger surface area90

. small pellets have been found to be less affected than larger pellets by

the compaction process. Haslam et al91

correlated this to the individual bead strength i.e. the

smaller beads were significantly stronger, relative to their size, than the larger ones.

Ragnarson et al92

reported that increasing the particle size resulted in more damage to the

coating.

Shape of the pellets

Shape of the pellets was found to have a bearing on the compression behavior and tablet

forming ability of granular material formed from microcrystalline cellulose. A change in

granule shape towards a more irregular shape induced a more complex compression behavior

of the granules during compression. An irregular shape and a rough surface texture make the

granules less sensitive to lubrication in terms of their compatibility. This was possibly the

result of a rupture of the lubricant films due to deformation or attrition during compression, or

of an incomplete surface coverage of the granules by the lubricant before compression93, 94

.

Density of the pellets

Density of pellet is of particular importance especially if it is required to achieve prolonged

gastric residence. Clarke et al95

investigated the comparative gastrointestinal transit of pellet

systems of density 1.5, 2.0 and 2.4 g/cm3 and found no difference in gastrointestinal transit

time. Deverux et al96

reported the gastrointestinal transit 2.8 g/cm3 with the same of a control

formulation of density 1.5 g/cm3 and found significantly delayed gastric emptying of the

heavier formulation in both fed and fasting conditions. Density and size of the pellets play an

important role in this regard. If pellets are compressed with excipients of smaller particle size

and lesser density, weight variation occurs because of segregation. This problem can be

solved if pellets with a narrow size distribution are compressed together with excipient of

similar size, shape and density97

. The particle size and density of these excipient should not

differ too much from that of the coarse components, i.e. the pellets or granules98

.

Polymer coating

The nature of the polymer type and amount of polymer coating has significant impact on the

compression induced changes in the film coating structure.



Nature of the polymer and polymer coating

Polymers used in the films coating of solid dosage forms fall into two broad groups; cellulosic

polymers and acrylic polymers99

. The utility of hydroxypropylmethyl cellulose (HPMC E 15)

as a controlled release film was investigated by Sadeghi et al100

. It was found that the drug

release from pellets coated with HPMC E 15 (up to 20 % w/w) was fast and completed within

1 hour. Many of the polymers used for controlled release have been formulated into aqueous

dispersions so as to overcome the disadvantages associated with the use of organic polymer

solutions, the polymer coating should be highly elastic and flexible to be able to adapt to the

deformation of the pellets without rupturing. Aulton and co workers101

found that the films

exhibiting a relatively high elastic modulus and apparent Newtonian viscosity provide the

highest protection to the pellet core and coating on compaction. The polymer coat should not

get ruptured during compression. It should have sufficient mechanical stability and should

remain intact during compression in order to control the drug release.

Solvent based coating have been found to be more flexible and has a higher degree of

mechanical stability than aqueous – based ones, and therefore less affected by compaction.

Both ethyl cellulose and methacrylate copolymers were investigated in this study. Ethyl

cellulose films cast from the plasticized pseudo latexes, aqua coat, and surelease were very

brittle and weak with low values of puncture strength and elongation102

.

Normally, the ductility of aqueous based coatings can be improved by addition of plasticizers,

but this is often accompanied by a reduction in the tensile strength of films coated beads to

increase with increasing plasticizer content, and as the degree of plasticization of the polymer

increased, the film coating become more elastic and was able to deform during compression.

Okarter and Singla103

investigated the effects of 6 %, 12 % and 18 % of four plasticizers

polyethylene glycol 400, propylene glycol, tributyl citrate and trithyl citrate on the release of

metoprolol tartarate from granules coated with a Eudragit RS 30 film. The type and

concentration of plasticizer were found to affect the drug release from the granules.

Dissolution became slower with increasing concentration of plasticizer and the resulting

improvement of the films104

.

Amount of polymer coating

The amount of coating has its own role in protecting the polymer film integrity during

compression. In general, a thicker coating can withstand damage better than a thinner one.

Beckert and co workers found that the elasticity improves with the coating thickness of elastic



coatings. In an investigation by Wagner et al.105

however, it was found that the coating must

be of at least a specific lowest thickness for the elasticity to have a synergistic effect on

reduction of the coating damage during compaction106

. In this study it was concluded that

thicker coatings offer better resistance to frictional forces, and consequently cracks that are

introduced into the coating during compression does not show an increased drug release.

Tableting excipients

It has been found that coated pellets can be compressed into tablets whilst retaining

controlled release of the drug, provided the effect of excipients and the compression force is

considered and determined107

. Several excipients have to be used to assist the compaction

process and to prevent the rupture and damage of the coated pellets during compression.

When reservoir pellets are compacted without including any excipients disintegration of the

tablets cannot be ensured and matrix tablets are often formed108, 109

.

Nature of the excipients

The ideal filler material should prevent the direct contact of the pellets and act as cushion

during compression. The theoretical void space of a powder of uniform spheres in closest

packing is 26%. The filler materials must fill this void space as to prevent adhesion and

fusion of the coated pellets during compression. The filler excipients can be either primary

powder particles or can be in the form of secondary agglomerates, such as granules or pellets.

The use of agglomerates is preferred, however, to reduce the risk of segregation owing to

difference in particle size110

.

The protective effect of an excipient depends on the particle size and the compaction

characteristic of the material. In general, materials that deform plastically, such as

microcrystalline cellulose and polyethylene glycol, give the best protective effect111

. Though

microcrystalline cellulose can be used as it is, due to particle size differences, segregation

may be encountered resulting in weight variation and content uniformity problems. Granules

produced by dry or wet granulation techniques having a similar size of the drug loaded beads

are able to minimize the segregation due to size similarities. However, the dry or wet

granulation of microcrystalline cellulose containing mixtures decreases their

compactibility112

. The addition of brittle materials such as dicalcium phosphate and lactose

was found to make the microcrystalline cellulose beads very hard, which are not easily

deformed or broken.



1.12 Diabetes mellitus and anti diabetic drugs

Diabetes mellitus is the most common chronic endocrine disorder that affects more than 100

million people worldwide. The world health organization projects that the number of

diabetics may exceed 350 million by 2030113

.

Diabetes mellitus is syndrome of disordered metabolism, usually due to a combination of

hereditary and environmental causes, resulting in abnormally high blood sugar levels

(hyperglycemia)114

. Blood glucose levels are controlled by a complex interaction of multiple

chemicals and hormones in the body.

Diabetes and its treatments can cause many complications. Acute complications such as

hypoglycemia, ketoacidosis and serious long term complications include cardiovascular

disease, chronic renal failure, retinal damage, nerve damage, poor healing of wounds etc115

.

All forms of diabetes have been treatable since insulin became available medically in 1921,

but there is no cure which is the basic treatment for Type I diabetes. Type II is managed with

a combination of dietary treatment, exercise, medications and insulin supplementation.

Hyperinsullinemia

Defective glucorecognition

β-cell failure

Figure 1.10: Metabolic staging of Type II diabetes

Beta cell

dysfunction

Peripher

al insulin

resistance

Impaired

glucose

tolerance

Early

diabetes

Late

diabetes



1.14.2 Path physiologic defects

Insulin resistance, results in increased hepatic glucose production (HGP) and decrease

glucose disposal, and impaired β-cell secretory function (both basal and glucose

stimulated). Loss of acute insulin response to a carbohydrate load, a prototypical defect

occurs early in the natural course of the disease. Generally when fasting plasma glucose

level reaches 115 mg/dL, it leads to postprandial hyperglycemia. And by the time

fasting plasma glucose levels reaches 140 mg/dL, 75 % of β-cell function has been lost.

In animal models, deposition of amyloid, a product of islet- amyloid polypeptide

normally produced in the β cell and secreted along with insulin, has been associated

with progressive loss of β-cell function and mass. Amyloid deposition contributes to

worsening β-cell function in patients with type 2 diabetes remains unclear. Insulin

resistance in the hepatocyte and peripheral tissues, particularly skeletal muscle, leads to

unrestrained HGP and diminished insulin-stimulated glucose uptake and utilization.

1.1.1 Occurrence of diabetes mellitus116

Pre- diabetes, as defined by the American Diabetes Association, is that state in which

blood glucose levels are higher than normal but not high enough to be diagnosed as

diabetes. India has the largest number of diabetic patients in the world, estimated to be-

40.9 million in the year 2007 and expected to increase to – 60.9 million by the year 2025.

It was 5.6% and 2.7% among urban and rural population respectively.

1.1.2 Oral hypoglycemic agents117

History

In contrast to the systematic studies that led to the isolation of insulin, sulfonylureas were

discovered accidentally. In 1942, Janbon and colleagues noted that some sulfonamides

caused hypoglycemia in experimental animals. Soon, 1-butyl-3-sulfonylurea

(carbutamide) became the first clinically useful sulfonylurea for the treatment of diabetes.

Although later withdrawn because of adverse effects on the bone marrow, this compound

led to the development of the entire class of sulfonylurea. Clinical trials of tolbutamide,

the first widely used member of this group, were instituted in patients with type 2 diabetes

mellitus in the early 1950s94

.

Since that time, approximately twenty different agents of this class have been in use

worldwide. In 1997, Repaglinide, the first member of a new class of oral insulin

secretagogues called meglitinides (benzoic acid derivatives), was approved for clinical use.



This agent has gained acceptance as a fast acting pre meal therapy to limit postprandial

hyperglycemia.

The goat‟s rue plant (Galega officials), used to treat diabetes in Europe in medieval times, and

was found in the early twentieth century to contain guanidine. Guanidine has hypoglycemic

properties but was too toxic for clinical use. During the 1920s, biguanides were investigated

for use in diabetes, but they were overshadowed by the discovery of insulin. Later, the anti

malarial agent chloroguanide was found to have weak hypoglycemic action. Shortly after the

introduction of the sulfonylurea, the first biguanides became available for clinical use.

However, phenformin, the primary drug in this group, was withdrawn from the market in the

United States and Europe because of an increased frequency of lactic acidosis associated with

its use. Another biguanide, metformin, has been used extensively in Europe without

significant adverse effect and was approved for use in the United State in 1995.

Thiazolidones were introduced in 1997 as the second major class of „insulin sensitizers.”

These agents bind to peroxisome proliferators- activated receptors (principally PPARγ),

resulting in increased glucose uptake in muscle and reduced endogenous glucose

production. The first of these agents, troglitazone, was withdrawn from use in the

United States in 2000 because of hepatic toxicity. Two other agents of this class,

rosiglitazone and pioglitazone, have not been associated with widespread liver toxicity

and are used worldwide. Of late it has been withdrawn.

Diabetes can be classified as

Type I Diabetes

Type I diabetes mellitus is characterized by loss of insulin - producing beta cells of the islets

of Langerhans in the pancreas leading to deficiency of insulin. This type of diabetes can be

further classified as immune -mediated or idiopathic145

. Type I diabetes can affect children

traditionally termed as 'Juvenile diabetes'. Treatment for the Type I diabetes is the

subcutaneous injections of insulin pump etc.

Type II Diabetes

Type II diabetes mellitus is the most common type of diabetes due to insulin resistance or

reduced insulin sensitivity, combined with relatively reduced insulin secretion which in some

cases becomes absolute. In Type II diabetes hyperglycemia can be reversed by a variety of



measures and medications that improve insulin sensitivity or reduce glucose production by the

liver.

The other type of diabetes is gestational diabetes which is a Type II diabetes affects women in

pregnancy.

Diabetes Type II can be treated with a) agents which increase the amount of insulin secreted

by pancreas, b) agents which increase the sensitivity of target organs to insulin and c) agents

which decrease the rate at which glucose is absorbed from gastrointestinal tract.

Several groups of drugs given orally are effective in Type II diabetes, often in combination.

The therapeutic combination in Type II may include insulin not because oral agents have

failed completely, but in search of desired combination of effects.

The anti diabetic drugs are broadly classified as

1. Insulin: Usually given subcutaneously either by injection or insulin pump.

2. Sulphonylureas: These were widely used oral hypoglycemics. They trigger

insulin release by direct action. Further categorised as

First generation agents e.g. Tolbutamide (Orinase), Chlorpropamide (Diabinese) etc.

Second generation agents e.g. Glipizide (Glucotrol), Gliclazide (Diamicron),

Glimepiride (Amaryl), Glyburide/Glibenclamide (Diabeta, Micronase, Glynase) etc.

3. Meglitinides: They help the pancreas produce insulin by closing potassium

channels and opening calcium channels and are often called 'short acting

secretagogues, e.g., Repaglinide (Prandin), Nateglinide (Starlix).

4. Biguanide: It reduces hepatic glucose output and increase uptake of glucose, e.g.,

Metformin Hydrochloride (Glucophage) is the first line of medication for Type II

Diabetes, Phenformin (DBI) etc.

5. Thiazolidones: Also known as glitazones. They bind to PPAR type of nuclear

regulatory proteins to regulate glucose and fats used for treatment of Type I, II

diabetes e.g., Rosiglitazone (Avandia) , Pioglitazone (Actos).

6. Alpha-glucosidase inhibitors: Agents which slow digestion of starch in the small

intestine, so that glucose from the meal enters blood stream slowly. e.g., Acarbose

(Glucobay)

7. Peptide analogs: Oral hypoglycemic drugs are widely used in the treatment of non

insulin dependent diabetes mellitus. However, the usage can be limited by some

reasons such as patient age and renal impairment etc. Hence, modified release of



hypoglycemics, as formulation administered once daily has been approved. It shows

good efficiency and appears of particular benefit to patient and well tolerated.

Improvement in understanding of pathogenesis of diabetes, its complication in therapy

and prevention of diabetes are critical in meeting health care challenges.

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