UNIVERSITAS INDONESIA

CONTROL DRUG RELEASE

Overview of controlled drug Physiological and biological Considerations in

Oral Formulation Development

Home Group 5

Member:

Deviani Ridofi (1206226072)

Muhammad Fahmi (1206212520)

Clara Novia (1306370985)

Claudia Maya (1306412180)

David Lazuardi (1306370814)

Pratiwi Rostiningtyas (1306370833)

ENGINEERING FACULTY

CHEMICAL ENGINEERING DEPARTEMENT

UNIVERSITAS INDONESIA

DEPOK

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 Abstract
Although healthy life-style is an appropriate being to become a healthy people, infections
and diseases can harm most of the humans even in a healthy status. Drugs are needed as a
replacement for the hormone therapy while the hormone itself is limited at their recovery and
toxicity assault. As so, drugs are created based on the target location, its properties and based on
their polymer created such things that it will released well either by degradation, swelling,
erosion or diffusion. Nowadays, technologies can make drugs such things that can be set to any
place of bodies such as injection, mouth swelling and so on. And the function are vary from
curing low-risk diseases until lethal sickness, even now there‟s a development to cure cancer
with drugs.

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 TABLE OF CONTENTS

Contents
Abstract ......................................................................................................................................................... 2
TABLE OF CONTENTS..................................................................................................................................... 3
CHAPTER I .................................................................................................................................................. 5
A. Overview of controlled drug release ..................................................................................................... 5
1. The Importance of Accelerators and Brakes in Homeostasis ........................................................... 5
2. Access ............................................................................................................................................... 5
3. Blood Flow........................................................................................................................................ 5
4. Potency, Affinity, Selectivity and Efficacy...................................................................................... 5
5. Drug Absorption: The Balance Between Solubility and Permeability ............................................. 6
6. Vignettes ........................................................................................................................................... 6
6.1. Zero Order Oral Delivery .......................................................................................................... 6
6.2. Oral Delivery Directed to the Gut and Colon ........................................................................... 6
6.3. Oral Delivery of Polypeptides................................................................................................... 6
6.4. Survey of Mechanisms .............................................................................................................. 7
6.5. Dissolution ................................................................................................................................ 7
6.6. Partitioning ................................................................................................................................ 7
6.7. Diffusion ................................................................................................................................... 7
7. Osmosis ............................................................................................................................................. 7
8. Swelling ............................................................................................................................................ 7
9. Erosion and Degradation................................................................................................................... 7
10. Regional Delivery and Targetting ................................................................................................. 7
B. Gastrointestinal tract and Controlled Drug Release .............................................................................. 8
1. Gastrointestinal tract ......................................................................................................................... 8
1.1. Mouth ........................................................................................................................................ 8
1.2. Esophagus ................................................................................................................................. 8
1.3. Stomach..................................................................................................................................... 8
1.4. Intestine (Small Intestine) ......................................................................................................... 9
1.5. Colon ......................................................................................................................................... 9

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 2. The structure of the digestive tract .................................................................................................... 9
2.1. Mucosa and mucin molecules ................................................................................................... 9
2.2. Mucoadhesive mechanism ...................................................................................................... 10
C. Delivery mechanism based on diffusion and swelling ........................................................................ 11
1. Diffusion-Controlled System ........................................................................................................... 11
1.1. Reservoir System ..................................................................................................................... 11
1.2. Monolithic System .................................................................................................................. 12
2. Swelling- Controlled Systems .......................................................................................................... 12
D. Introduction to delivery mechanism of polymer matrices .................................................................. 14
1. Factor Influencing Drug Release from Degradable Polymer Matrices ........................................... 14
2. Principles of Degradation and Erosion ........................................................................................... 15
3. Drug Release Characteristic of Degradable Polymeric Carriers ..................................................... 16
E. Biopharmaceutic Consideration for Oral CDR Formulation .............................................................. 18
1. Biopharmaceutic consideration and assessment for Oral CR formulation...................................... 18
2. Preformulation consideration for Drugs in Oral CR ....................................................................... 19
CHAPTER II............................................................................................................................................... 22
Conclusion .................................................................................................................................................. 22
Reference .................................................................................................................................................... 23

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 CHAPTER I

A. Overview of controlled drug release

1. The Importance of Accelerators and Brakes in Homeostasis
To produce homeostasis in human consistently, the tissue activities have to be balance by the
influence of opposing drives, (ex: muscles). For this, the body needs separate motor nerve
supplies and afferent and efferent sensory nerve fibers. In this way, drugs will used as the
supplementation of the body‟s natural response to infection or uncontrolled growth of tissues,
as in cancer

2. Access
Most drug absorption is mediated by passive diffusion through external surfaces and by a
combination of passive, facilitated, and active. Passive diffusion is a function of the drug‟s
mobility and solubility in the membrane, and is influenced by the drug‟s polarity, ionization
state, and size.
Once access to the systemic circulation is achieved, the physiological factors impinging on
target tissue concentration are principally total body volume of distribution.

3. Blood Flow
 Types of tissue with respect to blood flow:
1. Well-perfusion (heart, brain lung, liver, kidneys)
2. Less well-perfusion (skeletal muscle)
3. Poor perfusion (skin and adipose tissue)

Blood supply to the tissue affects the

time over which drug equilibrium
established in a tissue For poorly
perfused tissue, the peak shows
sustained release pattern, which make
the drug remains in tissue much longer
Figure 1 - The relationship between central
systemic (solid curve) and tissue (dashed
than in plasma
curve) concentrations in (a) well- and (b)
4. poorly perfused
Potency, Affinity, tissue and Efficacy
Selectivity
Potency of a drug is the amount of drug needed to produce an effect of given intensity,
Affinity is defined as concentration of drug required to bind to a receptor and Efficacy is a
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measure of the effect produced by a drug as a result of receptor binding. Potency varies
considerably, depending on receptor distribution and the modes and sites of delivery and
elimination processes.(Figure 1)

Figure 1 - Plot of (a) response against concentration and (b) the log-dose
versus response curve

Figure 2 - Illustrating log-dose response curves for

three chemically related compounds on receptor
action

High levels of control of an integrated process can be achieved because of the existence of many
transmitters which directed against particular tissue subtargets. Some drugs mimic the action of
transmitter, resulting in full or partial agonist action (Figure 3)

5. Drug Absorption: The Balance Between Solubility and Permeability

There are three main factors determining the drug absorption, such as: physiochemical
(influences of pH), physiological (membrane structure and function, local blood flow, gastric
emptying times, drug binding, etc), and addition factors of diet, race, and genetic influences.
Particle size is the term influences rate of dissolution. Dissolution profile shows the
characteristic rate of release in vitro. The shape of the release profile is controlled by the
physicochemical properties of the drug, supplemented by the release mechanism, which
subsequently affects absorption into the systemic circulation.

6. Vignettes
6.1. Zero Order Oral Delivery
Zero order, or constant rate release of drug is desirable in order to minimize swingsin
drug concentration in the blood. Such excursions, which may lead to periods of underexposure or
overexposure, are particularly likely to occur for drugs that are rapidly absorbed and rapidly
eliminated
6.2. Oral Delivery Directed to the Gut and Colon
Numerous drugs are susceptible to hydrolysis in the acidic environment of the stomach.
By encapsulating drug in such polymers, colon-specific drug delivery can be achieved. Further
encapsulation by a rapidly dissolving enteric coating would permit colon-specific delivery of
acid-labile drugs.
6.3. Oral Delivery of Polypeptides
Efficient delivery of polypeptides, if possible, will have enormous payoffs. While
encapsulated in the particles, the polypeptide molecules are protected from attack by enzymes.
By these means, it is postulated that bioavailability will be improved.
Delivery of Drugs Through the Skin
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 Because the skin is so accessible, much effort has been devoted to expanding the
spectrum of transdermally deliverable drugs using more complex delivery systems. Ideas
discussed in this vignette may apply to drug delivery across other well perfused epithelia,
including the rectum, vagina, scrotum, cornea and sclera, and the buccal and nasal mucosae.
6.4. Survey of Mechanisms
The previous vignettes highlighted several controlled-release mechanisms, including
dissolution, partitioning, diffusion, osmosis, swelling, erosion, and targeting. Basic principles
associated with these mechanisms are presented in this section.
6.5. Dissolution
Dissolution involves transfer of drug from its solid phase to the surrounding medium,
which may be water, polymer, or tissue. Dissolution rate increases with solubility and decreases
with drug particle size, and commonly controlled by diffusion.
6.6. Partitioning
The partition coefficient is a measure of the relative affinity for drug between the two
phases, and is roughly given by the ratio of drug solubilities in the two phases, and determines
how fast a drug will pass out of the gut, across barrier.
6.7. Diffusion
Drug partitions preferentially into the left medium, but diffuses more rapidly in the right
medium. Diffusion of a substance occurs down its concentration gradient as drug molecules tend
to move from regions of higher concentration to regions of lower concentration. The diffusion
coefficient is a measure of the molecule‟s mobility in the medium. Diffusion is an efficient
means of mass transport over short distance, but its effectiveness decreases over long distances.

7. Osmosis
Osmosis is a phenomenon that occurs when a membrane that is permeable to water but
not to particular solutes, called osmolytes, separates aqueous solution of the osmolytes. Osmotic
pumps displaces drug through an orifice. Another way to use osmosis is to coat individual drug
particles with semipermeable polymers. After release from a capsule, these particles are exposed
to gastric fluid.

8. Swelling
Swelling is a prelude to polymer dissolution. Swelling controlled release systems are
typically glassy polymers at room and body temperatures. Swelling in a polymer may be induced
or accelerated by drugs or other additives, which act as effective osmolytes, drawing water into
the polymer.

9. Erosion and Degradation

Erosion of polymer monoliths occurs when components of the release medium,especially
water, attack covalent bonds in the polymer matrix. For hydrolytically labile bonds, availability
of water is an important determinant of local erosion rate.

10. Regional Delivery and Targetting

This mechanism is targeted to preferred site of action and kept away from sites associated
with toxicity.
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 B. Gastrointestinal tract and Controlled Drug Release
1. Gastrointestinal tract
The human gastrointestinal tract (GI tract or GIT) is an organ system responsible for
transporting and digesting foodstuffs, absorbing nutrients, and expelling waste. The tract consists
of the stomach and intestines, and is divided into the upper and lower gastrointestinal tracts

Figure 4. gastrointestinal tract and arrangement of mucosa

In the administration of drugs through the gastrointestinal tract, of drugs will go through the
following stages:
1.1. Mouth
Start of oral drug delivery. Here a change in the structure of the food is so much smoother.
The role of the mucous membrane as protective, not absoptif. Food degraded by saliva.
1.2. Esophagus
The surface of esophagus is mucous mambrane with a protective function as in the mouth.
Food is driven by peristaltic wave. There ia a several factors of drug delivery in here.
Structure of the drug itself, dosage form, age of subject and pre-existing disease.
1.3. Stomach
Stomach allows a regulated supply of calories to small intestine by control of rate of emtying
accoding to food type and its is lined by a secretory epithelium.
The pH indside stomach will elevate temporarily by dilution if a medication taken with a
water. There are some differences of medicine inregulating gastric emptying.
Tablets will be emptied at various time after ingestion depends on posture, volume of food
taken ad calorific value of food taken before/with drug. Pellets and disintegrated dosage
form empty from stomach as a series of pulses or distributed in meal when fed. Large tablets
will stay in the stomach for prolonged periods of time. Drug will be absorbed in most
permeable part of intestine.

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 1.4. Intestine (Small Intestine)
Design for digestion of food and assimilation of smaller building blocks of fats, proteins, and
carbohydrates. Type mucosa secretive / absorptive for the digestion and assimilation. Most
drugs are absorbed by passive diffusion or facilitated diffusion in their unionized state. pH
will determine the degree of ionization, thus will controls the efficiency of absorption.
1.5. Colon
Only first part of colon (ascending and transverse) contribute to drug absorption. In colon,
the absorptive of capacity of drug reduced because fluid levels very restricted but this can be
balanced by long period of residence time in ascending colon.

2. The structure of the digestive tract

2.1. Mucosa and mucin molecules
The first membrane barriers in gastrointerstinal tract that functional food or drug
encounters. Consisting of mucosa and mucin molecules. Mucosa acts as a protective
membrane. There are three properties and characteristics:
o Viscoelastic
o Loosely adherent : can be removed with suction and can be destroyed with weak
shear forces
o Firmly adherent: located under loosely, more resistent and can be destroyed if use
a power of 2 times the power to destroy loosely adherent.
o Hidrophobicity : to protect the epithelium.
o Variations of acid (pH): for there is pH gradient

Mucin molecule are glycoproteins of high molecular weight, consists of protein backbone
10-30% of the total weight, consists of a single polypeptide chain (serine, theronine,
proline), carbohydrate side chains, cysteine, and N and C terminal.

Figure 5. Structure and composition of a basic unit of mucin, from Dekker et al. (2002).
For efficient delivery and release of drug, the delivery system must get to the mucus layer and
diffuse through the mucus layer in order to reach blood stream. One way to improve the
efficiency is adhesion of controlled-release formulation to mucus layer. When bio adhesion
involves the attachment of a carrier to mucus, this referred as mucoadhesion.
A mucoadhesive controlled-release formulation offers advantages over more traditional dosage
forms, including:
 increased residence time leading to enhanced adsorption
 improved intimacy of contact with various biological membranes
 improved bioavailability through the protection of bioactive molecules from physical
and chemical degradation
 targeting and localization of a release device at a specific site.

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 2.2. Mucoadhesive mechanism

Bioadhesive is a phenomenon that depends on the nature of the bioadhesive. The first phase
involves a tight contact between bioadhesif and membranes, both from surface bioadhesif which
has good wetting, as well as from development bioadhesif. In the second stage, after the holding
of contacts, bioadheshif penetration into the tissue surface crevices or among a chain of
bioadhesive with mucus occurs. At the molecular level, mucoadhesive can be explained by the
interaction of molecules. The interaction between two molecules made up of attraction and
repulsion. Interaction appeal arises from the style of Van der Waals, electrostatic attraction,
hydrogen bonds and hydrophobic interactions. Interaction repulsion occurs because of
electrostatic repulsion and steric repulsion. For mucoadhesive to occur, interaction appeal must
be greater than the repulsion of non-specific.

3 main categories of applications in the preparation of mucoadhesive drug delivery systems are:

1. Prolong the residence time (contact). This possibility has been studied intensively for the
delivery system / controlled release of the drug that is given orally and ocular route of
administration.

2. intensive contacts with the absorbing membrane. Mucoadhesive tablet or laminate showed
favorable drug release properties when used by oral. Drug in the form of micro particles has
been successfully used in medicine through nasal application. In addition, the open scope to
provide rectal and vaginal medication.

3. Localization of drug delivery system. In some cases, the drug is absorbed preferentially in
certain areas (specific) from the gastrointestinal tract, also called the window of absorption
(absorption window).

Factors influencing the mucoadhesive:

1. Factors associated with polymer: molecular weight; The concentration of active polymer;
The flexibility of the polymer chain; spacial confirmation; development
2. Factors related to the environment: pH polymer-substrate interface; force applied; initial
contact time
3. Physiological factors: mucin conditions; disease condition

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 C. Delivery mechanism based on diffusion and swelling
1. Diffusion-Controlled System
Diffusion is a process of moving molecules from a solution of high concentration to low
concentration and just mass transport mechanism when other process are not involved in the
control of drug release. We can use Fick‟s First Law to relate diffusion flux,

Where,
J= Mass flow per unit area
D= diffusion coefficient or diffusivity
There are two basic devices that are driven by diffusion:
1.1. Reservoir System
Membrane-controlled reservoir devices, the drug is contained in a core, which is surrounded by a
polymer membrane, and it is released by diffusion through this rate-controlling membrane. rate
controlling element is non-swellable water insoluble polymer. (M.Phil.Pharmaceutics_Sustained
Release Formulations).

Figure 6. Reservoir devices have a coating that controls the release rate. Diagram courtesy of AS Hoffman,
University of Washington, Seattle, WA.
Reservoir systems can be further classified as having either a “nonconstant activity source” or a
“constant activity source”.

a. Non constant activity source

The characteristic of non-constant activity sources diffusion is:
 If all drug is rapidly dissolved, the system acts as a reservoir device with a
nonconstant activity source.
 Drug concentration at inner membrane‟s surface decreases with time. Uf the
membrane does not swell or shrink, does not disssolve or change significantly
during the release period, the length of the diffusion pathway (membrane
thickness) is time independent.

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 b. Constant Activity Sources
The characteristic of constant activity sources diffusion is:
 Concentration gradient of drug inside the membrane is constant
 Drug is released at constant rate
 Zero order release kinetics
1.2. Monolithic System
Monolithic devices, the drug is uniformly dispersed or dissolved in the polymer, and it is
released by diffusion from the polymer. The release rates of monolithic devices decrease as a
function of time and distance. Rate controlling element is water swellable material drug reservoir
is prepared by homogeneously dispersing drug particle in rate controlling polymer matrix from
either a lipophilic or a hydrophilic polimer.

Figure 7. A schematic of the monolithic devices. Diagram courtesy of AS Hoffman, University of Washington,
Seattle, WA.

2. Swelling- Controlled Systems

Swelling-controlled usually incorporate drugs in a hydrophilic polymer that is stiff or glassy
when dry, but swells when placed in an aqueous environment. The key features of polymer
swelling: in the dry state (nonswollen state), the polymer network is dense and the mobility of
the macromolecules is very much restricted.
Upon contact with water, the polymer chains “relax,” with two major consequences:
– the mobility of the macromolecules significantly increases and
– the volume of the system increases.

Figure 8. A typical oral tablet is a good example of swelling-controlled devices. Diagram courtesy of AS Hoffman, University of
Washington, Seattle, WA

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 Figure 9. Polymer relaxation-controlled penetration of a liquid into a thin, polymeric film: concentration–position profile of a
liquid (e.g., release medium) at a given time point within the system. One surface of the film is exposed to the bulk fluid (left-
hand side). Three different zones can be distinguished inside the film: (1) swollen network (high liquid content, high mobility of
macromolecules and liquid molecules); (2) swelling zone (polymer chain relaxation); and (3) nonswollen network (low mobility
of macromolecules, “free” of liquid).

Figure 10. Schematic presentation of a drug-loaded polymeric network in the nonswollen state (top) and upon liquid penetration
into the system (bottom). If the polymer is soluble in water, an erosion front separates the bulk fluid from the swollen polymeric
network. Crosses represent dissolved drug molecules, black diamonds nondissolved drug particles cartoon). Upon contact with
aqueous media, water diffuses into the system, resulting in: (1) polymer swelling and (2) drug dissolution. Once dissolved, the
drug molecules (crosses) diffuse out into the release medium. If the polymer is water soluble, polymer dissolution takes place at
the system‟s surface and two moving boundaries can be distinguished: (1) the erosion front, separating the bulk fluid and the
delivery device and (2) the swelling front, separating the swollen polymeric network containing only dissolved drug and the still
dry polymeric network containing drug particles.

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 D. Introduction to delivery mechanism of polymer matrices
Controlled drug delivery technology represents one of the frontier areas of science, which
involves multidisciplinary scientific approach, contributing to the human welfare. Controlled
drug delivery is talking about how to release a pharmaceutical agent to maintain therapeutic level
of the drug in the body for a sustained period in time systematically. Polymers have been used in
controlled drug delivery for many years as a means of prolonging the action of therapeutic agent
in the body without the need to remove the device after treatment. Commercial success of such
matrix of polymer based drug delivery systems is expected to depend not only their clinical
performance for therapeutical application but also benefit for patients convenience, marketing
and hospitalization costs.
Polymer-based controlled release formulations for parenteral administration are of
ongoing academic and industrial interest. Parenteral body is the part of the body elsewhere the
mouth and alimentary canal. The term degradation/biodegradation usually refers to a breakdown
of polymers at the molecular level, i.e., chain cleavage that leads to degradation products that are
safely eliminated by the body. Figure 1. illustrates the differentiation of diffusion, degradation,
and swelling drug degradable mechanisms.

Figure 11. Schematic illustrations of diffusion, degradation, and swelling release mechanisms of drug-carrying magnetic PLGA
spheres.

1. Factor Influencing Drug Release from Degradable Polymer Matrices

In general, factors of controlling drug release behavior can be classified intro two major
groups; physical process and chemical/physicochemical molecular properties associated with the
involved materials and the environmental conditions such as properties related to the engineered
shape of the drug carrier. Characteristics pharmacokinetics of carrier type is need several
requirement as like as the desired release rates, duration of release and total dose; the route of
administration; type of drug carrier; specific shapes or dimensions of the carrier; other design
criteria. Environmental conditions for drug release depend on temperature, pH, and for in vivo
studies sometimes result in faster drug release than in vitro studies is presence of enzyme. The
physicochemical of the drug molecules is another key when discussing release rates. In low
solubility drugs are typically characterized by lower diffusion rates due to a lower concentration
gradient of the drug from inside to the outside matrix. Figure 2 will explain about those factors in
a graph below

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 Figure.12 Scheme of major factors that may influence drug release rates from drug carriers based

on degradable polymers

2. Principles of Degradation and Erosion

The degradation is the molecular breakdown of polymers is governed by both their
chemical composition, architecture and morphology as well as a complex interplay of
environmental conditions and device properties

Figure 13. The embedded drug and matrix degradation products are released as matrix erodes.
Source :http://www.nature.com/nmat/journal/v7/n11/full/nmat2309.html

In principle, there are three concepts of polymer degradation with relevance for
controlled drug release, linear polymers as most often used for controlled drug release matrices
can degrade into mono- or oligomers by random or selective scission of bonds in the polymer
main chain; linear polymers may contain side chains polymer backbone, which enable aqueous
solubility of the polymer; polymer network may disintegrate into water-soluble linear polymer
chains by selective degradation of netpoints. Besides that, the structure of copolymers can
substantially influence the polymer degradation.

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 Polymer erosion is the release of degraded or nondegraded polymeric material, resulting
in mass loss of the sample, may in principle derive from degradation induced by exposure to
different factors, including heat, light or oxidative stress. In polymer erosion has four steps such
as wetting of the polymer surface including a possible internal porous structure; water uptake
with a material-spesific rate into the polymer bulk; degradation of the polymer following a
characteristics pathway with a material- and possibly geometry dependent rate; if possible,
diffusion controlled removal of degradation products.

Figure 14 Schematic Illustration of surface erosion and bulk erosion

3. Drug Release Characteristic of Degradable Polymeric Carriers

1. Microparticles
Microparticles as drug carriers are the largest number of degradable parenteral controlled release
products. It is because their injectability through needles of smaller diameters as well as the
advantages of all multiple unit dosage form, which is a simple preparation procedure. The most
common techniques for the microencapsulation of drugs such as:
a) Emulsion techniques: w1/o/w2; s/o/w; o/w; o1/o2
b) Ammonolysis
c) Organic phase separation
d) Melting techniques: melting polymer and drug, cooling, grinding
e) Spray drying
f) SCF (Supercritical Fluids), Solvent and Antisolvent
2. Preform Implants
In Situ Forming Drug DepotsPolymer processing to form the implants can in principle be
conducted starting from a polymer solution, melt, or powdered material.Implants from solid
polymers are typically prepared either in a rod-like shape for subcutaneous injection or as
disks/wafers for implantation such as during open surgery. Some commonly employed methods
are Solvent casting, Solvent extrusion, Melt casting, Melt extrusion, and Powder compression.
When comparing microparticles and implants as possible drug carrier, it is very obvious that
different release rates can be expected even if both carriers were prepared from identical
polymers and had a similar level of porosity.
3. In Situ Forming Drug Depots

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 In situ forming drug depots are based on injectable formulations such as more or
lessviscous polymer solutions that form a depot during and/or after administration.Injectable in
situ forming implants are classified into five categories, according to their mechanism of depot
formation:
i) Thermoplastic pastes
ii) In situ cross linked systems
iii) In situ polymer precipitation
iv) Thermally induced gelling system
v) In situ solidifying organogels

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 E. Biopharmaceutic Consideration for Oral CDR Formulation
1. Biopharmaceutic consideration and assessment for Oral CR formulation
In a Gastrointestinal System (GI Tract), the drug circulation usually consist of 3 main
steps : Formulation Release, Dissolution and Passing through GI Membrane (Figure x). In order
to design an effective drug release, usually the drug is designed so that it will be continuously
absorbed throughout the GI system or it would have specific target on the GI tract.
In order to achieve a successful drug formulation in Oral drug, there are several factor
that we need to consider. First, from the drug‟s properties such as solubility and permeability.
Second, we need to consider the state of the GI Tract such as its colonic stability and GI
elimination and metabolism path. Because of these factors, the drug‟s dissolution rate will
change with time and position in GI tract.

Figure 15. Drug formulation in GI Tract

From the drug properties, the solubility will affect the dissolution rate based on the
Noyes-Whitney expression. However, solubility is also affected by the drug‟s chemical
properties. On some cases, its solubility could be pH-dependent and this condition makes the
drug as a poor candidate for oral formulation. Another thing such as the impact of bile salts in
vivo could also be considered. In order to choose the correct drug, usually the drug is tested using
in silico or USP buffer with variability in pH. The common way to predict a good oral
formulation is by using the ratio of the drug‟s dose and its solubility. If the ratio is small, it will
be easier to formulate a succesfull formulation.
Table 1. GI physiology relevant to Drug Absorption

Second properties that we need to consider is permeability.Permeability is how the drug

cross through the GI membrane. There are 2 main pathway for drug : the transcelluler route (for
hydrophobic compound) and paracellular route (for hydrophilic compound). These transport
pathways could be divided into passive transport or carrier-mediated transport. Similar to
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solubility, permeability also change according to position within the GI Tract. It is because of the
site-dependent permeability which usually happens in carrier-mediated transport. In order to
identify its permeability, Corrigan had formulated a „rule of thumb‟ based on the drug‟s relative
colonic bioavailability to the small intesntines (Frelcolon). In order to predict the absorption
profile, usually we use in vitro method such as the Caco-2-monolayers or Ussing chamber. On
the other hand, we could also predict using animals‟ metabolism for the in vivo method.
Now from the GI tract, we also consider the colonic stability. There is a unique condition
in human colon where there are many complex microorganism live there. These organisms help
maintain the health and process in colon. The colon metabolism mainly consist of reaction
hydrolysis and reduction than oxidation. This cause drug‟s instability during the release In
addition, this condition is too complex to be mimicked in vitro. That‟s why people refer to use
human feces or animal metabolism although these methods couldn‟t give a similar condition to
those in the body.
Lastly, there are some consideration we need to show in GI elimination and metabolism.
On some cases, there could be intestinal elimination mechanism by the efflux transporter, such as
P-gp (P-glycoprotein). This mechanism is affected by the drug concentration and could change
variably based on the position in GI Tract.

2. Preformulation consideration for Drugs in Oral CR

After knowing the aspect in Oral formulation, now we will move to how to evaluate these
aspects. There are 3 ways to evaluate via dissolution, in vivo study and Pharmacokinetic (PK)
simulation. Dissolution test are conducted in vitro where the environment condition mimic the in
vivo. This test is done because the dissolution must be the rate-limiting step in absorption.
Meanwhile, the in vivo study use the deconvolution method which use an orally administered
drug as a reference to determine one unit impulse function of a solution then calculate the input
rate for CR drug formulation. Last, we have the PK simulation. In this method, we asses drug
candidate then try to alter the release rate and dose in order to achieve a good formulation.
In drug substance, we also need to know the performance and dosage of Active
Pharmaceutic Ingredient (API). After evaluating the solubility and permeability of the drug, we
could asses the impact of biological factor on drug delivery. Physiological differences in gastric
condition could affect the dissolution profile and its release mechanism, for example during
gastric emptying and other different condition. Disease also affect the absorption rate, for
example the disease-related, drug-induced or surgical-induced. For example, drug therapy
impacts colonic transit time and at the end will affect the bioavailability of the CR dosage form.
Condition in the lower GI tract could also affect drug release formulation. For example, diet
could affect colonic mucosa, secretory content, and motility.
By knowing the drug properties, we could do preparative work in order to obtain the
formulation. So it is important to do preformulation study where we analyze the drug substances‟
particulate and mechanical properties, its stability and compatibility. Then we should also
consider the Active Pharmaceutic Ingredient (API) solubility and the partition coefficient.
In preformulation study, we analyze the particulate and mechanical properties of the drug
such as its particle size, bulk powder, and compression.This properties needs to be evaluated in
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order to achieve a good uniformity which affect the patient‟s safety and efficiacy. Particle size
needs to be small enough to not only achieve uniformity but also avoid cohesive agglomeration.
This properties could be assessed using Microscopic Image Examination, combined with Laser
light scattering method and sieve analysis.
In addition we also need to analyze the bulk powder properties such as powder density,
angle of repose, flow rate and its shear stress. These properties are important because even
though the particle is similar, it could have many different arrangements during the processing.
In powder density, we compare the pour density and tapped density of the particle. In angle of
repose, we try to measure its conical shape angle when poured in a flat surface. Flow rate could
be evaluated using flow meter, and the shear stress could be tested using shear cell tester which
evaluate its translational and rotational movement. Lastly, in evaluating the compressional
properties, we could determine the suitable excipient to act as the filler in drug.
Next, we try to analyze drug stability and compatibility by several method. First, we try
to forcibly degradate it using the solid state and solution state degradation study. The degradation
of the drug is tested in many variable such as temperature, light, reaction, etc. This solution state
test will show us the degradation mechanism of the drug, while the solid state will enable us to
select the suitable excipient and packaging material. Second, we try to evaluate the pH modifier.
This method consists of 3 steps: finding the optimum pH, finding compatible buffer solution and
mixing the buffer with API in solid state in order to analyze the stability.
After evaluate the pH, we try to identify the degradant in order to revise a method of
stabilization of the drug. Then we continue with the excipient compatibility test. It is done to
avoid the case which the excipient suddenly become incompatible and reduce the drug stability.
Last, we identify the potential excipient incompatibility based on the interaction between the
functional group. It was done in solid excipient degradation mechanism.
However, in drug delivery we also need to consider the API Solubility aspect. There are
several type of solubility such as equilibrium solubility, kinetic solubility, pH-solubility profile,
and etc. In equilibrium solubility, we analyze the rate of drug leaving the solid surface and the
water entering it. This type of solubility is affected by temperature too. On the other hand,
kinetic solubility means a condition where turbidity has been achieved when dissolving drug
compound in a solution. It happens in non-solid state since it requires less energy to break the
bonding in the compound.
In solubility, as we know it is pH-dependent that‟s why we should know how the API
solubility profile. In addition, we should also consider the condition of the GI tract as shown
below in figure x. Not only the condition of the GI tract,but we also need to know how the food
affect the drug solubility. For example, water-soluble food will be harder to dissolute when in the
presence of food although water-insoluble food will be easier to dissolute in the presence of
food.
Moreover, in GI tract there would be salts or other buffer solution together with food
which could affect the API Solubility. This substance‟s presence could resulted in 4 different
mechanism: salting in, salting out, Ksp control and pH control. Salting in means increase in
solubility, and salting out means reduce in solubility.
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 Table 2. Physiological Buffer System

At last, we will discuss about the partition coefficient. Partition happens when a neutral
compound partitioned to a lipid phase and it is indepent of the pH condition. It is important to
know and measure partition coefficient since mostly GI liquid is Lipophilic. We could estimate
the partition coefficient based on its chemical structure. This partition coefficient could be used
to predict poor oral absorption for passively diffused drugs.

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 CHAPTER II

Conclusion
 Blood supply to the tissue affects the time over which drug equilibrium established in a tissue.
For poorly perfused tissue, the peak shows sustained release pattern, which make the drug
remains in tissue much longer than in plasma

 Potency varies considerably, depending on receptor distribution and the modes and sites of
delivery and elimination processes.

 Dissolution rate determines the process of release of ingredient into solution, Dissolution
profile shows the characteristic rate of release in vitro. The shape of the release profile is
controlled by the physicochemical properties of the drug, supplemented by the release
mechanism.

 In oreder todrug can be absorbed to blood stream and reach the target, we must know the
structure of administration, in this case is gastrointestnal tract. In gastrointestinal tract, there
are membrane and molecules that help drug delivery. The drug shape also have an effect of
drug absorption itself.

 Diffusion is a process of moving molecules from a solution of high concentration to low

concentration, and Swelling-controlled usually incorporate drugs in a hydrophilic polymer
that is stiff or glassy when dry, but swells when placed in an aqueous environment.

 In order to achieve a successful Oral DR formulation, we need to consider drug‟s properties

and also the condition of the GI tract. We also need to evaluate each aspect using in vitro, in
vivo or even simulation method.

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