A PROJECT REPORT ON

CONTROL DRUG
DELIVERYSY SYSTEM
NOVEL DRUG DELIVERY SYSTEM

BACHELOR OF PHARMACY
SESSION 2023-2024

GUIDED BY,
Dr. Sunil Jain ( Asst. Prof.,M.Pharm,PhD)

Department of PharmacyGGU , BILASPUR

SUBMITTED BY,
Sanjana Jaiswal, Akash Verma, Ekta Rathore, Laxminarayan
Sahu , Shubham Jaiswal , Simone Mukherjee
1
•RATIONALES•

The basic rationale of a controlled release drug delivery system is

➤To optimize the biopharmaceutics, pharmacokinetics, and pharmacodynamics

properties of a drug in such a way so that

➤Its utility is maximized through reduction in side effects

➤ Cure or control of disease condition in the shortest possible time by using smallest
quantity of drug,

➤ Administered by most suitable route.

➤The immediate release drug delivery system lacks some features like dose maintenance,
controlled release rate and site targeting.

➤ Achieve prolong therapeutic effect.

➤Predictability in drug release kinetics.

➤Deliver the drug at pre determined rate, locally or systematically.

∆ INTRODUCTION ∆

Controlled drug delivery is one which delivers the drug at a predetermined rate, for locally or
systemically, for a specified period of time.

To get Continuous oral delivery of drugs at predictable and reproducible kinetics for
predetermined period throughout the course of GIT.

Controlled release drug delivery employs drug-encapsulating devices from which therapeutic
agents may be released at controlled rates for long periods of time, ranging from days to
months.

Such systems offer numerous advantages over traditional methods of drug delivery,
including tailoring of drug release rates, protection of fragile drugs and increased patient
comfort and compliance.

Controlled drug delivery systems can include the maintenance of drug levels within a desired
range, the need for fewer administrations, optimal use of the drug in question, and increased
patient compliance.

•HISTORY OF CRDD•

The science of controlled release was first originated from the development of oral sustained
release products in the 1940s and early 1950s.

The first patent for oral sustained release preparation went in the favour of Lipowski;

His preparation contained small coated beads that were releasing the drug slowly &
constantly.

This idea later developed by Blythe and launched the first marketed sustained release
product in 1952.

Over the past 30 years as the complication involves in the marketing of new drug increased
and various advantages recognized of Controlled release drug delivery system (CRDDS),
the greater attention is being paid in this field.

THE IDEAL DRUG DELIVERY SYSTEM SHOULD BE…

➤ Inert

➤Biocompatible

➤Mechanically strong

➤Comfortable for the patient

➤ Capable of achieving high drug loading

➤Safe from accidental release

➤ Simple to administer and remove

➤Easy to fabricate and sterilize.

•TERMINOLOGY•

•P’COKINETIC AND P’CODYNAMIC•

•SELECTION OF DRUG CANDIDATES•

✓BIOPHARMACEUTIC CHARACTERISTICS OF DRUG TO QUALIFY FOR CDDS

➤ Molecular weight/ size: < 1000

➤Solubility: > 0.1 µg/ml for pH 1 to pH 7.8

➤Pka Non ionized moiety: > 0.1% at pH 1 to pH 7.8

➤Apparent partition coefficient: High

➤Absorption mechanism: Diffusion

➤ General absorbability: From all Gl segments

➤Release: Should not be influenced by pH and enzymes

✓CHARACTERISTICS THAT MAKE A DRUG UNSUITABLE FOR CRDD

Following candidates are generally not suitable for ER dosage forms

➤ Short elimination half-life

➤Long elimination half-life

➤ Narrow therapeutic index

➤Poor absorption

➤Active absorption

➤ Low or slow absorption

➤ Extensive first pass effect

# PROPERTIES #

The release rate of drugs from controlled drug delivery system are affected by the following
two major factors:

1) physicochemical factors, and

2) Biological factors.

PHYSIOCHEMICAL FACTORS

The following physicochemical properties of the drugs should be considered while selecting
Drug candidates for controlled and sustained release dosage forms:

1)Molecular Size and Diffusivity.

Drugs formulated in sustained release Formulations dosage forms should diffuse through
various biological membranes and also through a rate controlling membrane or matrix.
Diffusivity is a drug's ability to pass through membranes, and it is a function of its molecular
size or weight, Molecular size of the diffusing species has a significant influence on the
diffusivity Value (D) of polymers. Thus, the value of D is related to the size and shape of the
cavities and of the drugs.

The diffusion coefficient values of drugs having intermediate molecular weight (150-400),
through flexible polymers, range from 10 to 10 cm²/sec; and the values in 10 order are the
most common. The diffusion coefficient values of drugs having molecular weight >500 are so
small (i.e., <10-

ideas/sect that their quantification is difficult. Thus, drugs having molecular weight should
display very slow releme kinetics in release devices where difhion through polymeric
membrane or matrix release mechanism 4.

2) Aqueous solubility.

Drugs are mostly weak acids or weak bates. Drugs formulated into sustained release
dosage forms with very difficulty if the feater solubility is low. While, it is difficult to delay the
dissolution drugs having a high water solubility and rapid dissolution rate Drugs havas a high
water solubility readily dissolve in water or gastrointestinal fluid, released in a burst, are
quickly absorbed and thus their concentration blood is more than the drugs having low water
solubility Incorporaing highly water soluble drug in the dosage form and retarding the drug
release is a difficult task, espacially when the drug dose is high The pri depende solutility in
physiological pH range is another problem for sustained rele dosage farms due to the
variation in piel of GIT and in dissolution rate

pH and pKa:

Highly ionised drug are poor candidates for oral sustained release formulations. Umenised
drugs. undergo appropriate absorption, while the ionised drugs undergo negligible
permeation as thei absorption rate is 4 times less than that of the unionised drugs An acidic
drug with při sensitive ionication has a pka range around 3.0-7.5, while a basic drug wa pili
sensitive ionisation has a Ka range around 7.0-11.0, and such drugs an ideal for optimum
positive absorption. The drug should be unionised at the site to an extent 0.1-5.0%

Partition cofficient:

It is the fraction of strug in an oil phase to that in adjacent aqueous phase Partition
coefficient (C) influences drug permeation across the biological membranes, and also trug
diffusion across the rat controlling membrane or matrix between the drug administration time
and drug elimination time. The drug should diffuse through various biological membranes
that act as lipid-like bamers. Apparent oil or water partitios coefficient is the major evaluation
criterion of the drug's membrant permeability fie, itu ability to penetrate these expressed as

Where

C. Equilitinum concentration of all forms of drug in an organic phase at equilibrium.

C Equilibrium concentration of all forms of drug in an aqueous phane

Generally, the drugs having a high IK value are highly oli-soluble and isading partition Into
the membranes, Hansch correlation defines the relationsh between tissue permeation and
partition coefficient for the drag Tpamelation dea arabolic
5) Permeability

Log R expresell lipophilicity, and molosalicatitity for pare the white Peuce the drug's permica
tut de mive transport across atestand epithchand Another important factor that determines
the drug permeability is the polarity of drug which is measured by the number of H-bood
accepton and H-band donors on the drug molecule

6) Mechanism and site of absorption:

Drugs to be abscoherolled retir mediatal transport de off stumble to be formulated us

controlled release Kystems For example, vitumis, Biz (a water-soluble vitaminjis required for
several metabolic reactions and for preventing medicul problems, especially hematopoietic
conditions and spinal cord related neuropathies. Vitamin B ingested in its free or non-protein
bound form, will bind to a carrier protein, namely -binders or trans-cobalamin 1. that is
secreted by the salivary glands in oropharyns and by the gastric mucosal cells in stomach.

7) Drug stability

Loss of drug through acid hydrolysis and/or metabolism in GIT is an important factar for simi
dosage forms. A solid drug degrades at a much slower rate than a drug in suspension or
solution form, thus, the relative bioavailability of a drug that is unstable in stomach can be
improved. The most appropriate controlling unit for the drugs that are unstable in intestine is
the one that releases its contents only in the stomach, therefore, drugs with stability
problems in any particular part of the GIT are considered as poor candidates to be
Incorporated into controlled release systems that deliver their content uniformly throughout
the length of GIT. In controlled drug delivery systems, the drugs are protected from
enzymatic degradation as they are incorporated into a polymeric matrix, thus, these systems
are beneficial for highly unstable drugs.

BIOLOGICAL FACTORS

The following biological properties of the drugs should be considere candidates for controlled
and sustained release dosage forms: selecting drug

1) Absorption: Rate, extent and uniformity of drug absorption are the factorsthat should be
taken into account for a drug to be formulated into a sustained release dosage form Drug
release hom a dosage form (and not absorption) isthe rate imiting step in drug delivery from
a sustained release system, thun, rapid rate of drag absorption relative to its release is
essential for an efficient system in controlled releasedosage forms. Krees Ka, and fins is
critical in case of oral administration. If a drug's transit time through the absorption half-life is
4 hours, a minimum absorption rate consuant (K) of 0.17-0.23 hour is necessary for a drug
to undergo 80-95% absorption over a transit time of 9-12 hours A drug having a rapid
absorption rate (ie, Ka 0.23-1 hour) has the first-order releuse rate constant (0) <0.17-1 hour,
and this results in poor bioavailability in many patients. therefore, slowly absorbed drugs are
difficult to formulate as controlled release dosage forms in which the drugs should essentially
meet the Kr ces Ka criteria

2) Distribution: Drug distribution in tissues and cells lowers the concentration of circulating
drug and can also be rate limiting in its equilibrium with blood and extravascular tissue, thus
it majorly affects the drug elimination kinetics Distribution involves binding of inding of a drug
to the tissues and blood proces Protein-bound drug molecules are inactive and cannot
petancate the autogied

membranes, Also, a high degree of protein binding resal resale in t therapeutic actic
Appament volume of distribution can important the drugs) is the magnitude of distribution
and protein binding in the body the proportionality constant of plasma drug concentration to
the total me of drug in the body. Thus, prior to designing sustained release syntem, should
gather information regarding the drug disposition

3) Protein Binding:

Many drugs bind to plasma proteins and show si effects on the duration of drug action. Drug
bound to blood proteins a mastly re-circulated (rather than getting eliminated). Drug bound to
pla proteins serve as a drug depot for a prolonged release of drug. The rate extent of oral
absorption of drug is also affected by the drug interaction and the binding period with mucin
like protein

4) Metabolism:

Drug metabolism involves either inactivation of en active drup or conversion of an inactive

drug into an active metabolite. It occurs in various tissues, containing more enzymes. Drugs
that get metabolised befor absorption, either in the lumen or in the intestinal tissues, are
released at slower rate, and thus result in reduced bioavailability. The intestinal wall enzyme
systems are mostly saturable. As the drug is released to these regiou at a slower rate. less
total drug is presented to the enzymatic process duringa specific period, and thus the drug
completely converts into its metabolites. Formulating these enzymatically-susceptible
compounds as prodrugs is another feasible solution.

Drugs that can induce or inhibit enzyme synthesis are considered as poor Candidates for
sustained release delivery systems as they cannot maintain uniform blood levels. Also drugs
whose bioavailability varies due to hepatic first-pass metabolism or intestinal metabolism are
not considered suitable candidates for sustained release delivery systeme

5) Elimination or Biological Half-life:

An oral sustained release product aims to maintain therapeutic blood levels for an extended
time period. For this, the drug should enter the blood circulation at a rate similar to ita
elimination (quantitatively described by the half-life). Each drug has its own characteristic
elimination rate, which is the sum of all elimination processes ie, metabolism, urinary
excretion, and the processes that eliminate the drug from blood circulation. Drugs. having a
short half-life are considered the best for sustained release delivery systems, as this reduces
the dosage frequency However, drugs having a very short biological half-life have limited.
use extremely large amounts of drug are required in each dosage unit in order to maintain
the sustained effect, thereby making the dosage form limiting large In other words, drugs
having a half life 2 hours are considered unsuitable for sustained release delivery systems.
Drugs having a long half-life, ie, hours, are also considered unsuitable for sustained release
delivery system as their effect is already sustained.

6) Duration of Action:

The drog's duration of action plays a significant role the formulation of controlled release
delivery system. Distrib metabolism, und elimination of the drug, however, affect the of
setion. Half-life of the drug is its residence time in the body.
•ADVANTAGES•

➤Improve patient convenience.

➤Reduction in fluctuation in steady state level.

➤Increase the safety margin of high potency drug.

➤Reduction in total health care cost.

➤Reduction in frequency of drug administration

➤Improved patient compliance

➤Reduction in total drug usage when compared with conventional therapy

➤Reduction in drug accumulation with chronic therapy

➤Reduction in drug toxicity (local/systemic)

➤Stabilization of medical condition (because of more uniform drug levels)

➤Improvement in bioavailability of some drugs because of spatial control

➤Economical to the health care providers and the patient

✓Commercial / Industrial Advantages✓

➤Illustration of innovative/technologicalleadership

➤Product life-cycle extension

➤Product differentiation

➤Market expansion

➤Patent extension.
•DISADVANTAGES•

➤Decrease systemic availability.

➤Poor invitro-invivo correlation.

➤Increased risk of taxicity.

➤Retrieval of drug is difficult in case of toxicity, poisoning or hyper sensitivity reaction.

➤The possible toxicity or non-biocompatibility of the materials used,

➤Undesirable by-products of degradation,

➤Any surgery required to implant or remove the system,

➤The chance of patient discomfort from the delivery device,

➤The higher cost of controlled-release systems compared with traditional pharmaceutical

formulations.
FACTORS AFFECTING DESIGN OF CRDDS
1. Selection of drug candidate
2. Medical Rationale
3. Biological Factors
4. Physico-Chemical Properties
5. In vitro analysis
6. Formulation optimization
7. In vivo data generation
8. Discussion with Regulatory Authorities
9. Data submission to Regulatory Authorities for Marketing, Authorization / Approval.

1.Selection of Drug Candidate

a. Very short or very long half-life:

✔In the design of CRDDS, it is necessary to determine the half-life of the drug candidate, as if it will be
either too high or too low, both cannot be considered.

In case of higher t12, such drugs have already the capability to remain in the body for longer periods, so
if formulated in CRDDS, then it’ll further enhance the same property & may lead to toxicity.

Thereby, it is necessary to go for drugs which have optimum half life.

b. Significant first pass metabolism

The primary problem with the conventional dosage form, is their incapability to by-pass the First pass
metabolism.

Thereby most of the drug contents gets converted to their respective metabolites and becomes inactive
or gets converted to toxic forms, which affects severely.

In such case, by formulating it into CRDDS eliminates the problem.

✓ But while formulating it in such form, it is necessary to consider the fate of the raw materials used in
the formulation and resistant to the First pass metabolism or have ability to bypass the same.

c. Poor absorption throughout the GI tract

✓ Most of the well versed molecules discovered so far have very poor absorption throughout the GIT
tract.

In such cases, formulation into a controlled release form, leads to increase in the release profile and
absorption phenomena progressively.

It is important to determine the solubility profile as thereby it’ll easier to determine the targettted site of
delivery.

d. Low solubility
Drugs with lower solubility can be formulated in the form of CRDDS, so that it reaches to the systemic
circulation by-passing the barriers.

e. Large no. Of dose

If the dose of the drug is higher or frequency of dosing is higher due to low bioavailability or higher
elimination rate, then the formulation of the same in the form CRDDS, expels out all such problems and
leads to patient compliance.

If the dose is too large then there are chances of formulation of bigger size that would not be favourable
as per patient compliance.

f. Narrow therapeutic window

✓ For drugs with low therapeutic window, directly affects the frequency of dosing and therapeutic effects
which decreases fast.

So, in order to extend its therapeutic window, CRDDS is the ideal method.

It is difficult to produce such formulation with low therapeutic window, as it’ll not be there in

The site for longer time, so release pattern is required to be controlled properly.

2. Medical Rationale
a. Frequency of dosing

✔The major problem with the conventional therapy, is the frequency with which the drug is
administered to the patient.

Sometimes it exceeds above 3 times a day, which becomes problematic for them to take continuously on
time without skipping.

Such huge problem can be reduced if such drugs are formulated as CRDDS, which will release the drug a
defined rate and thereby maintain the drug concentration within the blood at steady state.

b. Patient Compliance

✔The primary concern in the context of patient is their convenience about the drug intake regimen.

Most of the conventional formulations due to low bioavailability, low duration of action, etc. Given many
times which leads to changes of dose skip that may affect the patient health directly.

✓ Such concerns can be reduced in CRDDS, but we need to consider the route of administration, size of
the final product and patient viewpoint at the same time.

c. Drug intake

In this case, the formulation type directly affects the patient compatibility.

In case of very large dose of drug, the formulation size increases which may be a problem for paediatric
and geriatric patients to take.
✓ Thereby, CRDDS allows the efficiency of reducing the dose or changing the route of administration with
enhanced ease of therapeutic effects.

But we need to understand that how much of drug is required to be given, as it is too high, then again
CRDDS cannot be considered.

d. Fluctuations of serum concentration

✓ Conventional dosage forms shows valleys and peaks in the plasma drug conc. Vs time peak.

Such fluctuations causes increase or decrease of the therapeutic effect within the body, which also
affects the other systems.

Such fluctuations have been eliminated by CRDDS, as it gives initial straight line in the graph with further
forms the steady state conc. Throughout.

e. Reduced side effects

✓ The formulation of CRDDS directly reduces the side effects as it localized or targets the site of disease
without getting accumulated to off-sites.

f. Sustained efficacy

✓ Efficacy of the drug incorporated within the CRDDS have pronounced efficacy for sustainable time
compared to the conventional dosage forms.

a. Absorption

✓ Absorption efficiency differs throughout the GIT, which directly affects the extent of drug

Absorption from the site.

3. Biological Rationale
Most of the drugs are poorly soluble and poorly permeable, thereby less absorbable. Thus, in such cases,
the use of CRDDS, enables them to be carried out into the cell easily.

Even it enables some drugs to be get absorbed in stomach by creating a micro-environment which was
actually expected to be absorbed through intestine, but due to irritation have been prevented.

b. Distribution
Distribution of drug from the conventional dosage form directly gets distributed throughout the body,
and gets accumulated to some of the off-sites, which may lead to toxicity.

Such instances can be prevented by CRDDS, which can be site-targetted and specific towards

The diseases condition area and thus preventing accumulation in other sites.

It also enables the complete drug to be reached to the required site, unlike the conventional forms.

c. Elimination.
There are so many drugs available, which accumulates in the organs like liver, pancreas, etc. And
becomes fatal sometimes.

Removal of such unwanted accumulated portion is quite hectic for the system due to slow elimination
rate.

In such cases, CRDDS again plays a major role as the accumulation in off-sites are comparatively
negligible and also the released drug is easily expresses the action and then gets eliminated safely.

d. Dose dependent Bioavailability

Due to low bioavailability of most drugs, higher and sometimes repeated doses are given at certain
intervals of time.

✓This leads to patient inconvenience and most importantly the changes of missing the dose.

Such problems can be eliminated by using the CRDDS as the tool.

e. Drug-Protein Binding

One of the major problem with conventional dosage form is the lesser availability of the drug in the
blood due to higher protein binding.

✓ This binding decreases the action of drug and thereby the effective therapeutic effect diminishes.

But in case of CRDDS, this problem can be eradicated by formulating it in several carriers which will
further help in delivering the drug in required quantity at the desired site.

f. Duration of Action (Half Life)

Many drugs have either too higher half-life or have very low half-life which creates huge problem in
conventional delivery systems.

In case of higher half-life, the CRDDS approach is not required, as it already have the ability

To remain in the body for longer periods.

✓ For drugs with smaller half-life, the CRDDS approach directly helps in both extending the release and at
a steady rate for long hours.

g. Margin of safety

✔ In conventional daosage form, the margin of safety is quite low compared to CRDDS, due to
accumulation at off-sites, less target specific, protein-binding, etc.

When it comes to safety, again the major concern comes is the elimination of the polymers and other
excipients used in the CRDDS without accumulation or side effects.

The types of polymers used must be biodegradable enough so that the alternate effects of its
metabolites are less and without toxic effects.

h. Disease Condition
Another parameter which defines the CRDDS, is the condition of the patient and the kind of disease it
have.

✓ Generally the targeting and route of delivery system is determined by the type of disease focussed.

4. Pharmaco-kinetic/Dynamic Considerations
a. Dose Dumping

✓ With so many merits, still there is one of the major problem in case of CRDDS is the chances of Dose
dumping.

✓ Dose dumping refers to the accidental release of the drug from the CRDDS which may lead to toxicity.

✓ If it a multiple dose drug delivery formulation, then it could fatal and may cause death.

✓ Such case is possible if there is some error in the formulation aspect like inefficient coating. Polymer or
excipient interaction, etc. Or maybe because of problem in drug intake by the patients or may be
packaging errors.

So while formulating, it is necessary to assess the drug entrapment, coating efficiency, etc. Parameters
for formulating a safer CRDDS.

b. First Pass metabolism

The major concern in case of CRDDS is the ability of such system to bypass the First-pass metabolism.

First pass metabolism refers to the absorption of the drug from the GIT and then reaching to liver, where
it gets converted to its active or inactive metabolites and recirculated back into the GIT.
It is a type of metabolism process which leads to decreasing the drug ability to act and thereby
elimination.

So, the CRDDS system should be well enough to cope up in this scenario, or may be formulated to deliver
through other route with same efficiency.

c. Enzyme induction/inhibition on multiple dosing

✔ Another important factor includes is the either induction or inhibition of body’s biological enzymatic
systems which may leads to certain adverse effects.

So, while formulating, it is necessary to understand the site and its other biological considerations for
proper delivery without adverse reactions on the normal processes running within the body.

d. Urinary pH variability (on elimination)

✔ Another problem includes the nature of the materials which have been used in the formulations, as
sometimes the change in urinary pH may occurs which may be toxic for the urnary system and may lead
to side effects.

e. Prolonged drug absorption

✓Some of the drugs requires more time in absorption which may leads to least absorption than required
and thereby decrease in potency.

f. Variability in GI motility

One of the major concern is the Gl motility which differs based on conditions like food presence, area of
the GIT, type of formulation, etc.

Thus, it is necessary to formulate the type of CRDDS, which manages the time and extent of absorption
based on the motility factors and time of Gl emptying.

5. Physico-Chemical Considerations
a. Solubility & pKa,

The solubility of a solid substance is defined as.....

“the concentration at which the solution phase is in equilibrium with a given solid phase at a stated
temperature & pressure.”

To improve solubility:

Solvation

Complexation

Hydration

Recrystallization

Co-solvation

Use of surface active agents

. NOTE: A classification is given as per the permeability & solubility profile, known as BCS Classification.

Determination of Solubility:

1. Semi quantitative method

2. Accurate-quantitative method
3. pH change method

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 oral controlled release formulations.

Controlled release formulations of such drugs may be aimed at making their dissolution more uniform
rather than reducing it.

b. Partition Coefficient

The partition coefficient is defined as........

The concentration ratio of unionized drug distributed between two phases at equilibrium.”

Given by the Noyes-Whitney’s Equation: P= [A]/([A]00)

. The logarithm (base 10) of the partition coefficient (log10P) is often used.

For ionizable drugs, where the ionized species does not partition into the organic phase, the APPARENT
partition coefficient, (D), can be calculated as:.

Acids logoDlogioPlog10 (1+10 (pll-pka))

Bases logoDlogioPlogio (1+10 (pKa-pH))

The octanol-water partition coefficient, (log10Pow), has been widely used as a measurement for
determining the relative lipophilicity of a drug.

Drugs that are very lipid soluble or very water-soluble i.e., extremes in partition coefficient, will
demonstrate

✓ either low flux into the tissues or

Rapid flux followed by accumulation in tissues.

Both cases are undesirable for controlled release system.

c. Mol.size & Diffusivity

In addition to diffusion through a variety of biological membranes, drugs in many CRDDS must diffuse
through a rate controlling membrane or matrix.

The ability of drug to pass through membranes, its so called diffusivity, is a function of its molecular size
(or molecular weight).

An important influence upon the value of diffusivity, D, in polymers is the molecular size of the diffusing
species.

The value of D thus is related to the size and shape of the cavities as well as size and shape

Of the drugs.

Molecular size of the drug plays a major role when it comes to diffusion of the drug through a biological
membrane.

1. Mass spectroscopy (MS or LC-MS) are generally used as the most common methods to
determine the molecular size of the drug.
2. Fourier Transform IR spectroscopy (FTIR) is also used to determine the molecular structure.

Diffusion of the drug from the matrix or encapsulated form determines the release rate of the drug from
the polymer.

Diffusivity is the rate determining step in CRDDS.

d. Dose Size
. Size of the drug plays a major role in determining the size of the final finished product.

. In case, the dose already high, then formulating the same into controlled release will further increase
the overall dosage size & thereby reduced patient compliance.

. For drugs with an elimination half-life of less than 2 hours as well as those administered in large doses,
a controlled release dosage form may need to carry a prohibitively large quantity of drug.

e. Complexation

Complexation is one of the well known method to entrap the drug within a complexing agent like ẞ-
cyclodextrin complex.

These complexes could be helpful in entrapping drugs of very high molecular weight which have low
diffusivity through the membrane.

From formulation point of view, this property also facilitates in increasing the solubility of the drug in the
required solvent.

f. Ionization Constant

This factor have important effects on a wide range of issues including, Dissolution, Membrane partition,
Complexation, Chemical stability & drug absorption.

From the site of release of the drug, its absorption depends upon its ionization constant.

. And, it has been depicted that drugs in unionized form are absorbed faster than the ionized species.

The Henderson-Hasselbalch eq. Provides an estimate of ionized & unionized drug conc, by function of
pH..

Acidic drugs: pKa=-log10(Ka)=pH+log10([HA]/[A-])

Basic drugs: pKa=-log10(Kb) = pH + log10((HB+]/[B-])

Where:

Ka or Kb = ionization constant for acid/basic drugs

[HA] conc. Of unionized acid

[A-] = conc. Of ionized acid

[HB+] = conc. Of the unionized base

[B] conc. Of the ionized base

g. Drug stability

Since most oral controlled release systems are designed to release their contents over much of the
length of Gl tract,

Drugs that are unstable in the environment of the intestine

Drugs that are unstable in the environment of the stomach

Might be difficult to formulate into prolonged release system.

In order to counter-act such problems, several modified-release methods have been adopted that
restricts the release at the required site of the GIT.

h. Protein Binding

It refers to the formation of complex with the blood proteins (like albumin) with the absorbed drug.

This complex leads to....

✓Inhibition of therapeutic effect of such amount

Half-life is increased (compared to invitro studies)

Toxicity profiles elevated

Thus, in most of the cases, protein binding is undesirable.

Many drugs are highly protein binding (may be 95%), thus the need of formulating a modified drug or
drug delivery system starts.

NOTE: Generally, the values of diffusion coefficient for intermediate molecular weight drugs i.e., 150-
400 Dalton, through flexible polymers range from 10-6 to 10-9 cm³/sec, with values on the order of 10-8
being most common.

NOTE: For drugs with molecular weight greater than 500 Dalton, the diffusion coefficients in many
polymers frequently are so small that they are difficult to quantify, i.e., less than 10-12 cm³/sec.

NOTE: Thus, high molecular weight of drug should be expected to display very slow release kinetics in
sustained release devices where diffusion through polymeric membrane or matrix is the release
mechanism.