Preformulation studies

Prepared by
Ms. Ayushi Chourasia
Assistant Professor
IPS Academy College of Pharmacy, Indore
 INTRODUCTION
WHAT IS PREFORMULATION?
“It is the study of the physical and chemical properties of the
drug prior to compounding process”.
 Preformulation commences when a newly synthesized drug shows sufficient
pharmacologic promise in animal models to warrant evaluation in man.
 These studies should focus on physicochemical properties of new compound that
affect drug performance & development of efficacious dosage form.
 This properties may provide;
1. A rationale for formulation design
2. Support the need for molecular modification.
Goals of preformulation
 To establish the physicochemical parameters of a new drug.
 To establish its physical characteristics .
 To establish its compatibility with common excipients.
 Providing a scientific data to support the dosage form design and
 evaluation of the product efficacy and stability.
In short
 Quantization of physical and chemical properties will assist in
developing
 a. Stable
 b. Safe
 c. Effective formulation
THE MAJOR AREAS OF PREFORMULATION STUDY

I. Physical description and Bulk Characterization:

 Crystallinity and Polymorphism
 Hygroscopicity
 Fine Particle Characterization
 Thermal Effects
 Powder Flow
II. Solubility Analysis :
 Ionization Constant- pKa
 pH Solubility Profile
 Common Ion Effect
 Solubilization
 Partition Coefficient
 Dissolution
III. Stability Analysis :
 Solid-State Stability
 Solution-Phase Stability
 Compatibility Studies: Stability in the Presence of
 Excipients
Physical description and bulk
characterization
PHYSICAL CHARACTERIZATION

 Drugs can be used therapeutically as solids, liquid and gases.

 Liquid drugs are used to a much lesser extent than solid drugs and
even less frequently than gases.
 Solid materials are preferred in formulation work because of their
ease of preparation into tablets and capsules.
 The majority of drug substances in use occur as solid materials.
 Most of them are pure chemical compounds of either:
Amorphous or Crystalline in nature
BULK CHARACTERIZATION
Bulks properties such as particle size, bulk density,
surface morphology may be changed during the
development process and to avoid mislead
predictions of solubility and stability bulk
characterization study is important.
 CRYSTALLINITY AND POLYMORPHISM
Solid drug materials may occur as:
a. Amorphous (higher solubility)
b. Crystalline (higher stability)
AMORPHOUS DRUGS
 Amorphous drugs have randomly arranged atoms or molecules.
 Amorphous forms are typically prepared by precipitation, lyophilization, or
rapid cooling method.
E.g. Novobiocin :
CRYSTALLINE DRUGS
 Crystals are characterized by repetitious spacing of constituent atoms or
molecules in a three dimensional array.
 Crystalline forms of drugs may be used because of greater stability than the
corresponding amorphous form.
For example: the crystalline forms of penicillin G as Potassium or sodium salt is
considerably more stable and result in excellent therapeutic response than
amorphous forms.
POLYMORPHISM
Polymorphism is the ability of a compound to
crystallize as more than one distinct crystalline
species with different internal lattices or crystal
packing arrangement even they are chemically
identical depending on the variation in ;
 a. Temperature
 b. Solvent
 c. Time
 Different crystalline forms are called polymorphs.
Polymorphs are of 2 types
1. Enantiotropic polymorph
The polymorph which can be changed from one form into another
by varying temp or pressure is called as Enantiotropic polymorph.
Eg. Sulphur.
2. Monotropic polymorph
One polymorph which is unstable at all temp. & pressure is called as
Monotropic polymorph.
Eg. Glyceryl stearate.
THERMAL ANALYSIS
 Differential scanning calorimetry and Differential thermal analysis:
[DSC & DTA]
Measure the heat loss or gain resulting from physical or chemical changes within a
sample as function of temperature.
 Thermo gravimetric analysis (TGA):
It measure changes in sample weight as a function of time (isothermal) or function
of time (isothermal) or temperature.
Desolvation and decomposition processes are frequently monitored by TGA.
Applications:
 Purity, polymorphism, solvation, degradation, and excipient compatibility.
 Thermal analysis can be used to investigate and predict any physicochemical
interactions between components in the formulation.
 It is used for selection of chemically compatible excipients.
HYGROSCOPICITY
 Many drugs , particularly water-soluble salts, have a tendency to adsorb
atmospheric moisture.
 Changes in moisture level can greatly influence many parameters such as ;
chemical stability, flow ability, and compatibility.
 Adsorption and equilibrium of moisture content can depend upon ; atmospheric
humidity, temperature, surface area, exposure, and the mechanism for moisture
uptake.
Hygroscopic substances:
It adsorbs water because of hydrate formation or specific site adsorption.
Deliquescent materials:
Adsorb sufficient water to dissolve completely, as observed with sodium chloride on a
humid day.
Analytic methods for monitoring the moisture level are
 Gravimetric (weight gained),
 Karl Fischer titration,
 Gas chromatography
POWDER FLOW PROPERTIES
 Flow properties are significantly affected by:
Changes in particle size, density, shape, and moisture, which may arise from
processing or formulation.
 The powder flow properties can be characterized by the following methods:

The Angle of Repose:

 It is the maximum angle between the surface of a pile of powder and horizontal
plane.
Tanθ = h/r
 The rougher and more irregular the surface of the particles, the higher will be
the angle of repose.
 Lower values indicates better flow characteristics
 The acceptance criteria for angle of repose are:
 Compressibility:
 It can be characterized by the following methods;
1. Carr‟s compressibility index
2. Hausner`s ratio

 1. Carr’s compressibility index:

 Carr‟s index (%) =Tapped density–bulk density x100
Tapped density
 By decreasing the bulk and tapped density good flow properties
can be obtained.
 The acceptance criteria for carr’s index are :

Hausner’s ratio:
Hausner `s ratio = Tapped density
bulk density
The acceptance criteria for Hausner`s ratio are :
FINE PARTICLE CHARACTERIZATION
 Size, shape & surface morphology of drug particles affect the flow property,
dissolution &chemical reactivity of drugs.
Significance of Particle Size:
 Particle size of drugs may affect formulation and product efficacy.
 Certain physical and chemical properties of drug substances are affected by the
particle size distribution including; drug dissolution rate, content uniformity,
texture, stability, flow characteristics, and sedimentation rates.
 Particle size significantly influences the oral absorption profiles of certain
drugs.
 Satisfactory content uniformity in solid dosage forms depends to a large degree
on particle size and the equal distribution of the active ingredient throughout
the formulation.
METHODS TO EVALUATE PARTICLE SIZE AND
DISTRIBUTION

1. Sieving or screening
2. Optical microscopy
3. Sedimentation
4. Stream scanning
Solubility Analysis
 SOLUBILITY
 The solubility of drug is an important
physicochemical property because it affects the rate of
drug release into the dissolution medium and
consequently, the therapeutic efficacy of the
pharmaceutical product.
 The solubility of a candidate drug molecule is the
amount of the drug (solute) that dissolves in a given
solution (solvent) to produce a saturated solution at
constant temperature and pressure.
 General rules –
1. Polar solutes dissolve in polar solvents
2. Non-polar solutes dissolve in non-polar solvents
Common solvents used for solubility determination are:
 Water
 Benzyl Alcohol
 Isopropyl Alcohol
 Tweens
 Polysorbates
 Castor Oil
 Peanut Oil
 Sesame Oil
 Buffers etc
 Intrinsic Solubility
Intrinsic solubility is the equilibrium
solubility of the free acid or free base form of
an ionisable compound at a pH where it is
fully un-ionised. Equilibrium solubility is the
concentration of compound in a saturated
solution when excess solid is present, and
solution and solid are at equilibrium.
 Criteria for solubility determination
1. The solute and the solvent must be pure.
2. A saturated solution must be obtained before any sample
is removed for analysis.
3. The method of sample collection must be satisfactory.
4. The method of analysis must be reliable.
5. The temperature must be properly controlled.
Parameters evaluated during solubility
analysis.
 Ionization constant/ Drug Pka
 Partition coefficient
 Solubilization
 Thermal effect
 Common ion effect
 Dissolution
 Ionization Constant (pKa)
 For a compound containing basic or acidic functional groups,
solubility at a given pH is influenced by the compound‟s
ionization characteristics.
 The solubility of a compound in aqueous media is greater in the
ionized state than in the neutral state.
 Thus, solubility of ionizable compounds is dependent on the pH
of the solution.
 Determination of the dissociation constant for a drug capable of
ionization within a pH range of 1to10 is important since
solubility, and absorption, can be altered by changing pH.
 Many drugs are either weak acids or weak bases.
 In Solutions, these drugs exist between un-dissociated
molecules and their ions depending on the pH value of
the containing medium.
 It is important to fully understand the ionization or
dissociation characteristics of drug substances as their
absorption is greatly dependent to a large extent on their
degrees of ionization.
 The un-ionized species are more lipid-soluble, and thus
are presented and transported across the membrane
barriers by passive diffusion, unlike the ionized species
that are lipid insoluble with slow permeability.
The Henderson-Hasselbalch equation provides an estimate of the
ionized and un-ionized drug concentration at a particular pH.
 For acidic compounds:
pH = pKa + log ([ionized drug]/[un-ionized drug])
 For basic compounds:
pH = pKa + log ([un-ionized drug]/[ionized drug])
 pKa Ionization Site of
Drugs
Value absorption
Can be absorbed
Very weak acid Unionized at all pH
>8 throughout any region of
values
the GIT

Unionized in gastric
Moderate weak acid pH and ionized in Mostly absorbed from
2.5-7.5
intestinal pH stomach

ionized at all pH
Strongly acidic
<2 values Poorly absorbed from GIT

ionized at all pH
Strong base >11 Poorly absorbed from GIT
values
 Partition coefficient
 Partition coefficient (oil/water) is a measure of a drug‟s
lipophilicity and an indication of its ability to cross cell
membranes.
 It is defined as the ratio of un-ionized drug distributed
between the organic and aqueous phases at equilibrium.
Po/w = (Coil/C water)equilibrium
 Drugs having values of P much greater than 1 are classified
as lipophilic, whereas those with partition coefficients
much less than 1 are indicative of a hydrophilic drug
 For drug delivery, the lipophilic and hydrophilic balance
has been shown to be a contributing factor for the rate and
extent of drug absorption.
Methods to determine Partition coefficient
 Shake flask method
 Chromatographic method (TLC, HPTLC)
 Counter current and filter probe method
Applications of Partition coefficient
 Measure of lipophillic character of molecule
 Recovery of antibiotics from fermentation broth
 Extraction of dosage from biological fluid
 Absorption of drug from dosage form
 Study of distribution of flavoring oil between oil &
water in emulsion
Effects of partition coefficient:
 Partition coefficient influence permeation of a drug
across biological membrane.
 Following administration the drug must travel through a
variety of membranes to gain access to the target area.
 Drugs with extremely high partition co-efficient (very
oil-soluble) readily penetrate the membranes.
 While drugs with excessive aqueous water solubility can
not penetrate the membranes.
 Solubilization
“Solubilization is defined as the spontaneous passage of
poorly water soluble solute molecules into an aqueous
solution of a surfactants in which a thermodynamically
stable solution is formed ”.

It is defined as the preparation of the thermodynamically

stable solution of a substance normally insoluble or very
slightly soluble in a given solvent by addition of a
surfactant.
 The ability of surfactant solution to dissolve or
solubilize water-insoluble or partly soluble substances
starts at the critical micelle concentration (CMC) and
increases with the increase of the micelles.
 One important property of surfactants is the formation
of colloidal-sized clusters in solutions, known as
micelles, which have particular significance in
pharmacy because of their ability to increase the
solubility of sparingly soluble substances in water
Surfactants and Micelles
Surfactants are amphiphilic molecules composed of a
hydrophilic or polar moiety known as head and a hydrophobic or
nonpolar moiety known as tail.
 The surfactant head can be charged (anionic or cationic),
dipolar or non-charged (nonionic).
 Sodium dodecyl sulfate (SDS), dodecyl trimethyl ammonium
bromide (DTAB), n-dodecyl tetra (ethylene oxide) are typical
examples of anionic, cationic, non- ionic surfactants
When surfactant molecules are dissolved in water at concentrations
above the critical micelle concentration (cmc), they form aggregates
known as micelles. In a micelle, the hydrophobic tails flock to the
interior in order to minimize their contact with water, and the
hydrophilic heads remain on the outer surface in order to maximize
their contact with water

Schematic illustration of the reversible monomer-micelle thermodynamic

equilibrium. The black circles represent the surfactant heads (hydrophilic
moieties) and the black curved lines represent the surfactant tails (hydrophobic
moieties).
Schematic diagram of micellar solubilization of fatty
substance in water with the use of a dispersant.
 Thermal effect
 The effect of temperature on a candidate drug molecule can be
determined by measuring heat of solution.
 Heat of solution, also known as enthalpy of dissolution or
enthalpy of solution, represents the heat released or absorbed
when a solute dissolves completely in a large quantity of solvent.
 This is important as the solubility of a drug substance in a given
solvent is influenced by changes in temperature.
 The heat of solution can either be positive (endothermic) or
negative (exothermic) depending on the amount of energy
required to break the bonds present in the solutes, as well as, how
much energy is generated from the solid-solvent bond formation.
 Increased drug solubility can be achieved by increasing
temperature of solutions with positive heat of solution
(endothermic process).
 Common ion effect
 Common ion effect describes the effect on equilibrium that occurs
when a common ion i.e., an ion that is already present in a
solution is added to the solution.
 The addition of common ion significantly decreases the solubility
of a sparingly soluble electrolyte by shifting the equilibrium
towards the reactant and causing the solute to precipitate (salting
out).
 This shift in equilibrium/ salting out results from the removal of
water molecules as solvent owing to the competing hydration of
other ions.
 The reverse process, „salting in‟, arises with larger anions
(hydrotropes) which improves the solubility of poorly water-
soluble candidate drug molecules by opening the water structure.
 Dissolution
 Dissolution is a process in which a solid substance
solubilizes in a given solvent i.e. mass transfer from
the solid surface to the liquid phase.
 Rate of dissolution is the amount of drug substance
that goes in solution per unit time under
standardized conditions of liquid/solid interface,
temperature and solvent composition.
Mechanism of dissolution

Dissolution test determines the cumulative amount of drug

that goes into solution as a function of time Steps involved
 liberation of the solute or drug from the formulation
matrix (disintegration)
 dissolution of the drug (solubilization of the drug
particles) in the liquid medium.
The most commonly employed dissolution
test methods are
 The basket method (Apparatus 1)
 The paddle method (Apparatus 2)
 The basket and the paddle methods are
simple, robust, well standardized, and used
worldwide. These methods are flexible
enough to allow dissolution testing for a
variety of drug products.
Stability Analysis
 STABILITY –
The capacity of a drug or product to remain within established
specifications of identity , quality, purity in a specific period of
time.
OR
The capacity or the capability of a particular formulation in a
specific container to remain with in particular chemical ,
microbiological , therapeutically , and toxicological
specifications.
OR
USP defines stability of pharmaceutical product as , “extent to
which a product retains with in specified limits and throughout its
period of storage and use ( i.e. shelf life)”.
 Stability testing is used to:
 Provide evidence as to how the quality of the drug product varies
with time.
 Establish shelf life for the drug product.
 Determine recommended storage conditions.
 Determine container closure system suitability.
Why Stability studies are necessary ?
 Chemical degradation of the product leads to lowering of the
concentration of the drug in the dosage form.
 Toxic products may be formed , due to chemical degradation of
the active ingredient.
 OBJECTIVES

1. To determine maximum expiration date/ shelf life.

2. To provide better storage condition.
3. To determine the packaging components.
4. To gather information during preformulation stage to
produce a stable product.
 DRUG STABILITY

Drug stability is defined as the ability of the pharmaceutical dosage form

to maintain the physical, chemical, therapeutic and microbial properties
during the time of storage and usage by the patient.

The purpose of stability studies is to provide evidence on how the

quality of the active substance or pharmaceutical product varies with
time under the influence of environmental factor such temperature,
humidity and light.

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5
 TYPES OF STABILITY TESTING
SR. STUDY STORAGE TESTING Minimum Time
NO CONDITION TIMING Period Covered
. (MONTH) By Data At
Submission

1 LONG TERM 25º C ± 2º C 0, 3, 6, 9, 12, 12 months

(Ambient) 60%RH ± 5% 18, 24, 36, 48,
60.

2 INTERMEDIATE 30º C ± 2º C 0, 3, 6, 9, 12. 6 months

(controlled) 60%RH ± 5%

3 ACCELERATED 40º C ± 2º C 0,1, 2, 3, 6, 9. 6 months

(Short term) 75%RH ± 5%
 DEGRADATION PATHWAYS
Degradation of active drug leads to lowering of quantity of the
therapeutic agent in the dosage form

A toxic product formation may takes place due to decomposition

instability of drug product can lead to a decrease in its
BIOAVAILABILITY.

Changes in PHYSICAL APPEARANCE of given dosage form may

takes place.

Degradation may increase or decrease the POTENCY

of drug.
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 HYDROLYSIS
 The most likely cause of the drug instability is
hydrolysis.
 Hydrolysis may be defined as the reaction of the
compound with water.
 It is of two type
a) Ionic Hydrolysis
b) Molecular hydrolysis
Ionic hydrolysis
It occur with salt of weak acids, eg. Potassium acetate and
base of codeine phosphate interact with water to alkaline
and acidic solution respectively.

Molecular hydrolysis
Slower irreversible process involving cleavage of the
drug molecule.
 This form of hydrolysis is mainly responsible for the
decomposition of pharmaceutical products ester, amines.
 Most important systems containing water are
emulsion , suspension , solutions , etc.
 It is usually catalyzed by hydrogen ion(acid) or
hydroxyl ion(base).
 In this process active drug is decomposed with
solvent.
 Main classes of drugs that undergo hydrolysis are
the Esters ,Amide ,Alkali, Acid.
TYPES OF HYDROLYSIS:
(ON THE BASIS OF DRUG DEGRADATION)

ESTER HYDROLYSIS:

An acid-catalyzed ester hydrolysis involves the breakdown of an ester into its

corresponding carboxylic acid and alcohol. This is done by the addition of a
water molecule, using an acid as acatalyst.

58
Example of drugs which under go ester hydrolysis:

1. Tetracaine
2.Atropine
3.Physostigmine
4.Procaine
5.Asprin

59
 AMIDE HYDROLYSIS:

When amides are hydrolysed in the presence of dilute acids

such as dilute hydrochloric acid. The acid acts as a catalyst
for the reaction between the amide and water.

RCONHR(amide) + H2O  RCOOH + R-NH2(AMINE)

60
Examples of drugs which undergo amide hydrolysis:

1. Dibucaine
2. Ergometrine
3. Chloramphenicol
4. Niacinamide
5. Barbiturates

61
• Barbiturates, hydantoins, and imides contain functional groups related
to amides but have a tendency to be more reactive.
• Barbituric acids such as barbital, phenobarbital and amobarbital,
undergo ring-opening hydrolysis.

REACTION:

62
Protection against Hydrolysis :
 Avoiding contact with moisture at time of manufacture.
 Hydrolysis of certain drugs such as benzocaine and
procaine can be decreased by the addition of specific
complexing agent like caffeine to the drug solutions .
 Hydrolysis susceptible drugs such as penicillin and
derivatives can be prevented by formulating them in the
dry powder form instead of a liquid dosage form such as
solutions or suspensions.
 Preventive Measures for Hydrolysis:

(i) Adjustment of pH:

Rate of decomposition is critically dependent upon pH. In
the case of acid base catalyzed hydrolysis at minimum pH
the drug stability is maximum.
(ii) Choice of solvent:
 Aspirin is unstable in aq. Sol. So it is formulated in
alcohol.
 In some cases non-aq. Solvent increases the instability
of product e.g. Cyclamic acid in aq. sol. Hydrolyze in
slow rate while in alcohol it hydrolyze in high rate.
(iii) Addition of surfactants:
Addition of surfactants results into significant
improvement of drug stability. Because of micelles
formation. Surfactants are of two types cationic and
anionic.
(iv) Production of insoluble form of drug:
 Hydrolysis occur only with that portion of drug which is
in aq. Sol.
 Hydrolysis can be minimized by
· making suspensions
· pH adjustment of the aq. Vehicle.
· preparing insoluble salt of the drug.
(v) Modification of chemical structure:
Change of chemical structure of a chemical drug may
prevent the hydrolysis.
e.g. Alkyl to alkyl chain.
(vi) Presence of complexing agent:
Complexing agent form water soluble complex with drug
so that the rate of decomposition may be decreased. e.g.
caffeine decrease the rate of decomposition of local
anesthetics such as benzocaine, procaine & amethocaine.
 Oxidation:
Removal of an electropositive atom, radical or electron, or the
addition of an electronegative atom or radical.
 Oxidation is controlled by environment i.e, light ,trace elements ,
oxygen and oxidizing agent.
 Occurs when exposed to atmospheric oxygen.
Types:
 · Auto-oxidation
 · Photo-oxidation
(i) Auto-oxidation:
Oxidation in which the oxygen present in the air is
involved. This process proceeds slowly under the
influence of atmospheric oxygen
e.g. Oil, fats & unsaturated compound can undergo
auto- oxidation.
It is defined as a reaction of any material with molecular
oxygen which produces free radicals.
These free radicals are highly unsaturated and readily take
electron from other substance causing oxidation.
(ii) Photo-oxidation:

Oxidation in which removal of the electron is

involved without presence of O2. This type is less
frequently encountered.
e.g. It occurs in adrenaline, riboflavin & ascorbic
acid etc.
Functional group prone to oxidation are
 Alkenes
 substituted aromatic groups like toluene, phenols
 Ethers
 Thioethers
 Amines
 Photolysis
Exposure to light cause substantial degradation of drug
molecule. When molecules are exposed to electromagnetic
radiation they absorb light which cause increase in energy
which can :
 Cause decomposition.
 Result in light emission at a new wavelength
(fluorescence , phosphorescence).
Example of phototoxic drugs:
 Furosemide, acetazolamide, cynocobalamine.
Protection from photolysis :
 Use of amber colored bottles.
 Storing the product in dark , packaging in
cartons.
 Coating of tablets with polymer films.
RACEMIZATION

Racemization refers to partial conversion of

one enantiomer into another. It involves the
optically active form of a drug into its
enantiomorph.

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DECARBOXYLATION
Elimination of CO2 from compound. Drug
substances having a carboxylic acid group is
sometimes susceptible to decarboxylation,

EXAMPLE:
4-Aminosalicylic acid

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BCS CLASSIFICATION
OF DRUG
 The Biopharmaceutical Classification System
was first developed by in 1995,

Definition:
“The Biopharmaceutical Classification System is a
scientific framework for classifying a drug substance
based on its aqueous solubility & intestinal
permeability & dissolution rate”.
 SOLUBILITY
The Maximum Amount of solute dissolved in a given
solvent under standard conditions of temperature,
pressure and pH.

 Solubility is the ability of the drug to be solution after

dissolution

 The higher single unit dose is completely soluble in

250 ml at pH 1- 6.8 ( 37˚C ).
 PERMEABILITY
Permeability of the drug to pass the biological membrane which
is the lipophilic.

 Permeability is indirectly based on the extent of absorption of a

drug substance .

Drug substance is considered to be highly permeable, when the

extent of absorption in human determined to be 90% or more of
administered drug or compare to in vivo reference dose.
 DISSOLUTION
 It is process in which solid substance solubilizes in
given solvent i.e mass transfer from solid surface to
liquid phase.
 Using USP apparatus I at 100 rpm or USP apparatus II at
50 rpm .
 Dissolution Media [900 ml],
1. 0.1 N HCl or simulated gastric fluid (pH 1.2)
without enzyme.
2. pH 4.5 buffer & pH 6.8 buffer.
3. Simulated intestinal fluid without enzyme.
 Class I
Class I drugs exhibit a high absorption number
and a high dissolution number. The rate
limiting step is drug dissolution and if
dissolution is very rapid then gastric emptying
rate becomes the rate determining step. Rate of
absorption is higher than rate of excretion. e.g.
Metoprolol, Diltiazem, Verapamil, Propranolol.
 Class II
Class II drugs have a high absorption number but
a low dissolution number. In vivo drug dissolution
is then a rate limiting step for absorption except at a
very high dose number. The absorption for class II
drugs is usually slower than class I and occurs over a
longer period of time. In vitro- In vivo correlation
(IVIVC) is usually excepted for class I and class II
drugs. e.g. Phenytoin, Danazol, Ketoconazole,
Mefenamic acid, Nifedipine.
 Class III
For Class III drugs, permeability is rate limiting step
for drug absorption. These drugs exhibit a high
variation in the rate and extent of drug absorption.
Since the dissolution is rapid, the variation is
attributable to alteration of physiology and membrane
permeability rather than the dosage form factors. e.g.
Cimetidine, Acyclovir, Neomycin B, Captopril.
 Class IV
Class IV drugs exhibit a lot of problems for
effective oral administration. Fortunately,
extreme examples of class IV compounds are
the exception rather than the rule and are
rarely developed and reach the market.
Nevertheless a number of class IV drugs do
exist. e.g. Taxol, Griseofulvin.