UNIVERSIDAD DE ZAMBOANGA

School of Allied Medicine (SAM)

Pharmacy Department
PHARM CHEM – 2 LABORATORY
PHARMACEUTICAL, ORGANIC MEDICINAL CHEMISTRY

ACTIVITY NO.1

PHYSICO-CHEMICAL PROPERTIES OF DRUGS

Submitted by:
Jasher Dave C. Acabal- Researcher and Encoder
Claire M. Sangrenes- Researcher

Submitted to:
Prof. Ben Frazier U. Sabtula,RPh,MSPharm (CAR)
Instructor
Overview
As defined by Wagner: “ the study of the interrelationship of the physicochemical properties of the drug, the
dosage form in which the drug is givenThe term “Biopharmaceutics” first appeared in a review article, “Bio-
pharmaceutics : Absorption Aspects” edited by Dr. John G. Wagner in the Journal of Pharmaceutical Sciences
(Vol.50; 359-386, 1961). INTRODUCTION & the route of administration on the rate & extent of systemic drug
absorption.
Physiological factors: 1) Route of administration 2) Membrane physiology a) Nature of cell membrane b)
Transport processes 3) Age 4) Gastric emptying time 5) Intestinal transit time 6) Gastrointestinal pH 7) Disease
states 8) Blood flow through the GIT 9) Gastrointestinal contents: a) Food- drug interactions b) Fluids c) Other
normal GI contents 10) Pre-systemic metabolism by: a) Luminal enzymes b) Gut wall enzymes c) Bacterial
enzymes d) Hepatic enzymesFactors affecting drug absorption

Physicochemical factors: 1) Drug solubility3 Factors affecting drug absorption & dissolution rate 2) Particle
size & effective surface area 3) Polymorphism & amorphism 4) Pseudopolymorphism (hydrates/solvates) 5) Salt
form of the drug 6) Lipophilicity of the drug (pH- Partition-hypothesis) 7) pKa of drug & gastrointestinal pH 8)
Drug stability
Pharmaceutical factors: 1) Disintegration time (tablets/capsules) 2) Dissolution time 3) Manufacturing variables
4) Pharmaceutical ingredients (excipients/adjuvants) 5) Nature4 Factors affecting drug absorption & type of
dosage form 6) Product age & storage condition

Physical properties (2014/06/10 5 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya)
The physical properties of drug molecules can affect the structure and stability of formulations and may also
alter the bioavailability of the drugs from the dosage forms. • Hence, physical properties of drugs are important
in the dosage form design.
The following physical properties influence dosage form design.
1. Particle size
2. Polymorphism
3. Salt

Particle size - Small particles are particularly important in low-dose high-potency drug candidates, as large
particle populations are necessary to ensure adequate blend homogeneity, and for any drug whose aqueous
solubility is poor, as dissolution rate is directly proportional to surface area. • Commercial powders consist of
aggregation of small particles. • The particles size is usually denoted as coarse powder, fine powder and very
fine powder etc. In aerosols the particle size of 0.5 to 4 microns is optimal to exhibit its action. • Particle size is
also an important parameter in determining sedimentation rates in suspensions and emulsions. • The simplest
method for small quantities is the microscope. • The Coulter Counter and laser light scattering are widely used
for routine bulk analysis and research.
Partition coefficient - When a solute is shaken with two immiscible liquids, solute itself distribute in the liquids
in such a way that the concentration solute in the both the liquids will be the constant temperature. • If C1 and
C2 are the concentration of the substances in solvent 1 and 2, the distribution coefficient or partition coefficient
K = C1/C2. • Partition coefficients of a drug are helpful in the study of its absorption, distribution, metabolism and
elimination.
Polymorphism - It is the ability of the compound to crystallize as more than one distinct crystalline species with
different internal lattice. • Different crystalline forms are called polymorphs.
Polymorphs are of 2 types
1. Enatiotropic
2. Monotropic

Parameters of polymorphs to investigated are:

1. No.of polymers that exist
2. Relative degree of stability
3. Presence of glassy state
4. Stabilization of metastable forms
5. Solubility
6. Temperature stability range
Solubility -The amount of substance that passes into solution in order to establish equilibrium at constant
temperature and pressure to produce a saturated solution. < If solubility is1 mg/ml indicates need for salt
formation to improve solubility. < 37 °C to support Biopharmaceutical evaluation 4 °C to ensure Physical
stability. Solubility should ideally be measured at two temperatures: 4°C and 37°C. 1 mg/ml in pH= 1 to 7,
preformulation study should be initiated.
Descriptive Solubility- Parts of solvent required for one part of solute Very soluble < 1 Freely soluble 1 - 10
Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000 Very slightly soluble 1000 - 10,000
Insoluble > 10,000
Reverse phase HPLC offer accurate and efficient mean of collecting solubility data of drug. Analytic method that
are particularly useful for solubility measurement include HPLC, UV spectroscopy, Fluorescence spectroscopy
and Gas chromatography.  For e.g. A drug for oral administration should be examined for solubility in media
having isotonic chloride ion concentration and acidic pH.  Preformulation solubility studies focus on drug
solvent system that could occur during the delivery of drug candidate. Solubility Analysis
Salt formation -Salts prepared from strong acids or bases are freely soluble but very hygroscopic. • It is often
better to use a weaker acid or base to form the salt, provided any solubility requirements are met. • A less
soluble salt will generally be less hygroscopic and form less acidic or basic solutions. • The dissolution rate of a
particular salt is usually much greater than that of the parent drug. • Sodium and potassium salts of weak acids
dissolve much rapidly than do the parent acids.
Chemical properties - Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles
with shape of truncated cone. • The interior cavity is hydrophobic and the outside of the molecule is hydrophilic.
Drug stability -The potency should not fall below 95% under the recommended storage conditions and the
product should still look and perform as it did when first manufactured.
Drug degradation occurs by four main processes
1. Hydrolysis
2. Oxidation
3. Photolysis
4. Trace metal catalysis
Hydrolytic degradation -The most likely cause of drug instability is hydrolysis. • Water plays a dominant role
and in many cases it is implicated passively as a solvent vector between two reacting species in solution. • The
solution is often saturated, so that studies in dilute solution can be completely misleading. • Hydrolytic reactions
involve nucleophilic attack of labile bonds • When this attack is by a solvent other than water it is known as
solvolysis.
Some interactions between the drug molecules and the additives are given below
1. Carboxymethyl cellulose forms complex with quinine, procaine etc.
2. Carrageenan forms complex with chlorpromazine, antihistamine etc.
3. Sodium alginate forms complex with Ca ++ ions.
4. PVP and polyethyleneglycol interact with phenolic groups of resorcinol, tannic acid leading to precipitation.
Drug-excipient interaction.
Permeability -Measuring the rate of permeation across membranes that are used to gain an assessment of oral
absorption in humans. • These range from computational predictions and both physicochemical and biological
methods. • The biological methods can be further subdivided into in vitro, in situ and in vivo methods. In
general, the more complex the technique the more accurate is the assessment of oral absorption in humans.
Proteins and peptides
Nowadays most proteins and peptides used in therapy or under development are produced by recombinant
DNA or hybridoma technology (known as biotechnology or biotech products). • It is clear that pharmaceutical
proteins and peptides offer special challenges to the pharmaceutical formulator. • Proteins and peptides
structure, being stabilized by relatively weak physical bonds, is readily and irreversibly changed. • Examples are
human insulin, erythropoietin, monoclonal antibodies, cytokines and interferons
Formulation ingredients Components Quantity Phenobarbital 65.0 mg Lactose (fine powder) 40.0 mg Starch
10.0 mg Starch paste q. s. Talc 10.0 mg Mineral oils 4.0 mg
WHAT IS PARTITION COEFFICIENT
In the Chemical and Pharmaceutical Sciences a partition coefficient is the ratio of concentrations of a compound
in the two phases of a mixture of two immiscible liquids at equilibrium. The partition coefficient is a ratio of
concentrations of un-ionized compound between the two liquid phases. The logarithm of the ratio of the
concentrations of the un-ionized solute in the solvents is called log P: When one of the solvents is water and the
other is a non-polar solvent, then the log P value is also known as a measure of lipophilicity. For example, in an
octanol-water system:
Pharmacology - A drug's distribution coefficient strongly affects how easily the drug can reach its intended target
in the body, how strong an effect it will have once it reaches its target, and how long it will remain in the body in
an active form. 2. Pharmacokinetics - In the context of pharmacokinetics (what the body does to a drug), the
distribution coefficient has a strong influence on ADME properties of the drug. 3. Pharmacodynamics - In the
context of pharmacodynamics (what a drug does to the body), the hydrophobic effect is the major driving force
for the binding of drugs to their receptor targets. 4. Consumer products - Many other industries take into account
distribution coefficients for example in the formulation of make-up, topical ointments, dyes, hair colours and
many other consumer products. 5. Agrochemicals - Hydrophobic insecticides and herbicides tend to be more
active. Hydrophobic agrochemicals in general have longer half lives and therefore display increased risk of
adverse environmental impact. 6. Metallurgy - In metallurgy, the partition coefficient is an important factor in
determining how different impurities are distributed between molten and solidified metal. It is a critical parameter
for purification using zone melting, and determines how effectively an impurity can be removed using directional
solidification, described by the Scheil’s equation. 7. Environmental - The hydrophobicity of a compound can give
scientists an indication of how easily a compound might be taken up in groundwater to pollute waterways, and
its toxicity to animals and aquatic life. Partition coefficient can also used to predict the mobility of radionuclides in
groundwater.

https://link.springer.com/chapter/10.1007/7355_2013_3
 UNIVERSIDAD DE ZAMBOANGA
School of Allied Medicine (SAM)
Pharmacy Department
PHARM CHEM – 2 LABORATORY
PHARMACEUTICAL, ORGANIC MEDICINAL CHEMISTRY

Name: Jasher Dave C. Acabal Course/Sec: BSPH-3B Date Submitted: December 2, 2017
Group Name: Schedule: TTHS-6:00-8:00pm Date Performed: November 28-29, 2017

Experiment No. 1
PHYSICO-CHEMICAL PROPERTIES OF DRUGS

I. OBJECTIVE:
To determine the Physico-Chemical Properties of Drugs.
.
II. MATERIALS:
Textbook in Organic Medicinal Chemistry
Textbook in Organic Medicinal &Pharmaceutical Chemistry
Remington: The Science and Practice of Pharmacy
Applied Biopharmaceutics & Pharmacokinetics
InterNet Sources (provide the Web Address)

III. PROCEDURE:

1. Identify the different Physico-Chemical Properties of Drugs.

2. Explain how Property affects the Biological Action of Drugs.

IV. Physico-Chemical Properties in Relation to Biological Action of Drugs.

https://link.springer.com/chapter/10.1007/7355_2013_3

Physical Properties of Drugs Effects on Biological Action of Drugs

Solubility Drugs only modify cellular functions-do not create
effects.
Biological Effects – drugs alter the normal
biochemical functions of an organ, tissue, or cell e.g.
laxatives increase the activity of the GI tract (i.e.
stimulation) general anesthetics decrease activity of
cells in the CNS
Physical state May be distinguished according to:
Color- Tincture
Physical mass- Spangula
Physical form- Dimethicone
Radio-opacity

Polarity The difference in polarity between molecules affects

their behavior in the body.The polarity of a molecule
affects:its ability to dissolve in lipids,its ability to
pass through the lipid membranesthe degree to
which it may bind to an active site on an enzyme or
protein.
Heroin is much more potent than morphine (and
more addictive).The –OH groups on morphine are
more polar than the ethanoate ester groups on
heroin.Heroin is more lipid soluble in lipids.It can
more readily penetrate the blood-brain barrier and it
is absorbed in higher concentrations in the brain.
Particle size Particle size plays a major role in drug absorption &
Particle size reduction has been used to increase
the absorption of a large number of poorly soluble
drugs E.g. Bis-hydroxycoumarin, digoxin,
griseofulvinSmaller particle size, greater surface
area then higher will be dissolution rate, because
dissolution is thought to take place at the surface
area of the solute( Drug). this case is important
when the drug is poorly soluble (aqueous solubility).
 Melting point It is one of the parameters to judge the purity of
crude drugs containing lipids as constituents. They
may of animal or plant origin and contain fixed oils,
fats and waxes. The purity of the following crude
drugs can be ascertained by determining their
melting points in the range shown against each of
them.
1 COLOPHONY 75-85
2 BEES WAX 62-65
3 WOOL FAT 34-44
Salt formation Salts prepared from strong acids or bases are freely
soluble but very hygroscopic. • It is often better to
use a weaker acid or base to form the salt, provided
any solubility requirements are met. • A less soluble
salt will generally be less hygroscopic and form less
acidic or basic solutions. • The dissolution rate of a
particular salt is usually much greater than that of
the parent drug. • Sodium and potassium salts of
weak acids dissolve much rapidly than do the parent
acids.

Chemical Properties of Drugs

Partition Coefficient A drug's distribution coefficient strongly affects how
easily the drug can reach its intended target in the
body, how strong an effect it will have once it
reaches its target, and how long it will remain in the
body in an active form.
Isomerism Drug molecules must generraly interact with
biomolecules enzyme /receptors in a very specific
way to elicit a pharmacological response
Intermolecular forces Drug interact and binds to the binding sites
receptor/protein/enzyme through intermolecular
forces
Ionization Only the unionized form of a drugs can partion
through membranes
The ionized form is more water-soluble(required for
drugs administration and drug distribution in plasma

pH Most drugs are week acids and week bases

- An acidic drugs dissolves in a basic medium
- A basic drugs dissolves in an acidic medium
Fuctional Group Phase I and Ii reaction
Addition to p[olar functional group results in more
water soluble and excretable metabolites

VI. GUIDED QUESTIONS:

1. What are the Requirements for a Drug to exert its Biological Effect?

The drug must pass trough:

 Barriers
 Survive alternate sites of attachment/ storage
 Avoid metabolic destruction before it reaches the sites of action
 Allow favourable binding characteristics
 Dissociates from receptor and re-enter to the systemic circulation to be excreted

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2. What is the Interrelation of the Physico-Chemical Properties of the Drug to Its Biological Action?

In general, when a drug molecule enters the body, it will interact with one or more biopolymers found in
the extracellular fluid, in the cell membrane, and within cells .The type and the extent of this interaction
will depend on the kind and number of chemically reactive functional groups and the polarity of the drug
molecule . The drug-protein interaction does not involve covalent bonds that are relatively stable at body
temperatures. Instead, weak forces such as ionic bonds, hydrogen bonds, Van der Waals forces, dipole-
ion, and dipole-dipole forces are involved. The partition coefficient P, produced because of the presence
of drug through lipid membranes/water system found in the body, is given by P =
[drug] lipid /[drug] water , the Hansch equation. A biological response is produced by the interaction of a
drug with a functional or an organized group of molecules, which may be called the biological receptor
site.
The hydrophobic bond

This is a concept used to explain attractive interactions between nonpolar regions of the receptor and the
drug. Explanations such as the isopropyl moiety of the drug fits into a hydrophobic cleft on the receptor
composed of the hydrocarbon side chains of the amino acids valine, isoleucine, and leucine are
commonly used to explain why a nonpolar substituent at a particular position on the drug molecule is
important for activity. Also, the polypeptide chain is considered to be the primary level of protein structure
and the folding of the polypeptide chains into a specified structure maintained through hydrogen bonding
interactions (intramolecular) .

Hydrogen bond

Among the secondary forces, hydrogen bonding that occurs over short distances (2.5-2.7 Ε) is one of the
most important forces that affects the physical property of the compound. The important hydrogen
bonding groups are -OH, -NH, which can form either intermolecular or intramolecular hydrogen bonds.
Some examples are water, salicylic acid, and o-nitrophenol. The antipyretic and antirheumatic effects of
salicylic acid are because of its prostaglandin synthase-inhibitory effect.
Chelating
Chelation can be used for sequestration of metal ions , stabilization of drugs , and elimination of toxic
metals from intact organisms and also for improvement of metal absorption. An important example of
chelating agents is the radioactive transition state artificial metal, technetium ( 99m Tc), for albumin
injection used as radiotracers in diagnostic nuclear medicine practice .

Surface activity

Four different types of surface-active agents can be recognized: (a) anionic compounds, for example salt
of bile acids, salts of sulfate or phosphate esters of alcohols and salts of sulfonic acids; (b) cationic
compounds, for example high-molecular-weight aliphatic amines and quaternary ammonium derivatives;
(c) nonionic compounds, for example polyoxyethylene ethers and glycol esters of fatty acids; and (d)
amphoteric surfactants

The surface-active molecules can be formed at the surface of water or at the interface of polar and
nonpolar liquids with the nonpolar portion of the molecule oriented toward the nonpolar liquid and the
polar groups toward the polar liquids. Three different types of forces are involved in the orientations of
surface-active molecules, namely, Van der Waals, hydrogen bonds, and ion dipoles

Charge transfer interaction

In these interactions, electrons are not fully transferred; rather, electron density is distributed between
molecules the same way as in covalent bond. The molecule that accepts electron density is called the
acceptor and the molecule that donates electron density is called the donor . The charge transfer
interactions are weak in comparison with the covalent bonding because each of the molecules involved
in the interaction already has its primary valence requirements satisfied. The commonly known examples
of charge transfer complexes are aromatic molecules. The contribution of charge transfer interactions
toward drug activity has been determined in terms of molecular orbital calculations. The calculations of
the energy for the highest occupied molecular orbital and the lowest empty one of actinomycin and of
various purines have shown them to be in accordance with the observed electron-accepting and
electron-donating properties of the respective compounds. The interactions of Cu, Pd, and Ni chelates of
 8-hydroxyquinoline with various electron acceptors support charge transfer as a possible mechanism of
action of these compounds

3. What Route of Drug Administration will give Fast Drug Action? Explain.

Intravenous- is (IV) drug use in which the drug is injected directly into a vein and enters the bloodstream to
reach the brain. This is the quickest way of achieving a psycho-active drug effect. The drug effect is
experienced in less than one minute.

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4. What are the Different Forces involved in Drug-Receptor Interaction? Give Examples.

The Different Forces involved in Drug-Receptor Interaction

Hydrogen Bonds – bond formed by hydrogen atoms bound to electronegative atoms

Ionic Bonds – bond formed by the attraction between atoms of opposite charge
Covalent Bonds – bond formed by sharing electrons between atoms
Van der waals forces – bond formed when any two uncharged atoms approach each other very closely
Dipole-Dipole – bond formed between the positive end of one polar molecule and the negative end of
another polar molecule
Ion-Dipole – bond formed from the electrostatic attraction between an ion and a neutral molecule that
has a dipole.

https://link.springer.com/chapter/10.1007/7355_2013_3

5. What form of Drug is well Absorbed and Excreted in the Body?

Intravenous (IV) route of administration

6. What is the Importance of a Drug Receptor? What is the Principle of Drug Receptor Interaction?

DRUG RECEPTOR DRUG

RECEPTOR COMPLEX

Pharmacological effect

https://link.springer.com/chapter/10.1007/7355_2013_3
V. CONCLUSION:

Therefore I conclude that understanding the physicochemical properties of a compound such as solubility,
stability, form definition, solid-state properties, partition coefficient and ionization constant(s) is essential so that
the formulation process can be rational and streamlined. By integrating this knowledge with the
biopharmaceutical properties,