Physical Pharmacy
LECTURE NOTES INTRODUCTION
PHARMACEUTICS
 The word 'pharmaceutics' is used in pharmacy and the
pharmaceutical sciences to encompass a wide range of subject
areas that are all associated with the steps to which a drug is
subjected towards the end of its development.
 It encompasses the stages that follow on from the discovery or
synthesis of the drug, its isolation and purication, and testing for
advantageous pharmacological effects and absence of serious
toxicological problems
 Put at its simplest pharmaceutics converts a drug into a medicine.
 It means ‘knowledge or science of drugs’ .
 The art and applied science of dosage form design.
 It deals with Investigations of physical and chemical properties of
drug molecules necessary for efficient design of dosage forms.
 The general area of study concerned with the formulation,
manufacture, stability, and effectiveness of pharmaceutical dosage
forms is termed pharmaceutics.
 Deals with many aspects of interactions both inside and outside the
body
 Pharmaceutics deals with the formulation of a pure drug substance
into a dosage form.
 The pharmacologically active ingredient in a medicine.
 ALTERNATIVE NAME: 'medicinal agent',
Drug 'pharmacological agent', 'active principle', 'active
ingredient', increasingly or 'active pharmaceutical
ingredient (API),
Drug
 Means of administering drugs to the body in a safe,
Delivery
efficient, accurate, reproducible and convenient manner.
System
Three Major Considerations In The Design Of Dosage Forms
1  The physicochemical properties of the drug itself
 Biopharmaceutical considerations, such as how the
2 administration route of a dosage form affects the rate and extent
of drug absorption into the body, and
 Therapeutic considerations of the disease state and patient to be
treated, which in turn determine the most suitable type of dosage
3
form, possible routes of administration and the most suitable
duration of action and dose frequency for the drug in question
PHYSICAL PHARMACY
 Associated with the area of pharmacy that dealt with the
quantitative and theoretical principles of physicochemical science
as they applied to the practice of pharmacy.
 Concerned with the physical and chemical principles of materials
(drugs and other additives) that go into the formulation of dosage
forms. Integrates knowledge of mathematics, physics and chemistry
and applies them to the pharmaceutical dosage form developement
 This will help the pharmacist in selecting the right kind of materials.
 It focus on the theories behind the phenomena needed for dosage
form design.
PRINCIPLES OF DOSAGE FORM DESIGN
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Physical Pharmacy
LECTURE NOTES INTRODUCTION

 Drugs are rarely administered as pure chemical substances alone  Dosage forms can be designed for administration by alternative
and are almost always given as formulated preparations or delivery routes to maximize therapeutic response.
medicines.  Preparations can be taken orally or injected, as well as being applied
 These can vary from relatively simple solutions to complex drug to the skin or inhaled.
delivery systems through the use of appropriate additives or  However, it is necessary to relate the drug substance to the clinical
excipients in the formulations. indication being treated before the correct combination of drug and
 The excipients provide varied and specialized pharmaceutical dosage form can be made, since each disease or illness often
functions. requires a specific type of drug therapy.
 solubilize, suspend, thicken, preserve, emulsify, modify
dissolution, improve the compactability and avour drug
substances to form various medicines or dosage forms.
 The principal objective of dosage form design is to achieve a
predictable therapeutic response to a drug included in a formulation
which is capable of large scale manufacture with reproducible
product quality.
 To ensure product quality, numerous features are required:
 chemical and physical stability, with suitable preservation
against microbial contamination
 if appropriate, uniformity of dose of drug
 acceptability to users, including both prescriber and patient,
as well as suitable
 packaging and labelling
 Ideally, dosage forms should also be independent of patient-to-
patient variation, although in practice, this feature remains dif cult to
achieve
 There are numerous dosage forms into which a drug substance can
be incorporated for the convenient and efficacious treatment of a
disease.

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Physical Pharmacy
LECTURE NOTES INTRODUCTION

 Many drugs are formulated into several dosage forms of varying

strengths, each having selected pharmaceutical characteristics
which are suitable for a specific application.
 One such drug is the glucocorticoid prednisolone used in the
suppression of inflammatory and allergic disorders
 One such drug is the glucocorticoid prednisolone used in
the suppression of inflammatory and allergic disorders
 The analgesic paracetamol is also available in a range of dosage
forms and strengths to meet the specific needs of the user,
including tablets, dispersible tablets, pediatric soluble tablets,
pediatric oral solution, sugar-free oral solution, oral suspension,
double-strength oral suspension and suppositories.

BIOPHARMACEUTICAL ASPECTS OF DOSAGE FORM DESIGN

 Biopharmaceutics can be regarded as the study of the relationship
between the physical, chemical and biological sciences applied to
drugs, dosage forms and drug action.
 When the dosage form is designed to deliver drugs via the buccal,
respiratory, rectal, intramuscular or subcutaneous routes, the drug
passes directly into the circulation blood from absorbing tissues,
whilst the intravenous route provides the most direct route of all
 When delivered by the oral route, onset of drug action will be
delayed because of required transit time in the gastrointestinal tract
prior to absorption, the absorption process and factors associated
with hepatoenteric blood circulation
 The physical form of the oral dosage form will also influence
absorption rate and onset of action, with solutions acting faster than
suspensions, which in turn generally act faster than capsules and
tablets
Three Major Considerations In The Design Of Dosage Forms
Dosage  Are designed to provide the drug in a suitable form for
Forms absorption from each selected route of administration.
 The oral route is the most frequently used route for
drug administration.
 Oral dosage forms are intended usually for systemic
effects resulting from drug absorption through the
various epithelia and mucosa of the gastrointestinal
Oral Route
tract.
 A few drugs, however, are intended to dissolve in the
mouth for rapid absorption or for local effect in the
tract due to poor absorption by this route or low
aqueous solubility

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Physical Pharmacy
LECTURE NOTES INTRODUCTION
 Compared with other routes, the oral route is the
simplest, most convenient and safest means of drug
administration
 However, disadvantages include relatively slow onset
of action, possibilities of irregular absorption and
destruction of certain drugs
 The most popular oral dosage forms are tablets,
capsules, suspensions, solutions and emulsions.
 are prepared by compaction and contain drugs
Tablets and formulation additives which are included for
specific functions
 Are solid dosage forms containing drug and,
usually, appropriate filler(s), enclosed in a hard or
Capsules
soft shell composed primarily of gelatin or other
suitable polymeric material.
 Which contain finely divided drugs suspended in a
suitable vehicle, are a useful means of
Suspensions
administering large amounts of drugs that would
be inconvenient if taken in tablet or capsule form.
 Including formulations such as syrups and
linctuses, are absorbed more rapidly than solid
Solutions
dosage forms or suspensions since drug dissolution
is not required.
 Drugs given rectally in solution, suppository or
Rectal
emulsion form are generally administered for local
Route
rather than systemic effect
 Disadvantageously, the rectal route is inconvenient
and drug absorption is often irregular and difficult to
predict
 Are solid forms intended for introduction into
Suppositories body cavities (usually rectal but also vaginal and
urethral) where they melt, releasing the drug.
 The three main parenteral routes are subcutaneous,
intramuscular and intravenous.
 Other outes, such as intracardiac and intrathecal, are
used less frequently.
Rectal  The parenteral route is preferred when rapid
Route absorption is essential, as in emergency situations or
when patients are unconscious ornunable to accept
oral medication, and in cases when drugs are
destroyed, inactivated or poorly absorbed following
oral administration
 Drugs are applied topically, that is to the skin, mainly
for local action
 Whilst this route can also be used for systemic drug
delivery, percutaneous absorption is often poor and
Topical erratic, although several transdermal patches
Route delivering drug for systemic distribution (e.g. fentanyl
patches for severe pain management and nicotine
patches for cessation of smoking) are available.
 Pharmaceutical topical formulations - ointments,
creams and pastes - are composed of drug in a
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Physical Pharmacy
LECTURE NOTES INTRODUCTION

suitable semi solid base which is either hydrophobic or

hydrophilic in character.
 The lungs provide an excellent surface for absorption
when the drug is delivered in gaseous, aerosol mist or
Respiratory
ultrafine solid particle form
Route
 This delivery route is particularly useful for the direct
treatment of asthmatic problems  The rules for rounding off are based on whether the
digit to be dropped is equal to or greater than 5, as well
Review of Basic Mathematical Skills as the digits flanking that digit.
 The numbers 0, 1, 2, 3, 21, 22, 23, and so on, which can  The last digit to be retained is increased by one if the
be either positive or negative and can be arranged in digit to be dropped is greater than 5; e.g., 17.9 is
ascending order rounded up to 18
Integers  Where they increase as you move from left to right on  The last digit to be retained is left unaltered if the digit
the line. to be dropped is less than 5; e.g., 17.4 is rounded down
 Therefore, a negative integer such as 23 is smaller than to 17.
Rules for
22  If 5 is the digit to be dropped but is followed by nonzero
Rounding
The following examples and key concepts illustrate the digit(s), the last remaining digit is increased by one;
Off
special rules governing the role of zero and infinity in e.g., 17.512 is rounded up to 18 because digits 1 and 2
Numbers
mathematical operations: follow 5 and are not zero.
 Any number multiplied by zero equals zero, e.g., 12 X0 =  If 5 is the digit to be dropped and is followed by zero
0 only or no other digits, the last remaining digit should
Zero and be rounded up or down depending on whether it is an
 Any number multiplied by infinity (N) equals infinity,
Infinity even number or odd number.
e.g., 12 X ∞ = ∞
 Any umber divided by zero is mathematically  e.g.,17.5 is rounded up to 18 because the last remaining
undefined; e.g.,12/0= Undefined. digit, 7, is an o18.5 is rounded down to 18 because the
 Any number divided by infinity is mathematically last remaining digit is an even digit odd digit, but
undefined 
Significant  The number of significant figures is simply the number
Figures of figures that are known with degree of reliability.
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Physical Pharmacy
LECTURE NOTES INTRODUCTION

DENSITY (d)
 derived quantity and combines the units of mass and volume: -
Density = mass/volume
 mass per unit volume of a substance
 usually expressed as grams per cubic centimeter (g/cc)
 Density may be calculated by dividing mass by volume
 Because the gram is defined as the mass of 1 cc of water at 4C, the
density of water is 1 g/cc.
 Because the United States Pharmacopeia states that 1 mL may be
used as the equivalent of 1 cc, the density of water may be expressed
as 1 g/mL

Specific Gravity
 ratio, expressed decimally, of the weight of a substance to the weight
of an equal volume of a substance chosen as a standard, both
substances at the same temperature or the temperature of each
being known.
 WATER - used as the standard for the specific gravities of liquids
and solids;
 HYDROGEN - the most useful standard for gases
Pycnometer
 Specific gravity may be calculated by dividing the weight of a given
 Pycnometer a special glass bottle used to determine specific gravity.
substance by the weight of an equal volume of water, that is
𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑆𝑢𝑏𝑠𝑡𝑎𝑛𝑐𝑒  Generally available for laboratory use in volumes ranging from 1 mL
𝑆𝐺 = to 50 mL.
𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑒𝑞𝑢𝑎𝑙 𝑣𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝑤𝑎𝑡𝑒𝑟
 In using a pycnometer, it is first weighed empty and then weighed
 In the United States Pharmacopeia, the standard temperature for
again when filled to capacity with water.
specific gravities is 25C, except for that of alcohol, which is 15.56C by
 The weight of the water is calculated by difference.
government regulation.
 Since 1 g of water equals mL, the exact the volume of the
pycnometer becomes known

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Physical Pharmacy
LECTURE NOTES INTRODUCTION

 Then, when any other liquid subsequently is placed in the

pycnometer, it is of equal volume to the water, and its specific
gravity may be determined.
𝑊𝑆𝑢𝑏𝑠𝑡𝑎𝑛𝑐𝑒 − 𝑊𝑃𝑦𝑐𝑛𝑜𝑚𝑒𝑡𝑒𝑟
𝑊=
𝑊𝑊𝑎𝑡𝑒𝑟 − 𝑊𝑃𝑦𝑐𝑛𝑜𝑚𝑒𝑡𝑒𝑟

SYSTEMS OF MEASURE
 Primary system of measure in pharmacy and
Metric
medicine.
 system of measuring weight which uses pounds and
Avoirdupois
ounces as units
 historical system of mass and volume units used by
Apothecaries
veterinarians, physicians and apothecaries

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Physical Pharmacy
LECTURE NOTES INTRODUCTION

 sweetened, flavored, hydroalcoholic solutions

Elixirs
intended for oral administration
 pharmaceutical suspensions of fine particles that,
Magmas because of a high degree of physical attraction to the
aqueous vehicle, form a gelatinous mixture.
 semisolid systems consisting of either suspensions of
Gels small inorganic particles or large organic molecules
interpenetrated by a liquid.
 dry mixtures of finely divided medicinal and
Powders nonmedicinal agents intended for internal or external
use
 solid preparations containing one or more medicinal
agents in a flavored, sweetened base intended to
Lozenges
dissolve or disintegrate slowly in the mouth, releasing
medication generally for localized effects
IMPORTANT TERMINOLOGIES  semisolid preparations intended for topical
 solid dosage forms containing one or more medicinal Ointments application to the skin, eye, ear, or various mucous
Tablets
substances membranes
 Solid dosage forms in which one or more medicinal  semisolid dosage forms that contain one or more
Capsules and/or inert substances are enclosed within small Pastes drug substances intended for topical application to
shells of gelatin. the skin
 Liquid preparations that contain one or more  semisolid preparations containing one or more drug
Solutions chemical substances (solutes) dissolved in a solvent Creams
substances dissolved or dispersed in a suitable base
or mixture of solvents.  liquid preparations intended for external application
 concentrated aqueous solutions of a sugar or sugar Lotions
Syrups to the skin
substitute.  solid or semisolid adhesive masses spread across a
 preparations containing finely divided, undissolved suitable backing material and intended for external
Suspensions Plasters
drug particles dispersed throughout a liquid vehicle. application to a part of the body for protection or for
the medicinal benefit of added agents
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Physical Pharmacy
LECTURE NOTES INTRODUCTION

9
Physical Pharmacy
STATES OF MATTER

PHYSICAL SCIENCE States of matter

 includes chemistry and physics Sublimation  Solid to Gas
 study of the nature and properties of matter and energy in non-living  Solid to Liquid
Melting
systems  Or fusion
 Matter anything that has mass and takes up space Freezing  Liquid to Solid
 "stuff" of the universe - the atoms, molecules and ions that make-up  Liquid to Gas
all physical substances  At any given temperature, a certain number of the
Five known phases or states: Vaporization molecules in a liquid possess sufficient kinetic
 Solids energy to escape from the surface
 Liquids  Or Evaporization
 Gases Deposition  Gas to Solid
 Plasma  Gas to Liquid
 Bose-Einstein condensates  As the concentration of molecules in the vapor
Condensation
 Adding energy to matter causes a physical change causing matter phase increases, some molecules return to the
to move from one state to another. liquid phase
 adding thermal energy (heat) to liquid water causes it to become Ionization  Gas to Plasma
steam or vapour (a gas). Deionization  Plasma to Gas
 Taking away energy also physical change causes physical change
 liquid water becomes ice (a solid) when heat is removed Phase  Transformations from one phase to another
 These changes in states of matter and their inherent properties are Changes
studied and are applied in various area of pharmacy  The temperature at which the vapor pressure of a
liquid is equal to the external pressure.
Boiling point
 The normal boiling point of a liquid is the boiling
point when the external pressure is 1 atm.
 melting point of a solid (or the freezing point of a
Melting point liquid) is the temperature at which solid and liquid
phases coexist in equilibrium.

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Physical Pharmacy
STATES OF MATTER

 The normal melting point (or the normal freezing Homogeneous  composition of the mixture is the same throughout
point) of a substance is the melting point (or mixture the solution
freezing point) measured at 1 atm pressure. Heterogeneous  the composition is not uniform
mixture
Based on its composition and properties, Matter can be classified as
elements, pure compounds, pure substances and mixtures  can be measured and observed without changing the
Physical
composition or identity of a substance
property
 Color, melting point, boiling point, and density
 to observe this property, we must carry out a chemical
Chemical
change.
property
 flammability, toxicity, acidity, reactivity

INTRODUCTION TO THE STATES OF MATTER

 Solid, liquid and gas represents the three basic states of matter
 In pharmaceutical view point, basic three states are significant while
other two states has limited applications in pharmacy but they has
major applications in physics
 The plasma state is not related to blood plasma but it represents an
ionized gas at temperatures. very high temperatures
CLASSIFICATION OF MATTER  There is no sharp distinction between solid, liquid and gaseous states
 form of matter that has a constant composition because they may exist in any state depending upon intensity of
Substance intermolecular forces and physical forces like temperature and
 can be either an element or a compound
 cannot be separated into simpler substances by pressure.
Element  For a molecule to exist in aggregate as compound there must be
chemical means
 composed of two or more elements chemically some intramolecular binding force
Compound  Knowledge of these forces is important to understand the properties
united in fixed proportions
 combination of two or more substances substances of solids, liquids and gases as well as solutions, suspensions,
Mixture emulsions and powders etc
identities. retain in which their the distinct identities

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Physical Pharmacy
STATES OF MATTER

PLASMA
 fourth state of matter
 an ionized gas
 the most common state of matter in the universe
 e.g. Sun,stars
 Like a gas, plasma does not have definite shape or volume.
 Unlike gases, plasmas are electrically conductive, produce magnetic
fields and electric currents, and respond strongly to electromagnetic
forces
 Lightning, electric sparks, fluorescent lights, neon lights, plasma
televisions, some types of flame and the stars are all examples of
illuminated matter in the plasma state.
 A gas is usually converted to a plasma in one of two ways, either
from a huge voltage difference between two points, or by exposing it
to extremely high temperatures

BOSE-EINSTEIN CONDENSATES FORCES OF ATTRACTION

 First predicted by Professor Albert Einstein and Indian Intramolecular  hold atoms together in a molecule
mathematician Satyendra Nath Bose
Forces
 a state of matter that consists of a collection of absolute zero; atoms
Intermolecular  between molecules
near Forces
 Similar to solids but with less energy.
 superfluids, such as cold liquid helium,
 superconductors, such as the nucleons inside a neutron star.

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Physical Pharmacy
STATES OF MATTER

INTERMOLECULAR FORCES
 Attractive forces between molecules
 Primarily responsible for the bulk properties of matter
 Generally, intermolecular forces are much weaker than
intermolecular forces
 Less energy is usually required

Types of interaction Interacting Species

Ion-Ion Ions only
Ion-dipole Ions and polar molecules
Hydrogen bonding Molecules containing N,O,F; the link is a
shared H atoms
Dipole-dipole Polar molecules
Dipole-induced dipole At least one molecule must be polar
London-dispersion forces All types of molecules

TYPES OF INTRAMOLECULAR FORCES

INTRAMOLECULAR FORCES  Despite being relatively weak in nature, play an
Van Der
IONIC BOND  donates an electron to the other atom important role in pharmaceutical system especially in
Waals
COVALENT  electrons are shared equally between atoms the "flocculation" and "deflocculation" phenomena
forces
BOND commonly observed in pharmaceutical suspensions.
METAL  force between metal substance  DIPOLE – DIPOLE
BOND  occur in two polar molecules
Keesom
 do not occur in aqueous solutions that contain
Force
electrolytes
 Ex: water, HCl, alcohol, phenol
 DIPOLE INDUCED DIPOLE;
Debye force  between any polar molecule and non-polar
 Ex: ethylacetate, methylene chloride; ether

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Physical Pharmacy
STATES OF MATTER

 DISPERSION FORCES; GASES

London
 INDUCED DIPOLE INDUCED DIPOLE;
dispersion
 weakest intermolecular force
force
 Ex: carbon disulfide, carbon tetrachloride, hexane
 Attract an ion (either a cation or an anion) and a
polar molecule to each other
 A cation interacts more strongly with dipoles than
does an anion having a charge of the same
magnitude
 Commonly occur when solutions of ionic compounds
are dissolved in polar liquids-for example, NaCl
Ion-Dipole
dissolving in water
Forces
 Attractive interaction between an charged ion and
the induced dipole (non-potar molecule)
 Formation of lodide complex: Potassium ion (+) can
induced a dipole in a diatomic molecule. This is
important in solubility of iodine in solution of
potassium iodide.
 12 + KI = K13
 a primarily electrostatic force of attraction between a
hydrogen (H) atom which is covalently bound to a
more electronegative atom or group, particularly the
Hydrogen second-row elements nitrogen (N), oxygen (O), or
Bond fluorine (F)
 stronger and an important form of dipole-dipole
interactions
 water molecules
 The gaseous state is the simplest state amongst the three states of
matter.
 The molecules in gas are wide apart in empty space and are free to
move in any direction in the container they are contained in.
 The gas molecules exert pressure on the walls of the container in all
directions.
 Gases have indefinite expansion ability to fill the entire container.
 When two or more gases placed together they rapidly diffuse
throughout each other and form a homogenous mixture.
 Upon heating gas in the container → inside pressure increases and
its volume increases.
Kinetic Molecular Theory of Ideal Gases:
All matter is composed of tiny discrete particles (molecules or
1
atoms).
Ideal gases consist of small particles (molecules or atoms) that
2
are far apart in comparison to their own size.
These particles are dimensionless points, which occupy zero
3
volume.
These particles are in rapid, random and constant straight-line
4 motion. Well-defined and established laws of motion can describe
this motion.
There are no attractive forces between gas molecules or between
5
molecules and the sides of the container with which they collide.
6 Molecules collide with one another and the sides of the container.
7 Energy can be transferred in collisions among molecules.
Energy is conserved in these collisions, although one molecule
8
may gain energy at the expense of the other.
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Physical Pharmacy
STATES OF MATTER
Energy is distributed among the molecules in a fashion known as
9
the Maxwell-Boltzmann Distribution.
At any instant, the molecules in each sample of gas do not at all
10 possess the same amount of energy. The average kinetic energy
of all the molecules is proportional to the absolute temperature.
Measurable Characteristics Properties of the Gas
 The volume of container is the volume of gas sample
Volume
and is expressed in unit liter (L) or milliliter (ml).
 Temperature of gas is measured in Kelvin
temperature scale
 The product of pressure and volume per mole is
Temperature
proportional to the average molecular kinetic energy
 The average kinetic energy is proportional to the
absolute temperature
 Atmospheric pressure is measured using a
barometer
 Pressure of a gas is proportional to average force per
unit area that gas molecules exert on the walls of the
container
 The greater the number of gas molecules in each
Pressure container, the higher is the pressure as the greater
average number of collisions occurring with the wall
of the container
 Pressure is directly proportional to the kinetic energy
of the gas molecules therefore higher the
temperature the greater is the kinetic energy and
greater the pressure of the gas.
AEROSOLS
 a pressurized dosage forms containing one or more therapeutic
active ingredients which upon actuation emit a fine dispersion of
liquid and/or solid materials in a gaseous medium"
 Gases can be liquefied by increasing pressure
 When the pressure is reduced, the molecules expand and the liquid
reverts to a gas. This reversible change of state is the basic principle
involved in the preparation of pharmaceutical aerosols.
 In such products, the drug is dissolved or suspended in a 'propellant',
a material that is liquid under the pressure conditions existing inside
the container and forms a gas under normal atmospheric conditions
 Pharmaceutical aerosol may be dispensed as fine mist, wet spray,
quick breaking foam, stable foam, semi solid etc.
 FORMULATION OF AEROSOLS
 It consist of components: two essential
1. Product concentrate
2. Propellant characteristics.
CHLOROFLUOROCARBONS AND HYDRO FLUOROCARBONS
 have traditionally been utilized as propellants in these products
because of their physicochemical properties
 However, in the face of increasing environmental concerns (ozone
depletion) their use is tightly regulated which has led to the
increased use of other gases such as nitrogen and carbon dioxide
ADVANTAGES OF CHLOROFLUOROCARBONS AND HYDRO
FLUOROCARBONS
 Easily withdrawn of drug
 Easy and convenient to apply
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Physical Pharmacy
STATES OF MATTER

 Faster Onset of action PROPELLANTS

 Avoid the first pass metabolism  Responsible for developing proper pressure within the container
 No microorganism can enter  Provide driving force to expel the product from the container
 Release the contents in Controlled and Uniformly  Single or blend of various propellants is used.
 Protect the photosensitive medicaments and oxygen sensitive  Blend of solvents is used to achieve desired solubility
material  The propellants are selected to give the desired vapor pressure,
 Provides efficacy of a drug solubility and particle size.
 Irritation can be reduced
TYPES OF PROPELLANTS
DISADVANTAGES OF CHLOROFLUOROCARBONS AND HYDRO  Exist as liquids under pressure
FLUOROCARBONS Liquid gases  Because the aerosol is under pressure propellant
 Costly propellants exists mainly as a liquid, but it will also be in the head
 Difficult disposal of empty aerosol containers. space as a gas
 Allergic in some cases  occupy the head space above the liquid in the can
 Explosive  When the aerosol valve is opened the gas 'pushes' the
Compressed
 Some formulation is difficult liquid out of the can
gases
 Sometimes propellants may cause toxic reactions.  The amount of gas in the headspace remains the
propellants
same but it has more space, and as a result the
pressure will drop during the life of the can.
DESIRED CHARACTERISTICS OF CHLOROFLUOROCARBONS AND
HYDRO FLUOROCARBONS
 Less explosive PRODUCT CONCENTRATE:
 Uniform and constant dose delivery.  Active ingredient or mixture of active ingredients and other
 Non allergic necessary agents such as solvents, anti-oxidants and surfactants.
 Economic/Low cost
 Easy to handle INHALERS
 Non Breakable  The first nasal administration of drugs was primarily employed for
 Eco-friendly local drug effects.
 Nasally administered small dose display a rapid absorption that is
comparable to intravenously administered drugs.
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Physical Pharmacy
STATES OF MATTER
 MDI
- It is composed of four essential components: the base formulation
(Drug, propellant, excipients, etc.), the container, the metering valve
and the actuator (or mouth piece)
 the drug is delivered through a valve in a metered volume from a
volatile propellant, pressurized container.
IDEAL INHALATION DEVICES
 Such as, able to consent the inhalation of a
Effective sufficient fraction of drug with a particle size ≤ 6
μ, independently of the patient's inspiratory flow.
 Such as, able to always consent the inhalation of
Reproducible the same drug amount, also in terms of its
respirable fraction.
 such as, able to consent to know at any moment
Precise the amount (or the number of doses) of the drug
remaining in the device
 Such as, able to protect the drug(s) contained
Stable from the effects of temperature and/or humidity
changes
 Such as, easy to use in different circumstances
(particularly in critical conditions), and possibly
Comfortable
containing several doses of the drug(s) for a long
term use.
 such as, it should consent the use of other drugs
Versatile
by inhalation
Environmentally  such as not containing chemical contaminants
compatible
 such as, of acceptable cost, and possibly
Affordable
rechargeable
SUBSTANCES THAT EXISTS AS GASES
 02→ essential for our survival.
 Hydrogen cyanide (HCN) → a deadly poison.
 Carbon monoxide (CO), hydrogen sulfide (H2S), nitrogen dioxide
(NO2), 03, and sulfur dioxide (SO2) are somewhat less toxic.
 The gases He and Ne are chemically inert; - they do not react with
any other substance.
 Most gases are colorless.
 Exceptions are F2, C12, and NO2.
 The dark-brown color of NO2 is sometimes visible in polluted air.
ALL GASES HAVE THE FOLLOWING PHYSICAL CHARACTERISTICS:
 Gases assume the volume and shape of their containers.
 Gases are the most compressible of the states of matter.
 Gases will mix evenly and completely when confined to the same
container
 Gases have much lower densities than liquids and solids
LIQUIDS
 In the liquid state, the attractive forces between the atoms or
molecules are strong enough to hold the modules in close contact,
but not strong enough hold them in a fixed position like in a solid.
 The molecules are free to randomly move about in three dimensions
 Liquids in general have a defined flexible volume; i.e., liquids
conveniently take the shape of the container in which they are held.
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Physical Pharmacy
STATES OF MATTER
 Liquids differ from gases in having higher densities and viscosities,
and not being as compressible.
 Molecules in liquids also typically I have lower kinetic energy
compared to those in gases.
 Liquids respond to temperature changes and may transition to a
different state, i.e., solid or gas, depending on the magnitude and
direction of such change.
 Liquids tend to flow readily in response to external forces, and the
flow behavior is influenced by internal/external resistance, e.g.,
friction and viscosity.
PROPERTIES OF LIQUIDS
 the amount of energy required to stretch or increase the
surface of a liquid by a unit area
 A measure of the elastic force in the surface of a liquid
 Arises due to cohesive interactions (intermolecular
Surface attraction between like molecules) between the
Tension molecules in the liquid.
 Liquids that have strong intermolecular forces also have
high surface tensions.
 Water has a considerably greater surface tension
than most other liquids.
 a measure of a fluid's resistance to flow
 The greater the viscosity, the more slowly the liquid flows.
 The viscosity of a liquid usually decreases as temperature
Viscosity increases;
 Liquids that have strong intermolecular forces have
higher viscosities than those that have weak
intermolecular forces
 Water has a higher viscosity than many other liquids
because of its ability to form hydrogen bonds.
 An important property of liquids
 defined as the pressure exerted by a vapor in equilibrium
with a liquid at a given temperature in closed a system
 Because vapor pressure is a measure of a molecule's
escaping tendency from a liquid or solid, it depends on
temperature but does not depend on the amount of
liquid, atmospheric pressure, or presence of other vapors
Vapor
Pressure
 If a liquid is placed in an open container and heated until
the vapor pressure equals the atmospheric pressure, the
Boiling vapor will form bubbles that rise rapidly through the
Point liquid and escape into the gaseous state
 The temperature at which the vapor pressure of the
liquid equals the external or atmospheric pressure
Vapor pressure Boiling point
Vapor pressure is the force exerted by Boiling point is the temperature at which
the vapor released by a liquid or solid the vapor pressure is equal to the
substance in a closed container or space external structure applied on the liquid
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Physical Pharmacy
STATES OF MATTER

Defined for a closed system with a Defined for a system with a constant TYPES OF LIQUID CRYSTALS
constant temperature pressure  Thread-like textures as observed under polarizing
Related to both solid and liquid phases Related to only the liquid phase
Varies with temperature Varies with the atmospheric pressure
Nematic microscope.
Crystal  the most commonly used phase in liquid crystal
displays
MESAMORPHIC STATE
Cholesteric  forms a helical structure
 State of matter in which the degree of molecular order is
crystal  EX: cholesterol acetate
intermediate between the perfect three dimensional, long-range
Smectic  Parallel shape
positional and orientational order found in solid crystals and the
absence of long-range order found in isotropic liquids, gases, and
amorphous solids.
 does not meet the necessary requirements of any The three distinct
states of matter as solid, liquid, and gas
 also called as meso intermediate

LIQUID CRYSTALS
 Physically, they are observed to flow like liquids showing some
properties of crystalline solids. SOLID
 also known as mesophase and can be defined as the condensed  The state, in which a substance has no tendency to flow under stress,
matter that exhibit intermediate thermodynamic phase between the resists forces that tend to deform it, and remain in definite size and
crystalline solid and simple liquid state shape.
 They are free to move, but like to line up in about the same direction.  In solid state the molecules are closely bound to one another.
 The degree of mobility of the molecules in the LC's is less than that of  solid hold its shape.
a liquid  The volume of solid is fixed by the shape of solid.
 LC state is widespread in nature such as lipoidal forms found in  Solids can be divided into two categories
nerves, brain tissue and blood vessels  Crystalline
 DNA, lipids of cellular membranes and proteins are some examples  Amorphous
of well known liquid crystals

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Physical Pharmacy
STATES OF MATTER

CRYSTALLINE SOLID
 possesses rigid and long-range order
 its atoms, molecules, or ions occupy specific positions
 Ex: Ice, menthol or sodium chloride
 The basic repeating structural unit of a crystalline solid is a unit cell
 Arranged in a fixed geometric pattern or lattices.
 have definite shape and its units have an orderly arrangement as
well as they are practically in compressible
 Have definite melting points and so they pass sharply from solid to
liquid state Crystal Example
Units
 The forces responsible for the stabilit of any crystal can be ionic
Sodium chloride, calcium oxide, cesium chloride, potassium chloride,
forces, covalent bonds, van der Waals forces, hydrogen bonds, or a Cubic
zinc sulphide, diamond etc.
combination of these forces Tetragonal Titanium oxide, Urea, Tin etc
Potassium sulfate, potassium nitrate, barium sulfate, calcium
Othorhombic
Atoms or group of atoms forming a building block of the carbonate, Iodine (I2) etc.
Unit Cell Trigonal Quartz, Sodium nitrate, Calcite, Calamine etc.
smallest acceptable size of the whole volume of a crystal Hexagonal Silver iodide, Ice, Graphite, Iodoform (I) etc.
Lattice Located at the corner of the unit cell and in some cases, at Calcium sulfate dehydrate, potassium chlorate, potassium ferric
Monoclinic
Points either faces or the centre of the unit cell. cyanide, sucrose etc.
 Every crystalline solid can be described in terms of one of the seven Triclinic Copper sulfate pentahydide, Potassium dichromate, boric acid etc.
types of unit cells:
 Cubic (NaCl), tetragonal (urea), orthorhombic (iodoform), TYPES OF SOLID CRYSTALS
monoclinic (sucrose) and triclinic (Boric acid)  Consists of specific molecules, which do not carry
charge
 Dipole-dipole and Van Der Waal’s forces hold the
Molecular molecules
Crystal  Has less binding energy
 Bound by weak forces and therefore, generally have
low melting and boiling points and are volatile in
nature
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Physical Pharmacy
STATES OF MATTER

 soft and easily compressible  They dissolve in all polar solvents

 Most molecular crystals melt below 200C.  consist of ions held together by ionic bonds
 Solid sulfur dioxide (SO2)  CsCI, ZnS, and CaF2, CuCl, BeS, CdS, and HgS
 Consists of atoms joined together by covalent bonds
 diamond, graphite, silicone and most organic crystals Types of Crystal Force(s) holding the General Properties Examples
units together
Covalent  lodine is also a covalent crystal because it has 10
Ionic Electrostatic Hard, brittle, high NaCl, LiF, MgO,
Crystal times higher lattice energy attraction melting point, poor CaCO3
 sometimes called covalent network crystals conductor of heat
and electricity
 two allotropes of carbon: diamond and graphite
Molecular Dispersion forces Soft, low melting Ar, CO2, I2, H20,
 consist of positively charged ion in the field of free Dipole-dipole forces, point, poor C12H22O11 (sucrose)
flowing electrons. Hydrogen bonds conductor of heat
and electricity
 The force of attraction between metallic crystals is
Covalent Covalent bond Hard, high melting C (diamond), SiO2
very strong and therefore they are compact and solid point, poor (quartz)
in nature conductor of heat
 good conductors of heat and electricity, hard and and electricity
Metallic Metallic Bond Soft to hard, low to All metallic elements
Metallic tough, malleable and ductile high melting point, for example”
Crystals  exhibit luster when freshly cut, have high melting and good conductor of Na, Mg, Fe, Cu
boiling points with exception of alkali metals, possess heat and electricity
elasticity and have high tensile strength.
 held together by metallic bonds, electrostatic AMORPHOUS SOLIDS
interactions between cations and delocalized  lack a well defined arrangement and long-range molecular order.
electrons  state of substance that consists of disordered arrangement of
 Copper, gold, aluminum, and iron molecules or that do not posses distinguishable crystal lattice
 consists of positive and negative ions  do not have characteristic melting points but they soften over wide
 They have high heats of vaporization, low vapour temperature range, generally, lower than melting point of crystalline
Iodine pressure, high melting and boiling points and are forms of same compounds.
Crystals hard and brittle.  Glass & Plastic
 They are insulators in solid state and good conductors
of electricity when dissolved in water

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Physical Pharmacy
STATES OF MATTER
 In pharmaceutical viewpoint, the beauty of amorphous forms is that
they have a higher dissolution rates and solubilities than the
crystalline forms.
 The examples of amorphous drugs are accupril/accuretic used to
treat high blood pressure and intraconazole used as an acne
medication
CRYSTALLINE SOLIDS
Crystalline solids are arranged in neat and orderly
fashion as fixed 3D crystal lattice or geometric
patterns. Examples are ice, methanol, penicillin G
and sodium chloride.
Practically incompressible.
Crystalline solids show definite melting point so
they pass sharply from solid to liquid state
Higher energy is required for molecule to escape
from a crystal form
take less time to remove solvent through the space
between crystals
Handling quality of crystalline materials is poor
Shows poor aqueous solubility because more
energy required by orderly arranged molecules for
dissolution
In crystalline solids melting happens
When crystalline solid is heated at a constant rate,
the temperature increases at a constant rate
They show poor absorption and low bioavailability
These solids are stable than amorphous solids
AMORPHOUS SOLIDS
Amorphous solids are just strewn in any old fashion
with random unoriented molecules. Examples are
glass, plastic, penicillin G, and novobiocin.
Practically compressible
Amorphous solids do not show definite melting
point so transition from solid to liquid takes place
at wide temperature range
Low energy is required for molecule to escape from
an amorphous form
Take comparatively more time to remove solvent
and is removed by diffusion
Handling quality of amorphous materials is better
Shows good aqueous solubility because minimal
energy required by randomly arranged molecules
for dissolution
In amorphous form glass transition happens
When crystalline solid is heated at a constant rate,
the temperature increases at different rates
They are rapidly absorbed and show higher
bioavailability
They are less stable than crystalline solids
SOLIDS
 Pharmaceutical solids rarely exist as 100% crystalline or 100%
amorphous forms..
 Polymorphism is the ability of a molecule to crystallize into more
than one different crystal structure.
 The term allotropy used for elements is synonymous to the
polymorphism
 Many substances due to differences in their intermolecular forces
exist in more than one crystalline or amorphous form (Polymorphs)
and substances are polymorphic. Called POLYMORPHIC
 polymorphs have same molecular composition but have different
crystalline forms
 Substance in two different forms is called dimorphic while in three
forms called trimorphic and so on
 Almost all long-chain organic compounds exhibit polymorphism
 Many drugs such as steroids (cortisone, testosterone, and
prednesolone), barbiturates and sulphonamides show property of
polymorphism.
 Sulphanilamide exist in four different a, ß, y and δ polymorphic
forms.
 Mebendazole has three polymorphic forms namely; Form A, B and C
 Other examples of drugs that show polymorphism are
oxytetracycline, mefenamic acid, phenyl butazone, terfenadine etc
TYPES OF POLYMORPHS
 When polymorphic change is not reversible
Monotropic  It occurs when one form is stable while other is
metastable
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Physical Pharmacy
STATES OF MATTER

 Metastable form may be converted to stable form
over the time
 The vapour pressure of both form are different
 Phosphorus - (Stable White and red
form)phosphorus
 If the change from one polymorph to another is
reversible
 At definite temperature one form is converted to
other form
Enantiotropic  Both forms have different vapour pressures
 For example rhombic a form of sulphur is converted
to other monoclinic ß form upon heating at 95.6 °C
and cooling at same temperature again it exist in its
original form and therefore they are enantiotropic.
IMPORTANCE OF POLYMORPHISM
 Polymorphism is pharmaceutically most important because different
polymorphs exhibit different physicochemical properties.
 It affects mechanical strength and other formulation aspects like
compressibility, flowability, hardness and binding strength etc.
 Unstable polymorphs are not suitable in design of dosage forms
because they get converted to stable polymorphs.
 Metastable polymorphs have higher energy level than the stable
form
 Metastable forms exhibit greater dissolution rates, better
bioavailability and superior therapeutic activity
 The particular polymorph formed by a drug depends on the
conditions of crystallisation; the solvent used, the rate of
crystallisation and the temperature
 Changes in polymorphic forms of vehicles such as theobroma oil,
used to make suppositories, could cause products with different and
unacceptable melting characteristics.
 Polymorphism is a phenomenon wherein one molecule several
different crystal phases can form, which can affect the
physicochemical properties of compounds such as melting point,
density, morphology, solubility and colour
 Drug polymorphism can have a significant effect therapeutic on
efficacy, especially when the dissolution rate is the stage for
determining the rate of absorption in the digestive tract
 The stability relationship between polymorphs and pharmaceutical
active ingredients (API) is an important step for the development of
drug formulations.
 This relationship makes it possible to identify polymorphic forms that
are suitable for normal conditions
 In drug development, a stable form of active pharmaceutical
ingredients (API) is always considered
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