INTRODUCTION
Advanced Physical pharmacy is a required three credit-hour course offered to the MS
students of the Pharmaceutics & Industrial Pharmacy program. The course discusses
states of matter, ideal and real gases, enthalpy and thermochemistry, introduction to
thermodynamics, intermolecular forces in liquids and solids, chemical equilibria and
entropy, Gibbs free energy, kinetics, solution theory, diffusion and dissolution principles.
The application of these subject areas to the preparation of solid and liquid dosage forms,
aerosol and other rate-controlled and targeted drug delivery systems is discussed in
subsequent courses. The material presented in this chapter aims to help the students:
1. Learn about and distinguish between the different forms and the three different states
of matter.
2. Understand that conversion of a drug molecule into a different state is due to physical
changes that are intimately related to intermolecular forces. Physical changes are
reversible. Chemical changes are usually related to the spatial arrangement of atoms
within the molecule (interatomic or intramolecular forces) and they always result in the
creation of a new substance.
3. Develop critical thinking of how the physicochemical properties of a formulated drug
product can be affected by the “inert” excipients and how one can go about detecting the
drug in a particular dosage form.
4. Understand the interplay between molecular structure, physical properties and
pharmacological action of a drug.
STATES OF MATTER
Matter is the material of the universe and it can be defined as anything that has mass
and occupies space. Based on its composition and properties, matter can be classified as
mixtures, pure substances, pure compounds and elements.
A substance is a form of matter that has a constant composition. The physicochemical
properties of a substance are dependent on the way its atoms are organized. For example,
n-butane has exactly the same chemical formula as iso-butane, C4H10. Their physical
properties, e.g., boiling and melting point as shown in Table I, vapor pressure at a given
temperature, and their chemical properties, e.g., reactivity to a carbocation or a free
radical, differ due to a different organization of the same atoms in each molecule, that is,
they have different structural formulas (n-butane: CH3-CH2-CH2-CH3; iso-butane: CH3-
CH(CH3)-CH3.
Table I. Physical Constants for n-butane and isobutene*
n-butane isobutane
Boiling point 0 °C -12 °C
Melting point -138 °C -159 °C
Relative density at -20 °C 0.622 0.604
Nitrogen (gas), water (liquid), glucose (solid) are examples of three different
substances existing in different physical states under normal conditions (1 atmosphere, 22
°C). Ice water, liquid water and vapor water, are examples of a substance in the three
different states. Reversible changes of the physical states of a substance are physical
changes. Physical changes are due to reorganization of the molecules in a substance.
Contrary to that, chemical changes are due to the way the substance’s atoms are
organized. Chemical changes may be irreversible, fully or not fully reversible (the
majority of chemical reactions are reversible only to some extent) and they always result
in a change of a substance to a new one having different properties. An example of an
irreversible chemical change is decomposition of water causing the molecules to break
apart and form hydrogen and oxygen, two new substances. The esterification of salicylic
Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University
PH931 Instructor: M. Savva, Ph.D.
4
acid with malonic anhydride to form aspirin (Fig. 1) is a reversible chemical change. The
product to reactant’s ratio of a reversible chemical reaction under a given set of
conditions at equilibrium, is always the same and is expressed by the equilibrium
constant, K of the reaction.
OH
O
OH
+ O
O
O
OH
O
O
O CH3
Fig. 1. Synthesis of aspirin from salicylic acid and malonic anhydride.
A compound is a form of substance in which two or more atoms (elements) are
chemically linked. Molecular compounds can be broken down to pure elements only by
chemical means.
An element is a substance that cannot be further divided by chemical means. It is
defined by its atomic number. Elements have isotopes. For example, the radioactive 125I
that is frequently used in thyroid cancer treatment is an isotope of the stable 127I. All
isotopes have the same atomic number but they have a different mass number (different
number of neutrons). Pharmaceutical scientists frequently use radioisotopes as a means to
Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University
PH931 Instructor: M. Savva, Ph.D.
5
follow the in vivo fate of (tagged) biologically active macromolecules and
synthetic drug
compounds.
A mixture is a combination of two or more substances in which the substances may or
may not retain their physicochemical properties intact. Mixtures are classified as
homogeneous and heterogeneous mixtures.
In homogenous mixtures of solids and liquids, the chemical and physical properties of
the individual substances cannot be detected (intact) by any method of instrumental
analysis. Fig. 2 shows the melting point of solid crystalline aspirin centered around 135
°C.
Melting-point curve of aspirin
0
20
40
60
80
100
120
40
80
120
134
134.2
134.6
135
150
170
200
Temperature
% of crystals remaining
aspirin, crystals
aspirin, solution
Fig. 2. Melting of aspirin crystals as determined by a scanning calorimeter that measures
the heat of fusion. No melting of aspirin can be detected in the aspirin solution since
the forces that hold the aspirin crystal have been destroyed by the solvent, during a
process called dissolution. Notice that the temperature scale is not linear.
Naturally in the aspirin solution the aspirin crystal is dissolved in water. The solvent
has destroyed the intermolecular forces that hold the aspirin molecules in a crystalline
arrangement, during the process of dissolution. Formation of a molecular dispersion
requires mutual interaction between solute and solvent. As a result, the properties of the
individual components of the mixture are altered. We are rather dealing with the unique
properties of homogenous mixtures that have resulted from the (spontaneous) mixing of
the individual substances. All the physical properties of aspirin are altered because of
interaction with the aqueous solvent. Similarly the properties of water are affected by the
presence of the solute. Absorption of electromagnetic radiation is another physical
property that is altered as a result of homogeneous mixing. Consider for example the
inhalation anesthetic halothane. The absorption of light in the visible and ultraviolet
region of halothane as pure liquid and as a solution in organic solvents is not the same.
It is important to note that contrary to the homogeneous mixtures of liquids and
solids, mixtures of gases are always homogeneous. The composition of a homogeneous
mixture is always the same throughout. Examples of gas, liquid and solid pharmaceutical
homogeneous mixtures, respectively, are: 1) nitrous oxide gas with oxygen at a ratio
80:20 by volume used for general anesthesia. 2) medicated simple syrup (85 % w/w), in
which sucrose is dissolved in water forming a molecular dispersion. 3) suppositories
composed of a mixture of PEG (polyethylene glycol) 8000 (40 %) and PEG 400 (60 %)
prepared by the melting method and allowed to congeal to the solid state at room
temperature.
Contrary to the above, a heterogeneous mixture is one in which the individual
components that make up the mixture retain their physicochemical properties intact. The
composition of a heterogeneous mixture may or may not be (statistically) uniform
throughout. The components of homogeneous and heterogeneous mixtures can be
separated and recovered as pure substances by means of physical methods. However, in
the case of homogenous mixtures one has to be very careful with the recovery of pure
solid substances. Consider for example the case of a simple syrup. Water can be removed
by boiling the solution and condensing the vapor to pure water with the aid of a
distillation apparatus, leaving behind the pure dry sugar powder. The compound is
successfully recovered in a pure, but not necessarily in the original, crystalline state.
Different crystalline states of a drug, called polymorphs, may present distinctly different
solubility, dissolution, bioavailability and pharmacological profiles.
A tablet prepared by direct compression of a drug, lactose, Actisol® and magnesium
stearate is an example of a heterogeneous solid mixture. Lactose grains remain separate
from the magnesium stearate and the drug grains. In order for the excipients to play their
role in the tablet, they have to retain their distinct identity along with their
physicochemical properties within the powder mixture. Actisol® is the disintegrant. Its
swelling properties facilitate tablet disintegration in aqueous media, a process that greatly
accelerates drug dissolution and absorption. Interaction of Actisol® with the drug or with
any of the other excipients would change or even neutralize the disintegration properties
of the excipient. Similarly, interaction of magnesium stearate (lubricant) with the other
excipients, could eliminate its lubricant properties. The tablet would stick to the punches
during compression resulting in a damaged or complete removal of the tablet surface; a
phenomenon known as “capping”. More importantly, active drug-excipient interaction
not previously anticipated by the pharmaceutical scientist could result in product
instability, inefficient therapy or toxicity. The presence of a basic excipient, like
carbonate salts commonly used in effervescent tablets, may cause hydrolysis of an ester
drug in the presence of moisture. Reduction of the quantity of the active drug in the
dosage form would result in lower blood concentration of the drug and inefficient
therapy. Similarly, interaction of the drug with excipients may result in a complex of
reduced solubility, thus, reduced absorption and inefficient therapy, again. A completely
different scenario arises when the crystalline state of a drug changes to less stable (higher
energy) crystalline state or to the least stable amorphous state, due to drug-excipient
interactions. The solubility of an amorphous solid is always higher that that of the
crystalline solid. Faster or increased solubility of the drug may result in increased levels
of drug in the blood, which in turn can cause toxicity.
Pharmaceutical suspensions are examples of heterogeneous liquid mixtures. They are
liquids in which the insoluble drug, present as fine particles, is somewhat uniformly
dispersed in aqueous media. Brownian motion due to the forces exerted by the water
molecules on the suspended drug molecules is primarily responsible for the suspension of
the particles. The larger the particles are, the more difficult it is to keep them uniformly
suspended in the water. Because the drug solubility is so small, the physicochemical
properties of drug and water in pharmaceutical suspensions remain practically intact.
Since drug and dispersion medium exist as two discrete phases, one cannot talk about
colligative properties of pharmaceutical suspensions.
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As previously discussed, matter exists in three distinct physical states: solid, liquid
and gas.
Molecules in a solid are held close together in an orderly fashion with very little
freedom of motion. Solids are characterized by: 1) shape 2) strong interatomic or
intermolecular interactions; high density 3) very little or no compressibility.
On the other hand, in a gas the component molecules are far apart. They are in
random rapid motion and they exert very small forces on each other. They are therefore
characterized, by: 1) no shape 2) weak or no intermolecular forces; low density 3) high
compressibility.
Liquids also do not have a shape. Their properties lie somewhere between those of
solids and gases. Intermolecular attractive forces in liquids are closer to those in solids
although they are significantly weaker. The molecules are close together but not as
rigidly as in solids and they can move past each other. Liquids are in general not
compressible.
Lastly, the physicochemical properties of matter are further classified into extensive
and intensive properties.
Gas Liquid Solid
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Extensive properties are additive; i.e. the value of an extensive property is
proportional to the quantity of the substance in the system. Mass and volume are
extensive properties. For example, mixing 25 grams Petrolatum Alba with 5 grams of 1
% hydrocortisone ointment will yield a total mass of 30 grams of hydrocortisone
hydrophilic ointment.
In contrast, the value of an intensive property such as temperature and density is not
dependent to the amount of a substance. For example, mixing 1 L of water 22 ºC with 1 L
of water 30 ºC will make a 2 L water of temperature somewhere in between 22 ºC and 30
ºC, but definitely not 52 ºC.
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