STATES OF MATTER

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.

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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.

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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.