Introduction:

With the application of phase rule it is possible to predict qualitatively by means of a diagram the
effect of changing pressure, temperature and concentration on a heterogeneous system in
equilibrium. This relationship governing all heterogeneous equilibria was first discovered as
early as 1874 by an American physicist Willard Gibbs. Gibb’s Phase Rule is may be stated
mathematically as follows:

F=C–P+2
Where F is the number of degree of freedom, C is the number of components and P is the number
of phases of the system.

Definition of Terms:

Phase (P): The homogeneous part of a heterogeneous system which is physically and chemically
different from other parts of the same system and bounded by surfaces of separation and
mechanically separable.

A system can consist of one or more phases. Some examples are given below:

One phase system:

(a) A pure substance in one physical state.

(b) A mixture of liquids which are completely miscible with each other in all proportions is
one phase liquid state, e.g. H2O/Alcohol etc.
(c) A pure gas or mixture of gases which do not react with each other.
(d) A solution of a solid in a liquid, NaCl/H2O, Sugar/H2O etc.
(e) A mixture of solids in the molten state.

Two phase systems:

(a) A pair of immiscible liquids, e.g. CCl4/H2O, C2H2Cl2/H2O etc.

(b) A liquid and its vapor.
(c) A solid substance and its liquid phase or vapor phase.
(d) A mixture of solids in the liquid (molten) phase and one of the solids in the solid state.
(e) A mixture of two solids which do not react each other.

Three phase systems:

(a) A pure substance existing in three phases together, e.g. ice, water and water vapor.
(b) A solid in two allotropic forms and the liquid mixture or in vapor phase.
(c) A mixture of two solids in the molten form and the two solids.
Component (C):

The number of component is defined as the minimum number of independently variable

chemical entities required to describe all parts of a system.

One component systems:

(a) Water: Water may exist in three different phases, solid, liquid and vapor. In each case the
chemical entity is H2O.
(b) Sulfur: Sulfur can exist in four phases- two allotropes (i) monoclinic (s) and (ii) rhombic
(s), as a liquid and as vapor. Again in all these phases the chemical constituent is the
same.

Two component systems:

(a) It CaCO3 is heated in a closed container it undergoes dissociation forming CaO and CO2.
When the system attains equilibrium all three chemical substances are present. These
three chemical entities are related by the equation—
CaCO3(s)  CaO (s) + CO2 (g)
There will be three phases, each of the chemical entities representing a phase as they are
bounded by a separate boundary, but the number of components will be two because all
the three phases can be described by mentioning any two of them as they are related by
the above equation.
(b) A solution of NaCl is a one phase system. The number of components in the system is,
however, two as the concentration can vary and the composition of the system cannot be
described by mentioning any one of them. Similarly the number of components in a
saturated solution of the salt is also two for the same reason.
(c) Systems in which salts form one or more hydrates are two component systems as the
composition of all phases (hydrates) and water can be described by the constituents, e.g.
the salt and water system.
(d) Pairs of partly miscible or immiscible liquids.
(e) Pairs of metals which are miscible in the liquid phase but form separate pure solid metal
phases.

Degrees of Freedom (F):

The degree of freedom is defined as the least number of variable factors (concentration, pressure
and temperature) which must be specified so that the remaining variables are fixed automatically
and the system is completely defined.

A system with F=0 is known as nonvariant or having no degree of freedom.

A system with F=1 is known as univariant or having one degree of freedom.
A system with F=2 is known as bivariant or having two degree of freedom.
Explanation of the term Degree of Freedom:
A system is defined completely when it retains the same state of equilibrium (or can be
reproduced exactly) with the specified variables. For examples-
(a) For a pure gas, F=2. For a given sample of any pure gas PV=RT. If the values of pressure
(P) and temperature (T) be specified, volume (V) can have only one definite value, or that
the volume (the third variable) is fixed automatically. Any other sample of the gas under
the same pressure and temperature as specified above will be identical with the first one.
Hence a system containing a pure gas has two degrees of freedom (F=2).
(b) For a mixture of gases, F=3. A system containing a mixture of two or more gases is
completely defined when its composition, temperature and pressure are specified. If
pressure and temperature only are specified, the third variable i.e., composition could be
varied. Since it is necessary to specify three variables to define the system completely, a
mixture of gases has three degree of freedom (F=3).
(c) For water ↔ water vapor, F=1. The system water in equilibrium with water vapor, has
two variables temperature and pressure. At a definite temperature the vapor pressure of
water can have only one fixed value. Thus if one variable (temperature or pressure) is
specified, the other is fixed automatically. Hence the system water has one degree of
freedom (F=1).
(d) For saturated NaCl solution, F=1. The saturated solution of sodium chloride in
equilibrium with solid sodium chloride and water vapor.
NaCl (solid) ↔ NaCl (solution) ↔ Water vapor
Thus system is completely defined if we specify temperature only. The other two
variables i.e., the composition of NaCl-solution (solubility) and vapor pressure have a
definite value at a fixed temperature. Hence the system has one degree of freedom.
(e) For ice-water-vapor system, F=0. In the system ice↔water↔vapor, the three phases
coexist at the freezing point of water. Since the freezing temperature of water has a fixed
value, the vapor pressure of water has also a definite value. The system has two variables
(temperature and pressure) and both these are already fixed. Thus the system is
completely defined automatically, there being no need to specify any variable. Hence it
has no degree of freedom (F=0).
Find the degree of freedom for the all systems in the following paragraph
One component water system:

Explanation of the Curve:

 The curve OA in the P-T (Pressure-Temperature) diagram in Figure 2-22 is known as the
vapor pressure curve. Its upper limit is at the critical temperature, 374°C for water, and its
lower end terminates at 0.0098°C, called the triple point. Along the vapor pressure curve,
vapor and liquid coexist in equilibrium.
 Curve OC is the sublimation curve, and here vapor and solid exist together in
equilibrium.
 Curve OB is the melting point curve, at which liquid and solid are in equilibrium. The
negative slope of OB shows that the freezing point of water decreases with increasing
external pressure.
 The result of changes in pressure (at fixed temperature) or changes in temperature (at
fixed pressure) becomes evident by referring to the phase diagram.
 If the temperature is held constant at t1, where water is in the gaseous state above the
critical temperature, no matter how much the pressure is raised (vertically along the
dashed line), the system remains as a gas.
 At a temperature t2 below the critical temperature, water vapor is converted into liquid
water by an increase of pressure because the compression brings the molecules within the
range of the attractive intermolecular forces.
 It is interesting to observe that at a temperature below the triple point, say t3, an increase
of pressure on water in the vapor state converts the vapor first to ice and then at higher
pressure into liquid water. This sequence, vapor → ice → liquid, is due to the fact that
ice occupies a larger volume than liquid water below the triple point.
 At the triple point, all three phases are in equilibrium, that is, the only equilibrium is at
this pressure at this temperature of 0.0098°C (or with respect to the phase rule, F = 0).
Summary of phase rule for one component water system
One component sulfur system:
Condensed Systems:
Systems in which the vapor phase is ignored and only solid and/or liquid phases are
considered are termed condensed systems.

In a single-component system the maximum number of degrees of freedom is two. This

situation arises when only one phase is present, that is, F = 1 - 1 + 2 = 2. But, a maximum
of three degrees of freedom is possible in a two-component system, for example,
temperature, pressure, and concentration.

To represent the effect of all these variables upon the phase equilibria of such a system, it
would be necessary to use a three-dimensional model rather than the planar figure used in
the case of water.

Because in practice we are primarily concerned with liquid and/or solid phases in the
particular system under examination, we frequently choose to disregard the vapor phase
and work under normal conditions of 1 atm pressure.

In this manner, we reduce the number of degrees of freedom by one. In a two-component

system, therefore, only two variables (temperature and concentration) remain, and we are
able to portray the interaction of these variables by the use of planar figures on
rectangular-coordinate graph paper.
Two-components Phenol-Water System:

A condensed Phase Diagram of Phenol-Water System

Explanation:

o The curve gbhci shows the limits of temperature and concentration within which two
liquid phases exist in equilibrium. The region outside this curve contains systems having
but one liquid phase.
o Starting at the point a, equivalent to a system containing 100% water (i.e., pure water) at
50°C, adding known increments of phenol to a fixed weight of water, the whole being
maintained at 50°C, will result in the formation of a single liquid phase until the point b
is reached, at which point a minute amount of a second phase appears.
o The concentration of phenol and water at which this occurs is 11% by weight of phenol in
water. Analysis of the second phase, which separates out on the bottom, shows it to
contain 63% by weight of phenol in water. This phenol-rich phase is denoted by the point
c on the phase diagram.
o As we prepare mixtures containing increasing quantities of phenol, that is, as we proceed
across the diagram from point b to point c, we form systems in which the amount of the
phenol-rich phase (B) continually increases, as denoted by the test tubes drawn in Figure
2-23. At the same time, the amount of the water-rich phase (A) decreases. Once the total
concentration of phenol exceeds 63% at 50°C, a single phenol-rich liquid phase is
formed.
 o The maximum temperature at which the two-phase region exists is termed the critical
solution, or upper consolute, temperature. In the case of the phenol-water system, this
66.8oC (point h is fig.2-23). All combinations of phenol and water above this temperature
are completely miscible and yield one-phase liquid systems.
o The line bc drawn across the region containing two phases is termed a tie line; it is
always parallel to the base line in two-component systems.
o An important feature of phase diagrams is that all systems prepared on a tie line, at
equilibrium, will separate into phases of constant composition. These phases are termed
conjugate phases.
o For example, any system represented by a point on the line bc at 50°C separates to give a
pair of conjugate phases whose compositions are b and c. The relative amounts of the two
layers or phases vary, however, as seen in Figure 2-23.
o Thus, if we prepare a system containing 24% by weight of phenol and 76% by weight of
water (point d), at equilibrium we have two liquid phases present in the tube. The upper
one, A, has a composition of 11% phenol in water (point b on the diagram), whereas the
lower layer, B, contains 63% phenol (point c on the diagram).
o Phase B will lie below phase A because it is rich in phenol, and phenol has a higher
density and water.

Activity: Find the degree of freedom at different points of Phenol-Water system.

Nicotine-Water System:

The phase diagram of nicotine-water system has both an upper and a lower consolute
temperature. Lower consolute temperatures arise presumably because of an interaction between
the components that brings about complete miscibility only at lower temperature.
Two component systems containing solid liquid phases: Eutectic mixtures

Thymol-Salol System:

Explanation:

 There are four regions: (i) a single liquid phase, (ii) a region containing solid salol and a
conjugate liquid phase, (iii) a region in which solid thymol is in equilibrium with a
conjugate liquid phase, and (iv) a region in which both components are present as pure
solid phases.

 Those regions containing two phases (ii, iii, and iv) are comparable to the two-phase
region of the phenol-water system shown in Figure 2-23. Thus, it is possible to explain
and calculate both the composition and relative amount of each phase from knowledge of
the tie lines and the phase boundaries.
 Suppose we prepare a system containing 60% by weight of thymol in salol and raise the
temperature of the mixture to 50°C. Such a system is represented by point x in Figure 2-
26. On cooling the system, we observe the following sequence of phase changes.
 The system remains as a single liquid until the temperature falls to 29°C, at which point a
minute amount of solid thymol separates out to form a two-phase solid-liquid system. At
25°C (room temperature), system x (denoted in Fig. 2-26 as x1) is composed of a liquid
phase, a1 (composition 53% thymol in salol), and pure solid thymol, b1. The weight ratio
of a1 to b1 is (100 - 60)/(60 - 53) = 40/7, that is, a1:b1 = 5.71:1.
 When the temperature is reduced to 20°C (point x2), the composition of the liquid phase
is a2 (45% by weight of thymol in salol), whereas the solid phase is still pure thymol, b2.
The phase ratio is a2:b2 = (100 - 60)/(60 - 45) = 40/15 = 2.67:1.
 At 15°C (point x3), the composition of the liquid phase is now 37% thymol in salol (a3)
and the weight ratio of liquid phase to pure solid thymol (a3:b3) is (100 - 60)/(60 - 37) -
40/23 = 1.74:1.
 Below 13°C, the liquid phase disappears altogether and the system contains two solid
phases of pure salol and pure thymol. Thus, at 10°C (point x4), the system contains an
equilibrium mixture of pure solid salol (a4) and pure solid thymol (b4) in a weight ratio of
(100 - 60)/(60 - 0) = 40/60 = 0.67:1.
 As system x is progressively cooled, the results indicate that more and more of the
thymol separates as solid. A similar sequence of phase changes is observed if system y is
cooled in a like manner. In this case, however, the solid phase that separates at 22oC is
pure salol.
 The lowest temperature at which a liquid phase can exist in the salol-thymol system is
13oC and this occurs in a mixture containing 34% thymol in salol. This point on the phase
diagram is known as the eutectic point. At the eutectic point, three phases (liquid, solid
salol, and solid thymol) coexist. The eutectic point therefore denotes an invariant system
because, in a condensed system, F = 2 - 3 + 1 = 0.
 The eutectic point is the point at which the liquid and solid phases have the same
composition (the eutectic composition). The solid phase is an intimate mixture of fine
crystals of the two compounds. The intimacy of the mixture gives rise to the phenomenon
of “contact melting,” which results in the lowest melting temperature over a composition
range.
 Alternately explained, a eutectic composition is the composition of two or more
compounds that exhibits a melting temperature lower than that of any other mixture of
the compounds. Mixtures of salol and camphor show similar behavior. In this
combination, the eutectic point occurs in a system containing 56% by weight of salol in
camphor at a temperature of 6°C.
Fundamentals of Pharmaceutical Freeze Drying
Definition:

Freeze drying pharmaceuticals uses a process called lyophilization to lower the temperature of
the product to below freezing, and then a high-pressure vacuum is applied to extract the water in
the form of vapor. The vapor collects on a condenser, turns back to ice and is removed. Finally, a
gradual temperature rise extracts all remaining 'bound' moisture from the product. This process
retains the physical structure and preserves the material for storage or transport.

Freeze drying is mainly used to remove the water from sensitive — mostly biological —
products without damaging them. As such, they can be preserved in a permanently storable state
and be subsequently reconstituted by replacing the water.

Process Principles

Examples of freeze-dried products are antibiotics, bacteria, sera, vaccines, diagnostic

medications, protein-containing and biotechnological products, cells and tissues, and chemicals.

The product to be dried is frozen under atmospheric pressure. Then, in an initial drying phase —
defined as primary drying — the water (as ice) is removed by sublimation; in the second phase —
secondary drying — it is removed by desorption. Freeze drying is done under vacuum. The
conditions under which the process takes place will determine the quality of the freeze-dried
product.

Some important aspects to be considered during the freeze-drying process are as follows:

Freezing: It is the step of transforming the basic product by abstracting heat to create a state that
is suitable for sublimation drying. When an aqueous product is cooled, crystal nuclei are formed.
The surrounding water is taken up around the nucleation sites, resulting in crystals of different
sizes and shapes. Freezing speed, composition of the basic product, water content, viscosity of
the liquid and the presence of non-crystallizing substance are all decisive factors in determining
the crystal shape and size, and in influencing the following sublimation process.
Primary Drying

At the beginning of the primary drying phase, ice sublimation takes place at the product surface.
As the process continues, the subliming surface withdraws into the product and the resulting
vapor must be conducted through the previously dried outer layers. This means that the drying
process depends on the speed of vapor transfer and removal, as well as the necessary heat of
sublimation. The heat required for sublimation is supplied by convection and thermal conduction
and, to a lesser degree, by thermal radiation.

Secondary Drying

In the secondary or final drying phase, the residual moisture content is reduced as much as
possible to ensure that the product is in a permanently storable state. The water bound by
adsorption at the internal surface of the product has to be removed. To achieve this, it is often
necessary to overcome water’s capillary forces. The freeze-drying plant must therefore be
designed to produce a high-pressure gradient during the secondary drying phase (in most cases, it
is not possible to raise the temperature without damaging the product). The secondary drying
process must be precisely controlled to prevent over-drying the product.

Advantages of Freeze-Drying Pharmaceuticals

The freeze-drying process has important applications in the pharmaceutical and biotechnology
industries, and pharmaceutical freeze drying is now a standard process used to stabilize, store or
increase the shelf life of drug products and other biologicals.

With freeze drying, delicate, unstable or heat-sensitive drugs and biologicals can be dried at low
temperatures without damaging their physical structure. Freeze-dried products can be
reconstituted quickly and easily, which is particularly valuable in the case of emergency vaccines
and antibodies, which need to be administered as quickly as possible.

Freezing alone has some major disadvantages:

 Maintaining frozen storage is costly and takes up a lot of space

 Transportation of frozen materials can be difficult and expensive

 Failure of freezing equipment would risk the total loss of the product

Conventional drying methods also have a major disadvantage as the high temperatures used can
cause chemical or physical changes to the product. For pharmaceuticals and bio-products, this
would cause a reduction in biological activity, which could render them ineffective.
Pharmaceuticals and Biologicals Suitable for Freeze Drying

 Vaccines and antibodies

 Penicillin

 Blood plasma

 Proteins

 Enzymes

 Hormones

 Viruses and bacteria