PHARMACUTICS 111
Presented by
AYEBARE JACOB
BALIMWIJUKA MARVIN
BBOSA TOM
CHEPTOEK ALBERT TOM
EMULU ENOS CHARLES
GWEBAYANGA COLLINE
BPHARM 3.2
VICTORIA UNIVERSITY
CRYSTALLIZATION
QUESTION
Fundamental Principles & Mechanisms:
I. Define pharmaceutical crystallization and explain its importance in drug development and
II. manufacturing (e.g., polymorphism, solubility, bioavailability, purification).
III. Describe the two main steps involved in crystallization: nucleation (primary and secondary)
IV. and crystal growth. Discuss the factors influencing each step.
V. Explain the concepts of supersaturation and solubility curves, and their relevance to controlling
VI. the crystallization process.
Equipment & Operational Aspects:
VII. Discuss different types of crystallizers used in the pharmaceutical industry (e.g., agitated tanks,
VIII. cooling crystallizers, evaporative crystallizers).
IX. Outline the critical process parameters (CPPs) that need to be controlled during crystallization
and how they impact the final product quality
Explain the role of seeding in crystallization and the considerations for seed crystal selection.
CONT
Applications in Pharmaceutical Manufacturing:
I. o Provide examples of drug substances where crystallization is a critical step in their
production.
II. o Discuss how crystallization can be used to obtain specific polymorphs or improve the purity of
active pharmaceutical ingredient (API).
Challenges, Innovations & Emerging Trends:
III. What are the challenges in achieving consistent crystal quality and controlling polymorphism
IV. during large-scale crystallization?
V. Discuss innovative crystallization techniques, such as Sono crystallization or reaction
crystallization, and their potential benefits.
Visual Aid Recommendations:
Suggest visual aids such as phase diagrams, illustrations of nucleation and crystal growth,
images of different crystal habits, and flowcharts of various crystallization processes.
Fundamental Principles &
Mechanisms
Definition
crystallization is a separation and purification process through which solid
particles are formed with a specific internal molecular arrangement,
typically from a solution, melt, or vapor.
It is pivotal in defining the physical and chemical properties of a drug
substance.
Pharmaceutical crystallization is the process by which a solid crystalline
form of a drug substance (active pharmaceutical ingredient) is generated
from a solution, melt, or vapor phase. During crystallization, molecules
arrange themselves into a highly ordered, repeating lattice structure.
This process is fundamental in drug development and manufacturing
because it allows purification of the API and control over its physical and
chemical properties such as crystal form, size, morphology and purity.
Cont
A crystal is defined as a solid particle, which is formed by the
solidification process in which structural units are arranged by a fixed
geometric pattern or lattice.
➤ Crystals are commonly obtained from liquid state. Example salt from
brine solution.
➤ Crystallization differ from precipitation in that product is deposited
from a supersaturated solution.
➤ Precipitation occurs when solutions of materials react chemically to
form a product which is sparingly soluble in the liquid and therefore
deposits outs.
Importance in drug development and
manufacturing
Purification:
Crystallization is a key technique for purifying APIs by separating the desired solid
crystalline phase from impurities dissolved in the solution. This improves the quality and
safety of the drug substance.
. Control of Polymorphism:
Polymorphism is the ability of a compound to crystallize into more than one distinct crystal
structure, each with different physical and chemical properties such as melting point,
solubility, stability, and mechanical behavior. Different polymorphs can significantly affect
a drug’s performance. For example, a more stable polymorph might have lower solubility,
reducing bioavailability, while a less stable form might dissolve faster but degrade more
easily. Identifying and controlling polymorphs during crystallization ensures consistent drug
efficacy, stability, and manufacturability
.
Continued
Solubility and Bioavailability:
The crystalline form influences the drug’s solubility-the ability of the
drug to dissolve in bodily fluids-and thus its bioavailability, which is
the extent and rate at which the drug reaches systemic circulation.
Optimizing crystallization conditions to produce a polymorph with
suitable solubility enhances therapeutic effectiveness
Stability:
Crystallization helps produce stable solid forms that resist
degradation during storage and handling, extending shelf life and
maintaining drug safety and efficacy
Theories or mechanism of
crystallization
The formation of crystal from solution involves three steps
• Supersaturation
• Nucleus formation
• Crystal Growth
Nucleation
Nucleation refers to the birth of very small bodies of molecules from which the
crystal forms.
• In solution, solute molecules, ions or atoms remain in constant random motion. This
is due thermodynamic energy of the solution system.
• When the solute particles (molecules, atoms or ions) moves and collide over each
other they may form aggregates.
• This aggregates are called clusters. These are loose aggregates, which usually
disappear quickly.
• Some clusters may become so big that they may arrange themselves in lattice
arrangement. These bodies of aggregates are called embryo.
• However, embryos are unstable and they may break into clusters again.
• Some embryo may grow to such a size that it remains in thermodynamic
equilibrium with the solution. They do not revert back to clusters. These bodies are
called nucleus (plural is nuclei).
Steps: Nucleation and Crystal
Growth
Nucleation: has two types ;
Primary Nucleation Which consist of Homogeneous and
heterogeneous Nuclation . Homogeneous nucleation occurs
spontaneously and uniformly throughout the solution at high level of
super saturation while heterogeneous nucleation occurs Due to
present of foreign particles eg dust
Secondary Nucleation: Initiated by the presence of existing crystals
(seeding). due to
mechanical agitation of collision in small crystals,
Super saturation and and solution flow around the crystals
Framentation of crystals
Crystal growth
This process can not happen unless the solution is supersaturated
It involves diffusion process and surface phenomenon
The solute molecules or ions reach the surface of the Crystal by diffusion
The surface of the molecules or ions are accepted by the crystals and
organized with the spaces
Nucleation vs. Crystal Growth process
(molecular clustering to structured lattice).
Supersaturation
• When the concentration of a compound in its solution is greater than
the saturation solubility of that compound in that solvent the condition is
known as supersaturation.
• This is an unstable state. From this supersaturates solution the excess
compound may be precipitated out or crystallize.
Supersaturation can be achieved by the following methods:
1. Evaporation of solvent from the solution.
2. Cooling of the solution.
3. Formation of new solute molecule as a result of chemical reaction•
4. Addition of a substance, which is more soluble in solvent than the
solid to be crystallized.
Supersaturation and Solubility
Curves
Supersaturation is the driving force of crystallization. It is the state where
solute concentration exceeds equilibrium solubility
It's represented by Mier's super saturation theory Shows relationship
between concentration and temperature at which crystals Will
spontaneously form in initially unseeded solution
Here, the supper solubility curve represents the limit at which necleus
formation begins spontaneously And the point at which Crystallisation
starts without any solid particle present
Solubility Curve plots solubility vs. temperature and divides zones into:
Stable Zone: No crystallization.
Metastable Zone: Crystallization needs seeding.
Labile Zone: Spontaneous nucleation
Solubility Curve showing
metastable and labile zones.
CONT
CONT
AB represent normal solubility
FG represents super solubility
Area between AB and FG is meta stable state
Solution at point C is expected to crystallize at P though it
doesn't. I however crystallize at point D since the theory states
that crystallization Nucleus formation occurs at FG And crystal
growth starts And there the concentration toughly follows DE
Conditions
The solute and solvent must be pure
The solution must be free from solid solute particles
The solution must be free from foreign particles
No temperature fluctuations
Equipment & Operational Aspects
Types of Crystallizers
1.Batch crystallizers
A. Agitated batch crystallizer
B. Wulf bock crystallizer
2.Continuous crystallizer
A. Swenson walker crystallizer
B. Oslo crystallizers(fluidized bed type)
subtypes
cooler crystallizer
evaporative crystallizer
vacuum crystallizer
c. Howard crystallizer
I- Batch crystallizers:
1- Agitated Batch crystallizer: Water is circulated though the cooling
coils and the solution is agitated by the propellers mounted on the
central shaft.
This agitation performs two functions:
1. It increases the rate of heat transfer and keeps
the temperature of the solution more uniform.
2. It keeps the fine crystals in suspension, thus it
gives them an opportunity to grow uniformly
instead of forming large crystals or aggregates.
(Production of uniform crystals)
The product of this operation is not only more
uniform but it also very much finer than that
from the older tanks.
Disadvantages
1. It is a batch or discontinuous
apparatus.
2. The solubility is the least at the
surface of the cooling coils.
Therefore, crystal growth is most
rapid at this point and the coils
rapidly build up with a mass of
crystals that decreases the rate of
heat transfer.
C
A
2- Swenson - Walker Crystallizer
A C A
B
B
It consists of an open trough A, which is wide, a water jacket
welded to the outside of the trough.
It also contains a slow - speed spiral agitator set as close as
possible to the bottom of the trough.
A number of units may be joined together to give increased
capacity.
The hot concentrated solution to be crystallized is fed at one
end of the trough and cooling water usually flows through the
jacket in counter - current to the solution.
In order to control crystal size, it is sometimes desirable to
introduce an extra amount of water into certain sections in
Functions of the spiral stirrer:
1. It Prevents the accumulation of crystals on the cooling surface.
2. It lifts the crystals that have already been formed and shower
them down through the solution.
In this manner, the crystals grow while they are freely suspended in
the liquid and therefore they are:
1. Fairly perfect individuals.
2. Uniform in size
3. Free from inclusions or aggregations.
At the end of the crystallizer there may be an overflow gate where
crystals and mother liquor overflow to a drain box from which the
mother liquor is returned to the process and the wet crystals are fed to
a centrifuge to remove mother liquor.
Advantages:
1. Large saving in floor space.
2. Large saving in material in process.
3. Saving in labor.
4. Uniform size crystals.
5. Free from inclusions and aggregations.
Wulf–Bock crystallizer:
It has similar characteristics to the swenson - walker
but it depends on air cooling and gives more uniform
crystals.
It consists of a shallow trough set inclined and
mounted on rollers so that it can be rocked from side
to side.
The slow rate of cooling in this crystallizer results in
General disadvantages of batch
crystallizers
1- Need more workers so they are of
high cost.
2- Need large floor space.
3- No control of the size and shape of
crystals.
Continuous crystallizer
1. Oslo crystallizers
a- Oslo cooler crystallizer
b- Oslo evaporative
crystallizer
c- Oslo vacuum crystallizer
2. Howard crystallizer
Oslo crystallizers: (or krystal crystallizers)
a- Oslo cooler crystallizers (or krystal
cooler crystallizers)
The mother liquor is withdrawn near the feed point of the crystallizer by a
circulating Pump and is passed through the cooler H where it becomes
supersaturated and then fed back to the bottom of the crystallizer through the
central pipe B
Some nuclei form spontaneously in the crystal bed and some forms as a result
of breakage of the crystals.
A vessel G can be used to remove very small nuclei that reach the upper layers
of the vessel E.
These nuclei pass again in the cooler and then to the vessel E through the tube
B.
The nuclei circulate with the mother liquor until they have grown sufficiently
large to be retained in the fluidized bed (liquid fluidization).
The final product is removed from the bottom of crystallizer though a valve M
and a uniform product is therefore obtained because the crystals are not
discharged until they have grown to the required size that settle opposing the
flow from tube B.
Advantages
1. Its a continuous crystallizer
2. Give uniform size crystals.
3. The size of crystals can be controlled by the pump flow
rate.
• It is used where large quantities of crystals of controlled
size are required.
• It is used for crystallization of KNO3
• Crystallization can be initiated by adding crystals to act
as nuclei.
b- Oslo evaporative crystallizer (crystal evaporation
crystallizer)
This method is used for substances not affected by
heat.
1. Small unclei reach the upper portion of the crystallizer
body and enter again in the heater and the cycle
repeated till the desired size is obtained.
2. So the size of crystals can be controlled.
In this apparatus, the solution is first passed through a heater and
then to a flash evaporator before being returned to the crystallizer.
This method is called adiabatic cooling.
The solution is heated and then introduced into a vacuum where the
total pressure is less than the vapor pressure of the solvent at the
temperature at which it is introduced.
The solvent must flash and the flashing must produce adiabatic
cooling, i.e. when the solution is introduced into a vacuum, Flash
evaporation occur. This results in drop in temperature and cooling
which helps supersaturation, and removing of a part of the solvent
leading to crystallization.
C. Oslo vacuum crystallizer:
Simple vacuum crystallizer A, crystallizer body; C,
vapor outlet; D, discharge pipe; E, product pump; F,
propeller stirrers, G, sight glass; H. condenser ( Swenson)
It acts by partial removal of vapor by vacuum
application which leads to superstation and crystal
formation. It is used mainly for crystallizing
thermolabile substances.
2- Haward crystallizer:
This crystallizer consists Cooling water outlet
Cooling water inlet
essentially of a vertical Mother
Liquor outlet
conical device through
Cooling water in
which solution flows in an Inner cooling cone
upward direction. The
upper end of the Cooling water out
crystallizer is the wide part
Cooling water out Solution in
of the cone. Cooling water in
A Concentric outer conical Crystal out
chamber serves as a
Crystals that are suspended in the
upward flowing stream of solution
must grow to such a size that they will
settle at the apex of the cone (bottom
of crystallizer) before they can escape.
By regulating the velocity of flow at
the bottom of the crystallizer, the size
of the product is controlled.
Critical Process Parameters (CPPs)
Temperature: Affects solubility and nucleation rate.
Cooling Rate: Impacts crystal size and form.
Agitation Speed: Controls mass transfer and
secondary nucleation.
Solvent System: Determines polymorphic outcome.
Supersaturation Control: Central to purity and
morphology.
Seeding in Crystallization
Seeding involves the addition of pre-formed crystals to
induce controlled crystallization.
Benefits:
Reduces induction time.
Promotes desired polymorph.
Improves size distribution.
Seed Selection Criteria:
Crystal form (polymorph-specific)
Size distribution
Purity and morphology
Applications in Pharmaceutical Manufacturing
Example Drug Substances
Paracetamol: Purified through cooling crystallization.
Carbamazepine: Exists in multiple polymorphs affecting
bioavailability.
Sulfathiazole: Crystallized to remove solvent residues.
Ritonavir: Notorious for polymorphic conversion impacting stability.
Crystallization for Polymorph Control
and Purity
Helps isolate the most stable or bioavailable polymorph.
Removes by-products and unreacted reagents.
Enhances mechanical properties (flowability, compressibility).
Challenges, Innovations & Emerging
Trends
Challenges in Large-Scale Crystallization
Polymorph Inconsistency: Uncontrolled polymorphic changes.
Scale-up Issues: Heat and mass transfer become inefficient.
Crystallization Kinetics: Difficult to predict.
Quality Assurance: Requires robust in-process controls.
Innovative Techniques
1. Sono crystallization:
Uses ultrasound to promote nucleation.
Produces smaller, more uniform crystals.
2. Anti-Solvent Crystallization:
Involves adding a poor solvent to induce crystallization.
Effective for poorly soluble APIs.
3. Reaction Crystallization:
Simultaneous formation and crystallization of product (e.g., salt formation).
4. Continuous Crystallization:
Enables process intensification and real-time control.
Sequence of steps to transfer from batch
to continuous crystallization process.
Visual Aid Recommendations:
Suggest visual aids such as
1. phase diagrams
2. illustrations of nucleation and crystal growth
3. images of different crystal habits
4. flowcharts of various crystallization processes.
Phase Diagrams
This phase diagram illustrates
the temperature and
composition dependence of
different phases, helping to
understand the solubility and
crystallization boundaries.
Nucleation and Crystal Growth
Visual
Illustrations of primary and
secondary nucleation, showing
small particle clusters leading
to larger crystals, with a visual
timeline.
These graphics explain the
initiation of crystal formation
(nucleation) and how crystals
grow over time. Understanding
these stages is essential for
controlling crystal size and
purity in pharmaceutical
processes.
. Crystal Habits Visual
Sketches of different crystal
shapes: needle, plate, and
prism.
Crystal habit affects
downstream processing such
as filtration, drying, and tablet
formulation. For example,
needle-shaped crystals may
clog filters, while plate-shaped
crystals may dry unevenly.
Recognizing and modifying
habit is part of crystallization
optimization.
Crystallization Process Flow chart
Visual
:A simplified flowchart showing
process inputs (e.g., seeding,
solvent), crystallization steps,
and outputs (API crystals,
mother liquor)
This visual outlines typical
crystallization methods (batch,
cooling, antisolvent). It’s useful
for illustrating control points,
raw material inputs, and
desired outputs, emphasizing
the systematic design of
pharmaceutical crystallization.
Supersaturation vs. Time Graph
Visual
Graph comparing controlled and
uncontrolled crystallization over
time, based on supersaturation
levels.
This diagram demonstrates the
importance of managing
supersaturation to favor
controlled nucleation and
growth. Controlled
supersaturation leads to uniform
crystals, while uncontrolled
conditions can result in rapid
nucleation, irregular crystals, or
undesired polymorphs.
References
Lachman, L., Lieberman, H.A., & Kanig, J.L. The Theory and Practice of
Industrial Pharmacy (3rd ed.).
Prions, p. 100. Retrieved July 10, 2010.4. Myerson, A. S. (2002).
Handbook of Industrial Crystallization. Butterworth-Heinemann.
