Final Finishing and Polishing
in Downstream Processing
1. Importance of Final
Purification
• Biotechnological products require different levels of
purification based on their intended use.
• Bulk products (e.g., industrial enzymes, organic
solvents) may be ready for marketing after initial
downstream processing.
• Pharmaceuticals and fine chemicals require additional
finishing steps for consumer acceptability and product
stability.
Key Finishing Steps
1.Crystallization
1.Used to remove closely related impurities.
2.Ensures high purity of the final product.
2.Drying
1.Removes residual solvents, including water.
2.Prevents degradation and enhances shelf life.
3.Formulation
1.Modifies the product to meet consumer requirements.
2.Ensures product stability and usability.
Crystallization
• Crystallization is the process where solid particles of a
specified size and shape are formed from a
homogeneous phase.
• It is a solid-liquid separation process in which mass
transfer of a solute occurs from the liquid to the solid
phase.
• This method is commonly used for final
purification because the obtained crystals are
of exceptional purity, free from even closely related
impurities.
Advantages of Crystallization
• Produces uniformly sized and shaped crystals,
facilitating separation through filtration or
centrifugation.
• Enhances product appearance and consumer
acceptance.
Methods of Crystallization
• Cooling Crystallization: The solution is cooled until it
reaches a saturated and then supersaturated state.
• Evaporation Crystallization: The solution is
concentrated through evaporation until supersaturation
is achieved.
Saturation and Supersaturation
• Saturation: The maximum concentration of solute that
remains thermodynamically stable in solution.
• Supersaturation: A state where the solution
contains more solute than the saturation limit,
making it thermodynamically unstable.
Supersaturation Coefficient (S)
• The degree of supersaturation is measured using
the supersaturation coefficient (S), given by:
•
• Where:
• Ct = Concentration of solute in the solvent at a given temperature.
• C0= Concentration of solute in a saturated solution at the same
temperature.
• At saturation: S=1
• Supersaturated solution: S>1
Crystallization Theory
• Basic Steps of Crystallization
• Crystallization consists of two fundamental steps:
1.Nucleation – The initial formation of crystal nuclei.
2.Crystal Growth – The subsequent growth of the
crystal from these nuclei.
• Supersaturation is the driving force for both steps.
• Crystallization only occurs in a supersaturated
solution.
Zones of Supersaturation
• Supersaturated solutions can be categorized into three
zones:
• Labile Zone: Nuclei form spontaneously from a clear
solution.
• Intermediate Zone: Both nucleation and crystal
growth occur.
• Metastable Zone: Excess solute deposits on existing
crystals, but no new nuclei form.
• The phase equilibrium and operating
conditions (e.g., agitation speed) control the
supersaturated state and the three zones.
Nucleation Mechanisms
• (a) Primary Nucleation (Homogeneous
Nucleation)
• Occurs due to random molecular fluctuations in the
homogeneous phase.
• Solute molecules cluster together to form nuclei.
• (b) Secondary Nucleation (Heterogeneous
Nucleation)
• Occurs in the presence of existing particles or
impurities.
• Initiated by:
• Addition of seed crystals
• Presence of dust particles
• Gas bubbles
• Mechanical shock
• Ultrasonic shock
• Crystal Growth
• Occurs after nucleation or the addition of seed material.
• Solubility and Crystal Size Relationship:
• Small crystals dissolve more easily than larger ones.
• In a supersaturated solution, small crystals dissolve, and larger
crystals grow.
• Factors Affecting Growth Rate:
• Transport of solute to the crystal surface
• Mechanism of surface deposition
• Stirring helps transport solute but does not significantly increase
growth rate.
• Impurities generally reduce crystal growth.
Crystal Growth Rate: distance moved per unit time in a
direction perpendicular to the face
• Growth occurs layer-by-layer at the crystal face.
• Solute molecules must:
• Diffuse through the solution to reach the crystal surface.
• Integrate into the crystal lattice (surface reaction).
• The overall crystal growth rate is governed by the equation:
dm/dt=kA(c−c∗)
Where:
• m = Crystal mass
• A = Surface area of the crystal
• c = Solute concentration in the supersaturated solution
• c∗ = Solute concentration at saturation
• k = Overall transfer coefficient (including mass transfer and surface reaction
effects)
6. McCabe’s ΔL Law
• McCabe proposed that all geometrically similar crystals
of the same material grow at the same rate under
identical conditions.
• Growth can be measured as an increase in crystal length
(ΔL, in mm).
• The growth rate (G) is given by:
• G=ΔL/Δt (in mm³/h)
• Applicability:
• Valid for crystals smaller than 0.3 mm (50 mesh).
• Not applicable when crystals undergo different treatments based
on size.
Crystallization Practice
Industrial Approaches to Crystallization
• In industrial crystallization, two main approaches are practiced:
1.Seeding Method:
1. Finely divided solute crystals (seeds) are added to a solution in
the metastable zone of supersaturation.
2. The seed crystals grow to the desired size without additional
nucleation.
2.Spontaneous Nucleation Method:
1. Nuclei form spontaneously or through secondary nucleation in
the labile zone of supersaturation.
2.Agitation helps in forming new crystals within the upper range of
the metastable zone.
Factors Affecting Commercial Crystallization
• In industrial crystallization, yield, purity, size, and
shape of crystals are crucial.
• Uniform Crystal Size is important to:
• Prevent caking during packaging.
• Improve ease of pouring, washing, and filtering.
• Crystal Shape Requirements:
• Certain applications require specific shapes (e.g., needle-like
or cubic crystals).
Crystal Systems and Growth Conditions
Crystals are classified into seven systems based on the arrangement of
constituent atoms or ions:
1.Cubic
2.Tetragonal
3.Orthorhombic
4.Hexagonal
5.Monoclinic
6.Triclinic
7.Trigonal
• The external form (habit) of a crystal depends on growth conditions.
• Different crystal faces grow at different rates, leading to:
• Faster-growing faces disappearing in the final crystal.
• Slow-growing faces dominating the finished crystal.
Effect of Supersaturation on Crystal Structure
• Highly supersaturated solutions lead to rapid
crystal growth, forming:
• Long needle-like crystals.
• Dendritic (tree-like) structures due to high specific
surface area, which helps dissipate heat released during
crystallization.
Role of Habit Modifiers in
Crystal Shape Modification
Certain chemicals, known as habit modifiers, can alter
crystal shape:
• Naturally present modifiers (e.g., raffinose in sugar beet)
• Deliberately added modifiers
Examples: Raffinose in sugar crystallization:
• At 1% concentration, it modifies sucrose crystals to cubic
shapes.
• At 2% concentration, it modifies them into thin, narrow plates.
• Potassium ferrocyanide in brine:
• Modifies sodium chloride crystals into dendritic shapes.
Crystal Inhibition and
Aggregation
• Extreme habit modification can lead to crystal
inhibition, where:
• Growth is significantly reduced on all faces.
• Crystal aggregation:
• Crystals adhere together, forming twinned or irregularly
shaped crystals.
Equipment for Crystallization
• Crystallizers may be batch or continuous type, the latter
being generally preferred.
• Crystallization cannot occur without supersaturation.
• A main function of any crystallizer is to cause a
supersaturated solution to form.
• Crystallizers bring about supersaturation either by:
(i) cooling the solution with negligible evaporation,
(ii) evaporation of the solvent with little or no cooling,
as in an evaporator crystallizer, or
(iii) combined cooling and evaporation, as
in adiabatic or vacuum crystallizers.
1. Types of Crystallizers
• Batch Crystallizers
• Used for small-scale operations.
• Often results in crystals of poor quality with non-uniform size.
• Example: Open tank crystallizers for antibiotics and low
molecular weight products.
• Continuous Crystallizers (preferred method)
• Ensures continuous operation and better control over crystal
size.
• Various methods to induce supersaturation.
2. Methods of Inducing Supersaturation
1.Cooling with negligible evaporation
1.Used for solutes whose solubility decreases significantly with
temperature.
2.Evaporation of solvent with little or no cooling
1.Common for substances like salt, where solubility is not
temperature-sensitive.
3.Combined cooling and evaporation
1.Used in adiabatic or vacuum crystallizers, where hot
solutions are introduced into a vacuum, causing solvent
evaporation and adiabatic cooling.
3. Importance of Supersaturation in
Crystallization
• Crystallization cannot occur without supersaturation.
• A key function of any crystallizer is to create and
maintain supersaturation.
4. Commercial Crystallizers and Their Operating
Methods
• A. Circulating Magma Method
• Process:
• Entire magma (suspension of crystals and liquid)
is circulated continuously.
• No separation between solid and liquid phases.
• Example: Circulating Magma Vacuum Crystallizer
B. Circulating Liquid Method
• Process:
• A separate stream of supersaturated liquid flows through
a fluidized bed of crystals.
• Crystals grow as liquid passes through.
• Saturated liquid is recycled through an evaporation/cooling
region to regenerate supersaturation.
• Example: Oslo Crystallizer
5. Open Tank Crystallizers (Batch Process)
• Used mainly for batch crystallization of antibiotics
and other fine chemicals.
• Process:
• Hot saturated solutions are allowed to cool.
• Seed material is added to initiate crystallization.
• After a set time, the mother liquor is drained, and
the crystals are removed.
• Drawback:
• Poor quality crystals with occluded mother liquor and non-
uniform size.
• 6. Factors Affecting Crystallization Equipment
Design
• Supersaturation control (to ensure uniform crystal
growth).
• Particle size distribution (critical for product quality).
• Contact method between supersaturated solution and
growing crystals.
