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CRYSTALLIZATION
Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D
Department of PharmaceuticsFaculty of Pharmacy
Omer Al-Mukhtar UniversityTobruk, Libya.
E-mail: [email protected]
2014/05/13 1Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.
CONTENTS
• Mier’s super saturation theory
• Factor affecting crystallization
• Continuous crystallizers
• Cooling crystallizers
• Evaporative crystallizers
• References
2014/05/13 2Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.
Crystallization
• Definition: Crystallization is the spontaneous arrangement of the molecules into regular geometric form supersaturated solution.
• Some times crystallization can also take place directly from vapour of the substances, such process is known as ‘SUBLIMATION’.
Example:
1. Solid camphor from camphor vapour
2. Solid iodine from Iodine vapour
2014/05/13 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 3
Applications of crystallization process
1. Purification of drugs
2. Better processing characteristics such as compressibility and wettability of drugs.
3. Easy handing transport and storage.
4. Improve the stability of various drugs.
5. Improve the bioavailability.
6. Drugs in different crystal form used in the production of certain sustained release dosage forms.
2014/05/13 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 4
Mier’s super saturation theory
• Mier’s theory of supersaturation states that a definite relationship between concentration and temperature at crystals which will form spontaneously in an unseeded solution.
• Curve AB indicates normal solubility, that means at any point the solute is in equilibrium with solute.
• Cure FG indicates super solubility which is parallel to the normal solubility, it also represents the limit at which nucleus formation begins.
2014/05/13 5Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.
Mier’s super saturation theory
2014/05/13 6Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.
A plot of temperature versus concentration of solute
Formation of crystals
• Metastable state indicates, unstable and undergoes changes and it is enclosed between the curves AB and FG.
• Consider a point ‘C’ near solubility curve, with definite composition and temperature, crystallization is expected to start from point ‘P’ but it does not occur.
• According to theory, crystallization takes place after point ‘P’ somewhere in the neighbour of the point ‘D’ when certain conditions are specified.
2014/05/13 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 7
Mier’s super saturation theory
Factor affecting crystallization
1. Solvent Considerations: Moderate solubility is best. Supersaturation leads to sudden precipitation and smaller crystal size.
2. Nucleation & Growth: Fewer nucleation sites are better. Too many nucleation sites (i.e. dust, hairs, etc.) lower the average crystal size.
3. Mechanics (Crystal Growth): mechanical disturbances are bad.
4. Time: Faster crystallization is not as good as slow crystallization. Faster crystallization higher chance of lower quality crystals.
5. Crystal Growing Techniques: Slow Evaporation, Slow Cooling, Variations
2014/05/13 8Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.
Continuous crystallizers
2014/05/13 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 9
Cooling crystallizers
2014/05/13 10Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.
Cooling crystallizers
• Concentrated solution gradually cooled below saturation temperature (50-60°C) to generate a supersaturated state.
• Yields well defined micron-sized crystals.• Shell and tube heat exchanger is used to cool
solution.
2014/05/13 11Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.
Cooling crystallizers
• Advantages: – High purity downstream
• Disadvantages:– Temperature change does not always have a positive effect
on supersaturation in proteins– Protein stability may be at risk– Solubility can be relatively insensitive to temperature at
high salt concentrations– Cooling will only help reach supersaturation in systems
where solubility and temperature are directly related
2014/05/13 12Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.
Evaporative crystallizers
2014/05/13 13Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.
Evaporative crystallizers
• Solute dissolves in solution when heated to a certain temperature (75°C).
• Slowly cooled until crystals precipitate.
• Shell and tube heat exchanger is used to heat and cool solution.
• Advantages:
– high purity levels downstream
• Disadvantages:
– Vaporization chamber requires high pressures
– Protein viability very sensitive to high temperatures
2014/05/13 14Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.
2014/05/13 15Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.
E-mail: [email protected]