1. CRYSTALLIZATION Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics Faculty of Pharmacy Omer Al-Mukhtar University Tobruk, Libya. E-mail: nanjwadebk@gmail.com 2014/05/131 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

2. CONTENTS Mier’s super saturation theory Factor affecting crystallization Continuous crystallizers Cooling crystallizers Evaporative crystallizers References 2014/05/132 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

3. 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

4. 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

5. 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. 2014/05/135 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

6. Mier’s super saturation theory 2014/05/136 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. A plot of temperature versus concentration of solute Formation of crystals

7. 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

8. 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 2014/05/138 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

9. Continuous crystallizers 2014/05/13 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 9

10. Cooling crystallizers 2014/05/1310 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

11. 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. 2014/05/1311 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

12. 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 2014/05/1312 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

13. Evaporative crystallizers 2014/05/1313 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

14. 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 2014/05/1314 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

15. 2014/05/1315 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. E-mail: nanjwadebk@gmail.com