Crystallization. Crystals.

Crystallization. Introduction. crystals. Mechanism. Phase diagram. Different types.

1. CRYSTALLIZATION

2. DEFINITION: “ Crystallization is a chemical solid–liquid separation technique, in which mass transfer of a solute from the liquid solution to a pure solid.”

3. • Spontaneous arrangement of the particle into a repetitive order. • i.e regular geometric patterns.

4. CRYSTALS: Crystal can be defined as a solid particle, which is formed by the solidification process under suitable environment in which structural units are arranged by a fixed geometric pattern or lattice . CRYSTAL STRUCTURE OF NACL

5. The smallest Geometric portion, Which repeats to build up the whole crystal is called a UNIT CELL.

6. In the Crystal, the angle between the two perpendiculars to the intersecting faces is termed as the axial angle . Axial length can be defined as distance between the centre of two atoms.

7. A finite number of symmetrical arrangement are possible for a crystal lattice and these may termed as crystal forms or crystal system. A chemical substance may exists more than one crystalline form is called polymorphs and these phenomenon is called polymorphism .

8. Crystalline solid have definite shapes and orderly arrangement of the unit. They have low solubility and dissolution. Amorphous Solid : They do not have specific shape Amorphe means without form Randomly arrangement of solid particles in the structure.

9. CRYSTAL HYDRATES : Some drugs have greater tendency to associate with water. The resulting product or substance is called Drug hydrates e.g. Na2CO3. 10H2O

10. CRYSTAL SOLVATES : Some drugs have greater tendency to associate with Solvents to produce crystalline forms of solvates The solvates are also called pseudomorphs . ISOMORPHS : When two or more substances posses the same crystalline form they are called as isomorphs.

11. CHARACTERISTICS OF CRYSTAL: Crystal lattice Crystal system or forms Crystal habit

12. CRYSTALLIZATION PROCESSES: A) Cooling Crystallization B) Evaporative Crystallization

13. COOLING CRYSTALLIZATION: The cooling crystallization can be applied when the solubility gradient of the solution increases steeply with falling temperature or when a vaporisation of the solvent has to be avoided. EVAPORATIVE CRYSTALLIZATION: Generating crystals by evaporating a solution at const. temperature Most of the industrial crystallizers are evaporative

14. CRYSTALLIZERS: Crystallizer can be of 3 types: Batch type crystallizer Continuous type crystallizer Forced circulation type crystallizer

15. A typical laboratory technique for crystal formation is to dissolve the solid in a solution in which it is partially soluble, usually at high temperatures to obtain supersaturation. The hot mixture is then filtered to remove any insoluble impurities. The filtrate is allowed to slowly cool which results in crystals formation.

16. MECHANISM OF CRYSTALLIZATION: Three major steps are involved in crystallization: 1. Super Saturation. 2. Nucleation. 3. Crystal Growth.

17. 1. Super Saturation of the solution : 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.

18. 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.

19. Supersaturation Phase diagrams Precipitatant concentration (salt, PEG etc.) Protein concentration Under-saturation (protein remains soluble; crystals dissolve) Nucleation zone Precipitation zone Solubility curve Metastable zone Crystals grow, but Nuclei form only infinitely slowly

20. 2 . Nucleation : These stable structures together form a nuclei. It is at the stage of nucleation that atoms arrange in periodic manner to form crystal structure . Step where solute molecules dispersed in the solvent start to gather into clusters on the nanometer scale. 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.

21. 3. Crystal Growth : “ Crystal growth is a diffusion process and a surface phenomenon. Every crystal is surrounded by a layer of liquid known as stagnant layer .” Once the crystals are formed, nuclei formation stops and crystal growth begins. From the bulk solution a solute particle (molecule, atom or ion) diffuse through this stagnant layer and then reaches the surface of the crystal. These particles then organize themselves in the crystal lattice. This phenomenon continues at the surface at a slow rate. This process will happen if the bulk solution is supersaturated.

22. Crystallization Principles Figure 1: Typical phase diagram. The components in solution consist of the product (ordinate) and the precipitating reagent (abscissa). The lines with arrows out line one possible way of performing the crystallization. The supersaturation must be above the a certain value before nucleation will begin Metastable region : the supersaturation is low that nucleation will not start Once the supersaturation has been raised enough to be in the labile region, nucleation can begin. At this point , crystals begin to grow, and the supersaturation decreases If the supersaturation becomes too high, the nucleation rate will be too great, and amorphous precipitate will result.

23. 24 Batch Crystallization Process Formation of solid particles within a homogeneous phase by modifying the solubility of the component of interest The change in solubility is accomplished by: decreasing the temperature of the solution Changing composition of solvent by adding a solvent in which the compound is insoluble In some cases crystallization is not achieved by a change in solubility →reactive crystallization

24. Yields and Heat and Material Balances in Crystallization Yields and material balance in crystallization The solution (mother liquor) and the solid crystals are in contact for enough time to reach equilibrium. Hence, the mother liquor is saturated at the final temperature at the final temperature of the process, and the final process, and the final concentration of the solute in the solution can be obtained from the solubility curve. The yield can be calculated knowing the initial concentration of solute, the final temperature, and the solubility at this temperature. In making the material balances, the calculations are straightforward when the solute crystals are anhydrous. Simple water and solute material balances are made. When the crystallizations are hydrated, some of the water in solution is removed with the crystals as a hydrate.

25. MIER’S SUPERSATURATION THEORY: Mier and Issac proposed a theory explaining a relationship between supersaturation and spontaneous crystallization. Mier’s theory points out that : The greater the degree of supersaturation, the more chance is of nuclei formation if the super-saturation passes a certain range of values, nuclei formation is extremely rapid.

26. Assumption: The solute and the solvent must be pure. The solution must be free from solid solute particles. The solution must be free from foreign solid particles.

27. Limitations of the Mier’s theory 1. According to Mier’s theory, crystallization starts at supersolubility curve (FG). But the general tendency is that crystallization takes place in an area rather than a line. 2. If the solution is kept for long periods, nucleation starts well below the super-solubility curve. 3. If the solution is available in large volume, nucleation starts well below the super-solubility curve. 4 . Mier’s theory is applicable only when pure solute and pure solvent is taken. In practice, it is impossible to get them in pure state . 5. During crystallization the solution may become contaminated with dust, particles from container etc. Nucleation may be initiated from these foreign particles also.

28. FACTORS AFFECTING CRYSTALLIZATION: PRESENCE OF ANOTHER SUBSTANCE SOLVENT NUCLEATION CRYSTAL GROWTH RATE OF COOLING TIME

29. PRESENCE OF ANOTHER SUBSTANCE IN MOTHER LIQUOR: Sodium chloride crystallized from aqueous solutions produces cubic crystals. If sodium chloride is crystallized from a solution containing a small amount of urea, the crystals obtained will have octahedral faces. Both types of crystals belong to the cubic crystal form but differ in habit.

30. SOLVENT CONSIDERATIONS: Moderate solubility is best (avoid supersaturation). Like dissolves like. Hydrogen bonding can help or hinder crystallization. Presence of benzene can help crystal growth. Avoid highly volatile solvents. Avoid long chain alkyl solvents can be significantly disordered in crystals. Choose solvents with “rigid geometries”.

31. NUCLEATION: Crystals initially form via “nucleating events”. After a crystallite has nucleated it must grow. Nucleation sites are necessary. Excess nucleation sites cause smaller average crystal size.

32. Crystal Growth: Crystals grow by the ordered deposition of the solute molecules onto the surface of a pre-existing crystal. Crystal growth is facilitated by the environment changing slowly over time. Keep crystal growth vessel away from sources of mechanical agitation (e.g. vibrations). Set-up away from vacuum pumps, rotovaps , hoods, doors, drawers, and so on Leave samples alone for 1 week, don't “check in” with it. Your crystals are not lonely.

33. TIME: Quality crystals grow best over time in near equilibrium conditions. The longer the time, the better the crystals. Faster crystallization is not as good as slow crystallization. Faster crystallization higher chance of lower quality crystals

34. 1. Purification of Drugs. 2. Better processing characteristics. 3. Ease of handling. 4. Better chemical stability. 5. Improved physical stability. 6. Improved bioavailability. 7. Sustained release formulation. 8. Miscellaneous. OBJECTIVES AND APPLICATIONS :

35. IMPORTANCE OF CRYSTALLIZATION 1- purification of drugs . 2- improve bioavailability of the drug and choose the most stable form. 3- a crystalline powder is easily handled ,stable , possesses good flow properties and an attractive appearance . 4- Crystallization from solution is important industrially because of the variety of materials that are marketed in the crystalline form. 5-Crystallization affords a practical method of obtaining pure chemical substances in a satisfactory condition for packaging and storing. A crystal formed from an impure solution is itself pure (unless mixed crystals occur).

36. 6- A drug may remain in different crystalline forms, some are stable , and rests are metastable . 7- The metastable forms have greater solubility in water, thus have better bioavailability. By controlling the conditions during crystallization, the quantity of metastable to stable forms may be controlled. 8- After crystallization water or solvent molecules may be entrapped within the crystal structure and thus form hydrates or solvates which have different physical properties that may be utilized in various pharmaceutical purpose . 9- Particles with various micromeritic properties, compressibility and wettability can be prepared by controlling the crystallization process.