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1. CRYSTALLISATION Prepared By:- Pankaj Singh Patel Department of Pharmaceutical Chemistry MET, Faculty of Pharmacy, Moradabad

2. CONTENT Definition of crystallization Importance of crystallization Crystal and crystal lattice Mechanism of crystallization Factor affecting crystallization Polymorph Crystal hydrate and solvate Isomorph Application

3. CYRSTALLISATION Crystallization can be defined as the process through which the atoms/molecules of a substance arrange themselves in a well-defined three-dimensional lattice and consequently, minimize the overall energy of the system. When a substance is subjected to crystallization, its atoms or molecules bind together through well-defined angles.  On adding a solid substance in a liquid and stirring it, the solid dissolves in the fluid. But when added more and more solid to the liquid, a point comes after which no more solid dissolves in the liquid. This point is called a saturation point and the fluid is called a saturation solution

4. IMPORTANCE Purification of drug Improve bioavailability of the drug and choose the most stable form A crystalline powder is easily handled , stable , possesses good flow properties and an attractive .

5. CRYTAL LATTICE The crystal lattice is the  symmetrical three-dimensional structural arrangements of atoms, ions or molecules (constituent particle) inside a crystalline solid as points.   It can be defined as the geometrical arrangement of the atoms, ions or molecules of the crystalline solid as points in space.

6. CRYSTAL LATTICE OF NaCl

7. IMPORTANCE OF CRYSTALLISATION Purification Improve bioavailability of the drug and choose the most stable form A crystalline powder is easily handled , stable , posses good flow properties and an attractive appearance .

8. SUPERSATURATION When the concentration of the compound in its solution is greater than the saturation solubility of that compound in that solvent the condition is known as super saturation . This is an unstable state From this supersaturates solution the excess compound may be precipitated out or crystallize .

9. Super saturation 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 .

10. The driving force needed for the nucleation and growth of a crystal is referred to as supersaturation and is defined as the difference in chemical potential between a molecule in solution and that in the bulk of the crystal phase: µ = µs − µc where µs is the chemical potential of a molecule in solution and µc is the chemical potential of the molecule in the bulk crystal. Following thermodynamics can be expressed as µ = kT ln S where k is the Boltzmann constant, T is the absolute temperature, and S is the supersaturation ratio. When µ > 0 the solution is said to be supersaturated, meaning that nucleation and/or growth is possible, whereas when µ < 0 the solution will be undersaturated and dissolution will take place.

11. MIER’S SUPERSATURATION THEORY In the year 1927, Miers, SIR, H.A. postulated a theory on super saturation. Miers theory explains growth of nuclei with respect to super solubility and solubility curve under some limitations . Let us know first about solubility curve. When equilibrium is attained at final temperature, mother liquor becomes saturated in crystallization process and rate of formation of nucleus is balanced by the rate of dissolution of nucleus. The equilibrium relationship is the solubility curve. Solubility data for different solids had been expressed as function of temperature. Solubility chart displays various types of profiles like curves with positive and high slope (KNO3), positive and very low slope (NaCl), negative slope (MnSO4−H2O).

12. For most of the materials, solubility curves follow firstly i.e. high and positive slope. Solubility curve represents the maximum concentration of solutions that can be obtained by bringing solute into equilibrium with solvent. This curve represents final concentration of mother liquor toward which supersaturated solution approaches. Super saturation is attained by decreasing temperature of highly concentrated solution or decreasing amount of solvent by evaporation or by both.

13. AB − super solubility curve, CD − solubility curve, E − Feed location, under saturation, F−solution cools to saturation, G − Metastable zone, nucleation begins, H− Concentration

14. NUCLEATION nucleation , the initial process that occurs in the  formation of a crystal  from a solution, a  liquid , or a vapour, in which a small number of ions, atoms, or molecules become arranged in a pattern characteristic of a crystalline solid, forming a site upon which additional particles are deposited as the crystal grows.

15. The rate of nucleation (i.e., the number of nuclei formed per unit time per unit volume) can be expressed by an Arrhenius-type equation:

16. where A also depends on supersaturation. A typical plot of J as a function of supersaturation (S) . It can be seen in this plot that the nucleation rate is virtually zero until a critical value of supersaturation is achieved, after which the rate increases exponentially. This critical supersaturation (µc) defines the so-called metastable zone where crystal growth can proceed without concomitant nucleation taking place.

17. CRYSTAL GROWTH Crystal growth is the series of processes by which an atom or a molecule is incorporated into the surface of a crystal, causing an increase in size. These different processes can be summarized into four steps 1) transport of atoms through solution; 2) attachment of atoms to the surface; 3) movement of atoms on the surface; 4) attachment of atoms to edges and kinks. The first process is the so-called transport process, whereas 2–4 are referred to as surface processes (and may involve several substeps). Since these different steps normally occur in series, the slowest process will control the overall crystal growth. Therefore, growth can be transport (when step 1 is the slowest) or surface controlled (when steps 2–4 are the slowest).

18. FACTOR AFFECTING CRYSTALLISATION In making icings, frostings, or candy like fondant and fudge, it is necessary to crystallize the sugar solution. For crystallization to occur, nuclei must form in the solution. To these nuclei the material of the solution is added to form crystals. Both the rate of formation of nuclei and the rate of crystallization are affected by the nature of the crystallizing substance, the concentration, the temperature, agitation, and the impurities present in the solution .

19. Nature of the crystallizing substance : Some substances like salt crystallize readily from water solution. It requires only a very slight super-saturation to start nuclear formation, and all excess salt in the solution beyond the saturation point is precipitated as crystals. Some substances do not form nuclei or crystallize so readily as salt. With sucrose it is often necessary to have a considerable degree of supersaturation before crystallization commences. Sucrose crystallizes more readily than levulose.

20. Formation of nuclei : Nuclei cannot form and crystallization cannot occur except from a supersaturated solution. The formation of nuclei, that is the uniting of atoms to form nuclei, is influenced by several factors. If a solution is left to stand, a few nuclei may form spontaneously in various places, and from these nuclei crystallization proceeds. When only a few nuclei develop spontaneously in the solution, the crystals grow to large size. Usually nuclei formation and crystallization do not begin immediately after supersaturation occurs. * The rate of nuclear formation may be favored by specks of dust in the solution. Agitation or stirring of a solution increases the rate of nuclear formation. A drop in temperature at first favors, and then retards, the formation of nuclei. Instead of spontaneous formation of nuclei, seeding a solution may be used to start crystallization.

21. Seeding : When crystals of the same material are added to start crystallization the process is called seeding. These crystals serve as nuclei for crystal growth. If the quantity of crystals added is large and the size of the crystals small, it serves as many nuclei in the solution and the resulting crystals are small. If the quantity of material added is very small, the nuclei formed are few in number and the crystals formed are large. One may think of all crystals as being large enough to be visible, whereas many of them may be very small, so small in fact that they may float in the air. If crystals are floating in the air there is the possibility that they may serve to seed solutions, and thus start crystallization.

22. Temperature at which crystallization occurs : It is a well-known fact that, in general, chemical precipitates come down more coarsely crystalline if crystallized at high temperatures. The sugars follow this general rule. Other things being equal, i.e., concentration, etc., the higher the temperature at which crystal formation occurs, the coarser the crystals formed.

23. Concentration of the solution : A more concentrated solution favors the formation of nuclei. Fondant syrup cooked to 114°C. Contains less water and is more concentrated than one cooked to 111°C. Thus nuclei form more readily in the one cooked to 114°C. Large, wellshaped crystals form more readily if the degree of supersaturation is not too great. The most favorable supersaturation for crystal growth, of a sucrose solution boiled to 112°C, is that between 70° and 90°C. Although crystallization occurs in a very short time when the syrup is stirred at these temperatures, the crystals formed are larger than when the syrup is cooled to a lower temperature. Supersaturation and a low temperature are desirable for the development of small crystals.

24. Rate of crystallization : To the nuclei formed in the solution new molecules from the solution are deposited, in a regular order or manner, so that each crystal has a typical shape. One side or face of a crystal may grow more rapidly than another. The rate at which the nuclei grow to larger size is called the rate of crystallization. The rate may be favored by the concentration of the solution and its temperature; it may be hindered by foreign substances.

25. Interfering substances : Some products can be added prevent the formation and growth of crystals. These products such as cream, butter, egg white etc., are called interfering agents. The agents coat the crystals and prevent the growth of large crystals.

26. Polymorph Certain drugs can exist in more than one crystalline form . Such a phenomena is known as polymorphism . About 63 % of barbiturates ,67 % of steroids and 40% of sulphonamides exhibit polymorphism . Although the drug is chemically indistinguishable in each form , polymorphs differ significantly with respect to a number of properties such as density , melting point , solubility and dissolution rate .

27. HYDRATES Hydrate , any  compound  containing  water  in the form of H 2 O   molecules , usually, but not always, with a definite content of water by weight. The best-known hydrates are  crystalline   solids  that lose their fundamental structures upon removal of the bound water. Exceptions to this are the  zeolites  ( aluminum   silicate minerals  or their  synthetic   analogues  that contain water in indefinite amounts) as well as similar  clay minerals , certain clays, and metallic  oxides , which have variable proportions of water in their hydrated forms; zeolites lose and regain water reversibly with little or no change in structure.

28. Examples of hydrates are Glauber’s  salt  ( sodium  sulfate decahydrate, Na 2 SO 4 ∙10H 2 O);  washing soda  (sodium carbonate decahydrate, Na 2 CO 3 ∙10H 2 O);  borax  (sodium tetraborate decahydrate, Na 2 B 4 O 7 ∙10H 2 O); the sulfates known as  vitriols  (e.g., Epsom salt, MgSO 4 ∙7H 2 O); and the double salts known collectively as  alums  (M + 2 SO 4 ∙M +3 2 (SO 4 ) 3 ∙24H 2 O, where M +  is a monopositive  cation , such as K + or NH4 + , and M 3+  is a tripositive cation, such as Al 3+  or Cr 3+ ).

29. Crystal solvate Crystal solvates tend to form during the process of crystallization with the help of a solvent. The crystalline solids that contains the molecules of solvent inside their crystal assembly (stoichiometrically or nonstoichiometrically) are known as solvates, also inappropriately, pseudopolymorphs. When water is the solvent molecule, then, the so formed solvates are termed as “hydrates” AMORPHOUS APIs : Producing Amorphous Active Pharmaceutical Ingredients offers an enhanced drug release that is caused by the increase in its dissolution rate  . This improvement enables higher bioavailability and bioactivity of such solid APIs.

30. ISOMORPHS : When two or more substances posses the same crystalline form they are called isomorph . AMORPHOUS APIs : Producing Amorphous Active Pharmaceutical Ingredients offers an enhanced drug release that is caused by the increase in its dissolution rate  . This improvement enables higher bioavailability and bioactivity of such solid APIs.

31. APPLICATION Purification of seawater Separation of alum crystals from impure samples In the pharmaceutical industry, crystallization is used as a separation and purification process for the synthesis and isolation of co-crystals, pure active pharmaceutical ingredients (API), controlled release pulmonary drug delivery, and separation of chiral isomers.

32. APPLICATION Purification of drugs Better processing characteristics such as compressibility and wettability of drug . Easy handling transport and storage Improve the bioavailability Drugs in different crystal from used in the production of certain sustained release drug .

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