Lecture 10. Crystallization PDF

Lecture. 10 Crystallization Dr. Salma M. Abdel-Hafez Lecturer Department of Pharmaceutics and Industrial Pharmacy Faculty of Pharmacy, Ain Shams University  Lecture outline Introduction Crystallization from vapors Crystallization from melts Crystallization f...

Lecture. 10 Crystallization Dr. Salma M. Abdel-Hafez Lecturer Department of Pharmaceutics and Industrial Pharmacy Faculty of Pharmacy, Ain Shams University  Lecture outline Introduction Crystallization from vapors Crystallization from melts Crystallization from solutions ▪ Factors affecting crystallization ▪ Controlling crystal size Crystallizers ▪ Batch agitated crystallizer ▪ Oslo crystallizers 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 2  Introduction ▪ Crystallization is the process by which atoms and molecules arrange themselves into definite geometrical pattern called crystals. ▪ As a unit operation, it describes the production of a solid, single- component, crystalline phase from a multicomponent fluid phase. ▪ Crystalline solids can be obtained from vapors, melts, or solutions (most important). ▪ Crystalline solids can be separated by either centrifugation or filtration, followed by drying. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 3  Importance of crystallization ▪ The importance of crystallization lies primarily in the purification achieved and in the physical properties of the product. ▪ A crystalline powder is easily handled, is stable, and often possesses good flow properties and an attractive appearance. Stages of crystallization ▪ There are two main stages of crystallization: nucleation and crystal growth. ▪ Nucleation describes the formation of small nuclei around which crystals grow. ▪ Without the formation of nuclei, crystal growth cannot occur. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 4  Introduction Crystallization from vapors Crystallization from melts Crystallization from solutions ▪ Factors affecting crystallization ▪ Controlling crystal size Crystallizers ▪ Batch agitated crystallizer ▪ Oslo crystallizers 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 5  Crystallization from vapors ▪ Crystallization from a vapor occurs naturally, for example, in the formation of frost or snow from water vapor. ▪ It is not further considered in pharmaceutical industry for obtaining a crystalline product. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 6  Introduction Crystallization from vapors Crystallization from melts Crystallization from solutions ▪ Factors affecting crystallization ▪ Controlling crystal size Crystallizers ▪ Batch agitated crystallizer ▪ Oslo crystallizers 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 7  Crystallization from melts ▪ A melt is the liquid form of a single material or the homogeneous liquid form of two or more materials that solidifies on cooling. ▪ Examples: The freezing water to form ice. Production of crystalline sulfur by melting pure sulfur in a vessel and allowing it to cool slowly. ▪ Crystallization in such a system is described by the following sequence: 1. Imposition of super cooling 2. Nucleation 3. Crystal growth. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 8  Crystallization from melts (cont.) ▪ If a melt is slowly cooled, the temperature will gradually fall. A metastable liquid region exists below the melting point, which can only be entered by cooling. ▪ In this metastable, super cooled region, the rate of spontaneous nucleation is negligible precluding the formation and growth of crystals. However, if a crystal seed is added, growth occurs. The deliberate seeding of a metastable system is commonly employed in industrial crystallization. ▪ With further cooling, spontaneous nucleation usually takes place. ▪ With some materials, lower temperatures increase the viscosity and prevent nucleation. The liquid then solidifies into a mass without crystallizing, a process known as vitrification, the products of which are called glasses. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 9  Crystallization from melts (cont.) Gradual cooling (decrease in temperature) Solid Metastable liquid Melt super cooled region Melting point ▪ Spontaneous ▪ Spontaneous nucleation nucleation and is negligible. crystal growth ▪ Crystal growth occurs upon deliberate seeding. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 10  Nucleation ▪ Spontaneous nucleation is considered to occur when sufficient molecules of low kinetic energy come together in such a way that the attraction between them is sufficient to overcome their momentum. ▪ The growth of a nucleus probably takes place over a very short time in a region of high local concentration. ▪ As the temperature falls, more low-energy molecules are present, and the nucleation rate rises. At low degrees of supercooling, little or no nucleation takes ▪ The decrease in nucleation rate at lower temperature is due to place. With further cooling, the rate of nucleation rises to a increased melt viscosity. maximum and then falls 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 11  Crystal growth ▪ The form of the crystal growth curve is again explained by the molecular kinetics. ▪ At temperatures just below the melting point, molecules have too much energy to remain in the crystal lattice. ▪ As the temperature falls, more molecules are retained, and the growth rate increases. ▪ However, upon further cooling, diffusion to and orientation at the crystal surface are depressed. The relation between growth ▪ The relation therefore indicates that excessive cooling may depress rate and temperature also the rate of crystallization by limiting the number of nuclei formed exhibits an optimum degree of supercooling. and crystal growth. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 12  Rate of nucleation and crystal growth ▪ Maximum crystal growth temperature is normally higher than the temperature of maximum nucleation. Recent Progress on Crystal Nucleation of Amorphous Solid Dispersion, Jie Zhang, Qing Jiang, Zhenling Xu, Qianqian Yang, Gangqiang Hao, Minzhuo Liu, and Zhihong Zeng, Crystal Growth & Design 2024 24 (20), 8655-8666. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 13  Introduction Crystallization from vapors Crystallization from melts Crystallization from solutions ▪ Factors affecting crystallization ▪ Controlling crystal size Crystallizers ▪ Batch agitated crystallizer ▪ Oslo crystallizers 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 14  Crystallization from solutions ▪ In pharmaceutical industry, crystallization from solution is the most important and common as compared to crystallization from a vapor or a melt. ▪ When a material crystallizes from a solution, nucleation and crystal growth occur simultaneously over a wide intermediate temperature range. ▪ The three basic steps are: 1. Induction of supersaturation 2. Nucleation 3. Crystal growth 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 15  Crystallization from solutions (cont.) ▪ A solution with temperature and concentration indicated by point A may be saturated by cooling to point B or by removing solvent to point C. With further cooling or concentration, the supersaturated metastable region is entered. ▪ If the degree of supersaturation is small, then spontaneous nucleation is highly improbable. Crystal growth, however, can occur if seeds are added. ▪ With greater supersaturation, spontaneous nucleation becomes more probable, and the metastable region is limited approximately by the line B′C′. ▪ If the solution is cooled to B′ or concentrated by solvent removal to C′, spontaneous nucleation is virtually certain. Crystal growth also occurs in these conditions. However, the rate of growth is depressed at low temperatures. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 16  Crystallization from solutions (cont.) Gradual decrease in solubility (e.g. by cooling or evaporation) After metastable Metastable region of Unsaturated region supersaturated solution solution Saturated solution ▪ Spontaneous Higher supersaturation Lower supersaturation nucleation is ▪ Spontaneous ▪ Spontaneous nucleation virtually nucleation is more is highly improbable. certain. probable. ▪ Crystal growth can ▪ Crystal growth ▪ Crystal growth is occur if seeds are is proceeding. possible. added. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 17  Factors affecting crystallization 1. 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 followed by crystal growth and precipitation. ▪ 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. 2. Degree of supersaturation ▪ A large degree of supersaturation promotes a high growth rate. 3. Temperature The temperature at which crystallization is performed affects the crystal form or degree of hydration required of the products. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 18  Factors affecting crystallization (cont.) 4. Agitation ▪ Agitation increases the growth rate. 5. Viscosity ▪ As the viscosity increases, the rate of crystal growth decreases because viscosity decease the rate of solute diffusion to the crystal surface. 6. Impurities ▪ Impurities may increase or retard the rate of nucleation with retardation being more common. ▪ Increase: Insoluble materials may act as nuclei and promote crystallization. ▪ Retard: Due to adsorption of the soluble impurities on the surface of the nuclei or crystal resulting in crystal shape modification. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 19  Controlling crystal size ▪ This is achieved by maintaining a degree of supersaturation at which nucleation and crystal growth proceed at appropriate rates. ▪ Control of the number of nuclei formed controls the size of the crystals deposited from a given quantity of solution. ▪ The larger the number of nuclei, the smaller the crystal size. ▪ Alternatively, crystal number and size can be controlled by adding the correct amount of artificial nuclei or seeds to a system in which little or no natural nucleation is taking place. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 20  Introduction Crystallization from vapors Crystallization from melts Crystallization from solutions ▪ Factors affecting crystallization ▪ Controlling crystal size Crystallizers ▪ Batch agitated crystallizer ▪ Oslo crystallizers 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 21  Crystallizers ▪ Crystallizers can be classified according to its operation into: Batch Continuous crystallizers crystallizers ▪ Alternatively, they can be classified according to the way of supersaturation into: Cooling Evaporative Vacuum crystallizers crystallizers crystallizers 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 22  Agitated batch cooling crystallizer ▪ Tanks agitated by stirrers and surrounded by jackets or coils through which cooling water can be circulated. ▪ This agitation performs two functions: 1. It increases the rate of heat transfer and keeps the temperature of the solution more uniform (avoids temperature gradients) 2. It keeps the fine crystals in suspension; thus, it gives them an opportunity to grow uniformly instead of forming large crystals or aggregates. (Production of uniform crystals) ▪ Disadvantages It is a batch or discontinuous apparatus. The solubility is the least at the surface of the cooling coils. Therefore, crystal growth is most rapid at this point and the coils rapidly build up with a mass of crystals that decreases the rate of heat transfer. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 23  Oslo crystallizer/Krystal crystallizer Main principles ▪ Continuous production of large even crystals. ▪ Types include cooling, evaporative and vacuum crystallizers. ▪ A metastable, supersaturated solution is released into the bottom of a mass of growing crystals on which the solute is deposited. ▪ The crystals are fluidized by the circulation of the solution, and classification in this zone allows the withdrawal of sufficiently large crystals from the bottom. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 24  Oslo cooling crystallizer The mother liquor is withdrawn near the feed point of the crystallizer by a circulating pump and is passed through the cooler H where it becomes supersaturated and then fed back to the bottom of the crystallizer through the central pipe B. A vessel G can be used to remove very small nuclei that reach the upper layers of the vessel E. These nuclei pass again in the cooler and then to the vessel E through the tube B. The nuclei circulate with the mother liquor until they have grown sufficiently large to be retained in the fluidized bed (liquid fluidization). The final product is removed from the bottom of crystallizer though a valve M and a uniform product is therefore obtained because the crystals are not discharged until they have grown to the required size that settle opposing the flow from tube B. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 25  Oslo evaporative crystallizer It consists of a vapor head that is connected with a long discharge tube extending well to the bottom of crystal growth chamber Feed solution is usually introduced by a pump into a heater and then sent to vapor head. The hot solutions in the chamber become supersaturated due to evaporation but crystals are not formed in this chamber. It is then introduced into the crystal growth chamber through the inlet pipe that causes a swirling motion within solution. Coarser particles remain at the bottom and finer particles remain at the top of crystal bed and re-circulated liquid carries away finest particles and enters the vapor chamber via the heater and pump. Coarse crystals are discharged through the bottom 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 26  Oslo vacuum crystallizer Vacuum crystallizers produce supersaturated conditions by solvent removal and cooling. A warm concentrated solution is introduced into a chamber maintained at low pressure (vacuum). The solution boils and cools adiabatically to the boiling point corresponding to the operating pressure. Crystallization follows concentration, and the product is removed from the bottom of the vessel. Suitable for crystallizing thermolabile substances. Advantages: absence of heat exchange surface. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 27  References Hickey, A., & Ganderton, D. Pharmaceutical Process Engineering. (2001). Chapter 9: Crystallization Acknowledgement The lecture content was thankfully provided by Dr. John Youshia. 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 28 10.12.2024 Dr. Salma M. Abdel-Hafez – Pharmaceutical Technology – Crystallization 29