Spherical Crystallization PPT
- 1. Pharmastuff.blogspot.com Spherical crystallization Topics covered What is spherical crystallization Methods of Preparation of spherical crystallization Steps involved in spherical crystallization Factor affecting process of spherical crystallization
- 3. Pharmastuff.blogspot.com Spherical crystallization is a particle design technique, by which crystallization and agglomeration can be carried out simultaneously in one step. Improves flowability and compressibility. Crystalline forms of a drug to be converted into different polymorphic form having better bioavailability. For masking of the bitter taste of drug. Spherical crystallization
- 4. Pharmastuff.blogspot.com Traditional method Granulation Drying Filtration Crystallization Drying Tabletting Drying Filtration Crystallization Spherical crystallization Tabletting Less equipment and space Lower labor costs Less processing time Lower energy consumption
- 5. Pharmastuff.blogspot.com General guide lines for the spherical agglomeration of drugs Chow et al postulated some general guide lines for the spherical agglomeration of drugs • For compounds that are water soluble, a water-immiscible organic solvent is used as the external medium and salt solutions of high concentration without common ions can be used as the bridging liquid. • For compounds that are soluble in one or more organic solvents water is employed as the external phase and a water-immiscible organic solvent as the bridging liquid.
- 6. Pharmastuff.blogspot.com . • For compounds that are only soluble in water-miscible organic solvents a saturated aqueous solution of the compound can serve as the external phase and an organic solvent mixture as the bridging solvent. • For compounds that are insoluble in water or any organic solvents a water-immiscible organic solvent can act as the external phase and a 20% calcium chloride solution as the bridging liquid. In addition, a binding agent such as PVP or PEG is required for agglomeration since the powders are not sufficiently soluble in the bridging liquids to allow binding through recrystallization and fusion. General guide lines for the spherical agglomeration of drugs
- 8. Pharmastuff.blogspot.com Wet Spherical agglomeration A near saturated solution of the drug in the good solvent is poured into the poor solvent. Crystals will precipitate immediately. In the spherical agglomeration method a third solvent called the bridging liquid is added in a smaller amount to promote the formation of agglomerates As a result of interfacial tension effects and capillary forces, the bridging liquid makes the crystals to adhere one another . WSA depends of choice of bridging liquid, the stirring speed and the concentration of solids (or of the solute) .
- 9. Pharmastuff.blogspot.com • Less than the optimum amount of bridging liquid produces plenty of fines and more thanoptimum produces very coarse particles. • Also the choice of bridging liquid, the stirringspeed and the concentration of solids (or of the solute) are of importance. In the case of lactose, the agglomerate size distribution was affected by both the size of raw particles andthe amount of bridging liquid used. At increasing stirring rate the agglomeration was reduced because of increasing disruptive forces. • Higher stirring rate produce agglomerates that are less porous and more resistant to mechanical stress, and the porosity decreases when the concentration of solid increases • The viscosity of the continuous phase has an effect on the size distribution of the agglomerates. The choice of bridging liquid has an influence on the rate of agglomeration and on the strength of the agglomerates. Wet Spherical agglomeration
- 10. Pharmastuff.blogspot.com • This technique is usually applied for the preparation of microspheres . • Here interaction between the drug and the good solvent is stronger than that of the good and poor solvents; hence the good solvent drug solution is dispersed in the poor solvent, producing quasi emulsion droplets, even if the solvents are normally miscible . This is because of an increase in the interfacial tension between good and poor solvent . • Then good solvent diffuses gradually out of the emulsion droplet into the outer poor solvent phase. The counter diffusion of the poor solvent into the droplet induces the crystallization of the drug within the droplet due to the decreasing solubility of the drug in the droplet containing the poor solvent. Quasi-Emulsion Solvent Diffusion method
- 11. Pharmastuff.blogspot.com • In this method, the mixture of three partially immiscible solvent i.e. acetone, ammonia water, dichloromethane was used as a crystallization system. • In this system ammonia water acted as bridging liquid as well as good solvent, Acetone was the water miscible but a poor solvent, thus Drug precipitated by solvent change without forming ammonium salt. • Water immiscible solvent such as hydrocarbons or halogenated hydrocarbons e.g. dichloromethane induced liberation of ammonia water Ammonia diffusion method
- 12. Pharmastuff.blogspot.com • Drug crystals are precipitated by neutralization of the base with acid. and then poured into an acidic solution containing polymers and bridging liquid under constant agitation • Spherical crystals of tolbutamide and phenytoin have been prepared by this technique. Neutralization Method
- 13. Pharmastuff.blogspot.com • It is a modification of the wet spherical crystallization technique in which drug is crystallized andagglomerated with an excipient or with another drug. • This process enables design of agglomerates containing two drugs or poorly compressible drug in combination with diluents and is restricted to water insoluble large-dose drugs only. • Difference in the physicochemical properties of drug molecules and excipient is a major challenge in the selection of the solvent system for the Crystal-co-agglomeration technique Crystal-co-agglomeration technique
- 14. Pharmastuff.blogspot.com flocculation zone, zero growth zone, fast growth zone and constant size zone A)Flocculation zone: In this zone, bridging liquid displaces the liquid from the surface of the crystals and these crystals are brought in close proximity by agitation. The adsorbed bridging liquid links the particles by forming bridge between them. B)Zero growth zone: During this growth phase, the entrapped fluid is squeezed out followed by squeezing of the bridging liquid onto the surface of small flocs. Loose floccules are transformed into tightly packed pellets C)Fast growth zone: The fast growth zone of the agglomerate takes place when sufficient bridging liquid has squeezed out of the surface of the small agglomerates. This formation of large size particle after random collision of well formed nucleus is known as coalescence. D)Constant size zone: In this zone agglomerates cease to grow or even show slight decrease in size. Here thefrequency of coalescence is balanced by the breakage frequency of agglomeration. The rate determining step in agglomeration growth occurs in zero growth zones when bridging liquid is squeezed out of the pores as the initial floccules are transformed into small agglomerates. Steps involved in Spherical Crystallization
- 15. Pharmastuff.blogspot.com 1.Solubility profile: Selection of solvent depends upon the solubility characteristics of the drug. The proportion of solvent to be used is determined by carrying out solubility studies and constructing a ternary phase diagram. 2.Mode and intensity of agitation: High speed agitation is necessary to disperse the bridging liquid throughout the system. Change in the agitation pattern or fluid flow will affect the shape of agglomerates. The extent of mechanical agitation and the concentration of bridging liquid determines the rate of formation of agglomerates and their final size. 3.Temperature of the system: It has a significant influence on the shape, size and texture of the agglomerates. The effect of temperature on spherical crystallization is probably due to its effect on the solubility of drug substance. 4.Residence time: It is defined as the time for which agglomerates remain suspended in the reaction mixture. Residence time affects the strength of agglomerates. 5.Amount of bridging Liquid: Median diameter of agglomerated crystals increases with decrease in the amount of bridging liquid in the three-solvent system. Insufficient bridging liquid produces plenty of fines and excess produces very coarse particles Factors affecting Spherical Crystallization
- 16. Pharmastuff.blogspot.com REFERENCES : 1.Patil et al (2009).,Spherical Crystallization: a Method to Improve Tabletability. Research J. Pharm. and Tech.2 (2): April.-June. 2009,REVIEW ARTICLE. 2. Gokul R ghenze et al (2011).,An overview to spherical crystalisation and its evaluation.Internation journal of applied pharmaceutics. Vol 3, Is.sue 3, 2011.REVIEW ARTICLE 3. Mahanty et al (2010)., Particle Design of Drugs by Spherical Crystallization Techniques. International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 • Issue 2 • July - September 2010 .REVIEW ATICLE. 4.Gupta et al (2010)., Spherical crystallization: a tool of particle engineering for making drug powder suitable for direct compression.IJPRD.REVIEW ARTICLE. 5. 1.Shangraw RF. Compressed tablets by direct compression. In: Lieberman HA, Lachman L, Schwartz JB. Pharmaceutical Dosage Forms: Tablets, vol. 1. Marcel Dekker, New York 1989; 195-246.
- 17. Pharmastuff.blogspot.com REFERENCES : 6.Sano A, Kuriki T, Kawashima Y, Takeuchi H, Hino T, Niwa T, Particle design of Tolbutamide by the spherical crystallization technique III micrometric properties and dissolution rate of tolbutamide spherical agglomerates produced by qesi emuslion solvent diffusion method, Chem. Pharm. Bull. 38: 733-739 (1990) 7.Kawashima Y, Cui F, Takeuchi H, Hino T, Niwa T, Kiuchi K. Parameters determining the agglomeration behavior and the micrometric properties of spherically agglomerated crystals prepared by spherical crystallization technique with miscible solvent system. Int J Pharm. 1995; 119: 139-147. 8. Sano A, Kuriki T, Kawashima Y, Takeuchi H, Hino T, Niwa T.Particle design of Tolbutamide by the spherical crystallization technique IV, Improved of dissolution and bioavailability of direct compression tablets prepared using Tolbutamide agglomerated crystals, Chem. Pharm. Bull. 40, pp 3030-3035. 9. Chavda V, Maheshwari RK. Tailoring of ketoprofen particle morphology via novel crystallo- coagglomerationtechnique to obtain a directly compressible material Asian J. Pharm. 2(1), pp 61-67. 10.Patil S. V. , Sahoo S. K. Pharmaceutical overview of spherical crystallization Research Library,Der Pharmacia Lettre, 2 (1), pp 421-426. 11. P.K. Kulkarni, B.G. Nagavi. Ind. Jr. Pharm. Eudc. 2002; 36(2), pp 66-73.