Preformulation Studies on Phenytoin Agglomerates Prepared by Hot Melt

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PREFORMULATION STUDIES ON PHENYTOIN AGGLOMERATES PREPARED BY HOT MELT

Dr. Maged Fawzy DEEF Pharmaceutical Industries Company, SA This work was a part of Master thesis presented in Faculty of Pharmacy, AlAzhar University, Egypt 2007

INTRODUCTION
Hot Melt
Hot melt agglomeration is one type of wet granulation techniques that may be utilized to enhance the dissolution profile of water insoluble drugs. Hot melt agglomeration is also called thermoplastic granulation and it may be defined as the process in which the granulation is achieved via utilization of granulating agent which is in the solid state at room temperature, this granulating agent has low melting point (40 -80)C. Melt agglomeration techniques: 1. In situ agglomeration, in which the whole powder bed including agglomerating agent are mixed and the bed temperature raised stepwise till reaching the melting point of the agglomerating agent. 2. Pump on melt agglomeration in which the melted agglomerating agent is added to pre-heated powder bedi . 3. Utilization high shear mixing in melt agglomeration, using mixer with impeller speed range 100 -500 rpm, as the intensive agitation raises the temperature of the powder bed enough to melt the agglomerating agent. 4. Spray congealing by atomizing a drug dispersion in a melted carrier, then allow the melted droplets to solidify.ii Advantages of Hot melt process: 1. No solvent is added. 2. Fewer processes are performed. 3. Drying step is eliminated. 4. Safe application to the environment. 5. Uniform distribution of the particles. Disadvantages of hot melt process: 1. It is a high energy input process. 2. The process could not be applied to thermolabile drugs. Rumpf iii-iv classified the mechanisms of agglomeration binding into: 1. Nucleation of primary particles (Figure 1A): as the system temperature raised to about 2/3 of the melting temperature of solids - by heat introduced to the system from external source or created during the below

process by friction - diffusion of molecules from one particle to another occurs forming solid bridge. 2. Coalescence (Figure 1B) takes place following random collision of well formed nuclei. The coalescence occurs only if the particles have excess surface moisture. 3. Layering (Figure 1C) is the growth mechanism of the formed nuclei which occurs by successive addition of material on already formed nuclei. 4. Abrasion transfer (Figure 1D) involves transfer of material from one particle to another without any preference in either direction. 5. Size reduction which has indirect effect on the growth mechanisms. Size reduction may occur via attrition (Figure 2A), breakage (Figure 2B) and shatter (Figure 2C). The produced fragments redistribute onto surviving nuclei and participate in the growth processiv. The agglomerating liquid plays an important role in determining the particle size of the produced granules. A uniform liquid distribution is an important factor for controlling the growth of nuclei. The interaction between the granulating liquid and the particle surface is dependent on the ability of the liquid to wet the particle surface, this is achieved if the granulating liquid has surface activity v. Models for moist agglomerates according the state of liquid in moist agglomeratesiv: 1. Pendular state, occurs when the liquid fill part of the void space to form discrete lens-like rings at the contact points between particles forming the agglomerates (Figure 3 A). 2. Funicular state occurs when the liquid bridge containing gas and pores filled with liquid are present and pockets of air are dispersed throughout the agglomerate (Figure 3 B) 3. Capillary state is reached when all void space within the agglomerate is completely filled with liquid and the primary particles are held together only by the surface tension of the droplet (there is no interparticle capillary bonding) (Figure 3 C) 4. Droplet state in which the liquid completely envelopes the agglomerates (Figure 3 D) .The...
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