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Thermal Analysis and Freeze-Drying of TBA/Water Cosolvent System

Author: ZuoJianGuo
Tutor: HuaZeZuo;LiuBaoLin
School: University of Shanghai for Science and Technology
Course: Refrigeration and Cryogenic Engineering
Keywords: Freeze-drying Tertiary butyl alcohol (TBA) Cosolvent Differential scanning calorimetry Cryomicroscopy Glass transition Devitrification Proliposome
CLC: TQ460.6
Type: PhD thesis
Year: 2005
Downloads: 405
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Freeze-drying, or lyophilization, is commonly used in the pharmaceutical and biotechnology industries to improve the stability of formulations. The overwhelming majority of the products are lyophilized from simple aqueous solutions. Water is typically solvent of significant quantity that must be removed from the solution via the freeze-drying process. But this is restricted to drugs that are soluble and stable in an aqueous medium. Organic or organic/water cosolvent system is often used for freeze-drying to reduce the degradation rate of the formulations or to increase solubility. Among non-aqueous solvents, tertiary butyl alcohol (TBA) is of particular interest because of its high freezing and eutectic temperature, high vapor pressure, low toxicity and high solubility in water. TBA has also been reported to alter the crystal habit of ice by forming relatively large needle-shaped ice crystals which result in decreased resistance of the partially dried solids to flow of water vapor during freeze-drying. Now TBA/water cosolvent system has been used for the production of some pharmaceutical products by freeze-drying.This research is part work of the projects Thermal Problem during Cooling and Heating of Organism in Clinical Medicine (50436030) and Heat and Mass Transfer in Freeze-drying for Food and Drug (50376040) supported by the National Natural Science Foundation of China.The main work and discovery are as follows.The shape and size of the ice crystals in the frozen TBA/water cosolvent system are relative to the concentration of TBA. 10% TBA binary aqueous solution forms needle-shaped ice crystals. Differential scanning calorimetry (DSC) was employed to study the freezing properties. TBA binary aqueous solution exhibits no Tg’, even in the case of fast cooling of the sample, but shows the endothermic melting peak of the eutectic at the temperature of -8.5℃. When the solution is cooled, metastable TBA crystals may appear which can be eliminated through annealing. Thermal history has pronounced effect on nucleation temperature, supercooling degree and the glass transition temperature (Tg’).For 10%TBA/10%sucrose/water ternary system, the ice crystals are still linear. The presence of sucrose hinders the crystallization of TBA during cooling. The residual TBA in the glassy state will cause a decrease in Tg’and will crystallize during heating. An increase in the cooling rate causes a decrease in Tg’. When the cooling rate is 10℃/min, the value of Tg’decreases from -32.5℃to -42℃and TBA devitrifies at -30℃during heating. For 10%TBA/10%sucrose/water ternary system, the critical heating rate is approximately 250℃/min. When the frozen solution is annealed at temperatures around the devitrification peak, TBA can crystallize completely and the value of Tg’increases from -42℃to -34.9℃. Annealing duration depends on annealing temperature. The devitrification will disappear after annealing at -37℃for 20 min. Annealing treatment at temperatures below Tg’also causes the crystallization of TBA, which indicates that TBA molecules still have appreciable mobility even at temperatures below Tg’and the glassy state is not stable. When the ratio of TBA to sucrose is less than 0.2, TBA can not crystallize during cooling.A new laboratory freeze-dryer is developed which includes a cascade refrigerating system. And the surface temperature of cold trap and shelf can be lower when the refrigerating unit is operated.Freeze-drying of mono-phase solutions of TBA/water cosolvent system can be used to prepare proliposome which forms liposome after rehydration. For solutions containing different lyoprotectants ( sucrose, maltose, lactose, mannitol ), the addition of TBA can cause a decrease of Tg’. To study the effect of sugar/polyol on the size of rehydration of freeze-dried proliposome, the size of liposome with different lyoprotectants ( sucrose, maltose, lactose, mannitol ) and different concentrations (3%, 5%, 10% (w/v)) was measured. The experimental results show that the size is between 200 and 900 nm. When sucrose is used as lyoprotectant, the size is the smallest. And the size decreases with increasing sucrose concentration. For 10% (w/v) sucrose solution, the size is about 235 nm. The size is the biggest when mannitol is used as lyoprotectant. Even increasing mannitol concentration can not cause a decrease of the size.

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