Lyophilization, drug crystallization

Another drying procedure that can yield changes in drug crystal form is that of freeze-drying, or lyophilization. In this approach, the material... 

An exothermic transition can sometimes be observed by DSC on crystallization of the amorphous form. This can be used to quantify the amorphous content of crystalline drugs. A calibration curve that consists of a plot of the enthalpy of crystallization as a function of crystalline content was used to determine if the lyophilized MK-0591 drug substance was... 

A drug solution is first frozen at atmospheric pressure, and then water is removed by a reduction of pressure in the lyophilizer chamber, coUecting the water as ice on a condenser. Samples are placed in glass vials and frozen, either before being put in the lyophilizer or on the lyophilizer shelves. The samples contain ice crystals, tmfrozen water, amorphous solids (including the therapeutic protein), and crystalline additives. Pressure is reduced, and the ice crystals sublime. This constitutes the primary drying. 

Another example of improved chemical stability for the lyophilized product includes the use of isopropyl alcohol in the freeze-drying of cefazolin sodium [19]. The presence of the isopropyl alcohol helped induce crystallization of the amorphous cefazolin sodium during the freezing phase. Use of the isopropyl alcohol with a thermal treatment phase enabled a freeze-dried crystalline form of the drug to be produced which possessed superior stability. Use of this co-solvent system also enabled the product to be more effectively processed with shorter... 

In another variation of the RESS process, referred to as RESS-SC, a solid cosolvent such as menthol was used to modulate the solubility of the drug (phenytoin) in the polymer (Thakur and Gupta 2006). It was shown that when drug particles were mixed with solid cosolvent such as menthol, the presence of solid cosolvent inhibited particle-particle interactions between drug particles, thereby hindering the crystal growth. As illustrated in Eig. 19.2, phenytoin particles are surrounded by menthol, which reduced interparticulate interactions with other phenytoin particles. The cosolvent (menthol) is then removed by downstream processing such as sublimation or lyophilization. 

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