Structure of Products Prepared by Freeze-Drying Solutions Containing Organic Solvents

Abstract

An increasing number of parenteral products are being prepared by freeze-drying techniques. In this method, a sterile aqueous solution of the drug is frozen in a sterile container and the ice and bound water are removed aseptically by sublimation and vacuum drying, respectively. The method reduces the particulate contamination and improves the product quality. The purity of the product may be increased and the dissolution rate on reconstitution is enhanced. Solutions of pharmaceutical powders, prepared for freeze-drying often contain various concentrations of organic solvent. The solvents may be added to reduce the degradation rate of the active material in water during processing or may be present as a residual impurity in the pharmaceutical powder or bulk intermediate used to prepare the freeze-drying solution. The presence of organic solvents affects the freezing characteristics of products cooled by conventional techniques. The solvents may freeze or remain present as an unfrozen liquid residue distributed throughout the ice matrix as an interconnecting capillary network. The solvents retain varying quantities of associated water and various concentrations of dissolved drug. The volumes vary and are related to the hydrophilic properties of the solvent. The presence of solvents affects the rate of drying and influences the choice of plant design, the production capacity, and the product quality. Products which are frozen, dry rapidly by direct sublimation drying. In semi-frozen systems, the products dry more slowly by the simultaneous sublimation of ice and the evaporation of the liquid solvents. In this paper, the freeze-drying properties of a number of drug solutions containing various organic solvents have been studied. Several drugs have been processed from aqueous solution containing up to 20% of ethanol, n. propanol, n. and tert. butanol, ethylacetate, dimethyl carbonate, acetonitrite, dichloromethane, methylethyl ketone, and methylisobutyl ketone. The studies have been conducted in a small research dryer and in both pilot plant and large scale industrial freeze dryers. In this paper, the principles of the methods are reviewed and the physical chemistry of the operation is discussed. The mechanisms of freeze-drying are elucidated and the characteristics of the finished products are compared.