(411e) A Multi-Scale Approach to Understanding Spray Dried Dispersion Impurity Generation

A common strategy to enhance the bioavailability of poorly soluble molecules is to generate an amorphous solid dispersion by spray-drying. This processes generally requires the dissolution of the drug molecule in an organic solvent, which is then spray-dried co-currently by means of a hot nitrogen gas stream to remove the majority of the solvent phase. Typical low boiling point organic solvents, such as acetone, dichloromethane, ethanol, or methanol, are often used due to the suitable solubility of drug substance. Larger scale spray dryers used to support late phase clinical and commercial production typically operate in a closed loop configuration. Residual amounts of gas phase solvent are recirculated and exposed to elevated temperatures during reheating of the gas stream to the desired process conditions.

Amine functional groups, often found in new drug molecules, are known to undergo nucleophilic substitution reactions promoted by aldehydes or ketones. Primary alcohols such as ethanol or methanol can undergo dehydrogenation in the presence of a metal oxide catalyst at high temperature and low pressure, yielding the corresponding aldehyde. Data suggests that these conditions exist in the heater of the recirculated drying gas in a spray drying process; sufficiently to generate measurable quantities of the aldehyde. The resulting aldehyde can react further to promote the chemical degradation of the amine group in the drug molecule. Furthermore, the presence of the aldehyde in some systems is known to induce strong non-linearities in the vapor-liquid equilibria by the generation of new species resulting from the interaction of the solvent and the generated aldehyde. This work studies the extent of formaldehyde formation and the speciation consequences in a closed-loop spray drying process in the presence of a stainless-steel heater, while spray-drying a methanol solution.