(549f) Isolation of Amorphous Peptides: Problems and Solutions

Natural and synthetic peptides, composed of a series of amino acids, are promising pharmaceutic modalities for the treatment of a wide variety of indications such as diabetes, cancer, migraine, heart failure and more. While producing peptides in a synthetic manner has several advantages such as being able to accommodate non-natural amino acids in the chain, it also comes with challenges around process complexity, elevated more so when following a hybrid approach that involves a couple dozen steps for API synthesis alone. To add to that, the drug substance manufacturing network is complex and spread around the globe, which often requires shipment of intermediates for downstream processing.

A common method for isolating solids that can be stored and shipped under stable conditions is freeze-drying or lyophilization. However, the lyophilization of peptides can sometimes be undesirable. Another way to isolate amorphous peptide intermediates and APIs is precipitation, which is easy to fit in any small molecule isolation equipment set.

Peptides are extremely prone to gelation. While the fundamentals of peptide gelation in organic media aren’t completely understood to date, we have, in part, learnt to navigate the challenging physical properties and isolate peptides robustly.

In this presentation, we will discuss the various considerations in designing a peptide precipitation process such as the sensitivity around solvent selection, temperature, addition order and rate, ageing, and mixing. We will further share, through the example of a model peptide, the challenges encountered during precipitation, filtration and washing. We will present phase diagrams for process design and mixing models for scale up. Ultimately, manufacturing data showing the successful isolation of gelation-prone peptides will be shared.