Salting-Out crystallization of glycopeptide Vancomycin: Phase behavior study to control the crystal habit

Needle-shaped crystals pose downstream processing issues in pharmaceutical manufacturing. Strategies to avoid needle-shaped crystal formation have been developed for small-molecule and protein pharmaceuticals. Controlling crystal habit of peptides, whose molecular weight lies between small molecules and proteins, has never been investigated. The present work studied phase behavior of salting-out room-temperature crystallization of glycopeptide vancomycin to determine crystallization conditions to avoid needle-shaped crystal formation. Batch crystallizations of prominent crystal habits identified from phase behavior study (i.e., needle and non-needle) were subsequently performed. Batch crystallization's products were evaluated in their production yield/capacity, purity, size distribution, thermal stability, interfacial water content, dissolution profile, and antibiotic activity. The results showed octahedral crystals as the predominant habit produced at higher yield across the range of pH, salt/peptide concentrations investigated. Needle crystal formation was avoided by pH and salt concentration controls. Both crystal habits exhibited many similar properties, but with distinct thermal stability and dissolution profiles.