(360c) Deagglomeration By Conical Milling of a Temperature Sensitive Amorphous Peptide

Conical milling is a common pharmaceutical unit operation in both drug substance and drug product processing. Milling is often implemented after granulation and drying operations as a method of particle size control or more simply as a pharmaceutical elegance operation. For traditional small molecule synthetic active pharmaceutical ingredients (APIs), basic milling process design criteria are well understood and conical mills can be implemented with limited-to-no development. For APIs that are amorphous, temperature sensitive, or both, additional understanding of the material properties and operating conditions are necessary. Characterization of second order thermal transitions of amorphous APIs are necessary to ensure the material remains a suitable solid without a transition to tacky material. Dynamic mechanical analysis and differential scanning calorimetry are used to assess the temperature depended physical property risks to the API during milling. An understanding of the API stability and the thermal profile of the conical mill along with the material characterization gives the necessary information for a rationale design of the milling operation. Applying this methodology to Compound A, an amorphous peptide, a direct scaling of the process from 20 g to 100 kg was successful, while ensuring robust control to deliver high purity API.