Evaluation of the polymorphic forms of ritonavir and lopinavir in raw materials and co-milled systems

Author(s)

Pinheiro, Lucas Barboza Moreira ; Tao, Songsheng ; Culbertson, Elizabeth ; de Araujo, Gabriel Lima Barros ; Billinge, Simon J. L. ; Ferreira, Fabio Furlan

• Document type: Journal article
• Source: International Journal of Pharmaceutics; v. 628, p. 9-pg., 2022-10-28.

Abstract

Recently, the U.S. Food and Drug Administration (FDA) approved the first oral antiviral drug to treat mild to moderate cases of coronavirus disease. The combination of nirmatrelvir with an already used protease inhibitor class drug, ritonavir, has led to Paxlovid (R). Several studies considered drug repositioning as the first trial for new drugs. The precise identification and quantification of polymorphs in raw materials and finished products are important to researchers involved in pharmaceutical development and quality control processes. In this work, we study the solid-state behavior of the antiretroviral drugs ritonavir and lopinavir in raw materials and in milled compositions. The results indicate that mixtures of ritonavir Forms I and II are found in different batches of raw materials from the same manufacturer; besides three equal crystalline samples, an amorphous batch was found in lopinavir. Furthermore, the milling process of the already amorphous lopinavir seems to facilitate the amorphization of ritonavir as well as the production of some unexpected crystalline forms of ritonavir. A phase transition of ritonavir Form I to Form II is only observed when co-milling with amorphous lopinavir. These findings reveal significant variations in phase purity of raw materials that affect the processing and solid-state properties, representing risks for the product quality. (AU)

• FAPESP's process: 17/16499-5 - Study of polymorphic forms of raw materials of ritonavir and lopinavir with the use of powder x-ray diffraction and the Rietveld method
• Grantee: Lucas Barboza Moreira Pinheiro
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 21/03640-7 - Synthesis and investigation of new crystalline forms of antineoplastic agents
• Grantee: Fabio Furlan Ferreira
• Support Opportunities: Regular Research Grants