DEVELOPMENT OF AN INTEGRATED METHODOLOGY FOR ANALYZING INTERACTIONS IN SOLID PHARMACEUTICAL FORMULATIONS USING ATOMIC FORCE MICROSCOPY AND PYTHON

The design and manufacture of medicines is a costly and time-consuming process for the pharmaceutical industry. Solid forms are the most widely used on the market, making it crucial to understand the interactions of formulation compounds during their development. This project aims to develop an integrated methodology for analyzing the compounds of a solid model formulation of efavirenz (EFV) produced by Farmanguinhos/Fiocruz. Samples of the compounds were deposited on double-sided adhesive tape on a stainless-steel disk. After applying a compressive force for 45 minutes, tablets of the inputs were obtained. Atomic force microscopy (AFM) was employed to study the morphology and interactions between the formulation compounds and EFV. The probe was functionalized with the Active Pharmaceutical Ingredient (API), and force maps were then obtained using the Force Volume method between EFV and the compounds. All processing steps were performed using Nanoscope Analysis software. The curves were adjusted with the Baseline Correction (0-90%) command. Subsequently, adhesion and maximum snap-in were determined with the Indentation command. This procedure was automated using the Run Autoprogram command, which allows the opening of 1024 curves from each image and the automatic retrieval of data. Due to the large amount of information generated, a Python pipeline was developed, using as indicators of a good force curve the coefficient of determination (R²) of the force curve slope and the condition snap-in<adhesion. This approach allowed the interaction ratio between the excipient and the API to be determined, ranking compounds from the lowest to the highest interaction with the API, and correlating these data with other techniques applied in the pharmaceutical industry, such as flowability quantification, dissolution, and bioavailability. The project also includes computational modeling of interactions between formulation compounds, using AFM data as validators and comparing interaction results with unsuccessful formulation components. These methodologies can significantly reduce the time and cost of developing new solid pharmaceutical formulations, as techniques like AFM use minimal pharmaceutical input.

This work was supported by Conselho Nac. Des. Cient. Tecnologico (CNPq 408525/2023-1), by Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ E-26/010.000983/2019, E-26/211.568/2021, E-26/210.042/2023 and E-26/200.210/2023), by Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES – master's scholarship), and by Fundação Oswaldo Cruz (FIOCRUZ)