Formulation and evaluation of atorvastatin calcium trihydrate Form I tablets
Karen Andrea Salazar-Barrantes, Ariadna Abdala-Saiz, José Roberto Vega-Baudrit, Mirtha Navarro-Hoyos, Andrea Mariela Araya-Sibaja
Abstract
Solid forms transformations and new crystal structures of an active pharmaceutical ingredient (API) can occur due to various manufacturing process conditions, especially if the drug substance is formulated as a hydrate. The conversion between hydrate and anhydrate forms caused by changes in temperature and humidity must be evaluated because of the risk of dehydration and phase transitions during the manufacturing process. Differences in physicochemical, mechanical, and rheological properties have been observed between solid forms of the same API that can cause manufacturing and product-related issues. Atorvastatin calcium trihydrate (ACT) is a synthetic lipid-lowering agent that was discovered during Lipitor® (its anhydrous form) Phase 3 clinical trials after passing Phase I and II. This case highlights the importance of routinely performing solid form screenings because of the probability of finding new solid forms during the development and scale-up process.
Introduction
Hydrates are one subtype of solid solvates, where water molecules are incorporated into the crystal lattice compound. Hydrates are considered novel solid forms that account for one-third of drugs developed [1]. Like every crystalline active pharmaceutical ingredient (API), hydrates are prone to polymorphism, which refers to the formation of different crystal structures of the same chemical molecule. Each of these crystalline structures can possess different mechanical, thermal, physical, and chemical properties that affect solubility, bioavailability, hygroscopicity, melting point, stability, compressibility, and other characteristics that ultimately determine drug performance [2], product quality and safety.
Materials and method
Materials
ACT, excipients, including microcrystalline cellulose 101 (MCC 101), calcium carbonate (CaCO3), lactose monohydrate (LM), croscarmellose sodium (CS), hydroxypropyl cellulose (HPC), magnesium stearate (MS), and polysorbate 80 (P80), API-excipient mixtures, and solids obtained at five points of the manufacturing process were kindly donated by Calox de Costa Rica (San José, Costa Rica).
Results and discussion
Compatibility study
As shown in Table 1, seven relevant excipients were selected to complement the materials used in a previous compatibility study at the preformulation level [3]. The appropriate selection of excipients is crucial, as it determines the fate of the final dosage form [13]. Thermal analysis provides quick, preliminary insights into potential interactions, allowing a direct evaluation of binary mixtures without requiring time-consuming stress conditions [14]. However, thermal analysis cannot fully predict compatibility, as the final formulation may differ from the preformulation mixtures [3].
Conclusions
Compatibility studies of ACT with excipients for solid dosage forms development showed no interactions, as confirmed by PXRD and FT-IR. However, the overlapping of characteristic bands in the spectra of calcium carbonate and magnesium stearate did not provide a clear indication of drug-excipient interaction. DSC analyses demonstrated a physical interaction between ACT and microcrystalline cellulose 101, likely heat-induced, with a lower melting temperature.
Acknowledgments
Authors thank the National Center for High Technology of Costa Rica CeNAT-CONARE, the National Laboratory of Nanotechnology (LANOTEC), CALOX de Costa Rica and the University of Costa Rica.
Citation: Salazar-Barrantes KA, Abdala-Saiz A, Vega-Baudrit JR, Navarro-Hoyos M, Araya-Sibaja AM (2025) Formulation and evaluation of atorvastatin calcium trihydrate Form I tablets. PLoS ONE 20(2): e0317407. https://doi.org/10.1371/journal.pone.0317407
Editor: Amjad Khan, Kohat University of Science and Technology (KUST), PAKISTAN
Received: May 20, 2024; Accepted: December 28, 2024; Published: February 13, 2025
Copyright: © 2025 Salazar-Barrantes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the main manuscript and in the Supplementary material.
Funding: CeNAT Scholarship Program.
Competing interests: The authors have declared that no competing interests exist.
