Formulation and evaluation of atorvastatin calcium trihydrate Form I tablets

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.

Therefore, in this contribution, ACT tablet formulation was performed and evaluated starting from the compatibility of 1:1 proportions of drug and the excipients microcrystalline cellulose 101 (MCC 101), calcium carbonate, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, and polysorbate 80. Then, 40 mg ACT tablets were prepared on a small pilot scale, and manufacturing process assessment was conducted by sampling process stages selected as critically prone to solid forms formation or phase transition. Final product quality was evaluated regarding weight variation, hardness, disintegration, dissolution, and assay tests. Powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) were applied to solid state evaluation. The starting raw material was confirmed to be ACT Form I. From the preformulation studies, PXRD, FT-IR and TGA analyses showed no interactions between ACT and excipients, while DSC results revealed a physical interaction with MCC 101, not considered an incompatibility. The effect of the tablet manufacturing process was achieved by amorphization, while some ACT long-range crystalline structure remained, as confirmed by PXRD, FT-IR and DSC. However, the tablets’ quality parameters were found to be within the acceptable range of both the pharmacopeia guidelines and manufacturer parameters regarding weight variation, hardness, disintegration, dissolution, and assay tests.

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.

It is well-known that solid forms transformations and new crystal structures of an API can arise due to various manufacturing process conditions. The conversion between hydrate and anhydrate forms caused by changes in temperature and humidity require special attention, particularly if the drug substance is formulated as a hydrate. Likewise, studying the interactions between various APIs and excipients during the pre-formulation stage is crucial, as the properties largely depend on the chosen excipients, their concentration, and API-excipient interactions [3]. Excipients are usually ignored by manufacturers, even though their solid form might affect stability, compressibility, wettability, and other crucial attributes in a continuous manufacturing operation [4]. Therefore, for the development of a pharmaceutical product of a hydrate drug, it is essential to understand the relationship between a particular solid form and its functional properties due to its impact on manufacturing processes and drug safety, effectiveness, and quality [4, 5]. To achieve this goal, the whole process needs to be studied to ensure there are no changes in the APIs crystal structure during its production.

Atorvastatin calcium trihydrate (ACT), chemically designated as [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate ([C33H34FN2O5]2Ca·3H2O; MW 1209,42 g/mol; Fig 1), is a synthetic lipid-lowering agent that belongs to Biopharmaceutics Classification System (BCS) class II [6].

Obesity has become one of the leading global health issues, with its prevalence more than doubling over the last three decades. It now contributes to approximately 1.3 million deaths each year and is characterized by an abnormal or excessive buildup of lipids in the body [7]. This significantly increases the risk of cardiovascular diseases, diabetes, and other metabolic disorders. A popular treatment for these disorders is ACT, an inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis [8, 9]. ACT is a hydrate form of the atorvastatin calcium anhydrous initially marketed by Pfizer under the name Lipitor®, holding the record of the best-selling medication in 2008 with a revenue of 12.4 billion dollars [8, 9]. It was indeed discovered during Phase 3 clinical trials after passing Phase I and II with the amorphous form [5]. This case highlights the importance of routinely perform solid form screenings because of the probability of finding new solid forms during the scale-up development process [5].

Considering ACT has a high incidence of polymorphs, hydrates, and solvates formation [10], the history of its parent compound and that to the best of our knowledge, there has not been reported a real tablet manufacturing process considering solid forms transformation for ACT form I. The present study aimed to contribute to the limited number of illustrative cases in the literature for this drug [11], starting with the drug-excipient interaction evaluation, the manufacturing process assessment and the final product quality test.

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Table 1. Excipients mixed with ACT and their codes used in the compatibility study

Following excipients are mentioned in the study besides other: Microcrystalline cellulose 101, Calcium carbonate, Lactose monohydrate, Croscarmellose sodium, Hydroxypropyl cellulose, Magnesium stearate, Polysorbate 80

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://journals.plos.org/plosone/article?id=10.1371/journal.pone.0317407

Read also our introduction article on Microcrystalline Cellulose here: