Formulation and evaluation of atorvastatin calcium trihydrate Form I tablets

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Chemical Engineering

Background:

• Solid form transformations of active pharmaceutical ingredients (APIs), particularly hydrates, can occur during manufacturing due to environmental factors like temperature and humidity.
• These transformations can alter physicochemical, mechanical, and rheological properties, potentially leading to manufacturing and product quality issues.
• Atorvastatin calcium trihydrate (ACT) is a lipid-lowering agent; its anhydrous form is known as Lipitor®.

Purpose of the Study:

• To evaluate the formulation and manufacturing process of atorvastatin calcium trihydrate (ACT) tablets.
• To assess the compatibility of ACT with common pharmaceutical excipients.
• To investigate the impact of tablet manufacturing on the solid-state properties of ACT and the quality of the final product.

Main Methods:

• Preformulation studies involving compatibility testing of ACT (Form I) with microcrystalline cellulose 101, calcium carbonate, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, and polysorbate 80 at a 1:1 ratio.
• Small pilot-scale manufacturing of 40 mg ACT tablets.
• Process assessment at critical stages for solid form changes.
• Characterization of raw materials and final products using Powder X-ray Diffraction (PXRD), Fourier Transform Infrared Spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), and Thermogravimetric Analysis (TGA).
• Evaluation of final tablet quality, including weight variation, hardness, disintegration, dissolution, and assay.

Main Results:

• Preformulation studies indicated no chemical interactions between ACT and excipients, although DSC revealed a physical interaction with microcrystalline cellulose 101.
• Tablet manufacturing resulted in partial amorphization of ACT, with some crystalline structure remaining, as confirmed by PXRD, FT-IR, and DSC.
• All evaluated tablet quality parameters (weight variation, hardness, disintegration, dissolution, assay) met pharmacopeial and manufacturer specifications.

Conclusions:

• The tablet formulation and manufacturing process for atorvastatin calcium trihydrate (ACT) are robust.
• Despite partial amorphization during processing, the final ACT tablets maintain acceptable quality and performance characteristics.
• Routine solid-form screening is crucial during drug development and scale-up to identify and manage potential polymorphic changes.