(T1030-03-21) Injection-Molded Coamorphous Tablets: Analysis of Intermolecular Interaction and Crystallization Propensity

Purpose: Manufacturing coamorphous products on an industrial scale remains a challenge. The materials in the amorphous state with high free energy provide a driving force for crystallization during the tablet manufacturing processes which introduce mechanical or chemical stress. In an effort to reduce the number of unit operations, this research attempted the simultaneous formulation of a coamorphous tablet through the injection molding technique. We focused on (i) a single-step preparation of a coamorphous tablet via injection molding from the bulk powder, and (ii) a characterization of the molecular state in the coamorphous. Mechanistic understanding of the formation and the stabilization effects of excipients were discussed deeply.

Methods: Weakly basic loratadine (LOR)−organic acid coamorphous was used as a model compound. As counter acids, anhydrous citric acid (CIT), succinic acid (SUC), L-tartaric acid (TAR), and L-malic acid (MAL) were selected by a differential scanning calorimetry (DSC) screening. An equimolar mixture of LOR and each acid, for a total of 10.0 g powder, was pre-mixed using a mortar and pestle and then loaded into a cylinder pot and heated to 140°C for 10 min. The molten samples were injected into a 3D printed mold cavity for the tablet and quenched at room temperature. Prepared tablets and grounds were subjected to X-ray diffractometry (XRD), modulated DSC, Fourier-transform infrared spectroscopy (FT-IR), and Terahertz spectroscopy (THz). The dissolution testing was performed in acidic medium (pH 1.2; 37°C). Physical stability of the coamorphous tablets in the 40°C/75%RH environment was evaluated by XRD.

Results: Each LOR−acids coamorphous tablet was produced by an injection molding technology (Figure 1). Four tablets, consisting of LOR−CIT, LOR−SUC, LOR−TAR, and LOR−MAL coamorphous systems, enhanced the dissolution ability of LOR and formed ionic interactions between the molecules. In addition, a physical stability of the coamorphous tablets was influenced by the acid used (SUC < MAL < TAR < CIT). The glass transition temperature analysis reveals the difference of interaction strength, and it was proved that the physical stability was in proportion to the loratadine−acids interaction strength. The measured THz spectra of coamorphous system resulted in broad absorption and baseline increases at higher frequencies, but interestingly, there are vague several peaks in each coamorphous spectrum. Pre-treated THz spectra demonstrated the peak width (FWHM) of our coamorphous systems had the order (SUC < MAL < TAR < CIT), which is evidence that the type of organic acid determined the molecular mobility (strength of interaction) in the coamorphous systems.

Conclusion: A coamorphization and tablet formation of a LOR were co-processed with organic acids using single-step injection molding. When the coamorphous system can be obtained by the addition of excipient which strongly interacts with LOR and can suppress the molecular mobility, the enough physical stability of amorphous phase and solubility enhancement of API can be accomplished simultaneously. A comprehensive understanding of the coamorphous formation via the injection molding and the roles of excipients can be the key to the single-step simultaneous formulation of coamorphous tablets.

Overview of injection-molded tablets of LOR−acid systems and dissolution profile of tables in 900 mL of acidic solution (mean ± SD; n = 3).

Smoothed, baseline-corrected, and area-normalized THz spectra of coamorphous at − 203°C (70 K). Each spectrum has a peak of polyethylene (diluent) at 2.3 THz.