Larotrectinib Ethanesulfonate Form E1 for Stable Formulation

The patent applies parameter changes by developing new salt forms (ethanesulfonate, methanesulfonate, hydrogen sulfate) and solid state forms (polymorphs, solvates, co-crystals) of Larotrectinib. Each salt and polymorphic form represents a change in physical and chemical parameters that directly impacts processing properties, stability, and bioavailability. For example, the ethanesulfonate salt form E1 with specific XRPD peaks provides improved chemical stability and handling characteristics compared to previous forms.

The patent employs composite materials by creating co-crystal forms of Larotrectinib combined with various co-formers (e.g., oxalic acid, malonic acid, succinic acid). These co-crystals represent composite structures where Larotrectinib forms a crystalline lattice with another compound, resulting in materials that exhibit improved processing properties and stability while maintaining the pharmacological activity of the parent compound.

The patent utilizes parameter changes by developing different solid state forms (amorphous, crystalline, solvated) of Larotrectinib salts. These forms exhibit different dissolution rates and profiles due to variations in crystal lattice energy, molecular packing, and solvent interactions. For instance, solvated forms may show enhanced dissolution in specific gastrointestinal conditions, thereby optimizing bioavailability.

The patent explores porous or less densely packed solid state forms of Larotrectinib salts that can facilitate faster dissolution rates. By creating forms with increased surface area-to-volume ratio or less rigid crystal structures, the patent enhances the dissolution profile, which directly impacts the rate and extent of absorption in the body.

The patent applies parameter changes by developing stable salt forms (ethanesulfonate, methanesulfonate, hydrogen sulfate) with controlled hygroscopicity, melting points, and crystalline structures. These parameter optimizations directly improve handling characteristics during manufacturing and storage, while the enhanced chemical and physical stability extends shelf-life. For example, the ethanesulfonate salt form E1 provides improved flowability and compressibility for tablet manufacturing.

The patent develops solid state forms and salts of Larotrectinib that exhibit reduced sensitivity to environmental factors such as moisture, oxygen, and light. By selecting salt forms and crystal structures with inherent stability against degradation, the patent creates materials that can be stored under less stringent conditions while maintaining potency and purity over extended periods.