Tolebrutinib Crystalline Polymorphs and Salt Forms
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Solution Overview
Problem
There is a need for additional solid state forms of Tolebrutinib and its salts to improve processing properties, stability, and bioavailability for the treatment of Multiple Sclerosis and myasthenia gravis.
Innovation Solution
The development of crystalline polymorphs, salts, and co-crystals of Tolebrutinib, including specific forms such as Tolebrutinib Form L1, Form L2, Form L3, Tolebrutinib hydrochloride salt Form H1, and Tolebrutinib:succinic acid Form S1, which can be used to prepare pharmaceutical compositions for enhanced therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If additional solid state forms of Tolebrutinib are developed, then stability and bioavailability are improved, but device complexity increases
Solution Approach 1:
The patent applies parameter changes by developing multiple crystalline polymorphs (Forms L1, L2, L3) and salt forms (hydrochloride, mesylate, fumarate, succinate) of Tolebrutinib, each with distinct physical and chemical parameters such as melting point, solubility, and crystal structure. These parameter variations enable optimization of stability and bioavailability while maintaining the same active pharmaceutical ingredient.
Solution Approach 2:
The patent employs composite materials by creating co-crystals and salt forms combining Tolebrutinib with different counterions or coformers (e.g., succinic acid, fumaric acid, hydrochloric acid). These composite solid state forms exhibit enhanced stability and solubility properties compared to the parent compound alone, facilitating improved pharmaceutical performance.
2Reliability
If additional solid state forms of Tolebrutinib are developed, then bioavailability is improved, but manufacturing precision requirements increase
Solution Approach 1:
The patent utilizes parameter changes by systematically varying the crystal structure and physical properties of Tolebrutinib through different polymorphic forms and salt preparations. Each form is characterized by specific X-ray diffraction patterns, melting points, and solubility profiles, enabling optimization of bioavailability while providing clear identification and control criteria for manufacturing.
Solution Approach 2:
The patent replaces complex manufacturing precision requirements with analytical characterization methods such as X-ray powder diffraction (XRPD), thermal analysis (DSC, TGA), and NMR spectroscopy. These analytical techniques provide definitive identification and purity assessment of solid state forms, reducing the need for extremely tight manufacturing tolerances while ensuring consistent bioavailability.
3Ease of manufacture
If crystalline polymorphs are developed, then processing properties are improved, but measurement precision requirements increase
Solution Approach 1:
The patent applies parameter changes by creating crystalline polymorphs with distinct physical properties including different crystal habits, melting points, and solubility characteristics. These parameter variations improve processing properties such as flowability, compressibility, and dissolution rate, while each form is characterized by specific measurement signatures for identification.
Solution Approach 2:
The patent utilizes characteristic X-ray diffraction patterns as identification signatures for each crystalline form, analogous to using color changes for identification. Each polymorph and salt form has a unique XRPD fingerprint pattern that provides unambiguous identification, reducing the need for highly precise measurements during manufacturing and quality control.
Data Source
AI summary
The present disclosure encompasses solid state forms of Tolebrutinib and of Tolebrutinib salts, in embodiments crystalline polymorphs of Tolebrutinib and of Tolebrutinib salts, processes for preparation thereof, and pharmaceutical compositions thereof. In particular, the present invention discloses crystalline polymorphs, salts and co-crystals of Tolebrutinib.