SCO-101 Crystal Form I Stability via Solvent Parameter Changes
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Solution Overview
Problem
The existing polymorphic form of SCO-101 is metastable and hygroscopic, posing challenges for pharmaceutical development and patient safety, as it forms solvates and has variable stability, necessitating the development of a more stable, non-hygroscopic crystal form for clinical use.
Innovation Solution
The development of thermodynamically stable crystal form I of SCO-101, characterized by specific X-ray powder diffraction peak maxima, and processes for converting metastable forms into this stable form, including solvent-based methods, temperature cycling, and storage conditions, to produce a non-hygroscopic and anhydrous polymorph.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If the conventional polymorphic form of SCO-101 is used, then the compound can be prepared by simple mixing in toluene, but the resulting crystal form is metastable and hygroscopic
Solution Approach 1:
The patent applies parameter changes by modifying the solvent system from pure toluene (aprotic) to a mixed solvent system containing both aprotic and protic solvents. This change in solvent composition parameter enables the formation of the thermodynamically stable crystal form I, which is non-hygroscopic and anhydrous, thereby resolving the contradiction between ease of preparation and crystal form stability.
Solution Approach 2:
The patent uses an intermediary approach by introducing a protic solvent as a mediator in the crystallization process. This protic solvent acts as a mediator that facilitates the formation of the stable crystal form I by interacting with the SCO-101 molecules during crystallization, enabling the transition from metastable to stable polymorphic form while maintaining processability.
2Adaptability or versatility
If the metastable polymorphic form is used, then the compound exhibits certain solubility properties, but it forms solvates and has variable stability
Solution Approach 1:
The patent employs parameter changes by altering the solvent system to include protic solvents, which fundamentally changes the crystallization outcome. This parameter modification ensures the formation of anhydrous, non-hygroscopic crystal form I that maintains consistent stability and does not form solvates, thereby improving reliability while preserving necessary solubility properties for pharmaceutical application.
3Stability of the object's composition
If the thermodynamically stable crystal form I is prepared using polar aprotic and polar protic solvents, then non-hygroscopic and anhydrous form is obtained, but the preparation process becomes more complex
Solution Approach 1:
The patent applies parameter changes by defining specific compositional ranges for the solvent system ( ratios of aprotic to protic solvent) and controlled temperature conditions. These parameter specifications enable the formation of stable crystal form I while providing clear process guidelines that manage complexity through quantifiable parameters rather than vague procedural steps.
Solution Approach 2:
The patent implements preliminary action by pre-establishing the optimal solvent system composition and temperature conditions before initiating crystallization. This preliminary configuration of the solvent system (mixing aprotic and protic solvents in specific ratios) ensures that when crystallization occurs, the thermodynamically stable form I is formed directly, avoiding the need for subsequent conversion steps and simplifying the overall process.
4Stability of the object's composition
If crystal form I is used, then non-hygroscopic and thermodynamically stable properties are achieved, but higher melting points and different physical properties are observed
Solution Approach 1:
The patent applies parameter changes by controlling the crystallization temperature and solvent system to selectively form crystal form I. The use of polar aprotic and polar protic solvents in specific combinations, along with controlled temperature conditions, enables the formation of the thermodynamically stable polymorph with its characteristic higher melting point and non-hygroscopic properties, accepting the temperature change as an inherent property of the stable form.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Crystal form I of SCO-101 is non-hygroscopic, thermodynamically stable, and exhibits superior properties, including higher melting points, enhancing its attractiveness for clinical development by ensuring stability and safety.
Implementation Method 1
The present inventors have found that the polymorphic form of SCO-101 prepared as in WO 2000/24707 is not a thermodynamically stable form but rather a metastable polymorphic form
Implementation Method 2
it is desired to obtain a more stable crystal form, free of solvates (anhydrous)
Implementation Method 3
exhibiting at least peak maxima at 2 Theta angles: 19.0±0.2, 21.2±0.2, and 23.4±0.2 in an X-ray powder diffraction (XRPD) diffractogram
Implementation Method 4
in an X-ray powder diffraction (XRPD) diffractogram when measured using Cu Kα radiation
Implementation Method 5
dissolving SCO-101 in one or more polar aprotic solvents at a first predefined temperature; adding one or more polar protic solvents to the one or more polar aprotic solvents
Implementation Method 6
performing one or more temperature cycles, wherein the temperature is cycled between a fourth predefined temperature and a fifth predefined temperature
Data Source
AI summary
The present invention relates to an improved crystal form of SCO-101, its preparation and use. Further, the invention relates to intermediary crystal forms of SCO-101 that can be converted to the improved crystal form of SCO-101.