Crenolanib Besylate Polymorphs for Stable Low-Hygroscopic Formulations
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Solution Overview
Problem
Existing pharmaceutical formulations of crenolanib besylate lack stability and specificity in treating proliferative diseases due to variations in solubility and hygroscopicity, which affect their efficacy and suitability for pharmaceutical compositions.
Innovation Solution
The discovery of novel polymorphic forms of crenolanib besylate, characterized by unique X-ray diffraction patterns and FT-IR spectra, provides forms with specific stability, solubility, and hygroscopic properties, including anhydrous, hemi-hydrate, and solvate forms, enhancing their suitability for pharmaceutical compositions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional pharmaceutical formulations of crenolanib besylate are used, then the compound can be administered for treating proliferative diseases, but the formulations lack stability and specificity due to variations in solubility and hygroscopicity
Solution Approach 1:
The patent identifies and characterizes multiple polymorphic forms of crenolanib besylate, each with distinct physical parameters including solubility, hygroscopicity, and crystal structure. By changing the polymorphic form parameter, the invention achieves formulations with improved stability and consistent composition, directly resolving the technical contradiction between reliability and compositional stability.
Solution Approach 2:
The patent utilizes phase transitions between different polymorphic forms of crenolanib besylate to create stable pharmaceutical formulations. By controlling the phase state and transitioning between polymorphic forms, the invention achieves formulations with improved stability and reduced hygroscopicity, thereby resolving the contradiction between formulation reliability and compositional consistency.
2Reliability
If polymorphic forms with improved stability are selected, then formulation reliability is enhanced, but the complexity of characterizing and selecting the appropriate form increases
Solution Approach 1:
The patent employs FT-IR spectroscopy, which detects characteristic absorption patterns that serve as molecular fingerprints for different polymorphic forms. These spectral patterns act as identifiable characteristics that simplify the characterization and selection process, reducing the complexity of identifying stable polymorphic forms while maintaining formulation reliability.
Solution Approach 2:
The patent replaces complex mechanical characterization methods with analytical techniques such as X-ray powder diffraction and FT-IR spectroscopy. These analytical methods provide rapid, non-destructive identification of polymorphic forms, simplifying the selection process while ensuring formulation stability and reliability.
3Reliability
If highly specific polymorphic forms are used, then therapeutic efficacy is improved, but the difficulty of detecting and measuring the specific form increases
Solution Approach 1:
The patent utilizes FT-IR spectroscopy to detect characteristic absorption patterns that serve as molecular fingerprints for different polymorphic forms. These spectral patterns provide clear, distinguishable signals that simplify the detection and measurement of specific polymorphic forms, enabling reliable identification without increasing measurement difficulty while maintaining therapeutic efficacy.
Solution Approach 2:
The patent creates and utilizes reference X-ray powder diffraction patterns for each polymorphic form. These reference patterns serve as templates for identification, allowing rapid and accurate detection of specific forms through pattern matching. This copying approach simplifies the measurement process while ensuring accurate identification of polymorphic forms with improved therapeutic efficacy.
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
The novel polymorphic forms of crenolanib besylate offer improved stability, solubility, and reduced hygroscopicity, leading to enhanced therapeutic efficacy in treating proliferative disorders such as leukemia and various cancers.
Implementation Method 1
Each polymorphic form can be uniquely identified by several different analytical methods including, but not limited to, X-ray powder diffraction peaks
Implementation Method 2
Each polymorphic form can be uniquely identified by several different analytical methods including, but not limited to, X-ray powder diffraction peaks, FT-IR spectra
Data Source
AI summary
present invention relates to novel crystalline polymorphs of 1-[2-[5-[(3-Methyl-3-oxetanyl) methoxy]-1H-benzimidazol-1-yl]-8-quinolinyl]-4-piperidinamine monobenzenesulfonate, and to methods for their preparation. The invention further relates to pharmaceutical compositions containing one or more forms and optionally one or more suitable pharmaceutical carriers. The invention also relates to methods of using the crystalline polymorphs of the invention in the treatment of disease.