Solid Forms of FASN Inhibitor Compound 1
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Solution Overview
Problem
There is a need for identifying and selecting appropriate solid forms of the bioactive compound (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (Compound 1) for therapeutic applications, as different solid forms exhibit varying properties and are not effectively addressed by existing technologies.
Innovation Solution
Novel solid forms and mixtures of Compound 1, such as Form B, Form C, Form X, and Mixture A, are identified and characterized using X-ray Powder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC), allowing for their preparation and conversion under specific physical conditions, and are used in pharmaceutical compositions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multiple solid forms of Compound 1 are developed, then pharmaceutical applications with improved stability and efficacy are achieved, but the complexity of identifying and selecting appropriate solid forms increases
Solution Approach 1:
The patent performs preliminary identification and characterization of multiple solid forms (Forms A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, X, Y, Z) with their respective properties before pharmaceutical application. Each form is pre-characterized using XRPD, DSC, and other analytical methods, allowing selection of the most appropriate form for specific therapeutic needs without requiring extensive trial-and-error testing later.
Solution Approach 2:
The patent systematically varies physical and chemical parameters (crystallization conditions, solvent systems, temperature, pressure) to generate different solid forms of Compound 1. By changing these parameters, multiple polymorphic forms with distinct stability and efficacy profiles are obtained, allowing optimization of pharmaceutical properties without altering the chemical structure of the active ingredient.
2Adaptability or versatility
If different solid forms with varying properties are created, then pharmaceutical acceptability is improved, but the difficulty of detecting and measuring the appropriate form increases
Solution Approach 1:
The patent employs various analytical techniques that produce detectable signals for characterizing solid forms. XRPD produces characteristic diffraction patterns with specific peak positions and intensities that serve as fingerprints for each polymorphic form. DSC produces thermal transition profiles with distinct melting points and enthalpy values. These detectable signals enable straightforward identification and differentiation of various solid forms.
Solution Approach 2:
The patent replaces complex mechanical identification methods with advanced analytical techniques. Instead of relying on physical manipulation or visual inspection, the patent uses X-ray diffraction, thermal analysis, and spectroscopic methods to detect and measure solid form characteristics. These techniques provide objective, quantitative data that simplify the detection and measurement process.
3Manufacturing precision
If solid forms are converted under specific physical conditions, then the desired solid form is obtained, but the process complexity increases
Solution Approach 1:
The patent utilizes phase transition phenomena to convert between different solid forms of Compound 1. By controlling temperature, pressure, and solvent conditions, the patent induces reversible or irreversible phase transitions between polymorphic forms. For example, heating a stable form may induce transformation to a metastable form, or solvent-mediated transformation can convert one polymorph to another. These phase transitions provide a relatively simple mechanism for solid form conversion compared to chemical modification.
Solution Approach 2:
The patent develops a universal approach to solid form conversion that can be applied across multiple polymorphic forms. The same general techniques (slurry methods, melt annealing, solvent-mediated transformation) can be used to convert between different forms, regardless of the specific starting or target polymorph. This multi-functional methodology reduces process complexity by providing a standardized framework for solid form conversion.
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 solid forms and mixtures provide distinct characteristics for pharmaceutical applications, enhancing the development of pharmaceutically acceptable dosage forms with improved stability and efficacy, particularly as inhibitors of fatty acid synthase (FASN).
Implementation Method 1
A novel Compound 1 Mixture A can be identified by X-ray Powder Diffraction (XRPD), having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3
Implementation Method 2
A novel Compound 1 Mixture A can be identified by XRPD having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3
Implementation Method 3
A novel Compound 1 Mixture A can be identified (i) by differential scanning calorimetry (DSC) having two endotherms at 226.2° C. and 229.1° C.
Implementation Method 4
A novel Compound 1 Mixture A can be identified (i) by differential scanning calorimetry (DSC) having two endotherms at 226.2° C. and 229.1° C.
Data Source
AI summary
The present disclosure reports solid forms of (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone: