Crystalline Cyclo-RGDFK Forms for Pharmaceutical Stability
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Solution Overview
Problem
The existing forms of cyclo-(Arg-Gly-Asp-DPhe-NMe-Val) are amorphous, which are unstable, hygroscopic, and pose challenges in pharmaceutical formulations due to polymorphic changes during processing, affecting stability and bioavailability.
Innovation Solution
Development of novel crystalline forms with specific lattice parameters and solvates that exhibit higher thermodynamic stability, reduced hygroscopicity, and improved handling and dissolution properties, including pseudopolymorphic forms like tetrasolvates and tetrahydrates.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If amorphous forms of cyclo-(Arg-Gly-Asp-DPhe-NMe-Val) are used, then the compound can be obtained through conventional synthesis methods, but the material exhibits instability, hygroscopicity, and polymorphic changes during processing
Solution Approach 1:
The patent changes the physical state parameter from amorphous to crystalline by controlling the formation process. Specific crystalline forms (Form I, Form II, Form III) are obtained through controlled precipitation from aqueous solutions at specific temperatures and pH levels, transforming the material from unstable amorphous state to stable crystalline state with defined lattice structures
Solution Approach 2:
The patent utilizes phase transition processes to convert the amorphous form into crystalline forms. Through controlled cooling, pH adjustment, and solvent evaporation, the material undergoes phase transition from amorphous precipitate to crystalline structure, achieving improved stability while maintaining manufacturability through standardized crystallization protocols
2Ease of manufacture
If amorphous forms are used, then the synthesis process is simpler, but the material exhibits hygroscopicity and poor handling properties
Solution Approach 1:
The patent changes the physical state from amorphous to crystalline, which fundamentally alters the hygroscopic properties. The crystalline forms (I, II, III) have defined lattice structures that prevent water absorption, eliminating hygroscopicity while maintaining relatively simple aqueous synthesis procedures
3Productivity
If amorphous forms are used, then the production process is faster, but polymorphic changes occur during processing affecting stability and bioavailability
Solution Approach 1:
The patent uses controlled phase transition to obtain crystalline forms directly during synthesis, preventing subsequent polymorphic changes. The crystalline forms are obtained through controlled precipitation and crystallization processes that lock the molecular arrangement in a stable configuration, eliminating polymorphic transitions while maintaining efficient production
Solution Approach 2:
The patent performs preliminary crystallization during the synthesis process itself, rather than allowing the material to remain amorphous and risk polymorphic changes later. By inducing crystallization at controlled stages of the synthesis process, the stable crystalline form is obtained directly, preventing future polymorphic transitions and ensuring reliability
4Stability of the object's composition
If crystalline forms with specific lattice parameters are developed, then thermodynamic stability and reduced hygroscopicity are achieved, but the production process becomes more complex
Solution Approach 1:
The patent achieves thermodynamic stability by controlling physical parameters (temperature, pH, solvent composition) during crystallization. The specific crystalline forms (I, II, III) with their distinct lattice parameters are obtained through systematic variation of these parameters, providing stability without requiring complex equipment - just controlled aqueous processing conditions
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 new crystalline forms provide enhanced stability, purity, and processing advantages, ensuring consistent pharmaceutical quality and extended shelf life, overcoming the limitations of amorphous forms.
Implementation Method 1
The invention relates to novel solid materials of {[(2S,5R,8S,11S)-5-benzyl-11-(3-guanidino-propyl)-8-isopropyl-7-methyl-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid}, methods for producing them... the solids obtained according to the described procedures appeared to be amorphous material... Development of novel crystalline forms with specific lattice parameters
Data Source
AI summary
The instant invention relates to novel solid materials of {[(2S,5R,8S,11S)-5-benzyl-11-(3-guanidino-propyl)-8-isopropyl-7-methyl-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid}, methods for producing them, and the use of said solid materials in pharmaceuticals.