Regadenoson Crystal Form E Preparation for Imaging Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current crystal forms of regadenoson, such as forms A, B, C, and D, face challenges including poor solubility, stability issues, and difficulties in large-scale production due to high melting points and complex preparation methods, making them unsuitable for effective radionuclide myocardial perfusion imaging.
Innovation Solution
A new crystal form, E, is developed using X-ray powder diffraction and infrared spectroscopy characterization, prepared by dissolving regadenoson in N,N-dimethylformamide with a low-boiling point polar solvent like dichloromethane, tetrahydrofuran, or acetonitrile, and concentrating under reduced pressure, resulting in a high-purity form with improved stability and solubility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If crystal form A is prepared by crystallization from protic solvent or polar solvent, then storage stability is improved, but solubility deteriorates (very poor solubility, mostly insoluble in common solvents)
Solution Approach 1:
The patent changes the solvent parameters by using aprotic solvents (acetonitrile, dimethyl sulfoxide) instead of protic or polar solvents, and controls temperature parameters (60°C for acetonitrile, ambient for DMSO) to obtain crystal form B with improved solubility while maintaining stability
2Quantity of substance
If crystal form A is prepared by using mixed solution of DMSO and water, then solubility is improved, but manufacturing precision deteriorates (very difficult to remove DMSO thoroughly, failing to obtain crystal form A at high purity)
Solution Approach 1:
The patent extracts and removes the problematic DMSO solvent by using alternative aprotic solvents (acetonitrile, dimethyl sulfoxide) that can be more easily removed, thereby obtaining high purity crystal form B without the difficulty of removing high-melting-point DMSO
Solution Approach 2:
The patent uses volatile aprotic solvents (acetonitrile with boiling point 82°C, dimethyl sulfoxide) that can be easily evaporated and removed, replacing the persistent DMSO that is difficult to remove due to its high melting point of 189°C
3Quantity of substance
If crystal form B is obtained by dissolving regadenoson in trifluoroethanol and concentrating under reduced pressure, then solubility is improved, but reliability deteriorates (very difficult to reproduce the preparation process, contains varying amounts of crystal water)
Solution Approach 1:
The patent changes the solvent from trifluoroethanol to aprotic solvents (acetonitrile, dimethyl sulfoxide) and optimizes temperature parameters (60°C for acetonitrile, ambient for DMSO), resulting in crystal form B with consistent properties and improved reproducibility
4Quantity of substance
If crystal form C is obtained by slurrying regadenoson in acetonitrile at 60°C, then solubility is improved, but stability deteriorates (unstable after losing crystal water under high temperature)
Solution Approach 1:
The patent optimizes the slurry temperature parameter from 60°C to ambient temperature for dimethyl sulfoxide, and controls the concentration and filtration parameters, resulting in crystal form B with both good solubility and improved thermal stability that does not lose crystal water under high temperature
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 E exhibits excellent performance in radionuclide myocardial perfusion imaging with good storage stability and low toxicity, suitable for long-term use as a stress agent, maintaining its form and purity without significant impurity changes until decomposition at 237°C.
Implementation Method 1
X-ray powder diffraction (XRPD), which is internationally acknowledged, is adopted to study and characterize the new crystal form of regadenoson
Implementation Method 2
X-ray powder diffraction pattern... Cu/K-alpha 1 (target), 40 KV-40 mA (operating voltage and current), I(max)=2244, 2θ=5-60 degrees (scan range)
Implementation Method 3
infrared spectroscopy (IR) is further adopted to study and characterize the crystal form E of the regadenoson
Implementation Method 4
infrared spectrum... there are absorption peaks at 3331.71, 3215.54, 2927.97, 1648.75, 1604.99, 1577.42, 1530.74, 1492.24, 1447.33, 1409.03, 1380.47, 1343.48, 1286.87, 1234.77, 1205.30, 1188.55, 1125.28, 1092.61, 1060.80, 1025.93, 983.13, 910.61, 866.49, 810.21, 791.76, 725.68, 663.00, 632.69, 511.09 and 410.05 cm−1
Implementation Method 5
The preparation method of crystal form E of regadenoson provided in the present invention comprises dissolving regadenoson in N,N-dimethylformamide, adding a suitable amount of a polar solvent, and concentrating under a reduced pressure
Implementation Method 6
dissolving regadenoson in N,N-dimethylformamide, adding a suitable amount of a polar solvent, and concentrating under a reduced pressure
Implementation Method 7
concentrating under a reduced pressure
Data Source
AI summary
The present invention relates to the field of medicinal chemistry, and discloses a new crystal form of regadenoson, i.e., a crystal form E of regadenoson, as well as a method for preparing the new crystal form of regadenoson. The crystal form E of regadenoson according to the present invention has excellent performances in terms of radionuclide myocardial perfusion imaging, and has a poor toxicity, good storage stability, and can be used in the preparation of a medicament used as a stress agent for radionuclide myocardial perfusion imaging.