Polymorph E Regadenoson Water Solubility
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Solution Overview
Problem
Existing polymorphs of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine, such as regadenoson, exhibit poor water solubility and stability issues, which complicates their use in diagnostic applications and production processes.
Innovation Solution
A new stable polymorph (E) is developed, characterized by specific XRPD and DSC patterns, with a higher dissolution rate in water compared to existing forms, achieved through a reproducible preparation method involving mixing with polar aprotic and protic solvents, followed by heating and cooling steps.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing polymorphs of regadenoson are used, then the substance can be produced and used in diagnostic applications, but the water solubility is poor and stability issues occur
Solution Approach 1:
The patent applies parameter changes by discovering and characterizing a new polymorph (polymorph E) with different crystal structure parameters. This polymorph exhibits improved dissolution kinetics and stability compared to existing polymorphs, while maintaining the same chemical composition. The specific XRPD pattern (peaks at 5.8°, 12.3°, 15.9°, 17.3°, 20.5°, 22.6°, 23.6°, 27.7°, and 29.2°) and DSC characteristics (endotherm transition between 258-264°C) define the new polymorphic form with optimized properties.
Solution Approach 2:
The patent employs composite material principles by creating a specific solvate or hydrate form of regadenoson with defined solvent molecules incorporated into the crystal lattice. This composite structure, characterized by specific XRPD and DSC patterns, achieves enhanced water solubility and stability through the synergistic arrangement of the active pharmaceutical ingredient and solvent molecules in a specific crystalline configuration.
2Reliability
If polymorph A is used, then it is relatively stable and can be prepared by crystallization, but the dissolution rate in water is slow
Solution Approach 1:
The patent resolves this contradiction by identifying polymorph E, which has different crystal packing parameters and molecular arrangement compared to polymorph A. The new polymorph maintains stability (as evidenced by its defined XRPD and DSC characteristics) while achieving approximately twofold higher dissolution rate in water, thereby optimizing both reliability and productivity parameters simultaneously.
3Ease of manufacture
If polymorph B is prepared, then it can be obtained by concentrating in trifluoroethanol, but the preparation is difficult to reproduce and X-RPD shows broad peaks that are difficult to measure
Solution Approach 1:
The patent addresses the reproducibility issue by defining polymorph E with sharp, well-defined XRPD peaks at specific angles (5.8°, 12.3°, 15.9°, 17.3°, 20.5°, 22.6°, 23.6°, 27.7°, and 29.2°), in contrast to the broad peaks of polymorph B. The recommended preparation method using acetonitrile at 60°C for 1-24 hours provides reproducible conditions for obtaining this clearly characterizable polymorph.
4Ease of manufacture
If polymorph C is prepared, then it can be obtained by heating in acetonitrile, but it contains variable amount of water and is converted to unstable forms by heating
Solution Approach 1:
The patent resolves the stability issue by defining polymorph E with specific thermal characteristics (DSC endotherm transition between 258-264°C) and controlled water content (0.5-5.0%). The preparation method specifies heating at 60°C for 1-24 hours, which produces a stable polymorph that resists conversion to unstable forms, unlike polymorph C which converts upon heating.
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
Polymorph E demonstrates a twofold higher dissolution rate in water compared to existing forms, enhancing the preparation of injectable solutions, reducing thermal exposure, and improving stability and production efficiency while meeting regulatory guidelines.
Implementation Method 1
Polymorph A is prepared by crystallization of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine from protic solvents or their mixtures with water (for example ethanol or an ethanol/water mixture) or by crystallization from polar aprotic solvents or their mixtures with water
Implementation Method 2
Polymorph C is prepared by heating of a suspension of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine in acetonitrile at 60° C. for prolonged periods
Implementation Method 3
The amorphous form is prepared by heating polymorph A to a temperature of 200° C. The amorphous form is unstable and in presence of air humidity it forms variable hydrates
Implementation Method 4
Polymorph B is prepared by concentrating 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine dissolved in trifluoroethanol
Data Source
AI summary
The invention relates to a compound which is, 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine, which is a selective A2A adenosine receptor agonist in myocardial imaging. The new polymorph of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine (designated as polymorph E) is characterized by an X-ray diffraction pattern of X-RPD showing the following reflections at 2 Theta=5.8°, 12.3°, 15.9°, 17.3°, 20.5°, 22.6°, 23.6°, 27.7°, and 29.2°; and further characterized by a DSC scan showing marked endotherm in the range of 258 to 264° C.; and further characterized by a specific IR spectra. The invention further relates to a method of preparing the polymorph by recrystallization from other polymorphic forms of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine by a procedure comprising the following operations: mixing of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine with a polar aprotic solvent, preferably with dimethylsulfoxide, and heating to form a saturated solution; cooling of the saturated solution with formation of a turbid solution of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine; addition of the turbid solution of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine to a protic solvent, preferably methanol, with separation of a gel-like precipitate; heating of the separated gel-like precipitate in the protic solvent to a boil with formation of a suspension of polymorph E; and cooling of the suspension, isolation and drying of polymorph E.