Crystalline Monohydrate Complex of Compound A and L-Proline
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Solution Overview
Problem
The existing methods for producing 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene do not yield a stable crystalline form, which is crucial for pharmaceutical applications due to issues with stability, polymorphous changes, and moisture absorption, affecting the uniform distribution and shelf life of medicaments.
Innovation Solution
A crystalline complex is formed between 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene and one or more natural amino acids, specifically L-proline, through a process involving solution preparation, precipitation, and drying, resulting in a stable crystalline form with characteristic X-ray powder diffraction patterns and thermal stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If the compound is produced using existing methods, then the active substance can be obtained, but it does not yield a stable crystalline form leading to poor stability and polymorphous changes
Solution Approach 1:
The patent applies parameter changes by forming a crystalline complex between compound A and natural amino acids (such as L-proline) in specific molar ratios (1:1, 1:2, 2:1). This chemical complexation changes the physical and chemical parameters of the compound, resulting in a stable crystalline form with defined melting points (89-110°C) and characteristic X-ray powder diffraction patterns, thereby resolving the instability and polymorphous issues of the original compound
Solution Approach 2:
The patent creates a composite crystalline material by combining compound A with natural amino acids to form a stable complex. This composite approach integrates two substances with complementary properties - the pharmacologically active compound A and the stabilizing amino acid - to produce a new material that maintains pharmaceutical activity while achieving the desired crystalline stability and consistency required for reliable pharmaceutical quality
2Manufacturing precision
If the active substance is ground to reduce particle size for uniform distribution, then distribution uniformity is improved, but breakdown of the substance occurs due to hard grinding conditions
Solution Approach 1:
The crystalline complex structure created by combining compound A with amino acids forms a more robust composite material that can withstand mechanical stress during grinding. The complexed structure protects the active substance from breakdown while allowing particle size reduction, enabling uniform distribution in pharmaceutical formulations without compromising substance integrity
Solution Approach 2:
The formation of the crystalline complex changes the mechanical properties of the compound, making it more resistant to degradation during particle size reduction. The complexed form allows the substance to be ground to suitable particle sizes for uniform distribution while maintaining chemical stability and preventing breakdown that would occur with the original compound
3Duration of action of stationary object
If the compound is stored to ensure long-term stability, then shelf life is extended, but moisture absorption increases reducing active substance content
Solution Approach 1:
The crystalline complex formation changes the hygroscopic properties of compound A. The complex with natural amino acids exhibits reduced moisture absorption compared to the original compound, allowing the substance to be stored for extended periods (shelf life extension) while maintaining stable active substance content and preventing the weight increase that would result from moisture uptake
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 crystalline complex exhibits high physical and chemical stability, mechanical stability during grinding, reduced moisture absorption, and favorable solubility, enabling the production of pharmaceutical compositions with a long shelf life and uniform distribution, suitable for inhibiting sodium-dependent glucose cotransporter SGLT2.
Implementation Method 1
A crystalline complex is formed between 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene and one or more natural amino acids, specifically L-proline, through a process involving solution preparation, precipitation, and drying
Implementation Method 2
resulting in a stable crystalline form with characteristic X-ray powder diffraction patterns and thermal stability
Data Source
Figure 1~2
AI summary
The invention relates to a mixture of crystalline forms comprising a crystalline monohydrate complex of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene (compound A) and L-Proline in admixture with another form or forms of compound A.