Cetagliptin Phosphate Crystallization for Improved Druggability
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Solution Overview
Problem
Cetagliptin in its free base form is a viscous oil with poor druggability, and there are no reports on its salts or crystal forms, limiting its pharmaceutical applications.
Innovation Solution
Development of crystalline phosphate salts of cetagliptin in specific crystal forms, such as form B, with defined X-ray powder diffraction patterns and thermal properties, and a 1:1 molar ratio with phosphoric acid, prepared through solvent evaporation or induced crystallization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If cetagliptin is used in free base form, then the chemical structure is simple, but the druggability is poor and it forms viscous oil
Solution Approach 1:
The patent applies parameter changes by converting cetagliptin from free base form to phosphate salt form, which fundamentally changes the physical and chemical parameters of the compound. This transformation converts the viscous oil into a crystalline solid with defined melting point and solubility characteristics, thereby improving druggability while maintaining the core chemical structure
Solution Approach 2:
The patent creates a composite material by forming a salt between cetagliptin (compound of formula I) and phosphoric acid. The resulting cetagliptin phosphate salt combines the pharmacological activity of cetagliptin with the beneficial physical properties of the phosphate salt form, including improved crystallinity, solubility, and stability
2Stability of the object's composition
If crystalline phosphate salts are developed, then the crystallinity and stability are improved, but the manufacturing process complexity increases
Solution Approach 1:
The patent utilizes phase transitions by controlling the crystallization process from solution to obtain specific crystal forms (Form A, Form B, and amorphous form). By manipulating solvent evaporation, cooling rates, and crystallization conditions, the patent achieves controlled phase transition from liquid solution to solid crystal, thereby improving stability while managing process complexity through systematic optimization
Solution Approach 2:
The patent applies preliminary action by pre-screening multiple solvents and crystallization conditions to identify the optimal parameters for obtaining stable crystal forms. This preliminary optimization work establishes standardized preparation methods that simplify subsequent manufacturing processes while ensuring consistent product quality and stability
3Reliability
If multiple crystal forms are screened, then the pharmaceutical effect is optimized, but the time and resources for development increase
Solution Approach 1:
The patent applies segmentation by systematically dividing the crystal form development into distinct categories (Form A, Form B, and amorphous form), each with specific preparation methods and characterization protocols. This segmented approach allows for organized screening and evaluation of different crystal forms, enabling efficient comparison and selection based on pharmaceutical performance criteria
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 phosphate form B exhibits high crystallinity, low hygroscopicity, good stability, and improved oral bioavailability, offering a better choice for drug development with effective inhibition of dipeptidyl peptidase and reduced hypoglycemic risk.
Implementation Method 1
amorphous phosphate of the compound of formula (I) is dissolved in ethanol, isopropyl alcohol or isoamyl alcohol, and solvent evaporation is performed to obtain a crystal form B
Implementation Method 2
the amorphous phosphate of the compound of formula (I) is dissolved in a mixed solvent of isoamyl alcohol and water or a mixed solvent of isopropyl alcohol and methyl tert-butyl ether, and a crystal seed of the crystal form B is added for induced crystallization to obtain the crystal form B
Implementation Method 3
its X-ray powder diffraction pattern has characteristic peaks at positions of which 2theta value is 15.2°±0.2°, 15.9°±0.2°, 19.2°±0.2° and 23.3°±0.2°
Data Source
Figure 1~2
Figure 3~4
Figure 5~6
AI summary
The present invention relates to a salt of a compound of formula (I), The salt is crystalline or amorphous phosphate, or crystalline or amorphous oxalate. Particularly, a crystal form B of the phosphate of the present invention has high crystallinity, low hygroscopicity and good stability, and the crystal form B of the phosphate is good in oral bioavailability, good in tolerance after long-term administration, difficult to induce hypoglycemia and good in inhibition effect on serum DPPIV.