Dapagliflozin Crystal Form E Preparation Method
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Solution Overview
Problem
Existing crystal forms of dapagliflozin have low melting points, making them unsuitable for drug production due to melting during the tableting process, and often exist as solvates or complexes with non-API components that can be harmful, affecting drug stability and compatibility.
Innovation Solution
A new crystal form E of dapagliflozin with specific X-ray powder diffraction peaks is developed, prepared by dissolving dapagliflozin in an ester solvent, adding a poor solvent, and using a seed crystal to precipitate a solvent-free compound with improved stability, and then removing the solvent under controlled conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Temperature
If existing crystal forms of dapagliflozin are used, then the drug can be prepared in crystalline state, but the melting point is too low causing the drug to melt during tableting process
Solution Approach 1:
The patent changes the crystal structure parameters by forming a co-crystal with L-proline, which fundamentally alters the melting point from below 35°C to 70°C. This parameter change in the crystal lattice structure resolves the contradiction by enabling the drug to maintain its solid state during tableting while remaining in crystalline form for stability.
Solution Approach 2:
The invention creates a composite crystal structure (co-crystal) combining dapagliflozin with L-proline in a 1:1 molar ratio. This composite material approach produces a new crystal form with enhanced melting point (70°C) that prevents melting during tableting, while the co-crystal structure maintains the drug's therapeutic activity.
2Stability of the object's composition
If solvates or complexes of dapagliflozin are used, then the drug can be made crystalline, but non-API components are present which can be harmful to the human body
Solution Approach 1:
The patent extracts and eliminates harmful non-API components (solvent molecules in solvates) by forming a co-crystal with a safe, pharmaceutically acceptable amino acid (L-proline). This extraction of harmful substances while retaining the beneficial crystalline structure resolves the contradiction between stability and safety.
Solution Approach 2:
The invention replaces potentially harmful solvent molecules with L-proline, a safe and biocompatible amino acid that is readily metabolized by the body. This substitution eliminates long-term harmful effects while maintaining the crystalline stability needed for drug storage and handling.
3Stability of the object's composition
If solvates or complexes with non-API components are used, then the drug can exist in crystalline form, but the compatibility of drug substances and auxiliary materials is affected
Solution Approach 1:
The patent changes the crystalline structure parameters by forming a co-crystal with L-proline, which has favorable physicochemical properties. This parameter change in the crystal lattice improves compatibility with common pharmaceutical excipients and auxiliary materials while maintaining stable crystalline form, resolving the contradiction between structural stability and formulation versatility.
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 crystal form E has a higher melting point of 70°C, improved stability, and reduced particle size distribution, enhancing drug safety, processing, and storage, while avoiding aggregation and clumping, and can be used as a safer and more effective SGLT-2 inhibitor.
Implementation Method 1
placing dapagliflozin in an ester solvent or a mixed solvent of an ester and other solvent to form a solution
Implementation Method 2
saturating the solution by cooling or addition of a poor solvent or by both cooling and addition of a poor solvent
Implementation Method 3
adding a seed crystal, stirring the solution to precipitate a solid
Implementation Method 4
converting the resulting solid to crystal form E by solvent removal
Data Source
Figure 1~2
Figure 3~4
AI summary
Disclosed are a new dapagliflozin crystal form and a preparation method and use thereof. In particular, disclosed are a crystal form E of 2-chloro-5-(β-D-glucopyranose-1-yl)-4'-ethyoxyldiphenylmethane and a preparation method therefor, and a pharmaceutical composition containing a therapeutically effective amount of the crystal form and the use thereof in treating type II diabetes.