Linagliptin Benzoate Form II Polymorph Hygroscopicity Reduction
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Solution Overview
Problem
The existing crystalline form of Linagliptin benzoate is hygroscopic, making it difficult to handle under common pharmaceutical processing conditions and requiring special packaging for storage, which complicates its use in formulations like wet granulation.
Innovation Solution
A novel polymorphic form of Linagliptin benzoate, designated as form II, which is less hygroscopic and can be characterized by specific XRPD patterns and FTIR spectra, allowing for standard pharmaceutical processing and storage without special containment, prepared through dissolving in acetonitrile, slow cooling, and drying.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If the crystalline form of Linagliptin benzoate (form I) is used, then the compound can be obtained with defined crystal structure, but it becomes hygroscopic and difficult to handle under pharmaceutical processing conditions
Solution Approach 1:
The patent applies parameter changes by discovering and utilizing a different polymorphic form (form II) of Linagliptin benzoate with distinct crystal structure parameters. This new form exhibits different hygroscopic properties and handling characteristics compared to form I, while maintaining the same chemical composition. The change in crystal packing parameters resolves the contradiction between structural stability and ease of handling.
Solution Approach 2:
The patent utilizes phase transitions by transitioning from polymorphic form I to form II through controlled crystallization processes. By controlling the crystallization conditions (temperature, solvent, cooling rate), the patent achieves transformation between different solid phases, each with different hygroscopic properties. This phase transition enables the compound to exhibit improved handling characteristics while maintaining structural integrity.
2Reliability
If the crystalline form of Linagliptin benzoate (form I) is used, then the compound has defined physical properties, but it requires special packaging for storage to maintain product quality
Solution Approach 1:
The patent changes the physical parameters of the crystalline form by discovering form II, which has different hygroscopicity and storage requirements. This parameter change allows the compound to be stored under standard conditions without special packaging, while still maintaining product quality stability. The new crystal form inherently resists moisture absorption, eliminating the need for complex packaging systems.
3Measurement precision
If the crystalline form of Linagliptin benzoate (form I) is used, then the compound can be characterized by specific XRPD patterns, but it exhibits poor processability for wet granulation
Solution Approach 1:
The patent changes the crystallographic parameters by identifying and utilizing form II, which has different XRPD patterns and processability characteristics. While maintaining the ability to be characterized by XRPD (in fact, providing more distinct patterns for form II), the new form exhibits improved processability for wet granulation and other pharmaceutical manufacturing processes.
Solution Approach 2:
The patent employs phase transitions to transform the compound from form I to form II, which has superior processability for wet granulation. By controlling the crystallization process, the patent achieves a solid phase that is easier to process while maintaining characteristic XRPD patterns for identification and characterization.
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
Linagliptin benzoate form II is easier to handle in pharmaceutical processing, stable under high humidity, and does not require special packaging, facilitating its use in pharmaceutical compositions for type 2 diabetes treatment.
Implementation Method 1
d) isolating the obtained crystals
Implementation Method 2
Form II of Linagliptin benzoate can be characterized by showing an XRPD pattern comprising characteristic peaks at 2-theta angles of 8.0±0.2°, 8.7±0.2°, 10.4±0.2°, 12.9±0.2°, 13.8±0.2° and 17.4±0.2°
Data Source
AI summary
The present invention relates to a novel polymorph of Linagliptin benzoate and to methods for its preparation. Furthermore the present invention relates to the use of the novel polymorph for the preparation of a medicament. In addition the present invention relates to pharmaceutical compositions comprising an effective amount of the novel polymorph of Linagliptin benzoate.