Treosulfan Crystalline Form B Dissolution Stability
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Solution Overview
Problem
The known crystalline forms of treosulfan suffer from agglomeration, leading to unpredictable dissolution behavior, uneven distribution in pharmaceutical compositions, and stability issues due to high amounts of methanesulfonic acid and water upon storage.
Innovation Solution
The development of crystalline form B of treosulfan, characterized by an X-ray powder diffraction pattern with specific peaks, which exhibits a narrower particle size distribution, reduced agglomeration, and lower amounts of methanesulfonic acid, enhancing stability and reconstitution efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If crystalline form A of treosulfan is used, then the powder can be dissolved in water to prepare infusion solution, but the powder forms agglomerates that are difficult to dissolve and protract the complete dissolution process
Solution Approach 1:
The patent changes the crystalline form parameter of treosulfan from form A to form B, which has different physical properties including particle size distribution and agglomeration characteristics. This parameter change results in form B exhibiting narrower particle size distribution and reduced agglomeration, thereby improving dissolution uniformity and reliability while maintaining dissolution speed.
2Duration of action of stationary object
If crystalline form A of treosulfan is used, then the powder can be stored, but high amounts of methanesulfonic acid and water are present upon storage leading to stability issues
Solution Approach 1:
The patent changes the crystalline form parameter from form A to form B, which inherently has lower content of methanesulfonic acid and water. This parameter change improves storage stability by reducing the harmful factors generated during storage, allowing the substance to maintain its properties over time without significant degradation.
3Productivity
If warm solvent is used to dissolve crystalline form A powder, then the dissolution process can be initiated, but the risk of undesired degradation is enhanced
Solution Approach 1:
The patent changes the crystalline form to form B, which has improved solubility characteristics that allow dissolution at lower temperatures. This parameter change enables faster reconstitution without requiring warm solvent, thereby reducing the degradation risk associated with thermal exposure while maintaining high productivity.
4Ease of manufacture
If crystalline form A of treosulfan is used, then the powder can be prepared for infusion, but the particle size distribution is broad leading to heterogeneous particles that affect processing
Solution Approach 1:
The patent changes the crystalline form parameter from form A to form B, which inherently exhibits narrower particle size distribution. This parameter change improves manufacturing precision by ensuring more uniform particle sizes, thereby facilitating easier and more consistent processing during pharmaceutical formulation without requiring additional size reduction steps.
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
Crystalline form B of treosulfan achieves improved uniformity and stability, reducing the time required for reconstitution to less than 2 minutes and maintaining low levels of methanesulfonic acid even after storage, thereby enhancing the efficacy and safety of pharmaceutical compositions.
Implementation Method 1
crystalline form B of treosulfan, which is characterized by an X-ray powder diffraction pattern having peaks at 20.87 and 23.47±0.20 degrees 2Θ
Data Source
AI summary
A crystalline form of treosulfan and methods to prepare it are described. This crystalline form of treosulfan is useful in pharmaceutical compositions for the treatment of cancer and for conditioning therapy before transplantation of bone marrow or blood stem cells.