FTY720 Hydrochloride Hydrate Crystalline Forms
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Solution Overview
Problem
The existing forms of FTY720 hydrochloride exhibit polymorphism, leading to instability and varying solubility, which affects its therapeutic efficacy and storage stability, particularly in the free base form.
Innovation Solution
The development of novel crystalline forms, including a hydrate form of FTY720 hydrochloride, characterized by specific X-ray powder diffraction patterns, which are more stable and have improved solubility, along with a process for converting between these forms by controlling temperature, and the formulation of pharmaceutical compositions with sugar alcohols for enhanced stability and uniform distribution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If the free base form of FTY720 is used, then the compound can be obtained in its basic structure, but it exhibits polymorphism leading to instability and varying solubility
Solution Approach 1:
The patent transforms the free base form into a hydrochloride salt form, changing the chemical parameter (protonation state) to eliminate polymorphism. This parameter change stabilizes the compound while maintaining therapeutic efficacy, as the hydrochloride salt exhibits consistent solubility and stability without the polymorphic transitions that plague the free base form.
2Quantity of substance
If conventional crystalline forms are used, then the compound can be stored, but solubility varies affecting therapeutic efficacy
Solution Approach 1:
By converting to the hydrochloride salt form, the patent fundamentally changes the solubility parameter. The ionic character of the hydrochloride salt dramatically improves aqueous solubility compared to the free base form, ensuring consistent bioavailability and therapeutic efficacy without the variability associated with different polymorphic forms.
3Stability of the object's composition
If temperature control is implemented to convert between forms, then stability can be improved, but the process complexity increases
Solution Approach 1:
The patent extracts the problematic polymorphic behavior by removing the free base form and replacing it with the hydrochloride salt form. This extraction eliminates the need for complex temperature control processes to manage polymorphic transitions, as the hydrochloride salt maintains stable crystalline form across the relevant temperature and humidity ranges.
Solution Approach 2:
The patent applies beforehand cushioning by pre-converting the compound to the hydrochloride salt form, which inherently resists environmental variations. This prior transformation cushions against future stability issues that would arise from temperature and humidity fluctuations, eliminating the need for complex process controls.
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 hydrate form of FTY720 hydrochloride demonstrates improved stability, solubility, and uniform distribution, leading to enhanced therapeutic efficacy and prolonged shelf life, making it suitable for treating autoimmune conditions and transplant rejection.
Implementation Method 1
FTY720 hydrochloride exhibits polymorphism. As the Examples given herein illustrate, FTY720 hydrochloride exists in a particular crystalline form (hereinafter Form I) at room temperature. Crystalline Form I undergoes a change to an alternative crystalline form (Form II) at a transition temperature of approximately 40 °C. Moreover, crystalline Form II undergoes a transition to a third crystalline form (Form III) at a temperature of approximately 66 °C.
Implementation Method 2
At a temperature of approximately 107 °C, FTY720 hydrochloride forms a phase with lower crystalline order. Accordingly, the present disclosure provides novel crystalline forms of FTY720 hydrochloride, including solvates, especially hydrates, thereof
Data Source
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AI summary
The present invention relates to crystalline forms and hydrates of 2-Amino-2-[2-(4-C2-20-alkyl-phenyl)ethyl]propane-1,3-diol, and to the use thereof, in particular in the treatment or prevention of various autoimmune conditions.