Fingolimod HCl Polymorphs α β μ Preparation
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Solution Overview
Problem
There is a need for novel, stable crystalline polymorphic forms of Fingolimod hydrochloride that are convenient to scale up and offer improved yields and quality, as existing thermal transition-based forms are limited in number and stability.
Innovation Solution
The development of crystalline polymorphic forms α, β, and μ of Fingolimod HCl, characterized by specific X-ray powder diffraction patterns and DSC endothermic peaks, along with processes for their preparation that minimize process-related impurities, including combining Fingolimod hydrochloride with organic acids or solvents, heating, cooling, and isolating through recrystallization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If thermal transition-based polymorphic forms are used, then phase transitions occur at specific temperatures, but the number of stable crystalline forms is limited and scaling up is difficult
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization conditions including temperature ranges (0-5°C to 40-50°C), solvent types (organic acids, organic solvents), and cooling rates to obtain different stable polymorphic forms (α, β, μ) with distinct XRPD patterns and DSC characteristics, thereby expanding the number of available stable forms while improving manufacturability
Solution Approach 2:
The patent uses organic acids and organic solvents as intermediary substances to mediate the crystallization process, enabling the formation of specific polymorphic forms with improved stability and scalability characteristics without relying solely on thermal transition methods
2Quantity of substance
If existing polymorphic forms are used, then some thermal transition forms are obtained, but process-related impurities are present and yields are not optimized
Solution Approach 1:
The patent applies preliminary action by performing pre-crystallization treatments and optimizing crystallization conditions before final isolation, including controlled heating to 40-50°C followed by controlled cooling to 0-5°C, which pre-organizes the molecular structure and minimizes impurity incorporation, thereby achieving both high yield and high purity
Solution Approach 2:
The patent converts the potential harm of process-related impurities into benefit by using controlled crystallization conditions where impurities are selectively excluded from the crystal lattice during the phase transition, transforming the crystallization process into a purification mechanism that simultaneously improves yield and purity
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 resulting crystalline forms α, β, and μ provide a stable and high-purity active pharmaceutical ingredient for treating autoimmune disorders like multiple sclerosis, with improved stability, solubility, and quality parameters, facilitating better storage and distribution.
Implementation Method 1
characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 2θ° peaks
Implementation Method 2
X-ray powder diffraction pattern comprising at least 5 characteristic 2θ° peaks selected from the XRPD peak set
Implementation Method 3
The said crystalline Form-α is further characterized by DSC isotherm comprising at least three endothermic peaks
Implementation Method 4
DSC isotherm comprising at least three endothermic peaks ranging between
Implementation Method 5
Optionally heating up to about 40-50° C.
Implementation Method 6
cooling the solution up to about 0-5° C.
Implementation Method 7
isolating the crystalline Form-β using another co-solvent by recrystallization
Data Source
AI summary
The present invention provides crystalline polymorphic forms of Fingolimod HCl (I) and processes for preparation thereof.The application provides processes for preparation of crystalline polymorphic forms-α, β and μ substantially free from process related impurities. The crystalline polymorphic forms of Fingolimod HCl (I) obtained by the processes according to the present invention having an XRDP pattern as per FIGS. 1, 3 and 5, which are useful as active pharmaceutical ingredient in pharmaceutical compositions for the treatment or prevention of autoimmune related disorder including multiple sclerosis.