Fingolimod Hydrochloride Crystallization Filterability
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Solution Overview
Problem
Existing processes for producing crystalline fingolimod hydrochloride result in a waxy or cotton-like solid with poor filterability and flowability, making large-scale processing and pharmaceutical formulation inconvenient.
Innovation Solution
A process involving contacting a fingolimod hydrochloride solution with an antisolvent at temperatures above 50°C, followed by cooling to below 40°C, using C1-C6 aliphatic alcohols as solvents and n-heptane as the antisolvent, to precipitate crystalline fingolimod hydrochloride with improved filterability and flowability, avoiding contamination with metastable forms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If crystallization is performed from ethanol solution at room temperature, then crystalline fingolimod hydrochloride can be obtained, but the crystal habit is waxy or cotton-like with poor filterability and flowability
Solution Approach 1:
The patent changes the temperature parameter during crystallization to at least 40°C (preferably 45-60°C), which fundamentally alters the crystal growth kinetics and produces well-defined crystalline forms with improved filterability and flowability, while maintaining Form I stability
Solution Approach 2:
The patent introduces an antisolvent (such as n-heptane, toluene, or ethyl acetate) as an intermediary substance to modify the crystallization process. The antisolvent interacts with the solvent-fingolimod hydrochloride system to promote formation of desirable crystal habits while maintaining the stable Form I polymorph
2Manufacturing precision
If crystallization is performed from ethyl acetate and ethanol mixture, then crystals can be obtained, but they still exhibit poor filterability and flowability
Solution Approach 1:
The patent raises the crystallization temperature to at least 40°C when using ethyl acetate and ethanol mixtures, which changes the solubility and supersaturation profiles, leading to formation of discrete crystals rather than waxy solids, thereby improving filterability and flowability
3Quantity of substance
If concentration of ethanolic solution is performed to obtain crystals, then solid product can be obtained, but it has poor filterability and flowability
Solution Approach 1:
Instead of concentrating the solution and then crystallizing, the patent performs crystallization at elevated temperature (at least 40°C) from the original or diluted solution, which directly produces filterable and flowable crystals without requiring concentration steps, maintaining yield while improving physical properties
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 process yields small, regular crystals with enhanced filterability and flowability, facilitating efficient large-scale production and ensuring the isolation of pure Form I crystalline fingolimod hydrochloride without contamination from other forms.
Implementation Method 1
contacting a solution of fingolimod hydrochloride in a solvent with an antisolvent at a temperature of at least 50°C wherein the temperature of the antisolvent before and during contacting it with the solvent is at least 40°C
Implementation Method 2
cooling the obtained solution to a temperature of below 40°C, whereby crystalline fingolimod hydrochloride precipitates
Data Source
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AI summary
The invention relates to a process of making crystalline fingolimod hydrochloride of Formula (1a), comprising a step of contacting a solution of fingolimod hydrochloride in a solvent with an antisolvent at an enhanced temperature, and cooling such solution whereby crystalline fingolimod hydrochloride precipitates, and isolating crystalline fingolimod hydrochloride from the liquid medium.