Halobetasol Propionate Crystallization Using Ethanol Solvents
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Solution Overview
Problem
Current methods for preparing halobetasol propionate are inefficient, as they often use toxic solvents and do not consistently produce the desired crystalline form, which is necessary for commercial-scale production with high yield and purity.
Innovation Solution
A process involving crystallization of halobetasol propionate from absolute ethanol or a mixture of ethanol and water, characterized by specific x-ray powder diffraction patterns and infrared spectra, which ensures the production of a non-toxic, high-purity crystalline form suitable for commercial scale.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional crystallization methods using toxic solvents (methylene chloride, toluene, methanol) are employed, then crystalline forms of halobetasol propionate can be obtained, but the process introduces harmful factors and requires toxic solvent handling
Solution Approach 1:
The patent changes the chemical composition parameter of the solvent system from toxic solvents (methylene chloride, toluene, methanol) to non-toxic solvents (ethanol, isopropanol, ethyl acetate). This substitution maintains the crystallization function while eliminating the harmful toxicity factor, directly resolving the technical contradiction between reliable crystalline form production and solvent safety.
2Adaptability or versatility
If multiple different solvent systems are used to prepare various crystalline forms, then diverse crystalline forms (Forms I-VI) can be obtained, but the process complexity increases and predictability decreases
Solution Approach 1:
The patent extracts and eliminates the unnecessary complexity from the crystallization process by identifying that only specific solvent systems (ethanol, isopropanol, ethyl acetate) are needed to produce the desired Form III. This removes the need to manage multiple solvent systems and crystalline forms, simplifying the process while maintaining the ability to produce the target crystalline form consistently.
Solution Approach 2:
The patent establishes that a limited set of solvent systems (ethanol, isopropanol, ethyl acetate) can universally produce Form III of halobetasol propionate. This multi-functional solvent approach replaces the need for multiple specialized solvent systems, reducing process complexity while maintaining versatility in producing the desired crystalline form.
3Quantity of substance
If crystallization is performed using toxic solvent systems, then halobetasol propionate can be crystallized, but the manufacturing process becomes less favorable for commercial scale production
Solution Approach 1:
The patent changes the solvent system parameters from toxic to non-toxic solvents, which directly improves manufacturing favorability for commercial scale production. The new solvent system (ethanol, isopropanol, or ethyl acetate) maintains effective crystallization capability while eliminating safety and environmental concerns, making the process more suitable for large-scale manufacturing.
4Manufacturing precision
If conventional recrystallization methods are used, then halobetasol propionate can be purified, but the yield and purity consistency is insufficient for commercial requirements
Solution Approach 1:
The patent optimizes the crystallization parameters by selecting specific solvent systems (ethanol, isopropanol, ethyl acetate) and controlling crystallization conditions to consistently produce Form III. This parameter optimization achieves both high purity (≥99.8%) and high yield (≥95%) with consistent results, meeting commercial production requirements that were not achieved with conventional methods.
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
This process effectively produces a crystalline form of halobetasol propionate with a purity of at least 99.8% and a yield of at least 95%, using non-toxic solvents, matching the form present in ULTRAVATE cream and suitable for large-scale pharmaceutical production.
Implementation Method 1
crystallization of halobetasol propionate from absolute ethanol or a mixture of ethanol and water
Data Source
AI summary
The present invention provides a process for preparing a crystalline form of halobetasol propionate, comprising the step of crystallizing halobetasol propionate from absolute ethanol or a mixture of ethanol and water, wherein the crystalline form of halobetasol propionate is characterized by an x-ray powder diffraction pattern having peaks at 10.0, 11.6, 12.9, 13.4, 14.5, 16.4, 17.6, and 23.5±0.2 degrees 2θ.