Anhydrous Polymorph Synthesis for Antifungal Drug Stability
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Solution Overview
Problem
There is a need for new or purer polymorphic forms of existing drug molecules to improve drug formulations, particularly for better bioavailability and stability, as different crystalline polymorphs exhibit varying properties such as ease of preparation, stability, and pharmacokinetics.
Innovation Solution
An anhydrous polymorph form of compound 1 is developed, along with a method for its synthesis, involving drying processes under vacuum at elevated temperatures and specific solvent mixtures to isolate the anhydrous form with minimal water content, which includes suspending a solution of the compound in a solvent mixture comprising hydrocarbon and C3-C10 alcohol solvents with controlled water content.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional hydration processes are used to prepare compound 1, then the compound can be obtained as a hydrate form, but the bioavailability and stability are reduced compared to the anhydrous form
Solution Approach 1:
The patent applies parameter changes by controlling temperature, pressure, and solvent composition during the crystallization process to favor the formation of the anhydrous polymorph over the hydrate form. Specific temperature ranges and solvent ratios are optimized to achieve the desired anhydrous form with high purity
Solution Approach 2:
The patent utilizes phase transitions during the crystallization process, controlling the transformation from solution to solid phase to obtain the anhydrous polymorph. The process involves careful control of cooling rates and solvent evaporation to promote the formation of the stable anhydrous crystalline structure
2Productivity
If the compound is prepared as a hydrate form, then the preparation process is simpler, but the pharmacokinetic properties are inferior
Solution Approach 1:
The patent employs parameter changes by adjusting crystallization conditions including temperature profiles, solvent composition ratios, and cooling rates to selectively obtain the anhydrous polymorph with superior pharmacokinetic properties
Solution Approach 2:
The patent applies preliminary action by pre-treating the solution with specific solvents and controlling the initial crystallization conditions to prevent formation of the hydrate form and ensure obtaining the anhydrous polymorph from the outset
3Manufacturing precision
If drying processes are applied to remove water, then the anhydrous form can be obtained, but water content may exceed 2 weight % without controlled drying conditions
Solution Approach 1:
The patent applies parameter changes by optimizing drying conditions including temperature, pressure, and time to achieve complete removal of water while minimizing energy consumption. The process uses controlled vacuum drying at specific temperature ranges to achieve the anhydrous form efficiently
Solution Approach 2:
The patent utilizes an inert atmosphere during the drying process, applying vacuum conditions to remove water while preventing re-absorption of moisture from the environment. This ensures consistent anhydrous form with controlled water content
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 anhydrous form of compound 1 demonstrates enhanced stability and bioavailability, as evidenced by higher maximal concentration and area-under-the-curve values in human pharmacokinetic studies compared to its hydrate form, indicating improved pharmacokinetic properties.
Implementation Method 1
the compound inhibits (or is identified to inhibit) lanosterol demethylase (CYP51). The compounds herein include those wherein the compound is identified as attaining affinity, at least in part, for a metalloenzyme by formation of one or more of the following types of chemical interactions or bonds to a metal: sigma bonds, covalent bonds, coordinate covalent bonds, ionic bonds, pi bonds, delta bonds, or backbonding interactions
Data Source
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AI summary
The present invention relates to polymorphic forms of compound 1 or 1a and processes for preparing compound 1 and 1a polymorphs, which are useful as antifungal agents. In particular, the invention seeks to provide a new methodology for preparing polymorphs of compound 1 and substituted derivatives thereof.