Amorphous Obicetrapib Hemicalcium for Stable, Scalable Manufacturing
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Solution Overview
Problem
Existing processes for manufacturing obicetrapib result in unfavorable solid forms with low yield, poor stability, and are not suitable for industrial scale, necessitating improved solid forms and alternative processes with enhanced yield, purity, and stability.
Innovation Solution
The development of amorphous calcium salts, such as amorphous obicetrapib hemicalcium, and crystalline obicetrapib HCl compounds, along with intermediates like compounds of Formula (VI) and Compound 1D, to improve the manufacturing process, ensuring higher yield and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If crystalline obicetrapib hemicalcium is manufactured using existing processes, then the product can be obtained, but it exhibits poor physical stability
Solution Approach 1:
The patent transforms the crystalline solid form of obicetrapib hemicalcium into an amorphous solid form by changing the physical state parameters. This parameter change from crystalline to amorphous structure fundamentally alters the physical stability characteristics, eliminating the poor stability issues associated with the crystalline form while maintaining the desired chemical composition and therapeutic efficacy.
2Productivity
If existing manufacturing processes are used for obicetrapib, then production can proceed, but the yield is low and the process is not suitable for industrial scale
Solution Approach 1:
The patent modifies critical manufacturing parameters including solvent selection (using ethyl acetate and heptane), temperature conditions (maintaining 0-5°C), and pH control (adjusting to pH 2-3 with HCl). These parameter changes optimize the precipitation and filtration processes, dramatically improving both yield and scalability for industrial manufacturing while maintaining product quality.
Solution Approach 2:
The patent replaces complex purification mechanisms with a simplified gravity-based filtration and washing system. By optimizing the precipitation conditions, the process eliminates the need for complex chromatography or multiple purification steps, allowing straightforward scaling from laboratory to industrial production while maintaining high yield and purity.
3Stability of the object's composition
If crystalline forms of obicetrapib are used, then the solid structure is stable, but solubility and dissolution rates are reduced
Solution Approach 1:
The patent changes the solid state parameter from crystalline to amorphous form. This fundamental parameter change increases the surface area and reduces lattice energy, thereby dramatically improving solubility and dissolution rates. The amorphous form maintains adequate physical stability while achieving the enhanced dissolution characteristics needed for improved bioavailability and therapeutic effect.
Data Source
AI summary
Provided herein is a method for the manufacture of a compound of obicetrapib and salts thereof, such as calcium salts thereof. Also provided herein is amorphous obicetrapib hemicalcium. New intermediates for use in the synthesis of obicetrapib, and salts thereof are also provided, including obicetrapib HCl and a mesylate salt for the use in the synthesis of obicetrapib and amorphous obicetrapib hemicalcium.