Obicetrapib Calcium Salt Forms for Stable Fast-Dissolving Manufacture
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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 salt forms of obicetrapib, such as amorphous obicetrapib hemicalcium, and crystalline obicetrapib HCl compounds, along with methods for their production, including the use of intermediates like compounds of Formula (VI) and Compound 1D, to enhance stability and solubility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If crystalline forms of obicetrapib are used, then the solid form is stable, but the solubility and dissolution rate are low
Solution Approach 1:
The patent changes the physical state parameter from crystalline to amorphous form, which fundamentally alters the molecular arrangement and eliminates long-range order. This parameter change increases solubility and dissolution rate while maintaining adequate physical stability through careful control of manufacturing conditions and storage environment.
Solution Approach 2:
The patent utilizes phase transition from crystalline to amorphous state to improve dissolution characteristics. The amorphous phase represents a different physical state with higher energy and less ordered structure, enabling faster dissolution. The patent carefully manages this phase transition through controlled precipitation or drying processes to achieve the desired amorphous form with improved bioavailability.
2Ease of manufacture
If existing manufacturing processes are used, then obicetrapib can be produced, but the yield is low and the process is not suitable for industrial scale
Solution Approach 1:
The patent optimizes critical process parameters including solvent selection, temperature profiles, pH control, and concentration levels to dramatically improve yield. By changing parameters such as using specific solvents (e.g., ethyl acetate, isopropyl alcohol) and controlling reaction conditions, the process achieves high yield suitable for industrial scale while maintaining ease of manufacture.
Solution Approach 2:
The patent employs intermediate compounds and protecting groups during synthesis to facilitate the manufacturing process. These intermediates enable selective reactions and improve overall yield by preventing side reactions. The use of intermediates such as esters or protected amino groups allows for stepwise synthesis with high efficiency and scalability.
3Ease of manufacture
If existing manufacturing processes are used, then obicetrapib can be produced, but the purity is poor
Solution Approach 1:
The patent uses protecting groups as intermediaries to shield sensitive functional groups during synthesis, preventing unwanted side reactions and ensuring high purity of the final product. These protecting groups are selectively introduced and removed in controlled steps, maintaining manufacturing feasibility while achieving excellent purity levels.
Solution Approach 2:
The patent optimizes purification parameters including solvent systems, temperature, and pH to enhance product purity. By carefully controlling crystallization conditions and using selective precipitation, the process achieves high purity while remaining economically viable for industrial production.
4Productivity
If amorphous forms are used, then solubility and dissolution rate improve, but physical stability may deteriorate
Solution Approach 1:
The patent carefully controls physical parameters such as moisture content, temperature, and packaging conditions to stabilize the amorphous form. By maintaining appropriate environmental conditions, the amorphous form achieves both high solubility and adequate physical stability for pharmaceutical use.
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.