Compound I′ Crystalline Form for Stable NEP Inhibitor Manufacturing
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Solution Overview
Problem
There is a need for a stable, crystalline form of NEP inhibitors that can be readily manufactured and has desirable chemical and physical stability, including a high melting point and small crystal size for effective drug delivery, as existing methods are unpredictable and lack reliable prediction of suitable crystalline forms.
Innovation Solution
A novel crystalline form of (2S,4R)-5-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid (Compound I′) is developed, which exhibits neprilysin inhibition activity and is characterized by specific PXRD patterns, DSC thermograms, and non-hygroscopic properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a crystalline form of NEP inhibitor is developed, then manufacturing stability and purity are improved, but prediction reliability of suitable crystalline forms deteriorates
Solution Approach 1:
The patent changes the physical parameters of the compound by developing specific crystalline forms (Form I, Form II, Form III) with distinct melting points and PXRD patterns. This allows the compound to achieve stable crystalline structures suitable for manufacturing while the patent acknowledges the unpredictability of form prediction remains a limitation.
Solution Approach 2:
The patent creates multiple crystalline forms (Form I, Form II, Form III) that are essentially copies of the same compound with different physical properties. These forms provide manufacturing stability and purity while each form has predictable characteristics that can be reproduced through specific crystallization processes.
2Productivity
If crystal size is reduced to increase dissolution and bioavailability, then drug delivery effectiveness is improved, but manufacturing control becomes more difficult
Solution Approach 1:
The patent utilizes different crystalline forms with distinct physical parameters (melting points, PXRD patterns) to achieve controlled crystal sizes. By selecting specific forms and controlling crystallization conditions, the patent achieves small crystal sizes for improved dissolution while maintaining manufacturing precision through defined process parameters.
Solution Approach 2:
The patent exploits phase transitions during crystallization to control crystal size. By controlling the crystallization process and selecting appropriate crystalline forms, the patent achieves small crystal sizes that enhance dissolution and bioavailability while maintaining manufacturability through controlled phase change processes.
3Stability of the object's composition
If thermal stability is increased to facilitate processing and storage, then material stability is improved, but processing temperature range becomes more limited
Solution Approach 1:
The patent develops crystalline forms with specific melting points (Form I: 214-218°C, Form II: 208-212°C, Form III: 198-202°C) to achieve thermal stability for manufacturing and storage. Each form provides a defined thermal profile that allows processing within acceptable temperature ranges while maintaining composition stability during storage.
Data Source
AI summary
In one aspect, the invention relates to a crystalline form of the structure:or a pharmaceutically acceptable salt thereof, having neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising this crystalline form; methods of using this crystalline form and its soluble form (I); and processes for preparing soluble (I) and crystalline (I′) forms.