SSTR4 Agonist Salt Forms for Stable Pharmaceutical Processing
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Solution Overview
Problem
There is a need for alternative solid-state forms of selective SSTR4 agonists with improved stability in excipients and favorable flow and bulk properties for the manufacturing of active pharmaceutical products.
Innovation Solution
Development of novel SSTR4 agonist salts, specifically (1S,5R)-(1α,5α,6α)-N-[1,1-dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide salts such as tartrate sesquihydrate, citrate, and malate, which exhibit improved stability and favorable flow and bulk properties, characterized by specific X-ray powder diffraction patterns.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional SSTR4 agonist formulations are used, then the basic pharmacological activity is maintained, but the stability in excipients and manufacturing properties (flow and bulk) are insufficient
Solution Approach 1:
The patent applies parameter changes by transforming the SSTR4 agonist into different salt forms (e.g., hydrochloride salt, sulfate salt) and crystal polymorphs. These parameter changes in chemical form and physical structure result in improved stability within pharmaceutical excipients while maintaining the desired flow and bulk properties for manufacturing. The specific salt and polymorph selections optimize both stability and manufacturability parameters simultaneously.
2Reliability
If alternative solid-state forms are developed, then stability and manufacturing properties are improved, but the complexity of formulation development increases
Solution Approach 1:
The patent utilizes parameter changes by systematically exploring different salt forms and crystal polymorphs of the SSTR4 agonist. By changing the chemical salt form and physical crystal structure parameters, the invention achieves improved stability and manufacturing properties without requiring entirely new formulation development pathways, thus managing complexity through controlled parameter variation rather than comprehensive redesign.
3Reliability
If selective SSTR4 agonists are used, then therapeutic efficacy is achieved, but the availability of solid-state forms with improved properties is limited
Solution Approach 1:
The patent applies parameter changes by developing multiple salt forms (hydrochloride, sulfate) and crystal polymorphs of the selective SSTR4 agonist. These parameter changes enable the same therapeutically active compound to exist in multiple solid-state forms, each with optimized properties for different applications, thereby enhancing adaptability and versatility while maintaining therapeutic efficacy.
Solution Approach 2:
The patent employs composite materials by creating salt compounds and polymorphic forms that combine the SSTR4 agonist with specific counterions and crystal structures. These composite solid-state forms provide enhanced stability, improved flow characteristics, and better bulk properties, expanding the availability of versatile solid-state forms for various pharmaceutical applications while preserving the selective agonist activity.
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 novel SSTR4 agonist salts demonstrate enhanced stability and manufacturing properties, enabling effective treatment of pain conditions such as chronic back pain, neuropathic pain, and osteoarthritis pain, with selective binding to SSTR4 receptors and minimal interference with other receptor types.
Implementation Method 1
The effects of somatostatin are mediated by a family of G protein-coupled receptors, of which five subtypes are known. These subtypes are divided into two subfamilies, the first comprising SSTR2, SSTR3 and SSTR5 and the second SSTR1 and SSTR4.
Implementation Method 2
The present invention provides a crystalline form of a compound of Formula I, characterized by an X-ray powder diffraction pattern using CuKα radiation comprising a peak at diffraction angle 2-theta of 15.2°, and one or more peaks at 10.6° and 21.9° (±0.2° respectively).
Data Source
AI summary
The present invention relates to specific salts of (1S,5R)-(1α,5α,6α)-N-[1,1-dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide, to pharmaceutical compositions comprising said salts, to methods of using said salts to treat physiological disorders, and to intermediates useful in the synthesis of the salts.