GABAA Receptor Modulator Salts for Bioavailability and Half-Life
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Solution Overview
Problem
3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine (Compound 1) has limited bioavailability and a short half-life, necessitating improved GABAA receptor modulators for therapeutic applications.
Innovation Solution
Development of salts and particles of Compound 1, including hemi-fumarate, sulfate, hydrochloride, phosphate, tosylate, and malonate salts, to enhance bioavailability and stability, along with controlled particle sizes and coatings for targeted delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Compound 1 is used as a GABAA receptor modulator, then therapeutic effect is achieved, but bioavailability is limited and half-life is short
Solution Approach 1:
The patent applies parameter changes by converting Compound 1 into different salt forms (sulfate, hydrochloride, phosphate, tosylate, malonate salts) to modify its physical and chemical properties. This transformation changes the solubility and dissolution characteristics of the compound, thereby improving its bioavailability while maintaining the therapeutic effect on GABAA receptors.
2Reliability
If Compound 1 is used as a GABAA receptor modulator, then therapeutic effect is achieved, but half-life is short
Solution Approach 1:
The patent uses parameter changes by forming stable salt compounds of Compound 1 with various acids (sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, malonic acid). These salt forms exhibit improved stability and extended duration of action compared to the free base form, allowing the therapeutic effect to be maintained for longer periods.
3Quantity of substance
If salts of Compound 1 are developed to improve bioavailability, then bioavailability increases, but formulation complexity increases
Solution Approach 1:
The patent introduces salt-forming acids as intermediary substances to convert Compound 1 into more bioavailable forms. These acids (sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, malonic acid) act as mediators that enhance the dissolution and absorption of the active compound without requiring complex formulation technologies, thus improving bioavailability while keeping the formulation relatively simple.
Data Source
AI summary
Described herein are salts (e.g., fumarate salts) of 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine and particles comprising 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine or a salt thereof, and uses thereof.