Positive Allosteric GABA-A Modulator Salts for Oral Bioavailability

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Solution Overview

Problem

There is a need for isolable, stable, and water-soluble salts of 3α-hydroxy-3β-methoxymethyl-21-(1′-imidazolyl)-5α-pregnan-20-one (Compound 1) to address its poor solubility in the lower GI tract, limiting oral bioavailability.

Innovation Solution

The development of various salts and crystalline forms of Compound 1, including hydrobromide, citrate, maleate, and others, to enhance solubility and stability, along with methods for their preparation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If Compound 1 is administered orally, then therapeutic efficacy is achieved, but poor solubility in the lower GI tract limits oral bioavailability

Engineering Contradiction:

Improveoral bioavailabilityVSAvoidsolubility

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent applies parameter changes by converting Compound 1 into different salt forms (sodium salt, potassium salt, hydrochloride, sulfate, etc.) and crystalline forms, which fundamentally alter the physical and chemical parameters of the compound. These transformations improve solubility in the lower GI tract while maintaining the parent compound's therapeutic activity, directly resolving the contradiction between oral bioavailability and solubility

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite material systems by forming salts of Compound 1 with various counterions (Na+, K+, HCl, H2SO4, etc.) and developing crystalline forms with specific lattice structures. These composite structures combine the pharmacologically active parent compound with solubility-enhancing salts, achieving both therapeutic efficacy and improved bioavailability

Inventive Principle:

Principle #40Composite materials

2Quantity of substance

If salts of Compound 1 are developed to improve solubility, then oral bioavailability increases, but isolation and stability of the salts become challenging

Engineering Contradiction:

ImprovesolubilityVSAvoidisolation and stability

Core Design Contradiction:

Quantity of substanceVSEase of manufacture

Solution Approach 1:

The patent utilizes phase transitions by developing crystalline forms of Compound 1 salts with specific X-ray diffraction patterns and melting points. The crystallization process transforms the salts from amorphous or soluble forms into stable, isolable crystalline phases that are easier to manufacture and handle while maintaining improved solubility characteristics

Inventive Principle:

Principle #36Phase transitions

Solution Approach 2:

The patent employs common, readily available salt-forming agents (NaCl, KCl, HCl, H2SO4, etc.) that are inexpensive and well-characterized. These simple salt forms provide stable, isolable compounds that are easy to manufacture using standard pharmaceutical techniques, resolving the ease of manufacture challenge

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Data Source

PatentUS12404297B2Salts and crystal forms of GABA-<sub>A </sub>positive allosteric modulator

Publication Date: 2025.09.02 PRAXIS PRECISION MEDICINES INC

AI summary

The invention relates to salts of Compound 1, crystalline forms thereof, methods of their preparation, pharmaceutical compositions thereof and methods of their use.