Pidolate and Malate Salts for Solubility and Injection Stability
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Solution Overview
Problem
The existing benzimidazole derivative, represented by formula 1, faces challenges with low water solubility and stability, particularly under acidic conditions, which complicates its use in pharmaceutical formulations, especially injections, due to degradation and precipitation issues.
Innovation Solution
The development of pidolate and malate salts of the benzimidazole derivative, which are amorphous or partially crystalline, enhances solubility and stability by forming co-crystals through intermolecular bonding with pyroglutamic and malic acids, respectively, ensuring stability and solubility requirements are met.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If the compound is used in acidic condition to increase solubility, then water solubility is improved, but stability deteriorates due to degradation
Solution Approach 1:
The patent changes the chemical form of the compound from free base to acid addition salt, which fundamentally alters the solubility and stability parameters. The acid addition salt form maintains stability while achieving acceptable solubility, resolving the contradiction between these two properties.
Solution Approach 2:
The patent creates a composite salt structure by combining the benzimidazole derivative with specific acids (e.g., hydrochloric acid, sulfuric acid) to form acid addition salts. This composite approach allows the compound to exhibit both improved solubility and maintained stability, as the salt form provides different physicochemical properties compared to the free base.
2Quantity of substance
If amorphous acid addition salts are used to improve solubility, then kinetic solubility is improved, but thermodynamic solubility and stability remain insufficient
Solution Approach 1:
The patent systematically varies parameters such as acid type, concentration, and formulation conditions to optimize the balance between kinetic and thermodynamic solubility. By selecting appropriate acids and controlling formulation parameters, the patent achieves both rapid dissolution and stable equilibrium solubility.
Solution Approach 2:
The patent uses specific acids (hydrochloric acid, sulfuric acid) as intermediaries to form stable salt complexes. These acids act as mediators that facilitate both the solubility enhancement and stability maintenance, bridging the gap between kinetic and thermodynamic properties.
3Reliability
If crystalline free base is used for stability, then storage stability is improved, but water solubility remains insufficient for formulation
Solution Approach 1:
The patent fundamentally changes the physical and chemical parameters of the compound by converting it to an acid addition salt form. This transformation maintains the stability characteristics of crystalline forms while significantly improving water solubility to levels suitable for pharmaceutical formulations.
Solution Approach 2:
The patent creates a composite salt structure that combines the stability of crystalline materials with the solubility enhancement provided by acid addition salts. The resulting salt form exhibits both crystalline stability and improved aqueous solubility, resolving the contradiction between these properties.
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 pidolate and malate salts provide excellent solubility and stability, suitable for pharmaceutical applications, particularly in injection formulations, maintaining solubility and preventing degradation even under in vivo pH conditions.
Implementation Method 1
forming co-crystals through intermolecular bonding with pyroglutamic and malic acids, respectively
Implementation Method 2
in case of an amorphous pharmaceutical ingredient, a surface area of a particle increases, so a kinetic solubility generally increases
Data Source
AI summary
The present invention relates to a pidolate salt and malate salt of a compound represented by a formula 1 with an excellent liquid-phase stability, solid-phase stability, water solubility, precipitation stability and hygroscopicity all together as a compound for preventing and treating diseases mediated by an acid pump antagonistic activity, as well as a method for preparing the same.