Tegoprazan Hydrochloride Salt for Solubility and Bioavailability
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Solution Overview
Problem
Existing benzimidazole derivative compounds, such as tegoprazan, face challenges in achieving optimal aqueous solubility, stability, and bioavailability, particularly when formulated into pharmaceutical products, which can be influenced by food intake and gastrointestinal pH fluctuations.
Innovation Solution
Development of a hydrochloride salt or hydrochloride hydrate of the benzimidazole derivative tegoprazan, which exhibits significantly higher solubility, stability, and bioavailability, maintaining immediate-release properties regardless of gastrointestinal pH changes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the freebase form of tegoprazan is used, then the compound has good light stability and low hygroscopicity, but the aqueous solubility is insufficient
Solution Approach 1:
The patent applies parameter changes by transforming the freebase form into its hydrochloride salt form, which fundamentally alters the chemical parameters of the compound. This transformation increases aqueous solubility while maintaining light stability and hygroscopicity characteristics, directly resolving the contradiction between solubility and stability.
Solution Approach 2:
The patent creates a composite structure by forming a salt compound between tegoprazan and hydrochloric acid. This composite material (hydrochloride salt) combines the beneficial properties of both components, achieving both high solubility and stability that neither the freebase nor the acid alone could provide.
2Quantity of substance
If previously known salts such as pidolate or malate are used, then aqueous solubility is improved, but stability and bioavailability are insufficient
Solution Approach 1:
The patent changes the chemical parameter by selecting hydrochloric acid as the counterion instead of previously known salts like pidolate or malate. This parameter change results in a hydrochloride salt that achieves both high aqueous solubility and superior stability, overcoming the limitations of earlier salt formulations.
Solution Approach 2:
The patent eliminates the need for complex, less stable salt formulations by using a simple and robust hydrochloride salt system. This approach replaces previously known salts with a more reliable alternative that provides consistent performance without requiring complex formulation strategies.
3Ease of manufacture
If the freebase form is used, then the compound can be formulated into tablets, but bioavailability is insufficient and affected by food intake
Solution Approach 1:
The patent transforms the freebase form into its hydrochloride salt form, fundamentally changing the pharmacokinetic parameters. This transformation ensures consistent bioavailability regardless of food intake by optimizing the compound's absorption characteristics, while still allowing for standard tablet formulation.
Solution Approach 2:
The hydrochloride salt acts as an intermediary form that bridges the gap between formulation capability and bioavailability. It maintains compatibility with standard pharmaceutical formulation processes while simultaneously improving absorption and reducing food-effect variability, serving as a mediating structure that achieves both goals.
4Reliability
If multiple salt forms are explored, then solubility and stability can be optimized, but development time and complexity increase
Solution Approach 1:
The patent makes a direct parameter change from freebase to hydrochloride salt form, which immediately improves pharmaceutical properties without requiring extensive screening of multiple salt options. This single, well-chosen parameter change achieves optimization while minimizing development time.
Solution Approach 2:
The patent adopts a streamlined approach by focusing on a single optimal salt form (hydrochloride) rather than exhaustively testing multiple possibilities. This strategy reduces development time and resource consumption while still achieving superior pharmaceutical properties, effectively discarding the need for prolonged multi-option exploration.
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 hydrochloride salt or hydrate demonstrates at least 10 times higher solubility than the freebase form, ensuring stable bioavailability and rapid drug action, with superior stability and disintegration characteristics, enhancing patient convenience and therapeutic efficacy.
Implementation Method 1
The hydrochloride salt or hydrochloride hydrate of the compound of Formula 1 has been confirmed to have a higher solubility at least 10 times or more compared to that of the existing commercially available freebase crystalline form A
Implementation Method 2
the hydrochloride hydrate showed the best stability in all aspects, and showed significantly better stability compared to other acid addition salts even when combined with pharmaceutically acceptable additives
Implementation Method 3
the hydrochloride salt or hydrochloride hydrate has significantly better overall liquid stability, solid stability, and photostability compared to other types of acid addition salts including known acid addition salts
Data Source
Figure 1A
Figure 1B
Figure 2A
AI summary
Provided are a hydrochloride or hydrochloride hydrate of a compound of Formula 1, and a pharmaceutical composition including the same.