Triazine Salt Crystal Forms for Stable API Manufacturing

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Solution Overview

Problem

Existing triazine compounds for treating primary aldosteronism lack specific salts and crystal forms with desirable physical properties, stability, and reproducibility, and their production methods involve hazardous intermediates, making large-scale manufacturing challenging.

Innovation Solution

Development of hydrobromide, sulfate, and succinate salts of Triazine compound A with stable crystal forms, such as Hydrobromide Form A, and a method to produce these salts and crystals efficiently, using controlled conditions to minimize impurities and hazards.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional triazine compounds are used for treating primary aldosteronism, then the basic therapeutic function is achieved, but the compounds lack specific salts and crystal forms with desirable physical properties and stability

Engineering Contradiction:

ImprovestabilityVSAvoidmanufacturing complexity

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent applies parameter changes by converting the triazine compound into different salt forms (hydrobromide, sulfate, succinate, tosilate) with distinct physical and chemical parameters. Each salt form exhibits improved stability characteristics, thermal properties, and crystalline structures, allowing selection of optimal forms for specific manufacturing and therapeutic needs

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent utilizes phase transitions by developing specific crystal forms (polymorphs) of the triazine compound salts. Different crystal forms exhibit distinct melting points, solubility characteristics, and stability profiles. The hydrobromide salt, for example, displays specific crystalline phases that enhance thermal stability and reduce hygroscopicity, directly addressing the reliability-manufacturability contradiction

Inventive Principle:

Principle #36Phase transitions

2Ease of manufacture

If production methods use hazardous intermediate compounds, then the triazine compound can be synthesized, but safety risks and manufacturing challenges increase

Engineering Contradiction:

Improvesynthesis feasibilityVSAvoidsafety hazards

Core Design Contradiction:

Ease of manufactureVSObject-affected harmful factors

Solution Approach 1:

The patent converts potentially harmful synthesis processes into beneficial outcomes by developing alternative production methods that avoid hazardous intermediates. The new methodology maintains synthesis feasibility while eliminating safety risks associated with explosive and genotoxic compounds, effectively turning a harmful manufacturing approach into a safe and compliant process

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Adaptability or versatility

If crystal forms are produced with varying conditions, then different crystal structures can be obtained, but reproducibility and stability decrease

Engineering Contradiction:

Improvecrystal form varietyVSAvoidreproducibility

Core Design Contradiction:

Adaptability or versatilityVSManufacturing precision

Solution Approach 1:

The patent applies local quality by establishing specific, localized manufacturing conditions for each crystal form. Rather than using broad, variable conditions, the patent defines precise parameters (temperature ranges, solvent compositions, pH levels, addition rates) for producing each polymorph. This ensures that the desired crystal form is reproducibly obtained while maintaining the ability to produce different forms when needed

Inventive Principle:

Principle #3Local quality

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 salts and crystals exhibit excellent thermal stability, reduced hygroscopicity, and stability under varying gastric conditions, enabling safe and reproducible production as active pharmaceutical ingredients.

Implementation Method 1

hydrobromide, sulfate, or succinate of the Triazine compound A have been found as salts that can produce excellent crystals that are excellent in terms of purity, thermal stability, hygroscopicity, deliquescency, chemical stability, and safety

Methodology Applied

Scientific EffectCrystallization: Crystallisation

Data Source

PatentUS20260008756A1Triazine compound salt, crystal form thereof, and production method therefor

Publication Date: 2026.01.08 TANABE PHARMA CORP

AI summary

The present invention provides a salt of a triazine compound which has an inhibitory action against aldosterone synthase and is useful as a drug, and especially as a drug for preventing or treating primary aldosteronism and the like, a crystal thereof, and a method for producing the same. Specifically, the present invention provides a pharmaceutically acceptable salt of 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine, wherein the salt is hydrobromide, sulfate, succinate, or tosilate, and the like.