Maleate Salt Cyclohexane Derivative Stability
Solution Overview
Problem
The existing cyclohexane derivative compound for treating mental diseases has stability and pharmacokinetic property issues during formulation, storage, and in vivo use, necessitating an improved compound form with enhanced stability and bioavailability.
Innovation Solution
A salt form of the cyclohexane derivative N'-[trans-4-[2-[4-(benzo[b]thiophen-7-yl)piperazin-1-yl]ethyl]cyclohexyl]-N,N-dimethylurea is developed, specifically a maleate salt with a 1:1 stoichiometric ratio, which improves stability and bioavailability by reducing hygroscopicity and extending half-life in vivo.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the cyclohexane derivative compound is used in its original form, then it shows D2/D3 antagonist effect and anti-schizophrenic effect, but it has poor stability during formulation and storage and poor pharmacokinetic properties
Solution Approach 1:
The patent applies parameter changes by converting the cyclohexane derivative compound into different salt forms (hydrochloride, sulfate, phosphate, maleate salts) with varying physical and chemical parameters. This transformation improves both stability during formulation and storage while enhancing pharmacokinetic properties such as bioavailability and half-life, thereby resolving the contradiction between reliability and productivity.
2Stability of the object's composition
If a salt form of the compound is developed to improve stability, then stability and storage properties are improved, but the complexity of formulation increases
Solution Approach 1:
The patent resolves this contradiction by systematically evaluating multiple salt forms (hydrochloride, sulfate, phosphate, maleate) with different physical and chemical parameters. Each salt form offers improved stability while varying in complexity, allowing selection of the optimal balance between stability enhancement and formulation simplicity for different application scenarios.
3Productivity
If the maleate salt is used, then bioavailability and half-life are improved, but the manufacturing process becomes more complex
Solution Approach 1:
The patent addresses this contradiction by developing the maleate salt form with optimized parameters that achieve superior bioavailability and extended half-life. The manufacturing process involves reacting the cyclohexane derivative with maleic acid in appropriate solvents, which, while more complex than simple salt formation, provides significant pharmacokinetic benefits that justify the additional manufacturing steps.
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 maleate salt exhibits higher bioavailability, longer half-life, and reduced individual differences in vivo, providing improved pharmacokinetic properties and stability, making it an ideal form for clinical use.
Implementation Method 1
a salt form of the cyclohexane derivative N'-[trans-4-[2-[4-(benzo[b]thiophen-7-yl)piperazin-1-yl]ethyl]cyclohexyl]-N,N-dimethylurea is developed, specifically a maleate salt with a 1:1 stoichiometric ratio, which improves stability and bioavailability by reducing hygroscopicity
Implementation Method 2
The X-ray powder diffraction pattern of the maleate of the present invention, expressed in 2Θ angle by using Cu-Ku radiation, has diffraction peaks at least at 11.804°±0.2°, 12.703°±0.2°, 13.493°±0.2°, 14.495°±0.2°, 15.096°±0.2°, 17.108°±0.2°, 19.104°±0.2°, 19.655°±0.2°, 20.023°±0.2°, 21.611°±0.2° and 24.088°±0.2°
Data Source
Figure 1~2A
Figure 2B~2C
Figure 3A~3B
AI summary
The present invention provides a maleate, phosphate, sulfate, hydrochloride of a cyclohexane derivative, N'-[trans-4-[2-[7-(benzo[b]thiophene)-7-piperazinyl]ethyl]cyclohexyl]-N,N-dimethylurea, as shown in Formula I and crystal forms thereof. The crystal forms have low hygroscopicity and good stability and are convenient for long-term storage and transportation; or the crystal forms have a long half-life in vivo, high bioavailability and small individual difference, and thus have obvious clinical application advantages.