Naphthyridine Amide Salt Crystal Forms for Clinical Stability
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Solution Overview
Problem
Existing 1,4-dihydro-1,6-naphthyridine amide compounds, such as (S)-4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-4-yl)-3-(methoxy-d3)benzonitrile, face undesirable physicochemical and biological properties that hinder their suitability for clinical use and industrial production, necessitating the development of pharmaceutically acceptable salts with improved stability and biological activity.
Innovation Solution
The development of pharmaceutically acceptable salts of the compound, including hydrochloride, sulfate, phosphate, hydrobromide, mesylate, p-toluenesulfonate, tartrate, maleate, citrate, and malate, through specific acid reactions and crystallization methods using solvents like acetone/water, acetonitrile/water, and isopropanol, with characteristic X-ray powder diffraction patterns for various crystal forms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the parent compound (S)-4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-4-yl)-3-(methoxy-d3)benzonitrile is used directly, then the molecular structure is maintained, but the physicochemical and biological properties are undesirable for clinical use
Solution Approach 1:
The patent applies parameter changes by forming pharmaceutically acceptable salts of the parent compound with various acids (hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, tartaric acid, maleic acid, citric acid, and malic acid). This chemical modification changes the physicochemical parameters of the compound, improving its stability, solubility, and biological activity, thereby making it suitable for clinical use and industrial production.
2Stability of the object's composition
If salt formation is performed to improve physicochemical properties, then stability and biological activity are enhanced, but the complexity of the compound structure increases
Solution Approach 1:
The patent forms salts by reacting the parent compound with various acids, which changes the chemical parameters of the compound. This creates new crystal forms with improved stability and biological activity while maintaining manageable structural complexity through systematic salt formation.
Solution Approach 2:
The patent creates composite salt structures by combining the parent compound with different acids, resulting in new crystalline materials with enhanced properties. Each salt form represents a composite structure that leverages the beneficial characteristics of both the parent compound and the acid counterion.
3Reliability
If multiple crystal forms are developed through intensive research, then polymorph stability is improved, but the research and development time increases
Solution Approach 1:
The patent systematically varies the acid counterion and crystallization conditions to generate multiple crystal forms with different polymorph stabilities. By changing the chemical parameters through salt formation, the patent efficiently explores the polymorph landscape without requiring extensive time-consuming research for each variant.
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 resulting crystal forms exhibit enhanced physicochemical and pharmaceutical properties, suitable for industrial production and clinical use, addressing the limitations of the parent compound.
Implementation Method 1
reacting the compound of formula 1, (S)-4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-4-yl)-3-(methoxy-d3)benzonitrile, with an acid
Implementation Method 2
The solvent used for salt formation in the present disclosure is selected from the group consisting of, but is not limited to, acetone/water, acetonitrile/water, isopropanol, isopropyl acetate, 4-methyl-2-pentanone, ethanol/dichloromethane, and n-heptane. Further, in an optional embodiment, the method for preparing the aforementioned pharmaceutically acceptable salt further comprises such a step as crystallization
Implementation Method 3
an X-ray powder diffraction pattern expressed in terms of 2θ angles, which are diffraction angles, of the crystal form has characteristic peaks at 7.401, 8.635, 9.630, 17.457, and 26.350
Data Source
Figure 1~2
Figure 3~4
Figure 5~6
AI summary
The present disclosure relates to a pharmaceutically acceptable salt (formula 1) and a crystal form of a 1,4-dihydro-1,6-naphthyridine amide compound, and a preparation method therefor. Specifically, provided in the present disclosure are a pharmaceutically acceptable salt and crystal form of (S)-4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-4-yl)-3-(methoxy-d3)benzonitrile, and a preparation method therefor. The corresponding crystal form has good stability and can be better used for clinical treatment.