Pyrroloquinoline Quinone Trilithium Salt Crystal Form Control

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Solution Overview

Problem

Current methods fail to effectively control and understand the polymorphic behavior of pyrroloquinoline quinone trilithium salt, which affects its physical properties and pharmaceutical applications, particularly in treating mental diseases and memory impairments.

Innovation Solution

A specific crystalline form of pyrroloquinoline quinone trilithium salt characterized by X-ray powder diffraction patterns and differential scanning calorimetry thermograms is developed, along with a preparation method involving lithium hydroxide and organic solvents, resulting in a stable crystal form suitable for pharmaceutical compositions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Manufacturing precision

If conventional preparation methods are used for pyrroloquinoline quinone trilithium salt, then the compound can be obtained, but the polymorphic behavior cannot be effectively controlled and understood, affecting physical properties and pharmaceutical applications

Engineering Contradiction:
Improvecrystalline form controlVSAvoidpolymorphic behavior understanding
Core Design Contradiction:
Manufacturing precisionVSDifficulty of detecting and measuring

Solution Approach 1:

The patent applies parameter changes by systematically varying preparation conditions including solvent types (water, ethanol, isopropanol, acetonitrile, tetrahydrofuran), temperatures (0-5°C, room temperature, -20°C), and pH levels to obtain different crystalline forms (Form I, Form II, Form III) of pyrroloquinoline quinone trilithium salt, each with distinct physical properties and applications

Inventive Principle:
Principle #35Parameter changes

Solution Approach 2:

The patent utilizes phase transitions during the crystallization process, where the compound transitions from dissolved state to solid crystalline forms under controlled conditions (cooling, solvent evaporation, temperature changes), enabling the formation of specific polymorphic structures with defined X-ray diffraction patterns and physical characteristics

Inventive Principle:
Principle #36Phase transitions

2Reliability

If different crystalline forms are obtained, then various physical properties (solubility, stability, bioavailability) are affected, but this requires complex preparation procedures with multiple steps and conditions

Engineering Contradiction:
Improvestorage stabilityVSAvoidpreparation procedure complexity
Core Design Contradiction:
ReliabilityVSDevice complexity

Solution Approach 1:

The patent achieves different stability profiles by changing preparation parameters: Form I (water solvent, room temperature) provides good stability, Form II (ethanol solvent, 0-5°C) enhances storage stability, and Form III (isopropanol solvent, -20°C) optimizes bioavailability, allowing selection based on specific pharmaceutical requirements

Inventive Principle:
Principle #35Parameter changes

Solution Approach 2:

The patent uses different solvents as intermediaries to mediate the crystallization process: water for Form I, ethanol for Form II, and isopropanol for Form III. Each solvent acts as a mediator that influences the crystal lattice formation, enabling control over the final physical properties without requiring complex multi-step procedures

Inventive Principle:
Principle #24Intermediary (Mediator)

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 crystalline form B of pyrroloquinoline quinone trilithium salt demonstrates improved stability and bioavailability, effectively treating memory impairments and cognitive issues in animal models with a dose-dependent effect, enhancing spatial memory and reducing cognitive impairment.

Implementation Method 1

pyrroloquinoline quinine is mixed with lithium hydroxide (weight ratio 4 : 1), followed by adding organic solvent for continuous stirring for 2 hours at 0-5 °C

Methodology Applied
Scientific EffectChemical reaction: Chemical Bonding

Implementation Method 2

the pyrroloquinoline quinone trilithium salt crystal is obtained by standing overnight at room temperature

Methodology Applied
Scientific EffectCrystallization: Crystallisation

Implementation Method 3

characterized by an X-ray powder diffraction pattern with significant peaks at diffraction angles (2θ values) of 6.222 ± 0.2°, 7.379 ± 0.2°, 7.941 ± 0.2°, and 23.631 ± 0.2°

Methodology Applied
Scientific EffectX-ray diffraction: X-Ray

Implementation Method 4

Its endothermic peak is around 90-96°C in the differential scanning calorimetry (DSC) thermogram

Methodology Applied
Scientific EffectDifferential scanning calorimetry: Calorimetry

Data Source

PatentEP2998305B1Pyrroloquinoline quinone lithium salt crystal and preparation method and application thereof
Publication Date: 2020.04.08 SHANGHAI RIXIN BIOTECHNOLOGY CO LTD
  • EP2998305B1 patent drawingFigure 1~2
  • EP2998305B1 patent drawingFigure 3~4
  • EP2998305B1 patent drawing

AI summary

The present invention provides pyrroloquinoline quinone lithium salt crystal and a preparation method and application thereof. Characteristic absorption peaks appear when the diffraction angles are 6.222 ± 0.2°, 7.379 ± 0.2°, 7.941 ± 0.2°, 23.631 ± 0.2°, 24.044 ± 0.2°, 25.497 ± 0.2°, 27.541 ± 0.2°, 30.736 ± 0.2°, and 32.306 ± 0.2° degrees in a powder X-ray diffraction pattern of the pyrroloquinoline quinine lithium salt crystal. The maximum value of thermal absorption of the pyrroloquinoline quinine lithium salt crystal appears between 90°C and 96°C through differential scanning calorimetry. Peaks appear when infrared spectroscopy of the pyrroloquinoline quinine lithium salt crystal is at 3396.03 cm-1, 1652.70 cm-1, 1604.48 cm-1, 1500.35 cm-1, 1355.71 cm-1, 1243.86 cm-1, 1147.44 cm-1, 808.03 cm-1, 761.74 cm-1, and 570.83 cm-1. The pyrroloquinoline quinine lithium salt polymorphism can be applied to preparation of medicines for curing memory damage.