Cibenzoline Succinate Crystal Form for Low-Hygroscopic Stability

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Solution Overview

Problem

Existing pharmaceutical formulations of cibenzoline succinate lack stability and uniformity due to the absence of a stable polymorphic form, leading to variations in solubility, dissolution rate, and bioavailability.

Innovation Solution

Development of three distinct crystalline forms of (−)-cibenzoline succinate, characterized by specific X-ray powder diffraction patterns and a triclinic crystal system, prepared through dissolution in a polar solvent followed by precipitation with a hydrocarbon solvent, ensuring stability and uniformity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If a stable polymorphic form of cibenzoline succinate is not established, then variations in solubility, dissolution rate, and bioavailability occur, but formulation stability and uniformity are compromised

Engineering Contradiction:

Improveformulation stabilityVSAvoidcrystalline form uniformity

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent identifies and characterizes three distinct polymorphic forms (Form 1, Form 2, and Form 3) of (-)-cibenzoline succinate, each with unique X-ray powder diffraction patterns. By establishing specific crystalline forms with defined physical and chemical parameters, the invention resolves the contradiction between formulation stability and compositional uniformity. Form 3, in particular, is highlighted as having low hygroscopicity and excellent stability, providing a reliable crystalline form for consistent bioavailability.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent replaces empirical formulation approaches with a systematic crystallization process based on specific solvent systems. By substituting trial-and-error methods with a defined crystallization protocol using polar solvents followed by hydrocarbon anti-solvents, the invention achieves both formulation stability and crystalline form uniformity through controlled phase transitions.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Adaptability or versatility

If multiple polymorphic forms exist without clear characterization, then formulation flexibility is available, but manufacturing precision and quality control become difficult

Engineering Contradiction:

Improveformulation flexibilityVSAvoidcrystalline form control

Core Design Contradiction:

Adaptability or versatilityVSManufacturing precision

Solution Approach 1:

The patent segments the polymorphic forms of (-)-cibenzoline succinate into three distinct categories (Form 1, Form 2, and Form 3), each characterized by unique X-ray powder diffraction patterns. This segmentation allows for precise identification and control of each polymorphic form, enabling manufacturers to select the appropriate form for specific formulation requirements while maintaining quality control through defined characterization criteria.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention establishes specific physical and chemical parameters for each polymorphic form, including X-ray powder diffraction peak positions, hygroscopicity characteristics, and stability profiles. By defining these parameters, the patent enables precise manufacturing control while maintaining formulation flexibility, as each form can be selectively produced and characterized according to its unique parameter set.

Inventive Principle:

Principle #35Parameter changes

3Quantity of substance

If hygroscopic crystalline forms are used, then initial solubility may be enhanced, but long-term storage stability and purity are reduced

Engineering Contradiction:

ImprovesolubilityVSAvoidstorage stability

Core Design Contradiction:

Quantity of substanceVSDuration of action of stationary object

Solution Approach 1:

The patent converts the potential harm of hygroscopicity into a benefit by characterizing the hygroscopic properties of each polymorphic form and selecting Form 3, which exhibits low hygroscopicity. This allows the formulation to maintain long-term storage stability and purity while still achieving adequate solubility through the controlled crystalline structure, thus converting the potential disadvantage of crystalline form selection into a advantage for storage stability.

Inventive Principle:

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

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 forms exhibit low hygroscopicity, excellent stability, and maintain high purity over long periods, enhancing the reliability and consistency of cibenzoline succinate formulations.

Implementation Method 1

dissolving (−)-cibenzoline succinate in a polar solvent

Methodology Applied

Scientific EffectDissolution: Solvation

Implementation Method 2

precipitating crystalline form 3 of (−)-cibenzoline succinate by adding a hydrocarbon solvent having 6 or more carbon atoms to the solution

Methodology Applied

Scientific EffectPrecipitation: Precipitation

Implementation Method 3

which has any one selected from the group consisting of the following X-ray powder diffraction patterns (XRPDs)

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Data Source

PatentUS12486237B2Polymorphic form of (-)-cibenzoline succinate

Publication Date: 2025.12.02 CELLTRION INC

AI summary

The present invention relates to a crystalline form of (−)-cibenzoline succinate. The present invention also provides a process for preparing (−)-cibenzoline succinate and crystalline form thereof. The crystalline form of (−)-cibenzoline succinate according to the present invention has low hygroscopicity, and excellent stability under accelerated conditions and long-term storage conditions, and may be stably maintained without a change in content thereof for a long period of time.