Chidamide Crystal Form A Purity and Solubility

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

The existing preparation method of chidamide lacks characterization of its crystal forms, leading to impurities and solvent residues, affecting its solubility, stability, and bioavailability, making it unsuitable for drug manufacturing.

Innovation Solution

Characterization and development of two novel crystal forms of chidamide, A and B, using X-ray powder diffraction, infrared spectrometry, and differential scanning calorimetry, along with a method to achieve high purity (>99%) and solvent-free preparation, involving specific ratios of reagents and conditions for dissolution and filtration.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of manufacture

If the existing preparation method of chidamide is used, then the synthesis process is simple, but the product contains impurities and solvent residues, resulting in low purity and poor quality

Engineering Contradiction:

Improvesynthesis process simplicityVSAvoidproduct purity

Core Design Contradiction:

Ease of manufactureVSManufacturing precision

Solution Approach 1:

The patent applies parameter changes by optimizing reaction conditions including solvent selection (acetonitrile, ethanol, or isopropyl alcohol), temperature control (0-25°C), pH adjustment (pH 6.5-7.5), and crystallization parameters to transform the synthesis process from producing amorphous precipitate to producing high-purity crystal form A with >99% purity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent utilizes phase transitions by controlling the crystallization process from solution to solid crystal form. The method involves dissolving chidamide hydrochloride in water, adjusting pH to precipitate the free base as crystal form A, and using controlled evaporation and filtration to obtain high-purity crystalline product, eliminating the amorphous precipitate issue

Inventive Principle:

Principle #36Phase transitions

2Productivity

If the existing preparation method is used, then the synthesis steps are few, but the product has poor solubility, stability, and bioavailability

Engineering Contradiction:

Improvesynthesis efficiencyVSAvoiddrug performance

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent improves drug performance by changing the physical state from amorphous to crystalline form A, which provides predictable solubility and stability characteristics. The controlled crystallization process ensures consistent particle size, morphology, and packing density, leading to reliable bioavailability and therapeutic performance

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

Instead of accepting the amorphous precipitate as the final product, the patent inverts the approach by deliberately inducing crystallization to form the desired crystal form A. This inversion transforms a disadvantageous amorphous state into a advantageous crystalline state with superior pharmacological properties

Inventive Principle:

Principle #13The other way round (Inversion)

3Loss of time

If crystal form characterization is not performed, then the development process is faster, but the quality and therapeutic efficacy cannot be ensured

Engineering Contradiction:

Improvedevelopment timeVSAvoidcrystal form quality

Core Design Contradiction:

Loss of timeVSManufacturing precision

Solution Approach 1:

The patent replaces complex multi-technique characterization with a simplified single-technique approach using XRPD for crystal form identification. This substitution maintains quality control while reducing development time and complexity, as XRPD provides definitive crystal structure information without requiring multiple complementary techniques

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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

Both crystal forms exhibit high bioavailability, stability, and solubility, suitable for drug product manufacturing and long-term storage, with favorable performance in oral absorption and toxicity, enabling effective treatment of cell differentiation and proliferation-related diseases.

Implementation Method 1

Novel crystal forms of chidamide have been investigated and characterized by a well-recognized method X-ray powder diffraction method (XRPD) in the present invention

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Implementation Method 2

The present invention further studies and characterizes a novel crystal form of chidamide by infrared spectrometry (IR)

Methodology Applied

Scientific EffectInfrared absorption: Infrared Radiation

Implementation Method 3

Other analysis technologies known in the art can also be used to characterize the crystalline form, such as the differential scanning calorimetry (DSC)

Methodology Applied

Scientific EffectCalorimetry: Calorimetry

Data Source

PatentEP2930169B1Crystal form of chidamide, preparation method and use thereof

Publication Date: 2018.07.18 SHENZHEN CHIPSCREEN BIOSCIENCES CO LTD

Figure 1
Figure 2
Figure 3

AI summary

The present invention belongs to the field of pharmaceutical chemistry, and disclosed are two crystal forms of Childamide, that is, Chidamide crystal form A and Chidamide crystal form B, and the method for preparing the new crystal forms of Chidamide. The Chidamide crystal form A and Chidamide crystal form B of the present invention can be used for preparing drugs for treating diseases related to cell differentiation and proliferation.