Imipridone Dihydrochloride Crystal Forms With Better Filterability

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Solution Overview

Problem

Existing crystalline forms of imidazoline imipridones, particularly imipridone-201 and imipridone-206 dihydrochloride salts, suffer from issues such as stability, filterability, and flowability, which affect their shelf life and bioavailability, and are difficult to handle in pharmaceutical manufacturing processes.

Innovation Solution

Development of new manufacturing processes for imipridone-201 and imipridone-206 dihydrochloride salts that result in X-ray crystal forms with improved processability, crystallizability, and filterability, using solvent exchange in acidic aqueous solutions without harmful solvents like dioxane, leading to increased long-term stability and high purity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If known crystalline forms of imipridone dihydrochloride salts are used, then the pharmaceutical active ingredient can be produced, but the stability and shelf life are insufficient

Engineering Contradiction:

ImprovestabilityVSAvoidshelf life

Core Design Contradiction:

Stability of the object's compositionVSDuration of action of stationary object

Solution Approach 1:

The patent applies parameter changes by modifying the crystallization conditions, specifically using solvent exchange with acetone or isopropanol at controlled temperatures (0-25°C) to obtain a new crystal form with improved stability properties. This changes the physical state parameters of the substance to achieve better long-term stability and shelf life.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent utilizes phase transitions through the crystallization process where the imipridone dihydrochloride salt transitions from a dissolved state to a crystalline solid state through solvent exchange. This controlled phase transition produces a specific crystal form with enhanced stability characteristics.

Inventive Principle:

Principle #36Phase transitions

2Ease of manufacture

If known crystalline forms are used, then the active ingredient can be obtained, but the filterability is poor

Engineering Contradiction:

ImprovefilterabilityVSAvoidmanufacturing efficiency

Core Design Contradiction:

Ease of manufactureVSProductivity

Solution Approach 1:

The patent changes the physical parameters of the crystallization process by using solvent exchange with specific solvents (acetone, isopropanol) at controlled temperatures, which produces crystals with improved filterability and easier handling characteristics, thereby enhancing manufacturing efficiency.

Inventive Principle:

Principle #35Parameter changes

3Ease of operation

If known crystalline forms are used, then the active ingredient can be produced, but the flowability is difficult to handle

Engineering Contradiction:

ImproveflowabilityVSAvoidhandling

Core Design Contradiction:

Ease of operationVSEase of manufacture

Solution Approach 1:

The patent modifies the crystallization parameters including solvent type (acetone, isopropanol), temperature (0-25°C), and concentration ratios to produce a crystal form with improved flowability and handling characteristics, making it easier to process in manufacturing operations.

Inventive Principle:

Principle #35Parameter changes

4Ease of manufacture

If solvent exchange with harmful solvents like dioxane is used, then crystallization can be achieved, but the purity and safety are compromised

Engineering Contradiction:

ImprovecrystallizationVSAvoidpurity

Core Design Contradiction:

Ease of manufactureVSObject-affected harmful factors

Solution Approach 1:

The patent converts the potential harm of using inappropriate solvents into a benefit by explicitly avoiding harmful solvents like dioxane and instead using safe solvents (acetone, isopropanol) that achieve effective crystallization while ensuring high purity and safety of the final product.

Inventive Principle:

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

Solution Approach 2:

The patent changes the solvent selection parameter from harmful solvents to safe, pharmaceutically acceptable solvents (acetone, isopropanol), maintaining effective crystallization while improving the purity and safety profile of the manufactured product.

Inventive Principle:

Principle #35Parameter changes

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 new crystal forms exhibit enhanced long-term stability, improved filterability, and high purity, ensuring stable pharmaceutical formulations with maintained bioavailability, and are suitable for use as anticancer agents.

Implementation Method 1

crystallized from aqueous HCl solution upon addition of a water-miscible organic solvent, preferably acetone or isopropanol

Methodology Applied

Scientific EffectCrystallisation: Crystallisation

Implementation Method 2

crystallization is triggered by solvent exchange, wherein the acidic aqueous solution contains HCl, and wherein the exchange solvent is preferably selected from ketones, esters, alcohols or ethers

Methodology Applied

Scientific EffectSolvent exchange:

Data Source

PatentEP4684834A1Crystalline forms of oncologically active imipridones and process for their preparation

Publication Date: 2026.01.28 BRIU

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AI summary

The present invention relates to the dihydrochloride salts of imipridone-201 and imipridone-206 in crystalline form, the X-ray powder diffractograms of which, when using Cu K-α radiation at 25°C, exhibit at least 3 of the following 2Θ (2 Theta) values with a tolerance of ± 0.2 each: at 6.9; 7.7; 9.6; 12.9; 15.5; 21.2; 21.4; 22.5; 23.1; 25.3; and 26.8 (imipridone-201) and 14.2, 21.3, 25.5, 26.0, and 27.7 (imipridone-201), as well as processes for their preparation and their pharmaceutical use.