Polymorph Control for 6-(Piperidin-4-yloxy)-2H-isoquinolin-1-one Hydrochloride

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Solution Overview

Problem

The existing methods for synthesizing 6-(Piperidin-4-yloxy)-2H-isoquinolin-1-one hydrochloride lack controlled and reproducible crystallization procedures, leading to unpredictable polymorphic forms with varying stability, solubility, and suitability for pharmaceutical applications.

Innovation Solution

Development of new crystalline polymorphs and hydrates of 6-(Piperidin-4-yloxy)-2H-isoquinolin-1-one hydrochloride, characterized by specific X-ray powder diffraction patterns and water content, which provide improved stability, solubility, and processability, including the dihydrate form that maintains constant water content across a broad range of humidities.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Manufacturing precision

If existing synthesis methods are used to produce 6-(Piperidin-4-yloxy)-2H-isoquinolin-1-one hydrochloride, then the compound can be obtained, but the crystallization procedure is uncontrolled and non-reproducible, leading to unpredictable polymorphic forms

Engineering Contradiction:

Improvecrystallization controlVSAvoidreproducibility

Core Design Contradiction:

Manufacturing precisionVSReliability

Solution Approach 1:

The patent applies parameter changes by systematically varying crystallization conditions including solvent type (water, ethanol, isopropanol, acetonitrile, methyl acetate), temperature ranges (0°C to 25°C), and pH levels to obtain different polymorphic forms. This controlled variation of parameters enables reproducible generation of specific polymorphs with desired properties.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent utilizes phase transitions during crystallization from solution to solid state. By controlling the solvent evaporation rate, cooling rate, and supersaturation level, specific polymorphic phases are obtained. The process exploits the fact that different polymorphs can be formed under different phase transition conditions.

Inventive Principle:

Principle #36Phase transitions

2Adaptability or versatility

If different polymorphic forms are obtained through uncontrolled crystallization, then various solid forms exist, but their stability, solubility, and suitability for pharmaceutical applications vary unpredictably

Engineering Contradiction:

Improveproperty variabilityVSAvoidpredictability

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent establishes structure-property relationships by systematically varying crystallization parameters and characterizing the resulting polymorphs. Each polymorph ( Forms I, II, III, IV and hydrates) is obtained under specific controlled conditions and characterized for stability, solubility, melting point, and X-ray diffraction patterns, enabling predictable selection based on pharmaceutical requirements.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent segments the single compound into multiple distinct polymorphic forms, each with unique and characterized properties. By isolating and characterizing each form individually under controlled synthesis conditions, the patent enables selective use of specific polymorphs for specific pharmaceutical applications based on their distinct properties.

Inventive Principle:

Principle #1Segmentation

3Ease of manufacture

If lyophilisation is used to obtain the compound as described in prior art, then the material can be produced, but no controlled or reproducible crystallisation procedure is provided

Engineering Contradiction:

Improveproduction methodVSAvoidcrystallization control

Core Design Contradiction:

Ease of manufactureVSManufacturing precision

Solution Approach 1:

The patent replaces lyophilisation with controlled solution crystallization followed by solvent removal. The compound is crystallized from various solvents under controlled temperature and concentration conditions, then isolated by filtration and dried. This provides reproducible crystalline forms without requiring lyophilisation equipment or procedures.

Inventive Principle:

Principle #36Phase transitions

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 crystalline forms offer enhanced stability, predictable solubility, and improved handling properties, making them suitable for pharmaceutical applications with increased storage stability and manufacturing reliability.

Implementation Method 1

the dihydrate form that maintains constant water content across a broad range of humidities

Methodology Applied

Scientific EffectHydration: Hydrates

Implementation Method 2

characterized by specific X-ray powder diffraction patterns

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Implementation Method 3

exhibits in an X-ray powder diffractogram using CuKα1 radiation at least a characteristic reflection within the two ranges selected from 1) 15.4 - 15.8 and 2) 16.5 -16.8 ± 0.2 degrees 2theta

Methodology Applied

Scientific EffectDiffraction: Diffraction

Data Source

PatentEP2729461B1Polymorphs of 6-(piperidin-4-yloxy)-2h-isoquinolin-1-one hydrochloride

Publication Date: 2016.01.20 SANOFI SA(FR)

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AI summary

The present invention relates to new crystalline polymorphs of 6 - (Piperidin-4 -yloxy) - 2H-isoquinolin- 1 -one hydrochloride, processes for their preparation and their use, in particular for the preparation of medicaments.