Roxadustat L-Proline Co-Crystal Thermal Stability

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Solution Overview

Problem

Roxadustat's existing solid-state forms, such as hydrates and solvates, are physically and chemically unstable, prone to phase transformations under temperature stress, and contain significant amounts of organic solvents, which poses challenges in drug development and therapeutic efficacy.

Innovation Solution

A co-crystal of roxadustat with L-proline is developed, which is thermally stable, free of organic solvents, and exhibits improved dissolution, solubility, and powder characteristics, characterized by specific PXRD, FTIR, and DSC profiles, ensuring stability and efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If hydrates and solvates of roxadustat are used, then dissolution rate and solubility can be improved, but physical stability deteriorates due to phase transformations under temperature stress

Engineering Contradiction:

Improvephysical stabilityVSAvoidtherapeutic efficacy

Core Design Contradiction:

Stability of the object's compositionVSReliability

Solution Approach 1:

The patent creates a co-crystal composite material combining roxadustat with L-proline or other amino acids. This composite structure provides both the desired dissolution properties and physical stability, resolving the contradiction between improved dissolution rate and physical stability. The co-crystal form maintains structural integrity under temperature stress while enhancing solubility and dissolution rate.

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The patent changes the physical and chemical parameters of roxadustat by forming co-crystals with different amino acids. This parameter change transforms the unstable hydrate/solvate forms into stable co-crystal forms that maintain their composition under temperature stress, while simultaneously improving dissolution rate and solubility through the co-crystal lattice structure.

Inventive Principle:

Principle #35Parameter changes

2Stability of the object's composition

If hydrates and solvates of roxadustat are used, then dissolution rate can be improved, but chemical stability deteriorates due to photodegradation

Engineering Contradiction:

Improvechemical stabilityVSAvoiddissolution rate

Core Design Contradiction:

Stability of the object's compositionVSSpeed

Solution Approach 1:

The co-crystal composite structure provides chemical stability against photodegradation while maintaining improved dissolution rate. The amino acid co-former acts as a protective component in the composite, reducing photodegradation susceptibility without compromising the dissolution enhancement provided by the co-crystal structure.

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The amino acid co-former serves as an intermediary substance that protects roxadustat from photodegradation. This mediator component reduces the direct exposure of roxadustat to degrading conditions while allowing the co-crystal structure to maintain improved dissolution properties.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Quantity of substance

If hydrates and solvates of roxadustat are used, then solubility can be improved, but purity deteriorates due to presence of organic solvents

Engineering Contradiction:

ImprovesolubilityVSAvoidorganic solvent content

Core Design Contradiction:

Quantity of substanceVSLoss of substance

Solution Approach 1:

The patent changes the solvent-free parameter by forming co-crystals with amino acids instead of using organic solvent-based hydrates and solvates. This parameter change eliminates organic solvent content while maintaining improved solubility through the co-crystal lattice structure, and simultaneously improves dissolution rate.

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 roxadustat L-proline co-crystal demonstrates enhanced thermal stability, chemical stability against photodegradation, and improved bioavailability, maintaining a robust formulation and safety profile throughout the drug's shelf-life.

Implementation Method 1

co-crystals are structurally more similar to solvates and hydrates, in that both contain more than one component in the crystal lattice and the interaction between these components is nonionic

Methodology Applied

Scientific EffectNonionic interaction: Van der Waals Force

Implementation Method 2

characterized by specific PXRD, FTIR, and DSC profiles

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Implementation Method 3

PXRD comprising reflections at 2-Theta angles

Methodology Applied

Scientific EffectPowder X-ray diffraction: Bragg Diffraction

Implementation Method 4

A co-crystal of roxadustat with L-proline is developed, which is thermally stable

Methodology Applied

Scientific EffectCrystallisation: Crystallisation

Implementation Method 5

chemical stability against photodegradation

Methodology Applied

Scientific EffectPhotostability: Absorption (EM radiation)

Data Source

PatentUS11192860B2Co-crystal of an orally available HIF prolyl hydroxylase inhibitor

Publication Date: 2021.12.07 SANDOZ LTD

AI summary

The present invention relates to a co-crystal of roxadustat with L-proline and to a process for its preparation. Furthermore, the invention relates to a pharmaceutical composition comprising said roxadustat L-proline co-crystal, at least one pharmaceutically acceptable excipient and optionally at least one photostabilizing agent. The pharmaceutical composition of the present invention can be used as a medicament, in particular for the treatment and/or prevention of anemia in patients with end-stage renal disease (ESRD) and/or chronic kidney disease (CKD).