AR509 Crystalline Forms CS8 and CS9 for Prostate Cancer Drug Solubility

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Solution Overview

Problem

The existing crystalline forms of ARN-509, such as forms A and B, exhibit poor solubility, dissolution, stability, and processability, which hinders their bioavailability and industrial application in treating prostate cancer.

Innovation Solution

The development of novel crystalline forms CS8 and CS9 of ARN-509, characterized by specific X-ray powder diffraction patterns and preparation processes involving solvents like alcohols, ethyl formate, and solvent mixtures, which enhance solubility, stability, and bioavailability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If prior art crystalline forms A and B are used, then the drug can be produced, but the solubility and dissolution are poor leading to reduced bioavailability

Engineering Contradiction:

ImprovebioavailabilityVSAvoidsolubility

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent applies parameter changes by modifying the crystalline structure parameters of ARN-509 to create new polymorphic forms (Forms I, II, III) with improved solubility and dissolution characteristics. This involves changing the molecular arrangement, intermolecular interactions, and crystal packing parameters to achieve better physicochemical properties while maintaining the drug's identity and therapeutic effect.

Inventive Principle:

Principle #35Parameter changes

2Stability of the object's composition

If prior art crystalline forms A and B are used, then the drug structure is stable, but the grinding stability is poor leading to transformation to amorphous form

Engineering Contradiction:

Improvecrystalline stabilityVSAvoidgrinding transformation

Core Design Contradiction:

Stability of the object's compositionVSObject-affected harmful factors

Solution Approach 1:

The patent applies beforehand cushioning by designing crystalline forms with inherent mechanical stability that can withstand grinding and processing operations. The new polymorphic forms are engineered to have robust crystal structures that resist transformation to amorphous forms during manufacturing processes, thereby preventing quality degradation before it occurs.

Inventive Principle:

Principle #11Beforehand cushioning (Prior cushioning)

3Ease of manufacture

If prior art crystalline forms are used, then the drug can be formulated, but the adhesion and compressibility are poor affecting tablet quality

Engineering Contradiction:

Improveformulation processabilityVSAvoidtablet quality

Core Design Contradiction:

Ease of manufactureVSManufacturing precision

Solution Approach 1:

The patent modifies the physical parameters of the crystalline forms to improve formulation properties. By changing the crystal morphology, surface characteristics, and mechanical properties of the new polymorphic forms, the drug exhibits better adhesion and compressibility, enabling high-quality tablet manufacturing with appropriate hardness and disintegration characteristics.

Inventive Principle:

Principle #35Parameter changes

4Adaptability or versatility

If multiple crystalline forms exist, then the drug has polymorphic options, but it is difficult to separate solvates from desired forms during preparation

Engineering Contradiction:

Improvecrystalline form optionsVSAvoidseparation difficulty

Core Design Contradiction:

Adaptability or versatilityVSEase of manufacture

Solution Approach 1:

The patent applies the extraction principle by developing preparation methods that selectively form the desired crystalline forms while excluding solvates. Through careful selection of solvents, temperature profiles, and crystallization conditions, the process extracts or prevents the formation of unwanted solvated species, yielding pure polymorphic forms directly without requiring complex separation steps.

Inventive Principle:

Principle #2Taking out (Extraction)

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

Form CS8 and CS9 demonstrate improved solubility, stability, and bioavailability, leading to better in vivo absorption and clinical efficacy, with enhanced processing characteristics suitable for pharmaceutical use.

Implementation Method 1

The process comprises: dissolving ARN-509 into a solvent of alcohols

Methodology Applied

Scientific EffectSolvation: Solvation

Implementation Method 2

cooling to -20°C.-16°C., precipitating solid to obtain Form CS8

Methodology Applied

Scientific EffectPrecipitation: Precipitation

Implementation Method 3

The X-ray powder diffraction pattern of Form CS8 shows characteristic peaks at 2theta values of 7.9±0.2°, 12.4±0.2° and 19.0±0.2°

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Data Source

PatentUS11066384B2Crystalline forms of ARN-509, preparation method and use thereof

Publication Date: 2021.07.20 CRYSTAL PHARMA CO LTD

AI summary

The present disclosure relates to novel crystalline forms of ARN-509 (structure shown in formula I), processes for preparation of the novel crystalline forms, pharmaceutical composition of the novel crystalline forms, and uses of the novel crystalline forms for preparing drug products of androgen receptor antagonists and for treating prostate cancer. The crystalline forms of ARN-509 provided by the present disclosure have one or more improved properties compared with the prior art, and is of great value to the future optimization and development of drugs.