Crystalline R-Configured Piperazine Forms for Stability and Solubility

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Solution Overview

Problem

The unpredictability and complexity in discovering and selecting solid forms of pharmaceutical compounds, such as (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate, affect their solubility, stability, and bioavailability, posing challenges in drug development and formulation.

Innovation Solution

The development of novel crystalline forms of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate, characterized by specific X-ray diffraction patterns and thermal properties, which are prepared through methods like solvent recrystallization and characterized by techniques like XRPD and DSC.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If polymorphic forms of a compound are discovered, then solubility and bioavailability are improved, but the complexity of identifying and selecting the optimal solid form increases

Engineering Contradiction:

ImprovesolubilityVSAvoidcomplexity of identifying and selecting solid form

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by systematically varying crystallization conditions (solvent type, temperature, pH, concentration) to generate different polymorphic forms of the compound. This allows optimization of solubility and bioavailability parameters while managing the complexity through structured experimental design rather than random exploration.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent utilizes phase transitions during crystallization processes to generate different solid forms (polymorphs) of the compound. By controlling the phase transition conditions (cooling rates, solvent evaporation, precipitation methods), the patent achieves improved solubility and bioavailability while systematically managing the complexity of solid form selection.

Inventive Principle:

Principle #36Phase transitions

2Stability of the object's composition

If crystalline forms are developed, then stability under manufacturing and storage conditions is improved, but the unpredictability of crystal structure formation remains

Engineering Contradiction:

ImprovestabilityVSAvoidpredictability of crystal structure

Core Design Contradiction:

Stability of the object's compositionVSReliability

Solution Approach 1:

The patent applies preliminary action by conducting extensive preliminary crystallization studies to identify stable polymorphic forms before final formulation development. This upfront work establishes reliable crystal structures that demonstrate stability under manufacturing and storage conditions, reducing unpredictability in later stages.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent utilizes feedback mechanisms through systematic characterization (XRD, DSC, TGA) of crystalline forms to determine stability properties. This feedback information guides the selection and optimization of crystal forms, improving predictability of stability under manufacturing and storage conditions while managing the inherent unpredictability of crystal formation.

Inventive Principle:

Principle #23Feedback

3Adaptability or versatility

If multiple solid forms are characterized, then the ability to optimize pharmaceutical properties is improved, but the time and resources required for characterization increase

Engineering Contradiction:

Improveability to optimize pharmaceutical propertiesVSAvoidtime for characterization

Core Design Contradiction:

Adaptability or versatilityVSLoss of time

Solution Approach 1:

The patent applies segmentation by dividing the characterization process into distinct modules (XRD for crystal structure, DSC for thermal properties, TGA for compositional stability, solubility studies, dissolution studies). This segmented approach allows systematic evaluation of multiple solid forms using standardized protocols, optimizing pharmaceutical properties while managing time and resource requirements through efficient workflow organization.

Inventive Principle:

Principle #1Segmentation

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

These crystalline forms enhance the stability and solubility of the compound, facilitating the development of effective pharmaceutical formulations for treating disorders related to MAGL and FAAH activity, including pain, neurological disorders, and cancer.

Implementation Method 1

prepared through methods like solvent recrystallization

Methodology Applied

Scientific EffectRecrystallization: Crystallisation

Implementation Method 2

characterized by techniques like XRPD

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Implementation Method 3

characterized by specific X-ray diffraction patterns

Methodology Applied

Scientific EffectDiffraction: Diffraction

Implementation Method 4

characterized by techniques like XRPD and DSC

Methodology Applied

Scientific EffectDifferential scanning calorimetry: Calorimetry

Data Source

PatentUS12410133B2Crystalline (r)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate, compositions and methods of use thereof

Publication Date: 2025.09.09 CELGENE CORP

AI summary

Provided herein are crystalline forms of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate. Pharmaceutical compositions comprising crystalline forms of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate are also disclosed.