Free Base Crystalline Form of Compound 1 for Solubility

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Solution Overview

Problem

The efficient delivery of biologically relevant amounts of (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide (Compound 1) is challenging due to issues with solubility, dissolution rate, and bioavailability, while maintaining stability and potency.

Innovation Solution

A free base crystalline form of Compound 1 is developed, characterized by specific X-ray powder diffraction patterns and differential scanning calorimetry features, suitable for various pharmaceutical compositions, including oral, topical, and parenteral dosage forms, to improve solubility and bioavailability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If Compound 1 is administered to treat C5a mediated diseases, then therapeutic efficacy is achieved, but solubility and bioavailability are insufficient

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidsolubility

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent applies parameter changes by modifying the physical form of Compound 1 from amorphous to crystalline state, and specifically identifying a novel polymorphic form (Form A) with distinct X-ray diffraction patterns. This phase transition changes the solubility parameters while maintaining the therapeutic activity of the compound, directly resolving the contradiction between efficacy and solubility.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite pharmaceutical formulations containing Compound 1 in specific crystalline forms combined with excipients and carriers. These composite materials enhance the solubility and bioavailability characteristics of the active compound while preserving its therapeutic efficacy against C5a mediated diseases.

Inventive Principle:

Principle #40Composite materials

2Reliability

If Compound 1 is administered to treat C5a mediated diseases, then therapeutic efficacy is achieved, but dissolution rate is insufficient

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoiddissolution rate

Core Design Contradiction:

ReliabilityVSSpeed

Solution Approach 1:

The patent modifies the dissolution rate parameter by establishing Compound 1 in a specific crystalline polymorphic form (Form A) with defined crystal lattice structure. This solid state engineering approach changes the dissolution kinetics while maintaining the compound's biological activity and therapeutic efficacy.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If Compound 1 is administered to treat C5a mediated diseases, then therapeutic efficacy is achieved, but bioavailability is insufficient

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidbioavailability

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent improves bioavailability by changing the physical state of Compound 1 to a specific crystalline polymorphic form with optimized solubility characteristics. This parameter change in the solid state structure enhances the compound's absorption and bioavailability while preserving its therapeutic efficacy.

Inventive Principle:

Principle #35Parameter changes

4Quantity of substance

If solubility is enhanced to improve bioavailability, then bioavailability is improved, but stability may be compromised

Engineering Contradiction:

ImprovebioavailabilityVSAvoidstability

Core Design Contradiction:

Quantity of substanceVSStability of the object's composition

Solution Approach 1:

The patent resolves this contradiction by identifying and characterizing a specific crystalline polymorphic form (Form A) of Compound 1 that achieves an optimal balance between solubility/bioavailability and stability. The defined crystal lattice structure provides stability while the polymorphic characteristics enhance solubility, eliminating the need to trade one for the other.

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 free base crystalline form enhances the biological characteristics of Compound 1, such as solubility and bioavailability, without compromising stability and potency, making it suitable for treating C5a-mediated diseases effectively.

Implementation Method 1

The free base crystalline form of Compound 1 is characterized by an X-ray powder diffraction pattern comprising peaks at 8.1, 8.4, 14.1, 16.9, and 19.0 degrees 2θ (±0.2 degrees 2θ)

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Implementation Method 2

X-ray powder diffraction pattern comprising peaks at 8.1, 8.4, 14.1, 16.9, and 19.0 degrees 2θ

Methodology Applied

Scientific EffectBragg diffraction: Bragg Diffraction

Implementation Method 3

The free base crystalline form of Compound 1 is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak at around 216° C.

Methodology Applied

Scientific EffectDifferential scanning calorimetry: Calorimetry

Data Source

PatentUS11026935B2Free base crystalline form of a complement component C5a receptor

Publication Date: 2021.06.08 CHEMOCENTRYX INC

AI summary

Provided herein is a free base crystalline form of a complement component 5a receptor having the formula of Compound 1Also provided herein are pharmaceutical compositions and methods of treatment using the crystalline free base form of Compound 1 described herein.