ALP001E Crystalline and Salt Forms for Stability and Solubility

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Solution Overview

Problem

ALP001E, a glucagon receptor antagonist, exhibits poor aqueous solubility and stability issues due to hydrolytic degradation in the presence of moisture, making it challenging to develop stable forms with desirable in vitro release and bioavailability.

Innovation Solution

The development of crystalline and salt forms of ALP001E through specific solvent crystallization processes, characterized by distinct X-ray diffraction patterns, to enhance stability and solubility, including solvents like ethanol, isopropanol, and acetonitrile, and controlled crystallization temperatures.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If ALP001E is formulated in conventional forms, then manufacturing is simplified, but stability deteriorates due to hydrolytic degradation in the presence of moisture

Engineering Contradiction:

ImprovestabilityVSAvoidcomplexity of crystallization process

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by systematically varying crystallization conditions including solvent type (ethanol, isopropanol, acetonitrile, or combinations), temperature ranges (0-25°C, 25-40°C, or 40-60°C), and solvent volumes to produce distinct crystalline forms (Form A, B, C, D, E) with different stability profiles. This resolves the contradiction by finding optimal parameter combinations that enhance stability while maintaining process feasibility

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite materials by creating crystalline forms with specific molecular packing arrangements and intermolecular interactions. The different crystalline forms represent composite structures at the molecular level, where the arrangement of ALP001E molecules in the crystal lattice provides enhanced stability against hydrolytic degradation while maintaining manufacturability

Inventive Principle:

Principle #40Composite materials

2Reliability

If ALP001E is formulated to improve solubility, then bioavailability is enhanced, but stability worsens due to increased exposure to moisture and hydrolytic pathways

Engineering Contradiction:

ImprovestabilityVSAvoidease of formulation

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent applies local quality by creating different crystalline forms with distinct local molecular environments and packing arrangements. Each crystalline form (A, B, C, D, E) has unique local structural characteristics that influence both solubility and stability properties, allowing optimization of the stability-solubility-tradability triangle for different formulation needs

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent segments the formulation space by identifying and characterizing multiple distinct crystalline forms, each with different physicochemical properties. This segmentation allows formulators to select the most appropriate crystalline form for specific application requirements, balancing stability, solubility, and manufacturability concerns

Inventive Principle:

Principle #1Segmentation

3Manufacturing precision

If conventional crystallization methods are used, then process complexity is reduced, but manufacturing precision deteriorates due to inconsistent crystal formation and solubility

Engineering Contradiction:

Improvecrystallization controlVSAvoidcomplexity of crystallization process

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The patent applies preliminary action by establishing specific crystallization protocols that pre-determine the formation of desired crystalline forms. The methods specify predetermined solvent combinations, temperature profiles, and addition sequences that guide the crystallization process toward consistent formation of target crystalline forms, thereby improving manufacturing precision while providing clear procedural guidance

Inventive Principle:

Principle #10Preliminary action

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 crystalline and salt forms of ALP001E provide improved stability and solubility, facilitating effective in vitro release and bioavailability, suitable for pharmaceutical compositions to treat disorders associated with glucagon.

Implementation Method 1

crystallizing the compound of formula (1) in a solvent to obtain the aforesaid crystalline form of the compound of formula (1)

Methodology Applied

Scientific EffectCrystallization: Crystallisation

Implementation Method 2

characterized by an X-ray diffraction (XRD) pattern having peaks at about 14.2, 15.6, 16.4, 20.1, 20.5 and 21.2°±0.2° 2θ

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Data Source

PatentUS12358881B2Processes for producing amide compounds, and their crystalline and salt form

Publication Date: 2025.07.15 ALPHALA CO LTD

AI summary

Disclosed is processes for producing amide compounds, and their crystalline and salts form. Herein, one of the amide compounds is represented by the following formula (1): which is characterized by an X-ray diffraction (XRD) pattern having peaks at about 14.2, 15.6, 16.4, 20.1, 20.5 and 21.2°±0.2° 2θ.