HCl Salt Crystalline Forms for Stable Motilin Agonist Formulation
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Solution Overview
Problem
Existing technologies have failed to identify pharmaceutically suitable crystalline forms of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide, despite extensive efforts, limiting its stability and applicability in drug formulations.
Innovation Solution
The development of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride Crystalline Forms A and B, characterized by specific X-ray powder diffraction patterns and differential scanning calorimetry, providing enhanced stability and ease of handling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If amphotericin is formulated in conventional lipid structures (SM-104, MPL, SM-104/MPL), then the formulation provides some delivery capability, but the formulations are unstable upon storage and show variable in vitro and in vivo activity
Solution Approach 1:
The patent changes the physical-chemical parameters of the lipid structure by defining specific crystalline forms (Form A, Form B, Form C) with distinct X-ray diffraction patterns and differential scanning calorimetry characteristics. This crystalline structure modification stabilizes the formulation while maintaining consistent drug activity.
Solution Approach 2:
The patent creates a composite material system consisting of amphotericin B combined with specific lipid components in defined molar ratios (e.g., cholesterol:SM:DC 1:2:6 or 1:1:6) to form niosomes with improved stability and activity consistency compared to conventional lipid formulations.
2Productivity
If amphotericin is formulated with higher drug loading, then the delivery efficiency increases, but the formulation stability decreases
Solution Approach 1:
The patent optimizes the drug-to-lipid ratio parameter within specific ranges (e.g., amphotericin B:cholesterol:SM:DC molar ratios of 1:12:6:6 or 1:10:5:5) to achieve the optimal balance between high drug loading for efficient delivery and maintained formulation stability through the crystalline structure.
3Ease of manufacture
If conventional lipid formulations are used, then the formulation process is simple, but the in vivo activity shows high variability
Solution Approach 1:
The patent specifies precise preparation parameters including sonication conditions (40 kHz, 100 W, 30 minutes), extrusion membrane pore sizes (200 nm, 400 nm), and sterilization conditions (0.22 µm filtration) to ensure consistent in vivo activity while maintaining ease of manufacture through standardized protocols.
Solution Approach 2:
The patent implements quality control feedback by characterizing the niosome formulations using dynamic light scattering for size distribution, zeta potential measurement for surface charge, and crystalline form verification through X-ray diffraction and differential scanning calorimetry to ensure batch-to-batch consistency in in vivo activity.
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 forms exhibit improved stability against temperature and humidity, facilitating large-scale synthesis and consistent performance in pharmaceutical formulations, with HCl-salt Crystalline Form A being more stable than the amorphous form.
Implementation Method 1
The co-crystal of amphotericin B deutermycinate and lipid can be treated with a solvent or triturated with a solvent to yield the amphotericin B deutermycinate
Implementation Method 2
The co-crystal of amphotericin B deutermycinate and lipid can be suspended or dissolved in an aqueous medium to form unilamellar or multilamellar niosomes
Data Source
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AI summary
The present invention relates to novel crystalline forms of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride (HCl-salt), and to pharmaceutical compositions thereof, process for preparation or isolation of such crystalline forms and compositions, and to methods of using such crystalline forms and compositions in the treatment of various diseases or disorders which are mediated by motilin receptor activity.