Nitroxoline Prodrug Crystal Forms for Solubility and Stability
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Solution Overview
Problem
Nitroxoline, an antibacterial drug with anti-tumor potential, has a short biological half-life due to the liver's first-pass effect, requiring frequent administration and increasing production costs due to low water solubility, which complicates patient compliance and drug stability.
Innovation Solution
Development of crystal forms of the nitroxoline prodrug ((5-nitroquinolin-8-yl)oxy)methyl-isobutyryl-L-prolinate, specifically crystal forms A and B, with improved water solubility and stability, achieved through controlled crystallization methods using various solvent systems.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nitroxoline is administered frequently to maintain continuous drug exposure, then the therapeutic effect is improved, but patient compliance deteriorates and economic loss increases
Solution Approach 1:
The patent modifies the physical and chemical parameters of nitroxoline by developing a prodrug formulation with improved solubility characteristics. This allows the drug to be administered less frequently (reducing from TID/QID to potentially once or twice daily) while maintaining continuous therapeutic exposure, thereby improving patient compliance without sacrificing efficacy
Solution Approach 2:
The patent utilizes polymorphism research to identify and develop specific crystal forms of the nitroxoline prodrug that exhibit improved solubility and stability. By transitioning from poorly soluble forms to optimized crystal forms, the drug achieves sustained release characteristics that maintain continuous exposure with reduced dosing frequency
2Quantity of substance
If nitroxoline is prepared as immediate-release formulation to improve solubility, then water solubility is improved, but production cost increases
Solution Approach 1:
The patent changes the chemical structure of nitroxoline by creating a prodrug derivative that inherently possesses improved water solubility. This molecular modification eliminates the need for complex immediate-release formulation technologies, thereby reducing production costs while achieving the desired solubility improvement
Solution Approach 2:
The patent introduces a prodrug intermediary compound that serves as a bridge between the original nitroxoline molecule and its activated form. This intermediary structure improves solubility and stability during storage and administration, while being easily convertible to the active drug in vivo, thus avoiding the need for expensive formulation technologies
3Quantity of substance
If amorphous form of nitroxoline prodrug is used, then water solubility is improved, but stability deteriorates
Solution Approach 1:
The patent systematically investigates polymorphic transitions and identifies specific stable crystal forms of the nitroxoline prodrug that maintain both improved solubility and enhanced stability. By controlling the crystallization process to produce these specific polymorphic forms, the patent achieves a balance between solubility improvement and stability maintenance, avoiding the instability issues associated with amorphous forms
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 crystal forms enhance nitroxoline's stability and solubility, reducing the frequency of administration, lowering production costs, and improving drug efficacy and industrial suitability.
Implementation Method 1
the X-ray powder diffraction pattern thereof, which is obtained by using Cu-Kα irradiation and expressed in 2θ angle, comprises characteristic peaks at 5.74±0.2°, 6.78±0.2°, 10.86±0.2°, 13.54±0.2°, 16.70±0.2° and 22.65±0.2°
Data Source
AI summary
The present invention relates to a crystal form of a nitroxoline prodrug, a pharmaceutical composition containing same, and a preparation method therefor and an application thereof. An X-ray powder diffraction pattern of a crystal form A comprises characteristic peaks at 5.74±0.2°, 6.78±0.2°, 10.86±0.2°, 13.54±0.2°, 16.70±0.2°, and 22.65±0.2°; an X-ray powder diffraction pattern of a crystal form B comprises characteristic peaks at 5.44±0.2°, 10.90±0.2°, 14.09±0.2°, 16.17±0.2°, 17.92±0.2°, 20.66±0.2°, and 23.13±0.2°. Compared with nitroxoline, the crystal forms A and the B in the present application are not prone to staining, have low requirements for equipment, and are more suitable for industrial production; the stable properties are more conducive to quality control on industrial production and stability in drug efficacy.