Quinazoline Crystal Forms for Stable Topical Ophthalmic Formulations
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Solution Overview
Problem
Formulating hydrophobic ophthalmic drugs into aqueous topical compositions is challenging due to agglomeration issues, which affect stability and quality, and existing treatments for chronic ocular surface pain are inadequate.
Innovation Solution
Development of crystalline forms of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile, characterized by specific X-ray diffraction patterns, and their formulation with pharmaceutically acceptable excipients for topical ocular use, including crystal forms K′, M, Q, and hydrate HB, to create stable ophthalmic formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If hydrophobic ophthalmic drugs are formulated into aqueous topical compositions, then the drug can be delivered topically to the ocular surface, but the drug is prone to agglomeration which causes stability and quality issues
Solution Approach 1:
The patent applies parameter changes by identifying and characterizing different polymorphic forms (Crystal Form K, Crystal Form M, Crystal Form Q, and Hydrate HB) of the hydrophobic drug compound. Each polymorphic form has distinct X-ray diffraction patterns, solubility characteristics, and stability profiles. By selecting specific polymorphic forms and controlling crystallization parameters (solvent systems, temperature, pH), the formulation achieves both topical deliverability and long-term stability without agglomeration
Solution Approach 2:
The patent creates composite ophthalmic formulations by combining the hydrophobic drug compound in specific polymorphic forms with aqueous vehicle components including buffers, surfactants, and preservatives. This composite approach allows the hydrophobic drug to be stably suspended or dissolved in the aqueous medium, preventing agglomeration while maintaining topical applicability. The formulation includes multiple excipients that work synergistically to stabilize the drug compound
2Reliability
If existing treatments are used for chronic ocular surface pain, then some symptom relief may be achieved, but the pain remains unresolved and long-term therapy is not sustainable
Solution Approach 1:
The patent addresses long-term therapy sustainability by optimizing drug compound parameters including selecting specific polymorphic forms with enhanced solubility and stability characteristics. The formulation parameters (pH, buffer capacity, surfactant concentration) are carefully controlled to ensure consistent drug release and efficacy over extended treatment periods, enabling sustainable long-term therapy for chronic pain conditions
3Stability of the object's composition
If different polymorphic forms are identified and formulated, then stability and quality issues are improved, but the formulation process becomes more complex
Solution Approach 1:
The patent applies preliminary action by pre-characterizing multiple polymorphic forms of the drug compound with their distinct X-ray diffraction patterns, solubility profiles, and stability characteristics before formulation development. This preliminary characterization allows formulators to select the most suitable polymorphic form early in the development process and establish appropriate control parameters, simplifying subsequent formulation work rather than dealing with polymorphic issues during later stages
Solution Approach 2:
The patent uses X-ray diffraction analysis as an intermediary tool to identify, characterize, and control polymorphic forms throughout the formulation process. This analytical intermediary enables precise monitoring and control of crystal form, ensuring formulation stability while providing a clear methodology for managing polymorphic complexity through systematic identification and characterization
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 provide stable ophthalmic formulations that effectively alleviate chronic ocular surface pain, reducing symptoms such as ocular discomfort and hyperemia, and are suitable for long-term therapy.
Implementation Method 1
characterized by an X ray diffraction pattern having three or more peaks at 2θ values selected from 5.3, 12.3, and 22.5±0.2 °2θ
Implementation Method 2
comprising evaporating a solution of compound I in about 1:1 (v/v) n-butanol/dichloromethane, to crystallize compound I as crystal form K′
Data Source
AI summary
The present disclosure provides polymorphs and formulations of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I). The present disclosure further provides methods for treating ocular surface pain by administering 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I). The present invention also provides 5 methods for treating dry eye disease and ocular hyperemia by administering 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile.