Compound 1 Mono-tosylate Polymorphs for Ocular Drug Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for novel and useful polymorphic crystalline structures of Compound 1 mono-tosylate, a Rho-associated protein kinase inhibitor, to address issues of physical properties such as filterability, hygroscopicity, and stability, which are crucial for reliable pharmaceutical formulation and manufacturing.
Innovation Solution
The development of new polymorphic forms of Compound 1 mono-tosylate, characterized by unique XRPD patterns, DSC, and FT-IR data, including crystalline forms 1, 2, 3, 4, 5, and 6, which are synthesized and isolated for use in pharmaceutical compositions, particularly for ocular diseases, and their formulation in biodegradable polymer matrices for controlled release.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional pharmaceutical forms of Compound 1 mono-tosylate are used, then the compound can be formulated for administration, but the physical properties such as filterability, hygroscopicity, and stability are insufficient for reliable manufacturing
Solution Approach 1:
The patent applies parameter changes by discovering and utilizing different polymorphic forms (crystalline forms 1-6) of Compound 1 mono-tosylate, each with distinct physical properties. By changing the crystalline structure parameters through controlled crystallization conditions, the invention achieves improved filterability, reduced hygroscopicity, and enhanced stability, thereby resolving the manufacturing reliability issues
Solution Approach 2:
The patent creates composite pharmaceutical compositions by combining specific polymorphic forms of Compound 1 mono-tosylate with excipients and polymers. These composite formulations leverage the advantageous physical properties of selected polymorphs to achieve reliable manufacturing characteristics while maintaining therapeutic efficacy
2Productivity
If multiple polymorphic forms are developed, then physical properties such as solubility and dissolution rates are improved, but the complexity of selecting and characterizing the correct form increases
Solution Approach 1:
The patent replaces complex physical characterization methods with X-ray powder diffraction (XRPD) patterns as the primary identification tool for distinguishing polymorphic forms. This substitution provides a rapid, reliable, and standardized method for identifying the correct polymorph, reducing the complexity of characterization while enabling efficient selection of forms with optimal dissolution rates
Solution Approach 2:
The patent systematically varies crystallization parameters (solvent type, temperature, pH) to generate different polymorphic forms with distinct XRPD patterns and dissolution characteristics. This controlled parameter variation enables the discovery of forms with improved productivity while providing clear diagnostic criteria for their identification
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
These polymorphic forms exhibit enhanced stability, bioavailability, and controlled release profiles, improving the reliability and efficacy of pharmaceutical compositions for treating ocular diseases, with specific forms like crystalline form 1 showing improved solubility and dissolution rates.
Implementation Method 1
an x-ray powder diffraction (XRPD) pattern having two or more signals
Implementation Method 2
differential scanning calorimetry (DSC)
Implementation Method 3
Fourier-transform infra-red
Data Source
AI summary
Provided herein are solid forms of alpha-(aminomethyl)-4-(hydroxymethyl)-N-6-isoquinolinyl-(S)-benzeneacetamide mono-tosylate salt (“Compound 1 mono-tosylate”), pharmaceutical compositions containing the solid forms, methods of producing the solid forms, and methods of treating various ocular diseases or disorders by administering the solid forms.