Pharmaceutical Salt Forms for RAGE Disease Treatment
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Solution Overview
Problem
Current drug forms of COMPOUND I are limited in their ability to effectively inhibit RAGE activity in vitro and in vivo, and they lack properties suitable for large-scale manufacturing and formulation, necessitating the development of new pharmaceutically acceptable salt forms with improved physical properties.
Innovation Solution
The development of new pharmaceutically acceptable salt forms of COMPOUND I, including crystalline and amorphous forms, hydrates, and solvates, such as saccharinate, vanillate, hydrochloride, fumarate, maleate, galactarate, phosphate, L-tartrate, hippurate, L-malate, oxalate, gentisate, mesylate, hydrobromide, and 4-aminosalicylate, which are characterized by specific XRPD patterns, DSC profiles, and NMR shifts, to enhance storage stability, bioavailability, and manufacturing feasibility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If new pharmaceutically acceptable salt forms of COMPOUND I are developed, then storage stability and bioavailability are improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies parameter changes by developing multiple salt forms (hydrochloride, hydrobromide, mesylate, fumarate, maleate, oxalate, saccharinate, vanillate, galactarate, L-tartrate, hippurate, L-malate, gentisate, 4-aminosalicylate) of COMPOUND I, each with distinct physical properties including solubility, dissociation, true density, melting point, crystal shape, compaction behavior, flow properties, and solid state stability. This allows selection of optimal salt forms for different manufacturing and formulation needs while improving storage stability and bioavailability
Solution Approach 2:
The patent creates composite pharmaceutical materials by combining COMPOUND I with various pharmaceutically acceptable acids to form salt compounds. Each salt form represents a composite material with specific characteristics optimized for particular applications, balancing manufacturing feasibility with improved therapeutic performance
2Reliability
If new pharmaceutically acceptable salt forms of COMPOUND I are developed, then dissolution rates and bioavailability are improved, but formulation complexity increases
Solution Approach 1:
The patent utilizes parameter changes by systematically varying the acid component in salt formation with COMPOUND I, resulting in different dissolution rates and bioavailability profiles. The choice of acid (strong vs. weak, organic vs. inorganic) directly influences the dissociation constant and solubility characteristics, enabling optimization of bioavailability while providing formulation flexibility
Solution Approach 2:
The patent segments the formulation development into distinct salt form options, each with characterized properties. This segmentation allows formulators to select the most appropriate salt form for specific delivery routes and therapeutic indications, reducing overall formulation complexity through modular selection rather than developing a single complex formulation system
3Reliability
If multiple salt forms with specific physical properties are produced, then therapeutic efficacy is enhanced, but production costs increase
Solution Approach 1:
The patent employs parameter changes by adjusting the salt formation conditions (choice of acid, solvent system, temperature, pH) to produce COMPOUND I salts with optimized therapeutic efficacy. Each salt form offers improved properties for specific applications, allowing cost-effective production by selecting the most appropriate form for each indication rather than producing all variants
Solution Approach 2:
The patent considers the use of inexpensive, readily available pharmaceutically acceptable acids (such as hydrochloric acid, hydrobromic acid, mesylic acid, fumaric acid, maleic acid, oxalic acid) for salt formation. These common reagents reduce production costs while still providing the desired therapeutic efficacy improvements through enhanced solubility and stability
Data Source
AI summary
The present invention relates to pharmaceutically acceptable salts of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethylamine (“COMPOUND I”) useful in the treatment of RAGE mediated diseases.