Crystalline Salt Forms of Compound 1 for Storage Stability
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Solution Overview
Problem
Existing forms of 1-methyl-5-(2′-methyl-[1,1′-biphenyl]-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid (Compound 1) face challenges in isolation, manufacturing, formulation development, and storage stability, necessitating the development of alternative forms with improved physical and chemical stability for various routes of administration.
Innovation Solution
The Tris salt Form C of Compound 1 is identified as superior, exhibiting sharp XRPD peaks, minimal residual solvents, low hygroscopicity, and faster absorption, making it suitable for oral solid dosage forms, with crystalline forms A and C showing better thermodynamic stability and pharmacokinetic properties compared to the free acid form.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the free acid form of Compound 1 is used, then the compound can be isolated and manufactured, but it exhibits poor physical stability and slow absorption
Solution Approach 1:
The patent applies parameter changes by converting the free acid form of Compound 1 into salt forms (specifically Tris salt Form C) with different physicochemical properties. This transformation changes the solubility, crystallinity, and dissolution characteristics of the compound, thereby improving both physical stability and absorption rate. The salt formation modifies the molecular state without changing the core pharmacological activity.
2Stability of the object's composition
If alternative forms of Compound 1 are developed to improve storage stability, then storage stability is enhanced, but the complexity of isolation and manufacturing increases
Solution Approach 1:
The patent uses salt formation as an intermediary approach to achieve stable storage forms while maintaining ease of manufacture. The Tris salt Form C acts as a stable intermediate that can be easily synthesized from the free acid form through simple salt formation reactions. This intermediary form provides the desired storage stability without requiring complex isolation or manufacturing processes.
3Reliability
If crystalline forms with sharp XRPD peaks are selected, then physical and chemical stability is improved, but the selection process becomes more complex
Solution Approach 1:
The patent applies self-service by allowing the crystalline form to self-select and self-stabilize under specific crystallization conditions. Tris salt Form C exhibits inherent thermodynamic stability and forms sharp XRPD peaks under controlled crystallization conditions without requiring complex selection processes. The material's own properties guide it to form the most stable crystalline structure.
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
Tris salt Form C demonstrates enhanced physical stability, faster absorption, and higher maximum concentration, indicating its suitability for oral solid dosage forms with improved storage stability and pharmacokinetic profiles.
Implementation Method 1
sharp XRPD peaks
Implementation Method 2
thermogravimetric analysis (TGA) data reflects negligible weight loss
Implementation Method 3
The differential scanning calorimetry (DSC) data for the Tris salt Form A and Tris salt Form C of Compound 1 (see Table 9) further indicates one sharp melting endotherm prior to decomposition
Data Source
AI summary
Provided herein are various salts, including tris(hydroxymethyl)aminomethane salts and sodium salts, as well as various crystalline forms of the compound represented by the structural formula:Also provided are pharmaceutical compositions comprising these salts and crystalline forms, methods for their manufacture, and uses thereof for treating conditions, including but not limited to conditions that would benefit from inhibition of dihydroorotate dehydrogenase (DHODH).