Lesinurad Crystalline Forms Stability and Solubility
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Solution Overview
Problem
Existing crystalline forms of Lesinurad face issues such as propensity to convert, agglomeration, low solubility, hygroscopicity, and incorporation of toxic solvents, making them impractical for commercial use due to regulatory and safety concerns.
Innovation Solution
Development of novel crystalline forms of Lesinurad using pharmaceutically acceptable solvents and co-crystal formers like nicotinamide, which provide improved properties such as stability, solubility, and reduced hygroscopicity, and can be prepared through industrially advantageous processes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If known crystalline forms of Lesinurad are used, then manufacturing processes can be established, but the products suffer from conversion to other forms, agglomeration, low solubility, and hygroscopicity
Solution Approach 1:
The patent applies parameter changes by discovering and utilizing specific crystalline forms ( Forms I, II, III, IV, V, and VI) with distinct PXRD patterns and physical properties. Each form exhibits different stability, solubility, and hygroscopicity characteristics, allowing selection of the optimal form for specific manufacturing and formulation requirements
Solution Approach 2:
The patent employs short-chain alcohols (C1-C6, preferably C1-C3) as solvents for crystallization. These volatile solvents evaporate completely during drying, leaving no harmful residues. The process uses readily available, low-cost alcohols like methanol, ethanol, and propanol that can be easily removed, avoiding the need for complex solvent removal steps
2Ease of manufacture
If crystalline forms prepared with chlorinated solvents are used, then crystallization can be achieved, but toxic solvent residues exceed ICH guideline limits for pharmaceutical products
Solution Approach 1:
The patent replaces persistent, toxic chlorinated solvents with volatile, non-toxic short-chain alcohols (C1-C6). These alcohols serve their crystallization function effectively and then completely evaporate during standard drying procedures, leaving no harmful residues in the final pharmaceutical product
Solution Approach 2:
The patent changes the solvent parameter from chlorinated compounds to non-chlorinated short-chain alcohols. This substitution maintains the crystallization capability while fundamentally eliminating the toxicity issue, as the new solvents are either GRAS (Generally Recognized As Safe) or have acceptable pharmacopeial standards
3Quantity of substance
If Lesinurad crystalline forms are prepared, then the active pharmaceutical ingredient can be obtained, but solubility remains limited affecting bioavailability
Solution Approach 1:
The patent utilizes different crystalline forms with varying solubility characteristics. By selecting specific forms (e.g., Form I, II, or III) and controlling crystallization conditions with different alcohols, the solubility parameter can be optimized for the intended application, balancing stability and dissolution requirements
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 novel crystalline forms exhibit enhanced stability, solubility, and reduced hygroscopicity, allowing for more efficient and safe manufacturing and formulation of Lesinurad, meeting specific needs in drug product manufacturing and regulatory compliance.
Implementation Method 1
Form 2 is described as a free flowing solid having lower solubility than Form 1 in certain aqueous conditions
Implementation Method 2
Form 1 can undergo conversion to Form 2
Implementation Method 3
Form III is identified as being anhydrous, with hygroscopicity under some conditions
Data Source
AI summary
The present invention provides novel crystalline forms of Lesinurad, pharmaceutical compositions including these crystalline forms, and their use in the treatment of hyperuricemia associated with gout. Specific crystalline forms provided by the present invention include Lesinurad Forms APO-I, a hemi-methanolate, APO-II, a hemi-ethanolate, and APO-III, a co-crystal of Lesinurad and nicotinamide.