Linsitinib Crystalline Salts for Solubility
Solution Overview
Problem
Linsitinib, a small-molecule inhibitor of the human insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR), faces challenges with poor pH-related solubility, which affects its efficacy and tolerability, particularly in oral administration for treating conditions like thyroid eye disease.
Innovation Solution
Development of crystalline esylate and L-malate salts of Linsitinib, which enhance solubility and absorption, allowing for improved pharmaceutical formulations and treatment methods for IGF-1R and IR-mediated conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Linsitinib is administered as an anhydrous/non-solvated free base, then it shows promising therapeutic effects, but it suffers from poor pH-related solubility
Solution Approach 1:
The patent applies parameter changes by converting Linsitinib from its free base form to salt forms (esyrate and L-malate salts). This chemical parameter transformation fundamentally alters the solubility characteristics of the compound, enabling it to achieve both therapeutic efficacy and improved pH-related solubility. The salt forms maintain the pharmacological activity while resolving the solubility limitation of the free base form.
2Quantity of substance
If new salt forms of Linsitinib are developed to enhance pH-related solubility, then dissolution and pharmacokinetic profiles are improved, but the drug formulation becomes more complex
Solution Approach 1:
Rather than complicating the formulation of the free base form, the patent directly changes the chemical parameter of the active ingredient itself by developing specific salt forms. This approach simplifies the overall formulation strategy, as the improved solubility is inherent to the salt forms themselves, eliminating the need for complex solubilizing excipients or specialized delivery systems.
Data Source
AI summary
The present invention provides salts and crystalline forms of Linsitinib (OSI-906; cis-3-[8-amino-1-(2-phenyl-7-quinolinyl)imidazo[1,5-a]pyrazin-3-yl]-1-methyl-cyclobutanol). These forms of Linsitinib provide increased solubility and improved pharmacokinetic profiles for orally administered pharmaceutical formulations. Accordingly, the invention enables improved methods for treating human insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR) mediated conditions.