Menin Inhibitor Salt Formulation for Stability and Solubility
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Solution Overview
Problem
Current formulations of Compound A, an inhibitor of the menin-MLL interaction, suffer from instability in both solution and solid forms, and a propensity to form undesirable solvates with organic solvents, leading to poor stability and solubility in pharmaceutical compositions.
Innovation Solution
Development of a Compound A monocitrate monohydrate Form A salt, characterized by specific PXRD peaks, and a pharmaceutical composition comprising this salt with excipients such as microcrystalline cellulose, crospovidone, sodium bicarbonate, hydrophobic colloidal silica, and magnesium stearate, to enhance stability and solubility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Compound A is formulated in conventional pharmaceutical compositions, then it can be administered to patients, but it forms undesirable solvates with organic solvents leading to poor stability
Solution Approach 1:
The patent extracts and eliminates the problematic interaction between Compound A and organic solvents by formulating the compound in salt form (monocitrate monohydrate). This transformation removes the compound's tendency to form undesirable solvates while maintaining its therapeutic activity, thereby resolving the stability issue without sacrificing efficacy.
Solution Approach 2:
The patent changes the chemical parameter of Compound A by converting it to its monocitrate monohydrate salt form. This parameter change fundamentally alters the compound's solvation behavior, preventing the formation of unstable solvates with organic solvents while improving overall formulation stability and reliability.
2Ease of operation
If Compound A is administered in tablet form, then it provides convenient dosing, but it exhibits low solubility
Solution Approach 1:
The patent changes the physical-chemical parameter of Compound A by forming it as a monohydrate salt, which significantly improves solubility compared to the free base form. This parameter change enables the compound to maintain adequate solubility in tablet formulations while preserving the convenient oral dosing route.
3Adaptability or versatility
If Compound A is formulated in liquid form, then it allows flexible dosing, but it produces very bad taste
Solution Approach 1:
The patent extracts the problematic taste property from Compound A by converting it to its monocitrate monohydrate salt form. This transformation removes the bitter taste characteristic of the free base while maintaining the compound's pharmacological activity, enabling liquid formulations to be palatable enough for patient acceptance.
Solution Approach 2:
The patent changes the sensory parameter of Compound A through salt formation, which fundamentally alters its taste profile. The monocitrate monohydrate form exhibits significantly improved taste characteristics compared to the free base, making liquid formulations acceptable for oral administration despite the flexibility benefits.
4Reliability
If Compound A is stored in solid form, then it maintains stability, but it lacks solubility for effective delivery
Solution Approach 1:
The patent changes the physical-chemical parameter of Compound A by forming the monocitrate monohydrate salt, which simultaneously optimizes both stability and solubility. The monohydrate crystalline form provides enhanced solid-state stability while the salt structure enables improved solubility in aqueous media, resolving the contradiction between these two critical parameters.
Data Source
AI summary
The present disclosure relates to a novel salt and salt forms of Compound A.The disclosure is also directed to pharmaceutical compositions containing at Compound A citrate salt or salt forms and to the therapeutic use of such salts, salt forms, and compositions thereof.