Succinate Salt Crystal Form for Stable Octahydrothienoquinoline API
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Solution Overview
Problem
The hydrochloride salt of the compound (B) is unstable to heat and has poor storage stability due to high hygroscopicity, making it unsuitable for use as a drug substance.
Innovation Solution
The development of a succinate salt of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea, which exhibits excellent storage stability, crystallinity, and solubility, suitable for industrial production as a drug substance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the hydrochloride salt of compound (B) is used as a drug substance, then the compound provides dopamine D2 receptor agonist action, but the storage stability is poor due to high hygroscopicity and crystal form transition
Solution Approach 1:
The patent changes the salt form parameter from hydrochloride salt to succinate salt, which fundamentally alters the physical and chemical properties of the compound. This parameter change resolves the hygroscopicity issue and improves storage stability while maintaining the pharmacological activity.
Solution Approach 2:
The invention creates a composite salt structure by combining compound (B) with succinic acid to form a succinate salt. This composite material approach allows the compound to benefit from the stabilizing properties of the succinate anion, reducing hygroscopicity and preventing crystal form transitions during storage.
2Reliability
If the hydrochloride salt of compound (B) is used, then the compound has pharmacological activity, but heat stability is poor
Solution Approach 1:
The patent changes the salt form parameter from hydrochloride to succinate, which fundamentally alters the thermal stability characteristics. The succinate salt form exhibits superior heat stability compared to the hydrochloride salt, allowing the compound to maintain its integrity under elevated temperature conditions during storage and processing.
3Reliability
If a different salt form is developed to improve storage stability, then storage stability improves, but the compound must be重新developed and characterized
Solution Approach 1:
The succinate salt acts as an intermediary form that bridges the pharmacological activity of compound (B) and the desired storage stability. By using succinic acid as a mediator to form the salt, the invention achieves improved stability without requiring complete redevelopment of the active pharmaceutical ingredient, thus reducing overall development complexity.
Data Source
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AI summary
[Problem] An object of the present invention is to provide a compound which has high storage stability and is suitable for use as a drug substance. [Solution] The present invention relates to a succinate salt of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a, 5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea, which is suitable as a drug substance having excellent storage stability and crystallinity and is useful for the treatment or prevention of Parkinson's disease, restless legs syndrome, hyperprolactinemia or the like.