ITI-007 Salt Forms for Solubility and Stability
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Solution Overview
Problem
The production and formulation of ITI-007, a potent 5-HT2A receptor ligand, face challenges due to its poor solubility and instability, particularly in its free base form and existing salt forms like hydrochloride and toluenesulfonic acid, necessitating the development of stable and pharmaceutically acceptable alternative salts and polymorphs.
Innovation Solution
An extensive salt screen was conducted to identify novel salts and polymorphs, resulting in the discovery of oxalate, 4-aminosalicylate, and cyclamate salt forms of ITI-007, which are characterized by their stability and suitability for galenic formulations, involving specific crystallization and purification processes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ITI-007 is used in free base form, then it maintains its pharmacological activity, but it exhibits poor solubility and instability
Solution Approach 1:
The patent applies parameter changes by converting ITI-007 from its free base form to various salt forms (oxalate, 4-aminosalicylate, cyclamate) with different physical and chemical properties. This transformation changes the molecular state while preserving the core pharmacophore, thereby maintaining pharmacological activity while improving solubility and stability characteristics.
Solution Approach 2:
The patent creates composite material structures by forming salt compounds between ITI-007 and various acids. These composite salts combine the active pharmaceutical ingredient with counterions to produce materials that exhibit both the desired biological activity and improved physicochemical properties including enhanced solubility and stability.
2Stability of the object's composition
If hydrochloride salt form is used, then solubility is improved, but the salt becomes hygroscopic and shows poor stability
Solution Approach 1:
The patent addresses this contradiction by changing the counterion parameter from chloride to alternative anions (oxalate, 4-aminosalicylate, cyclamate). This parameter change modifies the salt's hygroscopicity and stability characteristics while maintaining improved solubility compared to the free base form.
3Reliability
If toluenesulfonic acid addition salt is used, then stability is improved, but solubility remains insufficient for optimal formulation
Solution Approach 1:
The patent resolves this contradiction by changing the acid counterion parameter from toluenesulfonic acid to alternative acids (oxalic acid, 4-aminosalicylic acid, cyclamic acid). This parameter modification adjusts both the stability and solubility parameters simultaneously, achieving an optimal balance for pharmaceutical formulation.
4Reliability
If extensive salt screening is conducted to find stable salts, then suitable salt forms are identified, but the development time and complexity increase
Solution Approach 1:
The patent applies universality by developing a systematic salt screening methodology that can be applied across multiple compounds. The approach uses a standardized panel of acids and systematic evaluation criteria that can identify suitable salt forms for various pharmaceutical compounds, reducing development complexity through method standardization.
Data Source
AI summary
The disclosure provides new, stable, pharmaceutically acceptable salt forms of 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one, together with methods of making and using them, and pharmaceutical compositions comprising them.