Amorphous Solid Dispersion Formulation for Stable ITI-007
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Solution Overview
Problem
ITI-007, a potent 5-HT2A receptor ligand, faces challenges in formulation due to its oily, sticky solid form with poor solubility and stability issues, particularly in hydrochloride and toluenesulfonic acid salt forms, necessitating the development of stable, pharmaceutically acceptable solid forms for effective galenic formulations.
Innovation Solution
Formulating ITI-007 as amorphous solid dispersions with excipients such as cellulose acetate, cellulose acetate phthalate, and hydroxypropyl methyl cellulose phthalate, along with optional antioxidants and surfactants, to stabilize the compound and prevent crystallization during storage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ITI-007 is formulated as amorphous solid dispersion, then chemical stability is improved, but manufacturing complexity increases
Solution Approach 1:
Excipients such as cellulose acetate, cellulose acetate phthalate, and hydroxypropyl methyl cellulose phthalate are used as intermediary substances to stabilize the amorphous form of ITI-007. These excipients form a matrix that prevents crystallization and maintains the drug in a stable amorphous state during storage and handling, thereby improving chemical stability while enabling practical manufacturing through established solid dispersion techniques
Solution Approach 2:
The physical state of ITI-007 is changed from crystalline to amorphous form, and salt forms (hydrochloride, toluenesulfonic acid) are converted to free base form in the solid dispersion. This parameter change in molecular arrangement and physical state fundamentally improves chemical stability by eliminating the ordered crystal structure that facilitates degradation pathways
2Reliability
If amorphous forms are used, then dissolution characteristics and bioavailability are improved, but physical stability deteriorates
Solution Approach 1:
The excipients act as physical stabilizers that form a rigid matrix around the amorphous ITI-007 molecules, preventing them from reorganizing into crystalline structures. This intermediary matrix maintains the high-energy amorphous state while protecting against physical instability, allowing the formulation to retain improved dissolution characteristics without reverting to crystalline form during storage
Solution Approach 2:
The formulation creates a composite material system where ITI-007 is dispersed within a polymer matrix of excipients. This composite structure combines the beneficial dissolution properties of the amorphous drug with the stabilizing properties of the excipient matrix, achieving both improved bioavailability and enhanced physical stability
3Quantity of substance
If salts of ITI-007 are made, then solubility is improved, but stability deteriorates
Solution Approach 1:
The unstable salt forms (hydrochloride, toluenesulfonic acid salts) are extracted or avoided in favor of formulating the free base form of ITI-007 within the amorphous solid dispersion matrix. The excipient matrix provides the necessary solubility enhancement without requiring stable salt formation, thereby eliminating the stability problems associated with salt forms while maintaining improved solubility characteristics
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 amorphous solid dispersions exhibit high chemical stability, maintaining over 90% stability after 7 days at 75% relative humidity and 40°C, with no texture changes, and provide a stable form for pharmaceutical compositions.
Implementation Method 1
Pure amorphous drug forms tend to be unstable. As amorphous forms are thermodynamically unstable relative to the corresponding crystal forms, it is well known that amorphous forms would revert back to the stable crystalline form. Therefore, in order to utilize the amorphous form of a drug, it is necessary to stabilize it to inhibit crystallization of the drug active during the period of product storage.
Data Source
AI summary
The disclosure provides new, stable, pharmaceutically acceptable amorphous solid dispersions 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.