Compound A Injection Formulation for Solubility and Stability
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Solution Overview
Problem
Compound A, a potential anticancer agent, is poorly soluble in the solvent system used for Compound AST-3424, making it challenging to develop a suitable injection preparation for clinical trials and commercial production.
Innovation Solution
A stable injection preparation for Compound A is developed using a solvent system comprising C2-C8 alcohols, non-ionic surfactants, and hydrotropic agents like N,N-dimethylacetamide, along with specific surfactants such as polyoxyethylene (35) castor oil, to enhance solubility and stability, allowing for a concentrated form that requires dilution before use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If the formulation of Compound AST-3424 (ethanol and propylene glycol mixed solvent) is used for Compound A, then the preparation method is simple and consistent with existing technology, but Compound A is poorly soluble in this solvent system
Solution Approach 1:
The patent changes the solvent system parameters by replacing propylene glycol with specific surfactants (Tween 80, Span 80, or a combination thereof) while maintaining ethanol as the base solvent. This parameter change enables Compound A to achieve adequate solubility (≥10 mg/mL) while keeping the formulation process simple and consistent with existing manufacturing capabilities.
Solution Approach 2:
The patent introduces surfactants (Tween 80 or Span 80) as intermediary substances that act as solubilizing agents between Compound A and the ethanol solvent system. These surfactants facilitate the dissolution of Compound A in the mixed solvent system, resolving the solubility issue without complicating the manufacturing process.
2Reliability
If a concentrated injection preparation is developed to meet clinical trial requirements, then the product can be stored stably and administered reliably, but the preparation process becomes more complex requiring specific solvent systems
Solution Approach 1:
The patent optimizes the solvent system parameters by selecting specific surfactants (Tween 80, Span 80) and their concentrations in the mixed solvent system. This parameter optimization enables the concentrated injection preparation to achieve both storage stability and administration reliability while maintaining a manageable preparation process through defined compositional ranges.
Solution Approach 2:
The patent creates a composite solvent system combining ethanol with specific surfactants (Tween 80, Span 80, or their combination) to form a synergistic formulation. This composite material approach enhances the reliability of the concentrated injection preparation for storage and administration while the composite nature provides built-in solubilizing capabilities that simplify the overall preparation process.
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 injection preparation meets the requirements for long-term clinical trials and commercial production, ensuring stability and solubility, and can be administered as a ready-to-use solution without prior dilution, suitable for various injection routes.
Implementation Method 1
the solvent system used for Compound AST-3424; that is, the concept of using a formulation similar to that of AST-3424 to study and screen out a liquid preparation for Compound A was unrealistic
Implementation Method 2
hydrotropic agents like N,N-dimethylacetamide, along with specific surfactants such as polyoxyethylene (35) castor oil, to enhance solubility and stability
Data Source
AI summary
An injection preparation and a preparation method therefor, and a compatible medicinal liquid and a preparation method therefor. Upon performing tests, the provided injection preparation and compatible medicinal liquid thereof meet the requirements of long-term clinical trials and commercial production and sales. The injection preparation is a solution containing a compound of the following formula I, wherein the solvent of the solution contains C2-C8 alcohol, and can also contain another cosolvent or solubilizer. The preferred injection preparation is a mixed solution of DMA, ELP and ethanol which contains 10 mg/ml of a compound of formula (I), wherein DMA is a cosolvent, and ELP is a solubilizer. For the ready-to-use injection (compatible medicinal liquid) of the compound of following formula (I), the solvent thereof is water, the solute thereof comprises the compound of formula I, DMA, ELP, ethanol, an isosmotic adjusting agent and a pH regulator, the concentration of compound A in the injection is 0.016-1.10 mg/ml, the pH of the injection is 7.4, and the injection is an isosmotic solution. Further disclosed is a method for preparing the above-mentioned injection preparation and a method for preparing the above-mentioned compatible medicinal liquid of the injection.