Amorphous Solid Dispersion for Lipophilic Drug Stability
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Solution Overview
Problem
The compound shown in Formula (I), a novel oral thyroid hormone receptor-β agonist, has low solubility in hydrochloric acid solution, buffer, and water, limiting its use as a drug candidate due to its lipophilic and insoluble nature, and existing formulations require refrigeration for stability, making long-term room temperature storage and administration challenging.
Innovation Solution
A pharmaceutical composition comprising the compound mixed with copovidone or hydroxypropyl methylcellulose and undergoing hot melt extrusion, which increases solubility and stability at room temperature, allowing for extended storage and improved bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If the compound is formulated with conventional excipients to improve solubility, then dissolution rate is improved, but storage stability deteriorates requiring refrigeration below 15°C
Solution Approach 1:
The patent changes the physical and chemical parameters of the formulation by using hot melt extrusion processing at controlled temperatures (50-80°C) to create an amorphous solid dispersion. This transforms the crystalline compound into an amorphous state within the copovidone matrix, fundamentally altering its dissolution behavior and thermal stability characteristics, enabling room temperature storage while maintaining high dissolution rates
Solution Approach 2:
The patent creates a composite material system consisting of the thyroid hormone receptor-β agonist compound embedded within a copovidone polymer matrix. This composite structure combines the pharmacological activity of the compound with the stabilizing and solubilizing properties of copovidone, achieving both improved dissolution and enhanced storage stability at room temperature
2Reliability
If refrigeration storage is implemented to maintain stability, then storage stability is improved, but ease of operation deteriorates due to cold chain requirements
Solution Approach 1:
The patent modifies the formulation's thermal stability parameters through hot melt extrusion processing, creating a formulation that remains stable at room temperature (20-25°C) without requiring refrigeration. This parameter change eliminates the need for cold chain storage while maintaining drug stability, significantly improving ease of operation and patient compliance
3Reliability
If low temperature storage is required to prevent degradation, then reliability is improved, but loss of energy increases due to refrigeration requirements
Solution Approach 1:
The patent changes the formulation's thermal characteristics through hot melt extrusion processing, creating a thermally stable product that can be stored at room temperature. This eliminates the continuous energy consumption associated with refrigeration while maintaining drug stability, significantly reducing energy loss in storage and transportation
4Productivity
If the compound is processed at high temperature to improve dissolution, then dissolution rate is improved, but thermal degradation increases
Solution Approach 1:
The patent utilizes phase transition principles by controlling the thermal processing to transform the compound from crystalline to amorphous state during hot melt extrusion. The process temperature (50-80°C) is carefully controlled to be above the glass transition temperature of copovidone for proper mixing, but below the degradation temperature of the compound, achieving dissolution enhancement without thermal degradation
Solution Approach 2:
The copovidone polymer acts as an intermediary material that protects the thermally sensitive compound during processing. The copovidone matrix absorbs and distributes the thermal energy, preventing direct thermal degradation of the compound while still enabling the dissolution enhancement through amorphization
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 hot melt extrusion process enhances the dissolution rate of the compound, maintaining supersaturation and stability at room temperature, improving patient compliance and reducing storage and transportation costs while maintaining therapeutic effectiveness.
Implementation Method 1
the high temperature hot melt extrusion process (greater than 80° C.) is suitable for the preparation of solubilized compositions of the compound of formula (I)
Implementation Method 2
15 to 45 parts of copovidone with a glass transition temperature of 90° C. to 130° C.
Implementation Method 3
products prepared with the formulations and methods described in the present application exhibit increased dissolution of the compound of formula (I), and long-term stability at room temperature
Data Source
AI summary
Pharmaceutical compositions suitable for long-term storage at room temperature are described. The pharmaceutical composition comprises the compound of formula (1)and can be used for the treatment of steatohepatitis. Also described are methods for preparing the pharmaceutical composition and methods of treatment using the pharmaceutical compositions.