Pralsetinib Amorphous Solid Dispersion Effervescent Release
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Solution Overview
Problem
Pralsetinib, a potent RET inhibitor, has low aqueous solubility, which poses challenges in formulating an immediate release dosage form due to its delayed dissolution from polymer matrices and the inefficacy of conventional disintegration agents in breaking up the matrix for rapid release.
Innovation Solution
The development of pharmaceutical compositions comprising an amorphous solid dispersion of pralsetinib with a hydrophilic polymer, such as hydroxypropyl methylcellulose, and an effervescent couple like citric acid and sodium bicarbonate, which facilitates immediate release by disrupting the polymer matrix.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If pralsetinib is formulated with a hydrophilic polymer matrix to enhance aqueous solubility, then solubility is improved, but release rate deteriorates due to delayed dissolution from the polymer matrix
Solution Approach 1:
The polymer matrix is segmented and disrupted by effervescent agents (carbon dioxide generation from citric acid and sodium bicarbonate reaction), breaking the continuous polymer network into smaller fragments. This segmentation allows trapped pralsetinib to be released rapidly while the amorphous solid dispersion maintains solubility enhancement.
Solution Approach 2:
The physical state of the polymer matrix is changed from intact to disrupted through effervescent action. The chemical reaction generates gas bubbles that physically fragment the matrix structure, transforming it from a barrier to a release-promoting structure. This parameter change enables immediate release while preserving solubility benefits.
2Speed
If conventional disintegration agents are used to break up the polymer matrix, then release rate should improve, but they prove ineffective in achieving rapid release
Solution Approach 1:
Effervescent agents (citric acid and sodium bicarbonate) serve as intermediary substances that mediate between the polymer matrix and the disintegration process. The chemical reaction between these intermediaries generates carbon dioxide gas, which physically disrupts the matrix more effectively than conventional mechanical disintegration agents, enabling reliable rapid release.
3Quantity of substance
If an amorphous solid dispersion is formed to enhance solubility, then aqueous solubility is improved, but formulation complexity increases
Solution Approach 1:
Multiple functions are merged into a single effervescent mechanism: solubility enhancement through amorphous solid dispersion, matrix disruption through gas generation, and rapid release promotion. The effervescent couple (citric acid and sodium bicarbonate) combines disintegration and release enhancement functions, simplifying the overall formulation approach despite the amorphous dispersion component.
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 solution enables rapid and effective release of pralsetinib, overcoming the solubility and formulation challenges of the drug, ensuring a therapeutic effect in treating RET-altered cancers like NSCLC and MTC.
Implementation Method 1
an effervescent couple like citric acid and sodium bicarbonate, which facilitates immediate release by disrupting the polymer matrix
Implementation Method 2
an amorphous solid dispersion of pralsetinib, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable hydrophilic polymer
Data Source
AI summary
The present disclosure relates to pharmaceutical composition comprising 1) an amorphous solid dispersion comprising pralsetinib, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable hydrophilic polymer; and 2) an effervescent couple; and crystalline forms of pralsetinib and pralsetinib hydrochloride salt, which are useful as a RET selective inhibitors. The present disclosure also provides pharmaceutically acceptable compositions comprising the crystalline forms and methods of using said compositions in the treatment of various disorders.