Darolutamide Nanocrystalline Form for Higher Solubility and Lower Dose
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Solution Overview
Problem
Existing crystalline forms of darolutamide, such as Form I, exhibit poor solubility and bioavailability, necessitating high doses for therapeutic efficacy, leading to increased side effects and formulation challenges.
Innovation Solution
Development of a nanocrystalline form (Form NC) with a higher specific surface area (SSA) and broad X-ray diffraction peaks, characterized by crystallites below 100 nm, enhancing solubility and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional crystalline forms (Form I) are used, then the drug can be manufactured with standard processes, but the solubility and bioavailability are poor, requiring high doses
Solution Approach 1:
The patent changes the physical parameters of the drug by creating a nanocrystalline form with particle sizes between 1-100 nm, which fundamentally alters the surface area to volume ratio and improves dissolution rate and bioavailability, allowing dose reduction
Solution Approach 2:
The invention transitions from conventional micrometer-scale crystals to nanometer-scale crystals, representing a dimensional change in particle size that enhances solubility and bioavailability characteristics
2Reliability
If high doses are administered to achieve therapeutic plasma concentrations, then therapeutic efficacy is reached, but side effects increase and pill burden increases
Solution Approach 1:
By changing the particle size parameter to the nanoscale range, the drug achieves improved bioavailability that allows therapeutic efficacy to be reached at lower doses, thereby reducing side effects and pill burden
3Speed
If crystalline Form I is ground to increase specific surface area, then dissolution rate may improve, but crystallinity decreases significantly and amorphous material forms
Solution Approach 1:
The invention performs preliminary action by directly forming nanocrystals during the crystallization process rather than attempting to grind conventional crystals, thereby achieving high surface area while maintaining crystallinity from the outset
Solution Approach 2:
The patent changes the nucleation and growth parameters during crystallization to directly produce nanocrystalline structures, avoiding the need for mechanical size reduction that would compromise crystallinity
4Reliability
If nanocrystalline form is prepared, then solubility and bioavailability are enhanced, but the manufacturing process becomes more complex
Solution Approach 1:
The patent modifies crystallization parameters (temperature, solvent composition, addition rate) to directly produce nanocrystals using conventional equipment, achieving enhanced bioavailability without requiring complex nanotechnology manufacturing processes
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
Form NC demonstrates eight times higher solubility and improved bioavailability, allowing for reduced daily doses and decreased side effects, while maintaining chemical and physical stability.
Implementation Method 1
nanocrystalline form (Form NC) with improved properties: as for example with good chemical and physical stability, high solubility, enhanced bioavailability
Implementation Method 2
broad X-ray diffraction peaks, characterized by crystallites below 100 nm
Implementation Method 3
powder X-ray diffractogram comprising broad peaks at 10.2, 14.4, and 17.8 ± 0.2 degrees 2-Theta
Data Source
Figure 1~3
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AI summary
The present invention relates to a crystalline form of darolutamide and to the process for its preparation. Furthermore, the invention relates to the use of said crystalline form for the preparation of a pharmaceutical composition useful for treating prostate cancer.