Crystalline Hydrated Form B of Olaparib Preparation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current crystalline forms of Olaparib, such as forms A and L, have limitations in solubility, stability, and bioavailability, which affect their therapeutic efficacy, particularly in treating tumors with HR-dependent DNA DSB repair deficiencies like ovarian, breast, or prostate cancer.
Innovation Solution
A process for preparing the crystalline hydrated form B of Olaparib, which exhibits improved solubility and stability, involving dissolution in polar solvents, addition of an anti-solvent, and controlled temperature and stirring conditions to achieve a form with specific IR, DSC, and XRPD characteristics, allowing for enhanced handling and preparation of solid oral forms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If crystalline forms A or L of Olaparib are used, then the compound can be handled and processed, but solubility and bioavailability are limited
Solution Approach 1:
The patent changes the physical and chemical parameters of Olaparib by creating a new crystalline hydrated form B with specific water content (3-7%) and distinct crystal structure. This parameter change in hydration state and molecular arrangement resolves the contradiction by achieving both improved solubility (1.5-2.0 mg/mL) and stable crystalline characteristics that facilitate handling and manufacturing.
Solution Approach 2:
The invention creates a composite crystalline structure by forming a hydrate complex where Olaparib molecules are organized in a specific lattice with incorporated water molecules. This composite arrangement of drug molecules and water in defined stoichiometric ratios achieves enhanced solubility while maintaining crystalline stability for manufacturing.
2Reliability
If the amorphous form of Olaparib is used, then solubility is improved, but stability in humid environments deteriorates
Solution Approach 1:
The patent transforms the amorphous form into a crystalline hydrated form by changing the physical state parameter from amorphous to crystalline and controlling water content at 3-7%. This parameter transformation resolves the contradiction by providing both high solubility (comparable to amorphous form) and excellent stability in humid environments, as the crystalline structure with defined hydration is non-hygroscopic.
Solution Approach 2:
The invention converts the potential harm of water exposure (which causes hygroscopicity in amorphous forms) into a beneficial hydrated crystalline structure. By intentionally incorporating water molecules into the crystal lattice at controlled ratios, the patent eliminates hygroscopic instability while maintaining high solubility, thus converting the harmful effect into a beneficial property.
3Productivity
If existing crystalline forms are used, then manufacturing is feasible, but therapeutic efficacy is reduced
Solution Approach 1:
The patent optimizes therapeutic efficacy by changing the crystalline form parameter from forms A or L to hydrated form B, which has superior solubility (1.5-2.0 mg/mL). This parameter change in crystal structure and hydration state enhances bioavailability and therapeutic efficacy while maintaining manufacturing feasibility through well-defined crystallization conditions and stable physical properties.
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 crystalline hydrated form B of Olaparib demonstrates superior solubility and stability, maintaining physicochemical characteristics even in water-saturated environments, potentially improving therapeutic outcomes for cancer treatment by enhancing bioavailability and stability.
Implementation Method 1
Olaparib in crystalline form is dissolved in a polar solvent such as methanol, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide or acetic acid
Implementation Method 2
The solution of Olaparib is added to an anti-solvent, preferably a polar protic anti-solvent such as water... The resulting suspension is left under stirring... to obtain crystalline hydrated form B
Data Source
Figure 1
Figure 2
Figure 3
AI summary
Disclosed are a novel crystalline form and an amorphous form of Olaparib, and the process for their preparation.