Crystalline PLK1 Inhibitor Forms for Stability and Bioavailability
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Solution Overview
Problem
Existing small molecule PLK1 inhibitors, such as compound (I), have a narrow therapeutic window and cause significant haematological toxicity due to their effect on both cancer cells and normal cells, necessitating the development of new solid state forms with improved properties for better handling, stability, and bioavailability.
Innovation Solution
Development of crystalline forms of compound (I), including pharmaceutically acceptable salts and co-crystals, such as hydrochloride, maleate, and L-malate, which exhibit enhanced properties like improved storage stability, ease of handling, and bioavailability through techniques like crystallization and solvent-mediated transformation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If compound (I) is used as a PLK1 inhibitor, then anti-proliferative activity is improved, but haematological toxicity increases
Solution Approach 1:
The patent applies parameter changes by developing different solid state forms (polymorphs, solvates, co-crystals) of compound (I), each with distinct physical and chemical properties. These structural variations in the crystalline lattice modify the compound's dissolution rate, bioavailability, and pharmacokinetic profile, thereby adjusting the therapeutic window to reduce haematological toxicity while preserving anti-proliferative activity
Solution Approach 2:
The patent employs composite material strategies by forming co-crystals of compound (I) with various co-formers (e.g., organic acids, bases). These co-crystalline composite structures combine compound (I) with pharmaceutically acceptable materials to create new solid state forms that exhibit improved safety profiles, including reduced haematological toxicity, while maintaining the desired anti-proliferative effect
2Speed
If amorphous form of compound (I) is used, then dissolution rate is improved, but stability deteriorates
Solution Approach 1:
The patent applies phase transitions by deliberately converting compound (I) between different solid state phases. Amorphous forms with high dissolution rates are transformed into stable crystalline forms (polymorphs, solvates, co-crystals) that maintain improved dissolution characteristics while achieving the storage stability required for pharmaceutical formulation and long-term storage
3Reliability
If new solid state forms are developed, then bioavailability is improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies preliminary action by pre-characterizing multiple solid state forms of compound (I) during the research and development phase. Different polymorphs, solvates, and co-crystals are synthesized, purified, and characterized in advance to identify forms with optimal bioavailability. This preliminary work enables selection of the most suitable solid state form for scale-up manufacturing, reducing complexity during commercial production
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 forms of compound (I) provide improved therapeutic efficacy by maintaining pharmacological activity while reducing toxicity and enhancing handling, stability, and bioavailability, making them suitable for treating proliferative disorders and other conditions.
Implementation Method 1
Development of crystalline forms of compound (I), including pharmaceutically acceptable salts and co-crystals
Implementation Method 2
through techniques like crystallization and solvent-mediated transformation
Data Source
AI summary
The present invention relates to new crystalline forms of a pyrimido-diazepine derivative which exhibits excellent anti-tumour activity. The invention also relates to a pharmaceutical composition containing said crystalline forms as an active ingredient, and use thereof in the prevention or treatment of disease. The invention further relates to a process for preparing the crystalline forms.