Rucaparib Tosylate Crystal Forms for Stability and Bioavailability
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Solution Overview
Problem
There is a need for additional solid state forms of Rucaparib Tosylate to improve processing properties, stability, and bioavailability for the treatment of cancers such as advanced ovarian cancer and prostate cancer, as existing forms may not adequately address these requirements.
Innovation Solution
The development of new solid state forms of Rucaparib Tosylate, including crystalline forms X, III, XII, XIII, and IX, characterized by specific X-ray powder diffraction patterns and particle size distributions, which can be prepared through controlled crystallization processes using solvents like ethanol, 2-propanol, and acetonitrile, and converted into other forms for pharmaceutical compositions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing solid state forms of Rucaparib Tosylate are used, then the formulation can be manufactured, but the processing properties, stability, and bioavailability are not adequately optimized
Solution Approach 1:
The patent applies parameter changes by discovering and characterizing multiple polymorphic forms (Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII) of Rucaparib Tosylate, each with distinct crystal structures, melting points, thermal behaviors, XRD patterns, and dissolution profiles. This allows selection of optimal forms for specific processing and stability requirements
Solution Approach 2:
The patent creates composite material systems by forming solvates and hydrates of Rucaparib Tosylate with various solvents including ethanol, isopropanol, acetonitrile, toluene, and water. These composite crystalline structures combine the API with solvent molecules in defined stoichiometric ratios, providing tailored physical properties for different formulation needs
2Quantity of substance
If high drug loading is required for effective treatment, then the therapeutic efficacy is improved, but the manufacturability and compressibility become more challenging
Solution Approach 1:
The patent utilizes parameter changes by selecting specific polymorphic forms and solvate structures that inherently provide better compressibility and flow properties. The crystalline nature and intermolecular interactions in these solid state forms enable high drug loading (45% w/w or more) while maintaining manufacturability through direct compression or minimal processing
3Reliability
If the dissolution profile is changed to improve bioavailability, then the therapeutic effect is enhanced, but the formulation complexity increases
Solution Approach 1:
The patent achieves dissolution profile modification through parameter changes in the solid state structure itself. Different polymorphic forms and solvates exhibit distinct dissolution rates and profiles due to variations in crystal packing, lattice energy, and solvent interaction. This provides bioavailability enhancement through material selection rather than complex formulation strategies
Solution Approach 2:
The patent uses solvents as intermediaries during the crystallization process to form specific solvate structures. These solvent molecules act as mediators that organize the API molecules into desired crystal arrangements, which then provide the targeted dissolution characteristics in the final formulation
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
These new solid state forms exhibit improved stability, solubility, and handling characteristics, making them suitable for pharmaceutical formulations, particularly for treating cancers with deleterious BRCA mutations and other malignancies, enhancing treatment efficacy.
Implementation Method 1
X-ray diffraction (XRD) pattern
Implementation Method 2
Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes
Implementation Method 3
thermal behaviors (e.g., measured by thermogravimetric analysis—'TGA ', or differential scanning calorimetry—'DSC')
Implementation Method 4
thermal behaviors (e.g., measured by thermogravimetric analysis—'TGA ', or differential scanning calorimetry—'DSC')
Implementation Method 5
melting point
Implementation Method 6
changing the dissolution profile in a favorable direction
Data Source
AI summary
The present disclosure encompasses solid state forms of Rucaparib Tosylate, and pharmaceutical compositions thereof.