Niraparib Tosylate Co-Crystals for Solubility and Flow
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Solution Overview
Problem
Niraparib tosylate, a poly(ADP-ribose) polymerase inhibitor, has low aqueous solubility and poor flowability due to its cohesive nature, making it challenging for effective formulation and administration, particularly in solid oral dosage forms, where particle size reduction techniques like milling can induce static charge and worsen flow properties.
Innovation Solution
Development of novel crystalline forms of niraparib tosylate co-crystallized with urea or oxalic acid, which exhibit improved intrinsic dissolution rates and reduced chargeability, along with efficient, substantially solvent-free manufacturing processes, addressing the solubility and flowability issues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If particle size reduction techniques like milling are used to improve solubility, then aqueous solubility is improved, but static charge increases and flow properties worsen
Solution Approach 1:
The patent changes the crystalline form parameters of niraparib tosylate by developing new polymorphic forms and co-crystalline forms with different molecular packing arrangements. This fundamentally alters the surface properties and charge characteristics of the particles, allowing improved solubility without the adverse flow property changes that occur with conventional size reduction
Solution Approach 2:
The patent creates co-crystalline forms by combining niraparib tosylate with other molecular components in a defined stoichiometric ratio within a crystal lattice. This composite approach modifies the surface properties and intermolecular interactions, reducing static charge generation while maintaining or improving solubility characteristics
2Quantity of substance
If vigorous mechanical agitation is applied to reduce particle size, then solubility improves, but cohesive powders develop agglomerates and lumps
Solution Approach 1:
By changing the crystalline form parameters through polymorphism and co-crystallization, the patent modifies the surface energy and interparticle forces of the powder. This reduces the cohesive tendencies that lead to agglomeration during processing, allowing for better homogeneity while maintaining solubility benefits
3Stability of the object's composition
If crystalline Form I is used as a non-hygroscopic solid, then physical stability is improved, but aqueous solubility remains low
Solution Approach 1:
The patent forms co-crystals by combining niraparib tosylate with co-formers in a defined stoichiometric ratio within a crystal lattice. This composite structure modifies the solubility characteristics while maintaining physical stability, as the co-crystalline form provides a stable solid state with improved dissolution 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 new crystalline forms enhance bioavailability and manufacturing efficiency by improving solubility and flow properties, offering a more stable and effective pharmaceutical product for cancer treatment.
Implementation Method 1
Development of novel crystalline forms of niraparib tosylate co-crystallized with urea or oxalic acid
Data Source
AI summary
The present invention provides novel crystalline forms of niraparib tosylate. Specific crystalline forms provided by the present invention include niraparib tosylate Form APO-I, a co-crystal of niraparib tosylate and urea, and niraparib tosylate Form APO-II, a co-crystal of niraparib tosylate and oxalic acid. Also provided are pharmaceutical compositions including the niraparib tosylate crystalline forms, and the use of these forms in treatment or prevention of conditions which can be ameliorated by the inhibition of poly(ADP-ribose) polymerase (PARP), in particular certain forms of cancer.