Birinapant Form H Crystallization for Stability and Shelf Life
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Solution Overview
Problem
There is an ongoing need for new forms of the SMAC mimetic birinapant with improved stability, solubility, and shelf life to effectively treat cell proliferative disorders such as cancer.
Innovation Solution
The development of a crystalline Form H of birinapant, which provides enhanced bioavailability, stability, and manufacturability, allowing for the preparation and use of pharmaceutical compositions for treating cell proliferative disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If new crystalline forms of birinapant are developed, then stability and shelf life are improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies parameter changes by developing multiple crystalline forms (polymorphs) of birinapant with different physical and chemical parameters. Each polymorph (Forms A through H) has distinct characteristics including different solubilities, stabilities, and melting points. This allows selection of the optimal crystalline form for specific manufacturing and storage requirements, resolving the contradiction between improved stability and manufacturing complexity.
Solution Approach 2:
The patent segments the single birinapant compound into multiple distinct crystalline forms, each with optimized properties for different applications. By dividing the drug substance into separate polymorphic forms with characterized properties, the patent enables targeted selection for specific manufacturing processes and storage conditions, thereby improving overall stability while managing manufacturing complexity through systematic characterization.
2Duration of action of stationary object
If new crystalline forms of birinapant are developed, then shelf life is improved, but ease of manufacture decreases
Solution Approach 1:
The patent utilizes parameter changes by establishing multiple crystalline forms with different physical parameters optimized for various manufacturing approaches. Each polymorph has characterized properties including solubility, stability, and processing characteristics, allowing selection of the most manufacturable form for specific production requirements while ensuring extended shelf life.
Solution Approach 2:
The patent applies preliminary action by providing comprehensive characterization and validation of multiple crystalline forms before manufacturing scale-up. By pre-characterizing the physical and chemical properties of each polymorph including stability data, solubility profiles, and processing behavior, the patent enables informed selection of the optimal form for manufacturing, thereby extending shelf life while maintaining ease of manufacture.
3Reliability
If crystalline Form H is used, then bioavailability is improved, but manufacturing process complexity increases
Solution Approach 1:
The patent applies parameter changes by developing Crystalline Form H with optimized physical parameters specifically for improved bioavailability. The form exhibits enhanced dissolution properties and solubility characteristics compared to other polymorphs. By systematically characterizing and validating the manufacturing process for Form H, the patent achieves improved bioavailability while managing process complexity through controlled parameter optimization.
Data Source
AI summary
Provided herein is a specific crystalline form of the anti-cancer drug birinapant, designated Form H. Compositions comprising Form H are disclosed, as well as methods of use thereof. Methods of preparation of the specific crystalline form are also provided. Form H is suitable for manufacturing drug product under GMP guidelines. Birinapant is a peptidomimetic of second mitochondrial-derived activator of caspases (SMAC), and inhibits proteins of the IAP (Inhibitor of Apoptosis Protein) family.