SNAC Polymorphic Forms for Heparin Bioavailability
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Solution Overview
Problem
Current pharmaceutical formulations of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) lack stable polymorphic forms that effectively facilitate the delivery of active agents, particularly heparin, for treating thrombosis, due to limitations in solubility and stability.
Innovation Solution
Development of six polymorphic forms (Forms I-VI) and an amorphous form of SNAC, including hydrates and co-solvates, which are prepared through specific thermal and humidity-controlled methods to enhance stability and solubility, allowing for the creation of pharmaceutical compositions with high SNAC content and improved bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional pharmaceutical formulations of SNAC are used, then the formulation can be prepared, but the solubility and stability are insufficient to effectively facilitate delivery of active agents
Solution Approach 1:
The patent applies parameter changes by identifying and characterizing six distinct polymorphic forms (Forms I-VI) of SNAC, each with different crystal structures and physical properties. By changing the polymorphic form parameter, the patent achieves different solubility and stability profiles, allowing selection of the optimal form for specific delivery applications. This is accomplished through controlled crystallization processes varying temperature, solvent, and drying conditions.
Solution Approach 2:
The patent creates composite material systems by formulating SNAC in various polymorphic forms with specific active agents (particularly heparin) and excipients. The composite formulation approach allows the stable polymorphic forms of SNAC to work synergistically with active agents, enhancing overall solubility, stability, and bioavailability of the drug delivery system.
2Productivity
If high SNAC content is used to improve delivery efficiency, then the delivery effectiveness increases, but the formulation stability decreases
Solution Approach 1:
By changing the polymorphic form parameter of SNAC in the formulation, the patent achieves different physical stability profiles while maintaining high SNAC content. Certain polymorphic forms are inherently more stable at high concentrations, allowing the formulation to maintain both high SNAC content for efficient delivery and adequate stability for storage and handling.
3Quantity of substance
If amorphous SNAC is used to improve solubility, then the solubility increases, but the stability and manufacturability decrease
Solution Approach 1:
The patent addresses this contradiction by providing multiple crystalline polymorphic forms with intermediate properties between amorphous and highly crystalline states. These polymorphic forms offer improved stability compared to amorphous SNAC while maintaining adequate solubility for effective delivery, representing an optimized parameter state that balances both requirements.
4Reliability
If multiple polymorphic forms are developed to optimize delivery, then the delivery effectiveness improves, but the manufacturing complexity increases
Solution Approach 1:
The patent manages manufacturing complexity by establishing specific, reproducible crystallization parameters for each polymorphic form. By defining precise temperature, solvent, and drying conditions for producing Forms I-VI, the patent enables manufacturers to select and produce the appropriate polymorphic form through controlled parameter changes rather than requiring complex multi-step processes.
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 polymorphic forms of SNAC significantly improve the bioavailability and stability of heparin, enabling effective oral administration and treatment of thrombosis by maintaining therapeutic levels in plasma, as demonstrated by plasma heparin concentration graphs and dissolution rate studies.
Implementation Method 1
Development of six polymorphic forms (Forms I-VI) and an amorphous form of SNAC, including hydrates and co-solvates, which are prepared through specific thermal and humidity-controlled methods
Implementation Method 2
heating Form III, V, or VI of SNAC or a mixture thereof to at least 50° C. (but preferably less than 110° C.) for a time sufficient to form Form I of SNAC
Implementation Method 3
lyophilizing any form of SNAC other than Form I to yield Form I
Data Source
AI summary
The present invention relates to crystalline polymorphic forms of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate (“SNAC”), including two hydrates, a methanol solvate, and an ethanol solvate, of SNAC. More specifically, the present invention provide six polymorphic forms of SNAC (hereafter referred to as Forms I-VI). The present invention also provides an amorphous form of SNAC.