Hydrogen Sulphate Salt Composition for Solubility and Stability
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Solution Overview
Problem
The free-base form of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide exhibits low solubility and dissolution rate, leading to poor bioavailability and instability during formulation processing and storage, which affects its therapeutic efficacy.
Innovation Solution
A pharmaceutical composition comprising the hydrogen sulphate salt of the compound dispersed in a carrier matrix made of d-alpha-tocopheryl polyethylene glycol 1000 succinate, polyglycolised glycerides, polyethylene glycols, or hard fats maintains the stability of the Agent during processing and storage, ensuring high solubility and dissolution rates.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If the free-base form of the Agent is used, then the compound can be formulated, but it exhibits low solubility and dissolution rate leading to poor bioavailability
Solution Approach 1:
The patent changes the chemical form of the Agent from free-base to hydrogen sulphate salt, which fundamentally alters the solubility and dissolution characteristics. This parameter change transforms the compound from BCS Class 4 (low solubility, low permeability) to a form with improved pharmaceutical properties, achieving both high solubility and high bioavailability simultaneously.
Solution Approach 2:
The patent creates a composite pharmaceutical composition by combining the hydrogen sulphate salt of the Agent with specific carrier matrices (d-alpha-tocopheryl polyethylene glycol 1000 succinate, polyglycolised glycerides, polyethylene glycols, or hard fats). This composite formulation maintains the stability and enhanced solubility properties of the salt form while ensuring proper delivery and absorption.
2Stability of the object's composition
If the free-base form of the Agent is used, then the compound can be stored, but it is unstable during formulation processing and storage
Solution Approach 1:
The patent changes the chemical form from free-base to hydrogen sulphate salt, which fundamentally alters the stability profile. The salt form is specifically designed to be stable during formulation processing and storage, preventing degradation and maintaining therapeutic efficacy throughout the product lifecycle.
Solution Approach 2:
The hydrogen sulphate salt acts as an intermediary form that bridges the Agent and its active pharmaceutical form. This salt form provides stability during handling and storage while maintaining the ability to deliver the active compound effectively, serving as a stable carrier that preserves therapeutic properties.
3Ease of operation
If conventional tablet formulation is used, then the Agent can be delivered, but bioavailability is relatively poor (approximately 18% in dogs)
Solution Approach 1:
The patent changes the formulation parameters by using the hydrogen sulphate salt form combined with specific carrier matrices (d-alpha-tocopheryl polyethylene glycol 1000 succinate, polyglycolised glycerides, polyethylene glycols, or hard fats). This parameter change transforms the delivery system to achieve high bioavailability while maintaining ease of oral administration through conventional dosage forms.
Data Source
AI summary
The invention concerns pharmaceutical compositions containing a hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide and solvates, crystalline forms and amorphous forms thereof, to the use of said compositions as a medicament; and to processes for the preparation of said compositions.