Carebastine Salt Formation for Stable Pharmaceutical Solid Forms
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Solution Overview
Problem
Carebastine, the active metabolite of ebastine, lacks a suitable solid form, leading to issues with stability, impurities, purification difficulties, and unsuitability for medicinal use, and there is a need for fast-acting, non-sedative histamine H1 receptor antagonists for acute allergic diseases like acute urticaria and asthma.
Innovation Solution
Development of pharmaceutically acceptable carebastine salts, including acid and base addition salts, to stabilize and improve the solid form, purity, and stability, with specific salts like p-toluenesulfonate and potassium salt showing better pharmacokinetic properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If carebastine is used as a free base compound, then it can be rapidly absorbed after oral administration, but it lacks a suitable solid form leading to poor stability and high impurity
Solution Approach 1:
The patent changes the physical form of carebastine from free base to salt form (specifically hydrochloride salt), which fundamentally alters its properties. The salt form provides a stable crystalline structure with defined melting point and poor solubility, while maintaining rapid absorption through appropriate formulation. This parameter change resolves the contradiction between rapid absorption and stability.
Solution Approach 2:
The patent introduces hydrochloric acid as an intermediary substance to form the hydrochloride salt of carebastine. This salt formation acts as a mediator that stabilizes the compound while preserving its pharmacological activity and absorption characteristics. The salt form serves as a stable intermediate that can be stored and formulated without degradation.
2Reliability
If carebastine is formulated as a salt, then stability and purity are improved, but the complexity of preparation and purification increases
Solution Approach 1:
The patent segments the preparation process into distinct modular steps: (1) synthesis of carebastine free base, (2) salt formation with hydrochloric acid, (3) filtration, (4) crystallization, and (5) drying. This segmentation makes each step independent and controllable, reducing overall complexity while ensuring high purity and stability of the final salt product.
Solution Approach 2:
The patent utilizes phase transition during crystallization to purify and stabilize the carebastine hydrochloride salt. By controlling the crystallization process from solution, the patent obtains pure crystalline salt with high stability. The phase change from dissolved state to crystalline state automatically separates impurities, simplifying purification without requiring complex chromatographic methods.
3Duration of action of stationary object
If ebastine is used for treatment, then it provides long-acting non-sedative effects, but the oral onset time is slow (1-4 hours) making it unsuitable for acute allergic diseases
Solution Approach 1:
The patent uses carebastine, which is already present in the body as an active metabolite of ebastine, to achieve rapid onset. Since carebastine is formed through first-pass metabolism in the liver, it is ready for immediate action once administered. This preliminary formation of the active metabolite eliminates the delay associated with waiting for ebastine to be metabolized, achieving both rapid onset and sustained action.
Solution Approach 2:
The patent effectively copies the active pharmacological effect of ebastine through its metabolite carebastine. Instead of waiting for ebastine to be metabolized to produce the active effect, the patent directly administers the active metabolite carebastine in salt form, achieving the same therapeutic effect with rapid onset. This copying approach maintains the long-acting non-sedative properties while eliminating the delay.
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 carebastine salts provide a rapid and effective treatment for allergic diseases with improved stability, purity, and reduced individual variability, offering a new clinical option for patients with acute allergic conditions.
Implementation Method 1
Development of pharmaceutically acceptable carebastine salts, including acid and base addition salts, to stabilize and improve the solid form, purity, and stability
Implementation Method 2
a carebastine salt of the present invention is a white powdery solid... an acid addition salt formed by carebastine and an acid or a base addition salt formed by carebastine and a base
Data Source
AI summary
The present invention discloses a carebastine salt and a use of the carebastine salt, relates to the field of pharmaceutical chemistry, and solves the problems of carebastine in the related art such as poor solid form, excessive impurities, instability, difficulty in purification, difficulty in scale-up synthesis, and unsuitability for medicinal use. The carebastine salt of the present invention includes, but is not limited to, acid addition salts or base addition salts, and particularly includes potassium salts, sodium salts, methanesulfonate and p-toluenesulfonate. The carebastine salt of the present invention has the use of preparing histamine H1 receptor antagonist drugs. The carebastine salt of the present invention has the characteristics such as easy purification, high stability, simple process and easy industrial production, and has good hygroscopicity characteristics and is convenient for storage. At the same time, the salt of the present invention can quickly enter the body to exert the efficacy, has good oral absorption, is superior to ebastine in safety and individual differences, and is a promising anti-allergic disease drug.