Blarcamesine Salt Polymorphs for Stability and Dissolution Control
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Solution Overview
Problem
There is a need for additional solid state forms of Blarcamesine HCl and other salts to improve processing, handling, stability, and bioavailability for the treatment of Neurodegenerative and Neurodevelopmental Diseases such as Alzheimer's disease, Parkinson's disease dementia, and Rett syndrome.
Innovation Solution
The development of crystalline polymorphs of Blarcamesine salts, including Blarcamesine HCl, HBr, Tosylate, Maleate, Camphorsulfonate, and Besylate, which can be used to prepare pharmaceutical compositions and formulations, enhancing properties like chemical stability, dissolution profile, and shelf-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional solid state forms of Blarcamesine HCl are used, then the compound can be provided in existing forms, but processing, handling, stability, and bioavailability are limited
Solution Approach 1:
The patent applies parameter changes by developing multiple crystalline polymorphs (Forms A, B, C) with different crystal structures and physical properties. Each polymorph exhibits distinct melting points, dissolution rates, and stability characteristics. By changing the crystalline structure parameter, the invention optimizes processing properties while maintaining stability, resolving the contradiction between ease of manufacture and reliability.
Solution Approach 2:
The patent creates composite solid state forms by combining Blarcamesine HCl with different counterions to form various salt compounds (e.g., Blarcamesine HCl, Blarcamesine HBr, Blarcamesine Tosylate). These composite salt forms exhibit enhanced processing characteristics, improved dissolution profiles, and increased stability compared to the free base, thereby resolving the technical contradiction.
2Productivity
If existing solid state forms are used, then formulation can be maintained, but dissolution profile and bioavailability are suboptimal
Solution Approach 1:
The patent utilizes parameter changes by creating polymorphs with different crystal packing arrangements and intermolecular forces. This changes the physical state parameters to achieve faster dissolution rates and improved bioavailability. Specifically, Form A exhibits rapid dissolution, while Forms B and C provide enhanced stability, allowing optimization of both productivity and reliability.
Solution Approach 2:
The patent applies local quality by creating different solid state forms with localized property variations. Each polymorph and salt form has specific local characteristics (e.g., Form A with high dissolution rate, Form B with high stability) that can be selected based on the specific therapeutic requirement, thereby optimizing both dissolution rate and bioavailability.
3Ease of operation
If multiple solid state forms are developed, then processing and handling characteristics are improved, but formulation complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the solid state forms into distinct categories (polymorphs A, B, C and various salt forms). Each segment has specific handling and processing characteristics that can be independently optimized. This segmentation allows formulation scientists to select appropriate forms for specific applications without managing unnecessary complexity.
Solution Approach 2:
The patent creates multi-functional solid state forms that can serve multiple purposes. For example, Blarcamesine HCl salt forms can be used for both immediate release formulations (requiring fast dissolution) and extended release formulations (requiring controlled dissolution). This multi-functionality reduces the need for entirely separate formulations, thereby managing complexity while maintaining ease of operation.
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 crystalline polymorphs provide improved chemical stability, dissolution rate, and handling characteristics, offering better processing and handling properties, thus enhancing the effectiveness of Blarcamesine salts for treating Neurodegenerative and Neurodevelopmental Diseases.
Implementation Method 1
Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis—'TGA', or differential scanning calorimetry—'DSC'), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state (13C) NMR spectrum.
Implementation Method 2
The present disclosure provides crystalline polymorphs of Blarcamesine salts including Blarcamesine HCl, Blarcamesine HBr, Blarcamesine Tosylate, Blarcamesine Maleate, Blarcamesine Camphorsufonate and Blarcamesine Besylate, processes for preparation thereof
Data Source
AI summary
The present disclosure encompasses a novel solid state form of Blarcamesine and salts thereof, processes for preparation thereof, and pharmaceutical compositions thereof.