Polymorph Form II of (R)-2-[2-amino-3-(indol-3-yl)propionylamino]-2-methylpropionic acid
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Solution Overview
Problem
There is a significant unmet medical need for ultrapure compounds to treat amyloid-beta (Aβ) toxicity-related diseases such as Alzheimer's disease, glaucoma, and age-related macular degeneration, as current treatments often involve impurities that can lead to cumulative exposure over decades, especially with oral dosing.
Innovation Solution
A novel polymorph form (Form II) of (R)-2-[2-amino-3-(indol-3-yl)propionylamino]-2-methylpropionic acid is developed, characterized by a specific X-ray powder diffraction pattern and FT-IR spectrum, which can be prepared through a process involving mixing with aqueous HCl, adjusting pH, and precipitation, resulting in a highly pure form with enhanced solubility and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatment compounds are used, then treatment coverage is provided, but impurity exposure accumulates over decades
Solution Approach 1:
The patent changes the crystalline form parameter of the active pharmaceutical ingredient from conventional forms to a specific polymorph form with defined X-ray diffraction characteristics. This parameter change enables the compound to achieve high purity (99.999% area%) while maintaining treatment efficacy, thereby resolving the contradiction between providing treatment coverage and avoiding cumulative impurity exposure over decades of therapy
Solution Approach 2:
The patent employs aqueous acid treatment and pH adjustment processes to isolate and purify the compound through precipitation. The hydraulic process of dissolving in aqueous HCl, adjusting pH to neutralize and precipitate the compound, and filtering the precipitate enables removal of impurities while maintaining high purity levels, thus addressing the impurity exposure issue
2Ease of operation
If oral dosing is used for long-term treatment, then treatment accessibility is improved, but cumulative impurity exposure increases
Solution Approach 1:
The patent changes the purity parameter of the oral formulation from conventional levels to ultra-high purity (99.999% area%). This parameter change allows long-term oral dosing to be administered with minimal cumulative impurity exposure, thereby maintaining treatment accessibility while resolving the contradiction between ease of operation and harmful impurity accumulation
3Reliability
If high purity compound is produced, then impurity exposure is reduced, but manufacturing complexity increases
Solution Approach 1:
The patent employs a hydraulic purification process using aqueous acid treatment, pH adjustment, and precipitation. This approach achieves high purity (99.999% area%) through a relatively simple multi-step process involving dissolving in aqueous HCl, adjusting pH to precipitate the compound, and filtering, thereby reducing manufacturing complexity while maintaining high purity
Solution Approach 2:
The patent utilizes phase transition through precipitation to achieve purification. By adjusting the pH of the aqueous solution, the compound transitions from dissolved state to solid precipitate form, enabling separation from impurities. This phase transition method achieves high purity without requiring complex purification equipment or multiple chromatographic steps
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 novel polymorph form achieves high purity (up to 99.999% area% by IPC-HPLC) and increased solubility, reducing the risk of impurity exposure and improving treatment efficacy for Aβ-associated diseases.
Implementation Method 1
acts as a modulator of Aβ aggregation, preventing the formation of toxic oligomeric and fibrillar species, while promoting aggregation into nontoxic off pathway
Implementation Method 2
characterized by an X-ray powder diffraction pattern using CuKa radiation (λ = 0.15418 nm) displaying peaks at °2θ (d value Å) angles of 5.87 (15.067), 11.91(7.432), 17.99 (4.931), 30.35 (2.945)
Implementation Method 3
mixing compound (R)-2-[2-amino-3-(indol-3-yl)propionylamino]-2-methylpropionic acid with an aqueous HCl to provide a solution of the compound
Implementation Method 4
cooling the solution to about 0-5 °C, followed by adjusting the pH of the solution to about 5.6 with a base; stirring the solution at about 0-5 °C until precipitation is complete
Data Source
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AI summary
This invention relates to a novel polymorph form of compound (R)-2-[2-amino-3-(indol-3- yl)propionylamino]-2-methylpropionic acid, a process for making the novel polymorph form of the compound, and uses thereof for making other polymorph forms of the compound. The invention further relates to composition comprising novel polymorph form of the compound and a pharmaceutically acceptable carrier or excipient.