Benzo[c]Chroman Salt Polymorphs for Stable Drug Manufacturing
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Solution Overview
Problem
The chemical stability of pharmaceutically active compounds is affected by their crystal forms, leading to issues such as poor product stability, fine precipitation, and agglomeration, which complicates production and scale-up.
Innovation Solution
Development of pharmaceutically acceptable salts of benzo[c]chromane compounds in specific crystal forms, including hydrochloride, methanesulfonate, phosphate, L-tartrate, and hydrobromide salts, with defined stoichiometric ratios and characterized by unique X-ray powder diffraction patterns and differential scanning calorimetry profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If amorphous drug product is used, then ease of manufacture is improved, but product stability deteriorates due to poor chemical stability, fine precipitation, and agglomeration
Solution Approach 1:
The patent applies phase transition by converting the amorphous drug substance into a crystalline form. This is achieved through specific crystallization processes that produce a defined crystal structure, thereby improving chemical stability and reducing agglomeration while maintaining manufacturability through controlled phase change from amorphous to crystalline state
Solution Approach 2:
The patent creates a composite material system by forming a salt compound (e.g., hydrochloride salt) of the benzo[c]chromane compound. This composite structure combines the active pharmaceutical ingredient with a counterion in a specific stoichiometric ratio, resulting in improved stability and reduced precipitation while maintaining ease of manufacture through standardized salt formation procedures
2Device complexity
If polymorphic forms are not controlled, then manufacturing process is simplified, but product quality deteriorates due to variations in crystal structure affecting stability
Solution Approach 1:
The patent applies parameter changes by establishing specific crystallization conditions (temperature, solvent composition, pH, stoichiometric ratio) that produce a single, well-defined polymorphic form. This controlled parameter approach ensures consistent crystal structure and stability while maintaining a relatively simple manufacturing process through standardized condition specifications
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
Enhances the chemical stability and processability of the compounds, improving their suitability for pharmaceutical applications.
Implementation Method 1
The present disclosure provides a pharmaceutically acceptable salt of a compound of formula I, wherein the pharmaceutically acceptable salt is an acid addition salt
Implementation Method 2
WO 2022/117059 provides a cathepsin C inhibitor... The crystal form of a pharmaceutically active ingredient often affects the chemical stability of a drug
Implementation Method 3
different crystallization and storage conditions may lead to changes in the crystal structure of a compound
Implementation Method 4
characterized by unique X-ray powder diffraction patterns and differential scanning calorimetry profiles
Data Source
AI summary
A pharmaceutically acceptable salt of a benzo[c]chroman compound and a polymorphic form and use of the pharmaceutically acceptable salt. The pharmaceutically acceptable salt is selected from hydrochloride, methanesulfonate, phosphate, L-tartrate, maleate, p-toluenesulfonate, sulfate, fumarate, succinate, citrate, malate, and hydrobromide. The pharmaceutically acceptable salt and the polymorphic form thereof improve the bioavailability and the stability, and as a cathepsin C inhibitor, can be used for treating asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, α1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, rheumatoid arthritis, sinusitis, hidradenitis suppurativa, or cancer.