Pharmaceutical Salt Forms for Solubility and Bioavailability
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Solution Overview
Problem
The unpredictability of crystalline forms of compounds like 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide affects their physicochemical properties, such as solubility and bioavailability, making it difficult to develop effective pharmaceutical formulations for FGFR-related diseases.
Innovation Solution
Development of pharmaceutically acceptable salts, such as hemitartrate and monohydrochloride forms, which exhibit increased solubility and bioavailability, along with specific crystalline forms like Form A-III, Form B-II, and Form C-I, to enhance the pharmacokinetic characteristics of the compound.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If the compound is used in free form, then the structure is simple, but the solubility and bioavailability are poor
Solution Approach 1:
The patent applies parameter changes by converting the compound from its free base form to salt forms (such as hydrochloride, sulfate, nitrate, phosphate, and tartrate salts). This chemical modification changes the physicochemical parameters of the compound, specifically improving solubility in aqueous media and enhancing bioavailability while maintaining the core molecular structure and biological activity.
Solution Approach 2:
The patent uses salt-forming acids as intermediaries to transform the free base compound into pharmaceutically useful salt forms. These acid intermediaries (e.g., hydrochloric acid, sulfuric acid, phosphoric acid) facilitate the conversion process and enable the compound to achieve desired solubility and bioavailability characteristics without directly modifying the core active molecule.
2Reliability
If crystalline forms are developed to improve solubility, then the pharmacokinetic properties improve, but the development process becomes complex and unpredictable
Solution Approach 1:
The patent applies preliminary action by pre-establishing and characterizing multiple stable crystalline forms and salt forms of the compound before pharmaceutical formulation development. By proactively identifying and stabilizing specific crystalline forms (such as Form A, Form B, Form C) and their corresponding salts, the patent eliminates the need for unpredictable crystalline form development during later formulation stages, thereby reducing overall development complexity.
Solution Approach 2:
The patent systematically explores and establishes multiple crystalline forms with different physical parameters (solubility, stability, melting point, X-ray diffraction patterns). By characterizing these different forms and selecting the most suitable ones for pharmaceutical use, the patent transforms the unpredictable nature of crystalline form development into a controlled process with known, reproducible parameters.
Data Source
AI summary
The present invention relates to the salts of a compound and the crystalline forms thereof. More specifically, the present invention belongs to the pharmaceutical field, and provides the pharmaceutically acceptable salts of the compound.