Riociguat Crystalline Forms for Drug Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The existing crystalline forms of Riociguat, a Guanylate cyclase agonist, are not fully characterized in terms of polymorphs, solubility, and stability, which affects drug formulation and bioavailability.
Innovation Solution
Identification and characterization of novel crystalline forms (forms I, II, III, and IV) of Riociguat, including XRPD patterns and DSC curves, to determine their solubility, stability, and bioavailability, along with a method for preparing these forms through solvent selection and crystallization processes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If recrystallization from methanol is used to obtain compound (I), then a crystal form is obtained, but the crystal form is not fully characterized and may not have optimal solubility and stability
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization conditions including solvent type (methanol, DMSO, water, ethyl acetate, acetone, THF, toluene, ethanol), temperature (room temperature, refrigeration, heating), and concentration to obtain different crystal forms with distinct XRPD patterns, thereby achieving both characterization completeness and optimal stability-solubility profiles
Solution Approach 2:
The patent utilizes phase transitions through controlled crystallization processes where the compound transitions from dissolved state to various crystalline phases (Form I, Form II, Form III, Form IV) with different molecular packing arrangements, each exhibiting unique diffraction patterns and stability characteristics that can be selected for specific formulation requirements
2Adaptability or versatility
If multiple crystalline forms are investigated, then solubility and stability can be optimized, but the complexity of characterization and analysis increases
Solution Approach 1:
The patent segments the crystalline forms into distinct categories (Form I, Form II, Form III, Form IV) each with characteristic XRPD patterns, allowing systematic identification and selection of appropriate forms for different formulation needs without requiring comprehensive analysis of all possible polymorphs
Solution Approach 2:
The patent employs XRPD as an intermediary technique to rapidly identify and characterize different crystal forms, providing a straightforward method to distinguish between forms based on their diffraction patterns without requiring complex structural analysis, thus managing characterization complexity while maintaining formulation flexibility
3Loss of time
If crystal forms are not fully characterized, then development time is reduced, but drug formulation and bioavailability are affected
Solution Approach 1:
The patent performs preliminary characterization actions by establishing XRPD patterns and key properties for each crystal form early in the development process, creating a reference framework that enables rapid formulation development without requiring exhaustive analysis at each subsequent stage, thus reducing development time while maintaining formulation efficiency
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 crystalline forms exhibit good solubility, low hygroscopicity, and stability under various conditions, enhancing drug stability and bioavailability, making them suitable for formulation and industrialization.
Implementation Method 1
X-ray powder diffraction (XRPD) pattern comprising one or more peaks at about 25.47, 17.69 and 27.23 degrees in term of two theta
Implementation Method 2
DSC curve comprising the endothermic peak at about 268.95° C.
Implementation Method 3
the compound of formula (I) may present in many novel crystalline forms including form I, form II, form III and form IV
Data Source
AI summary
A novel crystalline form or amorphous of formula (I) and preparation method thereof are disclosed in present invention, wherein the novel crystalline form is substantially pure crystalline form I, form II, form III or form IV. The novel crystalline forms disclosed herein have good solubility, low hydroscopicity and good stability at high temperature (60° C.), high humidity (RH is 90%±5%) and/or under light (4500+/−500 Lux), which benefit for storage, meet the requirements of drug stability and therefore, making formula (I) suitable for formulation preparation and with high bioavailability.