Etoricoxib Solvates for Stable Crystal Forms
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Solution Overview
Problem
Etoricoxib crystal forms exhibit poor thermal stability, impurity, small size, and wide size distribution, leading to challenges in pharmaceutical applications, and unsolvated forms have low solubility, limiting clinical efficacy.
Innovation Solution
Development of etoricoxib solvates using hydrogen bond donor or acceptor solvents with specific polarity ranges to form stable crystal forms with improved solubility and processing efficiency, employing cooling or suspension crystallization methods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If cooling crystallization is used to prepare etoricoxib crystal form V, then crystal stability is improved, but explosive nucleation occurs causing small crystal size and wide size distribution
Solution Approach 1:
The patent applies preliminary action by adding seed crystals before cooling crystallization. The seed crystals provide pre-formed nucleation sites that control the crystallization process, preventing explosive nucleation and ensuring uniform crystal growth. This preliminary introduction of crystal structure guides the subsequent crystallization to produce crystals with narrow size distribution while maintaining stability.
Solution Approach 2:
The patent employs parameter changes by carefully controlling the cooling rate during crystallization. By optimizing the cooling rate parameter and maintaining specific temperature ranges, the process achieves controlled crystallization that produces stable crystal form V with uniform size distribution, avoiding both explosive nucleation and poor stability.
2Ease of manufacture
If suspension crystallization is used to prepare etoricoxib crystal form I, then ease of manufacture is improved, but crystal form transformation occurs during storage and transportation
Solution Approach 1:
The patent uses preliminary action by introducing seed crystals of the desired stable form before crystallization. This pre-establishes the crystal structure template, guiding the crystallization process to form the stable polymorph directly rather than the metastable form I, thereby preventing subsequent crystal form transformation during storage and transportation.
Solution Approach 2:
The patent applies parameter changes by optimizing crystallization conditions including temperature, solvent composition, and cooling rate to favor the formation of the stable crystal form. By carefully controlling these parameters, the process directly produces the stable polymorph with ease of manufacture while eliminating the instability issue of crystal form transformation.
3Quantity of substance
If hydrate forms are used, then solubility is improved, but thermal stability deteriorates due to dehydration and crystal form transformation
Solution Approach 1:
The patent applies taking out by removing water molecules from the crystal structure to form anhydrous forms. By extracting the water component that causes thermal instability through dehydration, the patent creates stable anhydrous crystal forms that maintain good solubility characteristics without the thermal stability problems associated with hydrate decomposition and crystal form transformation.
Solution Approach 2:
The patent employs parameter changes by controlling the hydration state during crystallization. By optimizing solvent composition and crystallization conditions to produce anhydrous forms rather than hydrates, the patent achieves a balance between solubility and thermal stability, creating forms that do not undergo dehydration-induced crystal form transformation.
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 solvates demonstrate enhanced thermal stability, large crystal size, narrow size distribution, and improved solubility, addressing the limitations of existing crystal forms and improving drug efficacy.
Implementation Method 1
Development of etoricoxib solvates using hydrogen bond donor or acceptor solvents with specific polarity ranges to form stable crystal forms
Implementation Method 2
employing cooling or suspension crystallization methods
Implementation Method 3
employing cooling or suspension crystallization methods
Data Source
AI summary
The disclosure relates to etoricoxib solvates and a preparation method thereof. A solvent is a hydrogen bond donor solvent with a polarity value π* ranging from 60 to 100 or a hydrogen bond acceptor solvent with a polarity value π* ranging from 92 to 100. Solvents with a polarity value π* within the above range all can form corresponding etoricoxib solvates with etoricoxib. The etoricoxib solvate can be prepared by cooling crystallization or suspension crystallization. A 1,2-propanediol solvate of etoricoxib and a dimethyl sulfoxide (DMSO) solvate of etoricoxib provided in the present disclosure have high thermal stability, unique crystal form, large size, concentrated distribution, and prominent flowability and is safe, pharmaceutically acceptable, and not easy to agglomerate. Compared with etoricoxib, the etoricoxib solvates exhibit significantly improved solubility. Moreover, preparation of the solvates requires low consumption in time, energy, and solvent, and has high efficiency, with a molar yield higher than 90%.