Pemetrexed Diacid Crystal Forms for Mild, High-Yield Crystallization
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Solution Overview
Problem
Existing crystalline forms of pemetrexed diacid face issues such as solvent residue control, high drying temperatures leading to degradation, lengthy crystallization periods, and operational difficulties in large-scale production, resulting in low yields and inefficiencies.
Innovation Solution
Development of novel crystalline forms (Form 1 and Form 2) of pemetrexed diacid characterized by specific PXRD patterns and TGA profiles, prepared under mild conditions using controlled pH adjustments and solvent mixtures, enabling high yields and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If solvents with higher boiling points are used in crystalline forms (C, D, E), then the crystallization process is facilitated, but solvent residue control becomes more difficult and requires increased burden during drug product preparation
Solution Approach 1:
The patent changes the physical-chemical parameters of the solvent system by selecting isopropanol (boiling point 82.6°C) instead of high-boiling solvents like DMSO or DMF. This parameter change facilitates both crystallization and subsequent solvent removal, resolving the contradiction between ease of manufacture and manufacturing precision regarding solvent residue control.
2Quantity of substance
If very high temperature (160-200°C) is applied in drying step for anhydrous crystalline forms (F, G), then complete drying is achieved, but pemetrexed diacid degradation risk increases
Solution Approach 1:
The patent changes the drying temperature parameter from very high temperature (160-200°C) to moderate temperature (40-60°C) by using a crystalline form that incorporates water in its structure. This parameter change allows complete drying without degradation, resolving the contradiction between drying completeness and drug stability.
Solution Approach 2:
The patent creates a composite crystalline structure (crystalline form A) that incorporates water molecules into the crystal lattice. This composite structure allows the material to be dried at lower temperatures while still achieving complete solvent removal, resolving the contradiction between drying completeness and stability.
3Ease of manufacture
If crystalline form A is used, then the crystallization process is simplified, but filtration becomes difficult resulting in time-consuming operation and low yield
Solution Approach 1:
The patent modifies the local quality of the crystalline structure by changing the solvent system to isopropanol, which produces crystals with different morphological properties. This local change in crystal structure improves filtration characteristics while maintaining the simplified crystallization process, resolving the contradiction between ease of manufacture and productivity.
4Ease of manufacture
If crystalline form B is used, then the crystallization process is simplified, but the crystallization period becomes very long (up to 18 hours) reducing efficiency
Solution Approach 1:
The patent changes the solvent parameter from water or ethanol to isopropanol, which significantly reduces the crystallization time from up to 18 hours to approximately 2-4 hours while maintaining the simplicity of the crystallization process. This parameter change resolves the contradiction between ease of manufacture and time efficiency.
5Ease of manufacture
If pH adjustment and heating are used to promote dissolution, then dissolution is enhanced, but unwanted discoloration develops requiring additional color treatment steps
Solution Approach 1:
The patent changes the temperature parameter from high temperature (40°C to near boiling point) to low temperature (15-25°C) by using isopropanol as the solvent. This parameter change allows effective dissolution without thermal degradation that causes discoloration, thereby eliminating the need for additional color treatment steps and resolving the contradiction between ease of manufacture and process complexity.
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 are stable, easily prepared on a large scale with high yields (>90%), and free from inter-conversion issues, overcoming the shortcomings of previous forms.
Implementation Method 1
dissolving pemetrexed disodium in a mixture of water and isopropanol to form a solution
Implementation Method 2
adjusting the pH value of the solution to about 2.5 to 3.5 with an acid
Implementation Method 3
isolating the precipitate
Implementation Method 4
crystallizing pemetrexed diacid by the following steps
Data Source
Figure 1
Figure 2
AI summary
Crystalline forms of pemetrexed diacid are provided (Forms 1 and 2) which are readily produced for either laboratory-scale or industrial scale. Processes for the preparation of Forms 1 and 2 are also provided.