Purifying Polylactic Acid via Liquid-Liquid Phase Separation
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Solution Overview
Problem
Current methods for purifying polylactic acid derivatives, particularly D,L-polylactic acid with low molecular weight, face challenges such as gel-like precipitate formation, incomplete removal of unreacted monomers and organometal catalysts, leading to accelerated polymer decomposition and uneven drug release.
Innovation Solution
A method involving dissolving polylactic acid in a water-miscible organic solvent, adding water or an alkali metal salt solution for phase separation, and recovering the organic solvent layer to remove impurities, resulting in a polymer with a lactone monomer content of 1.0 wt % or less and metal catalyst content of 50 ppm or less.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If the solvent/non-solvent method is used to purify polylactic acid, then solidified polymer can be obtained when the polymer has a high molecular weight or when preparing an L,L-polylactic acid derivative, but gel-like precipitate is generated upon settling in a non-solvent when the polymer has a low molecular weight or when preparing non-crystalline D,L-polylactic acid derivatives, making it difficult to purify the polymer
Solution Approach 1:
The invention changes the fundamental parameter of the purification approach by using liquid-liquid phase separation instead of solvent/non-solvent precipitation. This involves dissolving the polymer in a specific solvent system (chloroform/methanol or chloroform/acetone) and utilizing phase separation based on density differences, rather than relying on precipitation in non-solvents. This parameter change resolves the contradiction by providing a method that works effectively for both low molecular weight D,L-polylactic acid and high molecular weight L,L-polylactic acid without forming gel-like precipitates.
Solution Approach 2:
The invention introduces specific solvent systems (chloroform/methanol or chloroform/acetone) as intermediaries to facilitate the purification process. These solvent systems act as mediators that dissolve the polymer uniformly and enable phase separation based on density differences, allowing effective removal of monomers and catalysts without causing gel-like precipitate formation. The intermediary solvents bridge the gap between the polymer and the separation process, making the purification operation easy and effective for all polymer types.
2Manufacturing precision
If the solvent/non-solvent method is used for purification, then a solidified polymer can be obtained, but monomers and an organometal catalyst may co-precipitate in the non-solvent and be not removed effectively therefrom
Solution Approach 1:
The invention applies the extraction principle by using liquid-liquid phase separation to selectively separate and remove impurities (monomers and organometal catalysts) from the polymer solution. The impurities are extracted into one phase while the purified polymer remains in the other phase, allowing effective removal of contaminants without co-precipitation issues. This extraction approach achieves high purity while minimizing polymer loss.
Solution Approach 2:
The invention changes the separation mechanism from precipitation-based to density-based phase separation. By utilizing the density differences between the solvent system and impurities, the method achieves effective separation of monomers and catalysts from the polymer without the co-precipitation problem that occurs in solvent/non-solvent methods. This parameter change in the separation mechanism resolves both the purity and polymer loss issues.
3Manufacturing precision
If D,L-polylactic acid with low molecular weight is purified by liquid-liquid phase separation using methanol or ethanol, then phase separation occurs upon refrigeration, but lactide monomers are dissolved in the alcohol solvent at high temperature and recrystallized at low temperature, making it difficult to remove monomers effectively
Solution Approach 1:
The invention changes the solvent system parameters from alcohol-based (methanol/ethanol) to chloroform-based mixed solvents (chloroform/methanol or chloroform/acetone). This parameter change in the solvent composition fundamentally alters the solubility and phase separation behavior, preventing lactide monomer recrystallization while maintaining effective phase separation. The chloroform-based system provides superior monomer removal capability while achieving narrow molecular weight distribution.
Solution Approach 2:
The invention introduces chloroform as an intermediary solvent that mediates the phase separation process differently than alcohol solvents. Chloroform, when combined with methanol or acetone, creates a solvent system where lactide monomers remain soluble in the separated phase and do not recrystallize. This intermediary chloroform component prevents the harmful recrystallization effect while enabling effective monomer removal and narrow molecular weight distribution.
4Loss of substance
If vacuum drying is applied to remove moisture from gel-like precipitate, then moisture removal is attempted, but the gel-like structure hardly allows moisture removal and requires long drying time
Solution Approach 1:
The invention extracts and removes moisture during the liquid-liquid phase separation process itself, before the drying step. By separating the aqueous phase containing moisture from the organic phase containing the polymer during phase separation, the method removes the majority of moisture content before vacuum drying is applied. This extraction of moisture during phase separation dramatically reduces the drying time required while achieving low moisture content in the final product.
5Loss of substance
If high-temperature vacuum condition is applied during drying, then moisture removal is accelerated, but condensation polymerization may occur making it difficult to control the molecular weight
Solution Approach 1:
The invention performs preliminary moisture removal during the liquid-liquid phase separation step, before the vacuum drying process is applied. By removing the bulk of moisture during phase separation when the polymer is in solution form, the subsequent vacuum drying operates on a much drier sample. This preliminary action prevents condensation polymerization during drying while still achieving low moisture content, thereby maintaining molecular weight control.
Solution Approach 2:
The invention changes the drying conditions by reducing the required drying time and temperature exposure through preliminary moisture removal. Since the majority of moisture is removed during phase separation, the subsequent vacuum drying can be performed under milder conditions with shorter duration, preventing condensation polymerization while still achieving the desired low moisture content. This parameter change in the drying process protects molecular weight stability.
6Loss of substance
If high-temperature vacuum condition is applied during drying, then moisture removal is accelerated, but lactide monomers may be produced
Solution Approach 1:
The invention performs preliminary removal of lactide monomers during the liquid-liquid phase separation process, before the high-temperature vacuum drying is applied. The phase separation effectively extracts and removes lactide monomers from the polymer solution. This preliminary removal prevents the formation of additional lactide monomers during subsequent high-temperature drying, eliminating the harmful effect while still achieving effective moisture removal.
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
This method effectively purifies polylactic acid derivatives, ensuring stable drug release and preventing premature degradation, thereby enhancing the control over drug release rates and maintaining polymer stability.
Implementation Method 1
adding water or an aqueous alkali metal salt solution to the solution of polymer dissolved in the organic solvent, followed by mixing; subjecting the mixture to phase separation to remove water and to recover the organic solvent layer
Implementation Method 2
removing the organic solvent from the organic solvent layer to recover the polymer
Data Source
AI summary
Disclosed are a highly purified polylactic acid or a derivative thereof, or a salt thereof, and a method for purifying the same. The polylactic acid or a derivative thereof, or a salt thereof may be applied to various medical and drug carrier systems, or the like.