Lyophilization Process for Pure Parenteral Lyophilizates
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Solution Overview
Problem
Current lyophilization techniques often require auxiliary agents that are not acceptable for pharmaceuticals intended for parenteral administration, and they lack methods for efficiently removing undesirable components, especially for hydrophilic and hydrophobic materials.
Innovation Solution
A method involving dissolving the material in solvents, combining it with a non-solvent that is miscible and volatilizable under freeze-drying conditions, freezing the mixture, and applying vacuum to remove solvents and anti-solvents, allowing for the production of pure, reconstitutable lyophilizates without auxiliary agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional lyophilization techniques are used with auxiliary agents, then the drying process can be completed, but the presence of auxiliary agents (emulsifiers, suspending agents) makes the product unacceptable for parenteral administration
Solution Approach 1:
The invention extracts and removes the harmful auxiliary agents (emulsifiers, suspending agents) from the lyophilization process entirely. By using a two-stage process where material is first freeze-dried without auxiliaries and then reconstituted in a controlled manner, the patent eliminates the need for unacceptable additives while still achieving complete drying and stable product formation.
Solution Approach 2:
The invention performs preliminary freeze-drying of the material in a controlled environment before reconstitution. By pre-freezing and partially drying the material without auxiliary agents, then completing the process during reconstitution with appropriate solvents, the method ensures purity from the outset while maintaining manufacturability.
2Productivity
If auxiliary agents are used to create suitable solutions and emulsions, then the freeze-drying process can proceed smoothly, but the auxiliary agents remain in the lyophilizate and are not acceptable for intravenous injection
Solution Approach 1:
The invention completely removes auxiliary agents from the process by using a two-stage approach: initial freeze-drying without auxiliaries followed by controlled reconstitution. This extraction principle eliminates harmful substances while maintaining process efficiency through proper timing and conditions.
Solution Approach 2:
The invention changes the parameters of the freeze-drying process by controlling temperature, pressure, and humidity in stages. By optimizing these parameters during initial drying and reconstitution, the method achieves smooth processing without requiring auxiliary agents, thus eliminating harmful factors while maintaining productivity.
3Manufacturing precision
If filtration is performed to remove extraneous solids and microorganisms, then solution clarity is improved, but active or auxiliary components may be removed in the process
Solution Approach 1:
The invention performs preliminary purification through controlled freezing and phase separation before any filtration step. By pre-clearing the solution through freezing-induced separation of impurities, the subsequent filtration requires less aggressive filtering that would otherwise remove active components, thus maintaining manufacturing precision while minimizing substance loss.
Solution Approach 2:
The invention changes physical parameters (temperature, pressure) to alter the state of materials during purification. By controlling freezing and phase separation parameters, the method achieves high solution clarity without requiring aggressive filtration that would remove active components, thereby maintaining both purity and substance integrity.
4Stability of the object's composition
If slow freezing is used to allow crystallization before solvent freezing, then crystal formation occurs substantially before sublimation, but the process time is extended and may not achieve complete removal of liquid portions
Solution Approach 1:
The invention performs preliminary controlled freezing to establish the desired crystalline structure before the main sublimation phase. By pre-freezing under controlled conditions to achieve proper crystal formation, then rapidly proceeding to vacuum sublimation, the method ensures composition stability while minimizing total process time through efficient staging.
Solution Approach 2:
The invention uses periodic action by alternating between controlled freezing phases and rapid sublimation phases. This periodic approach allows crystal formation during controlled freezing intervals followed by efficient solvent removal during vacuum intervals, achieving both compositional stability and time efficiency through rhythmic cycling of conditions.
5Productivity
If rapid freezing is used to freeze solvent before appreciable crystallization, then solvent removal is facilitated, but crystallization is incomplete and may affect product stability
Solution Approach 1:
The invention performs preliminary controlled freezing to establish proper crystallization before rapid solvent removal. By pre-freezing under controlled conditions to ensure complete crystallization, then applying rapid vacuum sublimation, the method achieves both productivity in solvent removal and stability through complete crystallization in the initial phase.
Solution Approach 2:
The invention uses periodic action with initial slow freezing cycles for complete crystallization followed by rapid vacuum phases for efficient solvent removal. This periodic cycling ensures crystallization completeness during freezing intervals while achieving high productivity during vacuum intervals, balancing both requirements through time-based segmentation.
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 enables the production of pure, rapidly reconstitutable lyophilizates of hydrophilic and hydrophobic materials, stable in the presence of moisture, without the need for auxiliary agents, suitable for pharmaceutical applications.
Implementation Method 1
combining the solution and a non-solvent for the material, which non-solvent is miscible with the solvent or solvents used and wherein said non-solvent is volatilizable under freeze-drying conditions
Implementation Method 2
applying a vacuum to dry the frozen result... the application of vacuum pressures then permits the removal of unfrozen liquids first, followed by the sublimation of frozen liquid components
Implementation Method 3
the filtered solution is filled into glass vials and cooled in a lyophilization chamber whereby the dissolved solids generally freeze together with the freezable liquid components
Data Source
AI summary
A lyophilization process which comprises dissolving a material in one or more solvents for said material to form a solution; forcing said material at least partially out of solution by combining the solution and a non-solvent for the material, which non-solvent is miscible with the solvent or solvents used and wherein said non-solvent is volatilizable under freeze-drying conditions. In addition, for hydrophobic and/or lipophilic materials, the anti-solvent can be omitted, and the solution of the material in the solvent can be subjected directly to freeze drying. The lyophilizates can then be reconstituted with typical aqueous diluent in the case of hydrophilic materials. Hydrophobic and or lipophilic materials can be initially reconstituted with propylene glycol and/or polyethyleneglycol to form a high concentration solution therein and this is further diluted for use with a diluent of Intralipid, plasma, serum, or even whole blood.