Lyophilization l Sandesh Bhattarai

  Introduction   Lyophilization is the process in which water is removed from a product after it is frozen and placed under a vacuum, allowi...

 

Introduction  

Lyophilization is the process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase. In the pharmaceutical field, lyophilization has become an important subject to ongoing development and its expansion. Lyophilization is carried out using a simple principle of physics i.e. sublimation. The process consists of three separate, unique, and interdependent processes: freezing, primary drying (sublimation), and secondary drying (desorption). 

Steps involved in lyophilization

 

Freezing stage 

The product is frozen below its solidification temperature. Freezing is done rapidly. The freezing phase is the most critical in the whole freeze-drying process because the product can be spoiled if improperly done. Most samples that are to be freeze-dried are eutectics, which are mixtures of substances that freeze at a lower temperature than the surrounding water. 

 

Primary drying 

The primary drying process reduces the major quantity of solvent from a product while the matrix is in a frozen state. During the primary drying phase, the pressure is lowered and heat is supplied to the material for the ice to sublime. In this initial drying phase, about 95% of the water in the material is sublimated. This phase may be slow because, if too much heat is added, the structure of the material could be altered. The heat is brought mainly by conduction, convection, or radiation.

 

Secondary drying 

This phase of drying eliminates the final traces of water that remain due to absorption. The temperature is raised higher than in the primary drying phase (50⁰C to 60⁰C) to break any physicochemical interactions that have formed between the water molecules and the frozen materials. At the end of the operation, the final residual water content in the product is extremely low. 

 

Packing 

After drying the vacuum is replaced by filtered dry air or nitrogen to establish atmospheric pressure. Ampoules are sealed by either tip sealing or pull sealing method. Vials and bottles are sealed with rubber closures and aluminum caps. 

 

The basic component of Lyophilizer 

 

Chamber 

The chamber contains shelves or shelves for processing products. The chamber can also fit with a stoppering system. It is typically made of stainless steel and usually highly polished on the inside and insulated and clad on the outside.

  

Shelves 

The shelf's design is made more complicated because of the several functions it has to perform. The shelf acts as a heat ex-changer, removing energy from the product during freezing and supplying energy to the product during the primary and secondary drying segments of the freeze-drying cycle.

  

Process condenser  

The process condenser is designed to trap the solvent, which is usually water, during the drying process. The process condenser will consist of coils or sometimes plates that are refrigerated to allow temperature. These refrigerated coils or plates may be in a vessel, separate to the chamber or they could be located within the same chamber as the shelves. 

 

Shelf fluid system 

The freeze-drying process requires that the product is first frozen and then the energy in the form of heat is applied throughout the drying phases of the cycle. This energy exchange is done by circulating a fluid through the shelves at the desired temperature. The temperature is set in an external heat exchange system consisting of cooling heat ex-changer and an electrical heater. The fluid circulated is normally silicone oil. This will be pumped around the circuit at low pressure in a sealed circuit using a pump.

 

Refrigeration system  

The product to be freeze-dried is either frozen before into the dryer or frozen whilst on the shelves. A considerable amount of energy is needed for this duty. Compressors or sometimes liquid nitrogen supplies the cooling energy. 

 

Vacuum system 

To remove the solvent in a reasonable time, a vacuum must be applied during the drying process. The vacuum level required will be typically in the range of 50 to 100µ bar. To achieve such a low vacuum, a two-stage rotary vacuum pump is used.

 

Control system 

Control may be entirely or usually fully automatic for production machines. The control elements required shelf temperature, pressure, and time. A control program will set up these values as required by the product or the process. The time may vary from a few hours to several days. Other data such as product temperatures and process condenser temperatures can also be recorded and logged. 

 

General lyophilization process  

The lyophilization process generally includes the following steps: 

• Dissolve the drug and excipients in a suitable solvent, generally water for injection.  
• Sterilize the bulk solution by passing through a 0.22-micron bacteria retentive filter.  
• Fill into individual sterile containers and partially stop the containers under aseptic conditions.
•  Transporting the partially stoppering containers to the lyophilizer and loading them into the chamber under aseptic conditions.  
• Freezing the solution by placing the partially stoppered containers on cooled shelves in the freeze-drying chamber or pre-freezing in another chamber.  
• Apply the vacuum to the chamber and heating the shelves to evaporate the water from the frozen state. 
• Complete stoppering of the vials usually by hydraulic or screw rod stoppering mechanism installed in the lyophilizer. 

Lyophilized product characteristics 

• Chemically stable  
• Intact cake  
• Sufficiently dry  
• Free of particulates  
• Uniform appearance  
• Reasonable reconstitution time 

 

Advantages 

• Removal of water at low temperature.   
• Thermolabile materials can be dried.   
• Good for oxygen or air-sensitive drugs.  
• Rapid reconstitution time.  
• Constituents of dried material remain homogeneously dispersed. 

 

Disadvantages 

• Many biological molecules are damaged by the stress associated with freezing, freeze-drying, or both.   
• Volatile compounds may be removed by high vacuum.  
• Cost may be an issue, depending on the product.
• Long a time process.

 

Conclusion 

This process is applicable to manufacture pharmaceutical products that are heat sensitive or unstable in an aqueous solution but are stable for a long period in a dry state. Lyophilization is a common method for the manufacturing parenteral when aqueous solution stability is an issue but cost-intensive. Certain drugs such as Penicillin, cephalosporin, erythromycin, chloramphenicol, etc. which are unstable in solution form are lyophilized when formulated as parenteral. Lyophilization generally increases the shelf-life of the pharmaceutical drug. Hence, one of the key objectives during freeze-drying process development is to minimize the drying time. 

 

Reference 

Pandhare, S., Harwalkar, M., Mahale, N., & Chaudhari, S., (2019). Lyophilization process of Pharmaceuticals, World Journal of Pharmaceutical Research, 1991-2000.