The full version of this lyophilisation feature can be read in the March issue of our digital magazine: http://www.pharmtech.com/ptedigital0310
The term 'lyophilisation' literally means to make a substance 'solventliking'. However, the purpose of lyophilisation (or freeze drying) is not always to improve the dissolution of poorly soluble compounds; other reasons are to increase a product's shelf life or to allow storage at ambient temperatures. For instance, where the characteristics of a liquid product deteriorate out of specification within 2 months of storage, freeze drying can easily extend this to 2 years. Furthermore, changing the storage temperature of your pharmaceutical product from - 20 °C to room temperature avoids the complications of cold chain supply management, facilitates transportation of the products and increases patient compliance.
Many different pharmaceuticals are freeze dried. Lipophilic small molecules benefit from freeze drying because it creates an increased surface area of the dispersed drug in the porous cake. This can accelerate dissolution significantly and improve bioavailability. When used as an intermediate process step, freeze drying can also facilitate further handling during processing. Additionally, biological compounds, such as larger peptides, proteins and antibodies, often offer acceptable stability only as freezedried formulations.
Two of the main types of formulations that are candidates for freeze drying are liposomal formulations and microsphere formulations. Liposomal formulations are often candidates because their physical shape needs to be maintained. Lipoplexes (liposomes with additional compounds or groups attached to them) are particularly vulnerable — lipid oxidation, aggregation or leakage of the active from the inner core are all potential threats to biological activity. As a result, these formulations must often be freeze dried to preserve their initial characteristics. Because freeze drying is a water-based process, however, it is imperative that the correct excipients are selected and optimised.
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Meanwhile, microsphere formulations used for the controlled release of actives are almost always freeze dried because the formation of a dry state is the only way to prevent premature release of the active before administration. In addition, the API that is encapsulated in the microspheres may also have stability issues that require lyophilisation.
When developing a freezedried formulation, the key considerations are:
- API stability. Some compounds, such as proteins, need to be protected with special cryo and lyoprotectants during the freezedrying cycle. There are many protectants available, but not all are suitable; for example, sucrose can be a good cryoprotectant, but will exclude all diabetic patients from the pharmaceutical's target population.
- Stability of the formulation before, during and after freeze drying. To increase a product's stability, the product will need to be stable during preparation of the formulation, during filling and during the freeze drying process itself. If it shows stability issues during freeze drying, or before that, the formulation is not optimised for freeze drying and you will need to go back to the laboratory. Complex formulations, such as lipoplexes, can be susceptible to degradation. For these formulations, a protectant with a high glass transition temperature (Tg) is essential because the solid matrix needs to remain amorphous during freeze drying.
- Excipients selection. When developing the formulation, you should take into account the fact that you will be using additional excipients to specifically protect your compound during freeze drying — a broad range of sugars, polyols, polymers and oligomers is available for this purpose. When deciding which excipients to use, specific information, such as the physical properties, like the ability of protectants to incorporate the active, flexibility of the backbone of the polymer, and glass transition temperature during freeze drying, should all be considered. Furthermore, the selection of pH, anti-oxidants and/or surfactants can also greatly improve the formulation's performance. You should choose wisely because any excess excipients that are not critical may have a negative influence on your final product.
- Physicochemical properties of API. It is not only the physicochemical properties of the excipient that are important; any available information regarding the compound's characteristics, such as solubility profiles and disintegration properties— anything to complete the picture of the compound will be considered as well. For example, a protein can affect the Tg of the excipients in a completely different way than poorly soluble small molecules can. The effect of buffer salts and the Tg of the freeze concentrated fraction is then investigated using a Temperature Modulated Differential Scanning Calorimeter (TMDSC), which enables a proper starting point for the selection of the product temperature during primary drying.
- Reconstitution time. Increasing the specific surface area of the cake accelerates dissolution. Furthermore, maintaining good wettability, especially when lipophilic molecules are incorporated, is beneficial in this respect.
- Reaching acceptable water content. Lower water content reduces molecular mobility and, hence, increases shelf life.
- Economics of freeze drying. Firstly, the freeze drying cycle time is of major importance. Minimizing the volume of solution per vial reduces cake height and shortens primary drying. A shorter freeze drying cycle is essential to minimize the cost of goods. Secondly, when it comes to scaling up during later clinical development phases, it is beneficial to use a higher concentration of the formulation because you can use smaller vials and, therefore, freeze dry more vials in a single batch.
- Freezing rate. One of the most critical steps in a freeze drying process, which is often taken too lightly, is the freezing of the formulation. The freezing rate at the start of a freeze drying run can be critical with respect to phase separation and concentration gradients in the vial because it can yield more dense layers at the top of the cake, forming a barrier for water transport. Furthermore, for the API to be incorporated in the cake, it is known that freezing rates are critical.1,2 In the early feasibility stage, small freeze dryers are used and vials are frozen?— sometimes simply with liquid nitrogen. The scalability of such a method and its freezing rate is difficult to translate to a production environment where industrial scale freeze dryers are used. It helps if the freeze drying process is first developed on a laboratory scale using test runs that mimic a feasible situation in your GMP environment— various freezing rates can be accurately mimicked and controlled in the laboratory using suitable freeze dryers. The amount of vials in a freeze dryer can sometimes have a noticeable effect on the cooling capacity of the shelves.
- Clinical use. What is the dose per vial to be administered? What is the route of administration? What is the reconstitution volume and the resulting ionic strength? These questions must be answered. During clinical development, dose range finding studies can complicate the decision of vial content. Highdose products present a freezedrying challenge in the sense that the formulation does not leave much room for freezedrying agents. In this case, it is not so much the API that presents the challenge, but the concentration in which it needs to be administered.