Practical Aspects of Freeze-Drying of Pharmaceutical and Biological Products Using Non-Aqueous Co-Solvent Systems

Practical Aspects of Freeze-Drying of Pharmaceutical and Biological Products Using Non-Aqueous Co-Solvent Systems
Winter 2003
Dirk L. Teagarden, Ph.D.
Pfizer Global Pharmaceutical Sciences, Department of Sterile Products Development
APR
Introduction
Freeze drying of pharmaceutical and biological solutions to produce an elegant stable powder has been a standard practice employed to manufacture many marketed pharmaceutical and biological products for over half a century. The majority of these products are freeze-dried from simple aqueous solutions. Water is typically the only solvent of significant quantity that is present which must be removed from the solution via the lyophilization process. However, frozen water (ice) is not the only frozen liquid which can sublime under reduced pressures. Numerous organic and mineral solvents have been shown to possess this property [1]. It should be noted that during the freeze-drying of pharmaceutical or biological products it is not atypical for small quantities of organic solvents to be present in either the active pharmaceutical ingredient or one of the excipients. These low levels of organic solvent are commonly found because they may be carried through as part of the manufacture of these individual components since the ingredient may be precipitated, crystallized, or spray dried from organic solvents. Therefore, many freeze-dried products may be dried from solutions which contain low levels of a variety of organic solvents. Additionally, there may be instances where freeze-drying from substantial quantities of organic solvents or mixtures of water and organic solvent may offer the formulation scientist advantages over simply drying from an aqueous solution. An example of at least one pharmaceutical product on the market which has utilized an organic co-solvent system during freezedrying is CAVERJECT? Sterile Powder [2,3]. This particular product has been successfully manufactured by freeze-drying from a 20% v/v tert-butanol/water co-solvent system.
There are many reasons why it may be beneficial to both product quality and process optimization to select a lyophilization process which employs a strictly organic or organic/water co-solvent system. A list of some of these potential advantages include: increases rate of sublimation and decreases drying time, increases chemical stability of the pre-dried bulk solution, increases chemical stability of the dried product, facilitates manufacture of bulk solution by increasing drug wettability and solubility in solution, improves reconstitution characteristics (e.g., decreases reconstitution time), and enhances sterility assurance for pre-dried bulk solution. However, the development scientist must be aware that use of these organic/water co-solvent systems can cause a multitude of problems. A list of some of these potential disadvantages include: toxicity concerns, operator safety concerns due to high degree of flammability or explosion potential, lack of compendia grades or monographs, may require special manufacturing facilities/equipment or storage areas, possess difficult handling properties, requires high purity solvent with known impurities at low levels, must reach acceptable residual solvent in final product, high cost to use, potential for splash/spattering of product in vial neck, and lack of regulatory familiarity. When developing a new freeze-dried product it is critical to evaluate and gain a proper understanding of the fundamental interrelationships between the formulation, the process, and the package since all must work in unison for a successful product to be developed. The knowledge gained from the interrelationships enables optimization of the formulation which can be successfully manufactured and packaged in a production scale setting. These same principles apply to the use of organic solvents in freeze-drying. The advantages and disadvantages for a particular organic co-solvent system must be carefully weighed before they are selected for use in the manufacture of a pharmaceutical or biological product, especially one that is an injectable dosage form.
Several pharmaceutical and biological products or drugs in various stages of formulation and/or clinical development have been manufactured via a process which required freeze-drying from organic cosolvent systems. These types of solvent systems were chosen for one or more of the advantages described earlier. Table 1 contains a list of examples of a few drug preparations which have been evaluated.
Additional uses for the technique of freeze-drying from organic cosolvent systems, other than in the manufacture of pharmaceuticals and/or biologicals, includes the preparation of biological specimens or the preparative isolation of excipients such as lecithin. The biological specimens can be prepared by lyophilization from organic cosolvent systems in order to improve specimen preservation for scanning electron microscopy examinations [4-6]. Tert-butanol appears to be the major organic solvent selected for this use. The surface structure of the specimen remains intact when employing rapid freezing followed by freeze-drying from an appropriate organic solvent such as tert-butanol [7]. The phospholipid, lecithin, has been shown to be readily prepared in a solvent free form via lyophilization from cyclohexane [8] or from benzene or ammonia [9].
David Baker [10] recently discussed the details of how freeze-drying with non-aqueous solvents affects the frozen matrix, process development, and formulation selection. Specifically he presented how use of co-solvents in lyophilized formulations impact the process by facilitating the manufacture of the bulk solution, stabilizing the bulk solution, influencing the freeze-drying process via its impact on the freezing process, ice structure, and accelerating the sublimation rate. This paper will concentrate on presenting the remaining practical issues surrounding the use of non-aqueous co-solvents for potential marketed product manufacture and regulatory evaluation/approval.
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