Injectable products require a unique formulation strategy. The formulated product must be sterile, pyrogen-free, and, in the case of solution, free of particulate matter. No coloring agent may be added solely for the purpose of coloring the parenteral preparation. The formulation should preferably be isotonic, and depending on the route of administration, certain excipients are not allowed. The injected drug by-passes natural defense barriers; hence, for any given drug, the risk of an adverse event may be greater or the effects difficult to reverse if administered as an injection rather than a non- Parenteral route. For this reason, ultra-high purity grades of excipients are available for parenteral administration.
Excipients are the integral part of pharmaceutical product development to achieve the desired product profile (stability and efficacy). Selection of excipients in a lyophilized formulation employs a need based approach, to develop a simple, stable and elegant formulation, with an economical process.
The following key points should be considered in selecting excipients for lyophilized products:
Influence of excipients on the overall quality, stability, and effectiveness of drug product
Compatibility of excipient with drug and the packaging system
The amount or percentage of excipients that can be added to the drug product
Route of administration
Whether the product is intended for single or multiple dose use
Excipients Used in Lyophilization
Bulking agents form the bulk of the lyophilized product and provide an adequate structure to the cake. These are generally used for low dose (high potency) drugs that per se do not have the necessary bulk to support their own structure. These are particularly more important when the total solid content is less than 2%. In such cases, a bulking agent is added to the formulation matrix. The structure of the lyophilized cake is important, since proper cake formation leads to proper pore formation that provides the means for vapor to escape from the product during the drying cycle. Loss of product structure blocks the path for vapor removal leading to an increased resistance in moisture removal and thus higher moisture content in the final product. Such localized high moisture content may lead to degradation of the active pharmaceutical ingredient during the shelf life.
Control of pH is critical to avoid degradation of drug during processing, storage and reconstitution, thereby necessitating addition of buffering agent in the lyophilized formulation. The choice of buffer depends on the pH stability profile of active ingredient as drug needs to be reconstituted and stored for some time before it could be administered to the patient. For this purpose, the pH of maximum stability of drug should be known and maintained. Selection of a suitable buffer and its concentration is important for sensitive molecules.
The buffering agent should have a high collapse temperature, be non-volatile and have a high glass transition temperature (Tg). A high collapse temperature would facilitate a faster primary drying, and its non-volatile nature would prevent pH drift, that might be detrimental to the product stability. Additionally, a high glass transition temperature (Tg) would ensure stability during storage.
Collapse temperature modifiers
Lyophilization of amorphous material requires the primary drying temperature to be kept below the collapse temperature of the formulation. However, some excipients in amorphous state have a very low collapse temperature, thus increasing the duration of primary drying significantly. In such case, collapse temperature modifiers are utilized, which shift the overall collapse temperature higher (owing to their high individual collapse temperatures), with a consequent reduction in the primary drying cycle, without compromising the product quality. Commonly used collapse temperature modifiers are dextran, gelatin and hydroxyethylstarch. However, it must be noted that their use in lyophilized formulations is not very frequent.
Parenteral formulations should be isotonic with human plasma so as to avoid damage to the tissues. However, not all drugs at their recommended dosage are isotonic with blood, thus requiring the addition of a tonicity adjusting agent to the formulation. The most commonly used tonacity agent is dextrose, while others, such as glycerol and sodium chloride are less commonly used. The addition of tonicity modifiers to the lyophilization mixture, however, can complicate the formulation development, since they may lower the collapse temperature of the entire formulation owing to their very low collapse temperatures, thus increasing the primary drying time significantly. An alternative approach is to add the tonicity modifier to the reconstitution diluent rather than the freeze dried product.
Antimicrobial agents are added to multi-dose formulations to prevent microbial growth during its shelf life. Benzyl alcohol and a mixture of ethyl- and methyl- parabens are commonly used. Additionally, phenol and mcresol are utilized in lyophilization. At very low levels, antimicrobial agents generally do not alter the collapse temperature of the formulation. Compatibility of antimicrobial agent with other ingredients in the formulation needs to be checked, when to the lyophilized cake. However, since the antimicrobial agent is not needed during the lyophilization process antimicrobial agents are often typically included in the diluent for reconstitution.
Surfactants may be added at low levels to aid reconstitution if the drug does not show good wetting behaviour. Surfactants are added to low dose products to minimize losses due to surface adsorption. Their addition in large quantity is not recommended due to the low glass transition temperature of commonly used nonionic surfactants. They can be included in the diluting medium so as to keep the lyophilized formulation simple.
Water is the most commonly used solvent for lyophilization. However, organic solvents are sometimes used to increase the primary drying rate by increasing the sublimation rates, improve product stability, decrease reconstitution time by improving drug wettability or solubility, and also enhance the sterility assurance of the sample solution. Since lyophilization works on the principle of vapor pressure differential, it is necessary for excipients to have low vapor pressure, to minimize their loss during the lyophilization
process. However, co-solvents are added due to their high vapor pressure to facilitate faster removal from the product during drying process and thus speeding up the lyophilization process.
Complexation is sometimes used to improve the solubility of drug in the solvent especially water. The addition of complexing agent may, however, lead to a reduction in the critical temperature of the formulation, thus complicating the formulation development.