1.3 Drug Product Formulation
1.3.2 Formulation Development
As discussed above, formulation development typically starts with consideration of the solubility of the drug as it might relate to the mode of delivery. This analysis leads formulators to the type of dosage form required. Each dosage form requires a series of excipients or other ingredients that are not the active ingredient but are justifi ed for the development of that dosage form (Rowe 2012 ). In any parenteral formulation, the use of nonessential ingredients should be avoided. This section presents general considerations for several types of excipients, including buffering agents, tonicity agents, antioxidants, preservatives, and bulking agents.
1.3.2.1 A Note on Excipients
When selecting excipients, the formulator should assure that any considered excipi-ent is approved for use by the FDA. New excipiexcipi-ents can be used, but they will require extensive toxicological evaluations in order to prove safety. The FDA pro-vides an inert ingredient database ( http://www.accessdata.fda.gov/scripts/cder/iig/
index.cfm ) that lists excipients and the ranges of their use in approved products.
Selecting from and conforming to this guide will help minimize development time and reduce the expense of additional toxicological studies.
Other chapters in this book will address the details for developing the various dosage forms. Remington’s pharmaceutical handbook may also be a great help to the pharmaceutical formulator (Gerbino 2005 ). This chapter, as an overview, will discuss the general excipient decisions that are typically made during the develop-ment of a parenteral product.
1.3.2.2 Buffering Agents and pH
In aqueous systems, the effect of pH must be assessed. If at all possible, the pH of the system should be set to as close as physiological pH (~7.4) as possible. However, many systems require an alternative pH in order to assure the stability of the drug itself. Thus, questions such as the following must be addressed:
• Is there a pH range where the solubility is optimum?
• Is there an optimum pH for stability?
By preparing multiple solutions representing a pH range and studying stability when each solution is subjected to stress conditions like heat, pH can be narrowed to an optimum range.
In addition to the pH value, the strength of the buffer used to prepare the formula-tion should also be considered in relaformula-tion to the locaformula-tion of the injecformula-tion or dose. For example, if the dosage form is intended for intravenous use, the buffer capacity of the product should be considered relative to blood (Ellison et al. 1958 ). If the pH of the formulation is similar to blood, this concern is less of an issue. However, if the pH of the formulation is substantially outside the physiological range, the buffer strength of the formulation should be suffi ciently low to ensure no signifi cant change to the blood at the site of administration.
A pH analysis should be made for other delivery routes as well (Agarwal et al.
2002 ; Irani 2008 ; Moskowitz et al. 2007 ). Each delivery route (inhalation, intrathe-cal, intra-articular, ophthalmic, etc.) has specifi c issues that must be addressed with regard to pH and buffer capacity.
Typical buffers used in parenteral systems include phosphate, citrate, and acetate buffers (Gerbino 2005 ). Sodium or potassium salts are also commonly used. Buffer choice depends on compatibilities of the buffer system and the type of process intended for manufacture. For example, phosphate buffers are typically not used for lyophilized materials because the pH changes dramatically over the course of the very low temperatures experienced in the lyophilization process. Similarly, acetate systems are not always used in lyophilization because the acetate buffer may tend to fl ash off during the lyo process.
The analyses discussed above apply to both the biocompatibility of the formula-tion to the patient and to the stability of the drug substance. In addiformula-tion, proteins and peptides are particularly sensitive to pH and to buffer choice (Carpenter and Manning 2002 ). Small shifts in pH and slight differences in buffer materials can result in undesirable unfolding and, consequently, instability or inactivity of the molecule. Often, protein and peptides are also sensitive to the overall ionic content of the formulation. Hence, care must be taken to optimize and balance the ion level in the formula while ensuring an appropriate buffer counterion and stabilizing pH.
1.3.2.3 Tonicity Agents and Osmolality
Similar to pH and buffer capacity, the tonicity of the formulation should be addressed in order to assure that the product is compatible with the tissues at the administra-tion site (Agarwal et al. 2002 ; Gerbino 2005 ; Irani 2008 ; Moskowitz et al. 2007 ).
The easiest way to assure that a drug substance is infused as an isotonic product is to administer the product in 0.9 % sodium chloride injection or in 5 % dextrose solution.
However, a more complex formulation is required at times, or a concentrated bolus dose of a solution formulation is necessary for rapid delivery. In such cases, sodium chloride is the most common tonicity-modifying agent added to the formula in order to assure biocompatibility at the injection site.
Even so, sometimes the molecule is not compatible with the chloride or the ions in general. In those cases, sugars are often used, in particular mannitol or trehalose.
These sugars offer the advantage of having no troublesome ionic content that can affect molecules, in particular proteins and peptides. In addition, sugars offer an aesthetically pleasing cake for lyophilized products.
Regardless of the tonicity agent used, a target range from ~275 to ~320 mOsm/
kg is typical for formulation development. This target range ensures that the tissues at the injection site will not be disrupted and that the drug product will not be pain-ful during administration.
1.3.2.4 Antioxidants
Oxidation of the drug substance is a common challenge during the development of many drug products (Gerbino 2005 ; Tonnesen 2004 ). The simplest way to minimize oxidation is to replace the oxygen in the package with an inert gas such as nitrogen or argon. The headspace of the vial/container can be replaced with nitrogen during the fi lling process. If the drug substance is more sensitive, then the bulk product vehicle is sparged with nitrogen during the processing in order to displace the oxy-gen and minimize any degradation occurring during manufacturing.
In some instances, nitrogen sparging or headspace replacement is not suffi cient to ensure the long-term shelf life of the product. In these cases, additional excipients must be added to scavenge the free radical oxygen atoms and prevent the degrada-tion of the drug. Components such as butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) might be added. Typically, only very low levels of these excipients are used. The range tends to be between 0.0003 and 0.03 %. Extremely oxygen-sensitive products may benefi t from an antioxidant such as bisulfi tes; how-ever, the patient population must be considered in order to avoid reactions.
In addition, the product may be sensitive to trace metals that may cause oxidative reactions with the drug. Ethylenediaminetetraacetic acid (EDTA) is a good chelator at low concentrations. Citric acid may also be used to chelate metals, thereby improving the stability of the drug in the product.
1.3.2.5 Preservatives
If the product is intended for a multiple use presentation, an antimicrobial preserva-tive should be considered (Meyer et al. 2007 ). Care should be taken here in consid-ering the patient population. For example, neonates can react to benzyl alcohol, a commonly used antimicrobial preservative.
Cresols are also used for their antimicrobial properties. In particular, metacresol is common in biotechnology products. Benzalkonium chloride is also used in vari-ous parenteral applications such as ophthalmics and inhalation solutions. In addi-tion, methyl and propyl parabens are also sometimes used in conjunction with each other for preservation of parenteral products.
Regardless of the preservative used, the formulator must still prove the antimicrobial nature of the excipient within the product itself. This means that the antimicrobial preservative effectiveness test should be performed on the drug product with a variety of levels of the antimicrobial present in the drug product.
For example, testing should be performed at the target level as well as several levels below the target concentration. It is not necessary to show the concentration at which the preservative effectiveness fails. However, it is important to show that the preservative system is still effective at levels far below the target level. The specifi -cation for the preservative can then be set based on the results of the antimicrobial testing. In this way, the robustness of the formulation can be proven.
However, the antimicrobial preservative test is a labor-intensive, 28-day test (Moser and Meyer 2011 ). Therefore, once the lowest level of preservative effective-ness is shown, an alternative method for confi rming an effective limit can be put into place. Typically, the alternative method is UV/HPLC. The lower limit specifi cation for the preservative is then confi rmed using this alternative test, but the alternative is predicated on the results of the antimicrobial work discussed above.
1.3.2.6 Bulking Agents and Cryoprotectants
Some products are so hydrolytically labile that they must be lyophilized to ensure long-term shelf life stability (Nail et al. 2002 ). Often, the level of drug substance in these products is in milligram quantities and is not suffi cient to provide an elegant- looking cake. Sometimes, the level of the drug substance is even microgram quantities and cannot even be seen in the vial by the clinician. Therefore, an excipient is used to create the cake so that the vial appears to have product and give a visual indication that the product is in good condition. These excipients are called “bulking agents.”
Bulking agents range from various amino acids to sodium chloride to a host of sugars. Glycine is an example of an amino acid that is used for bulking. However, amino acids are expensive. Sodium chloride can be diffi cult to freeze-dry, depend-ing on the circumstances. Therefore, sugars are the most commonly used bulkdepend-ing agents.
The most common sugar bulking agent in sterile product development is manni-tol. It is simple to handle and relatively easy to freeze-dry because mannitol/water solutions have a eutectic point just below 0 °C. Therefore, freeze-drying can be done at a reasonably high temperature and completed in relatively short periods of time.
Sucrose is also used for various protein products; however, freeze-drying sucrose- based products can be more challenging because the glass transition temperature of sucrose/water solutions changes as the concentration of sucrose increases during the drying of the water. At times, though, the use of sucrose is warranted because the stability of the drug substance is improved using sucrose rather than mannitol.
Trehalose is also used, in particular for antibody formulations such as Avastin ® and Herceptin ® . Trehalose, like mannitol, is also fairly easy to dry. The use of treha-lose is likely to become more common as the industry gains more fi eld experience with its use.
Most sugar bulking agents are also known to protect proteins and other drug substances sensitive to freezing, hence the term cryoprotectant. The alcohol groups on the sugars interact with various functional groups on the proteins, maintaining the proteins’ conformational structure during the extremes of drying. The interac-tion prevents aggregainterac-tion or agglomerainterac-tion of the protein that might be observed at the point of reconstitution. It also ensures the overall effi cacy of the drug for long- term shelf life.