Formulation | A Perfect Formulation

Semi-solid delivery design can give APIs their best chance for success

All images courtesy of Particle Sciences

Ostwald ripening is a thermodynamically driven process that is of special concern with sparingly soluble and amorphous materials.

Formulation excipients often make up over 99% of a drug product. Although technically referred to as inactive ingredients, the excipients make up the delivery system and play a key role in a drug product’s efficacy. A properly designed formulation should optimize the active pharmaceutical ingredient’s (API’s) therapeutic impact, delivering it to the right place, at the right time, in the right amount. A poorly designed formulation may partially or even totally mask the effectiveness of an API. For a variety of reasons, however, formulation is often ignored or is considered late in the development process, lessening the chances for a synergistic formulation and API combination. A formulation can and should be more than just a mode of transportation from package to patient.

The term semi-solid may be applied to any preparation that exhibits the behavior of a solid at rest but behaves as a liquid upon application of some external force such as shear.1 Semi-solids include aqueous-based gels, oil/hydrocarbon-based ointments, pastes, and emulsions of either the water-in-oil or oil-in-water variety.

Semi-solids are an extremely versatile dosage form and have been used for virtually all routes of application, including topical, mucosal, ocular, parenteral, and oral. Semi-solids allow direct application to the intended treatment site rather than through the indirect systemic route, increasing local benefit while minimizing toxic side effects. The drug must be delivered to the target site in a stable, bioavailable form; this delivery is the formulation’s job.

In a semi-solid formulation, the API may be present in solution, suspension, or some combination of the two states. Ultimately, the decision to use solution rather than suspension is dictated by the API’s inherent solubility characteristics, the desired release kinetics, and the dose volume/concentration required.

It is estimated that up to 40% of new APIs are poorly water-soluble, so an API may not possesses sufficient water solubility to dissolve into a simple aqueous gel.2 It is intuitive that solubilized API is more bioavailable, though there are pitfalls to consider. A solubilized API may precipitate out of solution upon application, yielding large crystals or polymorphs. This could occur due to solubility limitations upon interaction with bodily fluids or tissues and may give rise to reduced bioavailability or safety concerns. Alternately, an API may be so well solubilized in the formulation that it has no thermodynamic driving force to migrate from the formula into the tissue to achieve therapeutically relevant levels.

The surface area of the particulate is inversely proportional to its effective diameter, and bioavailability generally increases with surface area. Therefore, if an API is present as a suspension, reducing its particle size normally improves bioavailability. Particle size reduction can be accomplished using several top-down techniques such as simple grinding, wet-milling, or jet-milling, processes in which existing larger particles are reduced in size. Alternately, when top-down techniques do not provide the desired size, a bottom-up procedure such as controlled precipitation, in which particles at the desired size are grown from the solution state, may be used.

For an API whose synthesis process provides poor control over particle size, simple milling may often provide sufficient uniformity and homogeneity in the final formulation. The common potential pitfalls of particle size reduction include generation of polymorphs and Ostwald ripening. Ostwald ripening occurs when larger particulates grow over time, either by direct contact or by drawing material from the smaller particulates through limited solubility in the medium (see Figure 1, above).3 This is a thermodynamically driven process and is of special concern with sparingly soluble materials as well as amorphous materials. By its nature, milling may convert an API into the amorphous form—or induce amorphous regions—thereby increasing the potential for Ostwald ripening.

Overall, the particle size achieved is often dictated by the properties of the API itself, by its inherent amenability to particle-size reduction, and its stability at that size. Some applications, such as ocular formulations, may require nano-sized API particulates in order to avoid irritation. If required size is dictated by intended use, reducing particle size will be the driving concern in the formulation process and can become a very complex development issue. If that is the case, this issue should be addressed as early in formulation development as possible. Because of these issues, all APIs should be characterized both before and after any particle size manipulation.

Characterization of Particulate APIs

Proper dispersion is a three-step process. One step is wetting, in which the active pharmaceutical ingredient particle is dispersed into the liquid phase and its surface is covered completely with the suspending liquid.

Whenever an API is present as a suspension in the drug product, particle size distribution (PSD) and particle morphology should be well characterized. Because the PSD can drive a number of drug product properties, a thorough understanding of PSD in the final drug product is mandatory for bioavailability, stability, and possibly regulatory concerns. An API that exists as needles, for instance, may not be acceptable for delivery to sensitive mucosal or ocular tissues.

For semi-solids, an in vitro release test can measure the effect of particle size on API release from the formulation, though this will only be a relative measurement. It can, however, be useful as a development tool for establishing the relationship of PSD to drug release for a specific API/formulation.4

Once the desired particle size and shape are defined and characterized, the particles must be properly dispersed and stabilized in the formulation to achieve maximum benefit.

Particulates in the dry state, especially very fine sizes, almost always exist as agglomerates, clusters of small primary particles bound together, usually loosely but sometimes tightly. Proper dispersion is a three-step process involving wetting, de-agglomeration, and stabilization (see Figure 2, above). 5

Wetting is the process of dispersing the API particle into the liquid phase and covering its surface completely with the suspending liquid, including the spaces in between primary particles. This dispersion may be achieved by simply adding the API particulates to the suspending liquid, or it may require the use of a surfactant or a second liquid that has low contact angle with the particle surface. This is especially necessary when trying to wet a highly hydrophobic API into water, for example.

Wetting the particulates is followed by de-agglomeration, putting energy into the system to break the agglomerates into their primary particles (see Figure 3, p. 30). This technique can be facilitated by a surfactant that lowers the energy required, though proper formulation will always employ the minimum amount of surfactant needed.

Finally, once the particles are de-agglomerated, they must be stabilized against re-agglomeration. This may be accomplished by using the same surfactant that was used to wet and de-agglomerate the particles or by using a dispersant. Another, though less elegant, method for stabilizing the particles involves de-agglomerating them and then increasing the formulation viscosity to physically trap the particles in the dispersed state.

Regardless of the final particle size in the formulation, the PSD of a drug product formulation should always be well characterized and monitored over time during stability assessment. Though many instruments and methods designed to measure PSD exist, achieving precise and reproducible measurements is not always straightforward, especially in situ. Proper measurement of PSD often requires confirmation with multiple methods and extensive expertise in the limitations and interpretation of the data derived from those different methods. Control and characterization of PSD, an increasing regulatory concern due to the need to assure that the drug product provides consistent performance, have been the downfall of many efforts.6

Types of Semi-Solid

De-agglomeration puts energy into the system to break the agglomerates into their primary particles.

Formulations

The optimal type of semi-solid formulation depends on the combination of the API’s characteristics and the point of application. Pastes and ointments represent the simplest systems and may present a lower risk of adverse reactions because they contain fewer ingredients. They are also the least elegant, however, and, as such, present compliance issues. Additionally, such simple systems present the least opportunity to utilize the formulation itself as an active, contributing part of the drug product.

Aqueous gels and emulsions are more complex delivery vehicles and provide greater potential to enhance the impact of the API. Aqueous gels are usually the simpler of the two systems and are very amenable to mucosal delivery. Emulsions are more elegant for topical applications and can provide better patient compliance. Emulsions also provide the possibility to solubilize or isolate the API in one or the other phase of the emulsion. This can be done to try to minimize interactions with other formulation components or to maximize formulation stability. Properly formulated emulsions have roles in all avenues of drug delivery.

As an early step in formulation development, evaluation of the compatibilities of excipients with each other and with the API should always be performed. Excipient compatibility is often neglected due to tight timelines or budgets, but this step almost always saves time in the long run. Excipient incompatibility that may otherwise take months to appear in the formulation can be avoided early in the development process. It should be noted that excipient compatibility testing is useful but not foolproof.

Occasionally, incompatibilities show up even when a proper screening program has been conducted. Sometimes this is due to reactions that are set in motion only by a particular combination of ingredients and are missed in traditional compatibility programs.7 Increasingly, statistical design is employed to more thoroughly screen ingredients and pick up these secondary and higher order interactions. Because it is not always possible to predict where the formulation pathway may lead, several rounds of excipient compatibility testing may eventually be required.

Though not always easy, excipient compatibility should be as close as possible to expected use conditions, including pH and concentration. To minimize development and regulatory approval time, only excipients within their concentration limits, as listed in the Food and Drug Administration’s inactive ingredient list, and previously approved for a given route of administration should be used.

Rheological Properties

A formulation’s rheological profile should be dictated by its end use and should be considered and targeted prior to the onset of formulation development.

The proper rheological profile (see Figure 4, p. 31) for the formulation should be dictated by its end use and should be considered and targeted prior to the onset of formulation development. Formulating to optimize the desired rheology is often a complex process and must take into consideration the requirements for stability, dispensing from the primary packaging, application to the site of administration, and behavior once applied, including drug release. For example, a drug product intended to be spread over a large area of skin should flow and spread easily under the conditions of application, whereas a nasal spray should shear thin to facilitate spraying but may be required to "re-set" to prevent dripping once it is in the nose.

The water-soluble polymeric thickeners used in the formulation determine the rheological properties of aqueous gels and, for the most part, oil-in-water emulsions. For emulsions, there is an additional contribution from the concentration of the dispersed oil phase, especially at high oil-phase volume fraction. Choosing the correct thickener and concentration provides the ability to precisely tune the rheological behavior of the formulation according to end-use requirements. Many times, a combination of thickeners can provide a behavior that would not be possible with a single material. Water-soluble thickeners are available as non-ionic or ionic species and can, with thoughtful formulation, provide properties from thick liquids to rigid gels.

A properly designed formulation should optimize the API’s therapeutic impact, delivering it to the right place, at the right time, in the right amount.

An important point to consider when choosing a thickener system is the effect of bodily fluids on the formulation at the point of application. Salts and other materials present in these fluids may have significant effects on the thickener, which may lead to drastic changes in the rheological properties. Also, if the API is in suspension, it is critical that the rheological properties are sufficient to keep the particulates in suspension without settling, creaming, or stratification.

A thickened formulation without the proper thixotropy or pseudoplastic (shear-thinning) characteristics may slow the settling of the API but will not prevent it in the long term. One can often re-suspend particulates with simple shaking, but "shake before use" instructions are generally undesirable. Ideally, for optimal resistance to particulate API migration, the thickener system employed should exhibit Ellis plastic flow, a shear-thinning behavior that requires a certain amount of shear to initiate flow.

In contrast, the rheological properties of water-in-oil emulsions are mainly controlled by the ratio of the internal phase (water) to the external phase (oil), in parallel with the size and uniformity of the emulsion droplets. The overall viscosity of a water-in-oil emulsion may also be adjusted by the addition of soluble waxes to the oil phase during processing to thicken or gel the oil phase. The concentrations of waxes used should be kept at a minimum, however; they can make the formulation sticky or "draggy" upon application, an important consideration if the emulsion is to be applied topically. Although water-in-oil emulsions can provide the most elegant formulations for skin application, as demonstrated by their wide use in the personal care industry, they are not as easy to tailor for a preparation with stringent rheological requirements.

In the end, the rheological properties of the formulation should be measured and well characterized. Complex rheological characterization is a very useful tool both to predict and to monitor the stability of the formulation over time.

Microbial Preservation

Preservatives should be chosen carefully to assure adequate broad-spectrum antimicrobial effectiveness at the lowest concentration possible; they are among the ingredients most associated with perceived and real adverse reactions and, to some extent, incompatibility with other formulation components. Once the formulation is defined, preservative effectiveness should be confirmed using United States Pharmacopeia antimicrobial effectiveness testing. The requirements for microbial preservation differ depending on whether the formulation is intended as a single- or multiple-dose product.

Increasing the complexity of a formulation will always increase the potential of API stability issues, adverse side effects such as irritation, and potential complications in the regulatory path.

Beyond the basic formulation considerations and design, further formulation components may be used to maximize the potential benefit of the delivery vehicle to the overall performance of the drug product.

In addition to thickening properties, water-soluble polymers may also be used to provide the added benefit of bioadhesive properties for mucosal applications. Used in this way, the long polymeric chains penetrate and become entangled within the body’s mucus network. An array of water-soluble materials specifically designed to serve this function, such as polycarbophil, can be found. Choosing the correct one involves a thorough understanding of the various underlying chemistries; the choice should always be based on a proper pre-formulation screen.

Many materials can be included to enhance API penetration and bioavailability. The choice of penetration enhancer will depend greatly on the API’s properties, the type of formulation, and the point of application. Mechanisms of penetration enhancement are based on either modification of the receptive tissue barrier, solubilization of the API, or a combination of the two. A successful penetration enhancer may range from something as simple as propylene glycol to specifically designed components like diethylene glycol monoethyl ether.

Keeping the formulation as simple as possible, while achieving the specified performance targets, should be the fundamental philosophy driving formulation. Additional excipients should only be included in a formulation if they provide a defined and demonstrated benefit. Increasing the complexity of a formulation will always increase the potential of API stability issues, adverse side effects such as irritation, and potential complications in the regulatory path.

Finally, unlike formulations in the personal care industry, seldom are pharmaceutical formulations’ aesthetic and tactile properties taken into account during semi-solid drug product development. More appealing products result in better compliance—a critical determinant for a successful clinical trial as well as for market adoption. n

Gwozdz is director of formulation services at Particle Sciences. Reach him at ggwozdz@particlesciences.com or (610) 861-4701.

References

1. Srivastava P. Excipients for semisolid formulations. In: Katdare A, Chaubal MV, eds. Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems. New York: Informa Healthcare USA Inc.; 2006:197-223.

2. Lee RW. Case study: development and scale-up of NanoCrystal particles. In: Burgess DJ, ed. Injectable Dispersed Systems: Formulation, Processing, and Performance. Boca Raton, Fla.: Informa Healthcare USA Inc.; 2005:355-370.

3. Nancollas GH. The growth of crystals in solution. Adv Colloid Interface Sci. 1979;10:215.

4. Fan Q, Mitchnick M, Loxley A. In vitro release testing: the issues and challenges involved in in vitro release testing for semi-solid formulations. Drug Deliv Technol. 2007;7(9):62-66.

5. Fairhurst D, Mitchnick MA. Fundamentals of particles in liquid dispersion. In: Lowe NJ, Shaath NA, Pathak MA, eds. Sunscreens: Development, Evaluation, and Regulatory Aspects. 2nd ed. New York: Marcel Dekker; 1997:324-350.

6. United States Food and Drug Administration. Center for Drug Evaluation and Research. Guidance for Industry: Nonsterile Semisolid Dosage Forms: Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation. FDA. Available at: http://www.fda.gov/CDER/guidance/1447fnl.pdf. Accessed March 18, 2009.

7. Moreton RC. Excipient interactions. In: Katdare A, Chaubal MV, eds. Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems. New York: Informa Healthcare USA Inc.; 2006:93-107.