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Surface chemistry is a phenomena formulation scientists have endeavoured to consider and explore for thousands of years since the days of alchemists, and still today. It deals with the study of incidences that occur at the surfaces (or interfaces) of substances; concepts include adsorption, heterogeneous catalysis, colloid formation, corrosion, crystallisation, solubilisation, and liposome encapsulation among others, some of which are critical to achieving the desired effect of current drugs. I will be looking further into the understanding of these phenomena and their integral role in development of effective novel drug formulations; such as by the use of STEALTH liposomal delivery systems and porous silicone vehicles which overcome problems like solubility and bioavailability.
Figure 1 shows forces at bulk and surface:
The surface is defined as a physical boundary between any condensed phases, like liquid, gas or solid states of matter. They separate one phase from the other and occur all around us, hence manipulation is critical in the midst of developing cutting edge medication that allow for optimum pharmaceutical outcomes from new and current drug formulations. The advancement achieved in surface chemistry has led to countless applications in a multitude of industries, for example, interfaces are critically important in biomedicine, biotechnology and pharmaceutics. There is a growing need for specific interfacial consideration that can be used routinely to solve pharmaceutical problems and improve product quality (Azarbayjani et al., 2009).
Such examples of interfaces include that which exist between oil and water in emulsions, metal and gas in nanoparticle technology, liquid and gas in aerosols etc. The atoms at surface display unique properties that are different to those atoms in bulk, whereas atoms in bulk are surrounded in all directions and have balanced forces of attraction; atoms at surface do not have a full complement of neighbours, the effect of which is unbalanced forces acting from outside. We call these residual asymmetric forces at that are at a relatively high energy, this causes adhesive forces between phases at surface (see fig. 1). In solid surfaces the electronic and crystallographic structure also differs and their surface energy is often greater than the surface tension of a typical liquid. The binding or adsorption of gases is strongly favoured at the surface by either chemisorption (chemical bond formation) or by weak van der Waals interactions that cause physisorption (physical adsorption) (Birdi et al., 1997). The need to measure and control these unbalanced forces and consider surface tension in pharmacokinetics are critical in the delivery of drug compounds, major applications in pharmaceutics ensure that a drug can be safely delivered to its site of action at a dose and rate that minimises side-effects and maximises therapeutic effects, without compromise of overall efficacy. Pharmacodynamics is dependent on the pharmacological properties, route and physicochemical characterization of the drug. Surface phenomena and selective drug formulation in specific dosage forms consequently play a significant role in how the active ingredient may reach the site of action, it includes the use of excipients and active ingredient to work together in formulation to maximise the desired therapeutic response, taking all pharmacological considerations into reason.
Research & Development and Rising Costs of Drug Formulation
Enormous sums of money are driven in by drug companies to research and develop these drugs and formulations. In some cases, delivery and targeting barriers may be so great as to preclude the use of an otherwise effective drug candidate (Hillery et al., 2001). The purpose of any delivery system is to enhance or facilitate the action of therapeutic compounds taking into account the carrier, the route, and the target. Ideally, using precise surface theory, a drug delivery system could deliver the correct amount of drug to the site of action at the correct rate and timing, bringing both therapeutic and commercial value to its health care product. Drug delivery has evolved into a strategy of processes or devices designed to enhance efficacy through controlled release, this may involve enhancing bioavailability possibly through the manipulation of surface chemistry and improving therapeutic index, Flynn defined this as "the use of whatever means possible, be it chemical, physiochemical or mechanical, to regulate a drug's access rateâ€¦" This proves the argument that it is important that every formulary selection is scrutinised, and surface chemistry seems to be a recurrent principle when making decisions, so the need to understand new concepts is compelling if not for the sheer amount of money invested by pharmaceutical companies in new formulation development, in a study called The Price of Innovation (DiMasi et al., 2003) it was estimated that new drug development costs at clinical trials were $802 Million, which certainly highlights the absolute need for financial worth owing to sound scientific research that unquestionably involves surface chemistry at each step. Furthermore, this is backed up by the increasing development of new formulations that capitalise on traditional surface phenomena.
Applications of Adsorption in Surface Science
Surfaces, formed by an endothermic process, are relatively unstable and involve positive free energy of formation. Surfaces contribute this energy to the total system, which may be unfavourable in drugs and needs to be minimised by either reducing surface area, altering spatial arrangement of surface particles or by making attractions with other compounds, such as excipients.
Applications of surface chemistry in industry include the use adsorption by the accumulation of a gas/liquid 'adsorbate' over the surface of a liquid/solid 'adsorbent'; occuring due to the positive free energy available that has tendency to attract adsorbate molecules and retain them, minimising the residual free energy. In practice, adsorption techniques could be used for removal of impurities from solutions e.g. Activated charcoal (oxygen treated charcoal) is used in chemical purification processes as a porous solid adsorbent, allowing removal of contaminants whether in water purification or even in selective removal of toxins in overdose treatments. Although charcoal is reported to have been used by the ancient Egyptians to cure a range of ailments, with our increased understanding of the surface science behind this chemisorption process, it has led us to the production of much superior treatment options; we now know factors like particle size/flow rate/exposure through the charcoal besides low pH and temperature will increase adsorption, therefore considering these pharmacological and physicochemical properties it has been possible to formulate suitable oral drugs e.g. Charcadote oral suspension indicated for treatment of poisoning by method of adsorbing toxic chemicals and safely removing them in waste. Such drug formulations are readily available and easy to take in an emergency, particularly important for children who are at higher risk to poisoning from household products. We can now also formulate as a topical agent for insect stings by adding water to the powdered form. Adsorption is also widely used in the removal of coloured dyes in solution to improve the aesthetics of drug products perhaps increasing compliance in general. Most notably, with the removal of any impurities through this formulation technique then ultimately drug safety can be improved and higher safety standards put in place.
The types of adsorption include physisorption (physical adsorption) or chemisorption (chemical adsorption) which is more common in drug formulation. The table 1 highlights their differences.
Table 1: Comparison of Physisorption and Chemisorption
1. Arises because of van der Waals' forces.
1. It is caused by chemical bond formation.
2. It is not specific in nature.
2. It is highly specific in nature.
3. It is reversible in nature.
3. It is irreversible.
4. Depends on the nature of gas. More easily liquefiable gases are adsorbed readily.
4. Depends on the nature of gas. Gases which can react with the adsorbent show chemisorption.
5. Enthalpy of adsorption is low, 20-40 kJ mol-1
5. Enthalpy of adsorption is high, 80-240 kJ mol-1
6. Low temperature is favourable for adsorption. It decreases with increase of temp
6. High temperature is favourable for absorption. It increases with the increase of temperature.
7. No appreciable activation energy is needed.
7. High activation energy is sometimes needed.
8. It depends on the surface area. It increases with an increase of surface area.
8. It also depends on the surface area. It too increases with an increase of surface area.
9. It results into multimolecular layers.
9. It results into unimolecular layer.
Colloidal Chemistry in Product Formulation
An interesting use of surface chemistry in drug formulation is the use of colloidal chemistry. A colloid is a substance (the internal phase, such as an insoluble drug compound) microscopically dispersed evenly throughout another substance (continuous phase). Colloid and surface scientists seek to understand the chemical and physical behaviour of various combinations of gasses, liquids, and solids. The chemical and physical nature of the interface between components determines the stability of the resulting colloidal system, hence, could be used in helping drug delivery for various new and existing dosage forms, particularly for problematic drug compounds.
By chemically modifying the surface of substances or by adding other components to modify interactions between the constituents, such as surfactants or surface active agents, the stability and performance of the resulting colloidal system can be enhanced; relying heavily on a large surface area: volume ratio. Table 2 shows the uses of colloidal systems in everyday product formulations.
Table 2: Uses of Colloidal Systems in Everyday Products
None (too miscible)
Applications of Surface Phenomena in Drug Formulation
In the application of drug formulation surface properties and their influence play an important role in improving bioavailability and solubility. More than 40% of compounds are identified by high throughput combinatorial screening programs as poorly water soluble (Speiser et al., 1998). Surface concept can be valuable for highly reactive chemical compounds allowing for their adsorption between two phases using suitable excipients to reduce surface tension and increase solubility in new formulations, I will be looking at the existing and future developments in drug formulation designs that embrace surface science to overcome limitations and benefit the value of a drug.
Surfactants in Dosage Forms
Adsorption differs to absorption, which is a bulk phenomenon, occurring in surfaces instead. The concept of adsorption is thus an important one identified in surfactants which are an ever-increasingly used excipient in drug formulation; uses in pharmaceutical products include laxatives, emulsions and cosmetics. When surfactants are dissolved in water they orientate at the surface so that the hydrophobic tail regions are removed from the aqueous environment (Schramm et al., 2003), (see fig. 2), surfactant molecules adsorb at the water surface replacing some of the molecules in the surface and consequently reduce surface tension as forces of attraction between surfactant and water molecule are less than between two water molecules, hence contraction force is reduced. With immiscible oil-water phases the interfacial tension which arises because of a similar imbalance of attractive forces, will be reduced by this adsorption forming films or lipid membranes, such as liposomes/micelles which can be used in drug encapsulation.
There is equilibrium between surfactant molecules at the surface of the solution and those in the bulk of the solution which is expressed by the Gibbs equation. The surface activity of a particular surfactant depends on the balance between its hydrophilic and hydrophobic properties. For a homologous series of surfactants: An increase in the length of the hydrophobic hydrocarbon chain increases the surface activity. This relationship between is expressed by Traube's rule (Attwood et al., 2012), which states that 'in dilute aqueous solutions of surfactants, the molar concentrations required to produce equal lowering of the surface tension of water decreases threefold for each additional CH2 group in the hydrocarbon chain of the solute', this is certainly a consideration for scientists when dispersing drugs in emulsions for use as topical agents.
Surfactants are particularly useful for water insoluble drug formulations, acting as solubilisers, stabilisers, emulsifiers and wetting agents. Analytical chemistry is involved in the determination of which surfactant is best to use based on drug solubility, tests methods include simple dissolving of solid drug in aqueous phase surfactant (at room temperature or temp. higher than solid surfactant melting point) until the drug cannot dissolve further, if required solubility can be enhanced further to improve formulation by adding a co-surfactant to a surfactant solution, this may be particularly useful for mixed micelle/emulsion drug formulations. To supplement the choosing process a drug-surfactant compatibility study must be done by precipitation/crystallisation, phase separation and colour change to reveal physical compatibility, and chemical stability of drug in surfactant solution.
They are known permeation enhancers therefore route of administration must also be taken into account considering the haemolytic potential of surfactants in parental formulation (Ross et al., 2004). Additional toxicology studies may be appropriate especially for oral dosage forms where non-approved pharmaceutical surfactants are used. Once decided, the surfactant can usually be used as a key primary stabiliser in prototype formulation tests where excipients such as sweeteners (for oral dosage) or tonicity agents (for parental dosage) can all be added together and tried.
Micelles and Nanoparticles
Figure 3 shows oil in water micelle encapsulation:
Using surfactants opens up the possibility of micelle drug delivery, they are relatively small spherical structures composed of few to thousands of molecules that attract one another to form structures (see fig. 3) that reduce surface tension within the surface of a cell, allowing encapsulation of drug ingredients to overcome limitations of bioavailability due to insolubility of a drug. They form when surfactant molecules reach a critical concentration (CMC) allowing organisation into micelle formation. The critical micelle concentration is the concentration above which micelle formation becomes appreciable. The oil in water aggregate forms because the hydrophilic heads congregate together in contact with the aqueous phase to form a sphere with the non-polar lipid hydrophobic tails on the inside. In water in oil aggregates of the micelle is inversed with the heads forming an inward sphere and tails protruding due to the non-polar solvent, though they are more unstable in drug formulation and usually have problems in oral absorption. Through the intelligent use of this surface phenomenon it is possible for drug encapsulation within the micelle sphere to allow for targeted drug delivery as the micelle acts as an emulsifier for the drug compound by itself being solubilised in the bulk solvent, despite the enclosed drug molecule being insoluble possibly due to its lipophilic properties. Surface factors taken into reason include solution conditions such as pH, temperature and surfactant concentration which affects shape and size of the formation, understanding these factors is required to allow the successful development of working targeted drug delivery systems. A good example of micelle use is in menopausal treatment by oral/transdermal administration of micellular nanoparticle Estradiol and Nicotine, this is a nanotechnology-based formulation that has achieved a breakthrough in transdermal therapeutics. The formulation represents a robust and versatile delivery system that can accommodate a range of therapeutic compounds having varying physicochemical properties (Lee et al., 2010), it allows for high concentrations of active ingredient to penetrate the skin, avoiding contact with the GI tract and hepatic first-pass metabolism, also it is more acceptable to patients. MNP drug delivery offers a potentially fast and inexpensive pharmaceutical development model by using drugs already proven safe and effective to create new proprietary formulations.
Further discoveries can help overcome complications that occur with micelles as they only form when CMC is exceeded and the temperature of the system is greater than the critical micelle temperature (Krafft temperature); hence there are limitations to what can be done in drug formulation due to the poor thermostability. Using surfactants or co-solvents although common, sometimes leads to increased side effects and organic residues, e.g. HP-Î²-cyclodextrin is the cause of nephrotoxicity of itraconazole in Sporanox (Willems et al., 2001). This is another limitation which surface scientists could work to overcome through better understanding of residual surface energy in complex formulation systems.
Figure 4 shows liposomal drug encapsulation with PEG coating and homing peptide used in drug delivery:
Similar advanced models of drug delivery to micelles that are important in surface chemistry include the incorporation of liposomes. They are artificially prepared vesicles composed of naturally occurring phospholipids that arrange as lipid bilayers that can also be used as vehicles for drug delivery. Liposomes are designed with the drug target in mind so could include lipid chains with surfactant properties and use of ligands to allow successful attachment to the targeted unhealthy tissue. They are pretty successful in that they can fuse with cell surface membranes to allow delivery into targeted cells without readily allowing dissolved hydrophilic solutes to pass in through it, carrying both hydrophobic and hydrophilic molecules inside the bilayer membrane (see fig. 4).
Whether the drug is encapsulated in the core or in the bilayer of the liposome is dependent on the characteristics of the drug and the encapsulation process (Lasic et al., 1992). In general, water-soluble hydrophilic drugs are encapsulated exclusively within the central aqueous core, whereas lipid-soluble lipophilic drugs are incorporated directly into the lipid bilayer membrane (as in fig. 4). Drugs with intermediate logP easily partition between the lipid and aqueous phases, both in the bilayer and in the aqueous core (Gulati et al., 1998).
Liposomal use in today's drug formulation is becoming more prevalent as scientists get to grips with pro-drugs and the factors involved with the pharmacokinetics of this system. Current liposomal drugs approved for use range from antifungals such as Amphotericin B administered parentally for systemic fungal infections or orally for treating thrush, to even liposomal delivery of Morphine as a post-surgical analgesic that maintains a therapeutic level in the bloodstream for up to 48 hours after parental administration. In a morphine sulphate formulation (DepoDur) the median diameter of the liposome particles is in the range of 17 to 23 Âµm, liposomes are suspended in a 0.9% sodium chloride solution in vials. Multivesicular liposomes are imperative in making formulations of controlled release as Morphine is gradually released from vesicles for longer duration of action.
Current advancements of Stealth liposomal technology have been manufactured by surface chemistry that avoids immune detection. Pegylated-STEALTH liposomal Doxorubicin (Doxil, Caelyx) was the first liposomal anticancer drug to be approved by the Food and Drug Administration indicated for metastatic breast cancer, (Zamboni et al., 2005). Stealth liposomes are constructed with Polyethylene Glycol (PEG) studding the outside of the membrane; in addition a biological species such as monoclonal antibodies, vitamins or antigens are attached as a ligand to the liposome in order to enable binding via the precise expression on the targeted drug delivery site. The PEG coating, which is inert in the body, allows for longer circulatory life for the drug delivery mechanism, the stabilising effect results from local surface concentration of highly hydrated functional groups that sterically inhibit both hydrophobic and electrostatic interactions of blood plasma at the liposome surface, therefore preventing opsonisation (Woodle et al., 1992). The theoretical advantages of liposomal-encapsulation and carrier-mediated chemotherapy drugs are increased solubility, prolonged duration of exposure, selective delivery of entrapped drug to the tumour site, improved therapeutic index, and potentially overcoming immune resistance associated with the regular anticancer agents, and prolonging circulation time. Liposomes retain the drug payload during circulation and preferentially accumulate in tissues with increased microvascular permeability, as often is the case of tumours. However, research in surface chemistry currently seeks to investigate at what amount of PEG coating the PEG actually hinders binding of the liposome to the elected delivery site, something critical to the development of efficient, less intrusive chemotherapy.
To deliver drugs to specific organs many organic systems have been devised, as previously explained. As mentioned previously there is, however, a novel way of preparing drugs for formulation also in the aim of overcoming the hurdle of insolubility, and this is through the use of nanoparticles. These molecules are difficult to formulate using conventional approaches and are associated with innumerable formulation-related performance issues that correlate to bioavailability. Formulating such compounds as pure drug nanoparticles is one of the newer drug-delivery strategies applied. Nanoparticles are typically defined as a discrete internal phase consisting of an active pharmaceutical ingredient having a physical diameter less than 1 micron in an external phase (Douglas et al., 1987). The formulations consist of water, drug, and excipients. In the form of liquid dispersions they exhibit an acceptable shelf-life and can be post processed into various types of solid dosage forms. Drug nanoparticles, the crystalline form known as nanocrystals, have been shown to improve bioavailability and enhance drug exposure for oral and parenteral dosage forms. The aim of formulation attempts is to increase the dissolution rate and thus to enhance absorption and bioavailability. This can be achieved by reducing the particle size in the nano-scale according to the Noyes-Whitney equation. Therefore, for this particular purpose, several industrial approaches are used such as jet-milling, high pressure homogenization, and spray-drying.
Drug nanocrystals are composed of 100% drug; there is no carrier material as in polymeric nanoparticles. Dispersion of drug nanocrystals in liquid media leads to so called "nanosuspensions" The dispersed particles are stabilised by surfactants or polymeric stabilizers. Dispersion media can be water, aqueous solutions or non-aqueous media e.g. liquid PEG, oils. The size reduction leads to an increased surface area and therefore to an increased dissolution rate (Noyes and Whitney, 1897). Therefore micronisation is a suitable way to successfully enhance the bioavailability of drugs where the dissolution speed is the rate limiting step. By the procedures of nanonisation, the particle surface is further increased and so does dissolution velocity making their comprehension of high value to scientists. The diagram below shows how surface area increases with micron/nanonisation:An external file that holds a picture, illustration, etc. Object name is ijn-3-295f1.jpg Object name is ijn-3-295f1.jpg
Other important applications of adsorption in surface chemistry include the control of humidity with Silica and aluminium gels, used as adsorbents for removing moisture and controlling humidity, this relates to novel drug formulation in the recently investigated use of porous Silicone (pSi) in drug delivery. Porous Silicone is thought to have significant potential as a drug vehicle as surface modification can be used to tailor drug-pSi interactions and by controlling drug crystallinity within the pores allows enhancement of drug solubility. Exploiting pSi for drug delivery conventionally involves loading the drug into the porous matrix which is then released into the body as the matrix begins to degrade. Native pSi has been used to successfully deliver a number of drugs (Vaccari et al., 2006), although it does possesses its limitations; it is highly reactive due to its hydride terminated surface, this can result in undesirable chemical reactions with loaded drugs. Through the exploration of surface manipulation of pSi, scientists have found that it's possible to stabilise the surface allowing for utilisation a variety of applications (Limnell et al., 2007).
The diagram below shows the modifications of pSi that make it a viable drug delivery system:
By developing a number of surface modification methods, pSi clearly demonstrates how the need to understand surface chemistry can be vital in the progress of use in specific applications and thus become increasingly useful in a wide range of fields, especially drug delivery.
Above all, the ideal formulation is one that can always overcome its limitations, whether through the manipulation of surface chemistry, addition of excipients, or physical/chemical property exploitation, the Holy Grail for formulation scientists is to find the best combination of active ingredient and excipient substances neither sacrifices drug efficiency nor effectiveness, yet is administered with ease and thus well received by the general public in terms of adherence.
As has been demonstrated in this critique, the world of drug formulation is exciting and ever expanding, and with the suitable use of surface phenomena and further breakthroughs in delivery systems, it may be possible to further progress in the pursuit of impeccable drug formulations that not only treat symptoms and are easy to take, but also are so on point that adverse effects and therapeutic limitations become a thing of the past.
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