This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.
Surface chemistry is a phenomenon formulation scientists have endeavoured to consider and explore for thousands of years since the early days of alchemists, and still do today. It deals with the study of incidences that occur at the surfaces (or interfaces) of substances; concepts include adsorption, heterogeneous catalysis, colloid formation, nanonisation, crystallisation, solubilisation, and liposome encapsulation among others, some of which are critical to achieving the desired effects 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 and porous silicone systems which can overcome problems like solubility, toxicity and bioavailability.
A 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 their 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 [  ].
Figure 1 shows forces at bulk and surface:
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 (see fig. 1)[  ]. We call these residual asymmetric forces at that are at a relatively high energy, this causes adhesive forces between phases at surface. Solid surface energy is often greater than the surface tension of a typical liquid. The binding or adsorption of gases is strongly favoured by either chemisorption (chemical bond formation) or by weak van der Waals interactions that cause physisorption (physical adsorption) [  ]. The need to measure and control these unbalanced forces and consider surface tension in pharmacokinetics are critical in the delivery of drug compounds in vivo (Lipinski, 2000). 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. Pharmacodynamics is dependent on the 'drug-like' properties, route and physicochemical characterization of the drug. Surface phenomena and selective drug formulation consequently play a significant role in how the drug may reach the site of action; it includes the use of excipients and active ingredient to work together in formulation to achieve 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 [  ]. 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 to improve 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[  ] 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 to overcome the main burden to drug bioavailability, which is poor water solubility.
Applications of Adsorption in Surface Science
Surfaces, are relatively unstable, they contribute positive free energy of formation 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, of a gas/liquid 'adsorbate' over the surface of a liquid/solid 'adsorbent'; occurring due to tendency to attract adsorbate molecules and retain them at surface, minimising 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 in water purification or even in the selective removal of toxins in poison/overdose treatments. Charcoal is reported to have been used by the ancient Egyptians to cure a range of ailments, although 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/surface area/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 ways 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. Patients can even formulate it as a topical agent for insect stings by adding water to the powdered form to make a topical paste. Adsorption is widely used in the removal of coloured dyes in solution to improve the aesthetics of drug products, and in Heterogeneous catalysis, extremely important in industry e.g. contact process for catalytic adsorption in production of sulphuric acid, which has many uses in drug formulation. Importance of chemical purification through adsorption in formulation technique ultimately means higher drug safety standards can also be preserved.
The types of adsorption include physisorption or chemisorption which is more common in drug formulation, 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.
Figure 2 shows how discovery of Porous Silicone can be used in formulation for successful drug delivery:
Other important applications of adsorption include the control of humidity with Silica and aluminium gels, used as adsorbents for removing moisture. As a novel drug formulation recent investigation in Porous Silicone (pSi) is thought to have significant potential as a drug vehicle as surface modifications 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 systemic circulation as the matrix begins to degrade [  ]. Native pSi has been used to successfully deliver a number of drugs, 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 [  ].
By developing a number of surface modification methods (see fig. 2) [  ], pSi clearly demonstrates how the need to understand surface chemistry can be vital in the progressive use in specific applications and thus become increasingly useful in a wide range of fields, especially drug delivery.
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 (internal phase, such as insoluble drug compound) microscopically dispersed evenly throughout continuous phase. Colloid and surface scientists seek to understand how the chemical and physical nature of the interface, between components, determines the stability of the resulting colloidal system.
By chemically modifying the surface of substances or by adding other components to modify interactions between the constituents, such as 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)
Novel 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 identified by high throughput combinatorial screening programs are poorly water soluble [  ].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.
Surfactant Choice 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; they act as solubilisers, stabilisers, emulsifiers and wetting agents in formulation. When surfactants are dissolved in water they orientate at the surface so that the hydrophobic tail regions are removed from the aqueous environment [  ], (see fig. 3)[  ], 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.
The surface activity of any particular surfactant depends on the balance between its hydrophilic and hydrophobic properties. An increase in the length of the hydrophobic hydrocarbon chain increases the surface activity and affects solubility. This relationship between is expressed by Traube's rule . The four categories of surfactant are: Non-ionic, Anionic, Cationic and Zwitterionic.
Non-ionic surfactants are the most commonly used in pharmaceuticals systems due to their stability, low toxicity and compatibility with other excipients, owing to them containing no charged moieties but retaining hydrophilic properties of hydroxyl groups in their head group. E.g. Polyoxyethylene (POE) sorbitan fatty acid esters are commonly found in oral, parenteral and topical formulations they are valuable emulsifiers for pharmaceuticals and cosmetics, allowing solubilisation for water insoluble substances such as vitamins, essential oils, fragrances, tannins, etc. [  ].Â
Anionic surfactants have negatively charged head groups, they contain carboxylate groups and include use in soaps and sulphates e.g. Sodium lauryl sulphate used as emulsifiers and solubilisers in pharmaceutical systems [  ]. Cationic surfactants have positively charged groups, their use in drug formulation is limited as they absorb easily onto negatively charged substrates such as skin, hair and glass, giving them limited use as preservatives against microbes where they adsorb readily into cell membrane causing lysis [  ] allowing increased shelf life of a formulation. Zwitterionic surfactants are pH dependant, exhibiting both cationic and anionic properties; they are very surface active and useful as emulsifiers. E.g. Lecithin is a phospholipid that is a good emulsifier of lipids and cholesterol, when combined with bile salts it can form mixed micelles that are effective solubilisers for cholesterol [  ].
Route of administration is important considering haemolytic potential of surfactants in parenteral formulation [  ] and additional toxicology studies may be appropriate as using surfactants or co-solvents in microemulsions can leads to increased side effects and organic residues, e.g. HP-Î²-cyclodextrin causes nephrotoxicity of itraconazole [  ]. Analytical chemistry is involved in the determination of which surfactant is best to use essentially based on drug solubility, tests methods include simple dissolving of solid drug in aqueous phase until the drug cannot dissolve further [  ]. To supplement the choosing process we must understand the physical compatibility of drug in surfactant solution with a compatibility study involving crystallisation, phase separation and colour change.
Figure 4 shows oil in water micelle encapsulation:
Micelles Formation and Nanoparticles
The use of surfactants opens up the curious 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. 4)[  ] that reduce surface tension, allowing encapsulation and dispersion of drug ingredients in solution to overcome limitations of bioavailability due to insolubility. Oil-in-water aggregates form (as in fig.4) because the hydrophilic heads congregate together in contact with the aqueous phase to form a sphere with the non-polar lipid hydrophobic tails concealed on the inside. In water-in-oil aggregates the micelle is inversed with the heads forming an inward sphere and tails protruding, they're more unstable in drug formulation and tend to have problems with oral absorption.
Through the intelligent use of this surface phenomenon it is possible for drug encapsulation within the micelle sphere which acts as an emulsifier for the hydrophobic drug compound by itself being solubilised and dispersed in the bulk solvent. 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 are required to build successful systems in formulation.
A good example of micelle use is in menopausal treatment by transdermal administration of micellular nanoparticle (MNP) Estradiol and Nicotine, both use nanotechnology-based formulations that have 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 [  ]; it allows for high concentrations of active ingredient to penetrate the skin for systemic therapy, avoiding contact with the GI tract and hepatic first-pass metabolism, also as a patch it is more accepted by 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.
There are some obstacles that occur with micelles as they only form when critical micelle concentration (CMC) and Krafft temperature are reached; hence there are limitations to what can be done in drug formulation due to the poor thermal properties and chemical stability.
Figure 5 shows liposomal drug encapsulation with PEG coating and homing peptide used in drug delivery:
Liposomal Delivery and STEALTH Liposomes
Similar advanced models of drug delivery that are of great importance in surface chemistry include the incorporation of liposomes. They are artificially prepared vesicles composed of naturally occurring phospholipids that arrange as lipid bilayers 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. 5)[  ] to overcome solubility issues.
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 [  ]. 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. 5). Drugs with intermediate logP partition between the lipid and aqueous phases easily, present in either the bilayer or in the aqueous core [  ]. 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 systemic antifungals such as Amphotericin-B, and parenteral Morphine as post-surgical analgesics [  ]. Multi-vesicular liposomes are imperative in making longer acting controlled release formulations possible.
Exciting advancements in STEALTH liposomal technology have been manufactured using surface techniques that avoid immune detection. Pegylated-STEALTH liposomal Doxorubicin (Doxil, Caelyx) was the first liposomal anticancer drug to be approved by the FDA indicated for metastatic breast cancer [  ]. Stealth liposomes are constructed with Polyethylene Glycol (PEG) studding the outside of the membrane; 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 (immune response) [  ]. Likewise a biological species such as monoclonal antibodies, antigens, or vitamins are attached to the liposome surface as a ligand in order to enable binding via the precise expression on the target drug delivery site. 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 bioavailability, improved therapeutic index, and potentially overcoming the restrictive immune resistance associated with the typical anticancer agents. Liposomes retain the drug payload during circulation and accumulate in tumour tissue possessing increased microvascular permeability. Future research by surface scientists can seek to investigate at what amount of PEG coating actually hinders binding of the liposome to the elected delivery site, something critical to the development of more efficient, less intrusive chemotherapy.
Figure 6 shows how surface area increase by micronisation/ nanonisation can be used to increase dissolution rate:
There are many organic systems that have been devised and understood as covered in this review. A novel way of preparing drugs for formulation still in development today is the adoption of nanoparticles in medicine to overcome the hurdles of bioavailability and immune-resistance. The focus is on drug molecules that are difficult to formulate using conventional approaches, such as in cancer therapy. 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 [  ]. The ability to make nanoparticles to exact specifications and to precisely govern their form size, surface charge and other properties at the nanoscale opens up the opportunity to carry drugs to new places and give them new functions. Nanoengineered drug carriers can slip selectively into cancerous tissue, or protect the drugs they carry from being destroyed before they reach their destination [  ]. 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 and hence increasing surface area according to the Noyes-Whitney equation (Noyes and Whitney, 1897). Therefore, for this particular purpose, several industrial approaches are used such as jet-milling, high pressure homogenisation, and spray-drying to achieve size reduction by micronisation and nanonisation (see fig.6)[  ].
The formulations consist of dispersion media, drug, and excipients. In the form of liquid dispersions "nanosuspensions", stabilised by surfactants or polymeric stabilizers they exhibit an acceptable shelf-life and can be post processed into various types of solid dosage forms. The crystalline form known as nanocrystals, have been shown to improve bioavailability and enhance drug exposure for oral and parenteral dosage forms. Drug nanocrystals are composed of 100% drug. The size reduction leads to an increased surface area and therefore enhanced bioavailability.
Overall, the ideal attitude for scientists is that any effective novel drug compound should rarely be considered ineligible for development and stringently pursued to overcome its formulation challenges and limitations through the clever manipulation of surface chemistry, addition of excipients, or exploiting physicochemical properties; the key strategy is to find the best combination of active ingredient and excipient substances that neither sacrifices drug efficiency nor effectiveness, yet are administered to patients with ease and thus well received in terms of compliance.
As has been demonstrated in this critique, the world of drug formulation is exciting and ever expanding, and with the right use of surface phenomena and further revolutions in delivery systems, it may be possible to further progress in the pursuit of impeccable medicines that not only treat symptoms and are easy to take, but that also are so on target that therapeutic limitations and adverse effects become a thing of the past.
Word count ~ 3300