The Effect of Milling on the Triboelectrification Properties of Flurbiprofen Salts - Literature review Example

The Effect of Milling on the Tribo-electrification Properties of Flurbiprofen Salts. Department 4th February 2013 INTRODUCTION Tribo-electrification is a common phenomenon that occurs in many powder handling industries such as pharmaceuticals, foods and detergents, etc. Powder handling processes such as inflated conveying, sifting, mixing and milling cause particles to make frequent contact among themselves and with the bulwarks of the processing gear. During these interfaces, charge transfer takes place through shearing, impact or friction, a process which is commonly known as tribo-electrification or tribo-electric charging. When materials become charged, their behaviour can change and as a result they can adhere to each other easier or repel other charged materials. Excessive tribo-electrification of powders can be a nuisance as it causes problems such as dust explosions, adhesion and coating or blockage of pipelines. It can also lead to powder loss and difficulties in controlling the powder flow. Pharmaceutical powders are usually partial conductors or paddings of small unit size and low bulk density, which provide idyllic environments for electrostatic effects. In the pharmaceuticals industry, the problem extends further to the end-product quality, where the tribo-electrification of powders may cause segregation. Segregation due to electrostatic effects is a relatively new area of research which has been identified as technologically important. A manifestation of this problem is susceptibility to a change in drug formulation in a number of processes such as tableting. The pharmaceuticals industry is heavily regulated with a limited number of excipients and tight limits on content uniformity, hence an in-depth understanding is very important in order to control the electrostatic effects and to ensure that the end product is effective and safe to use. The process of milling is utilised to reduce the average particle size of pharmaceutical powders. The end result is an increase in the surface area, which improves the dissolution rate and blend content uniformity. In some instances, however, milling causes triboelectrification of particles as the particles frequently make contact with each other and with the walls of the milling equipment, causing triboelectrification. Tribo-electrification refers to a process whereby two materials come into contact with one and are subsequently charged. Pharmaceutical powders are often smaller in particle size (less than 100 µm) and irregularly shaped with a low bulk density. They are prone to electrostatic charging because they normally have a high electrical resistance, preventing charge dissipation (Grosvenor and Staniforth, 1996). The behaviour of the materials after tribocharging may change, causing the materials to adhere to one and other or repel each other. Most pharmaceutical powders are inevitably charged when undergoing the process of manufacturing because of their inter-particle and particle collisions. An attractive of repulsive electrostatic forces usually results from the electrostatic charges of both positive and negative polarities. Consequently, electrostatic charging may result to segregation or agglomeration of particles in the course of powder transport, dispersion, and other usage processes. A number of studies have established that charged particles may cause contamination of tools since charged particles stick to the inner surfaces. The contaminating elements cause considerable impact on the charging process of powder and hence establish differences in charging in the course of the processing. The process of milling is usually applied in pharmaceutical manufacturing for reducing size of particles since crystallization alone cannot achieve a desirable and narrow particle size. However, milling causes generation of thermodynamically unbalanced and amorphous areas on the particles’ surfaces, which go through re-crystallisation when pharmaceutical drugs are stored. This degeneration impacts on the physiochemical properties of Active Pharmaceutical Ingredients (APIs) including physical stability, solubility, flow properties and aerosolisation characteristics, which causes significant impact on the performance of the drug product. In the process of therapeutically assembling granular solids into tablets, pharmaceutical industries undertake various manufacturing processes. Among these would be milling, which has been considered as a size reduction process that involves application of various forces on particles to produce the required pharmaceutical particulates using various mills. During milling, the powder particles could be charged either through collision or by friction. This could be either through the particles charging themselves or through these particles rubbing against the inside walls of the manufacturing vessel. Tribo-electrification causes the particles to either attract or repel other materials which eventually lead to possible outcomes such as difficulties in controlling powder flow, adhesion, blockages of pipelines and loss of powder. Various adaptations have been employed to reduce the effect of triboelectrification in pharmaceutical industries including co-milling and use of cyclone chargers, but the success rate still remains low. Flurbiprofen is a non-steroidal anti-inflammatory drug used to treat the inflammation and pain of arthritis. Flurbiprofen is a hydrophobic crystalline drug with poor compaction properties (Ramirez, 2010) with its chemical structure as shown in Fig.1 below. Figure 1: Structure of Flurbiprofen acid A series of flurbiprofen salts were formed in the past research, using flubriprofen acid and counterion bases of butylamine, AMP1, benzylamine, hexylamine, octylamine, tert-butylamine and tris(hydroxyymethyl)aminoethane.The formation of flurbiprofen salts using a selection of bases counterions was performed to improve the solubility and mechanical properties of the active drug (Ramirez, 2010). In addition, salt formation has been used to improve the physicochemical and solid state properties of an active pharmaceutical ingredient. However, very little work has been done investigating the effect of salt formation on electrostatic properties. The main aim of this project is to investigate the effect of milling on the triboelectrification of seven different Flurbiprofen-salts. Research into this aspect has not been heavily investigated or publicised and as such would be a vital contribution to the pharmaceutical industry. Understanding electrostatic properties would ensure that an improved flow is attained which ultimately may affect blend uniformity and powder compaction properties. Flurbiprofen is a hydrophobic crystalline drug with poor compaction properties. The formation of flurbiprofen salts will be performed to improve its physical properties. The preliminary results show that the active drug has a high tribo-electric charge; however, little work has been reported on the impact of salification on its tribo-electric properties. The main objective of this work is to gain a clearer understanding of the triboelectrification process of a series of Flurbiprofen salts formed and following the particle comminution process inside a stainless steel ball mill. Flurbiprofen is from family non-steroidal anti-inflammatory drugs family (NSAIDs), which is a member of the phenylkanoic acid, used in the treatment of the pain of arthritis and the inflammatory. Flurbiprofen is also applied in some kinds of throat lozenges as an active ingredient. Flurbiprofen has a low aqueous solubility (0.03 mg ml), hence it does not offer immediate relief of pain (Morimoto, 1992). Flurbiprofen (Flu) is a highly potent platelet aggregation used in the reduction of aggregation (Poul, Buchanan, & Grahame, 1993). This compound has a short half-life, which lasts for just 3 to 4 hours. Also, Flu has unfavorable physiochemical properties including low water solubility (27.7 μg/ml) and high water/oil partition coefficient [coefficient [log (KO/W) = 3.86]. These properties limit its wide transdermal application (Morimoto, 1992). Pharmaceutical salts and their use Salt is the component formed after the process of neutralization of a base or an acid. Pharmaceutical salt is used in the process of drug manufacturing. They help in converting of a basic or an acid into a salt through the process of neutralization reaction, which enhances aids in changing of the drug’s physiochemical properties. Different series of compounds can be produced by neutralizing the parent drug using different chemical species. Traditionally, this process is used to enhance solubility of drugs as well as drugs dissolution rates (Morimoto, 1992).Categorization of salts is based on the bond between the parent drug and the neutralization agent. Salts have two broad classifications including ionic and covalent. Figure 1 below shows the formation of the covalent pharmaceutical salt, which is known as flucticasone propionate. Figure 1. Formation of covalent pharmaceutical salt The salts with covalent bond are formed when the neutralization agent and the parent drug are brought together through electronic sharing. On the other hand, ionic salts do not maintain their chemical identity when dissolved. Ionic slats are formed by a chemical magnetism of neutralizing compounds and parent drugs which are oppositely charged as shown in figure 2 below. Figure 2: Formation of ionic pharmaceutical salt Under conditions of polar solutions, ionic bonds can be easily broken and reformed, a process that is highly influenced by the environmental conditions in the solution where the drug exists (5). When in solid state, the ionic salts do not necessarily exhibit their properties in solution, where in the presence of other ions the bonds can be formed and re-formed. Salt formation can become very complicated if the pharmaceutical active species possess both basic functional and multiple acidic groups in the same molecule. Drugs with at least one basic and one acidic ionisable functional group (a species called Zwitterrionic actives) can possibly form basic and acidic salts based on the environmental conditions. Most commonly, this species exists in dynamic equilibrium when in simple aqueous buffer solution (Agharkar, Lindenbaum and Higuchi, 1976). Crystallization of pharmaceutical actives is done by solution crystallization. Nevertheless, milling is preferred because it can be used to obtain a particle size range unlike Solution crystallization, which is faced with difficulties of controlling particle size (Chikhalia et al., 2006). This process helps in lowering the strength of the product, which is a means of controlling the dose and reducing its side effects. Also, the service area can further be increased through milling, which results in the formation of interparticular bonds lessening the density of tablets (De Gusseme et al., 2008). Improvements on mechanization have been achieved through product injectability and effectiveness of procaine penicillin G intramuscular suspension (Ober et al., 1958). Milling of Xemilofiban helps to form agglomerates when it is being processed – this achieves the required particle size (Mackin et al., 2002). In addition, extraction of crude vegetable drugs and animal glands can be achieved through milling the particle to an optimal size. The stability of pharmaceutical solids is increased through the removal of the occluded solvent by drying them and then taking them through a process of mechanization. Also, milling has been very useful in tablet manufacturing since it facilitates drying of wet masses following the process of granulation, which reduces the distance for the solvent to easily access the outer surface as well as amplifying the surface area (Cooper and Rees, 1972). Manufacturing of DPIs and metered dose inhalers (MDIs) can be done by equipment such as air jet milling. LiCalsi and Research team (2001) established that measles vaccine fine particles can be obtained by use of jet milling; they added that this could be further made into a powder aerosol system, which is used for immunization. However, the process of milling did not stimulate significant physical adjustments while making sure that viral potency and standard dose content were maintained. Elsewhere, Steckel and coworkers (2006) have made comparisons between use of fractionated and milled lactoses by use of filtered lactose for the preparation of DPIs. An improvement in aerosolization behavior was experienced following the use of milled and fractioned lactoses. The outcome was believed to result from the finest material produced in the course of milling, sticking to the surfaces of the larger particles preventing the drug from being fastened on the surface crevices of the lactose particles. In their study on micronised revatropate hydrochloride Ticehurst and co-workers (2000) established that a jet milling’s optimization of micronisation could aid in achievement of a respirable fraction of the drug. The micronized drug could be delivered in a suspension-MDIs or DPIs since it was found to be physically stable. In most cases, pharmaceutical powders are made of small particles of shielded material, which are usually in contact with the surface of their container or each other’s particles. As a result of this contact, the electrons are subjected to exchange of electrons during various processes that take place. This exchange of electrons takes place as a result of the differences between the contacting mediums. The differences in the contact mediums are caused by the diversity of the contact materials as well as the diversity in sizes of particles, roughness, and surface among other properties. Reduction of drugs particles increases the service area such that the particles have a large capability of having contact with the dissolution medium. Consequently, the dissolution swiftness is enhanced, which is directly correlated with the streamline layer which is in contact with the solid when the solvent is moving through the solid. This also causes a concentration gradient alongside the dissolution medium Electrostatic charging of particles leads to change of behavior of particulate solids causing them to adhere to each other or repel other charged materials. When tribo-electrification occurs in excess, it could also lead to dust explosions, blockage or coating of pipelines or even loss of powder and difficulties in the control of powder flow (Matsusaka et al., 2010). In the pharmaceutical industry, pharmaceutical powders are usually semiconductors or insulators of small particle size and low bulk density, providing ideal conditions for electrostatic effects (Supuk et al. 2009). Milling Milling is commonly used in medication additional production for reducing particle dimension crystalline active medication substances (APIs) as it is difficult to achieve a filter compound dimension submission via crystallization alone. However, milling leads to generation of thermodynamically volatile amorphous areas on compound areas which undergo re-crystallization on storage of medication products. This reversion affects physicochemical qualities of APIs such as solubility, actual balance and flow qualities actions gradually impacting performance of the medication product. Literature reports the use of co-milling in successfully enhancing solubility and actual balance of various APIs. Milling in pharmaceutical secondary manufacturing generates amorphous regions on the surfaces of the particles that exhibit thermodynamic instability that causes re-crystallization upon storage. Without the presence of any electric fields, charging would occur either through friction or contact between two solid surfaces. While contact charging would encompass direct contact followed by subsequent separation of surfaces without any rubbing, frictional charging would call for relative movement of the contacting surfaces. During milling, the contact between the particles that rub against one another and against the walls of the vessel leads to tribo-electrification of the materials being milled. Anderson (2012) defines tribo-electrification as the ability of pharmaceutical powder to pick up charges when in contact with other materials which causes poor mixture of particles, especially the small ones. Manufacturing processes such as milling cause frequent contact among the particles and with the walls of the vessels. These interactions lead to charge transfer through friction, impact and shearing, a process referred to as tribo-electric charging or tribo-electrification (Supuk et al., 2011). According to Crowley and Zografi (2002). Pharmaceutical particulates could be produced either through constructive or destructive methods. Constructive methods include freeze-drying, supercritical fluid techniques and crystallization. Of these three, the latter has been widely applied where the solid crystals would be produced by cooling, precipitating, evaporating or adding a solute or solvent in a liquid solution. This would cause nucleation which would result in crystal growth. Also, known as lyophilisation, freeze-drying involves freezing, sublimation then finally secondary drying. Using supercritical fluids, re-crystallization would occur through precipitation. Carbon dioxide has been commonly used as a supercritical fluid due its low critical temperature of 310C and also because it is inexpensive, non-toxic and non-flammable. Milling refers to the process of mechanically reducing the size of active pharmaceutical ingredients, APIs that are highly potent. In pharmaceutical milling, particles greater than 20 meshes would be produced through coarse milling, 200 to 20 mesh particles would be produced by intermediate milling and particles less than 200 mesh produced through fine milling. The aim of this would be to reduce the sizes and increase the surface area of these ingredients. Milling could be accomplished through communion, impaction, compression, shearing, attrition, cutting or grinding. The particles would, therefore, be subjected to a combination or one of compression, shear or tension forces. While compression crushes, shear and tension forces cut and elongate or pull apart respectively. The purpose of milling would be for these forces to increase the initial flaws that always exist on the particles. Above the yield value, the particles experience permanent deformation, hence the milling process (Crowley and Zografi, 2002). The rate of reduction depends on the initial size of the material, the reduction machine used, the material orientation in the machine and the period of subjection. The properties of the particles to be milled such as stickiness, moisture content, soapiness and hardness should be considered before embarking on the milling process. The choice of milling equipment would depend on the material type, its initial size, the material’s moisture content, the final size of the product needed and the range of abrasion. Coarse crushers do not have any use in pharmacy. Hammer and cutting mills constitute intermediate crushers while ball, fluid energy and oscillating granulator mills make up the fine crushers. Colloidal mills are also a classification of milling equipment. Advantages of milling The advantages of this process include increased rate of dissolution hence enhanced bioavailability. More so, milling improves important aspects in pharmaceutical manufacturing processes such as extraction rate, drying rate and flow rate. It improves mixing of ingredients so as to reduce discrepancies in content and weight uniformity of tablets. This ensures that dispersion of active ingredients and colors in tablet recipients dilutes is uniform. Finally, this process controls the distribution of particle size in dry granulation so as to limit segregation during handling and tableting. Limitations of milling Kwok, Glover and Chan (2005) observe possible disadvantages of milling which include the possibility of change in the API’s polymorphic form which limits its stability. Heat build-up during milling observed by Pu, Mazumder and Cooney (2009) could degrade the drugs through adsorption or oxidation as a result of increased surface area. Flow rate could also be limited due to decreased bulk density. Of importance to this paper would be the disadvantage of creation of static charge due to reduction in particle size which could lead to agglomeration of small drug particles which effectively reduces the surface area. This could further limit dissolution. Although milling is applied in very many processes, it is disadvantageous because it stimulates disorders in the crystal composition of molecular particles. This process is very difficult because the nature of these disorders is not well-understood; it therefore becomes hard to control for optimizing a formation set of rules (De Gusseme et al., 2008). The efficacy of the drug could also be affected by these disorders. These disorders may also cause undesirable changes such as polymorphic transformation, amorphous transformation, dehydration and chemical instability. Electrostatics and tribo-electrification During the process of pharmaceutical processes, the generation of electrostatic charges or static electrification is unavoidable. Examples of these processes include coating, milling, mixing of powder, spray drying, powder transport, and melt agglomeration. The generation of electrification also takes place during formulation of interactive mixtures for DPIs (Chow et al., 2008). Electrostatic charges is caused by, tribo-electrification, which results from contact charging or the charging from frictional impacts such as impaction, rolling, sliding or rubbing. When to materials that is of different characteristics meet and the part ways, this results to contact electrification, which leads to transfer of charge from one source to the other (Bailey, 1984). Therefore, a net charge is caused when two materials are set apart. The exchanging of charges serves to compensate the differences of surfaces. However, the contacting mediums can remain unchanged and the back flow disabled the severance of the mediums takes place very fast. The contact charging was first experienced in pharmaceutical sciences in the late 19th century, when it was thought that it could have had a strong effect of inter-particle forces (Bailey, 1984; Krupp, 1967; Lifshitz, 1956; Visser, 1972). The reason for this perception was because opposite charged particles tend to pull each other and hence boosting cohesion and slowing down flow ability. Some studies in early days established that electrostatic charges are produced when insulating materials are brought into contact before being set apart once more (Harper, 1967). However, real charge only occurs only when at least one of the contacting mediums is an electrical insulator. The contact charge is dissipated immediately by an electrically conducting material. The charge, which is transferred is opposite in the contacting bodies, though it is equal. Also, two uncharged particles with different work functions can experience charge transfer (Zeng et al., 2000). Work function represents the least amount of energy needed to get rid of the weakest electron from its location. Therefore, electrons are moved to a function with the lower work function of the substance with a higher work function (Bailey, 1993). Based on these rules, Elajnaf’s group (2006) suggested a triboelectric sequence where the substance with the highest sequence, but with a lower work function would experience the highest level of electropositive charge when it came in contact with the substances in the lower sequence. The study of Elajnaf (2006) and Eilbeck (1999) revealed that the generation of electrostatic charge was reliant of charge from the surface of the container as well as from the powder charge. This charge transfer requires free energy levels, though it can also be formed by the occurrence of displacement of impurities on the surface of the container (Bailey, 1984; Chow et al., 2008). Tribo-electrification becomes more difficult in presence of particulate systems whereby constraints such as time, area, contact pressure, and frequency are hard to quantify (Rowley, 2001). Contact surface characteristics such as surface texture, surface resistivity and contamination and particle properties such as surface resistivity, crystal properties and size as well as atmospheric conditions have been known to control the charging process (Elajnaf et al., 2006). The impacts of electrostatic charging have been studied on different pharmaceutical processes with the aim of improving the strength of the formulations. Bennett and a group (1999) studied the impact of particle size on the tribo-electrification of carriers for DPIs and found that mixes of fine particles lactose with coarser lactose reduces the enormity of the charge of coarser lactose in respect to mixing. Elsewhere, Chow’s group (2008) found that when RH was increased to 80%, the static charge of bulk lactose was considerably lowered while the dynamic charge of lactose exhibited a straight increase with RH. Charging of particles leads to their change of behavior causing them to easily adhere to each other or cause repulsion of other charged materials. When tribol-electrification occurs in excess, it could lead to adhesion, dust explosions, blockage or coating of pipelines or even loss of powder and difficulties in the control of powdery glow (Matsusaka 2010; Pingali, Tomassone&Mizzio 2010). In the pharmaceutical industry, “pharmaceutical powders are usually semiconductors or insulators of small particle size and low bulk density, providing ideal conditions for electrostatic effects” (Supuket al. 2011, p.209).Therefore, tribo-electrification could lead to segregation which compromises the quality of the end product. This would be manifested through susceptibility to change in the formulation of drugs in different processes like tableting. The pharmaceutical industry operates under tight regulations that tightly monitor uniformity in content, thus the need for controlling electrostatic effect and ensuring that the end product meets safety and effectiveness standards. According to Anderson (2012), there would be a huge cost to pay in case of failure to control the physical form of APIs hindering adherence to the required standards which would result into the interruption of clinical trials or a ban on sale of such drugs. Supuket, Seiler and Gadara (2009) argue that understanding the magnitude of charge would be useful in developing pharmaceutical formulations which involve mixing of APIs and excipients so as to avoid loss of particles through wall adhesion. The accumulated charges in a silo during the loading of powder could cause high electric potentials on the surface of the heap which could cause electrostatic discharges. With higher discharge energies exceeding the powder’s minimum ignition energy, the heap could self-ignite. This would be particularly risky with dust clouds or flammable vapors in the vicinity. While attractive forces cause agglomeration of particles hence inhibited flow, repulsive forces reduce the density of the bulk powder and the powder blends’ physical stability. This affects formulation doses metering and filling of containers during manufacturing (Pu, Mazumder& Cooney 2009). To minimize the effect of tribol-electrification, Supuket al. (2011) proposes particle charging with opposite polarity so as to form stable ordered mixtures which minimize segregation. Studies by Matsusakaet al. (2010) indicate that co-milling stable amorphous with appropriate additives effectively minimized surface electrostatic charging. But cases have been recorded where both components have charged with same polarities hence propagating the adherence of particles to the inner walls of the vessels as opposed to adherence among the particles themselves. This could probably explain the popularity of cyclone charger as a tribo-charging device that has interchangeable polymers and steel contact surfaces. Particles would be introduced through the sides using a carrier gas and would be charged through collision with the inside surfaces of the case cyclone charger. Nonetheless, this still suffers from the openness of its system with the risk of being exposed to active pharmaceutical ingredients, APIs. METHODOLOGY Experiment Outline A series of flurbiprofen salts were initially formed by combining flurbiprofen acid with a closely related series of amine counterions. The salts were then recrystallized in methanol, dried in Gallenkamp oven and milled using a single ball mill at 10 Hz. To investigate the tribo-electrification of bulk powders due to multiple contacts, a Retsch MM400 shaking machine has been modified where 100 milligrams of sample powder are placed in a 10ml container, which is subjected to shaking. The sample material is hence shaken, at a frequency of 20Hz during which it is impacting alternately against the rounded ends of the container. Preliminary data Salt formation was confirmed using Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FT-IR), and X-Ray Powder Diffraction (XRPD). Upon salt formed by the addition of the Union countries, the melting points of the salts (obtained by DSC). Project Plan A charging profile for each sample will be obtained following shaking at 0.5, 2, 5 and 10 minutes, with the charge-to-mass ratio (nC/g) documented for each material. The tribo-electrification of the salts will then be compared to Flurbiprofen itself. Formation of Flurbiprofen salt The ingredients for this salt include an acid called flurbiprofen (FBP) (244.26 g/mol), and bases such as butylamine, hexalamine, benzylamine , octylam, tert-butylamine, trishydroxymethyl and aminomethane. The solvents include acetonitile (Fisher Chemical), cyclohexalamine, methanol and n-hexylamine. To prepare the salt, the Equimolar (0.01 mole) of acid plus base were properly weighed and mixed at 261 delta range balance. The acid was dissolved in 40 ml acetonitrite while the base was dissolved in 40 ml acetonitrite. The two solutions are mixed thoroughly in a beaker and stirred continuously. The precipitate is then filtered using vacuum filtration and then dried overnight under vacuum using an oven. To confirm that the salt is being formed, Retch mm400 single ball is milled for some minutes. Formation of FBP Tris salt FBP(244.26 g /mol) is mixed with Tris (121.74 g/mol) to form 40 ml of acctonitrite. This is watched with 40 ml of warm methanol for 2 hours at 500 c. A vacuum filtration is done using stuart vacuum pump RE3022C. REFERENCES 1. W R HARPER. (1970). Triboelectrification. Physics Education. 5, 87-93 2. .水口, 仁, SATO, Y., ITO, S., UTA, K., & J. MIZUGUCHI. (2009). Electrical and Thermal Properties of Azo-Metal Complexes used as Charge-Control Agents. Journal of Imaging Science and Technology, 53(1): 010504-1-010504-9. Society for Imaging Science and Technology. http://hdl.handle.net/10131/7373. 3. MCCOWN, R., GROSS, F., & CALLE, C. (2006). Medium velocity impact triboelectrification experiments with JSC Mars-1 regolith simulant. Journal of Electrostatics. 64, 187-193. 4. MORALES AM, KIVILCIM M, PEYMAN GA, MAIN M, & MANZANO RP. (2009). Intravitreal toxicity of ketorolac tris salt and flurbiprofen. Ophthalmic Surgery, Lasers & Imaging : the Official Journal of the International Society for Imaging in the Eye. 40. 5. RAMIREZ, M., CONWAY, B., & TIMMINS, P. (2008). Solubility enhancement of flurbiprofen by salt formation. Journal of Pharmacy and Pharmacology. 60, 69. 6. LI, Q., TSUJI, H., KATO, Y., SAI, Y., KUBO, Y., & TSUJI, A. (2006). Characterization of the transdermal transport of flurbiprofen and indomethacin. Journal of Controlled Release.110, 542-556. 7. Agharkar, S., Lindenbaum, S .and Higuchi, P. , 1976. Enhancement of solubility of drug salts by hydrophilic counterions: Properties of organic salts of antimalarial drug. J. Pharm. Sci.65, pp.747-749. 8. Grosvenor, M.P., Staniforth, J.N., 1996. The influence of water on electrostatic charge retention and dissipation in pharmaceutical compacts for powder coating. Pharm. Res. 13, pp. 1725-1729. 9. Matsusaka, S., Maruyama, H., Matsuyama, H. and Ghadiri, H., 2010. Triboelectric charging of powders. a review, Chemical Engineering Science 65, pp. 5781–5807. 10. Morimoto, Y., Hatanaka, T. and Sugibayashi, K., et al., 1992. Predictionof skin permeability of drugs: comparison of human and hairless rat skin. J. Pharm. Pharmacol, 44, pp. 634-639. 11. Pingali, K.C., Hammond, S.V., Muzzio, F.J., Shinbrot, T., 2009. Use of static eliminator to improve powder flow. Int. J. Pharm. 269, pp.2-4. 12. Poul, J., Buchanan, N. and Grahame, R., 1993. Local action transcutaneous flurbiprofen in the treatment of soft tissue rheumatism. Br. J. Rheumatol, 32, pp.1000-1003. 13. Ramirez, M. , 2010. Mechanical Properties of Flurbiprofen. Salts, PhD. Thesis, University of Aston (2010), Birmingham, UK Read More