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

The Effect of Milling on the Triboelectrification Properties of Flurbiprofen Salts Insert (s) Submission Literature review Although there have been little research on the potential effects of milling on the triboelectrification properties of pharmaceutical powders such as Flurbiprofen salts, a number of previous publications suggests that milling significantly affects a number of physiochemical properties of active pharmaceutical ingredients and this may consequently increase their surface electrostatic charge. Triboelectric charging refers to a process by which two neutral surfaces are brought into contact, transfer charges and remain charged upon separation (Greason, 2000, p.248). This literature review seeks to investigate some of the electrostatic concepts as well as the potential effects of milling on the triboelectrification properties of Flurbiprofen salts. 1. Electrostatic or Electrification Properties and Basic Concepts Electrostatics is a phenomenon which generally involves the build up of charges on the surfaces of particles and objects which are in contact with each other. One of the most fundamental equations commonly used in electrostatics is Coulombs law which effectively describe the force between any two point electric charges. According to Coulombs law, the magnitude of electrostatic force between any two point charges is dependent on the magnitude of each charge as well as the distance between the charges. Work function The concept of work function generally refers to minimum energy (in electronvolts) required to remove an electron from a solid and transfer it to any point outside the surface of the solid. Work function represents the least amount of energy needed to get rid of the weakest electron from its location. Consequently, electrons are often 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. Contact Potential difference Contact Potential difference is an important concept that can be used to measure the changes in work function of a particle surface. An electrostatic potential usually exists between any two dissimilar electrical materials (such as conductors and semiconductors with different electron work functions) which are brought into physical contact. According to Elajnaf et al. (2006, p.102), 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. The impacts of electrostatic charging have been studied on different pharmaceutical processes with the aim of improving the strength of the formulations. On the other hand, Chow (2008, p.85) 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. Electrostatic Force Electrostatic force is a physical energy that is derived from stationary or slow moving charges. According to Greason (2000, p.245), electrostatic force is the reaction that holds together electromagnetic field created by tiny subatomic particles such as protons and electrons. Although the exchange of charges normally takes place any time the two surfaces contact and separate, it is worth noting that the charge exchange effects can only be best noticed when at least one of the contacting surfaces is has got high resistance to electrical flow. This is attributed to the fact that the charges transferring to or from high resistance surfaces are more likely to be trapped for a longer time and this consequently make their effects to be more visible. Electric field Electric field is widely defined as the electric force per unit charge. The direction of electric field is assumed to be dependent on the direction of the force it is likely to exert on a positive charge (Anderson, 2012, p.67).The electric field from any given number of point charges can effectively be obtained from the vector sum of the individual fields. In this regard, positive numbers are considered to be outward fields while negative charges are in ward fields. Tribo-electrification 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 (Rowley, 2001, p.52). Particle size The size of the particle to a large extent affects the rate of particle electrification. The smaller the size of the particle the higher the rate of electrification as it has the ability to acquire more charge compared to a larger particle. In order to reduce the size powdered particles are preferred than the solid ones. (Supuk and Ghadiri,2009). Contact Area  It has been isolated that the area of contact of the particle and the material or other particle results in the particle acquiring a particular type of charge that has impact in the process of electrification of the particle. To increase the surface area of contact the particles are grinded to powder form. Solid carry with them charge from the storage container and these charges have impact in the general electrification process. Particle Shape  The shape of the particle has an effect in the electrification of the particle as these particles have varying charging behavior depending with the shape of the particle. Supuk and Ghadiri( 2009) suggests that the particle size has two aspects as it affects the mean contact area as well as time of contact that ultimately has an effect on the electrification process. The authors also argued that rounded shapes are easily electrified as compared to other shapes this is attributed to sliding contact in particles that results to increased charge. Humidity and Temperature  According to Rowley (2001, p.52), humidity and temperature have a significance impact in the electrification process. Low humidity results to slow movement of particles hence higher charger acquisition which results to high levels of electrification. Temperatures on the other hand affects the electrification process as temperature results to improved kinetics and charge flow hence affecting the overall process. Surface Contamination  Surface contamination to a large extent hinders full electrification of the particle hence affecting the charge amount acquired on the particle. This contamination also results to repulsive forces in the particle that results to particle dissociation and reduced flow. Charge Transfer Models  Charge transfer has been isolated by many scholars to be based on electron donor electron acceptor kind of association. This model is based on ionization and electron affinity. This model is important as it has and impact on the electrification process of particles. Charge transfer bands are also formed to enhance the process of electron transfer resulting to full electrification. Electrostatic Segregation  Recent studies show that electrostatic interactions between particles may result to Particle segregation that earlier study attributed it to rotational speed, and particle size or density differences between species The Effect of Particle Adhesion  When materials become charged, their behavior 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. Particle-Wall Adhesion  Particle wall adhesion has an effect of reducing the flow of the particles as well as creating resistance that can result to blockage of pipes. When this is done it can result to powder loss and difficulty in controlling of the flow. From the current researches it has been found that particle wall adhesion is as a result of increased electrostatic force and in essence this particle adhesion have a significant impact on particle electrification (Morimoto and Hatanaka, 1992, p.628). Particle-Particle Collisions  As smaller particles of low density collide friction occurs that result to acquisition of electrostatic charges. In the process of collision depending with the rate of collision it affects electrification process. When particles collide they reduce in speed and increased ionization. Tribo-Electric Series Materials can be arranged in the order of their polarity of charges. Particles are arranged in the electrostatic series and those particles higher in the series have been found to have a higher level of charge compared to those lower in the series hence affecting the net effect of the charge. This affects electron affinity of a particle and in the therefore determine the overall charge on the particles. This series has and effect of affecting the kind of charge a particle acquires and the level of electrification (Greason, 2000, p.251). 2. Salts formulation and Basic Concepts 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 and Hatanaka, 1992, p.634).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. 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. 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. 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, p.). 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. Manufacturing of DPIs and metered dose inhalers (MDIs) can be done by equipment such as air jet milling. LiCalsi and Research team (2001, p.56) 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. Flurbiprofen salts 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 a nonsteroidal anti-inflammatory medicine that is administered principally orally. This medication is used intended for relieving symptoms of conditions such as osteoarthritis and rheumatoid arthritis. Flurbiprofen function by inhibiting the stroke of prostaglandins hormones, which cause inflammation and pain in the body. The sodium ions present in salt that the body requires in order to do a selection of necessary functions. Salt helps maintain the fluid in our blood cells that is used to transmit information in our nerves and muscles. Salt also helps in uptake and absorption of certain nutrients from our small intestines. The reason why this salt is made in pharmaceutical industry is because chloride does not have any of its own activity unlike nitrate, bromide among others. Salts as well by salt exchange, hydrochlorides are formed to some degree no matter what the offset ion of an API is in the pharmaceutical product. These salts also typically are significantly more soluble compared to free bases used to make them hence the hydrochloride typically improves the biodiversity. Lastly multiple forms of these salts result in several techniques for the count of hydrogen and chlorides ions to the pharmaceutical base we require to make into salt. Salts have different features; most salts are formed by neutralization of sodium hydroxide, NaOH, a base, with hydrogen chloride, which is an acid. Most salts are ionic compounds. Some salts are acid while others are basic salts since a salt may react with a solvent to yield different ions that the one already present in the salt. In addition to being to these characteristics salts are further categorized as simple, double or complex salts. In conclusion, salts have several physical properties such as; they are in crystal form, isometric, cubic, are clear to clear to white, are of critical humidity 20 degrees Celsius and finally they are of high boiling and melting points (Poul, Buchanan, & Grahame, 1993, p.234). 3. Milling and basic concepts 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. Potential advantages of milling pharmacological powders According to Morimoto and Hatanaka (1992, p.637), there are a number of advantages of this process some of which include increased rate of dissolution hence enhanced bioavailability. Additionally, 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 colours 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. Effect of milling on tribolelectrification Milling in pharmaceutical secondary manufacturing generates amorphous regions on the surfaces of the particles that exhibit thermodynamic instability that causes re-crystallisation upon storage (Pu, Mazumder and Cooney 2009, p.48).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. Kwok, Glover and Chan (2005, p.146) however appreciate that in a physical interaction, these modes of charging would rarely be discerned independently. During milling, the contact between the particles that rub against one another and against the walls of the vessel leads to triboelectrification of the materials being milled. Anderson (2012) defines tribolelectrification 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. Triboelectrificationoccurs commonly in most industries handling powders such as detergents, foods and pharmaceuticals and depends on constitution of the powder, the surfaces of the manufacturing vessels, relative humidity and particle size. 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 triboelectric charging or triboelectrification(Supuket al. 2011). Charging of particles leads to their change of behaviour causing them to easily adhere to each other or cause repulsion of other charged materials. When tribolelectrification 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 powder flow (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, tribolelectrification 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 tabletting. 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 tothe required standards which would result into the interruption of clinical trials or a ban on sale of such drugs. Supuk, Seiler and Ghadiri (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 vapours 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). 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. Lastly, to minimise the effect of tribolelectrification, Supuket al. (2011) proposes particle charging with opposite polarity so as to form stable ordered mixtures which minimise segregation. Additionally Studies by Matsusakaet al. (2010) indicate that co-milling stable amorphous with appropriate additives effectively minimised 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. References Anderson, N. G. 2012. Practical process research and development – A guide for organic chemists, 2nd ed. Oxford: Academic Press, Oxford. Crowder, T.M, Hickey, A.J, Louey, M.D & Orr, N. 2003. Pharmaceutical particulate science. Interpharm/CRC Press LLC, Boca Raton, Florida. Greason, W.D. 2000. Investigation of a Test Methodology for Triboelectrification. Journal of Electrostatics49, pp.245-256. 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, 1725-1729. Hickey, A.J, Mansour, H.M, Telko, M.J, Xu, Z, Smyth, H.D, Mulder, T, McLean, R, Langridge, J & Papadopoulos, D. 2007. Physical characterisation of component particles in dry powder inhalers. II dynamic characteristics’, Journal of Pharmaceutical Sciences. 96(5), pp. 1302 – 1319. Kwok, P.L, Glover, W & Chan, H.K .2005, ‘Electrostatic charge characteristics of aerosols produced from metered dose inhalers’, Journal ofPharmaceutical Sciences (94) 2789-2799. Matsusaka, S, Marumaya, H, Matsumaya, T &Ghadiri, M. 2010. Triboelectric charging of powders: A review, Journal of Chemical Engineering Science, vol. 65, 5781 – 5807. Morimoto, Y., Hatanaka, T. 1992. Predictionof skin permeability of drugs: comparison of human and hairless rat skin. J. Pharm. Pharmacol, 44, pp. 634-639 Pingali, K.C, Tomassone, M.S &Muzzio, F. 2010. Effects of shear and electrical properties on flow characteristics of pharmaceutical blends, Journal of American Institute of Chemical Engineers 56(3), pp. 570-582. Pu, Y, Mazumder, M & Cooney, C 2009, Effects of electrostatic charging on pharmaceutical powder blending homogeneity, Journal of Pharmaceutical Sciences, 98(7), pp.45-56. Rowley, G. 2001. Quantifying Electrostatic Interactions in Pharmaceutical Solid Systems”, International Journal of Pharmaceutics, 227, pp.47-55. Supuk, E, Seiler, C &Ghadiri, M 2009, Analysis of a sample test device for tribo-electric charging of bulk powders, Particulate Particles System Character Journal, vol. 26, 7 – 16. Supuk, E, Hassanpour, A, Ahmadian, H, Ghadiri, M & Matsuyama, T. 2011. Tribo-electrification and associated segregation of pharmaceutical bulk powders. KONA Powder and Particle Journal, (29) pp. 208-221. Read More