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MECHANICAL DISPERSING TREATMENTS and PROCESSING METHODS Or, Don't let the Application grind you down

By Dr. David Fairhurst

INTRODUCTION

The overwhelming majority of manufactured industrial products and increasingly those for health-care purposes involve, either in the final state or at some stage of their production, suspensions of particulate materials or emulsion droplets dispersed often at high volume fraction. One only has to look at the vast array of cosmetics, personal care, pharmaceuticals and other health-care products to recognize the importance of adequate dispersion. In decorative cosmetics for example, its importance to application properties and color is significant; the dispersion of colored organic/inorganic pigments and dyes affects brightness and gloss. In sunscreens, the quality of the dispersion not only affects the formulation aesthetics but also the performance (e.g. SPF factor)1. And, increasingly, with the advent of Active Pharmaceutical Active Ingredients (APIs) possessing poor overall solubility, optimal dispersion is necessary for maximizing bioavailability and uniformity of dose. The state of dispersion of any solid material directly affects suspension properties. For example, as particulate material is added to any liquid medium its flow becomes increasingly non-Newtonian and, with high particle concentrations, can become thixotropic. These rheological characteristics determine suspension functionality2,3, such as film forming, lubricity and efficacy. The importance of the process of dispersion and its profound effect on the economics and quality of the subsequent product has long been recognized4, 5. Many dry powders start as massive solid phases and require size reduction even prior to dispersion of the powder in a liquid. Conversely, agglomerates are formed when fine particles are handled, shaken, rolled or stored in a single position1; de-agglomeration and stabilization are necessary to obtain optimal dispersion. Further, all suspensions are inherently thermodynamically unstable. They will, through random motion of the particles over time, aggregate because of the natural and dominant tendency to decrease the large specific surface area and excess surface energy. This tendency becomes increasingly important the smaller the initial particle size (PS) and is especially significant for colloidal-sized particles (less than 1m). Finally, reduction of the particle size of an API prior to formulating can be an avenue to significantly increase the specific surface area and, subsequently , the overall bioavailability regardless of the route of administration.

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MUSINGS and JOTTINGS IV

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With drug products, for regulatory approval the milling technique must well characterized and reproducible; the product must perform the same every time. A process which provides poorly controlled PSD, or one which is not adequately characterized, can have great implications on the ultimate performance of the product, e.g. bioavailability. For crystalline materials, milling can also induce changes in crystalline form (polymorphs), or may even result in the introduction of some degree of amorphous physical state to the particulates. Again, both of these events may have practical, as well as regulatory, concerns for both stability and performance of the dispersion. Thus, for all the reasons above, milling is an important tool available to both the R&D formulator and process engineer. However, attention must be paid to any process of attrition or comminution to effect the dispersion process and/or to reduce the PS. It is not a case of one-size method fits all. Achieving stable, effective and elegant formulations containing particulates is a matter of proper milling. For example, if excessive mechanical energy is used it can easily result in a submicron-sized fraction of "fines", especially for crystalline material where fracture can occur at defect crystal planes. Such fines cannot be detected using either image analysis or particle size analysis using Fraunhofer diffraction. Indeed, monitoring the presence of nanoparticles in suspensions that have a broad particle size distribution is a general problem for current particle sizing instrumentation.

Methods and Equipment

Here, we will restrict ourselves to "top-down" wet milling processes where the two operations of size reduction of massive particles and the breaking down of agglomerates are combined; the former is recognized as a separate unit process in chemical engineering6. Milling may be brought about through four basic processes: impact, shear, extension and cavitation (Table 1), although some would suggest only two, viz those that emulsify, or that pull apart, by shear forces and those that comminute by fracture.

Table 1 Typical Milling Processes Impact Shear Kinetic-dispersion mill Roller mills Ball/pebble/sand mills High-speed disk impeller Jet mill 2-blade pug mill

Extension Extruder Cavitation Ultrasonic activators

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The degree of turbulence and shear vary considerably with the type of operation and application. The design and choice of milling equipment must be chosen with care for both the initial wetting of a powder (and sometimes deaeration) - often called the premix stage - and for final dispersion. In all cases the minimum mechanical agitation must suffice in order to avoid unwanted problems1. A fairly extensive review of commonly used machinery in industrial paint making is instructive; it illustrates the dependency of choice of equipment on factors such as the nature of the pigmented millbase and the quality and volume required7. In general, the smaller the initial PS the more difficult it becomes to reduce the PS further; it is very difficult to mill the size of the average particle to below 1m. This is found for both brittle crystalline solids (such as ceramic materials) and ductile amorphous waxy material (like polymers). This practical limit (ca 1m) is ascribed to the increasing resistance to breaking as the particle size decreases; this in turn derives from the smaller size of flaws/defects in small particles as compared with those in large ones8. In many applications, however, a particle size of about 1m is small enough. Below this limit lies the colloidal domain9; sizes in this range begin to assume vastly different properties from their larger siblings - one important unwanted property is Ostwald ripening10-12. The consequence of Ostwald ripening of suspensions is that larger particles grow at the expense of the smaller ones; it is an important mechanism for destabilizing all types of colloidal dispersions (emulsions and suspensions). In addition to the lower size limit, the particle size distribution obtained through milling is usually rather broad. As long as it is reproducible and well characterized, however, this may not always be a disadvantage depending on the final requirements of the product. With broad size distributions higher solid volume fractions can be obtained since smaller particles can be embedded in the voids between the larger particles. Mechanical dispersion techniques may be broadly characterized as low energy/low shear, low energy/high shear, and high energy/high shear. Some low energy techniques may, in certain cases, provide similar results to high energy techniques, if the suspension is processed for a longer time. The viscosity of the liquid vehicle can have significant implication on the efficiency of particle size reduction, as higher viscosities can absorb or diffuse the energy imparted and impede the movement of the particulates. Equipment used to generate shearing forces need only provide sufficient energy to attenuate an immiscible liquid with another (emulsification) or to separate agglomerates. Comminution requires higher energy input to break tightly bound aggregates or to shatter coherent solids. The generation of high-shear forces requires narrow gaps, or high rates of flow - or both. A compounder/extruder such as a Banbury mixer, used for example to blend carbon black and other fillers into rubber or plastics, functions

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at low speed but with a loading of high millbase viscosity. Here, two kneading arms rotate in opposite directions and at different speeds. They are so shaped that the milling mixture is pressed against the walls of the mill chamber forming a wedge during the kneading operation; the wedge is continuously formed and sheared. A three-roll mill is simply a set of rollers rotating in opposite directions with a small clearance between the rolls. For this type of mill a high viscosity of the loading millbase is critical; hence, the percent solids must be as high as possible. A big advantage of this method is that it can handle extremely viscous materials such as printing inks. The operation of a Colloid mill, typically used to emulsify liquids, depends on flow (by sucking) through a narrow, adjustable, gap between a variable very high-speed rotor and a stator. A Kady mill is very commonly used to disperse powders in liquids. This type of mill may be a batch or a continuous mixer in which the rotor turns within a labyrinth stator but can operate only with a loading of low viscosity mill base. A rotor/stator device can normally only operate efficiently with a low viscosity fluid and is limited in the PSD achievable. VariKinetic dispersers, such as the Gaulin, use variable-pitch impeller blades, the angle of which can be adjusted while the unit is in operation. Homogenizers are more commonly used to produce emulsions but can also be used in particulate size reduction. These piston/gap devices function through both cavitation and particle impact by forcing the oil/water, or particulate/vehicle, mixture at high pressure through a small orifice against a spring-loaded plunger. The lack of moving parts in an homogenizer often makes it preferable to the Colloid Mill. A Sonolator is a type of homogenizer in which a jet of liquid is pumped through an orifice against a blade-like obstacle in the jet stream. This produces a turbulent flow of the liquid that causes the blade to resonate at ultrasonic frequencies (tunable during operation). This results in a high level of cavitation, turbulence and shear. Ultrasonic activators convert conventional 60Hz line frequency to high (20kHz) frequency that is fed to an electrostrictive element. This, in turn, converts the signal to mechnical vibrations in tips of various shapes called "horns" which induces shear through cavitation of the liquid. Though in existence for many years, ultrasonic processing was not, until relatively recently, scalable to a commercial process. Ultrasonic processing is also be limited by the viscosity of the preparation. In the Microfluidizer, two streams of fluid are pumped under very high pressure and velocity through precisely defined microchannels within an interaction chamber (manufactured from sapphire or diamond). A variety of interaction chamber designs are available for specific applications and desired outcomes (particle reduction, emulsification, etc). Fine particles with a narrow

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particle size distribution are produced by a combination of shear, turbulence, impact and cavitation forces. A classical method, originally developed in the inks and coatings industry, is the "media mill". The simplest method of media milling is roller milling. Media and fluid are loaded into a jar or vessel which is then rotated on a shaft, or by rollers, and the "impacts" are driven by gravity. The sample container is often made of steel. The fineness of the grind depends on the size of the grinding media: the smaller the media, the finer the grind. The speed of rotation, the amount - and size - of the grinding media and the amount of fluid loading are all critical parameters that control the efficiency of the milling process. The impact depends on attaining a cascading motion and hence the media must be dense (eg, zirconia, 6 and tungsten carbide, 16). A pebble mill uses flint pebbles or porcelain balls; the inside of the sample container is lined with a non-metallic material. Media can be encased in plastic (polyurethane, polyethylene) to eliminate chemical interaction in particular with aggressive acids/bases. Stirred media mills use smaller grinding media resulting in a finer grind. In the Attritor, the grinding media is moved by a specially designed impellor (a series of staggered horizontal rods attached to a central shaft) rather than relying on the force of gravity (thus enabling the use of low-density polymeric media). In addition to impact, this motion generates shear fields leading to more efficient power consumption and shorter grinding times. These type of mills may be as simple as a pegged impellor immersed directly into a vessel containing a slurry of fluid and media, or quite complex involving high speed/high-energy, continuous flow with cooling and recirculation capabilities, available in several designs and configurations (Dyno, Netzsch and Drais mills) Sand mills consist of several impeller disks rotating at high speed and, as the name implies, use sand (Ottawa sand, 20-30 mesh) as the grinding media. The suspension is continuously pumped into the bottom of the mill and drained from the top; it produces the finest dispersions. Very efficient size reduction is attained by recirculation, intermittent milling action and putting mills in series. The Micronizer is a dry-process device in which particles are introduced into a stream of high-pressure gas (the "fluid") and then injected into a chamber creating a vortex of the fluidized gas and particulate material. Within the chamber, the particulates are subjected to additional gas flow from high-speed jet nozzles that results in particle-particle collisions at high kinetic energies. As particulates are broken down by these collisions, they are classified by centrifugal force and discharged by the mill. This method generates very little heat owing to the large volume of gas moving through the system and so it is particularly well-suited for materials of lower melting points or temperature sensitivity and for breaking up soft solids such as carbon blacks and polymers.

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The "jet mill" is technically not "impact" but "compression". In this type of mill, a gas jet pushes particles against an impact plate. It is highly efficient and can provide size reduction below 1m. Table 2 provides a general classification of high-shear mills (in order of their ability to handle mill base viscosity) and high-impact mills (in order of the size of the grinding media used).

Table 2 High-Shear and High Impact Mills High-Shear (increasing viscosity ) VariKinetic dispersers Kady Mills Colloid Mills Microfluidizer Homogenizer Sonolator Ultrasonic activators Three-roll mills High Impact (decreasing media size ) Ball and pebble mills

Attritor

Sand mills Dyno-Mill

Banbury mixer

Final thoughts

Excessive mechanical agitation results in (1) changes in particle size distribution, (2) changes in the total surface area and (3) changes in the surface chemistry. Further, excessive mechanical (or, indeed, thermal) energy increases the possibility of the collision of particles. The maximum collision energy attained using even a low-power (50W) ultrasonic bath is well in excess of that needed to promote re-aggregation. High-power sonicators and homogenizers can generate 400W of power and they also create considerable heat ­ enough to boil water. Thus, in the preparation of any suspension, the choice of milling device is

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predicated by the degree of useful mechanical agitation it provides or that specific formulation. In milling of particulate suspensions surface-active solutes ("surfactants") reduce the viscosity of the system and, keeping the millbase fluid, aid in the action of media mills. Although surfactants can contribute to the mechanical breakdown of agglomerated particles by promoting internal wetting, extreme care must be taken in their use. Surfactants are not to be confused with true dispersing aids or dispersants1,13. The two classes are frequently used interchangeably ­ often with deleterious results. True dispersants depend for their effects exclusively on adsorption at the liquid-solid interface; for surfactants primarily it is adsorption at the liquid-air interface and secondary at the solidliquid interface. The rate of adsorption is frequently slow, particularly with polymeric and macromolecular compounds so that intermittent milling is often found to be more efficient and sometimes more effective than continuous action; after some fresh interface is created, a quiescent period of time is allowed for adsorption to take place before more interface is created.

References

1. D. Fairhurst and M.A. Mitchnick in Sunscreens, eds. N.J. Lowe, N.A. Shaath and M.A. Pathak, Second Edition, Marcel Dekker, New York (1997) 2. F. R. Eirich (ed), Rheology, Theory and Applications, Vols I-V, Academic Press, New York (1956) 3. J. Goodwin and R. Hughes, Rheology for Chemists - An Introduction, RSC Publications, Cambridge (2000) 4. F.K Daniel, Natl. Paint, Varn. Lacquer Assoc. Sci. Sect. Circ., No.744 (1950) 5. S. Guggenheim, Off. Dig., 30 No.402, 729 (1958) 6. S. Bernotat and K. Schöert, in Ullmann's Encyclopedia of Industrial Chemistry, eds. W. Gerhartz, B. Elvers et al, Fifth Edition, Vol. B2, Wiley-VCH Verlag, Weinheim (1986) 7. F.K. Farkas in Paint and Surface Coatings: theory and practice, ed. R. Lambourne, Ellis Horwood, Chichester, (1987) 8. H.N. Stein, The Preparation of Dispersions in Liquids, Marcel Dekker, New York (1996) 9. D. Fennel Evans and H. Wennerström, The Colloidal Domain, VCH Publishers, New York (1994) 10. D.H. Everett, Basic Principles of Colloid Science, RSC Publications, London (1988). 11. G.H. Nancollas, Advances in Colloid and Interface Sci., 10 215 (1979) 12. W.I. Higuchi and J. Misra, J. Pharm. Sci., 51(5) 459 (1962) 13. D. Fairhurst and R. W. Lee, Particulate Suspensions, Drug Delivery Technology, Volume 8, No.8 (2008)

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