ABSTRACT

This third volume of the second edition offers information on specialized products such as emulsions, liposomes, polymers and polymeric pharmaceutical excipients. It explains the requirements for conducting clinical research and obtaining marketing approval for new drug products

chapter 10|34 pages

r

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PHASE MOLECULAR SHAPE ni l I)

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Fig. 9 Freeze fracture electron micrograph of ELimixed phosphoinositides (4:1) liposomes after 10 passes through a0.1 pirn polycarbonate filter. growth, particularly during storage, would be undesirable in most products. Fortunately the tendency of liposomes to aggregate and fuse can be controlled by the inclusion of small amounts of negatively charged lipids such as PS or PG or positively charged amphiphiles such as stearylamine in the formulation. Knowing the number and the sign of charged groups added and the valency and concentration of electrolytes in the me-dium, the magnitude of the electrostatic forces generated by these charged groups can be closely approximated by using the double layer theory. These results can then be correlated with physical stability of liposomes and used to guide formulation efforts. The amount of charged component and ionic conditions in a particular liposome dos-age form can be adjusted to produce a high-enough zeta potential to inhibit close ap-proach of vesicles and prevent their aggregation. In practice it is usually necessary to determine empirically the magnitude of the zeta potential required to prevent aggrega-tion in a particular system. However, once this has been done, it is possible to use the zeta potential as a quality control check to insure that each batch of liposomes contains sufficient charged groups to avoid aggregation during storage.

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°C for 20 min).

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REFERENCES

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CH-CH-CH--C

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A of of is

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Fig. 12 Scanning electron micrograph of D.L-PLA nanoparticles loaded with CGP 57813. (Ref. 51.) scanning force microscopy (also called atomic force microscopy), enable the visualiza-tion of nanoparticles at atmospheric pressure without gold coating [12,64]. Neverthe-less, the resolution obtained with these new tools is still lower than that with SEM. For size determination, transmission electron microscopy is not as widely used as PCS and SEM, but it is still a powerful method for determining the morphology of particles. With this technique, Fessi et al. [42] estimated the wall thickness of PLA nanocapsules. Krause et al. [18] described the highly porous structure of PLA nano-spheres prepared by the emulsion-evaporation procedure. VIII. IN VITRO RELEASE STUDIES In vitro release studies should in principle be useful for quality control as well as for the prediction of in vivo kinetics. Unfortunately, due to the very small size of the par-ticles, the release rate observed in vivo can differ greatly from the release obtained in a buffer solution. However, in vitro release studies remain very useful for quality control as well as for evaluation of the influence of process parameters on the release rate of active compounds. In vitro drug release from microdispersed systems has been exten-sively reviewed by Washington [65]. Depending on the type of polyester, drug release from nanoparticles can take place through several processes, of which the following appear to be the most important: (1) The drug may diffuse out of the carrier through the solid matrix; to allow complete release from the carriers, (the concentration of drug in the release medium should re-main infinitely low, which condition is known as sink condition); (2) The solvent may penetrate the nanoparticles and dissolve the drug, which then diffuses out into the re-lease medium. Depending on the physico-chemical characteristics of the particles, wa-ter can enter the particles through narrow pores or by hydration. Once the drug is dis-solved, the drug diffuses out of the particles. Here again, since diffusion is driving the

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VJ -° -o

chapter 1|9 pages

«-

chapter 214|5 pages

Kumar et al.

chapter 221|1 pages

2 2 1

chapter 7|36 pages

Polymeric Pharmaceutical Excipients

Joseph A. Ranucci and Irwin B. Silver stein
ByA. Ranucci B. Silverstein

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Fig. 1 Marine-type propeller. (From Ref. 8.) blending results. Depending on the depth of the vessel, a second propeller may be re-quired. Side-entry mixers normally provide good pumping action with a low initial cost. However, they are not currently in great demand in the pharmaceutical industry since they require an in-product seal mechanism that can be avoided with the top-entering designs. For blending applications in larger batches over 500 gal. marine propeller mix-ers are no longer the optimum choice. Turbine agitators that operate in the 20-120 rpm range are best for a good combination of low-shear mixing and lowest initial cost. These types of mixers should be installed on the centerline of tanks. To prevent vortexing and to optimize mixing, the vessel should be equipped with four vertical baffles that are 1/ 12 the diameter of the vessel. For miscible-liquid blending and also solids-suspension

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Scott and Tabibi phase into the other by feeding it into the vicinity of the mixing/dispersing element. In this way, the phase being added is quickly dispersed into the continuous phase. Although it is widely accepted that the higher the shear rate produced by the mixer the smaller the droplets and, hence, the more stable the emulsion, there is a major prob-lem that must be avoided if good results are to be obtained with high-speed mixing equipment. Every effort should be made to avoid incorporating air into the mix. Air forms a third phase that could ruin emulsion stability in a number of ways. Air usu-ally reduces the viscosity. The addition steps should be organized such that the impel-ler of the mixture is always submerged deeply enough to avoid surface turbulence or splashing. The arrangement of the mixer angle and/or baffles should avoid vortexing. Another alternative is to perform all of the emulsion-making steps in a vacuum-pro-cessing vessel. An additional method is to premix the components at low speeds and shear rates and then subsequently execute the high-shear portion of the process with in-line equipment in the absence of air. In short, aeration should be avoided. Sometimes the direct approach is not the most effective one. When one phase is first added to another, the small amount of liquid being added forms the internal phase. If more of this liquid is added there comes a point where the continuous phase loses its ability to hold all of the internal phase and the emulsion inverts to the opposite type, e.g., from O/W to W/O. Since it has been found that this practice (phase inversion) can yield small droplet sizes, this method is widely used in batch processing. To ex-ecute this maneuver, one needs to begin mixing with only a small amount of liquid in a batch that will later increase to usually more than four times the starting volume. Therefore, the mixer has to extend well to the bottom of the vessel. One way to avoid this small volume of starting liquid is by using an in-line mixer in a recirculation loop attached to the main mixing vessel as illustrated in Fig. 5. The initial phase is recirculated through the in-line high mixer and the phase to be inverted is then carefully metered directly into the recirculation line. This avoids Fig. 5 In-line mixer in recirculation loop to kettle.

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*! few inches up to around 3 ft depending on the manufacturer. The impellers are of cast construction, which reduces the cost but also obviates customizing of the impeller with-out incurring added cost. Propeller mixers can be installed on a vertical centerline, on an angle off the vertical, or through the sidewall of the process vessel. Centerline installation requires the use of baffles in the vessel. Side-entering designs offer the advantage of very ef-fective pumping for low horsepower and low initial cost in large vessels over 1000 gal. However, side-entering designs must have a seal that has to contend with side loads of the candlevered shaft. This has been a problem in some critical sanitary applications. However, if the batches are very large, a side-entering prop mixer may be a logical alternative to top-centerline-installed axial- and radial-flow turbines. The most often used installation configuration is the top-entering angled method. This method produces a good circulation pattern in the process mixing tank without the

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installation of baffles. Angle-mounted mixers are usually clamp-mounted onto a sup-port plate or channel affixed to the sidewall of the vessel. These are the "portable" mixer designs that are widely used. They offer ease of installation and low cost (Fig. 10). Propeller mixers, typically, are operated at around 300-400 rpm or at high speeds around 1750 rpm, depending on the manufacturer's standards. Usually, lower speed units with larger impeller diameters are the best choices for blending applications. However, a high-speed propeller, which may not be optimized with respect to cost and horsepower, may provide the higher shear rates required for a level of emulsifying or of dispersing of solid agglomerates. For drawing in solids from the top surface of the liquid, a second impeller is often specified. This works well in some instances. The propeller should not be so near the surface as to cause surface turbulence and aeration.

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Fig. 12 Radial (Rushton) type impeller. blade angle, it is best to work closely with the manufacturers of the mixer to specify an optimum design for the process. The preceding discussion of axial- and radial-flow turbines has been a very cur-sory survey of what can be a very involved and detailed study. As mentioned above, a large amount of research on these types of mixers is available [13,14]. A detailed dis-cussion of this subject would be beyond the scope of this work. If a blending or sus-pension problem occurs in large production batches, consultation of the references on mixing included at the end of this chapter or, even better, consulting the experts at the major manufacturers of this type of mixer, would be the best place to start. 3. Anchor Mixers An often overlooked mixing device, which is low speed and considered low capabil-ity, is the anchor agitator, so named for its anchorlike shape, as illustrated in Fig. 13. However, this slowly moving agitator makes it possible for many dispersion and emul-sification processes to be accomplished without overshear, aeration, and heat transfer problems. The anchor agitator is a slow (up to 50 rpm) device whose sole function is to rotate the contents of a batch in a radial direction without providing any significant shear. These are high-torque devices that must be designed sturdily to withstand the forces of the high viscosities. Anchor agitators are typically designed to be able to withstand a maximum viscosity beyond which they might actually bend or break. That is, the an-chor itself is built of materials strong enough to withstand the drag of the viscous liq-uid as it passes by the mixer. In addition, the motor has to supply the very high torque requirement that arises when the anchor is stirring viscous materials. When designing the mixer it is important not to understate the viscosity. This is especially important if there is a point in the process where the anchor must be stopped. If this happens, in the case of shear thinning materials, the agitator has to start up from rest in a viscosity much higher than that normally occurring during the process. Products exhibiting pseudoplastic or Bingham plastic behavior are very difficult to move when at rest.

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Fig. 14 Scraped-surface anchor agitator with auxiliary crossbar agitator. (From Ref. 20.) have many deleterious effects on it. First, the emulsion may have components that cannot stand the wall temperature, which may be as high as 110-125°C. This is even more important if the dosage has active ingredients that decompose at these temperatures. Second, if the temperature is hot enough, the product may actually stick or burn on the sidewall. Cooling of product through sidewall heat transfer can cause almost as many prob-lems as heating. During cooling, the viscosity of a product almost always increases. A viscous product that is not physically removed from the sidewall builds up and forms an insulating layer than resists efficient heat transfer. Again, once this condition oc-curs, it is very difficult to reverse it. There is a variety of different designs of scraper blades. Some are arranged in rows. Some are offset on either side of the anchor, allowing some overlap as an an-chor makes a complete revolution. Some actually are designed to allow the anchor to revolve in opposite directions, which can prevent the buildup of product on the fol-lowing edge of the anchor. Some designs use a spring to force the blade against the wall. Most modern designs use the force of the liquid flowing into the blade to bring it close to the wall. Scraped-surface agitators are definitely required in emulsification equipment where heat transfers are necessary. These anchor agitators with scraping blades can be just as simple anchors or part of complex multishaft mixers. 5. Counterrotation Anchor-type agitators have a decided weakness when handling high-viscosity products of more than about 75,000-100,000 centipoise. They tend to rotate only the product,

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without producing any appreciable velocity differences, so that almost no mixing oc-curs. By installing a stationary baffle, some mixing capability is added. This works well on materials with viscosities from 5000-25,000 centipoise. For the best results, with products between 100,000 and 250,000 centipoise, a counterrotating set of crossbars provides excellent blending. Such equipment is illustrated in Fig. 15. Some designs use the same motor, turning a pinion gear between two opposing bevel gears to provide rotation in opposite directions. Others provide a greater degree of flexibility by driving the two shafts on separate motors. In either case, there will be a hollow shaft driving the anchor agitator and an additional shaft located inside the hollow shaft to drive the inner crossbars [21]. B. High-Speed Dispersers A simple yet powerful device used extensively in industries other than pharmaceutical manufacturing for dispersion of solid particles in liquids is the high-speed disperser. Sometimes called a saw-blade disperser for the shape of the mixing impeller, this ma-chine consists of a variable-speed shaft connected to an impeller with a serrated edge. The mixer is designed to rotate at a high speed in order to produce shear and pumping (Fig. 16). This type of equipment is designed specifically to disperse powders, usually pig-ments, into liquids. Much has been written that high-speed dispersers are capable only of dispersing "easy" pigments [23]. This is true if the particles are hard agglomerates or individual hard particles with some strength. Furthermore, the high-speed disperser design is ineffective if the viscosity is low. The only shear stress that is delivered to Darticles is due to the hydraulic shear that is a product of the shear rate and the viscos-Fig. 15 Counterrotating agitator. (From Ref. 21.)

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Scott and Tabibi Fig. 16 High-speed disperser. (From Ref. 22.) ity. Hence, the high-speed disperser does its best job of deagglomerating particles when the viscosity is between 10,000 and 20,000 centipoise. If the shear rate is calculated in a fashion similar to the method used for a rotor/stator, it is found to be very low, since the "gap" between the disperser blade (rotor) and the vessel bottom (stator) is usually around 30 cm. For a disperser with a 30 cm blade running at 2000 rpm located 30 cm off the bottom of a vessel dv/dx = (7t) (30)(2000)/(30)(60) = 104 sec (6) where dv = velocity difference between the moving impeller and the stationary object (bottom of the vessel); and dx = distance between moving impeller and stationary object. Clearly, the maximum shear rates are higher than this in the vicinity of the blade tip, but there has not been much research into the velocity gradients set up by high-speed dispersers. Much of this lack of research is no doubt because the bulk of the commercial applications for the disperser deal with viscous liquids that are completely opaque, making the measurement of the various velocities difficult. However, there has

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Fig. 23 Baffle plate above surface. (From Ref. 29.) portant to avoid air incorporation or foaming), the baffle plate can be lowered to pre-vent splashing. This allows the mixer to be emulsifying at highest speed and, hence, highest shearing rates while avoiding aeration. All mixers or mixing systems must provide flow to all areas of the process ves-sel if they are to be deemed successful. In the case of these axial-flow rotor/stator mixers, the flow emanates from the mixing head and flows in a single direction. In order for the flow to reach every area of the vessel, it must deflect off the baffle plate and then the sidewall. If the mixer cannot produce enough flow to reach the sidewall, then a dead spot exists. The amount of flow required and the amount of flow produced by a given size mixer depends on the viscosity and the design of the specific mixer. The manufacturer should know the pumping capabilities of their mixers at different viscosities in order to select equipment for different size mixing vessels. Table 4 shows the abil-ity of a typical axial-flow rotor/stator mixer. The batch size that can be handled on a macroscale basis can be determined from Table 4 for the axial-flow rotor/stator mixer if the diameter of the process vessel and the diameter of the rotor are known. This is a trial-and-error problem. By choosing a batch size, vessel diameters can be obtained by use of standard-size vessels. If a fea-sible mixer can be installed in a standard-size vessel, the total system capital cost can probably be lowered. The rotor diameters that are available for trial-and-error solution are usually set by the manufacturer. That is, various sizes are available but not an in-finite variety. As an example, take a 1000 gal. process tank with a 72 in. diameter. If a6.5 in. diameter rotor unit is used, a viscosity of up to about 9000 centipoise can be pumped

chapter |1 pages

colloid mills, piston homogenizers, rotor/stator mixers, Microfluidizer™ (a registered trademark of Microfluidics International Corp.) technologies, ultrasonic mixers, and hybrid devices. Each uses a unique processing technique to shear a mixture or com-bine the flows of materials in order to form an emulsion or suspensions. Most of the time these devices are not used in a truly continuous process. Rather, after the compo-nents of a dispersed delivery system are combined and blended in a batch vessel, the components in the mixture are passed through the device, and the shearing and mixing that take place inside the device affect particle size reduction, dispersion, and emulsi-fication. 1. Rotor/Stator Mixer Disperser Emulsifiers "All mixers pump and all pumps mix." This is reflected in the earlier-shown power equation, Eq. (3). A type of in-line device that is very similar to a rotor/stator batch mixer is the rotor/stator continuous mixer disperser emulsifier. Indeed, most of the designs of this type of in-line high-shear device are essentially identical to the batch equipment designs of a given manufacturer. Since rotor/stator batch mixers are acting as submerged pumps, a design can be made that places the rotor/stator in a pump hous-ing and allows for product to be pumped through itself (Fig. 27). During the time the product is inside the rotor/stator mixing pump, the droplets and particles are subjected to a wide variety of high shear rates. All pumps of any kind impart some level of shear to the product that passes through the pump. Rotor/stator mixing pumps are designed with fine tolerance rotor/stator gaps that promote the high shear rates and high amounts of shear per pass through. Shear rates in a rotor/stator in-line mixer are equal to those in rotor/stator batch mixers. The maximum shear rates occur in the gap between the high-speed rotating Fig. 27 Rotor/stator in-line mixer disperser emulsifier. (From Ref. 31.)

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impeller and the stationary housing. Many ingenious designs are available that use various configurations with the purpose of increasing the probability that the solid par-ticles or liquid droplets travel through the rotor/stator zones where maximum shearing occurs. Almost all designs have some form of teeth or blades, which are meshed into an accompanying stationary housing as illustrated in Fig. 28. Of particular importance is the fact that, when a mixture containing solid particles or agglomerations or emulsion droplets is pumped through a fixed gap rotor/stator mixer, not all of the droplets or particles pass through the highest shearing zones. Some par-ticles passing through the machine may escape the rotor/stator gaps and be exposed only to some of the lower shear zones. The more open the design of the rotor/stator, the Fig. 28 Internal parts of rotor/stator mixer showing meshed teeth. (From Ref. 31.)

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greater the probability that the particles will miss the high shear zones on a single pass through the device. For this reason the discharge of many rotor/stator devices is re-stricted with a series of holes or bars, or with a grid, which performs two separate tasks. First, a discharge grid absolutely limits the maximum particle size that can exit the mixer. If the holes on the discharge grid are 2 mm, it is virtually impossible for par-ticles larger than that diameter to pass through the machine. Rotor/stator in-line mix-ers are made with restricting grids as small as 0.5 mm, and a wide range of larger sizes up to 50 mm or even unrestricted outlets. A sample of such grids is presented in Fig. 29. But even the smallest usable discharge grid does not necessarily provide abso-lute control of the required size distributions in the range of fine dispersion. This is the second reason for the restriction on the discharge. By putting a more limiting dis-charge on the outlet, the flow rate through the device for a given set of pumping cir-cumstances (viscosity, density, system suction, and discharge head) is reduced and the residence time in the machine for a given particle or droplet is increased. The longer residence time increases the probability that a particle has to travel through the highest shearing zones and, thereby, be reduced to the smallest size that the machine is capable of producing. • • • • " ' ; • " * * «L £ J- •-

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Fig. 31 Internals of colloid mill. (From Ref. 29.) colloid mills, typically equipped with rotor diameters of 10-30 cm, provide flow rates in the area of 4000-6000 L/hr, depending upon the viscosity. The key operating requirements of colloid mills are to feed the mill with a well-blended premix and to set the gap at the correct and reproducible setting. There is of-ten some difficulty with setting the gap at exactly the required distance, since the cali-bration of the gap can only be done at the manufacturer. This is less of a problem if the mill is well made and the product is not abrasive. If abrasive wear attacks the ro-tor or stator, the gap may become larger than the setting on the machine indicates. Colloid mills are generally used as "polishing" machines for emulsions or sus-pensions. That is, after the product has been totally and uniformly blended, the batch is passed through the colloid mill one or two times to further reduce the droplet or particle size. Whether or not multiple recycling passes are required depends on prod-uct requirements. Generally speaking, the colloid mill produces emulsions and suspen-sions with particle-size distributions smaller than the particle sizes obtainable using fixed gap rotor/stator mixers. They do represent an extra step in the process, and their use is suggested only when it is found that this added ability to disperse is necessary to produce a fine enough particle- or droplet-size product to enhance a product's stabil-ity. 3. Piston Homogenizers The most powerful device for producing emulsions and suspensions is the piston ho-mogenizer or high-pressure homogenizer. This device uses a high-power positive dis-placement piston-type pump to produce pressures of 3000-10,000 psig and then force

chapter |3 pages

Ultrasonic homogenizing systems are able to produce particle-size and droplet-size distributions that approach those of piston homogenizers with a lower power re-quirement. In order to work, they must be fed a well-blended premix or a metered feed of the liquid components. The vibrating element is an extra maintenance item, espe-cially in heavy or abrasive service. Overall, they offer an attractive option when fixed-gap rotor/stator devices do not produce the required size distributions. 5. Homogenizer/Extruder Another high-pressure homogenizer/extruder with an adjustable valve having produc-tion capacities from 8 mL/hr to 12,000 LL/hr is available. A positive displacement pump produces pressures up to 30,000 psig. The manufacturer claims that no O-ring is used in the product pass and pump seal, and this homogenizer/extruder was approved by the U.S. Food and Drug Administration for pharmaceutical use [36]. At this writing, in-formation concerning the internal structure is not available. The apparatus is capable of producing fine emulsions and liposomal dispersions. Figure 36 shows a laboratory unit. 6. Microfluidizer Technologies A more recent invention to find wide use in specialized forms of dispersed system dosage forms is the microfluidizer. This device uses a high-pressure positive-displacement pump operating at a pressure of 500-20,000 psig, which accelerates the process flow to up to 500 m/min through the interaction chamber. The interaction chamber consists of small channels known as microchannels. The microchannel diameters can be as narrow as 50 urn and cause the flow of product to occur as very thin sheets. The configuration of these microchannels within the interaction chamber resembles Y-shaped flow streams in which the process stream divides into these microchannels, creating two separate microstreams. The sum of cross-sectional areas of these two microstreams is less than the cross-sectional area of the pipe before division to two separate streams. This nar-rowing of the flow pass creates an (axisymmetric) elongational flow to generate high Fig. 36 Emulsiflex-C5, a high-pressure homogenizer. (From Ref. 36.)

chapter |2 pages

* ** Fig. 39 Cyclone-type homogenizer mixing chamber. (From Ref. 41.) chamber. The symmetry axes of these entry ports are perpendicular to the symmetry axis of the interaction chamber. This design is presented in Fig. 40, with only four entry ports. This machine is called Novamix® (a registered name for Micro Vesicular Sys-tems). It was originally designed to process and produce nonphospholipid lamellar mi-crostructures or lipid vesicles. The lipid vesicles are composed of two immiscible aqueous and lipid phases. The lipid phase consists, generally, of solid polyoxyethylene-derived amphiphiles that form micelles in aqueous media. Under the proper mixing conditions, i.e., a combination of shear, heat, and turbulence, followed by appropriate cooling, the micelles of these types of lipids fuse to form lipid vesicles. The two phases are metered carefully and heated in separate reservoirs and finally pumped to the interaction chamber for pro-cessing. The interaction chamber and pump heads are confined in an insulated com-partment that is maintained at the required temperature for the production of the lipid vesicles. The outlet is attached to a chilling device that cools the product at the required rate [43]. The flow pattern is similar to that of a cyclone, i.e., the flow of liquid is in a vertically positioned rotating cylinder along its vertical axis. The streamlines are con-centric circles with their radii decreasing toward the center of the cylinder. The de-crease is a function of cylinder radius, flow rate of fluid (speed of rotation), and other parameters like viscosity, density, and surface tension of the formulation. In curved type of flow with changing radii, there exists a pressure gradient, i.e. dPIdr = V /r (8) where P = pressure; r = vessel (interaction chamber) radius; V = tangential linear velocity; and p= the liquid density. Since the change in pressure is positive for a positive radius change, the pressure at successive points increases from the concave to the convex side of the streamline [39]. The exact change in pressure depends on the variation in tangential linear velocity, which is proportional to the speed of the rotation and the ra-dius. The flow pattern in the interaction chamber is neither a free vortex, due to the presence of an initial momentum from the pumps, nor a forced vortex, for the stream-

chapter |6 pages

put capacity and does not require premixing; it is fairly inexpensive and suitable for continuous operation. Major drawbacks to this equipment are its lack of availability, the need for special heating and cooling control systems, no available laboratory model, and the need for many trial-and-error runs in order to scale-up to production. 8. Static Mixers A true low-shear and low-energy requirement device for emulsifying immiscible liq-uid mixtures is the static mixer. Sometimes called a pipeline mixer, this device is ac-tually a series of specially designed baffles in a cylindrical pipe as shown in Fig. 42. These simple devices are used extensively for the preparation of unstable emulsions for liquid-liquid extraction purposes. Droplet sizes, obtainable using static mixers, have been studied extensively and vary with viscosity, interfacial tension, pressure drop, and static mixer design [45]. Size distributions obtainable range from 1000-100 |am. Hence, al-though there are very few emulsions stable in this region, the static mixer has seen application as an in-line premixer in continuous processes or in recirculation loops to batch-processing equipment. F. Nonmechanical Disperse Processing Recently a new processing technique became available for the production of stable and uniform liposomes. It uses the physico-chemical properties of the supercritical liquids rather than the mechanical forces of the pumps. One such a process technology is pre-sented in this section. 1. Critical Fluids Liposome Process Near-critical or supercritical fluid solvents with or without polar cosolvents (SuperFluids™) (Aphios, Corp., Woburn, MA) for the formation of uniform and stable liposomes having high encapsulation efficiencies has been used [46-48]. Supercritical or near-critical fluids as shown by the pressure-temperature diagram in Fig. 43, are gases such as carbon dioxide and propane that have been processed under ambient conditions. When compressed at conditions above their critical temperature and pres-sure, these substances become fluids with liquidlike density and the ability to dissolve other materials, and gaslike properties of low viscosity and high diffusivity. The gas-eous characteristics increase mass transfer rates, thereby significantly reducing process-ing time. Small added amounts of miscible polar cosolvents, such as alcohol, can be used to adjust polarity and to maximize the selectivity and capacity of the solvent. Fig. 42 Static mixer. (From Ref. 44.)

chapter |3 pages

„ , . large-scale production rate Scale-up ratio = — - n\ small-scale production rate Disperse system scale-up ratios may vary from 10 to 100 for laboratory to pilot-plant process translation and 10 to 200 for scaling from pilot-plant to commercial produc-tion. Actual production rates may vary considerably from expected production rates, since overall process efficiency is dependent on a wide range of factors. The process-ing of disperse systems, whether liquid-liquid or liquid-solid, is still relatively empiri-cal due to the substantial interfacial effects that predominate and control the relevant unit operations. Furthermore, unit operations may function in a rate-limiting manner as the scale of operation increases from the laboratory bench to the pilot plant to com-mercial production. Thus, although conventional wisdom suggests the necessity of scale-up studies, the appropriate approach is not necessarily initiated with miniaturized com-mercial processing systems [5]. The concept of scale-up has taken on a substantive regulatory aspect in more re-cent years with the issuance of Guidance 22-90 by the Food and Drug Administration's (FDA's) Office of Generic Drugs in September 1990 and the establishment of the Scale-Up and Post Approval Changes (SUPAC) Task Force by the FDA's Center for Drug Evaluation and Research. In May 1993, the American Association of Pharmaceutical Scientists, the Food and Drug Administration, and the United States Pharmacopeia cosponsored a workshop on the scale-up of liquid and semisolid disperse systems [6]. The primary finished product attribute to control during the scale-up of a disperse sys-tem, whether manufactured in identical, similar, or different equipment, is the degree of sameness of the finished product relative to previous lots. The consensus of the workshop committee was that four criteria be used to evaluate sameness: (1) adherence to raw material controls and specifications; (2) adherence to in-process controls; (3) adherence to finished product specifications; and (4) bioequivalence to previous lots. The aim of this chapter is to provide the formulator with an appreciation, on the one hand, of the complexity of the scale-up problem associated with disperse systems, and an awareness, on the other hand, that scale-up problems can be resolved, to a great extent, by drawing on the vast literature and experience of chemical engineering. In 1964, H. W. Fowler [7] initiated a series of progress reports in pharmaceutical engi-neering that appeared over time in the periodical Manufacturing Chemist. Fowler's ouevre was distinguished by his focus on fundamentals, i.e., on material properties and on operation and process mechanisms. His intention was "to look at the literature of chemical engineering and to discuss developments which are relevant to pharmacy." It is the present author's intention (in part, through this chapter on scale-up of disperse systems) to validate the interdisciplinary process that Fowler began more than 30 years

chapter |1 pages

itself, the influence of fines

chapter |2 pages

= (dT) } (22)

ByT-T=(T- TJe-*

chapter 10|9 pages

Scale-Up of Dispersed Parenteral Dosage Forms

Matthew Cherian and Joel B. Portnqff
ByMatthew Cherian

chapter |3 pages

Fig. 4 Principle of operation of rotor/stator homogenizer. late matter and can have compatibility problems with the product. [These sealing aids are now being made of polytetrafluoroethylene (PTFE), which improves the situation in most cases.] For manufacture of sterile products, the dispersing elements need to be sterilized, preferably by using steam. Experiments have shown that these elements are steam sterilizable in 15-30 min at 121 °C. These dispersers are available as in-line models or vertically mounted "probe"-style units (see Fig. 5). A colloid mill has several similarities with the rotor-stator type mixer. It has a stationary "stator" through the center of which the product is pumped at high pressure. The rotor moves close to the stator. The gap is often adjustable and is of the order of 0.1 mm. The adjustable feature of the gap often makes reproducibility of batches a challenge, as the screw type of adjusting mechanism for the rotor often is not repro-ducible to a high degree of accuracy. In a reciprocating design homogenizer, a piston moves in a cylinder and pushes the product through a nozzle whose opening is adjustable by means of a spring loaded Fig. 5 Dispersing element of an in-line unit. (Photo courtesy of Ika-Werke, Germany.)

chapter 11|16 pages

Quality Assurance

BySamir A. Hanna

chapter |16 pages

tis

chapter |17 pages

Table

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(25 °C

chapter 12|34 pages

Validation of Disperse Systems

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