Powders and Granules PDF

6 Powders and Granules Objectives After reading this chapter, the student will be able to: 1. Differentiate a powder from a granule 2. Explain how a drug's powder particle size influences the pharmaceutical dosage forms that will b...

6 Powders and Granules Objectives After reading this chapter, the student will be able to: 1. Differentiate a powder from a granule 2. Explain how a drug's powder particle size influences the pharmaceutical dosage forms that will be used to administer it 3. Define micromeritics, the angle of repose, levigation, spatulation, and trituration 4. Compare and contrast the various types of medicated powders, for ­example, bulk, divided 5. Provide examples of medicated powders used in prescription and ­nonprescription products 6. Differentiate between the fusion method and wet method for the ­preparation of effervescent granulated salts Most active and inactive pharmaceutical administer insoluble drugs such as calomel, ingredients occur in the solid state as amor- bismuth salts, mercury, and chalk. phous powders or as crystals of various mor- Powders as a solid dosage form have been phologic structures. The term “powder” has used historically as internal and external med- more than one connotation in pharmacy. It ications. For internal use, they can be taken may be used to describe the physical form of orally, administered through the nose as snuffs, a material, that is, a dry substance composed or blown into a body cavity as an insufflation. of finely divided particles. Or, it may be used For external use, solid powders can be applied to describe a type of pharmaceutical prepa- to compromised areas of the body. Powders ration, that is, a medicated powder intended have also been used to make solutions for for internal (i.e., oral powder) or external (i.e., topical and oral use and for use as douches. topical powder) use. A powder is defined as a Such traditional applications and modes of dosage form composed of a solid or mixture administration of the dosage form continue of solids reduced to a finely divided state and today. Additional applications have also been intended for internal or external use. developed; for example, powders containing a ­bioadhesive material can be applied to a spe- Historical Use cific body area such that the medication will adhere for a prolonged drug effect. Originally, powders were found to be a convenient mode of administering drugs Applications derived from hard vegetables such as roots (e.g., rhubarb), barks (e.g., cinchona), and Powders have qualities that make them an woods (e.g., charcoal). As synthetic drugs attractive dosage form for certain situations. were introduced, powders were used to Unlike a standardized capsule or tablet, 214 0002035885.INDD 214 11/29/2013 6:53:59 PM  Chapter 6 Powders and Granules 215 powders enable a primary care provider to example, large particles that are more dense easily alter the quantity of medication for tend to settle more rapidly than do small par- each dose. Powders can also aid in clinical ticles; particles that are more bulky will settle studies of drug preparations because the more slowly. This characteristic must be con- dose can be so readily adjusted. Doses can sidered in mixing or storing and shipping, be individually weighed and placed in pow- when powders of different particle size may der papers, envelopes, or small vials/bottles become segregated. Another concern stems (“Powder in a bottle” research studies are an from the fact that powder dosage forms have example). In another example, infants and a large surface area that is exposed to atmo- young children who cannot swallow tablets spheric conditions. Thus, powders should or capsules will accept powders that can be be dispensed in tight containers. Further, mixed with a formula or sprinkled in apple- because powders of small particle size pres- sauce or some other appropriate food. Also, ent a greater surface area to the atmosphere, if a drug is too bulky to be prepared as a cap- they are more reactive in nature and can sule or tablet, it may be suitable for a powder adsorb larger quantities of gases, such as car- dosage form. Powders provide a rapid onset bon dioxide. However, if the powder has a of action because they are readily dispersed, smaller particle size, it can dissolve at a more have a large surface area, and usually require rapid rate, unless adsorbed gases prevent the only dissolution, not disintegration, before water from surrounding the individual par- absorption. ticles and wetting them, thereby decreasing Although the use of medicated powders per their wetting properties. An increase in sur- se in therapeutics is limited, the use of pow- face free energy can increase the absolute sol- dered substances in the preparation of other ubility of the drug and have a positive effect dosage forms is extensive. For example, pow- on its bioequivalence. dered drugs may be blended with powdered fillers and other pharmaceutical ingredients Topical Powders to fabricate solid dosage forms as tablets and capsules; they may be dissolved or suspended Topical powders should have a uniform, in solvents or liquid vehicles to make various small particle size that will not irritate the liquid dosage forms; or they may be incorpo- skin when applied. They should be impal- rated into semisolid bases in the preparation pable and free flowing, should easily adhere of medicated ointments and creams. to the skin, and should be passed through at Granules, which are prepared agglomer- least a No. 100-mesh sieve to minimize skin ates of powdered materials, may be used per irritation. The powder should be prepared so se for the medicinal value of their content, or that it adheres to the skin. they may be used for pharmaceutical pur- Highly sorptive powders should not poses, as in making tablets, as described later be used for topical powders that are to be in this and Chapters 7 and 8. applied to oozing wounds, as a hard crust may form. A more hydrophobic, water- repellent powder will prevent loss of water Powders from the skin and will not cake on the oozing surfaces. Talc, or any other naturally derived Composition product that is to be used on open wounds, Properly prepared, powders have a uniform, should first be sterilized to avoid an infection small particle size that has an elegant appear- in the area. ance. In general, powders are more stable Topical powders usually consist of a than are liquid dosage forms and are rapidly base or vehicle, such as cornstarch or talc; soluble, enabling the drug to be absorbed an adherent, such as magnesium stearate, quickly. calcium stearate, or zinc stearate; and pos- The properties of powders are related to sibly an active ingredient, along with an aro- the size and surface area of the particles. For matic material. The powder should provide 0002035885.INDD 215 11/29/2013 6:54:31 PM  216 SECTION iiI Solid Dosage Forms and Solid Modified-Release Drug Delivery Systems a large surface area, flow easily, and spread of passing through the openings of standard uniformly. The large surface area will aid in sieves of varying fineness in a specified absorbing perspiration and give a cooling period while being shaken, generally in a sensation to the skin. mechanical sieve shaker (2). Table 6.1 pres- ents the standard sieve numbers and the Insufflated Powders openings in each, expressed in millimeters and in microns. Sieves for such pharmaceu- Insufflated powders are finely divided pow- tical testing and measurement are gener- ders that are intended to be applied in a body ally made of wire cloth woven from brass, cavity, such as the ears, nose, vagina, tooth bronze, or other suitable wire. They are not socket, or throat. When using an insufflator, coated or plated. or “puffer,” the patient simply “puffs” the Powders of vegetable and animal origin desired quantity of powder onto the affected drugs are officially defined as follows (2): area or into the cavity. This device is particu- larly appropriate for anti-infectives. Also, a Very coarse (No. 8): All particles pass moisture-activated adherent, such as Polyox, through a No. 8 sieve, and not more than can be incorporated into the powder. Polyox 20% pass through a No. 60 sieve. is an ethylene oxide polymer with a high Coarse (No. 20): All particles pass through molecular weight that forms a viscous, muco- a No. 20 sieve, and not more than 40% adhesive gel when in contact with moisture. pass through a No. 60 sieve. The gel serves to provide a depot for long- Moderately coarse (No. 40): All particles term drug delivery spanning several hours. pass through a No. 40 sieve, and not more than 40% pass through a No. 80 sieve. Physicochemical Considerations Before their use in the preparation of phar- Table 6.1 Opening of Standard maceutical products, solid materials first are Sieves characterized to determine their chemical Sieve Number Sieve Opening and physical features, including morphol- 2.0 9.50 mm ogy, purity, solubility, flowability, stability, 3.5 5.60 mm particle size, uniformity, and compatibility with any other formulation components (1). 4.0 4.75 mm Drug and other materials commonly require 8.0 2.36 mm chemical or pharmaceutical processing to 10.0 2.00 mm imbue the features desired to enable both 20.0 850.00 μm the efficient production of a finished dosage 30.0 600.00 μm form and the optimum therapeutic efficacy. 40.0 425.00 μm This usually includes the adjustment and control of a powder's particle size. 50.0 300.00 μm 60.0 250.00 μm Particle Size and Analysis 70.0 212.00 μm 80.0 180.00 μm The particles of pharmaceutical powders and granules may range from being extremely 100.0 150.00 μm coarse, about 10 mm (1 cm) in diameter, to 120.0 125.00 μm extremely fine, approaching colloidal dimen- 200.0 75.00 μm sions of 1 μm or less. In order to characterize 230.0 63.00 μm the particle size of a given powder, the United 270.0 53.00 μm States Pharmacopeia (USP) uses these descrip- 325.0 45.00 μm tive terms: very coarse, coarse, moderately coarse, fine, and very fine, which are related 400.0 38.00 μm to the proportion of powder that is capable Source: USP 31–NF 26. 0002035885.INDD 216 11/29/2013 6:54:32 PM  Chapter 6 Powders and Granules 217 Fine (No. 60): All particles pass through a ­ ispersed in a liquid vehicle (e.g., fine d No. 60 sieve, and not more than 40% pass dispersions have particles ~0.5 to 10 μm) through a No. 100 sieve. Uniform distribution of a drug substance Very fine (No. 80): All particles pass in a powder mixture or solid dosage form through a No. 80 sieve. There is no limit to to ensure dose-to-dose content uniformity greater fineness. (3) Granules typically fall within the range of Penetrability of particles intended to be 4- to 12-sieve size, although granulations inhaled for deposition deep in the respira- of powders prepared in the 12- to 20-sieve tory tract (e.g., 1 to 5 μm) (4) range are sometimes used in tablet making. Lack of grittiness of solid particles in der- mal ointments, creams, and ophthalmic Dissolution rate of particles intended preparations (e.g., fine powders may be 50 to dissolve; drug micronization can in- to 100 μm in size) crease the rate of drug dissolution and its bioavailability. A number of methods exist for the determi- Suspendability of particles intended nation of particle size, including the follow- to remain undissolved but uniformly ing (Physical Pharmacy Capsule 6.1): Physical Pharmacy Capsule 6.1 Micromeritics Micromeritics is the science of small particles; a particle is any unit of matter having defined physical dimensions. It is important to study particles because most drug dosage forms are solids, solids are not static systems, the physical state of particles can be altered by physical manipulation, and particle characteristics can alter therapeutic effectiveness. Micromeritics is the study of a number of characteristics, including particle size and size distribution, shape, angle of repose, porosity, true volume, bulk volume, apparent density, and bulkiness. Particle Size A number of techniques can be used to determine particle size and size distributions. Particle size determinations are complicated by the fact that particles are not uniform in shape. Only two relatively simple examples are provided for a detailed calculation of the average particle size of a powder mixture. Other methods are generally discussed. The techniques used include the microscopic method and the sieving method. The microscopic method can include not fewer than 200 particles in a single plane using a calibrated ocular on a microscope. Given the following data, what is the average diameter of the particles? Size Of Counted No. Of Particles Per Particles (mm) Middle Value mm “d” Group “n” “nd” 40–60 50 15 750 60–80 70 25 1,750 80–100 90 95 8,550 100–120 110 140 15,400 120–140 130 80 10,400 ∑n = 355 ∑nd = 36,850 0002035885.INDD 217 11/29/2013 6:54:32 PM  218 SECTION iiI Solid Dosage Forms and Solid Modified-Release Drug Delivery Systems Physical Pharmacy Capsule 6.1 cont. Σ nd 36, 850 dav = = = 103.8 µm Σn 355 The sieving method entails using a set of US standard sieves in the desired size range. A stack of sieves is arranged in order, the powder placed in the top sieve, the stack shaken, the quantity of the powder resting on each sieve weighed, and this calculation performed: Arithmetic Mean % Retained ¥ Mean Sieve Opening (mm) Weight Retained (g) % Retained Opening (mm) 20/40 0.630 15.5 14.3 9.009 40/60 0.335 25.8 23.7 7.939 60/80 0.214 48.3 44.4 9.502 80/100 0.163 15.6 14.3 2.330 100/120 0.137 3.5 3.3 0.452 108.7 100.0 29.232 dav = ∑ (% retained) × (average size) = 29,232 = 0.2923 mm 100 100 Another method of particle size determination entails sedimentation using the Andreasen pipette, a special cylindrical container from which a sample can be removed from the lower portion at selected intervals. The powder is dispersed in a nonsolvent in the pipette and agi- tated, and 20-mL samples are removed over time. Each 20-mL sample is dried and weighed.The particle diameters can be calculated from this equation: 18 hη d= (ρi – ρe )gt where d is the diameter of the particles, h is the height of the liquid above the sampling tube orifice, h is the viscosity of the suspending liquid, ρi–ρe is the density difference between the suspending liquid and the particles, g is the gravitational constant, and t is the time in seconds. Other methods of particle size determinations include elutriation, centrifugation, per- meation, adsorption, electronic sensing zone (the Coulter counter), and light obstruction. The last includes both standard light and laser methods. In general, the resulting average particle sizes by these techniques can provide the average particle size by weight (sieve method, light scattering, sedimentation method) and the average particle size by volume (light scattering, electronic sensing zone, light obstruction, air permeation, and even the optical microscope). Angle of Repose The angle of repose is a relatively simple technique for estimating the flow properties of a pow- der. It can easily be determined by allowing a powder to flow through a funnel and fall freely 0002035885.INDD 218 11/29/2013 6:54:33 PM  Chapter 6 Powders and Granules 219 Physical Pharmacy Capsule 6.1 cont. onto a surface. The height and diameter of the resulting cone are measured, and the angle of repose is calculated from this equation: tan q = h/r where h is the height of the powder cone and r is the radius of the powder cone. Example 1 A powder was poured through the funnel and formed a cone 3.3 cm high and 9 cm in diam- eter. What is the angle of repose? tan q = h/r = 3.3/4.5 = 0.73 arc tan 0.73 = 36.25° Powders with a low angle of repose flow freely, and powders with a high angle of repose flow poorly. A number of factors, including shape and size, determine the flow properties of pow- ders. Spherical particles flow better than needles. Very fine particles do not flow as freely as large particles. In general, particles in the size range of 250 to 2,000 mm flow freely if the shape is amenable. Particles in the size range of 75 to 250 mm may flow freely or cause problems, depending on shape and other factors. With most particles smaller than 100 mm, flow is a problem. Porosity, Void, and Bulk Volume If spheres and the different ways they pack together are used as an example, two pos- sibilities arise. The closest packing may be rhombus–triangle, in which angles of 60 and 120 degrees are common. The space be- tween the particles, the void, is about 0.26, re- sulting in porosity, as described later, of about 26%. Another packing, cubical, with the cubes packed at 90-degree angles to each other, may be considered. This results in a void of about 0.47 or a porosity of about 47%. This is the most open type of packing. If particles are not uniform, the smaller particles will slip into the void spaces between the larger particles and decrease the void areas. Packing and flow are important, as they af- fect the size of the container required for pack- aging, the flow of granulations, the efficiency of the filling apparatus for making tablets and capsules, and the ease of working with the powders. The characteristics used to describe pow- ders include porosity, true volume, bulk volume, apparent density, true density, and bulkiness. Tapped density tester (Courtesy of Varian Inc.) The photo is a tapped density tester. 0002035885.INDD 219 11/29/2013 6:54:34 PM  220 SECTION iiI Solid Dosage Forms and Solid Modified-Release Drug Delivery Systems Physical Pharmacy Capsule 6.1 cont. Porosity is Void × 100 This value should be determined experimentally by measuring the volume occupied by a selected weight of a powder, Vbulk. The true volume, V, of a powder is the space occupied by the powder exclusive of spaces greater than the intramolecular space. Void can be defined as Vbulk − V Vbulk therefore, porosity is Vbulk − V × 100 Vbulk and the bulk volume is true volume + porosity. Apparent Density, True Density, and Bulkiness The apparent density, ra, is weight of the sample Vbulk The true density, r, is weight of the sample V The bulkiness, B, is the reciprocal of the apparent density, B = 1/ra Example 2 A selected powder has a true density (r) of 3.5 g/cc. Experimentally, 2.5 g of the powder mea- sures 40 mL in a cylindrical graduate. Calculate the true volume, void, porosity, apparent density, and bulkiness. True volume: Density =mass(weight)/volume Volume =mass(weight)/density 2.5 g/ /(3.5 g/cc)0.715 cc Void: Vbulk − V 40 mL − 0.715 mL = = 0.982 Vbulk 40 mL 0002035885.INDD 220 11/29/2013 6:54:36 PM  Chapter 6 Powders and Granules 221 Physical Pharmacy Capsule 6.1 cont. Porosity: Void × 100 = 0.982 × 100 = 98.2% Apparent density: 2.5 g (Pa) = = 0.0625 g/mL 40 mL Bulkiness: 1 1/ Pa= = 16 mL/g 0.06265(g/mL ) Powders with a low apparent density and a large bulk volume are considered light, and those with a high apparent density and a small bulk volume are considered heavy. Sieving, in which particles are passed by dimensions with a holographic camera, mechanical shaking through a series of allowing the particles to be individually sieves of known and successively smaller imaged and sized (range 1.4 to 100 μm) (6) size and the proportion of powder passing Cascade impaction, which is based on the through or being withheld on each sieve is principle that a particle driven by an air- determined (range about 40 to 9,500 μm, stream will hit a surface in its path, pro- depending upon sieve sizes) (2). vided its inertia is sufficient to overcome Microscopy, in which sample particles are the drag force that tends to keep it in the sized through the use of a calibrated grid airstream (7). Particles are separated into background or other measuring device various size ranges by successively in- (range 0.2 to 100 μm) creasing the velocity of the airstream in Sedimentation rate, in which particle size which they are carried. is determined by measuring the terminal Online methods for determining particle settling velocity of particles through a liq- sizes during production are available (8). uid medium in a gravitational or centrifu- gal environment (range 0.8 to 300 μm). These methods and others may be used for the Sedimentation rate may be calculated analysis of particle size and shape. For some from Stokes law. materials, a single method may be sufficient; Light energy diffraction or light scattering, however, a combination of methods is fre- in which particle size is determined by the quently preferred to provide greater certainty reduction in light reaching the sensor as of size and shape parameters. Most commer- the particle, dispersed in a liquid or gas, cial particle size analyzers are automated and passes through the sensing zone (range linked with computers for data processing, 0.2 to 500 μm) (4). Laser scattering utilizes distribution analysis, and printout. a He–Ne laser, silicon photo diode detec- The science of small particles is discussed tors, and an ultrasonic probe for particle further in Physical Pharmacy Capsule 6.1, dispersion (range 0.02 to 2,000 μm) (5). Micromeritics. Physical Pharmacy Capsule Laser holography, in which a pulsed la- 6.2, Particle Size Reduction, points out that a ser is fired through an aerosolized par- reduction in particle size increases the num- ticle spray and is photographed in three ber of particles and the total surface area. 0002035885.INDD 221 11/29/2013 6:54:37 PM  222 SECTION iiI Solid Dosage Forms and Solid Modified-Release Drug Delivery Systems Physical Pharmacy Capsule 6.2 Particle Size Reduction Comminution, reduction of the particle size of a solid substance to a finer state, is used to fa- cilitate crude drug extraction, increase the dissolution rates of a drug, aid in the formulation of pharmaceutically acceptable dosage forms, and enhance the absorption of drugs. The reduc- tion in the particle size of a solid is accompanied by a great increase in the specific surface area of that substance. An example of the increase in the number of particles formed and the resulting surface area is as follows: Example Increase in Number of Particles If a powder consists of cubes 1 mm on edge and it is reduced to particles 10 mm on edge, what is the number of particles produced? 1. 1 mm equals 1,000 mm. 2. 1,000/10 mm = 100 pieces produced on each edge; that is, if the cube is sliced into 100 pieces on the x-axis, each 10 mm long, 100 pieces result. 3. If this is repeated on the y- and z-axes, the result is 100 × 100 × 100 = 1 million particles ­produced, each 10 mm on edge, for each original particle 1 mm on edge. This can also be written as (102)3 = 106. Increase in Surface Area What increase in the surface area of the powder is produced by decreasing the particle size from 1 to 10 mm? 1. The 1-mm cube has six surfaces, each 1 mm on edge. Each face has a surface area of 1 mm2. Because there are six faces, this is 6-mm2 surface area per particle. 2. Each 10-mm cube has six surfaces, each 10 mm on edge. Each face has a surface area of 10 × 10 = 100 mm2. Because there are six faces, this is 6 × 100 mm2, or 600 mm2 surface area per particle. Since 106 particles resulted from comminuting the 1-mm cube, each 10 mm on edge, the surface area now is 600 mm2 × 106, or 6 × 108 mm2. 3. To get everything in the same units for ease of comparison, convert the 6 × 108 mm2 into square millimeters as follows. 4. Since there are 1,000 mm/mm, there must be 1,0002, or 1 million mm2/mm2. This is more ap- propriately expressed as 106 mm2/mm2, 6 × 108 µm2 = 6 × 102 mm2 106 µm2 /mm2 The surface areas have been increased from 6 to 600 mm2 by the reduction in particle size of cubes 1 mm on edge to cubes 10 mm on edge, a 100-fold increase in surface area. This can have a significant increase in the rate of dissolution of a drug product. Comminution of Drugs one with a smooth surface (as a glass mor- tar). Grinding a drug in a mortar to reduce its On a small scale, the pharmacist reduces the particle size is termed trituration or comminu- size of chemical substances by grinding with tion. On a large scale, various types of mills a mortar and pestle. A finer grinding action and pulverizers may be used to reduce par- is accomplished by using a mortar with a ticle size. Figure 6.1 shows one such piece of rough surface (as a porcelain mortar) than 0002035885.INDD 222 11/29/2013 6:54:38 PM  Chapter 6 Powders and Granules 223 8 track is commonly used to incorporate the materials. Mineral oil and glycerin are com- monly used levigating agents. Blending Powders When two or more powdered substances are to be combined to form a uniform mix- ture, it is best to reduce the particle size of each powder individually before weighing and blending. Depending on the nature of the ingredients, the amount of powder, and the equipment, powders may be blended by spatulation, trituration, sifting, and tumbling. Spatulation is blending small amounts of powders by movement of a spatula through them on a sheet of paper or an ointment tile. It is not suitable for large quantities of pow- ders or for powders containing potent sub- stances, because homogeneous blending is not as certain as other methods. Very little compression or compacting of the powder FIGURE 6.1 A FitzMill comminutor, model VFS-D6A- results from spatulation, which is especially PCS, used for particle reduction, with attached con- tainment system for protection of environment and suited to mixing solid substances that form prevention of product contamination. (Courtesy of the eutectic mixtures (or liquefy) when in close Fitzpatrick Company.) and prolonged contact with one another (Table 6.2). To diminish contact, a powder prepared from such substances is commonly equipment, a FitzMill comminuting machine mixed in the presence of an inert diluent, with a product containment system. Through such as light magnesium oxide or magne- the grinding action of rapidly moving blades sium carbonate, to separate the troublesome in the comminuting chamber, particles are agents physically. reduced in size and passed through a screen Trituration may be employed both to com- of desired dimension to the collection con- minute and to mix powders. If simple admix- tainer. The collection and containment sys- ture is desired without the special need for tem protects the environment from chemical comminution, the glass mortar is usually dust, reduces product loss, and prevents preferred. When a small amount of a potent product contamination. substance is to be mixed with a large amount Levigation is commonly used in small-scale of diluent, the geometric dilution method is preparation of ointments and suspensions used to ensure the uniform distribution of the to reduce the particle size and grittiness of potent drug. This method is especially indi- the added powders. A mortar and pestle cated when the potent substance and other or an ointment tile may be used. A paste is ingredients are the same color and a visible formed by combining the powder and a sign of mixing is lacking. By this method, the small amount of liquid (the levigating agent) potent drug is placed with an approximately in which the powder is insoluble. The paste equal volume of the diluent in a mortar and is then triturated, reducing the particle size. is mixed thoroughly by trituration. Then, a The levigated paste may then be added to second portion of diluent equal in volume the ointment base and the mixture made uni- to the mixture is added and the trituration form and smooth by rubbing them together repeated. This process is continued by add- with a spatula on the ointment tile. A figure ing an equal volume of diluent to the powder 0002035885.INDD 223 11/29/2013 6:54:38 PM  224 SECTION iiI Solid Dosage Forms and Solid Modified-Release Drug Delivery Systems Table 6.2 Substances that Soften or Liquify when Mixed Acetanilide Acetophenetidin Aminopyrine Antipyrine Aspirin Benzocaine Beta-naphthol Camphor Chloral hydrate Lidocaine FIGURE 6.2 Industrial-size solid-state processor or twin shell blender used to mix solid particles. (Courtesy Menthol of Abbott Laboratories.) Phenacetin Phenol sift or percolate through coarse particles and Phenyl salicylate end up at the bottom of the container and Prilocaine actually “lift” the larger particles to the sur- face. Fine, aerated powders with differences Resorcinol in particle size or density may result in a stria- Salicylic acid tion pattern and may occur during powder Thymol transfer. Dusting occurs when the finer, lighter mixture and repeating this until all of the diluent is incorporated. Some pharmacists add an inert colored powder to the diluent before mixing to permit visual inspection of the mixing process. Powders may also be mixed by passing them through sifters like those used in the kitchen to sift flour. Sifting results in a light, fluffy product. This process is not acceptable for the incorporation of potent drugs into a diluent powder. Another method of mixing powders is tumbling the powder in a rotating chamber. Special small-scale and large-scale motorized powder blenders mix powders by tumbling them (Figs. 6.2 to 6.5). Mixing by this process is thorough but time consuming. Such blend- ers are widely employed in industry, as are mixers that use motorized blades to blend powders in a large vessel. Segregation is an undesirable separation of the different components of the blend. Segregation may occur by sifting or percola- tion, air entrapment (fluidization), and particle FIGURE 6.3 Ribbon blender used for mixing powders entrapment (dusting). Fine particles tend to and preparing granulations. (Courtesy of Littleford Day.) 0002035885.INDD 224 11/29/2013 6:54:39 PM  Chapter 6 Powders and Granules 225 powders dry, one can mix them with a bulky powder adsorbent such as light magnesium oxide or magnesium carbonate. Also, these powders should be triturated very lightly on a pill tile by using a spatula for mixing rather than a mortar and pestle. The latter will cause compression and make the prob- lem worse. It may also be advisable to double wrap the papers. Mixing these powders with the bulky powders first and then performing a light blending can minimize the problem. Another approach is to first make the eutec- tic and then adsorb the paste or liquid that results onto a bulky powder. One also has the option of dispensing the ingredients sep- arately. After preparation, the charts can be FIGURE 6.4 Laboratory-scale V-blender. (Courtesy of dispensed in a plastic bag. GlobePharma.) Hygroscopic and Deliquescent particles remain suspended in air longer and Powders do not settle as quickly as the larger or denser particles. General guidelines to minimize or Hygroscopic powders will absorb moisture prevent segregation include (a) minimum from the air. Deliquescent powders will number of transfer steps and drop heights; (b) absorb moisture from the air to the extent that control of dust generation; (c) control of flu- they will partially or wholly liquefy. These idization of the powder; (d) slow fill/transfer problems must be overcome for the powder rate; (e) appropriate venting; (f ) use of a deflec- to be acceptable to the patient and usable. tor, vane, or distributor; and (g) proper hopper The best approach is to dispense the ingre- design and operating valves (if present). dients in tight containers and incorporate a desiccant packet or capsule when necessary. Eutectics The patient should be instructed to store the powder in a dry place in a tightly closed con- Some powders may become sticky or pasty, tainer. To lessen the extent of the problem, or they may liquefy when mixed together, the compounding pharmacist can in some such as those listed in Table 6.2. To keep the situations dilute the powder with an inert drying powder to reduce the amount of sur- face area exposed to the moisture. Common hygroscopic and deliquescent powders are listed in Table 6.3. Efflorescent Powders An efflorescent powder (Table 6.4) is a crystal- line powder that contains water of hydration or crystallization. This water can be liberated either during manipulations or on expo- sure to a low-humidity environment. If this occurs, the powder will become sticky and pasty, or it may even liquefy. One approach is to use an anhydrous salt form of the drug, FIGURE 6.5 Laboratory-scale Triple V-type blender. keeping in mind the potency differential (Courtesy of GlobePharma.) between its anhydrous form and its hydrated 0002035885.INDD 225 11/29/2013 6:54:40 PM  226 SECTION iiI Solid Dosage Forms and Solid Modified-Release Drug Delivery Systems Table 6.3 Common Hygroscopic Table 6.4 Common Efflorescent and Deliquescent Powders Powders Alums Ammonium bromide Atropine sulfate Ammonium chloride Caffeine Ammonium iodide Calcium lactate Calcium bromide Citric acid Calcium chloride Cocaine Ephedrine sulfate Codeine Hydrastin hydrochloride Codeine phosphate Hydrastine sulfate Codeine sulfate Hyoscyamine hydrobromide Ferrous sulfate Hyoscyamine sulfate Morphine acetate Iron and ammonium citrate Quinine bisulfate Lithium bromide Quinine hydrobromide Pepsin Quinine hydrochloride Phenobarbital sodium Scopolamine hydrobromide Physostigmine hydrobromide Sodium acetate Physostigmine hydrochloride Sodium carbonate (decahydrate) Physostigmine sulfate Sodium phosphate Pilocarpine alkaloid Strychnine sulfate Potassium acetate Terpin hydrate Potassium citrate Sodium bromide Sodium iodide of the powder. Pasty material can be added Sodium nitrate to dry powder by mixing it with increasing Zinc chloride quantities of the powder, which will dry out the paste. It is best to add some materi- als by preparing an alcoholic solution and form. Another method is to include a drying spraying it evenly on the powder, which has bulky powder and to use a light, noncom- been spread out on a pill tile. The alcohol, pacting method of mixing the powders. or another suitable solvent, should then be allowed to evaporate, leaving the ingredi- Explosive Mixtures ent uniformly dispersed. This method may be especially suitable for high-potency drugs Some combinations of powders (Table 6.5) or flavoring agents because it minimizes the may react violently when mixed together. possibility that clumps of active drug will Special precautions must be taken if it is nec- develop in the powder blend. essary to prepare a formulation containing these mixtures. Medicated Powders Incorporation of Liquids Some medicated powders are intended to A liquid that is to be incorporated into a dry be used internally and others, externally. powder can be adsorbed onto an inert mate- Most powders for internal use are taken rial (carrier) such as lactose or starch and orally after mixing with water or in the case then geometrically introduced into the bulk of infants in their infant formulas. Some 0002035885.INDD 226 11/29/2013 6:54:40 PM  Chapter 6 Powders and Granules 227 Table 6.5 Common Oxidizing and and still others for use as a vaginal douche. Reducing Agents that Medicated powders for external use are may React Violently dusted on the affected area from a sifter-type when Mixed container or applied from a powder aerosol. Powders intended for external use should Oxidizing Agents Reducing Agents bear a label marked external use only or a Bromine Alcohol similar label. Chlorates Bisulfites Medicated powders for oral use may be Chloric acid Bromides intended for local effects (e.g., laxatives) or systemic effects (e.g., analgesics) and may be Chlorine Charcoal preferred to counterpart tablets and capsules Chromates Glycerin by patients who have difficulty swallowing Dichromates Hydriodic acid solid dosage forms. The doses of some drugs Ethyl nitrite spirit Hypophosphites are too bulky to be formed into tablets or Hydrogen peroxide Hypophosphorous capsules of convenient size, so they may be acid administered as powders. For administra- Hypochlorites Iodides tion, they can be mixed with a liquid or soft Hypochlorous acid Lactose food. Powders taken orally for systemic use may be expected to result in faster rates of Iodine Nitrites (in some situations) dissolution and absorption than solid dosage forms, because there is immediate contact Nitrates Organic substances (in general) with the gastric fluids; however, the actual advantage in terms of therapeutic response Nitric acid Phosphorus may be negligible or only minimal, depend- Nitrites Sugar ing on the drug release characteristics of the Nitrohydrochloric acid Sulfides counterpart products. A primary disadvan- Nitrous acid Sulfites tage of the use of oral powders is the unde- Perborates Sulfur sirable taste of the drug. Permanganates Sulfurous acid Some medications, notably antibiotics for children, are intended for oral administra- Permanganic acid Tannic acid tion as liquids but are relatively unstable in Peroxides Tannins liquid form. They are provided to the phar- Potassium chlorate Thiosulfates macist by the manufacturer as a dry powder Potassium dichromate Volatile oils or granule for constitution with a specified Potassium nitrate quantity of purified water at the time of dis- Potassium pensing. Under labeled conditions of stor- permanganate age, the resultant product remains stable for Sodium peroxide the prescribed period of use, generally up to 2 weeks. Sterile dry powders intended to be Silver nitrate constituted with water or another suitable Silver oxide solvent prior to administration by injection Silver salts are discussed in Chapter 15. Trinitrophenol Aerosol Powders Some medicated powders are administered powders are intended to be inhaled for local by inhalation with the aid of dry powder and systemic effects. Other dry powders are inhalers (DPIs), which deliver micronized commercially packaged for constitution with particles of medication in metered quantities a liquid solvent or vehicle, some for admin- (Fig. 6.6). A DPI is a device used to administer istration orally, others for use as an injection, an inhalation powder in a finely divided state 0002035885.INDD 227 11/29/2013 6:54:40 PM  228 SECTION iiI Solid Dosage Forms and Solid Modified-Release Drug Delivery Systems agent, these products contain inert propel- lants and pharmaceutical diluents, such as crystalline alpha-lactose monohydrate, to aid the formulation's flow properties and metering uniformity and to protect the pow- der from humidity (9). Powder blowers or insufflators (Fig. 6.8) may be used to deliver dry powders to various parts of the body, for example, the nose, throat, lung, and vagina. Depression of the device's rubber bulb causes turbulence of the powder in the vessel, forc- ing it out through the orifice in the tip. Inhalation powders, commonly known as dry DPIs, consist of a mixture of active phar- maceutical ingredients (APIs) and typically the carrier; and all formulation components exist in a finely divided solid state packaged in a suitable container closure system. The dose is released from the packaging by a mechanism and is mobilized into a fine dispersion upon oral inhalation by the patient. The formulation may be packaged in premetered or device- FIGURE 6.6 Metered inhalation aerosol containing a metered units. Premetered DPIs contain a micronized medicated powder and inert propellants. previously measured amount of formulation Each dose is delivered through the mouthpiece upon ac- in individual units (e.g., capsules, blisters) tivation of the aerosol unit's valve. that are inserted into the device before use. Premetered DPIs may also contain premetered suitable for oral inhalation by the patient. An dose units as ordered multidose assemblies in inhalation powder is one used with a device the delivery system. Premetered DPIs include that aerosolizes and delivers an accurately a mechanism designed to pierce the capsule metered amount. or open the unit-dose container and allow Most of these products are used in the mobilization and aerosolization of the powder treatment of asthma and other bronchial dis- orders that require distribution of medication deep in the lungs (Fig. 6.7). To accomplish this, the particle size of the micronized medi- cation is prepared in the range of 1 to 6 μm in diameter. In addition to the therapeutic >10µ Lactose (30-60µ) 10µ Intal 6µ Cromolyn Sodium (2-6µ) FIGURE 6.8 A general-purpose powder blower or in- 3µ sufflator. The powder is placed in the vessel. When the 1µ rubber bulb is depressed, internal turbulence disperses