Page 1 of 64
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`Insys Exhibit 2001
`CFAD v. Insys
`IPR2015-01797
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`Page 2 of 64
`
`

`
`OBJECTIVES
`
`V i
`After reading this chapter, the student will be able to)’
`1. Differentiate between a suspension, an emulsion, algel, and onmagma
`2. Compare and contrast the different disperse systems, and list advcifitage
`V
`I
`and disadvantages of each system
`
`)
`
`3. Compare and contrast the following emulsification theories: surface tension,
`oriented-wedge, and interfacial film
`
`. Define and differentiate the following terms from one another: lyophobic.
`lyophilic, hydrophobic, hydrophilic, amphiphilic, imbibition, swelling, syneresis,
`thixotropy, and xerogel
`
`. Evaluate and select a proper disperse system and delivery method fora
`given purpose, patient population, and/or patient circumstance
`
`This chapter includes the main types of liq-
`uid preparations containing undissolved or
`immiscible drug distributed throughout a
`vehicle. In these preparations, the substance
`distributed is referred to as the dispersed phase,
`and the vehicle is termed the dispersing phase
`or dispersion medium. Together, they produce
`a dispersed or disperse system.
`The particles of the dispersed phase are
`usually solid materials that are insoluble in
`the dispersion medium. In the case of emul-
`sions, the dispersed phase is a liquid that
`is neither soluble nor miscible with the liq-
`uid of the dispersing phase. Emulsification
`results in the dispersion of liquid drug as fine
`droplets throughout the dispersing phase. In
`the case of an aerosol, the dispersed phase
`may be small air bubbles throughout a solu-
`tion or an emulsion. Dispersions also consist
`of droplets of a liquid (solution or suspen-
`sion) in air.
`The particles of the dispersed phase vary
`widely in size, from large particles visible
`to the naked eye down to particles of col-
`loidal dimension, falling between 1.0 nm
`
`and 0.5 pm. A discussion on the difference
`between particles and molecules is pro-
`vided in Physical Pharmacy Capsule 14.1.
`Dispersions
`containing coarse particles,
`usually 10 to 50 mm, are referred to as coarse
`dispersions; they include the suspensions and
`emulsions. Dispersions containing particles
`of smaller size are termed fine dispersions (0.5
`to 10 um) and, if the particles are in the col-
`loidal range, colloidal dispersions. Magmas and
`gels are fine dispersions.
`Largely because of their greater size, par-
`ticles in a coarse dispersion have a greater
`tendency to separate from the dispersion
`medium than do the particles of a fine disper-
`sion. Most solids in dispersion tend to settle
`to the bottom of the container because of their
`
`greater density than the dispersion medium,
`whereas most emulsified liquids for oral use
`are oils, which generally have less density
`than the aqueous medium in which they are
`dispersed, so they tend to rise toward the
`top of the preparation. Complete and uni-
`form redistribution of the dispersed phase
`is essential
`to the accurate administration
`
`445
`
`Page 3 of 64
`
`

`
`446
`
`SECTION VI - LIQUID DOSAGE FORMS
`
`PHYSICAL PHARMACY CAPSULE 'l4.l
`
`Particles Versus Molecules
`
`Particles of drug substances can actually range from an aggregation of two or more molecules
`to millions of molecules.The term ‘partic|e“ should not be confused with “molecule.” The mol-
`ecule is the smallest unit of any chemical compound that possesses all the native properties of
`that compound. Particles consist of numerous molecules, generally in a solid state (but can be
`liquid or gaseous). Dissolution is the solid to liquid transformation that converts solid drug par-
`ticles to individual, dissolved liquid molecules. Even the smallest invisible drug particle contains
`billions of molecules. Most nonprotein or small molecule organic drugs have formula weights
`ranging from 150 to 500.
`
`EXAMPLE
`
`Let's look at how many molecules may be present in a 1-ng particle of ibuprofen with a formula
`weight of 206:
`
`(l ng)(l g) (6.02 x l 023 molecules)
`(particle) (1x10°) (206 g) (Mole)
`
`= 2.923 X10" molecules
`
`This illustrates that a 1—ng invisible particle will contain 2.923,000,000.000 molecules.
`
`of uniform doses. For a properly prepared
`dispersion, this should be accomplished by
`moderate agitation of the container.
`The focus of this chapter is on dispersions
`of drugs administered orally or topically. The
`same basic pharmaceutical characteristics
`apply to dispersion systems administered by
`other routes. Included among these are oph-
`thalmic and otic suspensions and sterile sus-
`pensions for injection, covered in Chapters
`17 and 15, respectively.
`
`SUSPENSIONS
`
`Suspensions may be defined as prepara-
`tions containing finely divided drug par-
`ticles (the suspensoid) distributed somewhat
`uniformly throughout a vehicle in which the
`drug exhibits a minimum degree of solubil-
`ity. Some suspensions are available in ready-
`to-use form,
`that
`is, already distributed
`through a liquid vehicle with or without sta-
`bilizers and other additives (Fig. 14.1). Other
`preparations are available as dry powders
`intended for suspension in liquid vehicles.
`Generally, this type of product is a powder
`mixture containing the drug and suitable
`
`suspending and dispersing agents to be
`diluted and agitated with a specified quan-
`tity of vehicle, most often purified water.
`Figure 14.2 demonstrates preparation of this
`type of product. Drugs that are unstable if
`maintained for extended periods in the pres-
`ence of an aqueous vehicle (e.g., many anti-
`biotic drugs) are most frequently supplied as
`dry powder mixtures for reconstitution at the
`time of dispensing. This type of preparation
`is designated in the USP by a title of the form
`”for Oral Suspension.” Prepared suspen-
`sions not requiring reconstitution at the time
`of dispensing are simply designated as ”Oral
`Suspension.”
`
`Reasons for Suspensions
`
`reasons for preparing
`There are several
`suspensions. For example, certain drugs
`are chemically unstable in solution but
`stable when suspended. In this instance,
`the suspension ensures chemical stability
`while permitting liquid therapy. For many
`patients, the liquid form is preferred to the
`solid form of the same drug because of the
`ease of swallowing liquids and the flexibility
`
`Page 4 of 64
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`Page 5 of 64
`
`

`
`448
`
`SECTION VI - LIQUID DOSAGE FORMS
`
`be readily redispersed upon gentle shal<-
`ing of the container.
`. The particle size of the suspensoid should
`remain fairly constant throughout long
`periods of undisturbed standing.
`. The suspension should pour readily and
`.
`.
`evenly from its container.
`
`suspension,
`These main features of a
`which depend on the nature of the dis-
`persed phase, the dispersion medium, and
`
`pharmaceutical adjuncts, will be discussed
`briefly.
`
`Sedimentation Rate Of the
`Particles Of (J Suspension
`
`The various factors involved in the rate of
`
`settling of the particles of a suspension are
`embodied in the equation of Stokes law,
`which is presented inthe Physical Pharmacy
`Capsule 14.2.
`
`PHYSICAL PHARMACY CAPSULE 14.2
`
`Sedimentation Rate and Stokes Equation
`
`fi=d’(n-99):;
`dt
`1811
`
`Stokes equation:
`
`where
`
`dx/dt is the rate of settling.
`d is the diameter of the particles.
`p, is the density of the particle.
`pa is the density of the medium.
`g is the gravitational constant, and
`n is the viscosity of the medium.
`
`A number of factors can be adjusted to enhance the physical stability of a suspension.
`including the diameter of the particles and the density and viscosity of the medium.The effect
`of changing these is illustrated in the following example.
`
`EXAMPLE
`
`A powder has a density of 1.3 g/mL and an average particle diameter of 2.5 pg (assuming
`the particles to be spheres). According to the Stokes equation, this powder will settle In water
`(viscosity of 1 CP assumed) at this rate:
`
`(2.5><‘|0“')2 (1 .3—1.o) (980)
`I8 x 0.01
`
`=l.02 x l0“cm/s
`
`If the particle size of the powder is reduced to 0.25 pm and water is still used as the disper-
`sion medium, the powder will now settle at this rate:
`
`-6
`(2.5 x 1 04)’ (1 .3 — 1.o)(9ao) _
`wxom
`—l.02xl0 cm/s
`
`As is evident, a decrease in particle size by a factor of 10 results in a reduction in the rate of
`settling by a factor of l00.This enhanced effect is a result of the d factor in the Stokes equation
`being squared.
`
`Page 6 of 64
`
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`Page 7 of 64
`
`

`
`450
`
`SECTION VI - LIQUID DOSAGE FORMS
`
`is increased, it is done so only to a modest
`extent to avoid these difficulties.
`
`likely to become greatly larger or to form a
`solid cake upon standing.
`
`The viscosity characteristics of a suspen-
`sion may be altered not only by the vehicle
`used but also by the solid content. As the
`proportion of solid particles in a suspension
`increases, so does the viscosity. The viscos-
`ity of a pharmaceutical preparation may be
`determined through the use of a viscometer,
`such as a Brookfield viscometer, which mea-
`
`sures viscosity by the force required to rotate
`a spindle in the fluid being tested (Fig. 14.3).
`For the most part, the physical stability of
`a pharmaceutical suspension appears to be
`most appropriately adjusted by an alteration
`in the dispersed phase rather than through
`great changes in the dispersion medium. In
`most instances, the dispersion medium sup-
`ports the adjusted dispersed phase. These
`adjustments are concerned mainly with par-
`ticle size, uniformity of particle size, and sep-
`aration of the particles so that they are not
`
`Physical Features of the Dispersed
`Phase of a Suspension
`
`Probably the most important single consid-
`eration in a discussion of suspensions is the
`size of the particles. In most good pharma-
`ceutical suspensions, the particle diameter is
`1 to 50 pm.
`Generally, particle size reduction is accom-
`plished by dry milling prior to incorporation
`of the dispersed phase into the dispersion
`medium. One of the most rapid, conve-
`nient, and inexpensive methods of produc-
`ing fine drug powders of about 10 to 50 um
`size is micropulverization. Micropulverizers
`are high-speed attrition or impact mills that
`are efficient in reducing powders to the size
`acceptable for most oral and topical suspen-
`sions. For still finer particles, under 10 um,
`
`Synchronous motor
`
`Speed selector knob
`
`On—off toggle switch
`
`Clutch lever
`
`Knurled nut
`
`Handle
`
`Polnter
`
`Jewel bearing support /‘
`
`Spindle coupling nut
`
`Immersion mark
`
`Spindle body
`
`Gear train
`
`Circular
`bubble level
`
`Dial
`
`Calibrated
`spiral spring
`
`Upper shalt
`
`spindle guard
`
`Sample
`container
`
`FIGURE l4.3 The Brookfield viscometer. (Courtesy of Brooklield Engineering
`Laboratories.)
`
`Page 8 of 64
`
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`Page 9 of 64
`
`

`
`452
`
`SECTION Vi - LIQUID DOSAGE FORMS
`
`measurement of dosage and, from an aes-
`thetic point of view, produces too unsightly
`a supernatant layer. In many commercial
`suspensions, suspending agents are added to
`the dispersion medium to lend it structure.
`Carboxymethylcellulose (CMC), methylce1-
`lulose, microcrystalline cellulose, polyvinyl-
`pyrrolidone, xanthan gum, and bentonite are
`a few of the agents employed to thicken the
`dispersion medium and help suspend the
`suspensoid. When polymeric substances and
`hydrophilic colloids are used as suspending
`
`agents, appropriate tests must be performed
`to show that the agent does not interfere with
`availability of the drug. These materials can
`bind certain medicinal agents,
`rendering
`them unavailable or only slowly available for
`therapeutic function. Also, the amount of the
`suspending agent must not be such to render
`the suspension too viscous to agitate (to dis-
`tribute the suspensoid) or to pour. The study
`of flow characteristics is rheology. A sum-
`mary of the concepts of rheology is found in
`Physical Pharmacy Capsule 14.3.
`
`PHYSICAL PHARMACY CAPSULE 14.3
`
`Rheology
`
`Rheology, the study of flow, addresses the viscosity characteristics of powders, fluids. and
`semisolids. Materials are divided into two general categories, Newtonian and non-Newtonian,
`depending on their flow characteristics. Newtonian flow is characterized by constant viscosity,
`regardless of the shear rates applied. Non-Newtonian flow is characterized by a change in
`viscosity characteristics with increasing shear rates. Non-Nevvtonian flow includes plastic, pseu-
`doplastic, and dilatant flow.
`The Newton law of flow relates parallel layers of liquid: with the bottom layer fixed, when a
`force is placed on the top layer. the top plane moves at constant velocity, and each lower layer
`moves with a velocity directly proportional to its distance from the stationary bottom layer. The
`velocity gradient, or rate of shear (dv/dr), is the difference of velocity dv between two planes of
`liquid separated by the distance clr. The force (F’/A) applied to the top layer that is required to
`result in flow (rate of shear, G) is called the shearing stress (F). The relationship can be expressed:
`
`dv
`F’
`A ndr
`
`where 11 is the viscosity coefficient or viscosity.This relationship is often written:
`
`"=6
`
`where
`
`F = F’/A and
`G = dV/d|'.
`
`The higher the viscosity of a liquid, the greater the shearing stress required to produce a cer-
`tain rate of shear.A plot of F versus G yields a rheogram.A Newtonian fluid will plot as a straight
`line with the slope of the line being 11. The unit of viscosity is the poise. the shearing force
`required to produce a velocity of l cm/s between two parallel planes of liquid, each 1 cm? in
`area and separated by a distance of l cm.The most convenient unit to use is the centipoise,
`or cP (equivalent to 0.01 poise).
`These basic concepts can be illustrated in the following two graphs.
`
`Page 10 of 64
`
`

`
`CHAPTER 14 - DISPERSE SYSTEMS
`
`453
`
`PHYSICAL PHARMACY CAPSULE 14.3 CONT.
`
`RateofShear
`
`Shearing Stress
`
`Shear Rate
`
`EXAMPLE I
`What is the shear rate when an oil is rubbed into the skin with a relative rate of motion between
`
`the fingers and the skin of about 10 cm/ s and the film thickness is about 0.02 cm?
`-I
`10cm/s _
`0.02
`' 500 S
`
`G:
`
`The viscosity of Newtonian materials can be easily determined using a capillary viscometer,
`such as the Ostwald pipette, and the following relationship:
`
`where
`
`n’ = ktd
`
`n’ is viscosity;
`k is a coefficient, including such factors as the radius and length of the capillary, volume of
`the liquid flowing. pressure head, and so on;
`t is time: and
`
`d is density of the material.
`
`The official compendia, the USP and NF. use kinematic viscosity, the absolute viscosity divided
`by the density of the liquid, as follows:
`
`Kinematic viscosity = n’ / p
`
`The relative viscosity of a liquid can be obtained by using a capillary viscometer and compar-
`ing data with a second liquid of known viscosity, provided the densities of the two liquids are
`known. as follows:
`
`'1' / 112. = (o*)/ (vote)
`
`EXAMPLE 2
`
`At 25°C, water has a density of l g/mL and a viscosity of 0.895 cF!The time of flow of water in a
`capillary viscometer is 15 seconds. A 50% aqueous solution at glycerin has a flow time of 750
`seconds. The density of the glycerin solution is 1.216 g/mL. What is the viscosity of the glycerin
`solution?
`
`Page 11 of 64
`
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`Page 12 of 64
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`

`
`CHAPTER 14 - DISPEPSE SYSTEMS
`
`455
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`PHYSICAL PHARMACY CAPSULE 14.3 CONT.
`
`L S
`
`hear Rate
`
`RateofShear
`
`Shearing Stress
`
`Pseudoplastic substances begin flow when a shearing stress is applied: therefore, they exhibit
`no yield value. With increasing shearing stress, the rate of shear increases: consequently, these
`materials are also oalled shear-thinning systems. It is postulated that this occurs as the mol-
`ecules, primarily polymers. align themselves along the long axis and slip or slide past each other.
`
`
`Viscosity ,» 4- Yield Value
`g b
`
`RateofShear
`
`Viscosity
`
`Shearing Stress
`
`Shear Rate
`
`
`
`Dilatant materials are those that increase in volume when sheared. and the viscosity
`increases with increasing shear rate. These are also called shear-thickening systems. Dilatant
`systems are usually characterized by having a high percentage of solids in the formulation.
`
`RateofShear
`
`L K
`
`Viscosity
`
`Shearing Stress
`
`Shear Hate
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`
`
`

`
`456
`
`SECTION VI - LIQUID DOSAGE FOI?I\/I8
`
`PHYSICAL PHARMACY CAPSULE 14.3 CONT.
`
`The viscosity of non—Nevvtonian materials is determined using a viscometer capable of pro-
`ducing differing shear rates, measuring the shear stress, and plotting the results. Other types of
`flow not detailed here include thixotropic, antithixotropic, and rheopexic.Thixotropic flow is used
`to advantage in some pharmaceutical formulations. It
`is a reversible geI—soI transformation.
`Upon setting, a network gel forms and provides a rigid matrix that will stabilize suspensions and
`gels. When stressed (by shaking), the matrix relaxes and forms a sol with the characteristics of
`a liquid dosage form for ease of use. All of these unique flow types can be characterized by
`studying their respective rheograms.
`
`phase and the dispersion medium. In some
`instances, the dispersed phase has an affinity
`for the vehicle to be employed and is readily
`wetted by it, Other drugs are not penetrated
`easily by the vehicle and have a tendency to
`clump together or to float on the vehicle. In
`the latter case, the powder must first be wet-
`ted to make it more penetrable by the disper-
`sion medium. Alcohol, glycerin, propylene
`glycol, and other hygroscopic liquids are
`employed as wetting agents when an aque-
`ous vehicle is to be used as the dispersion
`phase. They function by displacing the air in
`the crevices of the particles, dispersing the
`particles, and allowing penetration of disper-
`sion medium into the powder. In large-scale
`preparation of suspensions, wetting agents
`
`Support of the suspensoid by the disper-
`sion medium may depend on several fac-
`tors: the density of the suspensoid, whether
`it is flocculated, and the amount of material
`
`requiring support.
`The solid content of a suspension intended
`for oral administration may vary consider-
`ably, depending on the dose of the drug to
`be administered, the volume of product to be
`administered, and the ability of the dispersion
`medium to support the concentration of drug
`while maintaining desirable features of viscos-
`ity and flow. Frequently, the usual adult oral
`suspension is designed to supply the dose of
`the particular drug in a convenient measure of
`5 mL or 1 teaspoonful. Pediatric suspensions
`are formulated to deliver the appropriate dose
`of drug by administering a dose-calibrated
`number of drops or with the use of a teaspoon.
`Figure 14.4 shows commonly packaged oral
`suspensions administered as pediatric drops.
`Some are accompanied by a calibrated drop-
`per, whereas other packages have the drop
`capability built into the container. On adrnin—
`istration, the drops may be placed directly in
`the infant's mouth or mixed with a small por-
`tion of food. Because many of the suspensions
`of antibiotic drugs intended for pediatric use
`are prepared in a highly flavored, sweetened,
`colored base, they are frequently referred to by
`their manufacturers and also popularly as syr-
`ups, even though in fact they are suspensions.
`
`Preparation of Suspensions
`
`In the preparation of a suspension, the phar-
`macist must be acquainted with the char-
`acteristics of both the intended dispersed
`
`FIGURE 14.4 Oral pediatric suspensions showing pack-
`age designs of a built-in dropper device and a calibrated
`dropper accompanying the medication container.
`
`Page 14 of 64
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`Page 15 of 64
`
`

`
`458
`
`SFCTION VI - IIQUID DOSAGE l-OIPMS
`
`
`
`FIGURE 14.6 Liquid filling. Bottles being conveyed after cleaning. As they pass through an indexing worm, the
`bottles are spaced accurately for filling and capping. (Courtesy of Paddock Laboratories.)
`
`the resin but is slowly released by the ion
`exchange process in the gastrointestinal tract.
`An example of this product type is hydro-
`codone polistirex (Tussionex Pennkinetic
`Extended-Release Suspension, CellTech).
`
`Extemporaneous Compounding of
`Suspensions
`
`Unfortunately, not all medicines are avail-
`able in a convenient, easy-to-take liquid dos-
`age form. Consequently, patients who are
`not able to swallow solid medicines, such as
`
`infants and the elderly, may present a special
`need. Thus, the pharmacist may have to use a
`solid dosage form of the drug and extempo-
`raneously compound a liquid product. A dif-
`ficulty that confronts the pharmacist is a lack
`of ready information on stability of a drug
`in a liquid vehicle. It is known that drugs in
`liquid form have faster decomposition rates
`than in solid form and some are affected by
`the pH of the medium. Leucovorin calcium
`when compounded from crushed tablets or
`the injectable form is most stable in milk or
`antacid and is unstable in acidic solutions.
`
`the
`To overcome this information gap,
`pharmacist can attempt to contact the man-
`ufacturer of the solid dosage form to attain
`stability information. A number of extem-
`poraneous formulations have appeared in
`
`the professional literature, such as for pred-
`nisone oral suspension (4) and ketoconazole
`suspension (5), and some manufacturers
`provide in the package insert a formula for
`preparation of an oral liquid form, such as
`Rifadin (rifampin, Aventis). A number of
`compilations of formulations based upon
`documented stability data and unpublished
`data compiled by manufacturers and practi-
`tioners are available for pharmacists to use,
`and hundreds of compounded liquid formu-
`lations are available through journals such
`as the International journal of Pharmaceutical
`Compounding.
`Typically, in formation of an extemporane-
`ous suspension, the contents of a capsule are
`emptied into a mortar or tablets crushed in
`a mortar with a pestle. The selected vehicle
`is slowly added to and mixed with the pow-
`der to create a paste and then diluted to the
`desired volume. The selected vehicle can be
`
`a commercial product, such as the Ora fam-
`ily of preparations (Ora-Sweet, Ora-Sweet SF,
`Ora-Plus, Ora-Blend, Paddock Laboratories).
`The extent of the formulation depends
`upon the patient. For example, a liquid sus-
`pension for a neonate should not include
`preservatives, colorings, flavorings, or alco-
`hol because of the potential for each of these
`to cause either acute or long-term adverse
`effects. Because this liquid product will
`
`Page 16 of 64
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`Page 17 of 64
`
`

`
`460
`
`SECTION VI - IIQUID DOSAGF FORMS
`
`ORAL SUSPENSIONS BY CATEGORY
`REPRESBITATIVE
`COMMERCIAL
`DRUG CONCENTRATION IN
`PRODUCTS
`COMMERCIAL PRODUCT
`
`ORAL SUSPENSION
`
`COMMENTS
`
`Counteract gastric hyperacidity.
`relieve distress in the upper
`gastrointestinal tract
`
`Antacids
`
`Alumina, magnesia.
`simethicone
`
`Mylanta Liquid
`(Johnson &
`Johnson Merck)
`
`Magaldrate
`
`Riopan Oral
`Suspension (Wyeth)
`
`Magnesia and
`alumina
`
`Aluminum hydroxide.
`magnesium
`carbonate
`
`Anfholmlnflcs
`
`Maalox Suspension
`(Novartis Consumer
`Health)
`Gaviscon
`Liquid Antacid
`(GIaxoSmithKlIne)
`
`Aluminum hydroxide.
`200 mg: magnesium
`hydroxide. 200 mg; and
`simethicone. 20 mg/5 mL
`
`Hydroxymagnesium
`aluminate 540 mg
`aluminum (chemical
`entity of aluminum and
`magnesium hydroxides)
`Aluminum hydroxide
`225 mg: magnesium
`hydroxide 200 mg/5 mL
`Aluminum hydroxide
`95 mg; magnesium
`carbonate 358 mg/15
`mL; sodium alginate
`
`Pyrantel pamoate
`
`Pin-X Oral
`
`250 mg/5 mL
`
`For worm infestations
`
`Thiabendazole
`
`Suspension (Effcon)
`Mintezcl Oral
`
`Suspension (Merck)
`
`500 mg/5 mL
`
`Anflbacterlals (Antibiotics)
`
`Ciprofloxacln
`
`Erythromycln estolate
`
`Cipro Oral
`Suspension
`(scherlng-Plough)
`Generic
`
`50 and 100 mg/mL
`
`125 and 250 mg/5 mL
`
`Anflbactorlals (Nonanflbloilc Anti-Infectlvcs)
`Methenamine
`Mandelamine
`mandelate
`Suspension Forte
`(various)
`
`500 mg/5 mL
`
`Indicated in the treatment
`of specific susceptible
`microorganisms
`
`Broad-spectru