Dosage Forms and Drug

DOSAGE FORMS AND DRUG DELIVERY SYSTEMS 37

Ram I. Mahato, PhDAssistant Professor, Department of Pharmaceutical SciencesUniversity of Tennessee College of Pharmacy

Contents

1. Introduction

2. Surfactants and Micelles

3. Dispersed Systems

4. Pharmaceutical Ingredients

5. Types of Commonly Used Dosage Forms

6. Targeted Drug Delivery Systems

7. Key Points

8. Questions and Answers

9. References

3. Dosage Forms and DrugDelivery Systems

1. Introduction

Pharmaceutical dosage forms are drug delivery systems.Some common examples are tablets, suppositories, injec-tions, and transdermal patches. To achieve an optimumresponse from any dosage form, a drug should be deliv-ered to its site of action at a rate and concentration thatboth minimize its side effects and maximize its therapeu-tic effects. The development of safe and effective drugdosage forms and delivery systems requires a thoroughunderstanding of physicochemical principles that allowa drug to be formulated into a pharmaceutical dosageform. Design of the appropriate dosage form or deliverysystem depends on the:

• Physicochemical properties of the drug, such as sol-ubility, oil-to-water partition coefficient (Ko/w), pKavalue, and molecular weight

• Dose of the drug

• Route of administration

• Type of drug delivery systems desired

• Pathologic condition to be treated

• Desired therapeutic effect

• Drug release from the delivery system

• Bioavailability of the drug at the absorption site

• Pharmacokinetics and pharmacodynamics of the drug

How Drug Molecules Move Across Barriersin the Body

Most drugs are absorbed from the site of their applica-tion by simple diffusion. Drug diffusion through a bar-rier may occur by simple molecular permeation knownas molecular diffusion or by movement through poresand channels known as pore-diffusion. In pore-diffu-sion, drug release rate is affected by degree of crys-tallinity and crystal size, degree of swelling, porousstructure, and tortuosity of polymers.

With passive molecular diffusion, a drug travels bypassive transport (does not require an external energysource) from a region of high concentration to a regionof low concentration. However, other transportprocesses occur in the body as well. For example,active transport of drugs can proceed from regions oflow concentration to regions of high concentration

through the pumping action of one or more biologictransport systems. These active transport systemsrequire an energy source such as an enzyme or bio-chemical carrier to ferry the drug across the mem-brane.

For passive molecular diffusion, Fick’s first law of dif-fusion states that the amount of material (M) flowingthrough a unit cross-section (S) of a barrier in unittime (t), which is known as the flux (J), is proportionalto the concentration gradient (dc/dx).

J = flux in g/cm2sS = cross section of barrier in cm2

dM/dt = rate of diffusion in g/s(M = mass in g; t = time in sec)

The flux is proportional to the concentration gradient,dC/dx:

D = diffusion coefficient of apenetrant in cm2/s

C = concentration in g/cm3 or g/mLx = distance in centimeters of move-

ment perpendicular to the surfaceof the barrier

The diffusion coefficient, D, is a physical chemicalproperty of the drug molecule. It is not constant andcan vary with changes in concentration, temperature,pressure, solvent properties, and chemical nature of thediffusant.

Fick’s first law of diffusion describes the diffusionprocess under the condition of steady state when theconcentration gradient (dc/dx) does not change withtime. Figure 1 shows the diaphragm of thickness “h”and cross-sectional area “S” which separates the twocompartments of the diffusion cell. Equating bothequations for flux, Fick’s first law of diffusion may bewritten as:

In which (C1 – C2)/h approximates dC/dx. Concentra-tions C1 and C2 within the membrane can be replacedby the partition coefficient multiplied by the concen-tration Cd in the donor compartment or Cr in the recep-tor compartment. The partition coefficient, K, is givenby K = C1/Cd = C2/CrHence,

Under sink conditions, the drug concentration in thereceptor compartment is much lower than the drug

38 APhA'S COMPLETE REVIEW FOR PHARMACY

J = dM

S • dt

J = –DdCdx

D(C1 – C2)

hJ = =

dM

S • dt

DSK(Cd – Cr)

h=

dM

dt

concentration in the donor compartment. Therefore Cr → 0. The above equation can be simplified as:

where D is the diffusion coefficient (cm2/s), S is thesurface area of the cross section of the barrier (cm2), K is the partition coefficient, Cd is the concentration ofdrug in the donor compartment (g/mL), h is the barrierthickness (cm), and P is the permeability coefficient(cm/s), where P = DK/h.

Drug transport and absorptionA drug travels by passive transport from a region ofhigh concentration to a region of low concentration. Incontrast, active transport of drugs requires an energysource such as an enzyme or biochemical carrier toferry the drug across the membrane. Active transportcan proceed from regions of low concentration toregions of high concentration through the pumpingaction of these biologic transport systems.

Transport of a drug by diffusion across a membranesuch as the gastrointestinal mucosa is represented byFick’s law:

where M is the amount of drug in the gut compartmentat time t, Dm is drug diffusivity in intestinal mem-brane, S is the surface area of GI membrane availablefor absorption, K is the partition coefficient betweenthe membrane and aqueous medium in the intestine, his the thickness of the GI membrane, Cg is the drug

concentration in the intestinal compartment, and Cp isthe drug concentration in the plasma compartment.

Since the gut compartment usually has a high drugconcentration compared to the plasma compartment,Cp may be omitted. Therefore, the above equation thenbecomes

This suggests that the rate of gastrointestinal absorp-tion of a drug by passive diffusion depends on the sur-face area of the membrane available for drug absorp-tion. The small intestine is the major site for drugabsorption due to the presence of villi and microvilli,which provide an enormous surface area for absorp-tion.

pH-Partition Theory and Its Limitation

The pH-Partition Theory states that drugs areabsorbed from the biological membranes by passivediffusion, depending on the fraction of un-ionizedform of the drug at the pH of the fluids close to thatbiological membrane. The degree of ionization of thedrug depends on both the pKa and the pH of the drugsolution. The gastrointestinal tract acts as a lipophilicbarrier and thus ionized drugs, compared to un-ionizedones, are more hydrophilic and have minimal mem-brane transport. The solution pH affects the overallpartition coefficient of an ionizable substance. The pKaof the molecule is the pH at which there is a 50:50mixture of conjugate acid-base forms. The conjugateacid form predominates at a pH lower than the pKa,and the conjugate base form is present at a pH higherthan that of the pKa. The extent of ionization of a drugmolecule, given by the following Henderson-Hasselbalch equations, describe a relationshipbetween ionized and non-ionized species of a weakelectrolyte:

Although pH-partition theory is useful, it often doesnot hold true for certain experimental observations.For example, most weak acids are well-absorbed fromthe small intestine, which is contrary to the predictionof the pH-partition hypothesis. Similarly, quaternaryammonium compounds are ionized at all pHs, but arereadily absorbed from the GI tract. These discrepanciesarise because pH-partition theory does not takeinto consideration the following (this list is not ex-haustive):


Figure 1.

Concentration gradient of diffusant across a diaphragmof a diffusion cell.

DSKCd

h=

dM

dt= PSCd

DmSK

h=

dM

dt(Cg – Cp)–

DmSK • Cg

h=

dM

dt–

• Large epithelial surface areas of small intestine com-pensates for ionization effects

• Long residence time in the small intestine also com-pensates for ionization effects

• Charged drugs, such as quaternary ammonium com-pounds and tetracyclines, may interact with oppositecharged organic ions, resulting in a neutral species,which is absorbable

• Some drugs are absorbed via active transport

The Noyes-Whitney Equation of Dissolution

The rate at which a solid drug of limited water solubil-ity dissolves in a solvent can be determined using theNoyes-Whitney equation:

where dM/dt is the rate of dissolution (mass/time), k isthe dissolution rate constant (cm/s) (k = D/h), S is thesurface area of exposed solid (cm2), D is the diffusioncoefficient of solute in solution (cm2/s), h is the thick-ness of diffusion layer (cm), Cs is the drug solubility(g/mL), and C is the drug concentration in bulk solu-tion at time t (g/mL).

Under sink conditions when C is much less than Cs,Noyes-Whitney equation can be simplified as:

where dC/dt is the dissolution rate (conc/time) and Vis the volume of the dissolution medium (mL)

Factors influencing dissolution rate• The dissolution rate of a drug may be influenced by

the physicochemical conditions in the GI tract. Forexample, the presence of foods that increase the vis-cosity of GI fluids decreases the diffusion coeffi-cient, D, of a drug and its dissolution rate.

• The thickness of the diffusion layer, h, is influencedby the degree of agitation experienced by each drugparticle in the GI tract. Hence an increase in gastricand/or intestinal motility may increase the dissolu-tion rate of poorly soluble drugs.

• The removal rate of dissolved drugs due to absorp-tion through the GI blood barrier and the GI fluidvolume affects drug concentration in the GI tract andthus also affects the dissolution rate.

• The dissolution rate of a weakly acidic drug in GIfluids is influenced by the drug solubility in the dif-fusion layer surrounding each dissolving drug parti-cle. The pH of the diffusion layer has significanteffect on the solubility of a weak electrolyte drugand its subsequent dissolution rate. The dissolutionrate of a weakly acidic drug in GI fluid (pH 1-3) isrelatively low because of its low solubility in the dif-fusion layer. If the pH in the diffusion layer could beincreased, the solubility (Cs) exhibited by the weakacidic drug in this layer (and hence the dissolutionrate of the drug in GI fluids) could be increased. Thepotassium or sodium salt form of the weakly acidicdrug has a relatively high solubility at the elevatedpH in the diffusion layer. Thus the dissolution of thedrug particles takes place at a faster rate.

• Particle size and the surface area of the drug havesignificant influence on the drug dissolution rate. Anincrease in the total effective surface area of drug incontact with GI fluids causes an increase in its dis-solution rate. The smaller the particle size, thegreater the effective surface area exhibited by agiven mass of drug and the higher the dissolutionrate. However, particle size reduction is not alwayshelpful and may fail to increase the bioavailability ofa drug. In case of certain hydrophobic drugs, exces-sive particle size reduction tends to cause re-aggre-gation into larger particles. To prevent the formationof aggregates, small drug particles are dispersed inpolyethylene glycol (PEG), polyvinylpyrrolidone(PVP), dextrose, or other agents. For example, a dis-persion of griseofulvin in PEG 4000 enhances itsdissolution rate and bioavailability. Certain drugssuch as penicillin G and erythromycin are unstablein gastric fluids and do not dissolve readily in them.Regarding such drugs, particle size reduction yieldsan increased rate of drug dissolution in gastric fluidand also increases the extent of drug degradation.

• Amorphous or noncrystalline forms of a drug mayhave faster dissolution rates than crystalline forms.

• Temperature also affects solubility. An increase intemperature will increase the solubility of a solidwith a positive heat of solution. The solid will there-fore dissolve at a more rapid rate on heating thesystem.

• Surface active agents will increase the dissolutionrates by lowering the interfacial tension, whichallows better wetting and penetration by the solvent.


=dM

dtk • S • (Cs – C)

Interfacial Electrical Properties

Most dispersed substances in a solvent such as wateracquire a surface electric charge by ionization, ionadsorption, and ion dissolution.

Ionization• Surface charge arising from ionization on the parti-

cles is the function of the pH of the environment andthe pKa of the drug. Proteins acquire charge throughthe ionization of carboxyl and amino groups toobtain COO– and NH3

+ ions. Ionization of thesegroups, and the net molecular charge, depends onthe pH of the medium. At pH below its isoelectricpoint (PI), a protein molecule is positively charged,–NH2 → NH3

+, and at pH above its PI, the protein isnegatively charged, –COOH → COO–. At the iso-electric point of a protein, the total number of posi-tive charges equals the total number of negativecharges and the net charge is zero. This may be rep-resented as follows:

• Often a protein is least soluble at its isoelectric pointand is readily precipitated by water-soluble saltssuch as ammonium sulfate.

Ion adsorption• A net surface charge can result from the unequal

adsorption of oppositely charged ions. Surfaces thatare already charged usually show a tendency toadsorb counter-ions. It is possible for counter-ionadsorption to cause a reversal of charge. Surfacantsstrongly adsorb by hydrophobic effect and thus willdetermine the surface charge when adsorbed.

Ion dissolution• Ionic substances can acquire a surface charge by

virtue of unequal dissolution of the oppositelycharged ions of which they are composed. For exam-ple, in a solution of silver iodide with excess [I–],the silver iodide particles carry a negative charge;however, the charge is positive if excess [Ag+] ispresent. The silver and iodide ions are referred to aspotential-determining ions since their concentrationsdetermine the electric potential at the particlesurface.

Adsorption at solid interfacesAdsorption of materials at solid interfaces may take

place from either an adjacent liquid or gas phase.Adsorption is different from absorption, since theprocess of absorption implies the penetration of anentity through the organ and tissues. The degree ofadsorption depends on the chemical nature of theadsorbent (a material that is being absorbed onto asubstrate, called adsorbate), the chemical nature of theadsorbate, the surface area of the adsorbent, the tem-perature and the partial pressure of the adsorbed gas.Adsorption can be physical or chemical in nature.

Physical adsorption• Physical adsorption is rapid, nonspecific, and rela-

tively weak. Furthermore, it is associated with vander Waals attractive forces and is reversible.Removal of the adsorbate from the adsorbent isknown as desorption. A physically adsorbed gas maybe desorbed from a solid by increasing the tempera-ture and reducing the pressure.

Chemical adsorption• Chemical adsorption or chemisorption is an irre-

versible process in which the adsorbent is attachedto the adsorbsate by primary chemical bonds.Chemisorption is specific, and may require an acti-vation energy; therefore the process is slow and onlya monomolecular chemisorbed layer is possible.

Factors affecting adsorption from solution

• Solubility of adsorbate: The extent of adsorption ofa solute is inversely proportional to its solubility inthe solvent from which adsorption occurs.

• Solute concentration: An increase in the solute con-centration causes an increase in the amount ofadsorption that occurs at equilibrium until a limitingvalue is reached.

• Temperature: An increase in temperature leads todecreased adsorption.

• pH: The influence of pH is through a change in theionization and solubility of the adsorbate drug mole-cule. For many simple small molecules, adsorptionincreases as the ionization of the drug is suppressed,ie, the extent of adsorption reaches a maximumwhen the drug is completely un-ionized. For ampho-teric compounds, adsorption is at a maximum at theisoelectric point. pH and solubility effects act inconcert since the un-ionized form of most drugs inaqueous solution has a low solubility.

• Surface area of adsorbent: An increased surfacearea, achieved by a reduction in particle size or the


use of a porous adsorbing material, increases theextent of adsorption.

Rheology

Rheology is the study of flow properties of liquids anddeformation of solids. The flow of simple liquids canbe described by viscosity, an expression of the resist-ance to flow; however, other complex dispersions can-not be simply expressed by viscosity.

According to Newton’s law of flow, the rate of flow(D) is directly proportional to the applied stress (τ).That is, τ = η • D, where η is the viscosity. Fluids thatobey Newton’s law of flow are referred to as New-tonian fluids and fluids which deviate are known asnon-Newtonian fluids. The force per unit area (F′/A)

shearing stress gives a straight line (Figure 2A), thus ηis a constant. In the case of Newtonian fluids, viscositydoes not change with increasing shear rate. Varioustypes of water and pharmaceutical dosage forms thatcontain a high percentage of water are examples of liq-uid dosage forms that have Newtonian flow properties.

Most pharmaceutical fluids (including colloidal disper-sions, emulsions, and liquid suspensions) do not followNewton’s law of flow, and the viscosity of the fluidvaries with the rate of shear. There are three types ofnon-Newtonian flow: plastic, pseudoplastic, and dila-tant (Figure 2B, C, and D).

Plastic flowSubstances that undergo plastic flow are called Bing-ham bodies, which are defined as substances that


Figure 2.

Plots of rate of shear as a function of shearing stress for (A) Newtonian, (B) plastic, (C) pseudoplastic, (D) dilatant, and (E) thixotropic flow.

required to bring about flow is called the shearingstress (F):

where η is the viscosity, dv/dr is the rate of shear = G(s–1), and F′/A units are in dynes per cm.2 For simpleNewtonian fluids, a plot of the rate of shear against

exhibit a yield value (Figure 2B). Plastic flow is asso-ciated with the presence of flocculated particles inconcentrated suspensions.

• Plastic flow does not begin until a shearing stress,corresponding to a yield value, f, is exceeded.

• The curve intersects the shearing stress axis but doesnot cross through the origin.

• The materials are said to be “elastic” at shearstresses below the yield value.

• Viscosity decreases with increasing shear rate atshear stress below the yield value.

Flocculated solidsFlocculated solids are light, fluffy conglomerates ofadjacent particles held together by weak van der Waalsforces. The yield value exists because a certain shear-ing stress must be exceeded in order to break up vander Waals forces. A plastic system resembles a New-tonian system at shear stresses above the yield value.Yield value, f, is an indicator of flocculation (higheryield value, greater degree of flocculation).

Pseudoplastic flow Pseudoplastic flow is exhibited by polymers in solu-tion. A large of number of pharmaceutical products,including natural and synthetic gums (eg, liquid dis-persions of tragacanth, sodium alginate, methyl cellu-lose, and sodium carboxymethylcellulose) exhibitpseudoplastic flow properties.

• Pseudoplastic substances begin flow when a shear-ing stress is applied, ie, there is no yield value (itdoes cross the origin).

• Viscosity of a pseudoplastic substance decreaseswith increasing shear rate.

• With increasing shearing stress, the rate of shearincreases; these materials are called shear-thinningsystems.

• Shear thinning occurs when molecules (polymers)align themselves along their long axes and slip andslide past each other.

Dilatant flowCertain suspensions with a high percentage of dis-persed solids exhibit an increase in resistance to flowwith increasing rates of shear. This type of behaviormay be exhibited by dispersions containing a high per-centage (≥50%) of small, deflocculated particles.

• Dilatant materials increase in volume when sheared.

• They are also known as shear-thickening systems(opposite of pseudoplastic systems).

• When the stress is removed, the dilatant systemreturns to its original state of fluidity.

• Viscosity increases with increasing shear rate.

• Dilatant materials may solidify under conditions ofhigh shear.

Thixotropy

Thixotropy is a nonchemical isothermal gel-sol-geltransformation. If a thixotropic gel is sheared (by sim-ple shaking), the weak bonds are broken and a lyopho-bic solution is formed. On standing the particles col-lide, flocculation occurs, and the gel is reformed. Theadvantage that thixotropic preparations have is that theparticles remain in suspension during storage, butwhen required for use, the pastes are readily madefluid by tapping or shaking. The shearing force on theinjection as it is pushed through the needle ensuresthat it is fluid when injected; however, the rapidresumption of the gel structure prevents excessivespreading in the tissues, and consequently a more com-pact depot is produced than with nonthixotropic sus-pensions. Flow curves (rheograms) for thixotropicmaterials are highly dependent on the rate at whichshear is increased or decreased and the length of timea sample is subjected to any one rate of shear.

Negative thixotropyNegative thixotropy is also known as antithixotropy,which represents an increase rather than a decrease inconsistency on the down-curve (an increase in thick-ness or resistance to flow with an increased time ofshear). It may result from an increased collision fre-quency of dispersed particles (or polymer molecules)in suspension, which causes increased interparticlebonding with time.

Shelf-life Stability of a Drug Product

The shelf life of a drug in a dosage form is the amountof time that the product can be stored before it be-comes unfit for use because of chemical decomposi-tion and/or physical deterioration. Shelf-life stability ofa dosage form can be determined by the Arrheniusequation given below:

k = A e Ev/RT, which can rewritten as

where k2 and k1 are the reaction rates at the absolutetemperatures T2 and T1, respectively, R is gas constant(1.987 cal/Kmol), Ev is the activation energy (cal/mol),and A is the constant (based on molecular weight andmolar volume of liquid).


2. Surfactants and Micelles

Surface active agents or surfactants have two distinctregions in one chemical structure. One area ishydrophilic (“water-liking”); another is hydrophobic(“water-hating”). The existence of two such moieties ina molecule is known as amphipathy and the moleculesare consequently referred to as amphipathic moleculesor amphiphiles. Depending on the number and natureof the polar and nonpolar groups present, the amphi-phile may be predominantly hydrophilic, lipophilic, orsomewhere in between. For example, straight chainalcohols, amines, and acids are amphiphiles thatchange from being predominantly hydrophilic to lipo-philic as the number of carbon atoms in the alkyl chainis increased. The hydrophobic portions are usually sat-urated or unsaturated hydrocarbon chains, or, lesscommonly, heterocyclic or aromatic ring systems.

Surfactants are classified according to the nature of thehydrophilic or hydrophobic groups. In addition, somesurfactants possess both positively and negativelycharged groups, and can exist as either anionic orcationic, depending on the pH of the solution. Thesesurfactants are known as ampholytic compounds.

At low concentrations in solutions, amphiphiles existas monomers. As the concentration is increased, aggre-gation occurs over a narrow concentration range. Theseaggregates, which may contain 50 or more monomers,are called micelles. Therefore, micelles are smallspherical structures composed of both hydrophilic andhydrophobic regions. The micelles are in dynamicequilibrium with free molecules (monomers) in solu-tion, ie, the micelles are continuously breaking downand reforming. The concentration of monomer atwhich micelles are formed is called the critical micel-lization concentration, or CMC. Surface tensiondecreases up to the CMC, but remains constant abovethe CMC. The longer the hydrophobic chain or thelower the polarity of the polar group, the greater thetendency for monomers to “escape” from the water toform micelles and hence lower the CMC.

Types of Micelles

In the case of amphiphiles in water, in dilute solution(still above but close to the CMC) the micelles areconsidered to be spherical in shape. At higher concen-trations they become more asymmetric and eventuallyassume cylindrical or lamellar structures. More oil-soluble surfactants have a tendency to self-associateinto “reverse micelles” in nonpolar solvents, with theirpolar groups oriented away from the solvent.

Factors Affecting CMC and Micellar Size

• Structure of hydrophobic group

• Nature of hydrophilic group: an increase in chainlength increases hydrophilicity and the CMC

• Nature of counter ions: Cl– < Br– < I– for cationicsurfactants and Na+ < K+ for anionic surfactants

• Addition of electrolytes to ionic surfactants decreas-es the CMC and increases the micellar size. In con-trast, micellar properties of nonionic surfactants areonly minimally affected by the addition of elec-trolytes.

• Effect of temperature

HLB (Hydrophile-Lipophile Balance) Systems

Griffin’s method of selecting emulsifying agents isbased on the balance between the hydrophilic andlipophilic portions of the emulsifying agent; this isnow widely known as the hydrophile-lipophile balance(HLB) system. The higher the HLB value of an emul-sifying agent, the more hydrophilic it is. The emulsify-ing agents with lower HLB values are less polar andmore lipophilic. The Spans, ie, sorbitan esters, arelipophilic and have low HLB values (1.8-8.6); theTweens, polyoxyethylene derivatives of the Spans, arehydrophilic and have high HLB values (9.6-16.7).Surfactants with the proper balance of hydrophilic andlipophilic affinities are effective emulsifying agentssince they concentrate at the oil-water interface. Thetype of an emulsion that is produced depends primarilyon the property of the emulsifying agent. The HLB ofan emulsifier or a combination of emulsifiers deter-mines whether an o/w or w/o emulsion results. In gen-eral, o/w emulsions are formed when the HLB of theemulsifier is within the range of about 9-12; w/o emul-sions are formed when the range is about 3-6. The typeof emulsion is a function of the relative solubility ofthe supernatant. An emulsifying agent with high HLBis preferentially soluble in water and results in the for-mation of an o/w emulsion. The reverse situation istrue with surfactants of low HLB value, which tend toform w/o emulsions.


3. Dispersed Systems

Dispersed systems consist of particulate matter, knownas the dispersed phase, distributed throughout a con-tinuous or dispersion medium. The particulate matter,or dispersed phase, consists of particles that rangefrom 1 nm to 0.5 mm (10–9 m to 5 x 10–7 m).Dispersed systems are classified as follows:

• Molecular dispersions: <1 nm, invisible under elec-tron microscopy (EM). Examples are oxygen mole-cules, ions, and glucose.

• Colloidal dispersions: 1 nm to 0.5 mm, visibleunder EM. Examples are colloidal silver sols andnatural and synthetic polymers.

• Coarse dispersions: larger than 0.5 mm, visibleunder light microscopy. Examples are grains of sand,emulsions, suspensions, and red blood cells.

Types of Colloidal Systems

Colloidal systems are classified as lyophilic or lyopho-bic. Their association is based on the interaction of theparticles or molecules of the dispersed phase with themolecules of the dispersion medium.

Lyophilic colloids Systems containing colloidal particles that interactwith the dispersion medium are referred to as lyophiliccolloids. Because of their affinity for the dispersionmedium, such materials form colloidal dispersionswith relative ease. For example, the dissolution of aca-cia or gelatin in water or celluloid in amyl acetateleads to the formation of a solution. Most lyophiliccolloids are polymers (eg, gelatin, acacia, povidone,albumin, rubber, and polystyrene).

Lyophobic colloidsLyophobic colloids, or inorganic particles dispersed inwater, are composed of materials that have little attrac-tion, if any, for the dispersion medium. Lyophobic col-loids are intrinsically unstable and irreversible.

Association colloidsAssociation (referring to amphiphilic colloids) colloidsare formed by the grouping or association of amphi-philes, ie, molecules that exhibit both lyophilic andlyophobic properties. At low concentrations, amphi-philes exist separately and do not form a colloid. Athigher concentrations, aggregation occurs at around 50or more monomers, which induces micelle formation.As with lyophilic colloids, formation of association

colloids is spontaneous, provided that the concentra-tion of the amphiphile in solution exceeds the CMC.

Zeta Potential and Its Effect on Colloidal Stability

Zeta (ζ) potential is defined as the difference in poten-tial between the surface of the tightly bound layer(shear plane) and the electroneutral region of the solu-tion. The ζ potential governs the degree of repulsionbetween adjacent, similarly charged, dispersed parti-cles. If ζ potential is reduced below a certain value, theattractive forces exceed the repulsive forces, and theparticles come together. This phenomenon is known asflocculation.

Stabilization is accomplished by providing the dis-persed particles with an electric charge and a protec-tive solvent sheath surrounding each particle to preventmutual adherence due to collision. This second effectis significant only in the case of lyophilic colloids.Lyophilic and association colloids are thermodynami-cally stable and exist in a true solution so that the sys-tem constitutes a single phase. In contrast, lyophobiccolloids are thermodynamically unstable, but can bestabilized by preventing aggregation/coagulation byproviding the dispersed particles with an electriccharge, which can prevent coagulation by repulsion oflike particles.


4. Pharmaceutical Ingredients

To turn a drug substance into a pharmaceutical dosageform or a drug delivery system, pharmaceutical ingre-dients are required. For example, in the preparation oftablets, diluents or fillers are commonly added toincrease the bulk of the formulation. Binders areadded to promote adhesion of the powdered drug toother ingredients. Lubricants assist the smooth tablet-ting process. Disintegrants promote tablet break-upafter administration. Coatings improve stability, con-trol disintegration, or enhance appearance. Similarly, inthe preparation of pharmaceutical solutions, preserva-tives are added to prevent microbial growth, stabilizersare added to prevent drug decomposition, and col-orants and flavorants are added to ensure product

appeal. Thus for each dosage form, the pharmaceuticalingredients establish the primary features of the prod-uct and control the physicochemical properties, drugrelease profiles, and bioavailability of the product.Table 1 lists some typical pharmaceutical ingredientsused in different dosage forms.


Table 1

Typical Pharmaceutical Ingredients

Ingredient type

Antifungal preservatives

Antimicrobial preservatives

Antioxidant

Emulsifying agent

Surfactant

Plasticizer

Suspending agent

Binders

Diluent

Disintegrant

Glidant

Lubricant

Humectant

Definition

Used in liquid and semisolid formulations to prevent growth of

fungi

Used in liquid and semi-solid formulations to prevent growth

of microorganisms

Used to prevent oxidation

Used to promote and maintain dispersion of finely divided

droplets of a liquid in a vehicle in which it is immiscible

Used to reduce surface or interfacial tension

Used to enhance coat spread over tablets, beads and

granules

Used to reduce sedimentation rate of drug particles

dispersed throughout a vehicle in; they are not soluble

Used to cause adhesion of powder particles in tablet

granulations

Used as fillers to create desired bulk, flow properties, and

compression characteristics in tablet and capsule

preparations

Used to promote disruption of solid mass into small particles

Used to improve flow properties of powder mixture

Used to reduce friction during tablet compression and

facilitate ejection of tablets from the die cavity

Used for prevention of dryness of ointments and creams

Examples

Anti-fungal: benzoic acid, butylparaben,

ethylparaben, sodium benzoate, sodium

propionate

Benzalkonium chloride, benzyl alcohol,

cetylpyridinium chloride, phenyl ethyl alcohol

Ascorbic acid, ascorbyl palmitate, sodium

ascorbate, sodium bisulfate, sodium

metabisulfite

Acacia, cetyl alcohol, glyceryl monostearate,

sorbitan monostearate

Polysorbate 80, sodium lauryl sulfate, sorbitan

monopalmitate

Glycerin, diethyl palmitate

Carbopol, hydroxymethylcellulose, hydroxypropyl

cellulose, methylcellulose, tragacanth

Acacia, alginic acid, ethylcellulose, starch, povidone

Kaolin, lactose, mannitol, cellulose, sorbitol, starch

Microcrystalline cellulose, carboxymethylcellulose

calcium, sodium alginate, sodium starch

glycollate, alginic acid

Colloidal silica, cornstarch, talc

Calcium stearate, magnesium stearate, mineral oil,

stearic acid, zinc stearate

Glycerin, propylene glycol, sorbitol

5. Types of Commonly Used Dosage Forms

Solutions, Syrups, and Elixirs

Solutions are homogeneous mixtures of one or moresolutes dispersed in a dissolving medium (solvent).Aqueous solutions containing a sugar or sugar substi-tute with or without added flavoring agents and drugsare classified as syrups. Sweetened hydroalcoholic(combinations of water and ethanol) solutions aretermed elixirs. Hydroalcoholic solutions of aromaticmaterials are termed spirits. Solutions intended fororal administration usually contain flavorants and col-orants to make the medication more attractive andpalatable to the patient. They may contain stabilizers tomaintain the physicochemical stability of the drug andpreservatives to prevent the growth of microorganismsin the solution. A drug dissolved in an aqueous solu-tion is in the most bioavailable form. Since the drug isalready in solution, no dissolution step is necessarybefore systemic absorption occurs. Solutions that areprepared to be sterile, pyrogen-free, and intended forparenteral administration are classified as injectables.

Some drugs, particularly certain antibiotics, have in-sufficient stability in aqueous solution to withstandlong shelf-lives. These drugs, formulated as dry pow-der or granule dosage forms, are reconstituted withpurified water immediately before dispensing to thepatient. The dry powder mixture contains all of the for-mulation components (ie, drug, flavorant, colorant,buffers, and others, except for the solvent). Examplesof dry powder mixtures intended for reconstitution tomake oral solutions include cloxacillin sodium, naf-cillin sodium, oxacillin sodium, penicillin V potas-sium, and potassium chloride.

Sucrose is the sugar most frequently employed insyrups; in special circumstances it may be replaced inwhole or in part by other sugars (eg, dextrose) or non-sugars (eg, sorbitol, glycerin, and propylene glycol).Most syrups consist of between 60 and 80% sucrose.Sucrose not only provides sweetness and viscosity tothe solution; it renders the solution inherently stable(unlike dilute sucrose solutions, which are unstable).

Elixirs are usually less sweet and less viscous thansyrups. Since elixirs contain a lower proportion ofsugar, they are consequently less effective than syrupsin masking the taste of drugs. In contrast to aqueoussyrups, elixirs are better able to maintain both water-soluble and alcohol-soluble components in solutiondue to their hydroalcoholic properties. These stablecharacteristics often make elixirs preferable to syrups.

All elixirs contain flavoring and coloring agents toenhance their palatability and appearance. Elixirs con-taining over 10-12% alcohol are usually self-preserv-ing and do not require the addition of antimicrobialagents for preservation. Alcohols precipitate traga-canth, acacia, agar, and inorganic salts from aqueoussolutions; therefore such substances should either beabsent from the aqueous phase or present in such lowconcentrations so as not to promote precipitation onstanding. Examples of some commonly used elixirsinclude dexamethasone elixir USP, pentobarbital elixirUSP, diphenhydramine HCl elixir, and digoxin elixir.

Tablets

Depending on the physicochemical properties of thedrug, site and extent of drug absorption in the gas-trointestinal (GI) tract, stability to heat or moisture,biocompatibility with other ingredients, solubility, anddose, the following types of tablets are commonly for-mulated:

• Tablets that are swallowed whole

• Effervescent tablets that need to be dissolved inwater prior to administration

• Chewable tablets are used when a faster rate of dis-solution and/or buccal absorption is desired. Chew-able tablets consist of a mild effervescent drug com-plex dispersed throughout a gum base. The drug isreleased from the dosage form by physical disrup-tion associated with chewing, chemical disruptioncaused by the interaction with the fluids in the oralcavity, and the presence of effervescent material. Forexample, antacid tablets should be chewed to obtainquick indigestion relief.

• Buccal and sublingual tablets dissolve slowly in themouth, cheek pouch (buccal), or under the tongue(sublingual). Buccal or sublingual absorption isoften desirable for drugs subject to extensive hepaticmetabolism, often referred to as the first-pass effect.Examples are isoprenaline sulfate (bronchodilator),glyceryl trinitrate (vasodilator), nitroglycerin, andtestosterone tablets. These tablets do not contain adisintegrant and are compressed lightly to produce afairly soft tablet.

• Controlled-release tablets are used to improvepatient compliance and to reduce side effects. Somewater-soluble drugs are formulated as sustained-release tablets so that their release and dissolution iscontrolled over a long period. A hydrophobic matrixcomposed of carnauba wax and partially hydroge-nated cottonseed oil were used to prepare sustained-


release tablets of a highly water-soluble drug, ABT-089, a cholinergic channel modulator for the treat-ment of cognitive disorders. Theo-Dur is a con-trolled-release tablet of theophylline and consists oftwo components: a matrix of compressed theoph-ylline crystals and coated theophylline granulesembedded in the matrix. In contact with fluid, the-ophylline diffuses slowly through the wall of the freegranules, which dissolves with time. After oraladministration of Theo-Dur 300 mg tablets to humansubjects, serum theophylline concentrations over 1mg/mL were maintained over 24 hours. To provide azero-order release of ibuprofen, core-in-cup tabletswere developed by compressing the mixture of ethylcellulose and carnauba wax, followed by compres-sion with core tablets containing ibuprofen. Drugswith unpleasant flavors that irritate the stomachwalls are formulated inside the tablets so as to bebound to ion-exchange resins and coated with awater-insoluble polymer membrane made of ethyl-cellulose or a similar substance. These drugs includecodeine, dextromethorphan, acetaminophen,ephedrine, and chlorpheniramine. Aspirin has beenshown to produce less gastric bleeding when formu-lated as a sustained-release formulation than conven-tional tablets. The combination of high- and low-vis-cosity grades of hydroxypropylmethylcellulose(HPMC) was used as the matrix base to preparediclofenac sodium and zileuton sustained-releasetablets. A ternary polymeric matrix system com-posed of protein, HPMC, and highly water-solubledrugs such as diltiazem HCl was developed by thedirect compression method. Xanthan gum was usedfor a hydrophilic matrix for sustained release ibupro-fen tablets. Sustained-release tablets can also be pre-pared by formulating inert polymers like polyvinylchloride, polyvinyl acetate, and methyl methacrylate.These polymers protect the tablet from disintegrationand also reduce the dissolution rate of the druginside the tablet. Examples of commonly used sus-tained-release drug delivery products are listed inTable 2.

• Coated tablets. There are several types of coatedtablets: film coated, sugar coated, gelatin coated (gelcaps), or enteric-coated tablets. Enteric coatings areresistant to gastric juices, but readily dissolve in thesmall intestine. These enteric coatings can protectdrugs against decomposition in the acid environmentof the stomach. Commonly used polymers forenteric coating are acid-impermeable polymers, suchas cellulose acetate trimellitate (CAT), hydrox-ypropylmethylcellulosephthalate (HPMCP),polyvinyl acetate phthalate (PVAP), cellulose acetatephthalate (CAP) and Eudragit. Aspirin has beenshown to produce less gastric bleeding when formu-

lated as enteric-coated sustained-release tablets thanconventional aspirin preparations. Film-coatedtablets are compressed tablets that are coated with athin layer of a water insoluble or water soluble poly-mer, such as HPMC, ethylcellulose, povidone orpolyethylene glycol. AbacavirTM is a capsule-shapedfilm-coated tablet containing a nucleoside reversetranscriptase inhibitor, which is a potent antiviralagent for the treatment of HIV infection.

Tablet formulationIn addition to the drug, the following materials areadded to make the powder system compatible withtablet formulation by the compression or granulationmethods:

• Diluents. A tablet should weigh at least 50 mg andtherefore very low-dose drugs invariably require adiluent or bulking agent to bring overall table weightto at least 50 mg. Commonly used diluents are lac-tose, dicalcium phosphate, starches, microcrystallinecellulose (MCC), dextrose, sucrose, mannitol, andsodium chloride. Dicalcium phosphate absorbs lessmoisture than lactose and is therefore used withhygroscopic drugs such as pethidine hydrochloride.

• Adsorbents are substances capable of holding quan-tities of fluids in an apparently dry state. Oil-solubledrugs or fluid extracts can be mixed with adsorbentsand then granulated and compressed into tablets.Examples are fumed silica, microcrystalline cellu-lose, magnesium carbonate, kaolin, and bentonite.

• Moistening agents are liquids that are used for wetgranulation. Examples include water, industrialmethylated spirits, and isopropanol.

• Binding agents (adhesives) bind powders together inthe wet granulation process. They also help bindgranules together during compression. Examplesinclude starch, gelatin, polyvinylpyrrolidone, alginicacid derivatives, cellulose derivatives, glucose, andsucrose. Choice of binders affects the dissolutionrate. For example, the tablet formulation offurosemide with PVP as the binder has t50 (timerequired for 50% of the drug to be released duringan in vitro dissolution study) of 3.65 minutes, butwith starch mucilage as the binder, the t50 of thetablets was 117 minutes.

• Glidants are added to tablet formulations to improvethe flow properties of the granulations. They act byreducing interparticulate friction. Commonly usedglidants are fumed (colloidal) silica, starch, and talc.



Table 2

Examples of Sustained-Release Drug Delivery Products

Dosage forms

Theo-Dur

Abacavir (Ziagen)

Sineme

Volmax

Voltaren

Efidac 24

DynaCirc CR

Capsules

Dexedrine

Spansules

Adderal XL

Ritalin LA

VIDEX EC

Ventolin HFA

Azmacort

Serevent

Osmotic system

Oros System

Ditropan XL

Covera-HS

Concerta

Viadur

Inserts

Pilocarpine

Occusert

Lacrisert

Progestasert

Atridox

Alora

CambiPatch

Androderm

Nicotine

transdermal

system

PEG-Intron

Pegasys

Liposomes

DoxilTM

DaunoXome

Lupron Depot

Zoladex Depot

Nutropin Depot

Manufacturer

ALZA Corp.

GlaxoWellcome Inc

Bristol Myers Squibb

ALZA Corp.

Novartis

ALZA Corp.

ALZA Corp.

SmithKline Beecham

Shire Pharmaceuticals

Novartis

Bristol Myers Squibb

GlaxoSmithKline

Adventis

GlaxoSmithKline

ALZA Corp.

ALZA Corp.

ALZA Corp.

ALZA Corp.

ALZA Corp.

ALZA Corp.

ALZA Corp.

ALZA Corp.

ALZA Corp.

Watson Pharmaceuticals, Inc.

Novartis



Schering-Plough

Roche

ALZA Corp.

NeXstar Pharmaceuticals

TAP Pharmaceuticals

AstraZeneca

Genentech

Active ingredients

Theophylline

Nucleoside reverse transcriptase inhibitor

Carbidopa + levodopa

Albuterol

Diclofenac sodium

Chlorpheniramine

Isradipine

Dextroamphetamine

Amphetamine + dextroamphetamine

Methylphenidate hydrochloride

Didanosine

Albuterol sulfate

Triamcinolone acetonide

Salmeterol

Oral delivery of different drugs

Oxybutynin chloride

Verapamil

Methylphenidate HCl

Leuprolide

Pilocarpine

Hydroxypropyl cellulose

Progesterone

Doxycycline

Estradiol

Estradiol/norethindrone acetate

Testosterone

Nicotine

PEGylated interferon

PEGylated interferon + ribavirin

Doxorubicin HCl

Daunorubicin

Luteinizing hormone-releasing hormone agonist

Goserelin acetate

Recombinant human growth hormone

Indications

Asthma

HIV-1 infection

Parkinson’s disease

Bronchospasm

Osteoarthritis and rheumatoid arthritis

Allergy symptom and nasal congestion

Hypertension

Narcolepsy

Attention deficit hyperactivity disorder

(ADHD)

HIV-1 infection

Aerosols

Bronchodilator

Asthma

Bronchodilator

Overreacting bladder

Antihypertensive

Attention deficit hyperactivity disorder

(ADHD)

Prostate cancer

Glaucoma

Ophthalmic moisturizer

Contraceptive

Periodontal disease

Menopausal symptoms

Vasomotor symptoms associated with

menopause

Testosterone deficiency

Smoking cessation

Hepatitis C

Hepatitis B, hepatitis C

Kaposi’s sarcoma

Kaposi’s sarcoma

Prostate cancer, endometriosis

Prostate cancer, endometriosis

Growth deficiencies

PEGylated proteins

PLGA/PLA microspheres

DURO implant systems

Controlled-release tablets

Transdermal patches

• Lubricants are required to prevent adherence of thegranules to the punch faces and dies. They alsoensure smooth ejection of the tablet from the die.Many lubricants also enhance the flow properties ofthe granules. Commonly used lubricants are magne-sium stearate, talc, stearic acid and its derivatives,PEG, paraffin, and sodium or magnesium lauryl sul-fate. Among these, magnesium stearate is the mostpopular lubricant, as it is effective as both a die andpunch lubricant. However, for many drugs, magne-sium stearate is chemically incompatible (eg,aspirin) and therefore talc or stearic acid is oftenused.

• Disintegrating agents are added to the tablets topromote breakup of the tablets when placed in theaqueous environment. This increases the effectivesurface area of drug particles to the GI fluid andpromotes rapid release of the drug. Disintegrants actby either bursting open the tablet and/or by promot-ing the rapid ingress of water into the center of thetablet or capsule. Examples include starch, cationicexchange resins, cross-linked polyvinylpyrrolidone,celluloses, modified starches, alginic acid and algi-nates, magnesium aluminum silicate, and cross-linked sodium carboxymethylcellulose. Amongthem, starch is the most popular disintegrant, as ithas a great affinity for water and swells when mois-tened, thus facilitating the rupture of the tabletmatrix.

Disintegration, dissolution, and absorptionFollowing oral administration, a tablet or other soliddosage form disintegrates into granules, and thesegranules deaggregate in turn into fine particles.Disintegration, deaggregation, and dissolution mayoccur simultaneously with the release of a drug fromthe tablet. The effectiveness of a tablet in releasing itsdrug for systemic absorption depends on the rate ofdisintegration of the dosage forms and deaggregationof the granules. A solid drug product has to disinte-grate into small particles and release the drug beforeabsorption can take place. However, tablets that areintended for chewing or sustained release do not haveto undergo disintegration. The various excipients fortablet formulation affect the rates of disintegration,dissolution, and absorption. Systemic absorption ofmost products consists of a succession of rate proc-esses, such as

• disintegration of the drug product and subsequentrelease of drug,

• dissolution of the drug in an aqueous environment,and

• absorption across cell membranes into the systemiccirculation.

Rate-limiting step for absorptionIn the process of tablet disintegration, dissolution, andabsorption, the rate at which drug reaches the circula-tory system is determined by the slowest step in thesequence. Disintegration of a tablet is usually morerapid than drug dissolution and absorption. For thedrug that has poor aqueous solubility, the rate at whichthe drug dissolves (dissolution) is often the sloweststep, and therefore exerts a rate-limiting effect on drugbioavailability. In contrast, for the drug that has a highaqueous solubility, the dissolution rate is rapid and therate at which the drug crosses or permeates cell mem-branes is the slowest or rate-limiting step.

Capsules

Capsules are solid dosage forms in which the drugsubstance is enclosed in either a hard or soft, water-soluble container or shell of gelatin. Coating of cap-sule shell or drug particles within the capsule canaffect bioavailability. There are two types of capsules:hard and soft capsules; however, hard gelatin capsulesare more versatile for controlled drug delivery.

Hard gelatin capsulesA hard gelatin capsule consists of two pieces, a capand a body, that fit one inside the other. They are pro-duced empty and are then filled in a separate opera-tion. Hard gelatin capsules are usually filled with pow-ders, granules, or pellets containing the drug. Afteringestion, the gelatin shell softens, swells, and beginsto dissolve in the gastrointestinal tract. Encapsulateddrugs are released rapidly and dispersed easily, leadingto high bioavailability. Capsules are supplied in a vari-ety of sizes, and high-speed filling machinery capableof filling ~1500 capsules per minute is available. Thehard gelatin empty capsules are numbered from 000,the largest size, to 5, which is the smallest. Theapproximate filling capacity of capsules ranges from6000 to 30 mg, depending on the types and bulk densi-ties of powdered drug materials.

Formulation of hard gelatin capsulesPowder formulations for encapsulation into hard gela-tin capsules require a careful consideration of the fill-ing process, such as lubricity, compactibility, and fluid-ity. Additives present in the capsule formulations, suchas amount and choice of fillers and lubricants, inclu-sion of disintegrants and surfactants, and the degree ofplug compaction, can influence drug release from thecapsule. Formulation factors influencing drug releaseand bioavailability are as follows:


• Fillers (or diluents). Active ingredient is mixed witha sufficient volume of a diluent, usually lactose,mannitol, starch, and dicalcium phosphate, to yieldthe desired amount of the drug in the capsule whenthe base is filled with the powder mixture.

• Glidants. The flow properties of the powder blendshould be adequate to assure a uniform flow ratefrom the hopper. Glidants such as silica, starch, talc,and magnesium stearate are used to improve the flu-idity. The optimal concentration of the glidant usedto improve the flow of a powder mixture is generallyless than 1%.

• Lubricants ease the ejection of plugs by reducingadhesion of powder to metal surfaces and frictionbetween sliding surfaces in contact with powder.Typical lubricants for capsule formulations includemagnesium stearate and stearic acid.

• Surfactants may be included in capsule formula-tions to increase wetting of the powder mass andenhance drug dissolution. The most commonly usedsurfactants in capsule formulations are 0.1-0.5% ofsodium lauryl sulfate and sodium docusate.

• Hydrophilization. Another approach for improvingthe wettability of poorly soluble drugs is to treat thedrug with a hydrophilic polymer solution. Powderwettability and dissolution rate of several drugsincluding hexobarbital and phenytoin from hard gel-atin capsules have been shown to be enhanced if thedrug is treated with methylcellulose or hydroxyethyl-cellulose.

Vancomycin HCl is highly hygroscopic antibiotic. Toachieve acceptable stability, Eli Lilly has developed ahard gelatin capsule filled with a PEG 6000 matrix ofvancomycin HCl, which produces plasma and urinelevels of the antibiotic similar to those obtained withthe solution of vancomycin HCl. Controlled-releasebeads and minitablets are often filled into gelatin cap-sules for convenient administration of an oral con-trolled-release dosage form. For example, sustained-release antihistamines, antitussives, and analgesics arefirst preformulated into extended-release microcap-sules or microspheres and then placed inside a gelatincapsule. Another example is enteric-coated lipaseminitablets that are placed in a gelatin capsule formore effective protection and dosing of these enzymes.

Soft gelatin capsulesSoft gelatin capsules are prepared from plasticized gel-atin by a rotary die process in which they are formed,filled, and sealed in a single operation. Soft gelatincapsules may contain a nonaqueous solution, a powder,

or a drug suspension, none of which solubilize the gel-atin shell. In contrast to hard gelatin capsules, soft gel-atin capsules contain ~30% glycerol as a plasticizer inaddition to gelatin and water. The moisture uptake ofsoft gelatin capsules plasticized with glycerol is con-siderably higher than that of hard gelatin capsules.Therefore oxygen-sensitive drugs should not be in-serted into soft gelatin capsules; nor should emulsions,since they are unstable and crack the shell of the cap-sule when the water is lost in the manufacturingprocess. Extreme acidic and basic pH must also beavoided, since a pH below 2.5 hydrolyzes gelatin,while a pH above 9 has a tanning effect on the gelatin.Insoluble drugs should be dispersed with an agent suchas beeswax, paraffin, or ethylcellulose. Surfactants arealso often added to promote wetting of the ingredients.Drugs that are commercially prepared in soft capsulesinclude declomycin, chlorotrianisene, digoxin, vitaminA, vitamin E, and chloral hydrate.

Formulation of soft gelatin capsulesFormulation of soft gelatin capsules involves liquid,rather than powder, technology. It requires careful con-sideration of the composition of the gelatin shell andfilling materials. The composition of the soft capsuleshell consists of two main ingredients: gelatin and aplasticizer. Water is used to form the capsule and otheradditives are often added as described below:

• Gelatin. Properties of gelatin shells are controlled bychoice of gelatin grade and by adjusting the concen-tration of plasticizer in the shell.

• Plasticizers. The main plasticizer used for soft gela-tin capsules is glycerol. Sorbitol and polypropyleneglycol are also used in combination with glycerol.Compared to hard gelatin capsules and tablet filmcoatings, a relatively large amount (~30%) of plasti-cizers are added in soft gelatin capsule formulationto ensure adequate flexibility.

• Water. The desirable water content of the gelatinsolution used to produce a soft gelatin capsule shelldepends on the viscosity of gelatin used and rangesbetween 0.7 and 1.3 parts of water to each part ofdry gelatin.

• Other additives. Preservatives are added to preventmold growth in the gelatin shell. Potassium sorbate,and methyl, ethyl, and propyl hydroxybenzoate arecommonly used as preservatives.

Emulsions

An emulsion is a thermodynamically unstable systemconsisting of at least two immiscible liquid phases, one


of which is dispersed as globules (dispersed phase) inthe other liquid phase (continuous phase), stabilizedby the presence of an emulsifying agent. Emulsifiedsystems range from lotions of relatively low viscosity,to ointments and creams, which are semisolid innature.

Types of emulsionsOne liquid phase in an emulsion is essentially polar(eg, aqueous), while the other is relatively nonpolar(eg, an oil).

• Oil-in-water (o/w) emulsion: When the oil phase isdispersed as globules throughout an aqueous contin-uous phase, the system is referred to as an oil-in-water (o/w) emulsion.

• Water-in-oil (w/o) emulsion: When the oil phaseserves as the continuous phase, the emulsion istermed an water-in-oil (w/o) emulsion.

• Multiple (w/o/w or o/w/o) emulsions: These areemulsions whose dispersed phase contains dropletsof another phase. Multiple emulsions are of interestas delayed-action drug delivery systems.

• Microemulsions: These consist of homogeneous trans-parent systems of low viscosity which contain a highpercentage of both oil and water and high concentra-tions of emulsifier mixture. Microemulsions formspontaneously when the components are mixed in theappropriate ratios and are thermodynamically stable.

Externally applied emulsions may be o/w or w/o. Theo/w emulsions employ the following emulsifiers:Sodium lauryl sulfate, triethanolamine stearate, sodi-um oleate, and glyceryl monostearate. The w/o emul-sions are used mainly for external applications andmay contain one or several of the following emulsi-fiers: calcium palmitate, sorbitan esters (Spans), cho-lesterol, and wool fats.

Interfacial free energy and emulsificationTwo immiscible liquids in emulsions often fail toremain mixed due to the greater cohesive forcebetween the molecules of each separate liquid than theadhesive force between the two liquids. This leads tophase separation, which is the state of minimum sur-face free energy. When one liquid is broken into smallparticles, the interfacial area of the globules constitutesa surface that is enormous compared with the surfacearea of the original liquid. The adsorption of a surfac-tant or other emulsifying agent at the globule interfacelowers the oil-to-water or water-to-oil interfacial ten-sion. In addition, the process of emulsification is madeeasier and the drug’s stability may be enhanced.

Emulsifying agentsTo prevent coalescence, it is necessary to introduce anemulsifying agent that forms a film around the dis-persed globules. Emulsifying agents may be dividedinto three groups:

• Surface active agents. Surfactants are adsorbed atoil-water interfaces to form monomolecular filmsand reduce interfacial tensions. Unless the interfa-cial tension is zero, there is a natural tendency forthe oil droplets to coalesce to reduce the area of oil-water contact, but the presence of the surfactantmonolayer at the surface of the droplet reduces thepossibility of collisions leading to coalescence. Toretain a high surface area for the dispersed phase,surface active agents must be used to decrease thesurface free energy. Often a mixture of surfactants isused: one with hydrophilic character and the otherwith hydrophobic character. A hydrophilic emulsify-ing agent is needed for the aqueous phase, and ahydrophobic emulsifying agent is needed for the oilphase. A complex film results, which produces anexcellent emulsion. Nonionic surfactants are widelyused in the production of stable emulsions. They areless toxic than ionic surfactants and are less sensitiveto electrolytes and pH variation. Examples includesorbitan esters, polysorbates, and others.

• Hydrophilic colloids. A number of hydrophilic col-loids are used as emulsifying agents. These includegelatin, casein, acacia, cellulose derivatives, andalginates. These materials adsorb at the oil-waterinterface and form multilayer films around the dis-persed droplets of oil in an o/w emulsion. Hydratedlyophilic colloids differ from surfactants since theydo not cause an appreciable lowering in interfacialtension. Their action is due to the fact that multi-molecular films are strong and resist coalescence.Additionally, they increase the viscosity of the dis-persion medium. Hydrophilic colloids are used forformation of o/w emulsions since the films arehydrophilic. Most cellulose derivatives are notcharged, but can sterically stabilize the systems.

• Finely divided solid particles are adsorbed at theinterface between two immiscible liquid phases andform a film of particles around the dispersed glob-ules. Finely divided solid particles that are wetted tosome degree by both oil and water can act as emulsi-fying agents. They are concentrated at the interfacewhere they produce a film of particles around thedispersed droplets so as to prevent coalescence.Finely divided solid particles that are wetted bywater form o/w emulsions; those that are wetted byoil form w/o emulsions.


Emulsion stabilityThe stability of an emulsion is characterized by theabsence of coalescence of the internal phase, theabsence of creaming, and maintenance of elegancewith respect to appearance, odor, color, and otherphysical properties. An emulsion becomes unstabledue to creaming, breaking, coalescence, phase inver-sion, and some other factors.

1. Creaming and sedimentation. Creaming is theupward movement of dispersed droplets relativeto the continuous phase, while sedimentation,the reverse process, is the downward movementof particles. These processes take place due tothe density differences in the two phases and canbe reversed by shaking. However, creaming isundesirable, because a creamed emulsionincreases the likelihood of coalescence due tothe close proximity of the globules in the cream.Factors which influence the rate of creaming aresimilar to those involved in the sedimentationrate of suspension particles and are indicated byStokes Law as follows:

where v is the velocity of creaming, d is theglobule diameter, ρs and ρo are the densities ofdispersed phase and dispersion medium respec-tively, ηo is the viscosity of the dispersionmedium (poise), and g is the acceleration ofgravity (981 cm/sec2). According to this equa-tion, the rate of creaming is decreased by:

• a reduction in the globule size,

• a decrease in the density difference betweenthe two phases, and

• an increase in the viscosity of the continuousphase.

This may be achieved by homogenizing theemulsion to reduce the globule size and increas-ing the viscosity of the continuous phase by theuse of thickening agents such as tragacanth ormethylcellulose.

2. Breaking, coalescence and aggregation.Creaming is different from breaking, sincecreaming is a reversible process, whereas break-ing is irreversible. When breaking occurs, sim-ple mixing fails to resuspend the globules in astable emulsified form, since the film surround-ing the particles has been destroyed and the oiltends to coalesce. Coalescence is the process by

which emulsified particles merge with eachother to form large particles. The major factorpreventing coalescence is the mechanicalstrength of the interfacial barrier. Formation of athick interfacial film is essential for minimalcoalescence. In aggregation, the disperseddroplets come together but do not fuse.Aggregation is to some extent reversible.

3. Phase inversion. An emulsion is said to invertwhen it changes from an o/w to a w/o emulsionor vice versa. Inversion can occur by the addi-tion of an electrolyte or by changing thephase:volume ratio. For example, an o/w emul-sion stabilized with sodium stearate can beinverted to an w/o emulsion by adding calciumchloride to form calcium stearate.

4. Preservation of emulsions. Growth of microor-ganisms in an emulsion can cause physical sepa-ration of the phases. Bacteria can degrade non-ionic and anionic emulsifying agents and there-fore preservatives must be added in adequateconcentrations to the product.

Suspensions

Suspensions are dispersions of finely divided solidparticles of a drug in a liquid medium in which thedrug is not readily soluble. Suspending agents areoften hydrophilic colloids (eg, cellulose derivatives,acacia, or xanthan gum) added to suspensions toincrease viscosity, inhibit agglomeration, and decreasesedimentation. Highly viscous suspensions may pro-long gastric emptying time, slow drug dissolution, anddecrease the absorption rate. A suspension that isthixotropic as well as pseudoplastic should prove to beuseful since it forms a gel on standing and becomesfluid when disturbed.

Suspended material should not settle rapidly. The parti-cles that do settle on the bottom should not form ahard cake, but should be readily redispersed into auniform mixture when shaken. Aggregation can beprevented if the particles have a similar electricalcharge.

FlocculationThe large surface area of the particles is associatedwith a surface free energy that makes the system ther-modynamically unstable. This makes particles highlyenergetic and tend to regroup, resulting in the decreasein total surface area and surface free energy. The parti-cles in a liquid suspension, therefore, tend to floccu-late. Flocculation is the formation of light, fluffy con-glomerates held together by weak van der Waals


forces. Aggregation occurs in a compact cake situation(growth and fusing together of crystals in the precipi-tates to form a solid aggregate). Flocculating agentscan prevent caking, whereas deflocculating agentsincrease the tendency to cake. Surfactants can reduceinterfacial tension, but it cannot be made equal to zero,so suspensions of insoluble particles tend to have apositive finite interfacial tension, and particles tend toflocculate.

Forces at the surface of a particle affect the degree offlocculation and agglomeration in a suspension. Forcesof attraction are of the London van der Waals type,whereas the repulsive forces arise from the interactionof the electric double layers surrounding each particle.When the repulsion energy is high, collision of theparticles is opposed; the system remains deflocculatedand when sedimentation is complete, the particlesform a close-packed arrangement with the smaller par-ticles filling the void between the larger ones. Thoseparticles lowest in the sediment are gradually pressedtogether by the weight of the ones above; the energybarrier is thus overcome, allowing the particles tocome into close contact with each other. To resuspendand redisperse these particles, it is necessary to over-come the high energy barrier. Since this is not easilyachieved by agitation, the particles tend to remainstrongly attracted to each other and form a hard cake.When the particles are flocculated, the energy barrieris still too large to be surmounted, and so the ap-proaching particles in the second energy minimum,which is at a distance of separation of perhaps 1000 to2000 Å, is sufficient to form the loosely structuralflocs.

Properties of deflocculated (dispersed) particles• They have a high zeta potential.

• Their repulsive forces exceed attractive (London)forces.

• They settle slowly.

• They have a pleasing appearance; the supernatantremains cloudy.

• They eventually form a sediment in which aggrega-tion occurs (caking).

• They are difficult to resuspend once caked.

Properties of flocculated particles• They have a lower zeta potential.

• Their forces of attraction predominate over therepulsive forces.

• They are weakly bonded.

• They settle rapidly.

• They have an unsightly appearance; the supernatantis clear.

• They do not form a cake.

• They are easily resuspended.

Sedimentation of flocculated particles“Flocs” tend to fall together, producing a distinctboundary between the sediment and the supernatantliquid. The liquid above the sediment is clear becauseeven the small particles present in the system are asso-ciated with flocs. In contrast to this are deflocculatedsystems with variable particle sizes; the large particleshere settle more rapidly than the smaller particles, andno clear boundary is formed. The supernatant remainsturbid for a longer period of time.

Formulation of suspensionsThere are two ways of formulating physically stablesuspensions:

• The use of a structured vehicle to maintain defloccu-lated particles in suspension. However, the majordisadvantage of deflocculated systems is that whenthe particles eventually settle, they form a compactcake.

• Production of flocs, which may settle rapidly, but areeasily resuspended with a minimum of agitation.Optimum physical stability is obtained when the sus-pension is formulated with flocculated particles in astructured vehicle of hydrophilic colloid type.

Ointments

Ointments are semisolid preparations intended forexternal application. Ointments are typically used as:

• Emollients to make the skin more pliable

• Protective barriers to prevent harmful substancesfrom coming in contact with the skin

• Vehicles in which to incorporate medication

Ointment bases are classified into four general groups:(1) hydrocarbon bases, (2) absorption bases, (3) water-removable bases, and (4) water-soluble bases.

1. Hydrocarbon (oleaginous) bases are anhydrous


and insoluble in water. They cannot absorb orcontain water and are not washable in water.

• Petrolatum is a good base for oil-insolubleingredients. It forms an occlusive film on theskin and absorbs less than 5% water undernormal conditions. Wax can be incorporatedto stiffen the base.

• Synthetic esters are used as constituents ofoleaginous bases. These esters include glyc-erol monostearate, isopropyl myristate, iso-propyl palmitate, butyl stearate, and butylpalmitate.

2. Absorption bases may be of two types: (1) thosethat permit the incorporation of aqueous solu-tions, resulting in the formation of water-in-oil(w/o) emulsions (eg, hydrophilic petrolatum andanhydrous lanolin), and (2) those that arealready w/o emulsions (emulsion bases), thatpermit the incorporation of small additionalquantities of aqueous solutions (eg, lanolin andcold cream). These bases are useful as emol-lients although they do not provide the degree ofocclusion afforded by the oleaginous bases.Absorption bases are also not easily removedfrom the skin with water. An aqueous solutionmay be first incorporated into the absorptionbase, and then this mixture added to the oleagi-nous base.

3. Emulsion bases, water washable or water re-movable bases commonly referred to as creams,represent the most commonly used type of oint-ment base. The majority of dermatologic drugproducts are formulated in an emulsion or creambase. Emulsion bases are washable and removedeasily from skin or clothing. An emulsion basecan be subdivided into three component parts,designated the oil phase, the emulsifier, and theaqueous phase. Drugs can be included in one ofthese phases or added to the formed emulsion.The oil phase, also known as the internal phase,is typically made up of petrolatum and/or liquidpetrolatum together with cetyl or stearyl alcohol.Types of emulsion bases include:

• Hydrophilic ointment is an o/w emulsion thatuses sodium lauryl sulfate as an emulsifyingagent. It is readily miscible with water and isremoved from the skin easily. The aqueousphase of an emulsion base contains the preser-vative(s) that are included to control microbialgrowth. The preservatives in the emulsion

include methylparaben, propylparaben, benzylalcohol, sorbic acid, or quaternary ammoniumcompounds. The aqueous phase also containsthe water-soluble components of the emulsionsystem, together with any additional stabiliz-ers, antioxidants, and buffers that may be nec-essary for stability and pH control.

• Cold cream is a semisolid white w/o emulsionprepared with cetyl ester wax, white wax,mineral oil, sodium borate, and purified water.Sodium borate combines with free fatty acidspresent in the waxes to form sodium soapsthat act as the emulsifiers. Cold cream isemployed as an emollient and ointment base.Eucerin cream is a w/o emulsion of petrola-tum, mineral oil, mineral wax, wool wax,alcohol, and bronopol. It is frequently pre-scribed as a vehicle for delivery of lactic acidand glycerin to treat dry skin.

• Lanolin is a w/o emulsion that containsapproximately 25% water and acts as an emol-lient and occlusive film on the skin, effec-tively preventing epidermal water loss.

• Vanishing cream is an o/w emulsion that con-tains a large percentage of water as well as ahumectant (eg, glycerin or propylene glycol)that retards surface evaporation. An excess ofstearic acid in the formula helps to form a thinfilm when the water evaporates.

4. Water-soluble bases may be anhydrous or maycontain some water. They are washable in waterand absorb water to the point of solubility.Polyethylene glycol (PEG) ointment is a blendof water-soluble PEG that forms a semisolidbase. This base can solubilize water-solubledrugs and some water-insoluble drugs. It is com-patible with a wide variety of drugs. This basecontains 40% PEG 4000 and 60% PEG 400.Another water-soluble base is the ointment pre-pared with propylene glycol and ethanol, whichform a clear gel when mixed with 2% hydroxy-propyl cellulose. This base is a commonly useddermatologic vehicle.

Incorporation of drugs into an ointmentDrugs may be incorporated into an ointment base bylevigation and fusion. Normally, drug substances are infine powered forms before being dispersed in the vehi-cle. Levigation of powders into a small portion of baseis facilitated by the use of a melted base or a smallquantity of compatible levigation aid, such as mineraloil or glycerin. Water-soluble salts are incorporated by


dissolving them in a small volume of water and incor-porating the aqueous solution into a compatible base.Fusion method is used when the base contains solidsthat have higher melting points (eg, waxes, cetyl alco-hol, or glyceryl monostearate).

Inserts, Implants, and Devices

Inserts, implants, and devices are used to control drugdelivery for localized or systemic drug effects. In thesesystems, drugs are embedded into biodegradable ornonbiodegradable materials to allow slow release ofthe drug. The inserts, implants, and devices are insert-ed into a variety of cavities (eg, vagina, buccal cavity,cul de sac of the eye, or subcutaneous tissue).

A number of degradable and nondegradable inserts arecurrently available for ophthalmic delivery. These oph-thalmic inserts can be insoluble, soluble, or bioerodi-ble. Insoluble inserts are further classified as diffu-sional, osmotic, and contact lens (Figure 4).

Diffusional and osmotic systems contain a reservoirthat is in contact with the inner surface of a controllerto which it supplies the drug. The reservoir contains aliquid, a gel, a colloid, a semisolid, a solid matrix, or acarrier containing drug. Carriers consist of hydrophilicor hydrophobic polymers. Degradable inserts consistof polyvinyl alcohol, hydroxypropylcellulose, poly-vinylpyrrolidone, and hyaluronic acid. Nondegradableinserts are prepared from insoluble materials such asethylene vinyl acetate copolymers and styrene-iso-prene-styrene block copolymers. The initial use of con-tact lenses was for vision correction; however, they arebecoming more useful as potential drug deliverydevices by presoaking them in drug solutions. The useof contact lenses can simultaneously correct vision andrelease drug.

Ocular inserts are no more affected by nasolacrimaldrainage and tear flow than conventional dosageforms, and instead can provide slow drug release andlonger residence times in the conjunctival cul-de-sac.Occusert is an interesting device consisting of a drugreservoir (eg, pilocarpine HCl in an alginate gel)enclosed by two release-controlling membranes madeof ethylene-vinyl acetate copolymer and enclosed by awhite ring, allowing positioning of the system in theeye. Pilocarpine Occusert has demonstrated slowrelease of pilocarpine which can effectively control theincreased intraocular pressure in glaucoma. Otherinserts (eg, medicated contact lenses, collagen shields,and minidiscs) have been shown to diminish the sys-temic absorption of ocularly applied drugs as a resultof decreased drainage into nasal cavity. Lacrisert is asoluble insert composed of hydroxypropylcellulose(HPC) and is useful in the treatment of dry eye syn-drome. The device is placed in the lower fornix whereit slowly dissolves over 6-8 hours to stabilize andthicken the tear film.

In addition to ophthalmic delivery, inserts are alsoused for localized delivery of drugs to various othertissues. For example, the Progestasert® device isdesigned for implantation into the uterine cavity, whereit releases 65 mg progesterone per day to provide con-traception for 1 year. Similarly, Transderm® relies onthe rate-limiting polymeric membranes to control drugrelease. ATRIDOXTM is a FDA-approved productdesigned for controlled-release delivery of the anti-biotic doxycycline for the treatment of periodontal dis-ease. When injected into the periodontal cavity, theformulation sets, forming a drug delivery depot thatdelivers the antibiotic to the cavity.

The ALZA Corporation developed DURO® implantsfor continuous therapy for up to 1 year. The non-degradable, osmotically driven system is intended toenable delivery of small drugs, peptides, proteins, andDNA for systemic or tissue-specific therapy. Viadur®

is a once-yearly implant for the palliative treatment ofadvanced prostate cancer.

One of the more commonly used devices is the oralosmotic pump, composed of a core tablet and a semi-permeable coating with a 0.3- to 4-mm diameter holeproduced by a laser beam for drug exit. This systemrequires only osmotic pressure to be effective, but thedrug release rate is dependent on the surface area,nature of the membrane, and the diameter of the hole.When the dosage form comes in contact with water,water is imbibed because of the resultant osmotic pres-sure of the core and the drug is released from the ori-fice at a controlled rate.


Figure 4.

Different types of ophthalmic inserts.

Transdermal Patches

Transdermal patches deliver drugs directly throughthe skin and into the bloodstream. In general, patchesare composed of three key compartments: a protectiveseal that forms the external surface and protects itfrom damage, a compartment that holds the medica-tion itself and has an adhesive backing to hold theentire patch on the skin surface, and a release liner thatprotects the adhesive layer during storage and isremoved just prior to application. WatsonPharmaceuticals, Inc. has developed Alora® (estradiol)and Androderm® (testosterone) transdermal patchesfor the treatment of menopausal symptoms andendogenous testosterone deficiency, respectively.

Aerosol Products

Aerosols are pressurized dosage forms designed todeliver drugs with the aid of a liquefied or propelledgas (propellant). Aerosol products consist of a pressur-izable container, a valve that allows the pressurizedproduct to be expelled from the container when theactuator is pressed, and a dip tube that conveys the for-mulation from the bottom of the container to the valveassembly. Inhalation devices broadly fall into three cat-egories: pressurized metered-dose inhalers (MDIs),nebulizers, and dry-powder inhalers (DPIs). The mostcommonly used inhalers on the market are MDIs. Theycontain active ingredient as a solution or as a suspen-sion of fine particles in a liquefied propellant heldunder high pressure. MDIs use special metering valvesto regulate the amount of formulation that is dispensedwith each dose. Nebulizers do not require propellantsand can generate large quantities of small dropletscapable of penetrating into the lung. Sustained releaseof drugs, such as bronchodilators and corticosteroidsfor the treatment of asthma and chronic obstructivepulmonary diseases, involves encapsulation of thedrugs in slowly degrading particles that can be inhaled.For accumulation in the alveolar zone of the lungs,which has very large surface area, inhaled liquid ordry-powder aerosols should have particle sizes in therange of 1-5 µm. Inhaled drugs play a very prominentrole in the treatment of asthma, because this route hassignificant advantages over oral or parenteral adminis-tration. Azmacort® (triamcinolone acetamide),Ventolin® HFA (albuterol sulfate), and Serevent® (sal-meterol) are examples of commercially availableaerosols for the treatment of asthma.

6. Targeted Drug Delivery Systems

Targeted drug delivery systems are drug carrier sys-tems that deliver the drug to the target or receptor sitein a manner that provides maximum therapeutic ac-tivity, prevents degradation or inactivation during tran-sit to the target sites, and protects the body fromadverse reactions because of inappropriate disposition.Design of an effective delivery system requires a thor-ough understanding of the drug, the disease, and thetarget site (Figure 5). Examples include macromolecu-lar drug carriers (protein drug carriers), particulatedrug delivery systems (eg, microspheres, nanospheres,and liposomes), monoclonal antibodies, and cells.Plasma clearance kinetics, tissue distribution, metabo-lism, and cellular interactions of a drug can be con-trolled by the use of a site-specific delivery system.Targeting of drugs to specific sites in the body can beachieved by linking particulate systems or macromo-lecular carriers to monoclonal antibodies or to cell-specific ligands (eg, asialofetuin, glycoproteins, orimmunoglobulins), or by alterations in the surfacecharacteristics so that they are not recognized by thereticuloendothelial systems (RES).

Macromolecular Carrier Systems

Both natural and synthetic water-soluble polymershave been used as macromolecular drug carriers. Thedrug can be attached to the polymer chain eitherdirectly or via a spacer. Attachment of polyethyleneglycol (PEG) to proteins can protect them from rapidhydrolysis or degradation within the body, and increaseblood circulation time and lower the immunogenicityof proteins. PEGylated forms of interferons, PEG-IntronTM and PegasysTM (for treatment of hepatitis C,to reduce dosing frequency from daily injections to


Figure 5.

Essential components of drug delivery.

once-a-week injection dosing), adenosine deaminase,and L-asparaginase are currently on the market.PEGylation improves macromole solubility and stabili-ty by minimizing the uptake by the cells of the reticu-loendothelial systems (RES). Since PEG drug conju-gates are not well absorbed from the gut, they aremainly used as injectables. The drug-polymer conju-gate may also contain a receptor-specific ligand toachieve selective access to, and interaction with, thetarget cells.

Particulate Drug Delivery Systems

LiposomesLiposomes are microscopic phospholipid vesiclescomposed of uni- or multilamellar lipid bilayers sur-rounding compartments. Multilamellar vesicles(MLVs) have diameters in the range of 1-5 µm.Sonication of MLVs results in the production of smallunilamellar vesicles (SUVs) with diameters in therange of 0.02-0.08 µm. Large unilamellar vesicles(LUVs) can also be made by evaporation underreduced pressure, resulting in liposomes with a diame-ter of 0.1-1 µm. The bilayer-forming lipid is the essen-tial part of the lamellar structure, while the other com-pounds are added to impart certain characteristics tothe vesicles. Water-soluble drugs can be entrapped inliposomes by intercalation in the aqueous bilayers,while lipid-soluble drugs can be entrapped within thehydrocarbon interiors of the lipid bilayers. Liposomescan encapsulate small-molecular-weight drugs, pro-teins, peptides, oligonucleotides, and genes. The use ofthe antifungal agent amphotericin B formulated inliposomes has been approved by the FDA. Since con-ventional liposomes are recognized by the immunesystems as foreign bodies, the ALZA Corporationdeveloped STEALTHTM liposomes, which evaderecognition by the immune system because of theirunique polyethylene glycol (PEG) coating. DoxilTM isa STEALTH liposome formulation of doxorubicinused for the treatment of AIDS-related Kaposi’ssarcoma.

MicroencapsulationMicroencapsulation is a technique that involves theencapsulation of small particles or solution of drugs ina polymer film or coat. Different methods of microen-capsulation result in either microcapsules or micro-spheres. For example, interfacial polymerization of amonomer almost always produces microcapsules,whereas solvent evaporation may result in micro-spheres or microcapsules, depending on the amount ofdrug loading. A microcapsule has drug located cen-trally within the particle, whereas a microsphere has itsdrug dispersed throughout the particle. Microcapsulesusually release their drug at a constant rate (zero-order

release), whereas microspheres typically give a first-order release of drugs. Small-molecular-weight drugs,proteins, oligonucleotides, and genes can be encapsu-lated into microparticles to provide their sustainedrelease at disease sites.

The most commonly used method of microencapsula-tion is coacervation, which involves addition of ahydrophilic substance to a colloidal drug dispersion.The hydrophilic substance, which acts as a coatingmaterial, may be selected from a variety of natural andsynthetic polymers, including shellacs, waxes, gelatin,starches, cellulose acetate phthalate, ethylcellulose,and others. Following dissolution of the coating mate-rials, the drug inside the microcapsule is available fordissolution and absorption.

Biodegradable polylactide (PLA) and its copolymerswith glycolide (polylactide-co-glycolide; PLGA) arecommonly used for preparation of microparticles fromwhich the drug can be released slowly over a period ofa month or so. Microspheres can be used in a widevariety of dosage forms, including tablets, capsules,and suspensions. Lupron Depot from TAPPharmaceuticals is a FDA-approved preparation ofPLGA microspheres for sustained release of a smallpeptide luteinizing hormone-releasing hormone(LHRH) agonist. More recently, PLGA microspheresof recombinant human growth hormone have beendeveloped and marked successfully by Genentech, Inc.under the trade name of Nutropin Depot.


7. Key Points

• Fick’s first law of diffusion describes the diffusionprocess under the steady-state conditions when thedrug concentration gradient does not change withtime.

• Drug absorption depends not only on the fraction ofun-ionized form of the drug, but also on the surfacearea available for absorption.

• The Noyes-Whitney equation can be used for deter-mination of the dissolution rate of a drug from itsdosage form, while the Arrhenius equation can beused for the determination of the shelf life of a drugdosage form.

• Surfactants consist of hydrophilic and hydrophobicgroups and can be used as emulsifying agents toreduce the interfacial tensions.

• The pharmaceutical dosage form contains the activedrug ingredient in association with nondrug (usuallyinert) ingredients (excipients). Together they com-prise the vehicle, or formulation matrix.

• Water-soluble drugs are often formulated as sus-tained-release tablets so that their release and disso-lution rates can controlled, while enteric-coatedtablets are used to protect drugs from gastric degra-dation.

• Capsules are solid dosage forms with hard or softgelatin shells that contain drugs and excipients.

• Aerosols are pressurized dosage forms designed todeliver drugs to pulmonary tissues with the aid of aliquefied or propelled gas.

• Inserts, implants, and devices allow slow release ofthe drug into a variety of cavities (eg, vagina, buccalcavity, cul de sac of the eye, and skin).

• Transdermal patches deliver drugs directly throughthe skin and into the bloodstream.

• The drug delivery system deals with the pharmaceu-tical formulation and the dynamic interactionsamong the drug, its formulation matrix, its container,and the physiologic milieu of the patient. Thesedynamic interactions are the subject of pharma-ceutics.

• Macromolecular drug carriers, such as protein-poly-mer conjugates, and particulate delivery systems

such as microspheres and liposomes, are commonlyused for delivery of drugs with small molecular sizesuch as peptides and proteins to different diseasetargets.

• Targeted (or site-specific) drug delivery systems areused for drug delivery to the target or receptor site ina manner that provides maximum therapeutic ac-tivity, by preventing degradation during transit to thetarget site while avoiding delivery to nontarget sites.


8. Questions and Answers

1. Which of the following is true for Fick’s firstlaw of diffusion?

A. Refers to the non–steady-state flowB. The amount of material flowing through a

unit cross section of a barrier in unit time isknown as the concentration gradient

C. Flux of material is proportional to the con-centration gradient

D. Diffusion occurs in the direction of increas-ing concentration

E. All of the above

2. Which equation describes the rate of drug disso-lution from a tablet?

A. Fick’s lawB. Henderson-Hasselbalch equationC. Michaelis-Menten equationD. Noyes-Whitney equationE. All of the above

3. The pH of a buffer system can be calculatedwith

A. the Henderson-Hasselbalch equation B. the Noyes-Whitney equationC. the Michaelis-Menten equationD. Yong’s equationE. All of the above

4. Which of the following is NOT true for gasadsorption on a solid?

A. Chemical adsorption is reversibleB. Physical adsorption is based on weak van der

Waals forcesC. Chemical adsorption may require activation

energyD. Chemical adsorption is specific to the sub-

strateE. All of the above

5. What is bioavailability?

A. Bioavailability is the measurement of the rateand extent of active drug that reaches the sys-temic circulation.

B. It is the relationship between the physical andchemical properties of a drug and its sys-temic absorption.

C. It is the movement of the drug into body tis-sues over time.

D. It is dissolution of the drug in the gastroin-testinal tract.

E. All of the above

6. Which of the following may be used to assessthe relative bioavailability of two chemicallyequivalent drug products in a crossover study?

A. Dissolution testB. Peak concentrationC. Time-to-peak concentrationD. Area under the plasma level time curveE. All of the above

7. What condition usually increases the rate ofdrug dissolution for a tablet?

A. Increase in the particle size of the drugB. Decrease in the surface area of the drugC. Use of the ionized, or salt, form of the drugD. Use of the free acid or free base form of the

drugE. Use of sugar coating around the tablet

8. The characteristics of an active transport processinclude all of the following EXCEPT:

A. Active transport moves drug moleculesagainst a concentration gradient

B. Active transport follows Fick’s law ofdiffusion

C. Active transport is a carrier-mediated trans-port system

D. Active transport requires energyE. Active transport of drug molecules may be

saturated at high drug concentrations

9. Which of the following dosage forms may uti-lize surface active agents in their formulations?

A. EmulsionsB. SuspensionsC. Colloidal dosage formsD. CreamsE. All of the above

10. Which of the following statements aboutlyophilic colloidal dispersions is true?

A. They tend to be more sensitive to the additionof electrolytes than lyophobic systems

B. They tend to be more viscous than lyophobicsystems

C. They can be precipitated by prolongeddialysis

D. They separate rapidly


E. All of the above

11. Which of the following is NOT true for tabletformulations?

A. A disintegrating agent promotes granule flowB. Lubricants prevent adherence of granules to

the punch faces of the tabletting machineC. Glidants promote flow of the granulesD. Binding agents are used for adhesion of pow-

der into granulesE. All of the above

12. The absorption rate of a drug is most rapidwhen the drug is formulated as

A. Controlled-release productB. Hard gelatin capsuleC. Compressed tabletD. SolutionE. Suspension

13. The passage of drug molecules from a region ofhigh drug concentration to a region of low drugconcentration is known as

A. Active transportB. Simple diffusion or passive transportC. PinocytosisD. BioavailabilityE. Biopharmaceutics

14. Which equation is used to predict the stability ofa drug product at room temperature from experi-ments at increased temperatures?

A. Stokes equationB. Arrhenius equationC. Michaelis-Menten equationD. Fick’s equation E. Noyes-Whitney equation

15. Choose which of the following statements istrue.

A. Flocculation is desirable for pharmaceuticalsuspensions.

B. The diffusion rate of molecules of a smallerparticle size is less than that of a largerparticle size.

C. Particle size of molecular dispersions islarger than a coarse dispersion.

D. Pseudoplastic flow is shear thickening typeand dilatant is shear thinning type.

E. All of the above are true statements.

16. Choose which of the following statements isfalse.

A. The Henderson-Hasselbalch equationdescribes the effect of physical parameters onthe stability of pharmaceutical suspensions.

B. The passive diffusion rate of hydrophobicdrugs across biological membranes is higherthan that of hydrophilic compounds.

C. When the dispersed phase in an emulsion for-mulation is heavier than the dispersion medi-um, creaming can still occur.

D. Targeted drug delivery systems deliver thedrug to the target or receptor site in a mannerthat provides maximum therapeutic activity.

E. All of the above are false statements.

17. Which of the following is an emulsifying agent? A. Sorbitan monooleate (Span 80)B. Polyoxyethylene sorbitan mono-oleate

(Tween 80)C. Sodium lauryl sulfateD. Gum acaciaE. All of the above

18. Which of the following surfactants is incompati-ble with bile salts?

A. Polysorbate 80B. Potassium stearateC. Sodium lauryl sulfateD. Benzalkonium chlorideE. All of the above

19. Which of the following statements is false?

A. The partition coefficient is the ratio of drugsolubility in n-octanol to that in water.

B. Absorption of a weak electrolyte drug doesnot depend on the extent to which the drugexists in its un-ionized form at the absorptionsite.

C. The drug dissolution rate can be determinedusing the Noyes-Whitney equation.

D. Amorphous forms of drug have faster disso-lution rates than crystalline forms.

E. All of the above are false.

20. Which of the following statements is true?

A. Most substances acquire a surface charge byionization, ion adsorption, and ion dis-solution.

B. The term “surface tension” is used for liquid-vapor and solid-vapor tensions.


C. At the isoelectric point, the total number ofpositive charges is equal to the total numberof negative charges.

D. All of the above are true.E. None of the above are true.

21. Agents that may be used in the enteric coatingof tablets include

A. Hydroxypropyl methylcelluloseB. CarboxymethylcelluloseC. Cellulose acetate phthalateD. All of the aboveE. None of the above

Answers

1. C. Fick’s first law of diffusion states that theamount of material flow through a unit cross-section of a barrier in unit time, which is knownas the flux, is proportional to the concentrationgradient. Fick’s first law of diffusion describesthe diffusion process under steady-state condi-tions when the concentration gradient does notchange with time.

2. D. The Noyes-Whitney equation describes therate of drug dissolution from a tablet. Fick’s firstlaw of diffusion is similar to the Noyes-Whitneyequation in that both equations describe drugmovement due to a concentration gradient. TheMichaelis-Menten equation involves enzymekinetics, whereas Henderson-Hasselbalch equa-tions are used for determination of pH of thebuffer and the extent of ionization of a drugmolecule.

3. A. The Henderson-Hasselbalch equation for aweak acid and its salt is represented as: pH =pKa + log [salt]/[acid], where pKa is the negativelog of the dissolution constant of a weak acid, as[salt]/[acid] is the ratio of the molar concentra-tion of salt and acid used to prepare a buffer.

4. A. Chemical absorption is an irreversibleprocess, which is specific and may require acti-vation energy, while physical adsorption isreversible and associated with van der Waalsforces.

5. A. Bioavailability is the measurement of the rateand extent of systemic circulation of an activedrug.

6. C. The plasma drug concentration versus timecurve measures the bioavailability of a drug

from a product. The peak plasma drug concen-tration (Cmax) relates to the intensity of the phar-macologic response, while the time for peakplasma drug concentration (Tmax) relates to therate of systemic absorption.

7. C. The ionized, or salt, form of a drug is gener-ally more water soluble and therefore dissolvesmore rapidly than the non-ionized (free acid orfree base) form of the drug. According to theNoyes-Whitney equation, the dissolution rate isdirectly proportional to the surface area andinversely proportional to the particle size.Therefore an increase in the particle size or adecrease in the surface area slows the dissolu-tion rate.

8. B. In passive transport, a drug travels from ahigh concentration to a low concentration, whileactive transport moves drug molecules against aconcentration gradient and requires energy.

9. E. Surface active agents facilitate emulsion for-mation by lowering the interfacial tensionbetween the oil and water phases. Adsorption ofsurfactants on insoluble particles enables theseparticles to be dispersed in the form of a sus-pension.

10. E. Most lyophilic colloids are organic molecules(including gelatin and acacia), they spontane-ously form colloidal solution, and tend to be vis-cous. Dispersion of lyophilic colloids is stable inthe presence of electrolytes.

11. A. Disintegrating agents are added to the tabletsto promote breakup of the tablets when placed inthe aqueous environment. Lubricants are re-quired to prevent adherence of the granules tothe punch faces and dies. Binding agents areadded to bind powders together in the granula-tion process. Glidants are added to tablet formu-lations to improve the flow properties of thegranulations.

12. D. For a drug in solution, no dissolution isrequired before absorption. Consequently, com-pared with other drug formulations, a drug inaqueous solution has the highest bioavailabilityrate, and is often used as the reference prepara-tion for other formulations.

13. B. In simple diffusion or passive transport, adrug travels from a high concentration to a lowconcentration, while active transport moves drugmolecules against a concentration gradient and


requires energy. Pinocytosis is a vesicular trans-port process of engulfment of small particles orfluid volumes.

14. B. Stability at room temperature can bepredicted from accelerated testing data by the Arrhenius equation: log (k2/k1) = Ea (T2 – T1)/(2.303 RT2T1), where k2 and k1 arethe rate constants at the absolute temperaturesT2 and T1, respectively; R is the gas constant;and Ea is the energy of activation. Stokes equa-tion is used to determine the sedimentation rateof a suspension, while the Noyes-Whitney equa-tion is used to determine the dissolution rate.

15. A. Flocculation is the formation of light, fluffyconglomerates held together by weak van derWaals forces and is a reversible process.Pseudoplastic flow is a shear thinning process,while dilatant is a shear thickening type process.

16. A. The Henderson-Hasselbalch equationdescribes the relationship between ionized andnon-ionized species of a weak electrolyte.

17. E. Surfactants such as sorbitan mono-oleate(Span 80), polyoxyethylene sorbitan mono-oleate (Tween 80), sodium lauryl sulfate, andgum acacia are surfactants used as emulsifiers.

18. D. Benzalkonium chloride is a cationic surfac-tant and can interact with bile salts.

19. B. According to pH partition theory, absorptionof a weak electrolyte drug depends on the extentto which the drug exists in its un-ionized form atthe absorption site. However, pH partitiontheory often does not hold true, as most weaklyacidic drugs are well absorbed from the smallintestine, possibly due to the large epithelial sur-face areas of the organ.

20. D. Most substances acquire a surface charge byionization, ion adsorption, and ion dissolution.At the isoelectric point, the total number of pos-itive charges is equal to the total number of neg-ative charges.

21. C. An enteric-coated tablet has a coating thatremains intact in the stomach, but dissolves inthe intestine when the pH exceeds 6. Otherenteric-coating materials include celluloseacetate trimellitate, polyvinyl acetate phthalate,and hydroxypropyl methylcellulose phthalate.

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