THE APhA COMPLETE REVIEW FOR PHARMACY, 7th Ed

3. Dosage Forms and Drug Delivery Systems - Ram I. Mahato, PhD

3-1. Introduction

Introduction

A pharmaceutical dosage form is the entity administered to patients so that they receive an effective dose of a drug. Some common examples are tablets, capsules, suppositories, injections, suspensions, and transdermal patches. Achieving an optimum response from any dosage form requires delivery of a drug to its site of action at a rate and a concentration that both minimize its side effects and maximize its therapeutic effects. The development of safe and effective pharmaceutical dosage forms and delivery systems requires a thorough understanding of physicochemical principles that allow a drug to be formulated into a pharmaceutical dosage form. Design of the appropriate dosage form or delivery system depends on the

• Physicochemical properties of the drug, such as solubility, oil-to-water partition coefficient (Ko/w), pKa value, molecular weight, and polymorphism

• 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 Barriers in the Body

Most drugs are absorbed from the site of their application by simple diffusion. Drug diffusion through a barrier may occur by simple molecular permeation known as molecular diffusion or by movement through pores and channels known as pore diffusion. In pore diffusion, drug release rate is affected by degree of crystallinity and crystal size, degree of swelling, porous structure, and tortuosity of polymers.

In passive molecular diffusion, a drug travels by passive transport (which does not require an external energy source) from a region of high concentration to a region of low concentration. However, other transport processes occur in the body as well. For example, active transport of drugs can proceed from regions of low concentration to regions of high concentration through the pumping action of one or more biologic transport systems. These active transport systems require an energy source such as an enzyme or biochemical carrier to ferry the drug across the membrane.

Fick's law of diffusion is a mathematical expression that describes passive diffusion. Fick's first law states that the amount of material (M) flowing through a unit cross-section (S) of a barrier in a unit of time (t), which is known as the flux (J), is proportional to the concentration gradient (dc/dx). 000164

where J = flux in g/cm2 × s; S = cross section of barrier in cm2dM/dt = rate of diffusion in g/s; M = mass in grams; and t = time in seconds.

The flux is proportional to the concentration gradient, dC/dx: 000059

where D = diffusion coefficient of a penetrant in cm2/s; C = concentration in g/cm3 or g/mL; and x = distance in centimeters of movement perpendicular to the surface of the barrier.

The diffusion coefficient, D, is a physicochemical property of the drug molecule. It is not constant and can vary with changes in concentration, temperature, pressure, solvent properties, molecular weight, and chemical nature of the diffusant. The larger the molecular weight is, the lower the diffusion coefficient will be.

Fick's first law of diffusion describes the diffusion process under the condition of steady state when the concentration gradient (dC/dx) does not change with time.

Figure 3-1 shows the diaphragm of thickness h and cross-sectional area S that separate the two compartments of the diffusion cell. Equating both equations for flux, Fick's first law of diffusion may be written as 000056

in which (C1 - C2)/h approximates dC/dx. Concentrations C1 and C2 within the membrane can be replaced by the partition coefficient multiplied by the concentration Cd in the donor compartment or Cr in the receptor compartment. The partition coefficient, K, is given by K = C1/Cd = C2/Cr. Hence,

000058

Under sink conditions, the drug concentration in the receptor compartment is much lower than the drug concentration in the donor compartment.

[Figure 3-1. Concentration Gradient of Diffusant across a Diaphragm of a Diffusion Cell]

Therefore, Cr 速 0. The preceding equation can be simplified as 000176

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

Transport of a drug by passive diffusion across a membrane such as the gastrointestinal (GI) mucosa is represented by Fick's law: 000231

where M is the amount of drug in the gut compartment at time t, Dm is drug diffusivity in the intestinal membrane, S is the surface area of GI membrane available for absorption, K is the partition coefficient between the membrane and aqueous medium in the intestine, h is the thickness of the GI membrane, Cg is the drug concentration in the intestinal compartment, and Cp is the drug concentration in the plasma compartment.

Because the gut compartment usually has a high drug concentration compared with the plasma compartment, Cp may be omitted. Therefore, the preceding equation then becomes

000000

This suggests that the rate of GI absorption of a drug by passive diffusion depends on the surface area of the membrane available for drug absorption. The small intestine is the major site for drug absorption because of the presence of villi and micro-villi, which provide an enormous surface area for absorption.

pH Partition Theory and Its Limitation

The pH partition theory states that drugs are absorbed from the biological membranes by passive diffusion, depending on the fraction of the un-ionized form of the drug at the pH of the fluids close to that biological membrane. The degree of ionization of the drug depends on both the pKa and the pH of the drug solution. The GI tract acts as a lipophilic barrier, and thus ionized drugs are more hydrophilic than un-ionized ones and have minimal membrane transport. The solution pH affects the overall partition coefficient of an ionizable substance. The pKa of the molecule is the pH at which there is a 50:50 mixture of conjugate acid-base forms. The conjugate acid form predominates at a pH lower than the pKa, and the conjugate base form is present at a pH higher than the pKa. The extent of ionization of a drug molecule is given by the following Henderson-Hasselbalch equations, which describe a relationship between ionized and nonionized species of a weak electrolyte: 000216

where [HA] is the concentration of un-ionized acid, [A-] is the concentration of ionized base, [B] is the concentration of un-ionized base, and [BH] is the concentration of ionized base. Although pH partition theory is useful, it often does not hold true for certain experimental observations. For example, most weak acids are well absorbed from the small intestine, which is contrary to the prediction of the pH partition hypothesis. Similarly, quaternary ammonium compounds are ionized at all pHs but are readily absorbed from the GI tract. These discrepancies arise because pH partition theory does not take into consideration the following factors, among others:

• Large epithelial surface areas of the small intestine compensate for ionization effects.

• Long residence time in the small intestine also compensates for ionization effects.

• Charged drugs, such as quaternary ammonium compounds and tetracyclines, may interact with opposite-charged organic ions, resulting in a neutral species that is absorbable.

• Some drugs are absorbed by means of active transport.

The Noyes-Whitney Equation of Dissolution

For most drugs, the rate at which the solid drug dissolves in a solvent (dissolution) is often the rate-limiting step in the drug's bioavailability. The rate at which a solid drug of limited water solubility dissolves in a solvent can be determined using the Noyes-Whitney equation: 000052

where dM/dt is the rate of dissolution (in mass/time), k is the dissolution rate constant (in cm/s) (k = D/h), S is the surface area of exposed solid (in cm2), D is the diffusion coefficient of solute in solution (in cm2/s), h is the thickness of the diffusion layer (in cm), Cs is the drug solubility (in g/mL), and C is the drug concentration in bulk solution at time t (in g/mL).

Under sink conditions, when C is much less than Cs, the Noyes-Whitney equation can be simplified as follows: 000122

where dC/dt is the dissolution rate (in concentration/time) and V is the volume of the dissolution medium (in mL).

The following factors influence the dissolution rate:

• The physicochemical conditions in the GI tract affect the dissolution rate. For example, the presence of foods that increase the viscosity of GI fluids decreases the diffusion coefficient, D, of a drug and its dissolution rate.

• The thickness of the diffusion layer, h, is influenced by the degree of agitation experienced by each drug particle in the GI tract. Hence, an increase in gastric or intestinal motility may increase the dissolution rate of poorly soluble drugs.

• The removal rate of dissolved drugs attributable to absorption through the gastrointestinal-blood barrier and the GI fluid volume affects drug concentration in the GI tract and thus also affects the dissolution rate.

• The dissolution rate of a weakly acidic drug in GI fluids is influenced by the drug solubility in the diffusion layer surrounding each dissolving drug particle. The pH of the diffusion layer significantly affects the solubility of a weak electrolyte drug and its subsequent dissolution rate. The dissolution rate of a weakly acidic drug in GI fluid (pH 1-3) is relatively low because of its low solubility in the diffusion layer. If the pH in the diffusion layer could be increased, the solubility (Cs) exhibited by the weak acidic drug in this layer (and hence the dissolution rate of the drug in GI fluids) could be increased. The potassium or sodium salt form of the weakly acidic drug has a relatively high solubility at the elevated pH in the diffusion layer. Thus, the dissolution of the drug particles takes place at a faster rate.

• Particle size and the surface area of the drug significantly influence the drug dissolution rate. An increase in the total effective surface area of drug in contact with GI fluids causes an increase in its dissolution rate. The smaller the particle size is, the greater will be the effective surface area exhibited by a given mass of drug and the higher the dissolution rate. However, particle size reduction is not always helpful and may fail to increase the bioavailability of a drug. In the case of certain hydrophobic drugs, excessive particle size reduction tends to cause reaggregation into larger particles. Preventing formation of aggregates requires dispersion of small drug particles in polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), dextrose, or other agents. For example, a dispersion of griseofulvin in PEG 4,000 enhances its dissolution rate and bioavailability. Certain drugs, such as penicillin G and erythromycin, are unstable in gastric fluids and do not dissolve readily in them. For such drugs, particle size reduction yields an increased rate of drug dissolution in gastric fluid and also increases the extent of drug degradation.

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

• Temperature also affects solubility. An increase in temperature will increase the solubility of a solid with a positive heat of solution. The solid will therefore dissolve at a more rapid rate on heating the system.

• Surface-active agents will increase dissolution rates by lowering interfacial tension, which allows better wetting and penetration by the solvent. Weakly acidic and basic drugs may be brought into solution by the solubilizing action of surfactants.

Interfacial Electrical Properties

Most dispersed substances in a solvent such as water acquire a surface electric charge by ionization, ion adsorption, and ion dissolution.

• Ionization: Surface charge arising from ionization on the particles is the function of the pH of the environment and the pKa of the drug. Proteins acquire charge through the ionization of carboxyl and amino groups to obtain COO-and NH3+ ions. Ionization of these groups, as well as the net molecular charge, depends on the pH of the medium. At a pH below its isoelectric point (PI), a protein molecule is positively charged, -NH2 速 NH3+, and at a pH above its PI, the protein is negatively charged, -COOH 速 COO-. At the PI of a protein, the total number of positive charges equals the total number of negative charges, and the net charge is zero. This state may be represented as follows:

R-NH2-COO-

Alkaline solution

 

000079

 
 

R-NH3-COO-

Isoelectric point (Zwitterion)

 

000079

 
 

R-NH3-COOH

Acidic solution

 

Often a protein is least soluble at its isoelectric point and is readily dissolved by water-soluble salts such as ammonium sulfate.

• Ion adsorption: A net surface charge can result from the unequal adsorption of oppositely charged ions. Surfaces that are already charged usually show a tendency to adsorb counterions. Counterion adsorption can cause a reversal of charge. Surfactants strongly adsorb by hydrophobic effect and thus will determine the surface charge when adsorbed.

• Ion dissolution: Ionic substances can acquire a surface charge by virtue of unequal dissolution of the oppositely charged ions of which they are composed. For example, 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+] is present. The silver and iodide ions are referred to as potential-determining ions because their concentrations determine the electric potential at the particle surface.

Adsorption at solid interfaces

Adsorption of materials at solid interfaces may take place from either an adjacent liquid or a gas phase. Adsorption is different from absorption: the process of absorption implies the penetration of an entity through the organs and tissues. The degree of adsorption depends on the chemical nature of the adsorbent (a material that is being adsorbed onto a substrate, called adsorbate), the chemical nature of the adsorbate, the surface area of the adsorbent, the temperature, and the partial pressure of the adsorbed gas. Adsorption can be physical or chemical in nature:

• Physical adsorption: Physical adsorption is rapid, nonspecific, and relatively weak. Furthermore, it is associated with van der Waals attractive forces and is reversible. Removal of the adsorbate from the adsorbent is known as desorption. A physically adsorbed gas may be desorbed from a solid by increasing the temperature and reducing the pressure. Physical adsorption is an exothermic process, and thus the amount of adsorption decreases with rise in temperature

• Chemical adsorption: Chemical adsorption or chemisorption is an irreversible process in which the adsorbent is attached to the adsorbate by primary chemical bonds. Chemisorption is specific and may require activation energy; therefore, the process is slow and only a monomolecular chemisorbed layer is possible.

Factors affecting adsorption from solution

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

• Solute concentration: An increase in the solute concentration causes an increase in the amount of adsorption that occurs at equilibrium until a limiting value is reached.

• Temperature: An increase in temperature leads to decreased adsorption.

• pH: The influence of pH is through a change in the ionization and solubility of the adsorbate drug molecule. For many simple small molecules, adsorption increases as the ionization of the drug is suppressed; that is, the extent of adsorption reaches a maximum when the drug is completely un-ionized. For amphoteric compounds, adsorption is at a maximum at the isoelectric point. Because the un-ionized form of most drugs in aqueous solution has a low solubility, pH and solubility effects act in concert.

• Surface area of adsorbent: An increased surface area, achieved by a reduction in particle size or by the use of a porous adsorbing material, increases the extent of adsorption.

Rheology

Rheology is the study of flow properties of liquids and the deformation of solids under the influence of stress. The flow of simple liquids can be described by viscosity, an expression of the resistance to flow; however, other complex dispersions cannot be expressed simply by viscosity. Materials are divided into two general categories, Newtonian and non-Newtonian, depending on their characteristics. Rheological properties are useful for the formulation and analysis of emulsions, suspensions, pastes, lotions, and suppositories. Pourability, spreadability, and syringeability of an emulsion are determined by its rheological properties.

According to Newton's law of viscous 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 that obey Newton's law of flow are referred to as Newtonian fluids, and fluids that deviate are known as non-Newtonian fluids. The force per unit area (F´/A) required to bring about flow is called the shearing stress (F): 000081

where η is the viscosity, dv/dr is the rate of shear = G (s-1), and F´/A units are in dynes per cm2. For simple Newtonian fluids, a plot of the rate of shear against shearing stress gives a straight line (

Figure 3-2 A); thus, η is a constant. In the case of Newtonian fluids, viscosity does not change with increasing shear rate. Various types of water and pharmaceutical dosage forms that contain a high percentage of water are examples of liquid dosage forms that have Newtonian flow properties.

Most pharmaceutical fluids (including colloidal dispersions, emulsions, and liquid suspensions) do not follow Newton's law of flow, and the viscosity of the fluid varies with the rate of shear. There are three types of non-Newtonian flow: plastic, pseudoplastic, and dilatant (Figure 3-2 BC, and D).

Plastic flow

Substances that undergo plastic flow are called Bingham bodies, which are defined as substances that exhibit a yield value (Figure 3-2 B). Plastic flow is associated with the presence of flocculated particles in concentrated suspensions. Flocculated solids are light, fluffy conglomerates of adjacent particles held together by weak van der Waals forces. The yield value exists because a certain shearing stress must be exceeded to break up van der Waals forces. A plastic system resembles a Newtonian system at shear stresses above the yield value. Yield value, f, is an indicator of flocculation (the higher the yield value, the greater the degree of flocculation). The characteristics of plastic flow materials can be summarized as follows:

• 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 does not cross through the origin.

• The materials are said to be "elastic" at shear stresses below the yield value.

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

[Figure 3-2. Plots of Rate of Shear as a Function of Shearing Stress for (A) Newtonian, (B) Plastic, (C) Pseudoplastic, (D) Dilatant, and (E) Thixotropic flow]

Pseudoplastic flow

Pseudoplastic flow is exhibited by polymers in solution. A large number of pharmaceutical products, including natural and synthetic gums (e.g., liquid dispersions of tragacanth, sodium alginate, methyl cellulose, and sodium carboxymethylcellulose), exhibit pseudoplastic flow properties. The characteristics of pseudoplastic flow materials can be summarized as follows:

• Pseudoplastic substances begin flow when a shearing stress is applied: that is, there is no yield value (it does cross the origin).

• The viscosity of a pseudoplastic substance decreases with increasing shear rate.

• With increasing shearing stress, the rate of shear increases; these materials are called shear-thinning systems.

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

Dilatant flow

Certain suspensions with a high percentage of dispersed solids exhibit an increase in resistance to flow with increasing rates of shear. Dilatant systems are usually suspensions with a high percentage of dispersed solids that exhibit an increase in resistance to flow with increasing rates of shear. Dispersions containing a high percentage (≥ 50%) of small, deflocculated particles may exhibit this type of behavior. The characteristics of dilatant flow materials can be summarized as follows:

• Dilatant materials increase in volume when sheared.

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

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

• Viscosity increases with increasing shear rate.

• Dilatant materials may solidify under conditions of high shear.

Thixotropy

Thixotropy is a nonchemical isothermal gel-sol-gel transformation. If a thixotropic gel is sheared (by simple shaking), the weak bonds are broken and a lyophobic solution is formed. On standing, the particles collide, flocculation occurs, and the gel is reformed. The advantage that thixotropic preparations have is that the particles remain in suspension during storage, but when required for use, the pastes are readily made fluid by tapping or shaking. The shearing force on the injection as it is pushed through the needle ensures that it is fluid when injected; however, the rapid resumption of the gel structure prevents excessive spreading in the tissues, and consequently a more compact depot is produced than with nonthixotropic suspensions. Thixotropy is a desirable property in liquid pharmaceutical preparations. A well-formulated thixotropic suspension will not settle out readily in the container and will become fluid on shaking. Flow curves (rheograms) for thixotropic materials are highly dependent on the rate at which shear is increased or decreased and the length of time a sample is subjected to any one rate of shear.

Negative thixotropy

Negative thixotropy is also known as antithixotropy, which represents an increase rather than a decrease in consistency on the down curve (an increase in thickness or resistance to flow with an increased time of shear). It may result from an increased collision frequency of dispersed particles (or polymer molecules) in suspension, which causes increased interparticle bonding with time.

Shelf-Life Stability of a Drug Product

The shelf life of a drug in a dosage form is the amount of time the product can be stored before it becomes unfit for use because of chemical decomposition, physical deterioration, or both. Shelf-life stability of a dosage form can be determined by the Arrhenius equation k = A × e-Ea/RT, which can be rewritten as

k = A · e-Ea/RT, which can be written as

000083

where k2 and k1 are the reaction rates at the absolute temperatures T2 and T1, respectively; R is the gas constant (1.987 cal/kmol), Ea is the activation energy (in cal/mol), and A is the constant (based on molecular weight and molar volume of liquid).

3-2. Surfactants and Micelles

Introduction

Surface-active agents, or surfactants, are substances that absorb to surfaces or interfaces to reduce surface or interfacial tension. They may be used as emulsifying agents, solubilizing agents, detergents, and wetting agents. Surfactants have two distinct regions in one chemical structure. One area is hydrophilic (water liking); another is hydrophobic (water hating). The existence of two such moieties in a molecule is known as amphipathy, and the molecules are consequently referred to as amphipathic molecules or amphiphiles. Depending on the number and nature of the polar and nonpolar groups present, the amphiphile may be predominantly hydrophilic, lipophilic, or somewhere in between. For example, straight chain alcohols, amines, and acids are amphiphiles that change from being predominantly hydrophilic to lipophilic as the number of carbon atoms in the alkyl chain is increased. The hydrophobic portions are usually saturated or unsaturated hydrocarbon chains or, less commonly, heterocyclic or aromatic ring systems.

Surfactants are classified according to the nature of the hydrophilic or hydrophobic groups. In addition, some surfactants possess both positively and negatively charged groups and can exist as either anionic or cationic, depending on the pH of the solution. These surfactants are known as ampholytic compounds.

At low concentrations in solutions, amphiphiles exist as monomers. As the concentration is increased, aggregation occurs over a narrow concentration range. These aggregates, which may contain 50 or more monomers, are called micelles. Therefore, micelles are small spherical structures composed of both hydrophilic and hydrophobic regions. The concentration of monomer at which micelles are formed is called the critical micellization concentration, or CMC. Surface tension decreases up to the CMC but remains constant above the CMC. The longer the hydrophobic chain or the lower the polarity of the polar group, the greater the tendency for monomers to "escape" from the water to form 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 are considered to be spherical in shape. At higher concentrations, they become more asymmetric and eventually assume cylindrical or lamellar structures. Oil-soluble surfactants have a tendency to self-associate into reverse micelles in nonpolar solvents, with their polar groups oriented away from the solvent.

Factors Affecting CMC and Micellar Size

• Structure of hydrophobic group: An increase in the hydrocarbon chain length causes a logarithmic decrease in the CMC.

• Nature of hydrophilic group: An increase in chain length increases hydrophilicity and the CMC. In general, nonionic surfactants have very low CMC values and high aggregation numbers compared with their ionic counterparts with similar hydrocarbon chains.

• Nature of counterions: Note that Cl- < Br- < I- for cationic surfactants, and Na+ < K+ for anionic surfactants.

• Electrolytes: The addition of electrolytes to ionic surfactants decreases the CMC and increases the micellar size. In contrast, micellar properties of nonionic surfactants are affected only minimally by the addition of electrolytes.

• Temperature: At temperatures up to the cloud point, an increase in micellar size and a decrease in CMC is noted for many nonionic surfactants but has little effect on that of ionic surfactants.

• Alcohol: CMCs are increased by the addition of alcohols.

Hydrophilic-Lipophilic Balance Systems

Griffin's method of selecting emulsifying agents is based on the balance between the hydrophilic and lipophilic portions of the emulsifying agent, now widely known as the hydrophilic-lipophilic balance (HLB) system. The higher the HLB value of an emulsifying agent, the more hydrophilic it is. The emulsifying agents with lower HLB values are less polar and more lipophilic. The Spans (i.e., sorbitan esters) are lipophilic and have low HLB values (1.8-8.6); the Tweens (polyoxyethylene derivatives of the Spans) are hydrophilic and have high HLB values (9.6-16.7). Surfactants with the proper balance of hydrophilic and lipophilic affinities are effective emulsifying agents because they concentrate at the oil-in-water (o/w) interface. The type of an emulsion that is produced depends primarily on the property of the emulsifying agent. The HLB of an emulsifier or a combination of emulsifiers determines whether an o/w or water-in-oil (w/o) emulsion results. In general, o/w emulsions are formed when the HLB of the emulsifier is within the range of about 9 to 12; w/o emulsions are formed when the range is about 3 to 6. The type of emulsion is a function of the relative solubility of the supernatant. An emulsifying agent with high HLB is preferentially soluble in water and results in the formation of an o/w emulsion. The reverse situation is true with surfactants of low HLB value, which tend to form w/o emulsions.

Micellar Solubilization

Micelles can be used to increase the solubility of materials that are normally insoluble or poorly soluble in the dispersion medium used. For example, surfactants are often used to increase the solubility of poorly soluble steroids. The factors affecting micellar solubilization are the nature of surfactants, the nature of solubilizates, and the temperature.

3-3. Dispersed Systems

Introduction

Dispersed systems consist of particulate matter, known as the dispersed phase, distributed throughout a continuous or dispersion medium. The particulate matter, or dispersed phase, consists of particles that range from 1 nanometer (nm) to 0.5 micrometer (10-9 m to 5 × 10-7 m). Depending on the dispersed phase, dispersed systems are classified as follows:

• Molecular dispersions: Less than 1 nm, invisible under electron microscopy. Examples are oxygen molecules, ions, and glucose.

• Coloidal dispersions: From 1 nm to 0.5 micrometer, visible under electron microscopy. Examples are colloidal silver sols and natural and synthetic polymers.

• Coarse dispersions: Greater than 0.5 micrometer, visible under light microscopy. Examples are grains of sand, emulsions, suspensions, and red blood cells.

Types of Colloidal Systems

On the basis of the interaction of the particles, molecules, or ions of the dispersed phase with the molecules of dispersion medium, colloidal systems are classified into three groups: lyophilic, lyophobic, and association colloids.

Lyophilic or hydrophilic colloids

Systems containing colloidal particles that interact with the dispersion medium are referred to as lyophilic colloids. In the case of lipophilic colloids, organic solvent is the dispersion medium, whereas water is used as the dispersion medium for hydrophilic colloids. Because of their affinity for the dispersion medium, such materials form colloidal dispersions with relative ease. For example, the dissolution of acacia or gelatin in water, or celluloid in amyl acetate, leads to the formation of a solution. Most lyophilic colloids are polymers (e.g., gelatin, acacia, povidone, albumin, rubber, and polystyrene).

Lyophobic or hydrophobic colloids

Lyophobic colloids are composed of materials that have little attraction for the dispersion medium. Lyophobic colloids are intrinsically unstable and irreversible. Hydrophobic colloids are generally composed of inorganic particles dispersed in water.

Association colloids

Association colloids (referring to amphiphilic colloids) are formed by the grouping or association of amphiphiles (i.e., molecules that exhibit both lyophilic and lyophobic properties). At low concentrations, amphiphiles exist separately and do not form a colloid. At higher concentrations, aggregation occurs at around 50 or more monomers, leading to micelle formation. As with lyophilic colloids, formation of association colloids is spontaneous if the concentration 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 potential between the surface of the tightly bound layer (shear plane) and the electroneutral region of the solution. The ζ potential governs the degree of repulsion between adjacent, similarly charged, dispersed particles. If ζ potential is reduced below a certain value, the attractive forces exceed the repulsive forces, and the particles come together. This phenomenon is known as flocculation.

Stabilization is accomplished by providing the dispersed particles with an electric charge and a protective solvent sheath surrounding each particle to prevent mutual adherence attributable to collision. This second effect is significant only in the case of lyophilic colloids. Lyophilic and association colloids are thermodynamically stable and exist in a true solution so that the system constitutes a single phase. In contrast, lyophobic colloids are thermodynamically unstable but can be stabilized by preventing aggregation or coagulation by providing the dispersed particles with an electric charge, which can prevent coagulation through repulsion of like particles.

3-4. Pharmaceutical Ingredients

Turning a drug substance into a pharmaceutical dosage form or a drug delivery system requires pharmaceutical ingredients. For example, in the preparation of tablets, diluents or fillers are commonly added to increase the bulk of the formulation. Binders are added to promote adhesion of the powdered drug to other ingredients. Lubricants assist the smooth tabletting process. Disintegrants promote tablet breakup after administration. Coatings improve stability, control disintegration, or enhance appearance. Similarly, in the preparation of pharmaceutical solutions, preservatives are added to prevent microbial growth, stabilizers are added to prevent drug decomposition, and colorants and flavorants are added to ensure product appeal. Thus, for each dosage form, the pharmaceutical ingredients establish the primary features of the product and control the physicochemical properties, drug-release profiles, and bioavailability of the product.

Table 3-1 lists some typical pharmaceutical ingredients used in different dosage forms.

3-5. Types of Commonly Used Dosage Forms

Solutions

Solutions are homogeneous mixtures of one or more solutes dispersed in a dissolving medium (solvent). Aqueous solutions containing a sugar or sugar substitute with or without added flavoring agents and drugs are classified as syrups. Sweetened hydroalcoholic (combinations of water and ethanol) solutions are termed elixirs. Hydroalcoholic solutions of aromatic materials are termed spirits. Tinctures are alcoholic or hydroalcoholic solutions of chemical or soluble constituents of vegetable drugs. Most tinctures are prepared by an extraction process. Mouthwashes are solutions used to cleanse the mouth or treat diseases of the oral membrane. Antibacterial topical solutions (e.g., benzalkonium chloride and strong iodine) will kill bacteria when applied to the skin or mucous membrane.

Solutions intended for oral administration usually contain flavorants and colorants to make the medication more attractive and palatable to the patient. They may contain stabilizers to maintain the physicochemical stability of the drug and preservatives to prevent the growth of microorganisms in the solution. A drug dissolved in an aqueous solution is in the most bioavailable form. Because the drug is already in solution, no dissolution step is necessary before systemic absorption occurs. Solutions that are prepared to be sterile, that are pyrogen free, and that are intended for parenteral administration are classified as injectables.

[Table 3-1. Typical Pharmaceutical Ingredients]

Some drugs, particularly certain antibiotics, have insufficient stability in aqueous solution to withstand long shelf lives. These drugs are formulated as dry powder or granule dosage forms for reconstitution with purified water immediately before dispensing to the patient. The dry powder mixture contains all of the formulation components—that is, drug, flavorant, colorant, buffers, and others—except for the solvent. Examples of dry powder mixtures intended for reconstitution to make oral solutions include cloxacillin sodium, nafcillin sodium, oxacillin sodium, and penicillin V potassium.

Sucrose is the sugar most frequently used in syrups; in special circumstances, it may be replaced in whole or in part by other sugars (e.g., dextrose) or nonsugars (e.g., sorbitol, glycerin, and propylene glycol). Most syrups consist of between 60% and 80% sucrose. Sucrose not only provides sweetness and viscosity to the solution, but also renders the solution inherently stable (unlike dilute sucrose solutions, which are unstable).

Compared with syrups, elixirs are usually less sweet and less viscous because they contain a lower proportion of sugar, and they are consequently less effective than syrups in masking the taste of drugs. In contrast to aqueous syrups, elixirs are better able to maintain both water-soluble and alcohol-soluble components in solution because of their hydroalcoholic properties. These stable characteristics often make elixirs preferable to syrups. All elixirs contain flavoring and coloring agents to enhance their palatability and appearance. Elixirs containing over 10% to 12% alcohol are usually self-preserving and do not require the addition of antimicrobial agents for preservation. Alcohols precipitate tragacanth, acacia, agar, and inorganic salts from aqueous solutions; therefore, such substances should either be absent from the aqueous phase or be present in such low concentrations as not to promote precipitation on standing. Examples of some commonly used elixirs include dexamethasone elixir USP, pentobarbital elixir USP, diphenhydramine hydrochloride elixir, and digoxin elixir.

Tablets

Depending on the physicochemical properties of the drug, site and extent of drug absorption in the GI tract, stability to heat or moisture, biocompatibility with other ingredients, solubility, and dose, the following types of tablets are commonly formulated:

• Swallowable tablets are intended to be swallowed whole and then disintegrate and release their medicaments in the GI tract.

• Effervescent tablets are dissolved in water before administration. In addition to the drug substance, these tablets contain sodium bicarbonate and an organic acid such as tartaric acid. These additives react in the presence of water, liberating carbon dioxide, which acts as a disintegrator and produces effervescence.

• Chewable tablets are used when a faster rate of dissolution or buccal absorption is desired. Chewable tablets consist of a mild effervescent drug complex dispersed throughout a gum base. The drug is released from the dosage form by physical disruption associated with chewing, chemical disruption caused by the interaction with the fluids in the oral cavity, and the presence of effervescent material. For example, antacid tablets should be chewed to obtain quick indigestion relief.

• Buccal and sublingual tablets dissolve slowly in the mouth, cheek pouch (buccal), or under the tongue (sublingual). Buccal or sublingual absorption is often desirable for drugs subject to extensive hepatic metabolism, often referred to as the first-pass effect. Examples are isoprenaline sulfate (a bronchodilator), glyceryl trinitrate (a vasodilator), nitroglycerin, and testosterone tablets. These tablets do not contain a disintegrant and are compressed lightly to produce a fairly soft tablet.

• Lozenges are compressed tablets that do not contain a disintegrant. Some lozenges contain antiseptics (e.g., benzalkonium) or antibiotics for local effects in the mouth.

• Controlled-release tablets are used to improve patient compliance and to reduce side effects. Some water-soluble drugs are formulated as sustained-release tablets so that their release and dissolution are controlled over a long period. A hydrophobic matrix composed of carnauba wax and partially hydrogenated cottonseed oil were used to prepare sustained-release tablets of a highly water-soluble drug, ABT-089, a cholinergic channel modulator for the treatment of cognitive disorders. Theo-Dur is a controlled-release tablet of theophylline and consists of two components: a matrix of compressed theophylline crystals and coated theophylline granules embedded in the matrix. In contact with fluid, theophylline diffuses slowly through the wall of the free granules, which dissolves with time. After oral administration of Theo-Dur 300 mg tablets to human subjects, serum theophylline concentrations over 1 mg/mL were maintained over 24 hours. Core-in-cup tablets, which provide a zero-order release of ibuprofen, were developed by compressing the mixture of ethyl cellulose and carnauba wax, followed by compression with core tablets containing ibuprofen. The combination of high- and low-viscosity grades of hydroxypropyl methylcellulose (HPMC) was used as the matrix base to prepare diclofenac sodium and zileuton sustained-release tablets. A ternary polymeric matrix system composed of protein, HPMC, and highly water-soluble drugs such as diltiazem hydrochloride was developed by the direct compression method. Xanthan gum was used for a hydrophilic matrix for sustained-release ibuprofen tablets. Sustained-release tablets can also be prepared by formulating inert polymers, such as polyvinyl chloride, polyvinyl acetate, and methyl methacrylate. These polymers protect the tablet from disintegration and reduce the dissolution rate of the drug inside the tablet. Examples of commonly used sustained-release drug delivery products are listed in

Table 3-2.

• Coated tablets are used to prevent decomposition or to minimize the unpleasant taste of certain drugs. Several types of coated tablets are made: film coated, sugar coated, gelatin coated (gel caps), or enteric coated. Enteric coatings are resistant to gastric juices but readily dissolve in the small intestine. These enteric coatings can protect drugs against decomposition in the acidic environment of the stomach. Commonly used polymers for enteric coating are acid-impermeable polymers, such as cellulose acetate trimellitate, HPMC

[Table 3-2. Examples of Sustained-Release Drug Delivery Products]

   phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, and EUDRAGIT. Aspirin formulated as enteric-coated sustained-release tablets has been shown to produce less gastric bleeding than do conventional aspirin preparations. Film-coated tablets are compressed tablets coated with a thin layer of a water-insoluble or water-soluble polymer, such as methylcellulose phthalate, ethylcellulose, povidone, or polyethylene glycol. Abacavir is a capsule-shaped film-coated tablet containing a nucleoside reverse transcriptase inhibitor, which is a potent antiviral agent for the treatment of HIV infection.

Tablet formulation

In addition to the drug, the following materials are added to make the powder system compatible with tablet formulation by the compression or granulation methods:

• Diluents or bulking agents are invariably added to very-low-dose drugs to bring overall tablet weight to at least 50 mg, which is the minimum desirable tablet weight. Commonly used diluents are lactose, dicalcium phosphate, starches, microcrystalline cellulose, dextrose, sucrose, mannitol, and sodium chloride. Dicalcium phosphate absorbs less moisture than lactose and is therefore used with hygroscopic drugs such as pethidine hydrochloride.

• Adsorbents are substances capable of holding quantities of fluids in an apparently dry state. Oil-soluble drugs or fluid extracts can be mixed with adsorbents and then granulated and compressed into tablets. Examples are fumed silica, microcrystalline cellulose, magnesium carbonate, kaolin, and bentonite.

• Moistening agents are liquids that are used for wet granulation. Examples include water, industrial methylated spirits, and isopropanol.

• Binding agents (adhesives) bind powders together in the wet granulation process. They also help bind granules together during compression. Examples include starches, gelatin, PVP, alginic acid derivatives, cellulose derivatives, glucose, and sucrose. Choice of binders affects the dissolution rate. For example, the tablet formulation of furosemide with PVP as the binder has a t50 (time required for 50% of the drug to be released during an in vitro dissolution study) of 3.65 minutes, but with starch mucilage as the binder, the t50 of the tablets was 117 minutes.

• Glidants are added to tablet formulations to improve the flow properties of the granulations. They act by reducing interparticle friction. Commonly used glidants are fumed (colloidal) silica, starch, and talc.

• Lubricants have a number of functions in tablet manufacture. They prevent adherence of the tablet material to the surfaces of the punch faces and dies, reduce interparticle friction, and facilitate the smooth ejection of the tablet from the die cavity. Many lubricants also enhance the flow properties of the granules. Commonly used lubricants are magnesium stearate, talc, stearic acid and its derivatives, PEG, paraffin, and sodium or magnesium lauryl sulfate. Among these lubricants, magnesium stearate is the most popular, because it is effective as both a die and a punch lubricant. However, for many drugs (e.g., aspirin), magnesium stearate is chemically incompatible; therefore, talc or stearic acid is often used. Most lubricants, with the exception of talc, are used in concentrations below 1%.

• Disintegrating agents are added to the tablets to promote breakup or disintegration after administration, which increases the effective surface area and promotes rapid release of the drug. Disintegrants act either by bursting open the tablet or by promoting the rapid ingress of water into the center of the tablet or capsule. Examples include starches, cationic exchange resins, cross-linked PVP, celluloses, modified starches, alginic acid and alginates, magnesium aluminum silicate, and cross-linked sodium carboxymethylcellulose. Among these agents, starch is the most popular disintegrant because it has a great affinity for water and swells when moistened, thus facilitating the rupture of the tablet matrix.

Disintegration, dissolution, and absorption

A solid drug product has to disintegrate into small particles and release the drug before absorption can take place. Tablets that are intended for chewing or sustained release do not have to undergo disintegration. The various excipients for tablet formulation affect the rates of disintegration, dissolution, and absorption. Systemic absorption of most products consists of a succession of rate processes, such as

• Disintegration of the drug product and subsequent release of drug

• Dissolution of the drug in an aqueous environment

• Absorption across cell membranes into the systemic circulation

In the process of tablet disintegration, dissolution, and absorption, the rate at which the drug reaches the circulatory system is determined by the slowest step in the sequence. Disintegration of a tablet is usually more rapid than drug dissolution and absorption. For the drug that has poor aqueous solubility, the rate at which the drug dissolves (dissolution) is often the slowest step, and it therefore exerts a rate-limiting effect on drug bioavailability. In contrast, for the drug that has a high aqueous solubility, the dissolution rate is rapid, and the rate at which the drug crosses or permeates cell membranes is the slowest or rate-limiting step.

Capsules

Capsules are the dosage forms in which unit doses or powder, semisolid, or liquid drugs are enclosed in a hard or soft, water-soluble container or shell of gelatin. Coating of the capsule shell or drug particles within the capsule can affect bioavailability. There are two types of capsules: hard and soft capsules; hard gelatin capsules are more versatile for controlled drug delivery.

Hard gelatin capsules

A hard gelatin capsule consists of two pieces, a cap and a body, that fit one inside the other. They are produced empty and are then filled in a separate operation. Hard gelatin capsules are usually filled with powders, granules, or pellets containing the drug. After ingestion, the gelatin shell softens, swells, and begins to dissolve in the GI tract. Encapsulated drugs are released rapidly and dispersed easily, leading to high bioavailability. Capsules are supplied in a variety of sizes, and high-speed filling machinery capable of filling approximately 1,500 capsules per minute is available. The hard gelatin empty capsules are numbered from 000, the largest size, to 5, which is the smallest. The approximate filling capacity of capsules ranges from 6,000 to 30 mg, depending on the types and bulk densities of powdered drug materials.

Powder formulations for encapsulation into hard gelatin capsules require careful consideration of the filling process, such as lubricity, compactibility, and fluidity. Additives present in the capsule formulations, such as the amount and choice of fillers and lubricants, the inclusion of disintegrants and surfactants, and the degree of plug compaction, can influence drug release from the capsule. Formulation factors influencing drug release and bioavailability are as follows:

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

• Glidants: The flow properties of the powder blend should be adequate to ensure a uniform flow rate from the hopper. Glidants such as silica, starch, talc, and magnesium stearate are used to improve the fluidity. The optimal concentration of the glidant used to improve the flow of a powder mixture is generally less than 1%.

• Lubricants: These ease the ejection of plugs by reducing adhesion of powder to metal surfaces and friction between sliding surfaces in contact with the powder. Typical lubricants for capsule formulations include magnesium stearate and stearic acid.

• Surfactants: These may be included in capsule formulations to increase wetting of the powder mass and to enhance drug dissolution. The most commonly used surfactants in capsule formulations are 0.1% to 0.5% sodium lauryl sulfate and sodium docusate.

• Wetting agents: Hydrophilic polymer is used as a wetting agent for improving the wettability of poorly soluble drugs. Powder wettability and dissolution rate of several drugs, including hexobarbital and phenytoin, from hard gelatin capsules have been shown to be enhanced if the drug is treated with methylcellulose or hydroxyethyl-cellulose.

Vancomycin hydrochloride is a highly hygroscopic antibiotic. To achieve acceptable stability, Eli Lilly has developed a hard gelatin capsule filled with a PEG 6,000 matrix of vancomycin hydrochloride, which produces plasma and urine levels of the antibiotic similar to those obtained with the solution of vancomycin hydrochloride. Controlled-release beads and minitablets are often filled into gelatin capsules for convenient administration of an oral controlled-release dosage form. For example, sustained-release antihistamines, antitussives, and analgesics are first preformulated into extended-release microcapsules or microspheres and then placed inside a gelatin capsule. Another example is enteric-coated lipase minitablets, which are placed in a gelatin capsule for more effective protection and dosing of these enzymes.

Soft gelatin capsules

Soft gelatin capsules are prepared from plasticized gelatin by a rotary die process. They are formed, filled, and sealed in a single operation. Soft gelatin capsules may contain a nonaqueous solution, a powder, or a drug suspension, none of which solubilize the gelatin shell. In contrast to hard gelatin capsules, soft gelatin capsules contain about 30% glycerol as a plasticizer in addition to gelatin and water. The moisture uptake of soft gelatin capsules plasticized with glycerol is considerably higher than that of hard gelatin capsules. Therefore, oxygen-sensitive drugs should not be inserted into soft gelatin capsules, nor should emulsions, because they are unstable and crack the shell of the capsule when water is lost in the manufacturing process. Extreme acidic and basic pH must also be avoided, because a pH below 2.5 hydrolyzes gelatin, while a pH above 9.0 has a tanning effect on the gelatin. Insoluble drugs should be dispersed with an agent such as beeswax, paraffin, or ethylcellulose. Surfactants are also often added to promote wetting of the ingredients. Drugs that are commercially prepared in soft capsules include declomycin, chlorotrianisene, digoxin, vitamin A, vitamin E, and chloral hydrate.

Formulation of soft gelatin capsules involves liquid, rather than powder, technology. It requires careful consideration of the composition of the gelatin shell and filling materials. The composition of the soft capsule shell consists of two main ingredients: gelatin and a plasticizer. Water is used to form the capsule, and other additives are often added as follows:

• Gelatin: Properties of gelatin shells are controlled by choice of gelatin grade and by adjustment of the concentration of plasticizer in the shell.

• Plasticizers: The main plasticizer used for soft gelatin capsules is glycerol. Sorbitol and polypropylene glycol are also used in combination with glycerol. Compared to hard gelatin capsules and tablet film coatings, a relatively large amount (~30%) of plasticizers is added in soft gelatin capsule formulation to ensure adequate flexibility.

• Water: The desirable water content of the gelatin solution used to produce a soft gelatin capsule shell depends on the viscosity of the gelatin used and ranges between 0.7 and 1.3 parts of water to each part of dry gelatin.

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

Emulsions

An emulsion is a thermodynamically unstable system that consists of at least two immiscible liquid phases—one of which is dispersed as globules (dispersed phase) in the other, a liquid phase (continuous phase)—that are stabilized by the presence of an emulsifying agent. Emulsified systems range from lotions of relatively low viscosity to ointments and creams, which are semisolid in nature.

Types of emulsions

One liquid phase in an emulsion is essentially polar (e.g., aqueous), whereas the other is relatively nonpolar (e.g., an oil).

• Oil-in-water emulsion: When the oil phase is dispersed as globules throughout an aqueous continuous phase, the system is referred to as an oil-in-water emulsion.

• Water-in-oil emulsion: When the oil phase serves as the continuous phase, the emulsion is termed a water-in-oil emulsion.

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

• Microemulsions: These consist of homogeneous transparent systems of low viscosity that contain a high percentage of both oil and water and high concentrations of emulsifier mixture. Microemulsions form spontaneously when the components are mixed in the appropriate ratios and are thermodynamically stable.

Externally applied emulsions may be o/w or w/o. The o/w emulsions use the following emulsifiers: sodium lauryl sulfate, triethanolamine stearate, sodium oleate, and glyceryl monostearate. The w/o emulsions are used mainly for external applications and may contain one or several of the following emulsifiers: calcium palmitate, sorbitan esters (Spans), cholesterol, and wool fats.

Interfacial free energy and emulsification

Two immiscible liquids in emulsions often fail to remain mixed because of the greater cohesive force between the molecules of each separate liquid, rather than the adhesive force between the two liquids. These forces lead to phase separation, which is the state of minimum surface free energy. When one liquid is broken into small particles, the interfacial area of the globules constitutes a surface area that is enormous compared with that of the original liquid. The adsorption of a surfactant or other emulsifying agent at the globule interface lowers the oil-to-water or water-to-oil interfacial tension. In addition, the process of emulsification is made easier, and the drug's stability may be enhanced.

Emulsifying agents

Preventing coalescence requires the introduction of an emulsifying agent that forms a film around the dispersed globules. Emulsifying agents may be divided into three groups:

• Surface-active agents: Surfactants are adsorbed at oil-water interfaces to form monomolecular films and to reduce interfacial tensions. Unless the interfacial tension is zero, the oil droplets have a natural tendency to coalesce to reduce the area of oil-water contact. The presence of the surfactant monolayer at the surface of the droplet reduces the possibility of collisions leading to coalescence. To retain a high surface area for the dispersed phase, surface-active agents must be used to decrease the surface free energy. Often a mixture of surfactants is used: one with hydrophilic character and the other with hydrophobic character. A hydrophilic emulsifying agent is needed for the aqueous phase, and a hydrophobic emulsifying agent is needed for the oil phase. A complex film results that produces an excellent emulsion. Nonionic surfactants are widely used in the production of stable emulsions. They are less toxic than ionic surfactants and are less sensitive to electrolytes and pH variation. Examples include sorbitan esters and polysorbates.

• Hydrophilic colloids: A number of hydrophilic colloids are used as emulsifying agents. They include gelatin, casein, acacia, cellulose derivatives, and alginates. These materials adsorb at the oil-water interface and form multilayer films around the dispersed droplets of oil in an o/w emulsion. Hydrated lyophilic colloids differ from surfactants because they do not appreciably lower interfacial tension. Their action is caused by the strong multimolecular film's resistance to coalescence. Additionally, they increase the viscosity of the dispersion medium. Hydrophilic colloids are used for formation of o/w emulsions because the films are hydrophilic. Most cellulose derivatives are not charged but can sterically stabilize the systems.

• Finely divided solid particles: These particles are adsorbed at the interface between two immiscible liquid phases and form a film of particles around the dispersed globules. Finely divided solid particles that are wetted to some degree by both oil and water can act as emulsifying agents. They are concentrated at the interface, where they produce a film of particles around the dispersed droplets that prevents coalescence. Finely divided solid particles that are wetted by water form o/w emulsions; those that are wetted by oil form w/o emulsions. Examples include bentonite, magnesium hydroxide, and aluminum hydroxide.

Types of instability in emulsions

The stability of an emulsion is characterized by the absence of coalescence of the internal phase, the absence of creaming, and the maintenance of elegance with respect to appearance, odor, color, and other physical properties. An emulsion becomes unstable because of creaming, breaking, coalescence, phase inversion, and some other factors.

Creaming and sedimentation

Creaming is the upward movement of dispersed droplets relative to the continuous phase, whereas sedimentation, the reverse process, is the downward movement of particles. Density differences in the two phases cause these processes, which can be reversed by shaking. Creaming is undesirable, however, because a creamed emulsion increases the likelihood of coalescence because of the proximity of the globules in the cream. Factors that influence the rate of creaming are similar to those involved in the sedimentation rate of suspension particles and are indicated by Stokes's Law as follows: 000208

where v is the velocity of creaming; d is the globule diameter; ρs and ρo are the densities of dispersed phase and dispersion medium, respectively; ηo is the viscosity of the dispersion medium (poise); and g is the acceleration of gravity (981 cm/s2). According to this equation, the rate of creaming is decreased by

• A reduction in the globule size

• A decrease in the density difference between the two phases

• An increase in the viscosity of the continuous phase

This decrease may be achieved by homogenizing the emulsion to reduce the globule size and increasing the viscosity of the continuous phase by the use of thickening agents such as tragacanth or methylcellulose.

Creaming, breaking, coalescence, and aggregation

Creaming is a reversible process, whereas breaking is irreversible. When breaking occurs, simple mixing fails to resuspend the globules in a stable emulsified form. Because the film surrounding the particles has been destroyed, the oil tends to coalesce. Coalescence is the process by which emulsified particles merge with each other to form large particles. The major factor preventing coalescence is the mechanical strength of the interfacial barrier. Formation of a thick interfacial film is essential for minimal coalescence. In aggregation, the dispersed droplets come together but do not fuse. Aggregation is to some extent reversible.

Phase inversion

An emulsion is said to invert when it changes from an o/w to a w/o emulsion or vice versa. Inversion can be caused by adding an electrolyte or by changing the phase-to-volume ratio. For example, an o/w emulsion stabilized with sodium stearate can be inverted to a w/o emulsion by adding calcium chloride to form calcium stearate.

Microbial growth

Growth of microorganisms in an emulsion can cause physical separation of the phases. Because bacteria can degrade nonionic and anionic emulsifying agents, preservatives must be added to the product in adequate concentrations to prevent bacterial growth.

Suspensions

Suspensions are dispersions of finely divided solid particles of a drug in a liquid medium in which the drug is not readily soluble. Suspending agents are often hydrophilic colloids (e.g., cellulose derivatives, acacia, or xanthan gum) added to suspensions to increase viscosity, inhibit agglomeration, and decrease sedimentation. Highly viscous suspensions may prolong gastric emptying time, slow drug dissolution, and decrease the absorption rate. A suspension that is thixotropic as well as pseudoplastic should prove useful because it forms a gel on standing and becomes fluid when disturbed.

Desired characteristics of suspensions

• Suspended material should settle slowly and should readily disperse on gentle shaking of the container.

• Particle size of the suspension should remain fairly constant.

• The suspension should pour readily and evenly from its container.

Flocculation

The large surface area of the particles is associated with a surface free energy that makes the system thermodynamically unstable. This instability makes particles highly energetic; they tend to regroup, resulting in the decrease in total surface area and surface free energy. The particles in a liquid suspension, therefore, tend to flocculate. Flocculation is the formation of light, fluffy conglomerates held together by weak van der Waals forces. Aggregation occurs when crystals come together to form a compact cake (growth and fusing together of crystals in the precipitate to form a solid aggregate). Flocculating agents can prevent caking, whereas deflocculating agents increase the tendency to cake. Surfactants can reduce interfacial tension, but they cannot reduce it to zero, so suspensions of insoluble particles tend to have a positive finite interfacial tension, and particles tend to flocculate.

Forces at the surface of a particle affect the degree of flocculation and agglomeration in a suspension. Forces of attraction are of the London-van der Waals type, whereas repulsive forces arise from the interaction of the electric double layers surrounding each particle. When the repulsion energy is high, collision of the particles is opposed. The system remains deflocculated, and when sedimentation is complete, the particles form a close-packed arrangement with the smaller particles filling the voids between the larger ones. Those particles that are lowest in the sediment are gradually pressed together by the weight of the ones above; the energy barrier is thus overcome, allowing the particles to come into close contact with each other. Resuspending and redispersing these particles requires that the high-energy barrier be overcome. Because agitation does not easily achieve this, the particles tend to remain strongly attracted to each other and form a hard cake. When the particles are flocculated, the energy barrier is still too large to be surmounted, and so the approaching particles in the second energy minimum, which are at a distance of separation of perhaps 1,000 to 2,000 A, are sufficient to form the loosely structural flocs.

Sedimentation of flocculated particles

Flocs tend to fall together, producing a distinct boundary between the sediment and the supernatant liquid. The liquid above the sediment is clear because even the small particles present in the system are associated with flocs. In deflocculated systems with variable particle sizes, by contrast, the large particles settle more rapidly than the smaller particles, and no clear boundary is formed. The supernatant remains turbid for a longer time.

Flocculation or deflocculation?

Whether a suspension is flocculated or deflocculated depends on the relative magnitudes of the electrostatic forces of repulsion and the forces of attraction between the particles. Flocculated systems form loose sediments that are easily redispersible, but the sedimentation rate is usually fast. In contrast, a suspension is deflocculated when the dispersed particles remain as discrete units and will settle slowly. This condition prevents the entrapment of liquid within the sediment, which leads to caking—a serious stability problem encountered in suspension formulation.

Flocculating agents

If the charge on the particle is neutralized, flocculation will occur. If a high charge density is imparted to the suspension particles, then deflocculation will be the result. The following flocculating agents are often used to convert the suspension from a deflocculated to a flocculated state:

• Electrolytes: The addition of an inorganic electrolyte to an aqueous suspension will alter the ζ potential of the dispersed particles. If this value is lowered sufficiently, then flocculation may occur. The most widely used electrolytes include sodium salts of acetates, phosphates, and citrates.

• Surfactants: Ionic surfactants may also cause flocculation by neutralizing the charge on each particle.

• Polymeric flocculating agents: Starches, alginates, cellulose derivatives, tragacanth, carbomers, and silicates are examples of polymeric flocculating agents that can be used to control the degree of flocculation. Their linear branched-chain molecules form a gel-like network within the system and become adsorbed on the surfaces of the dispersed particles, thus holding them in a flocculated state.

Formulation of suspensions

Physically stable suspensions can be formulated in two ways. One is to use a structured vehicle to maintain deflocculated particles in suspension. However, the major disadvantage of deflocculated systems is that when the particles eventually settle, they form a compact cake. The other is by production of flocs, which may settle rapidly but are easily resuspended with a minimum of agitation. Optimum physical stability is obtained when the suspension is formulated with flocculated particles in a structured vehicle of hydrophilic colloid type.

Ointments, Creams, and Gels

Ointments, creams, and gels are semisolid preparations intended for topical applications. These semisolid formulations are designed for local or systemic drug absorption.

Ointments are typically used as

• Emollients to make the skin more pliable

• Protective barriers to prevent harmful substances from 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.

Hydrocarbon bases

Hydrocarbon (oleaginous) bases are anhydrous and insoluble in water. They cannot absorb or contain water and are not washable in water.

Petrolatum is a good base for oil-insoluble ingredients. It forms an occlusive film on the skin and absorbs less than 5% water under normal conditions. Wax can be incorporated to stiffen the base. Synthetic esters are used as constituents of oleaginous bases. These esters include glycerol monostearate, isopropyl myristate, isopropyl palmitate, butyl stearate, and butyl palmitate.

Absorption bases

Absorption bases are of two types: (1) those that permit the incorporation of aqueous solutions, resulting in the formation of w/o emulsions (e.g., hydrophilic petrolatum and anhydrous lanolin), and (2) those that are already w/o emulsions (emulsion bases) and thus permit the incorporation of small additional quantities of aqueous solutions (e.g., lanolin and cold cream). These bases are useful as emollients although they do not provide the degree of occlusion afforded by the oleaginous bases. Absorption bases are also not easily removed from the skin with water. An aqueous solution may be first incorporated into the absorption base, and then this mixture added to the oleaginous base.

Water-removable bases

Emulsion, water-washable, or water-removable bases, commonly referred to as creams, represent the most commonly used type of ointment base. The majority of dermatologic drug products are formulated in an emulsion or cream base. Emulsion bases are washable and removed easily from skin or clothing. An emulsion base can be subdivided into three component parts: the oil phase, the emulsifier, and the aqueous phase. Drugs can be included in one of these phases or added to the formed emulsion. The oil phase, also known as the internal phase, is typically made up of petrolatum or liquid petrolatum together with cetyl or stearyl alcohol. Following are types of emulsion bases:

• Hydrophilic ointment is an o/w emulsion that uses sodium lauryl sulfate as an emulsifying agent. It is readily miscible with water and is removed from the skin easily. The aqueous phase of an emulsion base contains the preservatives that are included to control microbial growth. The preservatives in the emulsion include methylparaben, propylparaben, benzyl alcohol, sorbic acid, or quaternary ammonium compounds. The aqueous phase also contains the water-soluble components of the emulsion system, together with any additional stabilizers, antioxidants, and buffers that may be necessary for stability and pH control.

• Cold cream is a semisolid white w/o emulsion prepared with cetyl ester wax, white wax, mineral oil, sodium borate, and purified water. Sodium borate combines with free fatty acids present in the waxes to form sodium soaps that act as the emulsifiers. Cold cream is used as an emollient and ointment base. Eucerin cream is a w/o emulsion of petrolatum, mineral oil, mineral wax, wool wax, alcohol, and Bronopol. It is frequently prescribed as a vehicle for delivery of lactic acid and glycerin to treat dry skin.

• Lanolin is a w/o emulsion that contains approximately 25% water and acts as an emollient and occlusive film on the skin, effectively preventing epidermal water loss.

• Vanishing cream is an o/w emulsion that contains a large percentage of water as well as a humectant (e.g., glycerin or propylene glycol) that retards surface evaporation. An excess of stearic acid in the formula helps to form a thin film when the water evaporates.

Water-soluble bases

Water-soluble bases may be anhydrous or may contain some water. They are washable in water and absorb water to the point of solubility. Polyethylene glycol ointment is a blend of water-soluble PEG that forms a semisolid base. This base can solubilize water-soluble drugs and some water-insoluble drugs. It is compatible with a wide variety of drugs. It contains 40% PEG 4,000 and 60% PEG 400. Another water-soluble base is the ointment prepared with propylene glycol and ethanol, which form a clear gel when mixed with 2% hydroxypropyl cellulose. This base is a commonly used dermatologic vehicle.

Incorporation of drugs into an ointment

Drugs may be incorporated into an ointment base by levigation and fusion. Normally, drug substances are in fine powdered forms before being dispersed in the vehicle. Levigation of powders into a small portion of base is facilitated by the use of a melted base or a small quantity of compatible levigation aid, such as mineral oil or glycerin. Water-soluble salts are incorporated by dissolving them in a small volume of water and incorporating the aqueous solution into a compatible base. Fusion is used when the base contains solids that have higher melting points (e.g., waxes, cetyl alcohol, or glyceryl monostearate).

Suppositories

suppository is a solid dosage form intended for insertion into body orifices (e.g., rectum, vagina, or urethra). Once inserted, the suppository base melts, softens, or dissolves at body temperature, distributing its medications to the tissues of the region. Suppositories are used for local or systemic effects. Rectal suppositories intended for local action are often used to relieve the pain, irritation, itching, and inflammation associated with hemorrhoids. Vaginal suppositories intended for local effects are used mainly as contraceptives, as antiseptics in feminine hygiene, and to combat invading pathogens. The suppository base has a marked influence on the release of active constituents. Two main classes of suppository bases are in use: the glyceride-type fatty bases and the water-soluble ones. The main water-soluble and water-miscible suppository bases are glycerinated gelatin and polyethylene glycols. Polyethylene glycol suppositories do not melt at body temperature but rather dissolve slowly in the body's fluids. Examples of rectal suppositories include Thorazine (chlorpromazine) and Phenergan (promethazine).

Inserts, Implants, and Devices

Inserts, implants, and devices are used to control drug delivery for localized or systemic drug effects. In these systems, drugs are embedded into biodegradable or nonbiodegradable materials to allow slow release of the drug. The inserts, implants, and devices are inserted into a variety of cavities (e.g., vagina, buccal cavity, cul de sac of the eye, or subcutaneous tissue).

Degradable inserts consist of polyvinyl alcohol, hydroxypropyl cellulose, PVP, and hyaluronic acid. Nondegradable inserts are prepared from insoluble materials such as ethylene vinyl acetate copolymers and styrene-isoprene-styrene block copolymers. The initial use of contact lenses was for vision correction; however, they are becoming more useful as potential drug delivery devices by presoaking them in drug solutions. The use of contact lenses can simultaneously correct vision and release the drug.

A number of degradable and nondegradable inserts are currently available for ophthalmic delivery. These ophthalmic inserts can be insoluble, soluble, or bioerodible. Insoluble inserts are further classified as diffusional, osmotic, and contact lens (

Figure 3-3). Ocular inserts are no more affected by nasolacrimal drainage and tear flow than conventional dosage forms; they can provide slow drug release and longer residence times in the conjunctival cul de sac. Ocusert is an interesting device consisting of a drug reservoir (pilocarpine hydrochloride in an alginate gel) enclosed by two release-controlling membranes made of ethylene vinyl acetate copolymer and enclosed by a white ring, allowing positioning of the system in the eye. Pilocarpine Ocusert has demonstrated slow release of pilocarpine, which can effectively control the increased intraocular pressure in glaucoma. Other inserts (e.g., medicated contact lenses, collagen shields, and mini-discs) have been shown to diminish the systemic absorption of ocularly applied drugs as a result of decreased drainage into the nasal cavity. Lacrisert is a soluble insert composed of hydroxypropyl cellulose and is useful in the treatment of dry eye syndrome. The device is placed in the lower fornix, where it slowly dissolves over 6-8 hours to stabilize and thicken the tear film.

In addition to ophthalmic delivery, inserts are used for localized delivery of drugs to various other tissues. For example, the Progestasert device is designed for implantation into the uterine cavity, where it releases 65 mg progesterone per day to provide contraception for 1 year. Similarly, Transderm relies on the rate-limiting polymeric membranes to control

[Figure 3-3. Different Types of Ophthalmic inserts]

drug release. Atridox, approved by the U.S. Food and Drug Administration (FDA), is a product designed for controlled-release delivery of the antibiotic doxycycline for the treatment of periodontal disease. When injected into the periodontal cavity, the formulation sets, forming a drug delivery depot that delivers the antibiotic to the cavity.

An implant is a drug delivery system designed to deliver a drug moiety at a desired rate over a prolonged period. Implants are available in many forms, including polymeric implants and minipumps. Diffusional and osmotic symptoms contain a reservoir that is in contact with the inner surface of a controller, to which it supplies the drug. The reservoir contains a liquid, a gel, a colloid, a semisolid, a solid matrix, or a carrier that contains drug. Carriers consist of hydrophilic or hydrophobic polymers.

ALZA Corporation (acquired by Johnson & Johnson in May 2001) developed ALZET miniosmotic pumps, which permit easy manipulation of drug release rate over a range of periods (from 1 day to 4 weeks). ALZA Corporation also developed DUROS implants for continuous therapy for up to 1 year. The nondegradable, osmotically driven system is intended to enable delivery of small drugs, peptides, proteins, and DNA (deoxyribonucleic acid) for systemic or tissue-specific therapy. Viadur is a once-yearly implant for the palliative treatment of advanced prostate cancer.

One of the more commonly used devices is the oral osmotic pump, composed of a core tablet and a semipermeable coating with a 0.3-4.0 mm diameter hole, produced by a laser beam, for drug exit. This system requires only osmotic pressure to be effective, but the drug release rate depends on the surface area, the 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 pressure of the core, and the drug is released from the orifice at a controlled rate.

Transdermal Drug Delivery Systems

Transdermal drug delivery systems (often called transdermal patches) deliver drugs directly through the skin and into the bloodstream. Percutaneous absorption of a drug generally results from direct penetration of the drug through the stratum corneum. Once through the stratum corneum, drug molecules may pass through the deeper epidermal tissues and into the dermis. When the drug reaches the vascularized dermal area, it becomes available for absorption into the general circulation. Among the factors influencing percutaneous absorption are the physicochemical properties of the drug, including its molecular weight, solubility, and partition coefficient; the nature of the vehicle; and the condition of the skin. Chemical permeation enhancers or iontophoresis are often used to enhance the percutaneous absorption of a drug.

In general, patches are composed of three key compartments: a protective seal that forms the external surface and protects it from damage, a compartment that holds the medication itself and has an adhesive backing to hold the entire patch on the skin surface, and a release liner that protects the adhesive layer during storage and is removed just prior to application. Examples of transdermal patches include Estraderm (estradiol), Nicoderm (nicotine), Testoderm (testosterone), Alora (estradiol), and Androderm (testosterone).

Aerosol Products

Aerosols are pressurized dosage forms designed to deliver drugs with the aid of a liquefied or propelled gas (propellant). Aerosol products consist of a pressurizable container, a valve that allows the pressurized product to be expelled from the container when the actuator is pressed, and a dip tube that conveys the formulation from the bottom of the container to the valve assembly. Inhalation devices broadly fall into three categories: pressurized metered dose inhalers (MDIs), nebulizers, and dry powder inhalers. The most commonly used inhalers on the market are MDIs. They contain active ingredient as a solution or as a suspension of fine particles in a liquefied propellant held under high pressure. MDIs use special metering valves to regulate the amount of formulation dispensed with each dose. Nebulizers do not require propellants and can generate large quantities of small droplets capable of penetrating into the lung. Sustained release of drugs, such as bronchodilators and corticosteroids for the treatment of asthma and chronic obstructive pulmonary diseases, involves encapsulation of the drugs in slowly degrading particles that can be inhaled. For accumulation in the alveolar zone of the lungs, which has a very large surface area, inhaled liquid or dry powder aerosols should have particle sizes in the range of 1-5 micrometers. Inhaled drugs play a prominent role in the treatment of asthma, because this route has significant advantages over oral or parenteral administration. Azmacort (triamcinolone acetamide), Ventolin HFA (albuterol sulfate), and Serevent (salmeterol) are examples of commercially available aerosols for the treatment of asthma.

3-6. Targeted Drug Delivery Systems

Introduction

Targeted drug delivery systems are drug carrier systems that deliver the drug to the target or receptor site in a manner that provides maximum therapeutic activity, prevents degradation or inactivation during transit to the target sites, and protects the body from adverse reactions because of inappropriate disposition. Design of an effective delivery system requires a thorough understanding of the drug, the disease, and the target site (

Figure 3-4). Examples include macromolecular drug carriers (protein drug carriers); particulate drug delivery systems (e.g., microspheres, nanospheres, and liposomes); monoclonal antibodies; and cells. Plasma clearance kinetics, tissue distribution, metabolism, and cellular interactions of a drug can be controlled by the use of a site-specific delivery system. Targeting of drugs to specific sites in the body can be achieved by linking particulate systems or macromolecular carriers to monoclonal antibodies or to cell-specific ligands (e.g., asialofetuin, glycoproteins, or immunoglobulins) or by altering the surface characteristics so that they are not recognized by the reticuloendothelial systems.

Macromolecular Carrier Systems

Both natural and synthetic water-soluble polymers have been used as macromolecular drug carriers. The drug can be attached to the polymer chain either directly or via a spacer. Attachment of PEG to proteins can protect them from rapid hydrolysis or degradation within the body, increase blood circulation time, and lower the immunogenicity of proteins. PEGylated forms of interferons; PegIntron and PEGASYS (for treatment of hepatitis C, to reduce dosing frequency from daily injections to once-weekly injection dosing); adenosine deaminase; and L-asparaginase are currently on the market. PEGylation improves macromole solubility and stability by minimizing the uptake by the cells of the reticuloendothelial system. Because PEG drug conjugates are not well absorbed from the gut, they are mainly used as injectables. The drug-polymer conjugate may also contain a receptor-specific ligand to achieve selective access to, and interaction with, the target cells.

[Figure 3-4. Essential Components of Drug Delivery]

Particulate Drug Delivery Systems

Many particulate carriers have been designed for drug delivery and targeting. They include liposomes, micelles, microspheres, and nanoparticles.

Liposomes

Liposomes are microscopic phospholipid vesicles composed of uni- or multilamellar lipid bilayers surrounding compartments. Multilamellar vesicles have diameters in the range of 1.0-5.0 micrometers. Sonication of multilamellar vesicles results in the production of small unilamellar vesicles with diameters in the range of 0.02-0.08 micrometers. Large unilamellar vesicles can be made by evaporation under reduced pressure, resulting in liposomes with a diameter of 0.1-1.0 micrometer. The bilayer-forming lipid is the essential part of the lamellar structure, while the other compounds are added to impart certain characteristics to the vesicles. Water-soluble drugs can be entrapped in liposomes by intercalation in the aqueous bilayers, whereas lipid-soluble drugs can be entrapped within the hydrocarbon interiors of the lipid bilayers. Liposomes can encapsulate low-molecular-weight drugs, proteins, peptides, oligonucleotides, and genes. The use of the antifungal agent amphotericin B formulated in liposomes has been approved by the FDA. Because conventional liposomes are recognized by the immune system as foreign bodies, ALZA Corporation developed STEALTH liposomes, which evade recognition by the immune system because of their unique polyethylene glycol coating. Doxil is a STEALTH liposome formulation of doxorubicin, used for the treatment of AIDS-related Kaposi's sarcoma.

Microparticles and nanoparticles

Microencapsulation is a technique that involves the encapsulation of small particles or the solution of drugs in a polymer film or coat. Different methods of microencapsulation result in either microcapsules or microspheres. For example, interfacial polymerization of a monomer usually produces microcapsules, whereas solvent evaporation may result in microspheres or microcapsules, depending on the amount of drug loading. A microcapsule is a reservoir-type system in which the drug is located centrally within the particle, whereas a microsphere is a matrix-type system in which the drug is dispersed throughout the particle. Microcapsules usually release their drug at a constant rate (zero-order release), whereas microspheres typically give a first-order release of drugs. Low-molecular-weight drugs, proteins, oligonucleotides, and genes can be encapsulated into microparticles to provide their sustained release at disease sites.

The most commonly used method of microencapsulation is coacervation, which involves addition of a hydrophilic substance to a colloidal drug dispersion. The hydrophilic substance, which acts as a coating material, may be selected from a variety of natural and synthetic polymers, including shellacs, waxes, gelatin, starches, cellulose acetate phthalate, and ethylcellulose, among others. Following dissolution of the coating materials, the drug inside the microcapsule is available for dissolution and absorption.

Biodegradable polylactide and its copolymers with glycolide [poly(lactic-co-glycolic acid), or PLGA] are commonly used for preparation of microparticles from which the drug can be released slowly over a period of a month or so. Microspheres can be used in a wide variety of dosage forms, including tablets, capsules, and suspensions. Lupron Depot from TAP Pharmaceuticals is an FDA-approved preparation of PLGA microspheres for sustained release of a small peptide luteinizing hormone-releasing hormone agonist. More recently, PLGA microspheres of recombinant human growth hormone have been developed and marketed successfully by Genentech under the trade name Nutropin Depot.

3-7. Key Points

• Fick's first law of diffusion describes the diffusion process under steady-state conditions when the drug concentration gradient does not change with time.

• Drug absorption depends not only on the fraction of un-ionized form of the drug but also on the surface area available for absorption.

• The Noyes-Whitney equation can be used for determining the dissolution rate of a drug from its dosage form, whereas the Arrhenius equation can be used for determining the shelf life of a drug dosage form.

• Surfactants consist of hydrophilic and hydrophobic groups and can be used as emulsifying agents to reduce interfacial tensions.

• The pharmaceutical dosage form contains the active drug ingredient in association with nondrug (usually inert) ingredients (excipients). Together they form the vehicle, or formulation matrix.

• Water-soluble drugs are often formulated as sustained-release tablets so that their release and dissolution rates can be controlled, whereas enteric-coated tablets are used to protect drugs from gastric degradation.

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

• Aerosols are pressurized dosage forms designed to deliver drugs to pulmonary tissues with the aid of a liquefied or propelled gas.

• Inserts, implants, and devices allow slow release of the drug into a variety of cavities (e.g., vagina, buccal cavity, cul de sac of the eye, and skin).

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

• The drug delivery system deals with the pharmaceutical formulation and the dynamic interactions among the drug, its formulation matrix, its container, and the physiologic milieu of the patient. These dynamic interactions are the subject of pharmaceutics.

• Macromolecular drug carriers, such as protein-polymer conjugates, and particulate delivery systems, such as microspheres and liposomes, are commonly used for delivery of drugs with low molecular weight, such as peptides and proteins, to different disease targets.

• Targeted (or site-specific) drug delivery systems are used for drug delivery to the target or receptor site in a manner that provides maximum therapeutic activity, by preventing degradation during transit to the target site while avoiding delivery to nontarget sites.

3-8. Questions

1.

Which of the following is true for Fick's first law of diffusion?

A. It refers to the non-steady-state flow.

B. The amount of material flowing through a unit cross-section of a barrier in unit time is known as the concentration gradient.

C. Flux of material is proportional to the concentration gradient.

D. Diffusion occurs in the direction of increasing concentration.

E. All of the above are true.

 

2.

Which equation describes the rate of drug dissolution from a tablet?

A. Fick's law

B. Henderson-Hasselbalch equation

C. Michaelis-Menten equation

D. Noyes-Whitney equation

E. All of the above

 

3.

The pH of a buffer system can be calculated with

A. the Henderson-Hasselbalch equation.

B. the Noyes-Whitney equation.

C. the Michaelis-Menten equation.

D. Yong's equation.

E. all of the above.

 

4.

Which of the following is not true for gas adsorption on a solid?

A. Chemical adsorption is reversible.

B. Physical adsorption is based on weak van der Waals forces.

C. Chemical adsorption may require activation energy.

D. Chemical adsorption is specific to the substrate.

E. All of the above.

 

5.

What is bioavailability?

A. Bioavailability is the measurement of the rate and extent of active drug that reaches the systemic circulation.

B. It is the relationship between the physical and chemical properties of a drug and its systemic absorption.

C. It is the movement of the drug into body tissues over time.

D. It is dissolution of the drug in the GI tract.

E. All of the above describe bioavailability.

 

6.

Which of the following may be used to assess the relative bioavailability of two chemically equivalent drug products in a crossover study?

A. Dissolution test

B. Peak concentration

C. Time-to-peak concentration

D. Area under the plasma-level time curve

E. All of the above

 

7.

What condition usually increases the rate of drug dissolution for a tablet?

A. Increase in the particle size of the drug

B. Decrease in the surface area of the drug

C. Use of the ionized, or salt, form of the drug

D. Use of the free acid or free base form of the drug

E. Use of sugar coating around the tablet

 

8.

The characteristics of an active transport process include all of the following except

A. active transport moves drug molecules against a concentration gradient.

B. active transport follows Fick's law of diffusion.

C. active transport is a carrier-mediated transport system.

D. active transport requires energy.

E. active transport of drug molecules may be saturated at high drug concentrations.

 

9.

Which of the following dosage forms may use surface-active agents in their formulations?

A. Emulsions

B. Suspensions

C. Colloidal dosage forms

D. Creams

E. All of the above

 

10.

Which of the following statements about lyophilic colloidal dispersions is true?

A. They tend to be more sensitive to the addition of electrolytes than do lyophobic systems.

B. They tend to be more viscous than lyophobic systems.

C. They can be precipitated by prolonged dialysis.

D. They separate rapidly.

E. All of the above.

 

11.

Which of the following is not true for tablet formulations?

A. A disintegrating agent promotes granule flow.

B. Lubricants prevent adherence of granules to the punch faces of the tabletting machine.

C. Glidants promote flow of the granules.

D. Binding agents are used for adhesion of powder into granules.

E. All of the above.

 

12.

The absorption rate of a drug is most rapid when the drug is formulated as

A. a controlled-release product.

B. a hard gelatin capsule.

C. a compressed tablet.

D. a solution.

E. a suspension.

 

13.

The passage of drug molecules from a region of high drug concentration to a region of low drug concentration is known as

A. active transport.

B. simple diffusion or passive transport.

C. pinocytosis.

D. bioavailability.

E. biopharmaceutics.

 

14.

Which equation is used to predict the stability of a drug product at room temperature from experiments at increased temperatures?

A. Stokes's equation

B. Arrhenius equation

C. Michaelis-Menten equation

D. Fick's equation

E. Noyes-Whitney equation

 

15.

Choose which of the following statements is true.

A. Flocculation is desirable for pharmaceutical suspensions.

B. The diffusion rate of molecules of a smaller particle size is less than that of molecules of a larger particle size.

C. Particle size of molecular dispersions is larger than a coarse dispersion.

D. Pseudoplastic flow is shear-thickening type, and dilatant is shear-thinning type.

E. All of the above.

 

16.

Choose which of the following statements is false.

A. The Henderson-Hasselbalch equation describes the effect of physical parameters on the stability of pharmaceutical suspensions.

B. The passive diffusion rate of hydrophobic drugs across biological membranes is higher than that of hydrophilic compounds.

C. When the dispersed phase in an emulsion formulation is heavier than the dispersion medium, creaming can still occur.

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

E. All of the above.

 

17.

Which of the following is an emulsifying agent?

A. Sorbitan mono-oleate (Span 80)

B. Polyoxyethylene sorbitan mono-oleate (Tween 80)

C. Sodium lauryl sulfate

D. Gum acacia

E. All of the above

 

18.

Which of the following surfactants is incompatible with bile salts?

A. Polysorbate 80

B. Potassium stearate

C. Sodium lauryl sulfate

D. Benzalkonium chloride

E. All of the above

 

19.

Which of the following statements is false?

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

B. Absorption of a weak electrolyte drug does not depend on the extent to which the drug exists in its un-ionized form at the absorption site.

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

D. Amorphous forms of drug have faster dissolution rates than do crystalline forms.

E. All of the above.

 

20.

Which of the following statements is true?

A. Most substances acquire a surface charge by ionization, ion adsorption, and ion dissolution.

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

C. At the isoelectric point, the total number of positive charges is equal to the total number of negative charges.

D. All of the above.

E. None of the above.

 

21.

Agents that may be used in the enteric coating of tablets include

A. hydroxypropyl methylcellulose.

B. carboxymethylcellulose.

C. cellulose acetate phthalate.

D. all of the above.

E. none of the above.

 

3-9. Answers

1.

C. Fick's first law of diffusion states that the amount of material flow through a unit cross-section of a barrier in unit time, which is known as the flux, is proportional to the concentration gradient. Fick's first law of diffusion describes the diffusion process under steady-state conditions where the concentration gradient does not change with time.

 

2.

D. The Noyes-Whitney equation describes the rate of drug dissolution from a tablet. Fick's first law of diffusion is similar to the Noyes-Whitney equation in that both equations describe drug movement attributable to a concentration gradient. The Michaelis-Menten equation involves enzyme kinetics, whereas Henderson-Hasselbalch equations are used for determination of pH of the buffer and the extent of ionization of a drug molecule.

 

3.

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

 

4.

A. Chemical absorption is an irreversible process that is specific and may require activation energy, whereas physical adsorption is reversible and associated with van der Waals forces.

 

5.

A. Bioavailability is the measurement of the rate and extent of systemic circulation of an active drug.

 

6.

D. The plasma drug concentration versus time curve measures the bioavailability of a drug from a product. The peak plasma drug concentration (Cmax) relates to the intensity of the pharmacologic response, while the time for peak plasma drug concentration (Tmax) relates to the rate of systemic absorption.

 

7.

C. The ionized, or salt, form of a drug is generally more water soluble and therefore dissolves more rapidly than the nonionized (free acid or free base) form of the drug. According to the Noyes-Whitney equation, the dissolution rate is directly proportional to the surface area and inversely proportional to the particle size. Therefore, an increase in the particle size or a decrease in the surface area slows the dissolution rate.

 

8.

B. In passive transport, a drug travels from a high concentration to a low concentration, whereas active transport moves drug molecules against a concentration gradient and requires energy.

 

9.

E. Surface-active agents facilitate emulsion formation by lowering the interfacial tension between the oil and water phases. Adsorption of surfactants on insoluble particles enables these particles to be dispersed in the form of a suspension.

 

10.

B. Most lyophilic colloids are organic molecules (including gelatin and acacia); they spontaneously form colloidal solutions and tend to be viscous. Dispersion of lyophilic colloids is stable in the presence of electrolytes.

 

11.

A. Disintegrating agents are added to the tablets to promote breakup of the tablets when placed in the aqueous environment. Lubricants are required to prevent adherence of the granules to the punch faces and dies. Glidants are added to tablet formulations to improve the flow properties of the granulations. Binding agents are added to bind powders together in the granulation process.

 

12.

D. For a drug in solution, no dissolution is required before absorption. Consequently, compared with other drug formulations, a drug in aqueous solution has the highest bioavailability rate and is often used as the reference preparation for other formulations.

 

13.

B. In simple diffusion or passive transport, a drug travels from a high concentration to a low concentration, whereas active transport moves drug molecules against a concentration gradient and requires energy. Pinocytosis is a vesicular transport process of engulfment of small particles or fluid volumes.

 

14.

B. Stability at room temperature can be predicted from accelerated testing data by the Arrhenius equation: log (k2/k1) = Ea(T2 - T1)/(2.303 RT2T1), where k2 and k1 are the rate constants at the absolute temperatures T2 and T1, respectively; R is the gas constant; and Ea is the energy of activation. Stokes's equation is used to determine the sedimentation rate of a suspension, whereas the Noyes-Whitney equation is used to determine the dissolution rate.

 

15.

A. Flocculation is the formation of light, fluffy conglomerates held together by weak van der Waals forces and is a reversible process. Pseudoplastic flow is a shear-thinning process, whereas dilatant is a shear-thickening type process.

 

16.

A. The Henderson-Hasselbalch equation describes the relationship between ionized and nonionized species of a weak electrolyte.

 

17.

E. Sorbitan mono-oleate (Span 80), polyoxyethylene sorbitan monooleate (Tween 80), sodium lauryl sulfate, and gum acacia are surfactants used as emulsifiers.

 

18.

D. Benzalkonium chloride is a cationic surfactant and can interact with bile salts.

 

19.

B. According to pH partition theory, absorption of a weak electrolyte drug depends on the extent to which the drug exists in its unionized form at the absorption site. However, pH partition theory often does not hold true, because most weakly acidic drugs are well absorbed from the small intestine, possibly because of the large epithelial surface areas of the organ.

 

20.

D. Most substances acquire a surface charge by ionization, ion adsorption, and ion dissolution. At the isoelectric point, the total number of positive charges is equal to the total number of negative charges.

 

21.

C. An enteric-coated tablet has a coating that remains intact in the stomach, but dissolves in the intestine when the pH exceeds 6. Enteric-coating materials include cellulose acetate trimellitate, polyvinyl acetate phthalate, and hydroxypropyl methylcellulose phthalate.

 

3-10. References

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Aulton ME, ed. Pharmaceutics: The Science of Dosage Form Design. New York: Churchill Livingstone; 1988.

Banker GS, Rhodes CT, eds. Modern Pharmaceutics. 3rd ed. New York: Marcel Dekker; 1995.

Block LH, Collins CC. Biopharmaceutics and drug delivery systems. In: Shargel L, Mutnick AH, Souney PH, Swanson LN, eds. Comprehensive Pharmacy Review. New York: Lippincott Williams & Wilkins; 2001:78-91.

Block LH, Yu ABC. Pharmaceutical principles and drug dosage forms. In: Shargel L, Mutnick AH, Souney PH, Swanson LN, eds. Comprehensive Pharmacy Review. New York: Lippincott Williams & Wilkins; 2001:28-77.

Florence AT, Attwood D. Physicochemical Principles of Pharmacy. 3rd ed. Palgrave, N.Y.: Macmillan; 1998.

Gennaro AR, Gennaro AL, eds. Remington: The Science and Practice of Pharmacy. Baltimore: Lippincott, Williams & Wilkins; 2000.

Hillery AM. Advanced drug delivery and targeting: An introduction. In: Hillery AM, Lloyd AW, Swarbrick J, eds. Drug Delivery and Targeting: For Pharmacists and Pharmaceutical Scientists. New York: Taylor & Francis; 2001:63-82.

Mahato RI. Pharmaceutical Dosage Forms and Drug Delivery. New York: Taylor & Francis; 2007.

Martin A. Physical Pharmacy. 4th ed. Baltimore: Lippincott Williams & Wilkins; 1993.

Mathiowitz E, Kretz MR, Bannon-Peppas L. Microencapsulation. In: Mathiowitz E, ed. Encyclopedia of Controlled Drug Delivery. New York: John Wiley & Sons; 1999:493-546.

Washington N, Washington C, Wilson CG. Physiological Pharmaceutics: Barriers to Drug Absorption. 2nd ed. New York: Taylor & Francis; 2001.