Opposition against EP 2 538 925
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`Document TM3
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`THIRD EDITION
`
`Edited by
`Michael E. Aulton
`
`CHURCHILL
`LIVINGSTONE
`ELSEVIER
`
`MYLAN EXHIBIT 1009
`
`

`

`CHURCHILL
`LIVINGSTONE
`ELSEVIER
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`First edition 1988
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`ISI3N-13: 97804-UIOI083
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`

`Bioavailability - physicochemical and dosage
`form factors
`
`M. Ashford
`
`CHAPTER CONTENTS
`
`INTRODUCTION
`
`Introduction 286
`Physicochemical factors influencing bioavailability 286
`Dissolution and solubility 286
`Physiological factor-s affecting the dissolution rate of
`drugs 287
`Drug factors affecting dissolution rate 288
`Factors affecting the concentration
`in solution in the
`gastrc111testinal fluids 291
`Poorly soluble drugs 293
`Drug absorption 293
`Drug dissornlion and lrpid solubility 293
`Summary 295
`Dosage form factors influencing bioavailability 295
`lntrocluct,on 295
`influence of type of dosage form 295
`Aqueous solutions 296
`Aqueous suspensicns 297
`Liquid-filled capsules 297
`Powder-filled capsules 298
`Tablets 299
`Influence of exc1pients for conventional dosage fonns 301
`
`Summary 303
`
`References 303
`
`286
`
`As discussed in Chapter 20, the rate and extent of absorp(cid:173)
`tion are influenced by the physiological factors associ(cid:173)
`ated with the structure and function of the GI tract. This
`chapter discusses the physicoehemical properties of the
`drug and dosage form factors that influence bioavailabil(cid:173)
`ity. For a drug to be absorbed, it needs to be in solution
`and to be able to pass across the membrane. In the case
`ol' orally administered drugs. this is the gastrointestinal
`epithelium. The physicoehemical properties of the drug
`that will influence its passage into solution and transfer
`across membranes indude its dissolution rnte. pK.,. lipid
`solubility, chemical stability and complexution potential.
`
`PHYSICOCHEMICAL FACTORS
`INFLUENCING BIOAVAILABILITY
`
`Dissolution and solubility
`
`Solid drugs need to dissolve before they can be absorbed.
`The dissolution of drugs can be described by the
`Noyes-Whitney equation ( Eqn 21.1 ). This equation. first
`proposed in 1897. describes the rate of dissolution of
`spherical particles when the dissolution process is diffu(cid:173)
`sion eon trolled and involves no chemical reaction:
`
`dC/dt
`
`(21.1 l
`
`1·.l:e1'ti d('/r/1 i, :I',· 1:il.ci lll' dis:,lliUli'>ll ,;1· the: dlll?, l'itl
`I) i~; the di
`cuel!i<.:ie11t ul the
`in soluL,un
`in Ehe gastrointe,!i11a! fluids. A lo rhe effective surhKe
`:Fea of the drug 11c1rtieles in contnc! \Vith the gastrc>i11 ·
`le,tinal fluid,. /i 1, the thickness ol :hie diffusion
`C\ is th,· '>ai11ration soluhi!
`'\I\Juncl cad1
`tlH.' dn1g i11
`ill the· diil1
`illid ('IS::
`in the
`llui,b.
`the Noye,-\Vhitney equation i11
`ckscribing the dissulution of
`are cliscL!S,c'd
`
`

`

`BIOAVAILABILITY- PHYSICOCHEMICALAND DOSAGE FORM FACTORS
`
`Table 21.1 Physicochemical and physiological factors affecting drug dissolution in the gastrointestinal tract
`(adapted from Dressman et al 1998}
`
`Factor
`
`Physicochemical parameter
`
`Physiological parameter
`
`Effective sudace area of dr·ug
`
`Particle size. wettability
`
`Solubility ill diffusion layer·
`Amount of drug alr·eady dissolved
`
`Hydrophilrcity. crystal structure.
`solubilizJtion
`
`Diffusivity of drug
`
`Boullclary layer· thickness
`
`Volume of solve11t available
`
`Molecular. size
`
`Surfactallts ill gastric JU ice alld bile. pH. buffer
`capacity. brle. food compollellts
`
`Pem1eability. tr·ansil
`
`Viscosity of luminal contents
`
`Motility patterns and flow rate
`
`Gastrointestinal secretio11s. co-admrnrster-ed
`fluids
`
`in Chapter 2. Despite these limitations. the equation
`serves to illustrate and explain how various physico(cid:173)
`chemical and physiological factors can influence the rate
`of dissolution in the gastrointestinal tract. These are sum(cid:173)
`marized in Table 21.1 and are discussed in more detail in
`the next section.
`Figure 21. l illustrates the dissolution of a spherical
`drug particle in the gastrointestinal fluids.
`
`Physiological factors affecting the dissolution rate
`of drugs
`
`The environment of the gastrointestinal tract can affect
`the parameters of the Noyes-Whitney equation (Eqn
`21.1) and hence the dissolution rate of a drug. For
`instance. the diffusion coefficient. D. of the drug in the
`gastrointestinal fluids may be decreased by the presence
`of substances that increase the viscosity of the fluids.
`
`Hence the presence of food in the gastrointestinal tract
`may cause a decrease in dissolution rate of a drug by
`reducing the rate of diffusion of the drug molecules away
`from the diffusion layer surrounding each undissolved
`drug particle. Surfactants in gastric juice and bile salts
`will affect both the wettability of the drug, and hence the
`effective surface area, A, exposed to gastrointestinal flu(cid:173)
`ids. and the solubility of the drug in the gastrointestinal
`fluids via micellization. The thickness of the diffusion
`layer, h, will be influenced by the degree of agitation
`experienced by each drug particle in the gastrointestinal
`tract. Hence an increase in gastric and/or intestinal motil(cid:173)
`ity may increase the dissolution rate of a sparingly solu(cid:173)
`ble drug by decreasing the thickness of the diffusion
`layer around each drug particle.
`The concentration, C. of drug in solution in the bulk of
`the gastrointestinal fluids will be influenced by such fac(cid:173)
`tors as the rate of removal of dissolved drug by absorption
`
`t Diffusion layer
`
`Gastrointestinal
`barrier
`
`<=====-yl- '. /
`,. -~-_ .. _ -__ -_ -_ -, . -,- - .
`.
`,. ~
`.
`·,.
`' ' '
`'
`::;;--~
`
`'._
`
`'
`
`Drug
`particle
`
`~
`
`I
`
`I I .
`
`Diffusion of drug molecules
`through gastrointestinal contents
`
`Blood
`
`~--·
`
`I I '
`I
`I
`I
`
`I
`
`-<-----;: i1:
`
`Fig. 21.1 Schematic representation of the dissolution of a drng particle in the gastrointestinal fluids.
`
`287
`
`

`

`BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY
`
`through the gastrointestinal-blood barrier and by the
`volume of fluid available for dissolution, which in turn
`will be dependent on the position of the dmg in the gas(cid:173)
`trointestinal tract and the timing with respect to meal
`intake. In the stomach, the volume of fluid will be influ(cid:173)
`enced by the intake of fluid in the diet. According to the
`Noyes-Whitney equation. a low value of C will favour
`more rapid dissolution of the drug by virtue of increasing
`the value of the term ( C5 C). In the case of drugs whose
`absorption is dissolution rate limited, the value of C is
`normally kept very low by absorption of the drug. Hence
`dissolution occurs under sink conditions: that is. under
`conditions such that the value of ( C5 - Cl approximates to
`Thus for the dissolution of a drug from the gastroin(cid:173)
`testinal tract under sink conditions, the Noyes-Whitney
`equation can be expressed as:
`
`dC/dt
`
`(21.2)
`
`Drug factors affecting dissolution rate
`
`Drug factors that can influence the dissolution rate are
`the particle size, the wettability, the solubility and the
`form of the drug (whether a salt or a free form. crys(cid:173)
`talline or amorphous).
`Smj'ace area and particle size According to Eqn
`21. l, an increase in tl,le total surface area of drug in con(cid:173)
`tact with the gastrointestinal fluids will cause an increase
`in dissolution rate. Provided that each particle of drug is
`intimately wetted by the gastrointestinal fluids, the effec(cid:173)
`tive surface area exhibited by the drug will be directly
`proportional to the particle size of the drug. Hence the
`smaller the particle size, the greater the effective surface
`area exhibited by a given mass of drug and the higher the
`dissolution rate. Particle size reduction is thus likely to
`result in
`increased bioavnilability, provided that the
`absorption of the drug is dissolution rate limited.
`One of the classic examples of particle size effects on
`the bioavuilability of poorly soluble compounds is that of
`griseofulvin. where a reduction of particle size rrom
`0.4 m2 g- 1) to
`about I 0 ~tm (specific surface area
`2.7 ~tm (specillc surface area= 1.5 1112
`l was shown to
`produce approximately double the amount ol' drug
`absorbed in humans. Many poorly soluble, slowly dis(cid:173)
`solving drugs are routinely presented in mh:rnnized form
`lo increase their surface area.
`Examples of drugs where a reduction in particle size
`has been shown to imp rove the rate and extent of oral
`absorption and hence bioavailability are shown in Table
`2 l.2. Such improvements in biouvailability can result in
`an increased incidence of siue-effects: thus for certain
`drugs it is important that the particle size is well con(cid:173)
`trolled, and many pharmacopoeia state a requirement for
`particle size.
`
`288
`
`Examples of drugs where a reduction in
`has led to improvements in
`
`Therapeutic class
`
`Ca1d1ac glycoside
`Ant1fu11gal
`Hormone acetate
`Steroid
`Anl!diabelic
`,Ana\ges1c
`Antibacterial
`Non-steroidal
`Non-steroidal
`Analgesic
`
`For some drugs, particularly those that are hydropho(cid:173)
`bic in nature, micronization and other dry particle size
`reduction techniques can result in aggregation of the
`material. This will cause a consequent reduction in the
`effective surface area of the drug exposed to the gas(cid:173)
`trointestinal Auids and hence a reduction in its dissolu(cid:173)
`tion rate and bioavailability. Aspirin, phenacetin and
`phenobarbital are all prnne to aggregation during particle
`size reduction. One approach that may overeome this
`problem is to micronize or mill the drug with a wetting
`agent or hydrophilic carrier. To overcome aggregation
`and to achieve particle sizes in the nano-size region, wet
`milling in the presence of stabilizers has been used. The
`relative bioavailability of clanazol has been increased
`4009( by administering particles in the nanometer rather
`than the micrometre size range.
`As well as milling with wetting agents, the effective
`surface a1·ea of hydrophobic drugs can be increased by
`the uclclition of a wetting agent to the formulation. The
`presence of polysorbate 80 in a fine suspension of
`phenacetin (particle size less than 75 ~lm) greatly
`improved the rate and extent of absorption of the
`phenacetin in human volunteers compared to the same(cid:173)
`size suspension without a wetting agent. Polysorbate
`80 helps by increasing the wetting and solvent penetra(cid:173)
`tion of the particles and by minimizing aggregation of
`suspended particles. thereby maintaining a large effec(cid:173)
`tive surface area. Wettabi lity effects are highly drug
`specific.
`If an increase in the effective surface area of a drug
`does not increase its absorption rate, it is likely that the
`dissolution process is not rate limiting. For drugs such
`us penicillin G and erythrornycin. which are unstable in
`gastric fluids. their chemical degradation will be mini(cid:173)
`mized if they remain in the solid state. Thus particle size
`reduction would not only serve to increase their dissolu(cid:173)
`tion rate but would simultaneously increase chemical
`
`

`

`810AVAILA81LITY- PHYSICOCHEMICALAND DOSAGE FORM FACTORS
`
`degradation and therefore reduce the amount of intact
`drug available for absorption.
`Solubility ill the dUJ11sion laye1~ Cs The dis:-.olution
`rnte of a drug under sink conditions. according to the
`Noyes-Whitney equation, is directly proportionnl to its
`intrinsic solubility in the diffusion layer surrounding
`each dissolving drug particle, Cs. The aqueous solubility
`of a drug is dependent on the interactions between mole(cid:173)
`etdes within the crystal lattice, intermolecular interac(cid:173)
`tions with the solulion in which ir is dissolving. and the
`entropy changes associated with fusion and dissolution.
`Tn the case of drugs that nre weak electrolytes, their aque(cid:173)
`ous solubilities are dependent on pH (discussed in
`Chapter 2). Hence in the case of an orally administered
`solid dosage form containing a weak electrolyte drug. the
`dissolution rate of the drug will be inl1uenced by its sol(cid:173)
`ubility and the pH in the diffusion layer surrounding each
`dissolving drug particle. The pH in the diffusion layer
`the microclirnate pH
`for a weak electrolyte will be
`affected by the pK., and solubility of the dissolving
`drug and the pl(,, and solubility of the buffers in the
`bulk gastrointestinal fluids. Thus differences in dissolu(cid:173)
`tion rate will be expected in different regions of the
`gastrointestinnl trnct.
`The solubility of weakly acidic drugs increases with
`pH and so rn; a drug moves down the gastrointestinal tract
`from the stomach to the intestine. its solubility will
`increase. Conversely, the solubility of weak bases
`decreases with increasing pH. i.e. as the drug moves
`down the gnstrointeslinal tract. lt is important therefore
`for poorly soluble weak bases to dissolve rapidly in the
`stomaeh, as the rate of dissolution in the small intestine
`will be much slower. The :rntifungal drug ketoconazole,
`
`a weak base, is particularly sensitive to gastric pH.
`Dosing ketoconazole 2 hours nfter the administration ol'
`the H, blocker cimetidine. which reduces gustrie acid
`secretion. results in a signilicantly reduced rate and
`extent of absorption (\'an der Meer et al 1980). Similarly,
`in the case of the anti platelet drug dipyrimiclole, pretreat(cid:173)
`ment with the H, blocker l'amotidine reduces the peak
`plasma concentration by a factor of up to I 0 (Russell et al
`1994).
`Salts The dissolution rate of a weakly aeiclic drug in
`gastric fluid (pH 1-3.5) will be relatively low. If the pH
`in the diffusion layer could be increased, then the solu(cid:173)
`bility, C5 . exhibited by the acidic drug in this layer. and
`hence its dissolution rate in gastric fiuids, would be
`increased even though the bulk pH of gastric fluids
`remained at the same low value. The pH of the diffusion
`layer would be increased if the chemical nature of the
`weakly ncidic drug were changed from that of the free
`acid to a basie salt. for example the sodium or potassium
`form of the free acid. The pH of the diffusion layer sur(cid:173)
`rounding each particle of the salt form would be higher
`(e.g. 5-6) than the low bulk pH ( 1-3.5) of the gastric flu(cid:173)
`ids because of the neutralizing action of the strong anions
`(Na+ or J<+) ions present in the diffusion layer (fig. 21.2).
`Because the salt form of the weakly acidic drug has a
`relatively high solubility at the elevated pH in the diffu(cid:173)
`sion layer. dissolution of the drug particles will take
`place al a faster rate. When dissolved drug diffuses out
`of the diffusion layer into the bulk of the gastric fluid.
`where the pH is lower than that in the diffusion layer,
`precipitation of the free acid form is likely to occur. This
`will be n result of the overall solubility exhibited by the
`drug at the lower bulk pH. Thus the free acid form of the
`
`Diffusion layer
`(pH 5-6)
`
`N~~1
`
`Drug
`diffusion
`
`Sodium salt
`of acidic drug
`(NaA)
`
`A-
`
`Gastric fluid
`(pH 1-3)
`
`. .
`.
`0 . .
`. .·
`.
`
`'
`
`<
`
`.
`.
`. .
`. .
`
`Rapid
`redissolution
`
`Fine precipitate
`of free acid (HA)
`form of drug
`
`Gastrointestinal
`barrier
`
`Blood
`
`Absoprtion
`
`Fig. 21.2 Schematic representation of the dissolution process of a salt form of a weakly acidic drug in gastric fluid.
`
`289
`
`1:
`jl
`i
`!I
`ii
`!I
`!I
`ii
`ii
`!I
`I ! I
`·I
`.....
`
`

`

`BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY
`
`drug in solution, which is in excess of its solubility at the
`bulk pH of gastric fluid, will precipitate out, leaving a
`saturated (or near-saturated) solution of free acid in gas(cid:173)
`tric lhlid. Often this precipitated free acid will be in the
`form of very fine, non-ionized wetted particles which
`exhibit a very large total effective surface area in contact
`with gastric fluids. This large total effective surface area
`will facilitate rapid reclissolution of the precipitated par(cid:173)
`ticles of free acid when additional gastric fluid becomes
`available as a consequence of either dissolved drug
`being absorbed, additional fluid accumulating in the
`stomach or !he fine precipitated particles being emptied
`from the stomach to the intestine. This rapid redissolu(cid:173)
`tion will ensure that the concentration of free acid in
`solution in the bulk of the gastric fluids will be at or near
`to saturation.
`Thus the oral administration of a solid dosage form
`containing a strong basic salt of a weakly acidic drug
`a more rapid rate of drug dis(cid:173)
`would be expected to
`solution and On the case of drugs exhibiting dissolution
`rate-limited absorption) a more rapid rate of drug absorp(cid:173)
`tion than the free acid form of the drug.
`Many examples can be found of the effects of salts
`improving the rate and extent of absorption. The dissolu(cid:173)
`tion rate of the oral hypoglycaemic tolbutamide sodium in
`0.1 M HCI is 5000 times faster than that of the free acid.
`Oral administration of a non-disintegrating disc or the
`more rapidly dissolving sodium salt of tolbutamide pro(cid:173)
`duced n very rapid decrease in blood sugar level (a conse(cid:173)
`quence of the rapid rate of drug absorption), followed by
`a rapid recovery. In contrast, a non-disintegrating disc of
`the tolbulamicle free acid produces a much slower rate of
`decrease of blood sugar (a consequence of the slower rate
`of drug absorption) that is maintained over a longer
`period of time. The barbiturates are often administered
`in the form of sodium salts to achieve a rapid onset of
`sedation and provide more predictable effects.
`The non-steroidal antiinflarnmatory drug naproxen
`was originally marketed as the free acid for the treatment
`of rheumatoid and osteoarthritis. However, the sodium
`salt (naproxen sodium) is absorbed faster and is more
`effective in newer indications, such as mild to moderate
`pain (Sevelius et al 1980).
`Conversely. strongly acidic salt forms of weakly basic
`drugs, for example chlorpromazine hydrochloride, dis(cid:173)
`solve more rapidly in gastric and intestinal fluids than do
`the free bases (e.g. chlorpromazine). The presence of
`c1·· ions) in the diffusion
`strongly acidic anions
`layer around each drug particle ensures that the pH in
`that layer is lower than the bulk pH in either the gastric
`or the intestinal fluid. This lower pl-I will increase the
`solubility of the drug in the dilfosion layer.
`The oral administration of n salt form of a weakly
`basic drug in a solid oral dosage form generally ensures
`
`290
`
`that dissolution occurs in the gastric fluid before the drug
`passes into the small intestine where pH conditions are
`unfavourable. Thus the drug should be delivered to the
`major absorption site, the small intestine, in solution. If
`absorption is fast enough, precipitation of the dissolved
`drug is unlikely to significantly affect bioavailability. It is
`important to be aware that hydrochloride salts may expe(cid:173)
`rience a cornmon ion effect owing to the presence or
`chloride ions in the stomach (also discussed in Chapter
`24 ). The in vitro dissolution of a sulfate salt of an HIV
`protease inhibitor analogue is significantly greater in
`hydrochloric acid than that of the hydrochloride salt. The
`bioavailability of the sulfate salt is more than three times
`greater than that of the hydrochloride salt. These obser(cid:173)
`vations are attributed to the common ion effect of the
`hydrochloride (Loper et al 1999).
`The sodium salts of acidic drugs and the hydrochloride
`salts of basic drugs are by far the most common.
`However. many other salt forms are increasingly being
`employed (there is further information in Chapter 24).
`Some salts have a lower solubility and dissolution rate
`than the free form. for example aluminium salts of weak
`acids and palmonte salts of weak bases. In these eases
`insoluble films of either aluminium hydroxide or palmoic
`acid are found to coat the dissolving solids when the salts
`are exposed to a basic or an acidic environment, respec(cid:173)
`tively. In general, poorly soluble salts delay absorption
`and may therefore be used to sustain the release of the
`drug. A poorly soluble salt form is generally employed
`for suspension dosage forms.
`Although salt forms are often selected to improve
`bioavailability, other factors such as chemical stability,
`hygroscopicity, manufacturability and crystallinity will
`all be consiclerccl during salt selection and may preclude
`the choice of a particular salt. The sodium salt of aspirin,
`sodium acetylsalicylate. is much more prone to hydroly(cid:173)
`sis than is aspirin, acetylsalicylic acid, itself. One way to
`overcome chemical instabilities or other unclesirnble fea(cid:173)
`tures of salts is to form
`the salt in situ or to add
`basic/acidic excipients to the formulation of a weakly
`acidic or weakly basic drug. The presence of the basic
`excipients in the formulation or acidic drugs ensures
`that a relatively basic diffusion layer is formed around
`each dissolving particle. The inclusion of the basic
`clients aluminium dihyclroxyarninoacetate and magne(cid:173)
`sium carbonate in aspirin tablets was found to increase
`their dissolution rate and bionvailability.
`Clystalform
`Polymorphism Many drugs can exist in more than
`one crystalline form, e.g. chlornmphenicol palmitate.
`cortisone acetate. tetracyclines and sulfathiazole. This
`property is referred to as polymorphism and each crys(cid:173)
`talline form is known as a polymorph (discussed further
`in Chapter 8). As discussed in Chapter 2, a metastable
`
`

`

`BIOAVAILABILITY - PHYSICOCHEMICAL AND DOSAGE FORM FACTORS
`
`polymorph usually exhibits a greater dissolution rate
`than the corresponding stable polymorph. Consequently.
`the metnslable polymorphic form of a poorly soluble
`drug may exhibit an increased bioavailability compared
`to the stable polymorphic form.
`A classic example of the influence of polymorphism
`011 drug bioavailability is provided by ehlornmphenicol
`pal mi tale. This drng exists in three crystalline forms des(cid:173)
`ignated A. B and C. At normal temperuture and pressure.
`A is the stable polymorph. B is the metastable polymorph
`and C is the unstable polymorph. Polyrno1vh C is too
`unstable to be included in a dosage form but polymorph
`B. the metastable form, is sufficiently stable. The plasma
`profiles of chloramphenicol from orally administered
`suspensions containing rnrying proportions of the poly(cid:173)
`morphic forms A and B were investigated. The extent of
`absorption of chloramphenicol increases as the propor(cid:173)
`tion or the polymorphic form B of chlommphenicol
`palmitale is increased in each suspension. This was
`attributed to the more rapid in vivo rate or dissolution of
`the metastable polymorphic form, B, of chlornmphenicol
`palrnitate. Following dissolution. chlornmphenicol
`palrnit::ite is hydrolysed to give free chloramphcnicol in
`solution. which b then absorbed. The stable polymorphic
`form A of chlornmphenicol palmitate dissolves so slowly
`and consequently is hydrolysed so slowly to chloram(cid:173)
`phenicol in vivo that this polymorph is virtually ineffec(cid:173)
`tive. The
`importance of polymorphism
`to
`the
`gastrointestinal bioavai I ability of chloramphenicol
`palmitate is reflected by a limit being placed on the con(cid:173)
`tent of the inactive polymorphic form. A, in chloram(cid:173)
`phenicol palmitate mixture.
`In addition to different polymor(cid:173)
`Amorphous solids
`phic crystalline forms, a drug may exist in an amorphous
`form (see Chapter 8 ). Because the amorphous form usu(cid:173)
`ally dissolves more rapidly than the corresponding crys(cid:173)
`talline form(s), the possibility exists that there will be
`significanl differences in the bioavailabilities exhibited
`by the amorphous and crystalline forms of
`that
`show dissolution rate-limited bioavailability.
`A classic example of the influence of amorphous
`versus crystalline forms of a
`on its gastrointesti(cid:173)
`nal bioavailability is provided by the antibiotic novo(cid:173)
`biocin. The more soluble and rapidly dissolving
`amorphous form of novobiocin \Vas readily absorbed
`following oral administration of an aqueous suspension
`to humans and
`However, the Jess soluble and
`slower dissolving crystalline form was not absorbed to
`any significant extent. The crystalline form was thus
`therapeutically ineffective. A further important obser(cid:173)
`vation was made in lhc case of aqueous suspensions of
`novobiocin. The amorphous form slowly converts to
`the more thermodynamically stable crystalline form.
`with an accompanying loss of therapeutic effective-
`
`ness. Thus unless adequate precautions are tc1ke11 to
`ensure the stability of the less stable. more thcrnpeuti(cid:173)
`cally effective amorphous form of a drug in a dosage
`form. then unacceptable variations in therapeutic effec(cid:173)
`tiveness may occur.
`Several delivery technologies for poorly soluble drugs
`rely on stabilizing the clrng in its amorphous form to
`increase its dissolution and bioavai\ability.
`Solrntes Another variation in the crystalline form of
`a drug can occur if the drug is able to associate with sol(cid:173)
`vent molecules to produce crystalline forms known as
`solvates. When water is the solvent. the solvate formed is
`called a hydrate. Generally, the greater the solvation of
`the crystaL lhe lower are the solubility and dissolution
`rate in a solvent identical to the solvation molecules. As
`the solvated and non-solvated forms usually exhibit
`differences in dissolution rates, they may also exhibit
`differences in bioavnilability, particularly in the case of
`poorly soluble drugs that exhibit dissolution rnte-limitecl
`bioavailability.
`A valuable example is that of the antibiotic ampicillin.
`The faster dissolving anhydrous form of ampicillin was
`absorbed to a greater extent from both hard gelatin cap(cid:173)
`sules and an aqueous suspension than was the slower dis(cid:173)
`solving trihydrntc form. The anhydrous form of the
`hydrochloride salt of an HIV protease inhibitor. an nna-
`of inclinavir, has a much foster dissolution rate than
`the hyclralecl form in water. This is reflected by a signifi(cid:173)
`cantly greater rate and extent of absorption and overdou(cid:173)
`bling of the bioavnilability of the anhydrous form (Loper
`et al l 999).
`
`Factors affecting the concentration of drug in
`solution in the gastrointestinal fluids
`
`The rate and extent of absorption of a drug depend on
`the effective concentration of that drug. i.e. the concen(cid:173)
`tration of drug in solution in the gnstrointestinal fluids
`which is in an absorbable form. Complexntion, micellar
`solubilization, adsorption nncl chemical stability me the
`principal physicochemical properties that can influence
`the effective drug concentration in the gastrointestinal
`fluids.
`Complexatio11 Complexation of a drug may occur
`within the dosage form ancl/or in lhe gastrointestinal flu(cid:173)
`ids. and can be beneficial or detrimental to absorption.
`Mucin, a normal component of gastrointestinal fluids.
`with some drugs. The antibiotic streptomycin
`binds to mucin,
`reducing the available concen(cid:173)
`tration or lhe drug for absorption. It is thought that this
`may contribute to its poor bioavailability. Another exam(cid:173)
`ple of complexation is that between drugs and dietary
`components. as in the case of the telrncyclincs. which is
`cliscussccl in Chapter 20.
`
`291
`
`

`

`5. The tablet should be of sufficient mechanical
`strength to withstand fracture and erosion dming
`handling at all stages of its lifetime.
`6. The tablet should be chemically. physically and
`microbiologically stable during the lifetime of the
`product.
`7. The tablet should be formulated into a product
`acceptable to the patient.
`8. The tablet should be packed in a safe manner.
`
`TABLET MANUFACTURING
`
`Stages in tablet formation
`
`Tablets are prepared by forcing particles into close prox(cid:173)
`imity to each other by powder compression. which
`enables the particles to cohere into a porous, solid speci(cid:173)
`men of defined geometry. The compression takes place in
`a die by the action of two punches. the lower and the
`upper. by which the compressive force
`is applied.
`Pmvder cor11pressiu11 is defined as the reduction in vol(cid:173)
`ume of a powder owing to the application of a force.
`Because of the increased proximity of particle surfaces
`accomplished during compression. bonds are formed
`between particles which provide coherence to the pow(cid:173)
`der. i.e. a compact is formed. Compaction is defined as
`the formation of a solid specimen of defined geometry by
`powder compression.
`The process of tableting can be divided into three
`stages (sometimes known as the compaction cycle)
`(Fig. 31.1 J.
`
`Die filling
`
`This is normally accomplished by gravitational flow of
`the powder from a hopper via the die table into the die
`(although presses based on centrifugal die filling nre also
`used). The die is closed at its lower encl by the lower
`punch.
`
`Tablet formation
`
`The upper punch descends and enters the die and the
`powder is compressed until a tablet is formed. During the
`compression phase. the lower punch can be stationary or
`can move upwards in the die. After maximum applied
`force is reached. the upper punch leaves the powder, i.e.
`the decompression phase.
`
`Tablet ejection
`
`During this phase the lower punch rises until its tip
`reaches the level of the top of the die. The tablet is
`
`@ ---------Die, surface view
`' ' o ... _1
`
`Position 1
`Upper punch is raised;
`lower punch has dropped
`
`n_____- Die, section
`rv~· Lower punch
`
`}
`
`Foot of hopper shoe
`
`Granules
`
`Position 2
`Hopper shoe has moved
`forward over clie and
`granules fall into die
`
`Position 3
`Hopper shoe has moved
`back. Upper punch has
`come clown compressing
`granules into tablet
`
`Position 4
`Upper punch has moved
`upwards. Lower punch
`has moved upwards to
`eject tablet. The cycle
`is now repeated
`
`}
`
`}
`
`Fig. 31.1 The sequence of e