Bio Pharmaceutics- Absorption Aspects

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JOURNAL O F PharmaceuticalSciencesM ay 1961 volume 50, number 5

Review Article-Biopharmaceutics: Absorption Aspects

By J Q H N G . W A G N E RHEREAPPEARS to be a rapidly growing interest

Tin the effects that the dosage form of a givendrug and the route of administration have on thebiological effects elicited by the drug. Thisproblem has been discussed at some length in theliterature but is largely unrecognized by many inthe biological and medical professions. Often itis assumed that the nature and intensity of thebiological response obtained with a specificchemical compound in animals and man is dueonly to the inherent activi ty of the molecularstructure of the compound. However, sincedissolution, diffusion, absorption, transport, bind-ing, distribution, adsorption on and transferinto cells, metabolism, and excretion are alsointimately involved in drug action, the molecularstructure, although vitally important, is only onefactor in drug action. The term dosage formabove includes the chemical nature (salt orsimple derivative), physical state (amorphous orcrystalline, solvated or nonsolvated, polymorphicform, etc.) and the particle size distribution andsurface area of the drug itself i n the dosage form.

The term biopharmaceutics was recentlycoined (1) . In its broad sense we may define bio-pharmaceutics as the study of the relationshipbetween some of the physical and chemical prop-

Received from the Pharmacy Research Section, ProductResearch and Development The Upjohn C o .The author wishes to dank Drs. C. A. Schlagel, L. C.Schroeter W. Morozowich and E. N. Hiestand who offeredsuggestio& during th e prdparation of this manuscript, andDrs. E. R. Garrett and J . I . Northam who aided in prepara-tion of the material shown in Fig. 2 and in the Appendix.

erties of the drug and its dosage forms and thebiological effects observed following administra-tion of the drug in its various dosage forms.This broad definition would include drug la-tentiation (2) and the preparation of differentsalts of a given acidic or basic drug for the pur-pose of altering the biological effects elicited bythe parent drug. Hence, biopharmaceutics en-compasses the study of the relation between thenature and intensity of the biological effects ob-served in animals and man and the followingfactors: (a)simple chemical modification of drugssuch as formation of esters, salts, and complexes;(b ) modification of the physical state, particle sizeand/or surface area of the drug available to theabsorption sites; (c) presence or absence ofadjuvants in the dosage form with the drug;(d ) the type of dosage form in which the drug isadministered ; and ( e ) the pharmaceutical processor processes by which the dosage form is manu-factured.

Since biological screens in animals and man areoften one point determinations with respect totime, the effect of the above factors are often notascribed to biopharmaceutics but to the inherentactivity of the molecular structure of the partic-ular compound under investigation. Usually onemust obtain the intensity of the biological re-sponse as a function of time to ascertain the effectsof the factors outlined truly.

It deals onlywith pharmaceutical and other factors which

This review is circumscribed.

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Vol. 50, N o. 5 , M a y 1961 361ethylamide following intravenous administration inrabbits, ( b ) the salivary response to tincture ofbelladonna after oral administration to man, and( c ) the mydriatic effect of 9-methyl-3-oxo-9-azabi-cylo- [3.3, ] -nonan-7-yl-benzilate maleate adminis-tered orally to mice. These authors showed theutility of the pseudo first-order rate constants forthe design of oral sustained action products. How-ever, Nelson (12) published almost an identicalmathematical treatment three years previously.The principal difference between the papers is thatNelson used the rate constant obtained from theblood level-time plot, and Swintosky and Sturtevantused the rate constant obtained from the biologicalactivity-time plot.

Relating the intensity of the biological activi ty ofa specific drug t o the kinetics of its absorption, dis-tribu tion, and metabolism is actually the most funda-mental type of research one could perform withthat drug. It is unfortunate that so few investi-gators in the medical and biological professions havedone research in this area with specific drugs. Mostof the methods and mathematics are available, andthe rewards and results would be well worth-while, both scientifically and economically.A few references where investigators haveelucidated some of the relationships between bio-logical activity and blood and tissue levels wilt becited. Foldes, et al . (13), stated: Whatever theroute of administration, in the final analysis, thetoxicity of local anesthetic agents depends on theirplasma concentrations. In considering the phy-sical and physio-chemical factors affecting the actionof muscle relaxants, Foldes (14) stated: The inten-sity of action of muscle relaxants depends on theirconcentration a t the neuromuscular junction. This.in turn, depends on the plasma level of the agent.An example involving a metabolite is Nirvanol (5-ethyl-5-phenyl hydantoin) a metabolite in the dogand man of Mesantoin (3-meth~+5-ethyl-5-phenylhydantoin). Butler (15) reported tha t administ ra-tion of Mesantoin, in the usual clinical dosage sched-ule, can be expected to result in larger amounts ofNirvanol in the body tha n of unchanged Mesantoin.He had no convincing evidence th at the therapeuticeffects of Mesantoin could not be accounted for onthe basis of the Nirvanol which was produced.In the above examples the drugs considered exerta specific type of pharmacologic action. The anti-biotics, however, are administered to inhibit thegrowth or kill microorganisms in the bodies ofpatients. Eagle, et a l. (16), reported that the ra te atwhich bacteria die under the impact of penicillin inviva is independent of its absolute concentration,provided only th at the latter is in excess of t he levelwhich in uitro kills th e particular organism at themaximal rate. Large doses of penicillin are moreeffective th an small doses primarily because of th elonger time during which the9 provide effective con-centration. Knothe and Mahler (17) showed that ,in uitro, high concentrations (6.25 to 25 mcg./ml.) oftetracycline acted bacteriocidally against a largenumber of strains of Staph . aureus and Strep. faecalisbut low concentrations (0.78 to 6.0 mcg./ml.) hadonly a bacteriostatic action. They reported, how-ever, th at only intravenous administration oftetracycline is capable of providing concentrationsin the bacteriocidal range in man.An example where the biological effect is very

I II II II I0 00 (Ab)B Azo (At.) BA=0. 5 (Ab)B1=Y - I US U B T H R E S H O L D S U B M A X I M A L S U P R A M A X I M A LAMO UNTS AMO UNTS AMO UNTS

At3 +Fig. 1.-General shape of th e biological act ivi ty(BA)-body drug content ( A b ) curve.where the doses are in moles of compound, M W isthe molecular weight, and t i / , is t he biological half-life. The subscripts refer to compounds 1 and 2,respectively. In such a case the integrals,Ab.d t , in terms of moles of compound, would be thesame in each case and a true molecular comparisoncould be made. With one-point-in-time determina-tions of B A , the rate of absorption of drug obtainedwith different dosage forms of the same drug, anddifferent rate s of absorption of drug obtained withth e same type of dosage form with different drugs,can markedly affect results.If the slope of th e curve, ~ B A / , ~ A * ,t each A *value in Fig. 1 were calculated and plotted againstAa , the resulting plot would be very similar to a bloodlevel-time plot, i.e., like a bell-shaped curve whichis skewed t o the right. The area under the curvewould be unity. The A * value a t which B A ischanging most rapidly, i.e., ( d B A / d A b )= a maximum,would be approximately (Ab)Ba = 0.5 in this example.As it seems reasonable t oassume that a great many pharmacological effectsrun closely parallel to the drug concentration in .theblood, the conclusions to be drawn . . . in regard tosuch concentrations may directly apply to the magni-tude of the effects produced. In these cases, theBA versus t plot will be similar in shape to the bloodlevel (or At,)versus t plot. The area under the B A ,plot is the to tal integrated activity of the singledose and should really be used for comparison pur-poses rather than the peak BA values or, as in theusual case, just the value of B a a t some arbitrarytime t . Some pharamacologists and clinicians usethis more accurate estimate of activity. For ex-ample, Winter and Flataker (9) reported both themean peak response and the mean total response ininvestigation of the effects of hormones upon theresponse of animals to analgesic drugs. The meantotal response was the area under t he mean reactiontime-time after injection plots. Similarly, Houdeet al. ( lo), in testing analgesic drugs in man, totaledthe six hourly relief scores for each drug and ob-tained a n estimate of the area under the mean painrelief-time after administration plot . They sta tedth at i t was these total relief scores which they em-ployed for sta tistical analysis of drug effects.In the cases cited above, where the B A versus tplot is like a blood level plot, then one would expecttha t a plot of th e logarithm of BA eysus t would yielda straight line past the maximum value of B A .Swintosky and Sturtevant (11)published such plotsfor: ( a ) he pyretogenic effect of d-lysergic acid di-

L==o

In 1937 Teorell wrote:


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362remote with respect to the time of administration,bu t has been adequately explained on a kinetic basis,is that of digitoxin. Th e work of Okita, et al. (18),makes excellent reading. By use of biosynthetically-labeled digitoxin, administered intravenously topatients with congestive heart failure, they showedthat digitoxin has a very long residence time in thebody. After autopsy of some patients they showedthat only about 2 mcg. of digitoxin per 100 Gm. ofventrical tissue from the heart could be found andthat this represented less than 1%of the administereddose. Swintosky (19) reported the half-life ofdigitoxin, calculated from twenty-day urinary ex-cretion data to be 5.3 days, but , unfortunately, didnot relate i t to the work of Okita, et al. Okita alsofound that the myocardium has no special affinityfor digitoxin in comparison with other organs andthat the amount there a t any time after administra-tion is explicable on th e basis of the kinetics anddistribution. Another interesting aspect of thiswork was proof th at biliary excretion of unchangeddigitoxin is followed by reabsorption in the smallintestine. Hence, the drug keeps cycling back andforth between th e vascular system and the intest ine.Kinetics of Absorption.-The ra te of absorptionand the extent of absorption ( i. e., the per cent of thedose absorbed) are very important factors in deter-mining the magnitude of the blood and tissue levelswith respect to time after administration and, hence,in determining the intensity of biological activity.Nelson (20) and Dominguez ( 5 ) have publishedexcellent reviews on th e kinetics of absorption, dis-tribu tion, and excretion. This review will onlycontain sufficient material on this subject to makeother parts of the review more intelligible.Except for an intravenous injection in which therate of injection is experimentally controlled, in allother administrations a drug enters th e blood streama t an unknown rate. Under certain circumstancesthis rat e can be determined. Dominguez (5),Nelson ( Z l ) , Swintosky (22 ) , nd others have shownthat many substances administered orally exhibita steady state of diffusion during absorption, first-order metabolic conversion, and/or first-orderurinary excretion of unchanged drug and metab-olite(s). If these fundamental premises are ful-filled by a given drug then one can calculate the in-stantaneous rate of absorption at different timesafter oral administration by at least three knownmethods. The first method, that of Dominguez ( 5 ) ,requires a knowledge of th e volume of distr ibu tion ofthe drug. The method is based on application ofEq . 3:

J o u r n a l of Pharmaceutical Sciencesconstant (in hr. -l) for metabolic conversion of thedrug.From t he above we may also write

A + B = Ir,(ki + k2) = Vi.kb (Eq. 4 )where k b is the first-order rate constant for loss ofdrug from the blood. If there is no metabolic con-version of the drug then the third term of Eq. 3reduces to V l . g . C. If there is metabolic conversionof the drug, the constant B cannot be evaluated fromthe unchanged drug recovered in the urine because ofuncertainty about the complete absorption of thedrug, Independent experiments where the drug isadministered intravenously, however, allow com-putat ion of the constant B(5).Th e second method of calculating instantaneousrates of absorption is th at used by Nelson (21) andothers. This method involves application of equa-tion (5):

d2Ae dAeR = 1(i . + ;ii-) (Eq. 5 ).f kbwhere R = he instantaneous ra te of absorption a ttime ti n mg. /hr, f= the fraction of th e drug absorbedwhich is excreted unchanged in the urine; k b hasthe significance indicated above; d 2 A e / d t 2= hesecond deriva tive of a plot of cumulative amount(mg.) of unchanged drug excreted in the urineagainst time in hours; d A e / d t = he first derivativeof the same plot.The third method, th at of Domingnez ( 5 ) , nvolvesthe assumption that the blood concentration curve,Cversus t , can be fitted with a threc-term exponential

equation of the typeC = a e x p . - a t - c e x p . - r t + d e x p . - S t ( E q . 6 )Evaluation of the constants as he indicates allowsplo tting of the ra te of absorption (mg./hr.) as afunction of time and, hence, also of cumulativeamount absorbed as a function of time. Equation 6assumes th at th e rat e of absorption, R,nvolves thetwo exponential terms as follows

R = P(exp.-r t - exp.-St) (Eq. 7)where

R C ( r - 01) = Ad(./- - 1:)R =(1: (1:

Now Teorell ( 3 ) and others, including Kriiger-Thiemer (4). ssumed that t he rate of absorptioncould be represented by a single exponential func-tion leading to an equation of t he type

where R = the instantaneous rate of absorption attime t in mg./hour; Vl= he reduced volume of dis-tribution and V l = A / k 2 where V1 is in ml. and k2 inhr.-l, dC/dt= the instantaneous slope of the bloodlevel curve at time t ; C= the plasma concentrationin mg./ml.; A =the renal clearance with dimensionsml./hr. A is the slope of t he straigh t line when rat eof excretion of unchanged drug in the urine (mg./hr.)is plotted against plasma concentration, C, in me./-ml. B= th e slope of the straight line when rateof metabolic conversion of the drug (mg./hr .) isplotted against C n mg./ml. The dimensions areml./hr. B = V1.kl where k l is the first-order rate

where k is the first-order rat e constant for the absorp-tion process, Cois the amount absorbed divided by thevolume of distr ibution, and the other symbols havethe significance indicated above. In his article,Kriiger-Thiemer (4) tated that k may be gainedfrom Eq. 8 by series evolution for exp.-(k - b ) t ,whereby three approximations may be calculated.He gave the first and second of these approximations.The difficulty with application of this method, asDominguez ( 5 ) pointed out, is that Eq. 8 leads tothe conclusion tha t t he ra te of absorption jumps in-stantaneously from zero to its largest value eitherat the time of administration or after some lag


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Vol. 50 , No. 5, M a y 1961time. In real ity, for cases which have been in-vestigated the plasma level-time plot obtained fol-lowing oral administration had four points of in-flection. The first inflection point occurs shortlyafter administra tion, usually within the first one-halfto one hour. The second point of inflection corre-sponds to the time when the ra te of absorption is amaximum. The third point corresponds to the peakplasma level at which time t he instan taneous rat e ofabsorption is exactly equal to th e instantaneous ra teof excretion. After the maximum plasma level thereis a fourth point of inflection corresponding to thetime absorption has ceased and the plasma level-timeplot becomes a simple exponential function of time,namely C= Co.exp.--kbt. Hence, application of Eq.8 to obtain the rat e of absorption may lead to largeerrors. However, th e equation is very useful as asimple model torepresent an approximate blood level-time plot. A factor which was discussed by Nelson(20) is the effect of stomach emptying rat e on th enature of the absorption curve. Equations 7 and 8really describe th e amount of substance in compart-ment Cas a function of time for two consecutive first-order reactions. namely

s YA- - (Eq.9)(o r k ) (o r kb)It is conceivable that the A-+E reaction may bestomach emptying which has been shown to obeyfirst-order kinetics in many cases (see Gastrointes-tinal Physiology section).There are many problems connected with theapplication of these methods. Th e first methodnecessitates determination of the volume of dis-tribu tion of the drug which in many cases is subjectto considerable error. Th e second method requiresno knowledge of the volume of distribution, but thereis some doubt in the reviewers mind tha t t he deriva-tives, d A , / d t and d 2 A e / d t 2 ,can be obtained with con-siderable accuracy unless a large number of pointsare available for the excretion curve in the regionwhere th e derivatives are determined. Particularlywhere the drug has a long half-life (> ca. six hours)and the dosage form being studied allows slow ab-sorption of t he drug, one ma y interpret a certainsegment of a plot of cumulative amount of drug ex-creted against time as a stra ight line when in realitythe line is curved and has an inflection point in thisregion. The line may be only apparently linear be-cause the number of points are too small upon whichto make a sound stat istical decision. Some of themodel diagrams, Figure 2, illustrate this point well.Perhaps the difference is only of academic interes t inone sense but in another sense it may be quiteimportant. For example, one could conclude, oninsufficient evidence, that a given dosage form wasreleasing the drug at a constant, zero order rate,when in reality it may be releasing the drug at aslow first order rate. This could be true, for ex-ample, in the interpretat ion of t he kinetics of excre-tion of amphetamine from product F in the paperof Campbell et al. (23). The third method involvesassignment of two of the constants, namely a n d s .to the absorption process. This method has beenshown by Dominguez ( 5 ) to be applicable to theabsorption of creatinine in the dog and man. Suchequations as Equation 6 are useful to preparemodels to illustrate the relative effects of change

363in absorption rate, ka, and other factors wouldhave on plots of amount of drug in th e depot versustime, amount of drug in the body versus time, andcumulative amount excreted versus time. Themodels shown in Figure 2 illustrate this. The modelsare similar, but different in some aspects, to thoseof Teorell (3), De Jongh and Wijnans (24), VanGemert and Duyff ( 7 ) , Kriiger-Thiemer (4), andGarrett, et al. (see footnote).

Hypothetical Models of the Kinetics of Absorp-tion and Excretion Following Administration ofSlowly Releasing Dosage Forms.-The models (Fig.2 and Table I)2were designed to show the relativeeffects of stomach emptying and slow release of drug,by either a zero-order or first-order process, on a re-sulting hypQthetica1 blood level, if th e drug is re-moved from the blood by a first-order process. Inall cases, the r ate constant, k8 , for removal of drugfrom the blood (and other fluids of distribu-tion) is taken as 0.1155 hr.-l, which correspondsto a half-life of six hours ; this is th e averagevalue for salicylic acid in human subjects.In all cases, curve C would correspond to the bloodlevel, or actually, the fraction of t he total drugin the fluids of distribution. Curve D correspondsto th e fraction of the total drug which hasbeen excreted and/or metabolized t o time tIf the drug was not metabolized, but excretedunchanged in the urine, then curve D, in each case,would correspond to the cumulative amount of thedrug in the urine to time t. Curves A and B corre-spond t o the amounts of drug in compartments A andB, respectively. For example, in model I , curve Bcorresponds to the amount of slowly available drugstill present in the dosage form at any time t . Theconstant. kl, for release of drug in quickly availableform in model I, and for stomach emptying inmodels I1 and 111, was chosen as follows: when k l =1.0 hr.-l it requires 2.772 hr. (four half-lives) to re-lease or empty 93.75y0 of th e original material.Since X A = ~t t = O in both models I1 and 111, ako of 0.2 hr.-l in model I1 corresponds approximatelyto a k p of 0.5hr.-l in model I11on the basis tha t afterabout five hours essentially all the B+C process, ifconsidered alone, would be complete; similarly akoof 0.05hr.-in model I1corresponds approximatelyto a kp of 0.1 hr.-l in model I11 on the basis th at afterabout twenty hours essentially all the B+C process,if considered alone, would be complete.

Careful study of the plots in Fig. 2 (see Appendixalso) shows the effect of changing one of the rat econstants while the other two are held constantOne can also visualize why tissue levels of drug, orlevel of drug a t the site of action, would not usuallycorrespond with the blood level in relation to timesince the amount of drug in such tissues would in-volve one or more compartments and r ate constantsleading off from the C compartment. Hence, inthe usual case, one would no t expect peak biologicalaction to correspond with peak blood level in rela-

1 The plots shown in Fig. 2 were kindly provided by Dr. E .R. Garrett and C. D. Alway of the Department of Physicaland Analytical Chemistry of T h e Upjohn C o . The analol:computer used was described by Garrett ef al . [ J . P k a r m .E x g t l . T k e r a p . , 130, 106(1960)]. The pGogramming of theanalog computer for the plots shown in Fig. 2 will be de-scribed in a future article entitled: Pharmaceutical Applica-tion of the Analog Computer I.1 The differential equations and their solutions, shown inTable I, were kindly provided by Dr. J. I. Northam of theStatistical Section of The Upjohn Co.


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364tion to time. The plots help one to visualize thedifferences one obtains when a drug is given in aquickly available form and in a prolonged action orslowly releasing form. This can be seen, for ex-ample, by comparing curves A and B in model I.The Relationships Between Dosage Forms,Optimal Dosage Schedules, and the Kinetics ofAbsorption.-Most oral dosage forms may bebroadly divided into three types based upon therapidity with which the drug is absorbed after ad-minstration. The first type would be those which,when administered, allow extremely rapid absorptionof their contained drug. Many solutions, some sus-pensions containing the drug in very small particlesize, and some ordinary compressed tablets, whichrapidly disintegrate and liberate the drug in verysmall particle size, could be included in this group.The second type encompasses the true sustainedrelease or prolonged action dosage forms. A prop-

Journal of Pharmaceutical Scienceserlydesigned dosage formof this type producesafter asingle dose an essentially constant Ab, which is abovethat level needed for suitable therapeutic activitybut below the peak level obtained with the samedose of drug in a quickly available dosage form, for aperiod of time which is some multiple of t he timethat the quickly available dosage form would main-tain a level of drug above the level needed fortherapeutic activ ity. The principle, upon whichmost dosage forms of th e lat ter type is based, isslowing of the absorption r at e of the drug by slowingthe ra te a t which th e drug is released to t he absorp-tion sites in th e gastrointestinal tract. Properlydesigned and functioning, a sustained release or pro-longed action dosage form administered orally acts,during some time interval following administration,like a continuous, constant rate infusion or a con-st an t surface pellet implant. Some commercialproducts, which are marketed as sustained release or

' . O r_---

0.8

SET I SET 2M O DEL I

SET 3

SET I SET 2MODEL II

S E T 3


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Vol. 50 , No . 5 , M a y 1961

//I

SET I SET 2MODEL IU

SET 3Fig. 2.-Models of the kinetics of absorption, distribution, and excretion of drugs (see Appendix),

TABLE.--CONCENTRATION OF HYDROGENONANDHYDROXIDEONAT VARIOUSH VALUESConcentration of Ions inMicroequivalents /Liter(Micronormality) at 24O

PH Hydrogen Ion Hydroxide Ion1 100,000 0.00000012 10,000 0.0000013 1,000 0.000014 100 0.00015 10 0,0016 1 0.017 0 . 1 0.18 0.01 1 .0Microequivalent = 10-6 equivalent weight.

prolonged action forms, perform their intended func-tion while others apparently do not (23, 2 5 , 26).Many, and probably most, oral dosage forms fall intoa class intermediate between the above two types.A dosage form of t he thi rd type, we may sayarbitrarily, acts in such a manner t ha t the drug con-tained in i t enters the blood stream at instantaneousrates which are changing quite rapidly over a periodof time from one to several hours after administra-tion. The net result, following oral administrationof dosage forms in this group, is th at the maximumamount of drug in the body from a specific singledose occurs a t some time greater than one hour afteradministration and there are large variations in Aha t different times between the time of administra-tion and the time when the drug has, for all practicalpurposes, disappeared from the body.Another important field in therapeutics encom-passes the choice of the best type of dosage form andthe best type of dosage schedules for specificdrugs. A few far-sightedinvestigators (3,4,7,24,27)have attempted, using a mathematical approach,to formulate some general rules which may serveas a foundation for practical work in th is field of in-vestigation. Van Gemert and Duyff ( 7 ) stress the

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0

following: As to medical practice, it is stronglysuggested that the elimination rate (i.e., determina-tion of ka ) of important drugs be studied; this alonewould be a great help toward rational treatment.This statement, published ten years ago, appearsto have been lost in the literature and unappreciatedby th e large majority of clinical investigators andpharmacologists. Once th e k b of a specific drug isknown, then a rational approach to the calculationof optimal dosage schedules and choosing of suitabledosage forms can be made. Also, many of the equa-tions derived or reviewed by the above investiga-tors may be applied to any drug. Some of thepractical consequences of the calculations will now beconsidered.Van Gemert and Duyff ( 7 ) concluded the follow-ing: (a) If a drug is administered in a single dosewhich is not, or very infrequently, repeated then adose approximately equal to 2 .5 times t he dose givinga half-maximal effect [i. e., dose = 2.5is the most economical way of obtaining the desiredbiological activity , B A . (b ) If a drug is repetitivelyadministered then the economically favorable doseper unit of time, a nd the way in which it should bedivided into individual doses at the appropriateintervals, depend on the general shape of t he B Aversus A6 plot of t he drug in question. In general,they concluded, for low overall dosages the individualdoses can be fairly large, and correspondingly widelyspaced. For high overall dosages, however, treat-ment becomes, generally speaking, the more eco-nomical as the permanent infusion is more nearlyapproximated. As pointed out formerly, a properlydesigned and functioning sustained-released or pro-longed action dosage form and a constant surfacepellet implant are very similar to a permanentinfusion. Van Gemert and Duyff ( 7 ) pointed outthat these general rules apply not only to sub-stances artificially introduced, but also to drugsproduced by the body itself. Hence, one could con-clude these general rules apply to drugs which

=


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366 Journal of Pharmaceutical Sciencesin great p ar t by the solubility of the drug as definedabove. Other factors influence th e ra te of dissolu-tion of a drug but these will be discussed in anothersection.

Both the absolute particle size, and the particlesize and particle size dist ribut ion of a drug sample asit relates to surface area, may be important in the ra teof dissolution of a drug (30). When the particle sizeis greater than about 10 p, the rate of dissolution isdirectly proportional to th e surface area. Hencehere, surface area, and not particle size per se , is afactor controlling dissolution rate. However, whenparticles below 10 p in diameter are considered, theeffective particle radius and not the surface areamay be more important (30).Finely divided particles dissolve at a greater rateand have higher solubilities than similar macro par-ticles (31-34). Th e only energy difference betweenthe large and small crystalline forms is the surfaceenergy (32). Increase of solubility due to reduc-

tion in particle size only becomes significant (be-yond ca. 1%) for very small particles in the sub-micron range (32). Alexander (35) reported tha t thesolubility of amorphous silica in water is relatedexponentially to th e surface area of the silica.Hasegawa an d Nagai (34) published a mathematicalapproach to the tendency for small particles todissolve faster than larger particles.If a compound is no t very soluble it is sometimesdangerous to reduce the particle size to an extremelysmall range. For example, Desai, et aE. (36), e-ported t ha t r ats fed aerated silica gel for prolongedperiods developed abnormal large nodules in theirintestines. Similarly, Sasson (37) found barium sul-fate crystals in the lumen of intestinal glandsfollowing barium enemas; he said this may explainthe portal of entry and mechanism of formation ofbarium granulomas of the rectum occurring afterbarium enemas. Inhalation of extremely finelydivided compounds can be dangerous also. A com-mercial sample Ff amorphous silica, with a particlesize of ca. 200 A . , a B.E.T. surface area of 145,000cm.2/Gm., and a water solubility of 41 mg./L. at20.,caused more than doubling of t he lung weightsof albino rabbits which were exposed to an aerosolof the silica for eight hours each day for periods upto twenty-seven months (38).There have been reports (39-42) that a givenrange of particle sizes of a drug produced a biologicaleffect whereas larger particles produced little or noeffect. In such cases it is most probably true thatthe compounds absorption i s rate-limited by surfacearea. If the particle size is greater than a certainrange, th e range depending upon the compound, theninsufficient compound is absorbed to produce anobservable biological effect. This is obvious fromth e equations presented below in the section entitledDissolution Rate.

When particle size is discussed it is often difficultto get a mental picture of the size range. The sizedistribution of tobacco smoke particles from cig-arettes is in the range 0 to about 1 U. The biggestpeak on the distribution diagram occurs in th e par-ticle diameter range 0 to 0.14p (43). An extremelyfine micronized powder will have a particle sizedistribution, as measured by Coulter counter, offrom about 0.5 to 10 p, and a surface area in therange about 6 to 12 X lo4 cm2/Gm. A milledpowder will have a particle sue in the range of about

simulate endogenous active compounds or to drugswhich are converted t o a compound which also existsendogenously and is biologically active.Similarly, De Jongh and Wijnans (24) from theirmathematical analysis stated : Economy is in-creased on using a small dose which is frequentlyrepeated. Repetition of a dose, however small, a tthe right moment, is always more profitable if it isonly in equilibrium with the speed of elimination.By permissible extrapolation the great economy ofthe body on implantation of a crystalline tablet isexplained: there is then in a manner of speaking acontinuous infusion which may be compared withan infinitely often repeated infinitely small dose, withan infinitely small time interval.Boxer, et al . (6), derived equations for the accu-mulation of a drug given in several doses, D, a t con-stant intervals, A t , assuming the drug was ad-ministered by rapid intravenous infusion (it., allthe dose instantly in the volume of distribution).In such a case, when the logarithm of the amount ofdrug in the body ( A b ) is plotted against time oneobtains a series of saw-tooths extending upwardsuntil a t some time the median curve flattens out andthe value of Ab from that time on will fluctuate backand forth between two extreme levels. The equa-tions for the two extreme levels after a large numberof doses approach

where Ab, is the upper limiting vaIue of Ab at thest ar t of the interval At, is the lower limitingvalue of A b a t the end of the interval A t, and D is thedose administered.It is difficult to apply the equations of Boxer, et al.( 6 ) , o calculate the results after oral administra tionunless one has some knowledge of the rapid ity ofabsorption from the dosage form administered.If absorption is very rapid compared to the dosageinterval, A t , then the equations give a good estimateof the equilibrium situa tion (4, 28). However, theslower the absorption process, the less accurate areEqs. 10 and 11. For a sustained action prepara-tion, At-t.0, exp - & b A t + l and the denominators ofEqs. 10 and 11approach zero, hence, the ratios wouldapproach infinity for Eqs. 10 and 11 . I t is obviousone must be careful where these equations are ap-plied.Solubility, Particle Size, and Physical Form.-Theinitial rate of dissolution, i.e., the rate at very lowper cent saturations of the dissolution medium, isdirectly proportional to the solubility of the drug inthe dissolution medium as i t exists a t the solid-sideof the diffusion layer. In the case of gastroin-testinal absorption of drugs, the dissolution mediumis the gastrointestinal content at the particularphysical location of the drug particle in the tract.If the dissolution process is diffusion-controlled,then t he liquid in the diffusion layer right a t th einterface of the solid drug particle is essentially asaturated solution of the compound in the dissolu-tion medium except for ions and molecules depletedin any reaction occurring in the diffusion layer (29).Hence, the rate a t which molecules of the drugreach the bulk gasirointestinal content is determined


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Vol. 50, N o. 5 , M a y 196110 to 150 p and a surface area of the order of 0.4 t o6 X lo3 cm.2/Gm. Since most drugs are admin-istered in doses below 0.25Gm. i t is obvious tha t thetotal available surface area of doses of crystallinesubstances as received from the chemist, or justmilled, will be relatively small. The specificsurface, in ~m . ~ / c m . ~ ,s equal to 6/d for spheres, andvery near this value for truncated rods such as onefinds usually in a micronized powder. Hence, apowder with a mean particle diameter of 10 p willhave about ten times t he specific surface of the samecompound with a mean particle diameter of 100 p.Metastable polymorphs have higher solubilitiesthan th e more stable forms of the same compound(32, 44). Hence, everything else being equal, onecould deduce that the more soluble polymorphswould dissolve at faster rates and be more rapidlyabsorbed. An effect that is not often recognized isthat dry grinding can cause phase transitions insolids. Cleverley and Williams (45) reported thatgrinding of crystalline barbitur ic acid derivativesoften produce a change in polymorphic form.Similarly, Yamagnchi and Sakamoto (46) found tha tdr y grinding of gibbsite caused ultimate decomposi-tion of x-alumina. Palen (47) reported t ha t certainpolymorphic forms of chloramphenical were inertbiologically, and th at t he a-form of yellow iron oxideis biologically active yet does not affect ascorbic acidas much as other forms of iron oxide. Hydrates andother solvates of a given compound have differentsolubilities and ra tes of dissolution than t he non-solvated form (44). Hence conversion of a non-solvated compound to a solvated compound during,or subsequent to, formulation of a product may causedifficulties or produce an effect which is unexpected.Such transitions are temperature-dependent. Some-times only a complete study, where the logarithmof the solubility of t he compound is plotted againstthe reciprocal of the absolute temperature, can clearlydelineate the problem (44).The equation of Dyer (48)relating th e effect of pHon solubilization of weak acids and bases by sur-fac tants which form micelles may be of interest notonly from the standpoint of formulation, but alsofrom the standpoin t of oral absorption from solutionscontaining such agents. The equation reported byKrishnamurti and Mirza (49) relates the amount ofsubstance adsorbed by an adsorbent to its watersolubility. Their results agree with Freundlichs oldstatement : The strongly adsorbable substances arefor the most par t difficultly soluble in water: th eweakly adsorbable inorganic salts, acids, and basesare easily soluble.Dissolution Rate.-Fick (50) put diffusion on aquantitative basis by adopting the mathematicalequation of heat conduction derived snme yearsearlier by Fourier. One way of expressing Ficks lawis as follows: the quanti ty of solute, d W , whichdiffuses, a t constant temperature, through a n area ,A , in a time, dt , when the concentration changes bya n amount, dc , through a distance, d x , a t right anglesto the plane A , is given by the expression

367This law assumes that the only motion involved isdue to molecular agitation and was proved by Fickfor diffusion in one direction only, upward againstthe force of gravity.The Noyes-Whitney law formulated in 1897 (51)concerns the rate at which solids dissolve in theirown solutions when the surface area of exposedsolid changes negligibly. This law states that thera te of concentration change, d C / d t , is a t any instantdirectly proportional to the difference between theconcentration of a sa turated solution, C,, and theconcentration, C , existing in the solution a t this in-stant.

d C / d t = k ( C , - C) (Eq. 13)where k is a constant with dimensions l/time.Integration with c = 0 a t t = 0 yields

Iz(C, - C) = Zlt C, - kt (Eq. 14)or

C = C,(1 - exp.+) (Eq. 15)Noyes-Whitney explained the dissolution process onthe assumption that a very thin layer of saturatedsolution was formed a t th e surface of t he solid andthat the rate at which the solid dissolved wasgoverned by the ra te of diffusion from this saturatedlayer into the main body of the solution.A few years later, Briinner and Tolloczko ( 5 2 )showed th at the value of the constant k (in Eqs. 13,14, and 15) depended upon the surface area, S, ofsolid exposed, th e intensity of agitation or velocityof fluid across th e solid, th e temperature, the struc-tu re of the surface, and the experimental apparatus.Nernst and Briinner, who worked in Nernstslaboratory, advanced (53) a theoretical generaliza-tion of t he law to include all kinds of heterogeneousreactions. They postulated th at the velocity of aheterogeneous reaction was determined by thevelocities of the diffusion processes that accom-panied it. This included th e concept tha t theequilibrium is set up a t the boundary surface prac-tically instantaneously compared with the rate ofdiffusion. According to Davion (54), these con-siderations led to the following equation which, as afirst approximation, describes the dissolution of asolid by a diffusion controlled process.

d W / d t = D / h . S . ( C , - C) (Eq. 16)where h is the thickness of the diffusion layer andthe other symbols have the meanings above. Thisexplains the variation of the constant k with intensityof agitation since th e mure intense th e agitation,the thinner the diffusion layer, and hence the greaterwill be th e rate of dissolution, d W l d t ,Wilderman ( 5 5 )and Zdanovskii (56) subjected theentire Nernst-Briinner diffusion theory to severeanalysis and experimental study. Wildermandoubted that it explained the dissolution process.Zdanovskii, after experimentation with the dis-solution of inorganic salts, claimed t h a t he derivedthe following generalized equation. When the rate-determining step is the surface or interface process,the rate of dissolution is given by

d W / d t = aS(C, - C,) (Eq. 17)When the process is diffusion controlled, the rate ofdissolution is given by

Hence the diffusion coefficient, D , is the amount ofsolute which will cross 1 c m 2of cross section in unittime if the change in concentration per cm. in adirection perpendicular to this cross section is unity.


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368d W / d t = ( D / h ) S ( C , - C (Eq . 18)

For t he general case the equation is

Jouriial of Pharmaceutical Sciencesa series of salts of a weak acid and the parentweak acid, th e order of peak blood levels atta ined ,and the order of th e water solubilities of t he drugare the same. However, one should not lose sightof th e fact that i t is really t he relative rates of dis-solution both in zitro and in vivo which is the im-portant factor and such rates can be influenced byother factors than just solubility. This was pointedout by Nelson (64) who stated there was a poorcorrelation between the water solubilities and thesolution rates of a series of theophylline salts.To the reviewer's knowledge, Nelson (64) wasthe first to show that, with other factors remainingconstant, the dissolution rates of a series of saltsof a given weak acid determines the rate of build upof blood level with time an d the maximum blood levelattained. Earlier, Edwards (65) postulated th at thedissolution of an aspirin table t in the stomach andintestine would be the rate process controlling theabsorption of aspirin into the blood stream. In laterpublications, Nelson (66) showed th at : ( a )dissolu-tion rate was rate-determining in absorption ofvarious tetracycline preparations providing initialsurface area was restricted in the dosage form, ( b )the absorption of aspirin appeared to be rate-limited by the time necessary for the drug to dis-solve after ingestion as Edwards had predicted,and ( 6 ) th e absorption of benzylpenicillin was rate-limited by the intrinsic dissolution rate propertiesof th e potassium and procaine salts used.A technique for studying dissolution rates ofdrugs, which does not require an assay methodfor the dissolving specie, but is based on weightloss of a constant surface pellet, was reported byNelson (67 ). Using this method he showed th at thesodium sal ts of several weakly acidic drugs dissolvedmuch more rapidly than the corresponding weakacids in the p H range 1.5 to 9.0. Similarly heshowed th at admixture of tribasic sodium phosphatewith a weakly acidic drug increased the rate ofdissolution of al l the acids studied. In all cases amaximum occurred in a plot of initial ra te of dis-solution versus fraction of acid in th e mixutre. Thelocation of th e maximum appeared to be related t oth e dissociation constan t of th e acidic drug. Also,the maximum initial rates obtained with the mix-tures were lower than those obtained with the saltsof t he acid used.Equation 19 above may be written as

d W / d t = K.S.(C, - C) (Eq. 21)where W s the amount dissolved, t is the time, K isthe rate constant with dimensions distance/time,S is the surface area, C, is concentration of dissolvingsolid at the solid side of the diffusion layer, and Cis the concentration in the dissolution medium.A t very low per cent saturations of dissolving sub-stance in the dissolution medium, Nelson (64) showedth at this reduces to

d W / d t = KSC, (Eq. 22)which upon integration, with S considered a con-stan t, yields

W = KSC,t (Eq. 23)He pointed out that this should describe the in vivodissolution process from a constant surface dosageform too, since absorption from solution following

dW (D*h S(C, - C (Eq. 19)atwhere a is the rate constant of t he interface process,C, is the concentration a t saturation, C is the con-centration in the bulk solution, and C is theconcentration in the boundary diffusion layer (pre-sumably at the solid side). The other symbolshave the significance as defincd above. The ra teconstant, K , n the latte r equation is given by:

(Eq. 20)In 1931 Hixson and Crowell ( 5 7 )wrote a n excellentreview of the theory of the dissolution of solids andderived a new law (the cube root law) in which thevelocity of solution of a solid in a liquid is expressed

as a function of the surface area and the concentra-tion. The y claimed that the Noyes-Whitney lawin it s original form, without any assumptions regard-ing the mechanism by which the prdcess takes place,has been quite generally substantiated by experi-ment. For their derivations an d suggested applica-tions th e original paper should be consulted. Theequations of Hixson-Crowell have been used byWurster, et al. (58, 59), in their studies.King and Brodie (60) and Hixson and Baum (61)studied the dissolution rates of benzoic acid in dilu teaqueous sodium and potassium hydroxides. Theyexplained their data on th e basis of t he Ncrnst-Brunner two film model of diffusion controlledkinetics. This theory assumes linear concentrationgradients of all species in the diffusion layer. W. 1.Higucbi, et al. (29), showed where this theory wouldbe expected to fail. Using th e Nernst-Brunnermodel and assuming nonlinear concentration gra-dients in a single diffusion layer, these authorsderived equations which satisfactorily described theth e rate of dissolution of weak acids and bases invarious solutions and buffers. The y showed th atthe complex rat e equations could be reduced to moresimple equations under certain conditions which maybe readily determined by a consideration of thedissociation constants of the acids and bases in-volved.The long duration of action of zoxazolamine, acentrally acting muscle relaxant, was ascribed byBrodie and Hogben (6 2) to th e precipitation of th edrug in the intestines, and, due to the low solubilityof t he drug in the gut , i t is slowly absorbed duringa period of many hours after oral administration.Juncher and Raaschou (63) ascribed differences inblood levels of penicillin V, obtained after admin-istration of different salts and th e free acid of thispcnicillin, to differences in solubility of th e salts.The in vitro experiments, which the latter authorsperformed, were really experiments in which therates of dissolution of t he different salts and th efree acid were compared, and not their solubilities.The order of peak blood levels of penicillin V ob-tained in human subjects was the same as the orderof th e rates of dissolution of t he different forms invitro as their da ta show. The faster th e salt dis-solved in vitro a t pH 2 or 4, th e higher was th e aver-age peak plasma level. In this case, as in someothers, the order of the ra tes of dissolution of such


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Vol. 50, N o . 5 , M a y 1961dissolution would help keep C small in relation toC From in vitro da ta a plot of W / Sagainst t shouldyield a straight line with slope, KC,, having thedimensions mg./cm.*/hr. if W is in mg., S in cm.2,and t in hours. KC, is the initial rate of dissolutionand is the rate used by Nelson (64, 66, 67) and byW. I. Higuchi, et al. (29), in their plots. Hence, assta ted before, the initial rat e of dissolution is directlyproportional to the solubility of the drug in thedissolution medium as it exists on the solid side ofthe diffusion layer.By aor king a t pH values above those where thereare significant amounts of protonated form, Nelson(64) treated theophylline as a monobasic acid. Heobtained a linear plot by plotting the initial rate ofdissolution per unit surface area, i.e., KC., againstl+K,/[H+]d. Here K , was the acid dissociationconstant of theophylline and [H +] was obtained bymeasuring the pH of a saturated solution obtainedby adding theophylline to the buffer or dissolutionmedium at constant temperature. The [H +] insuch a saturated solution was considered to be thediffusion layer pH. If the profiles hypothesized byW. I. Higuchi, et ul. (29), are correct then no definitepH can, apparently, be assigned to the diffusionlayer. The pH will vary with the exact positionin the film. Certainly th e pH of the diffusion layerwhich Nelson describes is probably that pH righta t the interface of th e solid and t he diffusion layer.Hence this is really a problem in semantics.As Nelson (64) has shown, the tota l solubility, C,of a weak acid, HA, is given by:

369is th e most frequent cause of changes in acidity ofthe stomach. As his charts show, however, the highacidity is usually recovered within a short time afterthe meals are eaten.

In man the duodenal contents are usually in therange pH 5 to 7. This pH range corresponds to from10 to 0.1 microequivalents of hydrogen ion per L.,respectively. There is a gradual decrease in acidityin moving from the duodenum to the ileo-cecalvalve, ranging from approximately p H 5 t o 6, on theaverage, in the duodenum to about pH 8 in thelower ileum. This pH range corresponds to achange in hydrogen ion concentration of from about1 to 10 microequivalents per L. to about 0.01 micro-equivalents per L. The intestinal pH of the dog isvery comparable to tha t of man (77-79).

From the above it may be concluded that whena drug or its dosage units move from the stomachthrough the pylorus to the duodenum there is avery abrupt and marked change in acidity in prac-tically all human subjects or patients. The transferof a given particle, granule, or aliquot of solutioncontaining the drug through the pylorus takes only afraction of a second. However, as indicated below,the individual particles, granules, or aliquots ofthe solution from a given dose of the drug mayempty from the stomach over a prolonged periodof time. The abrupt change in acid ity noted abovecannot be stressed too much. For example, if thestomach contents havea p H of 1 and the duodenalcontents a pH of 6, then the difference in acidity oncrossing th e pylorus in terms of pH units is 5, but interms of hydrogen ion concentration is 99,999 micro-equivalents per L. and the difference in terms ofhydroxide ion concentration is 0.009 microequiv-alents per L.

However, if the duodenal contents have a pH of6 and the contents of the lower ileum have a pH of8, then the difference in terms of pH units is 2, butin terms of hydrogen ion concentration is only 0.99microequivalents per L. and the difference in termsof hydroxide ion concentration is only 0.99 micro-equivalents per L. Hence, th e magnitude of t hedifference in hydrogen ion concentration between thestomach and th e duodenal contents is very large anddwarfs th e relatively small change in hydrogen ionor hydroxyl ion concentration between th e duodenalcontents and t he lower small intestine.

Stomach Emptying Rate.-Gastric emptying interms of emptying time, th at is the time taken for thewhole or some recognizable consti tuent of a test mealor dosage form to leave the stomach, does not givemuch insight into the pat tern or kinetics of emptying(80). In 1898 Marbaix, in essence, indicated thatthe stomach empties by a pseudo first-order process;that is, the volume of meal remaining =(volume a tzero time).exp.-R't. Subsequently, this has beenverified in man (80) and the ra t (81). In some casesthere is a lag time before the stomach starts toempty; or there may be an initial faster pseudofirst-order rat e then a slower pseudo first-order rateis subsequently established. James (71) reviewedth e following factors influencing emptying of fluidtest meals from th e stomach of man: ( a ) Serial testmeals of different volumes have indicated th at onceth e exponential ra te of gastric emptying had beenestablished, the half-lives were longer for largermeals. However, the initial emptying ra te wasrelatively much larger for the larger meals. ( 6 )

C = [HA] + [A- ] = [HA] + [HA] .3[H +Iwhere [HA] is the intrinsic solubility of the nonion-ized form of the acid, usually determined a t verylow pH , [A-] is th e concentration of ionized acid,[H+] is the hydrogen ion concentration of thesaturated solution, and K , is the acid dissociationconstant.

GASTROINTESTINAL ABSORPTIONGastroin tes tinal Physiology.-A recent review byHogben (68) on the alimentary trac t emphasizes thephysiology of absorption and secretion. It ispertinent in this review to discuss those factors ingastrointestinal physiology which may be impor-ta nt in the absorption of drugs and in the mechanismof action of certain types of dosage forms.pH.-In man th e stomach contents are usuallyin the pH range 1 o 3.5 and pH 1 o 2.5 is the mostcommon range (69-76). The pH range 3. 5 to 1corresponds to from 320 to 100,000 microequivalentsof hydrogen ion per L., respectively. pH is not avivid way of expressing th e high acidities reached

in the stomach. This is clarified by a studyof Table I. It is easy during the stress and strainof a laboratory day to forget what the pH scalereally means. As an example, one should not aver-age pH values but convert to uH+ by the relation-ship, a,+ = 10-p". Average the uR+ values, thenif you wish, and reconvert to the pH scale. Jamesand others (71) have shown that during the nightthe human stomach usually has a low acidity (pH1 to 3) and that during the day the taking of meals


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370The exponential ra te was not continued to t he end forlarger meals, but the last portions tended to emptymore rapidly. This final phase started when th evolume of the meal retained in th e stomach was100 to 300 ml. for the meals of 1,250 ml., but only20 ml. when th e initial volume of the meal was 750ml. It was not seen at all with meals of 330 ml.initial volume. (c ) The osmotic pressure of t hemeal has an effect. For example, addition of sucrosein relatively large amounts t o a fluid test meal usuallycauses a more rapid initial stomach emptying butonce the exponential rate is established the rateis much slower when the subjects ate sucrose. ( d )Cold meals tend to empty faster than hot meals.( e ) The composition of th e tes t meal influences therate. ( f ) Most investigators are also agreed that agiven individual tends to be true to his type withrespect to gastric emptying rate.

Borgstrom, et a l. ( 7 3 ) ,found that a 500-Gm testmeal containing carbohydrate, fat , protein, and waterwas delivered from the stomach of human subjectsto th e duodenum in small portions over a four-hourperiod with a maximum amount during the secondhour. Other investigators have obtained similarresults (76, 82, 83), although healthy medical stu-dents appear to have more rapid stomach emptyingrates, probably due to increased mental pressures.Stomach emptying of larger solid units, such aslarge granules or tablets, appear to follow the samesor t of rules, but often the reported emptying t imesare longer and over a wider range. I f there is onlyone unit , such as an enteric coated or delayed action(laminated) tablet, we may be dealing with an all-

or-none effect. If the single enteric coated tabletstays in the stomach, the patient gets no medicine.If it is laminated, the outer dose dissolves rapidlyin the stomach but the inner dose, if protected by anenteric coating, may leave the stomach right awaygiving a double dose of drug, or it may st ay in th estomach anywhere from zero to twelve hours.Hence, the idealistic picture painted for such singleunit enteric medication is not supported by thescientific facts. However, if th e dose of drug isdivided into a large number of units, which stay in-tact in the stomach, then stomach emptying is grad-ual (84-86) and extends over a period of time prob-ably comparable to that following a meat meal orlonger. The net effect is th at medication is deliveredto t he absorption sites from the time of administra-tion, and continues to be delivered over a consider-able period of time postadministration. Bloodlevel studies in man with prednisolone in coatedform, where the dose was distributed amongst alarge number of individually coated units, indicatedthe above also (8).

For single enteric coated tablets administered tolarge numbers of human subjects, and followedby roentgenography or roentgenoscopy, the reviewerhas found tha t most of these sets of da ta in the litera-ture give one or two linear segments on normal prob-ability or logistic ruling graph paper. In construct-ing such plots one plots the cumulative percentageof tablets emptied from the stomach on the probabil-ity axis, or on the logistic axis, and the time, inhours, on the normal arithmetic axis. The da taare usually well represented by only one or twostraight lines. If only one line is obtained on logisticruling paper then t he equation of th e lines is given by(87):

Journal of Pharmaceutical Sciencescumulative yoof tablets emptied =

(m.5 )1001 + Antilog ( K - /f )where t is the time in hours, K is the time when 50%of th e tablets have emptied, and f is the slope factor,or a characteristic of t he spread of the plot. Theda ta of Bukey and Brew (88,891, Crane and Wruble(go),and Blythe, et al . (91), obtained by administra-tion of enteric coated tablets to human subjects,and the da ta of Wagner, et al. (92), obtained by ad-ministration of such tablets to the dog, all givelinear plots on either normal probability or logisticruling graph paper. These results strongly suggestth at th e emptying of single enteric coated tablets isjust a matter or probability and tha t one can explainth e results by the laws of probability. If one ex-trapolates this knowledge to the situation discussedabove, where a large number of individual units areadministered a t one time, with the drug dose dis-tributed amongst them, one could deduce that theunits would empty from the stomach also accord-ing to t he laws of probability. If they should emptyby a pseudo first-order rate, like liquid meals, thisshould not be too unexpected since the first-order rateconstant is a probability function. In this case,however, medication is being constantly deliveredto t he absorption sites and one does not get the all-or-none effect observed with enteric coated tablets.Because of th e above, it is qui te unscientific toaverage blood levels observed after administrationof single enteric coated tablets to large groups ofindividuals. However, it is perfectly acceptable toaverage blood levels following administration of aproduct where the dose is distributed amongst alarge numhcr of coated or uncoated units, such asgranules. Support for th e extrapolation of theda ta obtained on enteric coated tablets administeredto many different subjects to administration of alarge number of units which st ay intact in the stom-ach of one individual is given by the da ta of Deeband Becker (86). These authors showed that dl-amphetamine sulfate coated granules and d- and dl -amphetamine resin complex administered to ratswere emptied from the stomachs of the rats over verylong periods of time extending beyond fifteen hours.When their average percentage residual amphet-amine in the stomach was plotted on a logarithmicscale against time in hours, the different preparationsgive two to four linear segments. Even their con-trol, &amphetamine sulfate administered in 0.5%sodium carboxymethylcellulose, was not emptiedcompletely in an eight-hour period. The authorsfailed to mention that amphetamine sulfate andsodium carboxymethylcellulose would interact toform a poorly soluble salt-complex and that thisprobably influenced their control results. In fact,one of the sustained action products of amphetaminemarketed is just the interaction product cited above.Field, et al. (93), working with Resodec, stated thatthere was a delay in the stomach emptying of t heresin in dogs followed by a relatively rapid passagethrough t he intestines. In this case, the ammoniumand potassium ions on the resin product Resodecwere all exchanged for hydrogen ion while theresinate was in the stomachs of t he dogs.When a sulfonic acid resin and an amine drugare combined to give a resinate the following re-actions would be important both in vitro and inv izv .


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Vol. 50, No. 5 , M a y 1961+ - +R-SO$-HaN-R + X + $ R-SOIX +

amine drug resinate resin in acid cycle

371strongly basic resin by hydroxide ion. Rapidemptying of the acetylsalicylate ion in solution,followed by rapid absorption of th e resulting mole-cules in the intestine, or absorption of nonionizedacetylsalicylic acid in the stomach, would reduce theti ter of free drug in solution and drive all the drugoff the resin quite rapidly.

Other Important Factors.-Mucin may bind somedrugs, particularly drugs which are highly basiclike quarternary ammonium compounds, and inhibitabsorption of th e drug (94). Cavallito, et al., madesuggestions which may circumvent such binding(95, 96).The length of the intestinal tract is important inth e absorption of drugs since the dose must havetime to be absorbed, particularly if the dissolutionra te is low. Hirsch, et al. (97), reported variousintestinal distances which were determined on livinghuman subjects. These are considerably shorterthan the classical ones quoted in textbooks which

were determined on cadavers. The averages shownin Table I1 were calculated from these da ta . Esti-mates of the surface area involved in the gastro-intestinal tract were given by Edwards (65). Heestimated that 500 ml. of liquid in the small bowelwould occupy a length of intestine of the order of100 cm. bounded by a n area of about 700-800 sq.cm. Since the villi increase the apparent area by afactor of about four, the effective area of absorptionin this section is about 3,000 sq. cm. The effectivethickness of th e epithelial layer may be taken as 25p. On the other side of the membrane an adultcirculates about 3,000 ml. of blood plasma in abouthalf a minute.

IR/-NHdrug in solution (E q. 26)+R-S03-HaN-K 4- Y- ~ R-soa- f

amine drug resinate resin in basic cycleR-NH2 + HY

free base of amine drug (Eq. 27)Where X + s H + or another cation; and Y- is OH-or another anion.Similarly when a quaternary ammonium, or terti-ary amine type of exchange resin, is combined withan acidic drug to give a resinate, the following re-actions would be important both i n v it ro and in vivo.(R)a-kH-OOC-R +

resinate0//x+ e (R)~-&H + R-c-o-x+

resin in drug inhydrogen cycle solution (Eq. 28)(R)~-&H--OOC--R +

resinate0//Y- (R)s-N + R-C-O- + HYfree baseform of resin drug insolution (Eq. 29)

The positions of the equilibria depicted above willdepend upon the effective pK a or pKb of th e resin,the pKa or pKb of the drug involved, and the con-centrations of hydrogen ion and other cations in thestomach and t he concentrations of hydroxyl ion andother anions in the intestines. Amphetamine has apKb of 4.23 at 25 hence will be about 99% ionizedin solution a t pH 2.23 and about 99% as the free basea t p H 6.23. Sulfonic acids are extremely st rongacids. One would expect an amphetamine-sulfonicacid resinate to be quite stable in the stomach,which in terms of the above, means that the firstequilibrium (Eq. 26) would be expected to be far tothe left. However, once the resinate is emptied intothe intestine where the pH is between 6 and 8, thesecond equilibrium above goes far to the rightand the amphetamine is released as the freebase. Since absorption would occur very rapidly,the tite r of free amphetamine base would bevery low in the intestinal contents. These con-siderations possibly aid in explaining the resultsof Deeb and Becker (86) and of .Chapman,Shenoy, and Campbell (25). In the case ofcreatinine, however, Chapman, et al. (25), reportedno sustained effect from the resinate. Creatinineis a very weak base with a pKb about 10.5 at 40.Hence, one would not expect the sulfonic acid-creatinine resinate to be stable a t most stomachpH values. Similarly, acetylsalicylic acid has a pKaof 3.49 at 25. Therefore, even a t low pH valuesobserved in the stomach, one would expect much ofthe acetylsalicylic acid to be displaced from a

TABLE I.-AVERAGE LENGTHSOF INTESTINALSEGMENTSF TENPATIENTSF WnoM FIVEWEREOBESE~AverageValuesBody height 163 cm.Body weight 85 Kg.Distance from nose to anus 453 cm.Distance from nose to pylorus 64 cm.Distance from nose to ligament ofTreitz 83 cm.347 cm.istance from nose t o ileo-cecal valveLength of duodenumLength of jejunoileumLength of colonTotal small intestine

21 cm.261 cm.109 cm.282 cm.Calculated from the data of Hirsch J. Ahrens E. H.Jr., and Blankenhorn. 0.H. , Gasfroenter&&, 31, 27k(1956):

The ionic composition of the contents of the var-ious parts of the gastrointestinal tract may be im-portant in the absorption of certain drugs. For ex-ample, if t he drug formed a nonabsorbable chelatewith a metal ion, such as magnesium or calcium,then the amount of drug available for absorptionwould depend upon concentration of t he metal ion,the pH, and the concentration of drug in the tract.The ionic composition of the contents of the varioussegments of t he gastrointestinal tract is shown inTable I11 (75). Bernstein (74) gives the altera-tions in electrolyte pattern of the gastric juice inhealthy male adults following various stimuli com-pared with prestimulation levels. The stimuli wereinsulin, histamine, alcohol-histamine, and adrenalin.


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372 Journal of Pharmaceutical SciencesThe site of absorption of some drugs is also impor-

tant . Normal food appears to be absorbed very highup in th e small intestine. The absorption of fat,carbohydrates, and protein begins in the distal par tthe duodenum and is generally complete in thefirst 50 to 100 cm. of jejunum. The site is a littlehigher up for fat than for glucose and protein.Thus, the absorption of these foodstuffs occurs inthe proximal 20 to 40% of the length of the smallintestine (73). Similarly, some vitamins appear tobe absorbed in the proximal part of the smallintestine. The amount of ascorbic acid absorbed inone hour from a segment terminated 45 cm. beyondthe pylorus was not singificantly different than fromthe amount absorbed in the same time from a seg-ment terminated 90 cm. beyond the pylorus (98).The studies of Campbell, et al. (26, 99, loo), indicatethat riboflavin is also absorbed in the proximal partof the small intestine and is either decomposed ornot absorbed in the distal small intestine or largeintestine. Vitamin Biz, on the other hand, appearsto be absorbed throughout the tract (101) but thefraction of t he dose absorbed is very small (102).Bothwell, et al. (103), claim that ingested iron isabsorbed in th e ferrous form largely by the duodenumand that the excretion of absorbed iron into the gu t isnegligible. Using balance studies on large numbersof children, Schulz and Smith (104, 105) showedthat only an average of 10% of iron in food and foodsupplements was absorbed in normal children;however, iron-deficient children absorbed two tothree times as much food iron as did normal children.Similarly, only 12 to 15% of the 30 mg. largesttolerated dose of radioiron ferrous sulfate, givenonce or twice daily, was absorbed by normal children;iron-deficient children absorbed somewhat more(105). These studies seem to throw considerabledoubt a s to whether multivitamin products, with andwithout iron, should be administered in slowlydisintegrating or releasing dosage forms, especiallyof th e sustained action type (26). Many drugs,however, are absorbed both in the stomach andthroughout the small intestine. This seems to beparticularly true of drugs which are weak organicacids, weak organic bases, and their salts (23,94, 106,107). Salicylic acid has been shown to be absorbedthroughout the tract including the stomach, smallintestine, an d large intestine (94, 106). The resultsof Campbell, Nelson, an d Chapman (23) indicatetha t amphetamine,a weak base, is absorbed through-out the small and large intestines; in this case thestomach was excluded by the reviewer because ofthe results reported by Schanker (94). Nelson (107)has shown that 95 to 100% of an administered doseof tolbutamide is absorbed in human subjects.Similarly, Swintosky,etal. (108), reported tha t nearly100% of a n intravenously administered dose ofsulfaethylthiadiazole could be accounted for in theurine within seventy-two hours; when the drug wasgiven as a powder in hard gelatin capsules, an aver-age of about 93% of th e oral doses was absorbed.Many neutral molecules, such as the steroids, appearto be well absorbed also.There have been reports that the rate of absorp-tion of certain compounds is different in differentsegments of the intestinal tract. Fo r example,Cummins and Jussila (109) reported tha t glucoseand urea were absorbed very much faster in theupper than in the lower small human intestine.

L t j W i O ( D u 3 ' m


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Vol. SO , N o. 5, M a y 1961These studies were done by an intubation techniquewith solutions of the compounds. I t is possible th atall the authors were measuring were the differencesin apparent surface areas of the different segments.No kinetic measurements were done; only th eamount absorbed in thirty minutes was determined.Unless kinetic studies are done and t he effective sur-face areas known, one should probably not statethat ra tes of absorption are different. I t is possi-ble that with solutions of chemicals or drugs, sur-face area of the absorbing segment is the rate-limiting factor. With fine powders, both dissolutionrate and surface areas of the powder and th e segmentmay be involved, but the former is probably rate-limiting in most cases. With restricted surfacearea of the drug, such as in sustained or prolongedaction products, then the surface area of drug ex-posed and/or ra te of diffusion of drug from the prod-uct is rate-limiting the absorption process in mostcases. If a coating is involved the situation is morecomplex and much more difficult to interpret.

The actual mechanism of absorption b y the in-testinal epithelium has been th e subject of a greatdeal of study, particularly in the past few years.The review of Schanker (94) discusses many ofthese. Apparently, we can exclude active transportwhen considering th e absorption of most drugs.Recently it has been shown that most drugs areabsorbed by a simple diffusion mechanism. Theabsorption of some very large molecules and par-ticles, however, may not occur by a process of simplediffusion. Clark (110) demonstrated th at proteinsand colloidal materials administered orally tosuckling rats and mice were ingested by columnarabsorptive cells of the jejunum a nd ileum, but notby the duodenum. Clark (110) postulated th atingestion of the foreign materials was accomplishedby pinacytosis; th at is, by invagination of th e apicalcell membrane t o form vacuoles containing materialfrom the intestinal tract. Farquhar and Palade(111) showed th at ferritin molecules are absorbedin a similar manner and are transformed intodense bodies or droplets in the size range 0.5 to 2 p.There have been two reports (112) that insulin,administered orally to suckling rats two to eightdays old, causes a large drop in blood sugar levels.The same effect does not occur in twenty-one tothi rty day old rats. Both Clark (110)and Farquharand Palade (111) reported th at absorption of thelarge molecules with which they worked only oc-curred in young animals also.The pH-PartitionHypothesis.-In 1902 Overton( 113) demonstrated t ha t a number of organic com-pounds penetrate cells at ra tes roughly related totheir lipid/water partition coefficient. He con-cluded that the cell membrane is lipoidal in nature.For the next fifty-five years th e literature concerningabsorption and transport appeared to be mainly con-cerned with active transpor t and facilitated diffusion.In 1937 Huber and Huber (114) reported that cer-tain groups of similar compounds were absorbedfrom intestinal loops of the rat a t rates roughlyproportional to th e size of th e molecules. However,in each of these groups the rate s of absorption werealso related to the relative lipid/water parti tion co-efficients. The absolute amount of polyhydricalcohol or al iphatic acid amide absorbed was directlyproportional to the concentration in the intestinallumen; the percentage absorption remained con-stant over a wide range of concentrations. These

373and other experimental data indicated that theforeign molecules were absorbed from the intestineby a process of simple diffusion through a lipoid-sievety pe of boundary. Travel1 (115) in 1940noted thatlarge doses of alkaloids produced no toxic effectswhen the gastric contents were highly acidic. Whenth e gastric contents were made alkaline the animalsrapidly died, indicating that only the undissociatedfree bases of th e alkaloids were absorbed. This wasthe first indication that the gastric epithelium isselectively permeable to the undissociated form of adrug. Later, Shore, et al. (116), showed thatparenterally administered drugs are secreted directlyinto gastric juice. Th e concentration ratio (con-centration of d rug in gastric juice divided by con-centration of d rug in plasma) depends on the dis-sociation constant of the drug. Strong organic acidsappear in gastric juice in negligible concentrations,weak acids and bases in measurable concentrations,and strong bases in highest concentration. Theamount of the strongest organic bases transferredfrom the plasma to th e gastric juice is limited by therate a t which the drug is delivered to the gastricmucosa, i.e., by the r at e of gastric mucosal bloodflow. Th ed at a of Shore, et el. (116), were explainedby the concept th at the membrane separating plasmafrom gastric juice has the characteristics of a lipoidmembrane t ha t allows the passage of drugs in theirundissociated form while restricting passage of thedissociated form.

Brodie, Hogben, Schanker, Shore, and Tocco (117-121) developed the pH-partition hypothesis whichis a great advance in explaining th e rate and extentof absorption of acidic and basic drugs from th estomach and intestines of the ra t and the humanbeing. Their investigations and results wererecently reviewed by Schanker (94) and will not beextensively discussed in this review. The concepthas also been applied to the kinetics of penetration ofdrugs and other foreign compounds into cerebro-spinal fluid and t he brain (122).

Prior to the perfusion experiments in ra ts carriedout by Brodie, et el. (117-121), the intestine wascleared of a ll particulate matter by perfusion withdrug-free solutions for thirty minutes, and thenperfused with drug solution for thirty minutes todisplace th e washings. Although i t was not men-tioned by the authors, such treatment would mostprobably remove some of t he mucus or mucosub-stance (123) from the stomach wall and intestines.Their results would not include th e effects of inter-action of a given drug with mucus. Th e effect of foodon absorption of a given drug is also excluded by thenature of their experiments.

Complete understanding of the pH-part ition hy-pothesis requires reading the original manuscripts ofBrodie, et al. (117-121). Only a few of the most im-portan t aspects will be discussed here. For mostdrugs with molecular weights greater than 100,penetration through pores is relatively unimportant(119). Foreign organic substances penetrate themucosa as though th e boundary had the character-istics of a lipoid barrier. The passage of drugs acrossthese barriers is governed mainly by physical proc-esses and is predictable from the dissociation con-st an ts and the lipid-solubility of th e undissociatedmoiety (120). The drugs ar e absorbed by thepassive diffusion of the unionized form. In certaincases, such as quaternary ammonium compounds,


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374the intestinal mucosa may be slightly permeable toorganic ions (120). Th e pH at the site of absorp-tion is not necessarily the same as t he pH of thecontents in the center of t he intestinal lumen.Hogben, et a l. (120), calculated a virtual pH atthe site of absorption of 5.3, although the pH of theperfusion fluid on leaving the intestine was 6.6.This virtual pH is to a considerable extent, butnot completely, independent of the pH of t he bulksolution within th e lumen. In th e case of solutionsof drugs in the intestines, diffusion from the centerof the intestinal stream to th e intestinal wall becomesthe rate-limiting step when absorption is veryrapid. For this reason th e proportion of unionizedmoiety only becomes a rate-limiting factor when itis less than a critical value. For example, in the caseof salicylic acid the permeability of the mucosa issuch that the critical proportion is unionized : ionized= 1 : 200. When the ratio is greater tha n 1 :200,th e maximal rate of absorption of salicylic acid isattained (120). The relationship between th e lipidsolubilities of the unionized drug moieties and theirrates of intestinal absorption suggests that theintestinal blood barrier is lipoidal in nature. This isclear-cut for the highly lipid-soluble and verypoorly lipid-soluble drugs but is no t as clear-cut forcompounds of intermediate lipid-solubility. Thereason for the latter may be that the solvents usedto estimate the partition coefficients (chloroformand heptane, for example) are not the proper sol-vents. We need to know more about th e boundarysince any one solvent would not be expected to belike the boundary (120).

Schanker, et al. (119), pointed out that furtherevidence of a physical process in absorption wasseen in the failure of one drug to al ter the absorptionof another . They indicated tha t drug binding tonondialyzable materials in the intestinal perfusatewas less than 4% for most of the drugs investigated.However, true complex formation between twodrugs, or a drug and an adjuvant, may be expectedto alter absorption rate since the diffusion coef-ficients and solubilities of the complexes ma y bedifferent than the drug itself. Thus, individualdrugs should be studied as individual entities.One cannot generalize.The pH-partition hypothesis was applied to theabsorption of heparin recently (124, 125). When theinitial pH of the intestinal lumen of the dog wasabout 4.0, absorption of approximately 10% ofinstilled heparin occurred. During th e experimentthe pH returned to near neutrality and absorptionceased, The authors claimed tha t under normalcircumstances heparin absorption would be expectedto be limited to the stomach. Salafsky and Loomis(125) partially esterified heparin with methanol togive a product still possessing anticoagulant ac-tivi ty. Perfusion studies on this compound showedlimited but appreciable absorption of the ester did

occur from the duodenum.Although amine drugs are transferred readilyfrom plasma to gastric juice, as indicated above, th eactual amounts present in the stomach at anygiven time is small compared to the tota l amount inthe body since the volume of fluid in the stomach isvery small compared with the volume of the otherfluids of distribution. Th e quantitative aspects ofth e diffusion of weak acids and bases from plasmato gastric juice and urine was reviewed by Milne,

Journal of Pharmaceutical SciencesScribner, and Crawford (126). Further applicationof t he pH-partit ion hypothesis is presented in thesection on Percutaneous Absorption.

Factors Affecting Rate and Extent of AbsorptionUnder Normal Physiologic Conditions in Man andAnimals.-A review of the literature (127) indicatedthat the following factors may possibly influence rateand extent of intestinal absorption. Factors involv-ing the membrane or barrier: ( a ) special propertiesor vital functions of the epithelial cell; ( b )perme-ability of t he membrane; ( c ) electrical phenomena(th e magnitude and sign of the charge); ( d ) seg-mental activ ity of the bowel; (e) the absorbingsurface area per unit length of g ut ; (f) the degreeof villous activity; (g ) the degree of vascularity.Factors involving the substance absorbed: ( h )th e geometry an d functional groups of t he substance;(i) he presence or absence of a charge and its signand magnitude; ( j ) he diffusibility of the solute ;(k) he solute concentration on the two sides of t hemembrane; ( I ) the molecular size or molal volumeof the solute; (nz) the particle size of the substanceand its physical state; ( n ) the lypophilic andhydrophilic properties of the substance; ( 0 ) thesolubility and rate of dissolution of the substance.Miscellaneous factors: ( p ) the temperature; ( a )the gradient of absorbability down the tract; ( r )hydrostatic and intraintestinal pressure; (s) surfaceand interfacial tension; ( t ) pH of t he intestinalcontents; ( u ) enzymatic activity; ( v ) the concen-tration of simple ions in the intestinal contents;( w ) he presence or absence of mncus, complexingagents, emulsifying agents, etc.; ( x ) the grossanatomical position and relative activity of thesubject; ( y ) competition between molecules forabsorption; (2 ) the emptying ra te of the substancefrom the stomach.

Man y of these factors may be operative duringthe absorption of a given drug under normal condi-tions of its use in man. To study properly therelative importance of some of these one mustcontrol certain variables during experiments andinvestigate t he effects of certain changes in othervariables, such as was done by Brodie, et al. (107-121), in developing their pH-parti tion hypothesisfor acidic and basic substances. Many clinicaland pharmacologic reports in which the absorptionof two or more drugs, or the absorption of onedrug in the presence or absence of an adjuvant,have been compared are deficient in specifyingimportant facts which may have a bearing on theinterpretation of the results. In many cases authorshave reached conclusions which are not justified bythe data they present. A paper presented byNelson (128) a t a recent symposium, which will bepublished in the near future, reviews a number ofsuch reports. Hence these will not be consideredin this review. Instead, some examples where agiven variable has been isolated and shown to beimportan t in the absorption of the substance willbe presented.

Hydrolysis of Substances in the GastrointestinalTract.-If th e drug contains a linkage susceptible tohydrolysis it may, or may not, be hyrolyzed be-fore absorption. Flavin mononucleotide (F MN)and Aavin adenine dinucleotide (FAD) were studiedby Okuda (129). Homogenates of th e small in-testine rapidly dephosphorylated FMN probablydue to phosphomonaesterase in the mucous mem-


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Vol.50, No. 5, M a y 1961 375ten thousand times more rapid than tolbutamide inthe same medium. In buffered mediums of nearneutral pH about a two hundredfold differenceexisted in favor of th e salt. These large differencesmeasured in oitro reflect the differences observedbetween tolbutamide sodium and tolbutamidein vivo when administered t o normal human subjectsas shown in Fig. 3 (137). Tolbutamide sodium,administered orally, produces a very rapid fall inblood sugar comparable to tha t produced when thesame salt is administered intravenously to normalsubjects (138). The more slowly dissolving weakacid, tolbutamide, administered as the commercialcompressed tablet, produces a smooth, sustainedfall in blood sugar level, as the plots show. From95 to loo% of the doses of both tolbutamide,administered as the commercial compressed tablet,and its sodium salt, administered as compressedtablets, are absorbed following oral administration(107). Similar effects of different salts of theoph-ylline (64), tetracycline (66) and penicillin (63)were discussed before. Lee, et al. (139), reportedthat the potassium sal t of penicillin V producedhigher and earlier blood levels and was betterabsorbed in the stomach than the free acid. Wrightand Welch (140) reported similar results in fastinghuman subjects. This undoubtedly reflects largedifferences in dissolution rates of the potassium saltand the free acid in th e stomach contents.

brane. FAD was decomposed also to FMN andriboflavin. In pancreatic juice, free riboflavinwas not decomposed but F M N was about 45%dephosphorylated t o free riboflavin during twohours incubation at 37. Long, et al. (130), reportedthat the limiting factor governing absorption ofpropylene glycol distearate in the rat is the hy-drolysis ra te of the ester in the tract . Similarly,Vahouny and Treadwell (131) reported d at a whichwas in agreement with the concept that dietarycholesteryl esters are hydrolyzed in t he gastro-intestinal trac t prior t o absorption of th e cholesterolmoiety as free cholesterol. Glazko, et al. (132),did an excellent study with various esters of theantibiotic chloramphenicol. They found th at th eesters had to be hydrolyzed enzymatically beforeabsorption occurred; their da ta indicated thatdissolution rate and surface area were rate-limitingthe absorption process. It was reported that thebest blood levels were produced by dissolvingchloramphenicol palmitate in dimethylacetamideandinjecting the solutions forcibly into equal volumesof water containing 10% of polysorbate 80. Underthese conditions one would expect an extremelyfine dispersion of th e ester with a large surfacearea. On th e other hand, Blough, et al. (133),reported that in man 80% of t he propionyl eryth-romycin excreted in the urine exists as the intactbut inactive ester. Cope and Black (134) statedthat CI4-cortisone acetate is absorbed and excreteda t almost th e same rate as (214-cortisol; and thatonce absorbed th e former is readily converted intothe latter. The paradoxical dependency of theeffectiveness of A4-3-keto steroidal en01 ethers onth e route of administration was reported b y Ercoliand Gardi (135). The ethers were stated to haveenhanced oral activity compared with the parenthormones, bu t greatly decreased parenteral activity.These authors failed to mention the possibility thatthere may be a difference in hydrolytic rates ofthese ethers in th e gastrointestinal trac t comparedwith that in parenteral depots and that this maypossibly explain the differences.Dissolution Rate.-In a recent review (136) it wasstated t ha t: different sa lts of the same drug rarelydiffer pharmacologically; the differences are usually

based on physical properties. The authors thencited examples, and, unfortunately, includedchloramphenicol palmitate, which is an ester andnot a salt. Perhaps qualitatively, i. e., in the natureof th e biological response elicited, a series of saltsof th e same acidic or basic drug may n ot differappreciably. However, quant itatively there may bevast differences. The observed difference betweena weak acid or base and its salts,or between differentsalts, will be th e intensity of biological response inrelation to time after administration. This mustfollow from the fundamental factors consideredbefore. Each drug must be studied as a separateenti ty and t he effects of administration of th e weaklyacidic or basic drug itself, and of various salts,observed. Few generalizations can be made becauseof the large number of variables involved. How-ever, as Nelson (64) pointed out, the dissolutionra te of t he particular form largely determines thera te of build-up of blood level with time and themaximum blood level attained. Nelson (128) re-ported that, in ritro, the initial dissolution rate oftolbutamide sodium in acidic medium was nearly

% 6 O J , , , , , , , , , 10 I 2 3 4 5 6 7 8 9 10J T i w I N nounsFig. 3.-Illustration of the effect of difference indissolution rates of a weak acid an d its sodium salton the nature of the biological response-time plot.Day No. 1, 0--placebo, six normal subjects;

A- C . T. Orinase, 1.0-Gm. dose administered astwo tablets, 10normal subjects; x C. T. Orinasesodium, dose equivalent to 1.0 Gm. of Orinase ad-ministered as four tablets, 5 normal subjects. DayNO.2, * placebo, five normal subjects; x-.-.-.C. T. Orinase sodium, dose equivalent to 1.0 Gm. ofOrinase administered as four tablets, seven normalsubjects.In some cases physical form is exceedinglyimpor

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