Pharmaceutical Research, Vol. 12, No. 3, 1995
`
`Report
`
`A Theoretical Basis for a
`
`Biopharmaceutic Drug Classification:
`The Correlation of in Vitro Drug
`Product Dissolution and in
`
`Vivo Bioavailability
`
`Gordon L. Amidon,” Hans Lennernas,3
`Vinod P. Shah,‘‘* and John R. Crisons
`
`Received March 10, 1994; accepted October 3, 1994
`
`A biopharmaceutics drug classification scheme for correlating in
`vitro drug product dissolution and in viva bioavailability is proposed
`based on recognizing that drug dissolution and gastrointestinal per-
`meability are the fundamental parameters controlling rate and extent
`of drug absorption. This analysis uses a transport model and human
`permeability results for estimating in vivo drug absorption to illus-
`trate the primary importance of solubility and permeability on drug
`absorption. The fundamental parameters which define oral drug ab-
`sorption in humans resulting from this analysis are discussed and
`used as a basis for this classification scheme. These Biopharmaceutic
`Drug Classes are defined as: Case 1. High solubility-high permeabil-
`ity drugs, Case 2. Low solubility-high permeability drugs, Case 3.
`High solubility-low permeability drugs, and Case 4. Low solubility-
`low permeability drugs. Based on this classification scheme, sug-
`gestions are made for setting standards for in vitro drug dissolution
`testing methodology which will correlate with the in vivo process.
`This methodology must be based on the physiological and physical
`chemical properties controlling drug absorption. This analysis
`points out conditions under which no in vitro—in vivo correlation may
`be expected e.g. rapidly dissolving low permeability drugs. Further-
`more, it is suggested for example that for very rapidly dissolving high
`solubility drugs, e.g. 85% dissolution in less than 15 minutes, a
`simple one point dissolution test, is all that may be needed to insure
`bioavailability. For slowly dissolving drugs a dissolution profile is
`required with multiple time points in systems which would include
`low pH, physiological pH, and surfactants and the in vitro condi-
`tions should mimic the in vivo processes. This classification scheme
`provides a basis for establishing in vitro-in vivo correlations and for
`estimating the absorption of drugs based on the fundamental disso-
`lution and permeability properties of physiologic importance.
`
`KEY WORDS: bioavailability; drug absorption; mathematical mod-3
`cling; in vitro—in vivo correlation; intestinal permeability.
`
`INTRODUCTION
`
`Drug dissolution is a prerequisite to drug absorption and
`clinical response for almost all drugs given orally. Excep-
`
`1 College of Pharmacy, The University of Michigan, Ann Arbor,
`Michigan 48109-1065.
`2 To whom correspondence should be addressed.
`3 School of Pharmacy, Uppsala University, Box 580, S-751 23 Upp-
`sala, Sweden.
`4 FDA, HFD-602, Rockville, Maryland 20857.
`5 TSRL, Inc. 540 Avis Drive, Suite A, Ann Arbor, Michigan 48108.
`* The manuscript represents the personal opinions of this author
`and does not necessarily represent the views or policies of the
`Agency.
`
`tions to this general requirement such as ‘GI’ drugs, e.g.
`resins, antidiarrials, adsorbants, some laxatives, etc. are not
`considered in this report. While this recognition is obvious
`and correlations between in vitro dissolution and in vivo bio-
`availability for oral products are extensive, comprehensive
`models for predicting oral drug absorption based on drug
`dissolution have been limited (1-5). This is due, in part, to
`the complexity of the processes occurring in the gastrointes-
`tinal tract and in part to the complex pharmacokinetics of
`drugs making it difficult to obtain accurate adsorption esti-
`mates from systemic availability. For example, any effort to
`model the gastrointestinal tract requires consideration of;
`fasted/fed state, cyclical fasted state motility, gastric empty-
`ing and intestinal transit, variable lumen contents; e.g. pH,
`enzymes, surfactants and dietary lipids, as well as drug ab-
`sorption mechanism, permeability, and variation in drug
`physicochemical properties during gastrointestinal transit (6-
`13). Recently we have developed a simplified macroscopic
`approach to drug absorption and demonstrated a good cor-
`relation between the extent of drug absorption and the in-
`testinal membrane permeability in an animal model that is
`mechanism of absorption independent (2). In addition we
`have developed a drug dissolution and absorption model for
`water insoluble drugs that limits to the previous macroscopic
`result under appropriate conditions (3,13). These models
`point out very clearly that the key parameters controlling
`drug absorption are three dimensionless numbers; an Ab-
`sorption Number, An, a Dissolution Number, Dn and a Dose
`Number Do; representing the fundamental processes of
`membrane permeation, drug dissolution and dose, respec-
`tively. In this report we use this approach to set up a theo-
`retical basis for correlating in vitro drug dissolution with in
`vivo bioavailability. This analysis has considerable signifi-
`cance for drug bioavailability and bioequivalence standards
`and in vitro dissolution methodology since it clarifies the
`‘regimes’ of the drug absorption process and offers a basis
`for determining when and under what conditions in vitro-in
`vivo correlations are to be expected. Furthermore, this anal-
`ysis leads to the suggestion that drug bioavailability stan-
`dards should be set on the basis of a Biopharrnaceutics Drug
`Classification scheme that follows from this analysis.
`
`Theoretical Considerations
`
`The fundamental starting point for this analysis is;
`
`‘Iw = PM’-CV0
`
`equation 1
`
`where, Jw(x,y,z,t) is the drug flux (mass/area/time) through
`the intestinal wall at any position and time, Pw(x,y,x,t) is the
`permeability of this (complex) membrane, and Cw(x,y,z,t)
`the drug concentration at the membrane (intestinal) surface.
`This is Fick’s First Law applied to a membrane and applies
`at each point along the membrane (14) i.e. equation 1 is a
`local law pertaining to each point along the intestinal mem-
`brane. It is assumed that sink conditions (drug concentration
`equals zero) exist for the drug inside this complex membrane
`and that PW is an effective permeability. The plasma may be
`assumed to be the physiological sink since concentrations in
`the plasma are generally more than several orders of magni-
`tude below that in the intestinal lumen in humans (15).
`The drug absorption rate, i.e. the rate of loss of drug from
`
`413
`
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`
`414
`
`the intestinal lumen, assuming no luminal reactions, at any
`time is;
`
`Absorption Rate 2 dm / dt = fLP,,,CWdA
`
`equation 2
`
`where the double integral is over the entire gastrointestinal
`surface. The total mass, M, of drug absorbed at time t is:
`
`M(t) = [JL PwCwdAdt
`
`equation 3
`
`These mass balance relations are very general since the sur-
`face can be of arbitrary shape and the concentration at the
`membrane wall and permeability can have any dependence
`on position and time. For full generality the permeability,
`PW, must be considered to be position dependent as well as
`time dependent. The time dependence may be due to a de-
`pendence on drug concentration as in the case of carrier
`mediated transport,
`through indirect effects on the mem-
`brane of other components of the dosage form, or due to
`other physiological or biochemical variations such as mod-
`ulation of tight junction permeability, changes in luminal
`contents, up or down regulation of membrane transporters
`or changes in membrane structure or composition. The per-
`meability is very often position dependent from duodenum,
`jejunum, ileum and colon due to the different morphology
`and mucosal cell differentiation down the intestine e.g.
`amino acid and di/tripeptide transport in the jejunum and
`ileum, but not colon.
`Based on equations 1 and 2 above the following princi-
`ple for bioavailability may be stated:
`
`If two drug products, containing the same drug, have the same
`concentration time profile at the intestinal membrane surface
`then they will have the same rate and extent of absorption.
`
`This statement furthermore implies that;
`
`If two drug products have the same in vivo dissolution profile
`under all luminal conditions, they will have the same rate and
`extent of drug absorption.
`
`These general principles assume that there are no other com-
`ponents in the formulation that affect the membrane perme-
`ability and/or intestinal transit. If that were the case then the
`dissolution standard would have to include specifications for
`the dissolution of those components as well. This second
`statement follows from equations 1 and 2 since the in vivo
`dissolution rate will determine Cw(x,y,z,t). Due to variable
`gastrointestinal transit and lumen contents at time of dosing
`as well as differences in special populations, i.e. differences
`in the gastrointestinal state of an individual, intra individual,
`inter individual and special population gastrointestinal vari-
`ation, variation in the rate and extent of absorption are to be
`expected.
`
`Two aspects of this broad principle are considered in more
`detail below;
`i.) The relationship between in vivo drug dissolution
`and the solution or intestinal wall concentration, Cw,
`and
`ii.) The relationship between the in vivo dissolution and
`in vitro dissolution.
`
`Amidon, Lennernas, Shah, and Crison
`
`In Vivo Dissolution and Luminal/Surface Concentration
`
`The relationship between drug dissolution in vivo and
`the concentration of drug at the absorbing surface of equa-
`tion 2 or 3 is complex due to the complex hydrodynamics
`and contents of the gastrointestinal tract. Various ap-
`proaches to modeling these processes have been taken.
`These include; mixing tank and plug flow models, mixing
`tanks in series and dispersed plug flow models (1-5, 16-19). In
`virtually all models the wall permeability is treated as an
`effective wall permeability and includes an unknown aque-
`ous resistance" That is:
`
`PF = PHPW/(Pa + P”)
`
`Equation 4
`
`PW is the wall permeability discussed above. Pa is the appar-
`ent permeability to mass transport to the intestinal mem-
`brane. A lower limit to this permeability can be estimated
`using a laminar flow hydrodynamic model for the intestinal
`‘fluid’ (20,21). Turbulence due to intestinal wall contractions
`and curvature would lead to large values of P“. For laminar
`flow, P“ is estimated by:
`
`Pu”’(x) = 1.47(D / R)Gz"3 (x / L)‘/3 Equation 5
`
`in a circular tube, under sink conditions in the diffusional
`entrance region (21,22). Assuming a mixing length in the
`human intestine of 10 cm PM is estimated to be 2>< l0’5 cm/
`sec. (~ 0.072 cm/hr)7 in an aqueous fluid (i.e. viscosity of
`water). This represents a lower limit ofPa in this simple fluid
`model.
`
`An alternate line of reasoning however, suggests that P“
`is much larger than the above estimate and not a significant
`resistance to mass transportfor most cases ofdrug absorp-
`tion at least in the upper gastrointestinal tract. For two or-
`ganic molecules the aqueous permeability is principally a
`function of their aqueous diffusivity when the media is the
`same (eqn 5, (22)). Since, the extent of nutrient absorption is
`100 % over less than half of the small intestine, Pa must be
`at least this large in the upper small intestine. The measured
`permeability of glucose (15) in humans is about IX 10” cm/
`sec (3.6cm/hr). This provides an experimental estimate of
`the lower limit of P“ in vivo in the jejunum. Since the aque-
`ous diffusion coefficient of drugs such as ot—methyldopa, ci-
`metidine, or furosemide would be similar to that for nutrients
`such as glucose or the amino acids and their extent of ab-
`sorption is less than 100% it can be concluded that the lim-
`itation to drug absorption is not usually the aqueous mass
`transport coefficient, Pa. The intestinal wall permeabilities
`for drugs that are less than 100% absorbed must be signifi-
`cantly less than that for a nutrient such as glucose or an
`amino acid and Pa cannot be rate limiting for drugs that are
`in solution i.e. high solubility drugs. This implies that PW is
`the determining component in P6,, i.e.
`
`" The major exception to this is for laminar flow models where de-
`fined hydrodynamics are assumed. This is appropriate for more
`controlled intestinal perfusion systems and allows for a more direct
`estimate of the intestinal membrane permeability.
`7 The values used to obtain this estimate: D=5xl0“’ cm/sec, L = 200
`cm, R=l cm, Q=0.5 ml/min.
`
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`
`A Theoretical Basis for a Biopharmaceutic Drug Classification
`
`415
`
`Pg 2 PW(< 100% absorbed drugs)
`
`This indicates that the intestine can be treated as well mixed
`radially i.e. locally and that the intestinal membrane is the
`dominant resistance to drug absorption.
`Based on the above analysis, one would expect to ob-
`tain a good correlation between extent of drug absorption
`and intestinal membrane permeability for high solubility
`drugs that are dosed in solution or for high solubility drugs in
`dosage forms that dissolve very rapidly. Figure 1 shows a
`plot of fraction absorbed in humans vs. measured human
`jejunal membrane permeabilities (23-26). The insert in this
`plot is of Log(l00-F) vs. PW which is expected to be linear for
`a simple plug flow model of intestinal content movement (2).
`From this plot, a drug with a permeability greater than 2-4
`><10“‘ cm/sec or about 1 cm/hr would be well absorbed with
`the expected fraction absorbed being greater than 95%. The
`correlation in Figure 1 is absorption mechanism independent
`since it is measuring the actual mass transfer resistance to
`drug absorption for high solubility drugs (2,l I). This perme-
`ability can be used as a fundamental parameter for establish-
`ing drug properties that will lead to ‘good’ absorption rates.
`The maximal absorption rate occurs when the drug con-
`centration is at its solubility, C‘, and from equation 1 and 3,
`
`This represents solubility limited absorption and assumes
`that the dissolution rate is sufficiently rapid to keep the so-
`lution concentration at saturation.
`
`In Vitro—In Viva Drug Dissolution and Absorption
`
`In order to develop a more quantitative and predictive
`model for drug absorption rates, it is necessary to develop
`(microscopic) models of the flow, dissolution, absorption,
`and reaction processes occurring in the intestine. In general
`this is quite complex. However, a simple model that consid-
`ers a segment of intestine over which the permeability may
`be considered constant, a plug flow fluid with the suspended
`particles moving with the fluid, no significant particle-
`particle interactions (i.e. aggregation) and dissolution in the
`small particle limit, leads to the following pair of differential
`equations in dimensionless form (3);
`
`dr* / dz* = ‘(DH / 3)(1 * C*) / 7*
`
`equation 8
`
`dC* /dz* = DoDnr*(l — C*) — 2AnC* equation 9
`
`where
`
`Jmax = PwCf.~
`
`equation 6
`
`2* =z/L: (vi/L)t=t*
`
`M"“”‘(t) = KIL PeC,,,dAdt
`
`CS,C B C,
`
`t*=t/(L/vz)=2‘/(AL/Q)=t/(V/Q)
`
`where: L = tube length, vZ= axial fluid velocity in the tube,
`A = tube surface area area= 2TrRL, R : tube radius,
`Q = fluid flow rate = AVZ. The three important dimensionless
`groups are:
`
`CC S C,
`
`equation 7
`
`D0 = Dose Number
`
`.- '
`-
`_|
`I
`V
`A
`L Eucme
`Metoprolol . .
`.
`‘\ Bensarazide
`I
`L-dopa
`
`D-glucos
`
`A
`Naproxen
`
`. < Terbutaline
`
`Log(100-F)
`
`in(1:vb-'ao—N(97IIIII
`
`. A Enalaprilate
`I
`2
`
`0
`
`r
`4
`Human Permeability (104, cm/sec)
`
`
`
`
`
`FractionAbsorbed(Fa)
`
`0
`
`Fig. 1. Graph of the extent of absorption vs. human intestinal jeju-
`nal permeabilities.
`
`Dn 2 Dissolution Number =
`
`DC,
`r0
`
`4*rrr3,
`' 4+ ' [res
`3
`_ "lTV0p
`3
`
`I I,“ ‘ 3DCs / pré =
`
`[res / [Dim
`
`An =
`
`Absorption Number =
`
`Peff
`R 'trcs
`
`A -1
`_ tabs '
`
`[res
`
`rm — 1'rR2L / Q 2 mean residence time.
`
`[Dim ‘
`
`time required for a
`”(2)P i
`31)C3 _ particle of the drug to dissolve.
`
`/ V)Pej]' :
`
`tgbls : kabs :
`P .
`9”R 2 the effective absorption rate constant.
`
`2 -
`
`Where, in addition to the symbols defined previously, S is
`surface area, V is volume, M0 is the dose, and re is the initial
`particle radius.
`This analysis while simplified, emphasizes the three fun-
`damental parameters controlling drug dissolution and ab-
`
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`
`Amidon, Lennemas, Shah, and Crison
`
`For estimating in viva absorption, the extent of solubilization
`particularly in the small intestine is critical to making good
`estimates. Drugs with a high Dose Number must be effec-
`tively solubilized in vivo for good absorption. However, at
`the present time, a conservative estimate of the Dose Num-
`ber is recommended, i.e., the minimum solubility of the drug
`should be determined in the physiological pH range (1-8) and
`temperature.
`Table I presents some dose, solubility, Dose Number
`and estimated Dissolution Number data for a number of
`drugs. The drugs in Table I were chosen to illustrate the
`significance of the dose of a drug as well as its solubility. The
`drugs griseofulvin and digoxin are representative examples.
`Both compounds have similar solubilities (0.015 mg/ml and
`0.024 mg/ml respectively) and it can be assumed that based
`on the solubility data, both drugs should be absorbed
`equally. However, based on the Dose Number of the two
`compounds (133 for griseofulvin and 0.08 for digoxin) the
`fraction of a dose of digoxin absorbed is expected to be much
`greater than that of griseofulvin (Figure 2). The absorption of
`digoxin is up to 100% for a solubilized form (27). While the
`relative bioavailability of griseofulvin can be improved by a
`factor of 1.7 via micronization, suggesting incomplete bio-
`availability (28). It is important to note that the solubility,
`and therefore the Dose and Dissolution Number, of a drug in
`vivo is difficult to estimate precisely due to potential aggre-
`gation and the unknown extent of solubilization, hence the
`actual absorption of a compound can only be estimated to be
`in a range depending on the assumed in vivo surface area and
`solubilization. However, this analysis allows for compari-
`sons to be made among delivery systems and dosage forms
`for the same drug and estimates to be made based on as-
`sumed in vivo solubilization and surface area.
`
`Permeability—Solubility Drug Classification
`
`The above analysis suggests that correlations between
`drug dissolution and drug absorption are best done using the
`fundamental dimensionless groups, Do, Dn, and.An. How-
`ever, given the definition of these terms, it is clear that per-
`meability and solubility are key underlying parameters con-
`trolling drug absorption. Thus, drugs can be divided into
`high/low solubility-permeability classes and the expectations
`regarding in vitro-in vivo correlations more clearly stated.
`
`Fig. 2. Graph of estimated fraction dose absorbed vs Dissolution
`Number, Dn, and Dose Number, Do, for a high permeability drug.
`An = 10 corresponds to a drug with a permeability approximately
`that of glucose.
`
`sorption. Figure 2 shows a typical profile for high permeabil-
`ity drug. This profile for a high permeability drug (An= 10)8
`illustrates the sharp dependence of extent of drug absorption
`on the Dose and Dissolution Numbers when they are in crit-
`ical ranges around one for a well absorbed (high permeabil-
`ity) drug. It is also evident from the figure that at high dose
`numbers, the extent of absorption is only weakly dependent
`on the Dissolution Number. The limiting solution to equa-
`tions 8 and 9 for this region is
`
`F=2An/D0
`
`and is independent of dissolution rate (2,3). This is the sol-
`ubility limited absorption region. Thus,
`in certain regions
`drug absorption is very dependent on drug dissolution rate
`and dose and in other ranges it is only weakly dependent.
`
`8 Values for An 2 6 represent sink conditions for drugs with low
`solubility, high permeability. Assuming conservative estimates for
`the parameters which make up An. ie, Pa“ = 1 X 10‘3 cm/sec, t,e5
`= 180 min., and R = 1cm.An=10.
`
`Table 1. Calculated Parameters for Representative Drugs
`
`Drug
`
`Piroxicam
`Glyburide
`Cimetidine
`Chlorthiazide
`Digoxin
`Griseofulvin
`Carbamazepine
`
`Dose
`(mg)
`
`20
`20
`800
`500
`0.5
`500
`200
`
`Cgiin
`(mg/ml)“
`
`0.007
`<0.100
`6.000
`0.786
`0.024
`0.015
`0.260
`
`Vsol
`(ml)"
`
`2,857
`133
`556
`636
`20.8
`33,333
`769
`
`Do°
`
`11.4
`>0.80
`0.53
`2.54
`0.08
`133
`3.08
`
`Dnd
`(estimated intrinsic)
`
`0.15
`0.78
`129
`17.0
`0.52
`0.32
`5.61
`
`3 Minimum physiologic solubilities were determined in the physiological pH range (1-8) and temper-
`ature (31, 32).
`‘’ Volume of solvent required to completely dissolve the dose at minimum physiologic solubility.
`° D0 = Dose/V0/Cg“, initial gastric volume, V0 = 250 ml.
`‘‘ Assumptions: r0 = 25 um, D = 5 X 10‘6 cmz/sec, p = 1.2 gm/cm’, (tm) = 180 min. (33).
`
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`A Theoretical Basis for a Biopharmaceutic Drug Classification
`
`Table II. In Vitro—in Vivo (IVIV) Correlation Expectations for Immediate Release Products Based on Biopharmaceutics Class
`
`Class
`
`Solubility
`
`Permeability
`
`IVIV Correlation Expectation*
`
`I
`
`11
`
`111
`
`IV
`
`High
`
`Low
`
`High
`
`Low
`
`High
`
`High
`
`Low
`
`Low
`
`IVIV correlation if dissolution rate is slower that gastric emptying
`rate, otherwise limited or no correlation.
`IVIV correlation expected if in vitro dissolution rate is similar to
`in vivo dissolution rate, unless dose is very high (see
`discussion).
`Absorption (permeability) is rate determining and limited or no
`IVIV correlation with dissolution rate.
`Limited or no IVIV correlation expected
`
`* A limited correlation means that the dissolution rate while not rate controlling may be similar to the absorption rate and the extent of
`correlation will depend on the relative rates.
`
`These expectations are summarized in Table II and discussed
`in more detail below.
`
`Case 1. High Solubility—High Permeability Drugs. This
`is the case where the drug is well absorbed (though its sys-
`temic availability may be low due to first pass extraction/
`metabolism) and the rate limiting step to drug absorption is
`drug dissolution or gastric emptying if dissolution is very
`rapid. In this case the dissolution profile must be well de-
`fined and reproducible to insure bioavailability. For immedi-
`ate release dosage forms that dissolve very rapidly, the ab-
`sorption rate will be controlled by the gastric emptying rate
`and no correlation with dissolution rate is expected. In the
`fasted state the gastric emptying rate is both volume and
`motility phase dependent with a gastric half emptying time of
`between 5 and 22 min., and an overall average of 12 and 22
`min. for administered volumes of 50 and 200 ml respectively,
`Figure 3 (9). This suggests that a dissolution specification for
`immediate release (IR) dosage forms of perhaps 85% dis-
`solved in less than 15 min. may insure bioequivalence9.
`Case 2. Low Solubility—High Permeability Drugs. This
`is the class of drugs for which the dissolution profile must be
`most clearly defined and reproducible. More precisely this is
`the case where Absorption Number, An, is high and Disso-
`lution Number, Dn, is low. Drug dissolution in vivo is then
`the rate controlling step in drug absorption (except at very
`high Do) and absorption is usually slower than for Case 1.
`Since the intestinal luminal contents and the intestinal mem-
`brane change along the intestine, and much more of the in-
`testine is exposed to the drug, the dissolution profile will
`determine the concentration profile along the intestine for a
`much greater time and absorption will occur over an ex-
`tended period of time. Consequently, the dissolution profile
`must be determined for at least 4-6 time points and for at
`least 85% dissolution at several physiological pH’s. In addi-
`tion, media conditions reflective of the in vivo situation, such
`as addition of surfactants must be considered. Drugs in this
`class may be expected to have variable absorption due to the
`many formulation and in viva variables that can effect the
`dissolution profile. Dissolution media and methods that re-
`flect the in viva controlling process are particularly impor-
`tant in this case if good in vitro-in vivo correlations are to be
`obtained.
`
`9 Stochastic simulations could be used to more precisely define
`these dissolution limits.
`
`Case 3. High S0lubility—Low Permeability Drugs. For
`this class of drugs, permeability is the rate controlling step in
`drug absorption. While the dissolution profile must be well
`defined, the simplification in dissolution specification as in
`Class 1
`is applicable for immediate release dosage forms
`where drug input to the intestine is gastric emptying rate
`controlled. Both the rate and extent of drug absorption may
`be highly variable for this class of drugs, but if dissolution is
`fast i.e. 85% dissolved in less than 15 min., this variation will
`be due to the variable gastrointestinal transit, luminal con-
`tents, and membrane permeability rather than dosage form
`factors.
`
`Case 4. Low S0lubility—Low Permeability Drugs. This
`class of drugs present significant problems for effective oral
`delivery. The number of drugs that fall in this class will de-
`pend on the precise limits used for the permeability and sol-
`ubility classification.
`This classification of drugs follows naturally from the
`above theoretical analysis. While drug solubility and dose
`are readily available, and drug particle size often available,
`drug permeabilities are relatively less available, particularly
`in humans. Drug permeabilities in an animal model (rat) are
`more readily available and some human values are known.
`Recent methodological advances in the area of human intu-
`bation will undoubtedly provide more data in the future
`(15,23). Some of the available human permeability data were
`presented in Figure 1. More human data is necessary in
`
`I: 50 ml oral done
`
`I 200 ml oral dose
`
`\
`
`V
`Gastric Motility (IMMC) Phase
`Fig. 3. Graph of measured gastric half emptying times, T50, in hu-
`mans as a function of fasted state motility phase for administered
`volumes of 50 and 200 ml of water(9).
`
`TEVA EXHIBIT 1034
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05017858
`
`TEVA EXHIBIT 1034
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`418
`
`order to firmly establish the permeability classification cri-
`teria.
`
`Dissolution Media and Methodology
`
`The setting of in vitro standards must be done on the
`basis of reflecting the conditions existing in viva. There is a
`large amount of literature on dissolution methodology and
`media (29). It is not the purpose of this report to suggest a
`methodology or media as being most appropriate. In fact the
`preceding analysis suggests that all that should be required is
`that the in vitro methodology/media reflect the in vivo situ-
`ation when used to establish an IVIV correlation. There
`should be enough flexibility in the standards to allow for
`development of methods that truly reflect the in viva rate
`controlling process for a given drug. This is particularly true
`for a methodology that might be used as a surrogate for an in
`vivo bioavailability test”.
`For water insoluble drugs, the relevant media for disso-
`lution has been of considerable interest as a practical matter
`due to the large amount of media that may be required for a
`very water insoluble drug (30). The current approach that
`seems to be most appropriate is to use surfactants. The
`choice of surfactant can be important. While bile salts would
`be the logical choice based on physiological relevance, they
`are too expensive to be use on a routine basis. A surfactant
`such as sodium lauryl sulfate may be appropriate in many
`cases but the choice need not be limited to this surfactant.
`As noted above, the in viva solubilization is a critical con-
`sideration and the dissolution media should be guided by
`reflecting the in viva situation. If the drug is a case 2 drug
`(high permeability, low solubility) then absorption from so-
`lution is faster than dissolution and sink conditions are likely
`to prevail in vivo. As a general rule one should maintain sink
`conditions in the dissolution media if possible, such that the
`drug dissolves in less that 20-30% of the dissolution media.
`Other factors which need to be considered, especially
`for case 2 drugs, are particle aggregation and the effective
`particle size in viva. Quite often the first approach to increas-
`ing the dissolution rate of drugs in this class is micronization.
`This however, also increases the surface energy and hence
`potential for particle aggregation. When predicting in viva
`bioavailability from in vitro dissolution profiles, it is critical
`that the particle size used in the model reflect the in viva
`particle size. Therefore, it is important that the dissolution
`medium represent, as close as possible, the in viva dissolu-
`tion medium so that the apparent particle radius presented
`by the dosage form to the dissolution medium reflects in vivo
`conditions. Measuring the intrinsic dissolution rate, using for
`example rotating disk methodology, and then comparing the
`theoretical, measured particle(suspension), and dosage form
`dissolution rates can be a useful tool for determining when
`particle aggregation“ is significant (22,29).
`
`1° A routine quality control dissolution methodology may be based
`on somewhat different considerations and it is not being suggested
`that this more elaborate methodology replace routine quality con-
`trol methods. However, when used as a surrogate for bioavail-
`ability then the more elaborate methods may be required at least
`initially to establish the IVIV correlation.
`” Particle size change can occur during processing of the dosage
`
`Amidon, Lennernas, Shah, and Crison
`
`However, it must be emphasized that a strong argument
`for the physiological relevance of a particular surfactant con-
`taining dissolution media can not be made at this time. The
`dissolution media in viva is a complex medium of bile salts,
`lecithin, cholesterol and its esters and a wide range of lipid
`materials that can vary considerably with meal type and diet.
`The physical chemistry of these systems is extremely com-
`plex. However, models for dissolution in less complex mi-
`celle systems have been developed, and it is clear that the
`drug solubility in the micelle phase and the effective diffu-
`sivity of the drug loaded micelle are the two most important
`parameters that are needed to estimate the drug dissolution
`rate enhancement factor (29). Further research is needed in
`order to establish correlations between in viva representative
`media and the more readily available surfactant systems that
`could be used on a routine bases. The practical suggestion
`made above of using a dissolution media sufficient to dis-
`solve the full dose of the drug in 20-30% of the media volume
`represents a starting point. The in vitro solubilization, how-
`ever, should reflect the in viva solubilization.
`
`Further Consideration
`
`Several factors will need further consideration; drugs
`with pH dependent solubility, drugs which exhibit complex-
`ation phenomena with gastrointestinal contents, and drugs
`that are unstable in the gastrointestinal tract. For drugs that
`exhibit pH dependent solubility, based on equations 1 and 2
`governing drug absorption, it is the drug solubility at the pH
`of the local point in the intestine that is the most relevant pH.
`This pH of course varies down the intestine. The pH of the
`local region will influence the dissolution rate and possibility
`the drug permeability. This could be of importance if the
`dosage form altered the local pH, in which case it could alter
`the drug absorption rate as well as dissolution rate. In this
`case the dosage form dissolution specification may have to
`be extended to include these additional dosage form compo-
`nents”.
`For drugs that are unstable or interact with gastrointes-
`tinal contents in a manner so as to reduce their activity in
`solution e.g. complexation with ions or bile salts, dissolution
`rates can have a profound effect on drug absorption given the
`position dependence down the intestine of luminal composi-
`tion. This can be the case even if the drug has high perme-
`ability (well absorbed from solution). For these drugs, where
`dissolution is not rapid, a multiple point dissolution profile at
`several pH’s in addition to gastric pH should be required.
`In general, the position dependence of drug absorption
`can be due to local pH and lumen content differences down
`the GI tract as well as a changing permeability