CJQCD
`
`AMERICAN JOURNAL OF
`
`
`
`?_ ARMACEUTICAL EDUCATION
`
`
`
`:{f;
`
`‘M /‘AC’ /
`
`EXHIBIT
`
`The Official Publication ofthe American
`
`Ex. 1019
`
`nnnnnnnnnnnnnnnn16_m4Ass0ciation of ”C”6Ileges of Pharmacy
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:3)
`Ex. 1019, p. 1 of5
`(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:28)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)
`
`

`
`REPORTS
`71
`
`Minutes of the Meeting of the Board of Directors
`RODOWSKAS, Christopher A., Jr.
`
`PRESIDENT’S SECTION
`75
`
`Food For Thought
`SORBY, Donald L.
`
`COUNCIL OF DEANS CHAIRMAN’S SECTION
`76
`Political Action Revisited
`GRANBERG, C. Boyd
`
`COUNCIL OF FACULTIES CHAIRMAN’S SECTION
`77
`
`Obtaining Advanced Degrees in Pharmacy by Nontraditional Means
`LOWENTHAL, Werner
`
`COUNCIL OF SECTIONS CHAIRMAN’S SECTION
`78
`
`Role—ModeI Congruence — A Catalyst to Learning
`LEMBERGER, Max A.
`
`EDITOR’S SECTION
`79
`Instructions to Authors
`
`COCOLAS, George H.
`
`ANNOUNCEMENTS
`81
`
`General Announcements; Changes in Staff Titles; New Staff Members
`COCOLAS, George H.
`
`THE RECORD
`83
`
`General News; Grants and Awards
`COCOLAS, George H.
`
`
`
`'5‘-5’:E‘-38.3"-E."§"’-"5'
`
`'9'
`
`1"‘
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`
`BOOK REVIEWS
`87
`
`GUILLORY, K.J., LONGE, R.L., SNOW, B., KILSDONK, G.F., ABOO1
`R.R., GUMBHIR, A.K., HUNT, M.L., LAWRENCE, G.D.,
`IANN/t
`RONE, M., SPEEDIE, M.K., RITSCHEL, W.A., ABRAMSON,
`I-i
`KELLEY, C..l., SOWELL, J.W., THOMPSON, E.B., LOEFFLER, L.,r"
`BARFKNECHT, C.F., CLARKE, D.E., GRINGAUZ, A., JUN, H.Vl'V‘
`TIMMONS, H.F., STAUBUS, A.E., CARLSTEDT, B., SIDDONS, L.M]1;
`JOHNSON, H.D., BEAMER, R.L., WEART, C.W., BARLETTA, If
`FLAGSTAD, M.S., RUSSI, G., MITSCHER, L.A., LAMY, P.P., COKER,
`
`1'‘
`V4
`
`"‘
`
`‘i
`
`ta
`
`’
`
`RECENT PUBLICATIONS
`104
`
`New Journals and Special Publications; New Books
`COCOLAS, George H.
`
`CORRIGENDUM
`106
`
`COCOLAS, George H.
`
`ADVERTISEMENTS
`Pfizer Pharmaceuticals
`E.R. Squibb & Sons, Inc.
`Parke-Davis Division
`Prentice—Ha1l Publishers
`McNeil Laboratories
`Roche Laboratories
`CIBA
`
`(iii)
`(iv)
`(Vi)
`(vii)
`(vii)
`(viii)
`(3)
`(X1)
`(xii)
`(xiii)
`(xiv)
`(XV)
`(xvi)
`
`Eli Lilly and Company
`Ortho Pharmaceutical Corporation
`The Upjohn Company
`Burroughs Wellcome Company
`Abbott Laboratories
`
`American Association of Colleges of Pharmacy
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`Editorial office: School of Pharmacy, University
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`Sun-Kmneal-IPRZO16-01104
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:3)
`Ex. 1019, p. 2 of5
`(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:28)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:21)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)
`
`

`
` 7KLV PDWHULDO PD\ EH SURWHFWHG E\ &RS\ULJKW ODZ 7LWOH  86 &RGH

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Calculation of Drug Solubilities by Pharmacy Students
`
`Lindley A. Cates
`
`C0[[gg€ of Pharmacy, Um'versi'ty 0fH0ust0n, Houston TX 77004
`
`A method of estimating the solubilities of drugs in water is reported which is based on a principle applied
`in quantitative structure-activity relationships. This procedure involves correlation of partition coefficient
`values using the octanol/water system and aqueous solubility. After identifying the atoms or groups com-
`prising a com pound the students need to employ but a few approximate hydrophilic or lipophilic numbers
`assigned to these in calculating the log P value of the drug or chemical and then place the agent in the ap-
`propriate soluble or insoluble category. Although this method does not always provide exact categoriza-
`tion it does so in a great majority of cases and permits the student to recognize certain potential chemical
`and therapeutic incompatabilities.
`
`frequent questions asked medicinal
`One of the most
`chemistry faculty by pharmacy students is, “How do I
`know if a drug is soluble or insoluble in water?” These stu-
`dents were cognizant of’ the importance of such informa-
`tion in predicting chemical
`and therapeutic incom-
`patabilities. Prior to the introduction of the procedure
`described in this paper, along with a discussion of the acid-
`base character of drugs, many students were incapable of
`determining if an insoluble material will be formed during
`a reaction and whether or not water can be used as the sol-
`
`vent for a certain drug. A method, therefore, was devised
`to enable the students to estimate a drug’s solubility by
`assigning a numerical value to a molecule which relates to
`this property. This procedure, which is based on a scientific
`rationale, requires the use of only a few numerical values
`and a brief calculation time.
`
`PROCEDURE
`
`With the advent of quantitative structure-activity
`relationship (QSAR) concepts has come an increased
`awareness and use of physiochemical parameters such as
`partition coefficients and steric and electronic factors for
`
`correlation with biologic properties. The former constant is
`deemed most critical to a drug’s overall effect and most
`students are exposed to this principle during their phar-
`macy education.
`Most work has been done with partition coefficients
`based on the octanol/water system expressed as the logig
`OF log P. Although this is a measure of the solubility
`characteristics of the whole molecule, one normally uses
`lhelsum of the fragments of the molecule which have been
`assigned
`relative hydrophilic-lipophilic values,
`(‘It’),
`to
`Calculate log P. Using this procedure, a positive value for
`7*’ means the substituent, relative to H, favors the octanol
`Phase (i'.e.,
`lipophilic). And negative 7r value indicates its
`greater affinity for water (i'.e., hydrophilic).' The environ-
`ment Of the substituent can influence the relative 7r value,
`but. for the most part, such changes are small and can be
`neglected for our purposes.
`The method of calculating log P values of drugs was
`Sun-Amneal-|PR2016-01104
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:3)
`Ex. 1019, p. 3 of5
`(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:28)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:22)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)
`
`introduced while teaching a course in the medicinal chem-
`istry sequence to about 80 second professional year stu-
`dents and then applied to those agents being discussed
`throughout
`the semester. The students learned eight
`7r
`values as follows: C (aliphatic or C12) = 0.5; phenyl = 2.0;
`C(0)O or C(O)N = -0.7; O or N (in amines, hydroxyls and
`ethers but not in hydrazines or N-O compounds) = -1.0;
`and —S- = 0. These numbers were obtained by rounding off
`literature values; exceptions being the sulfide‘ and the
`amido group.‘ The students then needed only to identify
`these fragments in the molecule and calculate the sum of
`the Ti‘ values to calculate an approximate log P. After being
`given several examples in lecture and solving problems
`themselves at the chalkboard all students knew the 7r values
`
`and the only difficulty they occasionally experienced was
`identification of the appropriate fragments in a molecule
`(e.g.,
`in cyclic drugs).
`The USP provides official definitions of water
`solubilities wherein “soluble” is defined as 3.3 to 10 per-
`cent. For our purposes
`therefore,
`those drugs with
`solubilities above 3.3 percent are considered soluble and
`those below, insoluble. The solubilities of drugs used in this
`paper were taken from the Merck Index(l), Remi'ngi0ii's
`Pharmaceutical Sci'erice5(2) or the Handbook of C/ienii'sIr_t'
`and P/iysi'cs(3). The octanol/water log P values were from
`Hansch and Leo(4) and the 7r values are from three dif-
`ferent sources(4, 5 and 6).
`Having a definition of solubility and a means of
`calculating log P, what remains is a method of correlating
`these two parameters. Through the examination of a large
`number of log P and solubility values, an arbitrary stan-
`'The term "ii-“ more correctly refers to the system ofsubstituting atoms or
`groups for hydrogen while the fragment system of calculating log P
`values involves the summing of appropriate structural elements.
`In ap-
`proximating log P values this distinction normally is not critical.
`3Average of 0.'7l (aromatic) and 0.39 (aliphatic) values.
`‘Takeii from aliphatic SCH} (0.45) and aromatic SCH3 (0.61), each minus
`a methyl (0.5).
`4Although the literature rr values are -1.49 (aromatic) and -l.7l (aliphatic)
`the value of -0.7 gives more correct results when using the approximate
`calculation method (q.v., barbiturates, phenacetin. dibucaine, nicotin-
`amide and phenoxymethyl penicillin).
`
`American Journal of Pharmaceutical Education
`
`Vol. 45, Feb. 1981
`
`11
`
`

`
`dard was adopted whereby those drugs with positive log P
`values over 0.5 are considered water-insoluble and those
`
`with less than 0.5 log P are deemed soluble. An early use of
`log P and 1r in correlating chemical structure with aqueous
`solubility involved free-energy changes of
`liquids(7).
`Although this study included only four of 156 compounds
`with log P values less than 0.5, the dividing line between
`soluble and insoluble appears to be in the same range.
`Although this method is applicable to a large number of
`drugs it is, of course, restricted to those containing only C,
`Cl, N and 0. Other limitations should also be recognized,
`chief among these is
`the acid-base character of drugs.
`When dealing with acids or bases, log P values are normally
`determined at a pH, either very acid or alkaline, so that
`ionization is suppressed and only the neutral, most lipo-
`philic form is present. Since most drugs are either weak
`acids or bases this possible discrepancy must be taken into
`consideration. Scherrer and Howard(8) have pointed out
`that when an ionizable compound is equilibrated in a two-
`phase system at a pH at which it is partially ionized,
`its
`concentration in the organic phase is not determined by log
`P alone. These investigators,
`therefore,
`introduced dis-
`tribution coefficients (log D) as a correction based on the
`pKa of the compound. Log D is also termed the apparent
`partition coefficient (Papp), which is in turn related to the
`true (corrected) partition coefficient (Pcorr), Peon» is equal
`to Papp/(1-a), where C!
`is
`the degree of ionization.
`Although this correction is not readily adaptable to our es-
`timation method there have been a few drugs whose log P
`values have been determined using octanol/water at pH
`values that approximate those imparted to water by these
`agents and some examples will be presented later.
`
`APPLICATIONS AND DISCUSSION
`
`This method was initially applied to those CNS drugs
`covered in the medicinal chemistry course and described by
`the textbook(9). This consisted of 29 sedative—hypnotics,
`six central
`relaxants,
`three benzodiazepines,
`14 pheno-
`thiazines, 12 anticonvulsants and I2 miscellaneous drugs.
`A few more such agents could have been included if 7r
`values for Br and F were introduced. Of this total the
`
`solubilities of 72 (95 percent) were correctly determined
`with three anomalies and one ‘borderline’ estimation. The
`
`success rate with this classification of drugs is not unexpec-
`ted in view of the relationship between their log P values
`and depressant activity. It has been established that most
`organic drugs affecting the CNS require a log P of approx-
`imately 2 to pass the blood-brain barrier and gain access to
`the brain(l0). A partition coefficient of this magnitude
`would translate to a water-insoluble compound. Consider-
`ing all drugs, there are relatively few that are soluble in the
`non-salt form, a situation that should make easier the
`teaching of solubilities. To simply state that drugs in their
`free form are insoluble is not, however, satisfactory. In ad-
`dition, there are situations when it is important to be cogni-
`zant of relative solubilities, a comparison made possible us-
`ing the calculation method.
`Since one of the larger members of this class of CNS
`depressants are barbiturates it might be instructive to ex-
`amine the heterocycle common to these and at least one
`specificagent. Being cyclic ureides the barbiturates contain
`IWO 3m1d0 EFOUPS (-0-7 each), two carbons (0.5 each) and
`one carbonyl oxygen (-1.0) for a log P of -1.4. This com-
`pares favorably with the -l.35 reported for this barbituric
`Sun-Amneal-lPR2016-01104
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:3)
`(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:28)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:23)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)
`1Ex.1o19,p.4or5
`
`American Journal of Pharmaceutical Education
`
`Although there are few soluble drugs in the free form» '
`two CNS depressants chloral hydrate and paraldehyde fall
`Vol. 45, Feb. 1981
`
`acid portion(l0). The most water-soluble drug is
`diethylbarbital with a calculated log P of 0.6. This agent is
`also one of the few weakly acidic drugs whose log P has
`been determined in octanol/water at other than a low pH_
`At pH 81 its log P value is 0.18 and has a log P value of
`0.71 at pH 5. An environment closer to neutrality on the I
`acid side would have been preferred for our comparison I
`purposes but
`the value falls in the insoluble range ac.
`'
`cording to the established definition; the actual solubility is
`I
`0.7 percent.
`An examination of the anomalies and ‘borderline’
`drugs, which fall in the anticonvulsant and central relaxant
`classes, may also be of interest ethosuximide, containing I
`an amido group, six carbons and a carbonyl oxygen, has an
`estimated log P of 1.3 but is water-soluble. Trimethadione,
`a neutral drug with one each amido and carboxy groups
`and six carbons, calculates to 0.6 and is 5 percent soluble
`and is considered ‘borderline’. The carbamates methocar-
`
`I
`
`-‘
`I
`I
`'
`
`bamol, 2.5 percent soluble, and chlorphenesin carbamate,
`almost insoluble, have simplified and incorrect calculated
`log P values of -0.7 and 0.3, respectively. This discrepancy 1
`can be accounted for on the basis that the infrequently en-
`,
`countered carbamyl moiety actually has a 1r value of -1.15
`instead ofthe -1.7 used and an aromatic methoxy 1r value is
`-0.2 as compared to our value of -0.5. This situation exem-
`plifies the errors that can be introduced when an attempt is
`made to simplify the calculation process.
`The method was completely successful when applied to
`I’
`the 35 local anesthetics described in the student’s text. In-
`terestingly, the basic drug procaine which was recorded log ',
`P (octanol/water) values of -0.32 (pH 7) and 0.14 (pH 8) is
`I
`only 0.5 percent soluble. Our calculated value places this
`drug in the correct water-insoluble category. The proce-
`dure was also correct
`in assigning 34 analgesics and
`analgesic antagonists, 30 antihistamines and 25 nonquater-
`nized autonomic blocking agents, all water-insoluble.
`The salicylic acid derivatives, aspirin, salicylamide and
`salicyclic acid itself, were also examined. A true calculation I
`of the latter requires the introduction of an additional 1r
`value, that for intramolecular hydrogen bonding (IMHB).
`Without
`this
`factor
`salicylic acid log P value easily
`calculates as 0.3 but is only 0.2 percent soluble. If the 0.65
`IMHB value is added we get a log P value of 0.95 which -
`places it
`in the correct water-insoluble category. The
`literature value for this acid is 0.95 (pH 4); the pH of a
`saturated solution is 2.4. The need for applying the IMHB
`factor is infrequent but can be used during instruction in '
`emphasizing this phenomenon which is of importance in I
`biological action. It could also be pointed out that the I
`isomer, p-hydroxybenzoic acid, cannot undergo IMHB ‘
`and is eight times more soluble. Salicylamide has very close I.
`values in all respects to salicyclic acid while aspirin, 0.3 per-
`cent soluble, calculates to 1.1 log P without IMHB. As was I
`the case with procaine, our procedure gives correct
`_
`categorization of solubility while the experimental log P
`values for aspirin of -0.02 (pH 5) and -0.9 (pH 5.6) would ‘
`not. It appears that there are situations when exact, or even ,
`simplified, calculated values are more meaningful than ex-
`perimentally derived ones. One reason for this is the man)’ ,_
`experimental values, supposedly measured under like con-
`ditions but in different laboratories, that may vary for the
`same compound by as much as 1.5 log units. A variance OI
`0.5 units is common.
`
`I
`
`.
`
`'
`
`

`
`Tame l. Additional representative solubilities
`Log P
`Log P
`Calculated
`Observed
`5.0
`5.3
`4.3
`4.2
`3.1
`2.5
`2.5
`1.8
`2.4
`2.1
`2.1
`2.1
`1.8
`1.5
`1.6
`1.6
`1.5
`2.4
`1.5
`1.4
`1.3
`2.0
`0.5
`0.4
`0.5
`0.3
`0.5
`0.3
`0.0
`-0 3
`-0.2
`-0.4
`-0.7
`-0.6
`-1.5
`-1.78
`-1.6
`-1.7
`
`Drug or chemical
`Cjlorpromazine
`Dibucaine
`phenytoin
`Amphetamine
`Phenoxymethyl penicillin
`Amobarbital
`phcnacetin
`Phenobarbital
`Parachlorophenol
`Ethyl chloride
`Benzoic acid
`Thiazole
`propanol
`Acetylacetone
`Ethanol
`Nicotinamide
`Lactic Acid
`Glycerol
`Citric Acid
`
`Predicted
`solubility
`15
`1
`1
`1
`1
`I
`1
`I
`I
`I
`I
`B“
`B
`B
`sd
`S
`s
`s
`S
`
`Literature
`solubility
`I
`I
`I(1.5%)
`SS9
`1 (0.08%)
`I (0.08%)
`1 (0.1%)
`I (0.1%)
`SS (2.7%)
`1 (0.57%)
`1(0.33%)
`SS
`S
`S (12.5%)
`s
`S
`s
`s
`S
`
`aFrom Pomona College Medicinal Chemistry Project data. blnsoluble,
`
`°Borderlinesolubility.
`
`dSoluble. Cslightlysoluble.
`
`in this category and may be considered exceptions to the
`SAR requirement. Chloral hydrate is highly ionized as a
`result of the inductive influence of the chlorine atoms and
`is very soluble. Neither its log P, nor that of paraldehyde,
`has been determined in qctanol/water but it calculates by
`our method to 0.5 or ‘borderline’. Doubtless the true value
`is considerably lower because of the halogen effect. The
`neutral paraldehyde calculates correctly giving a 0 log P
`and is 12 percent soluble. The solubilities of some ad-
`ditional drugs and chemicals, arranged by increasing
`hydrophilicity and containing a variety of chemical group-
`ings, are shown in Table 1.
`After mastering the determination of drug solubilities
`using the eight constants the students will be able to
`proceed to drugs containing atoms or groups not yet con-
`sidered. Examples of these are the nitro and nitrate groups.
`The former has a 1r value of -0.85 (aliphatic) and -0.28
`(aromatic) which can be averaged and rounded off to -0.6,
`and not
`the -0.3 calculated by the previous method.
`Similarly the nitrate group, found in several vasodilators,
`has a 1r value of ca. 0.2 and not -4.0.
`
`It should be emphasized that this simplified method of
`estimation has only general application and cannot,
`Without becoming cumbersome, be applied with success in
`all cases. This is particulariy the case when electronic fac-
`tors play an important role. When examining the ampho—
`teric antibacterial sulfonamides, for example, we find that
`the addition of one or two methyl groups to the pyrimidine
`of sulfadiazine to give sulfamerazine and sulfamethazine
`Ylelds a progressive increase,
`instead of the expected
`decrease,
`in solubility. The effect of the methyl is to in-
`Crease the lability of the N‘ amide hydrogen and, thus the
`molecule’s hydrophilicity.
`
`the log P of heterocycles, such as those
`In general,
`found in sulfonamides, can be estimated by subtracting 0.5
`from phenyl (‘Ir = 2.0) or naphthalene (ir = 3.4) for each
`carbon substituted by a heteroatom and adding the 1r value
`for the latter. Thus, the calculated ‘Tl’ values for pyridine
`and isoquin oline are 0.5 (0.64 observed) and 1.9 (2.0 obser-
`ved), respectively, and permit the solubility determination
`of such drugs as nicotinamide and dibucaine, Table I.
`This method of determining drug solubilities has been
`enthusiastically received by the pharmacy students in our
`medicinal chemistry course. It has done much to dispel
`confusion and to increase their confidence in dealing with
`drugs as chemicals capable of causing therapeutic and dis-
`pensing problems. Provided its limitations are considered,
`it can be a useful tool in the teaching of an important and
`relevant topic.
`
`J. Pharm. Educ, 45,
`Am.
`ll/IS/80.
`References
`
`ll-13(l98l);
`
`received 9/3/80, accepted
`
`(1) The Merck Index, 9th ed., Merck and Co., Inc. Rahway NJ (1976).
`(2) Reminglorfs Pharmaceutical Sciences, 15th ed., Mack Printing Co.,
`Easton PA (1975).
`(3) Handbook of Chemistry and Physics, (edit.) Weast, R.C., Chemical
`Rubber Pub. Co., Cleveland OH (1977).
`(4)Hansch, C. and Leo, A., Substitution Constants for Correlation
`Analysis in Chemistry and Biology, John Wiley and Sons, New York
`NY (1979).
`(5) Leo. A., Hansch, C. and Elkins, D., Chem. R€l’.,
`(6) Tute, M.S., Adv. Drug Res., 6, 67(l97l).
`(7) Hansch, C., Quinlan, J.E. and Lawrence, G.L., J. Org. Chem., 33,
`347(l968).
`(8) Scherrer, R.A. and Howard, S.M., J. Med. Chem, 20, 53(l977).
`(9) Wilson. C.O., Gisvold, O. and Doerge, R.F., Textbook of Organic
`Medicinal and Pharmaceutical C/lemislry, 7th ed. J.B. Lippincott Co.,
`Philadelphia PA (1977).
`(10) Daniels, T.C. and Jorgensen, E.C., Op. cit. (9) pp. 22-23.
`
`71, 552(l97l).
`
`Sun-Amneal-|PR2016-01104
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:3)
`American Journal of Pharmaceutical Education
`Ex. 1019, p. 5 of5
`(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:28)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:24)(cid:3)(cid:82)(cid:73)(cid:3)(cid:24)
`
`Vol. 45, Feb. 1981
`
`13