In
`
`I
`
`“
`H.
`Ll um 7.1 m;<J;1I1I(( )1 ml
`
`n%
`[ . H T??? ‘H £113;@UI1IW I
`
`,'\«u
`
`I K
`
`,r]! )~__\,"‘/1*‘
`
`4
`
`\_
`
`I,‘
`
`I
`
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`
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`‘
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`{J[}\\1;i§']ij;i_iHlLl,_!I‘fl_ J a"‘«J!(iI‘ L1 %_U__a |_(_IL-_1:_1I.
`
`MYLAN PHARMS. INC. EXHIBIT 1021 PAGE 1
`
`

`
`18TH %'K
`
`EDITION
`
`’
`
`Bxemington s
`
`ALFONSO R GENNARO
`Editor, and Chairman
`of the Editorial Board
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1021 PAGE 2
`
`

`
`1 990
`
`MACK PUBLISHING COMPANY
`
`Eoston, Pennsylvania 18042
`
`MYLAN PHARMS. INC. EXHIBIT 1021 PAGE 3
`
`

`
`
`
`Entered according to Act of Congress, in the year 1885 by Joseph P Remington,
`in the Office of the Librarian of Congress, at Washington DC
`
`Copyright 1389, 1894, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by Joseph P Remington Estate
`Copyright 1948, 1951, by The Philadelphia College of Pharmacy and Science
`
`Copyright G) 1956, 1960, 1965. 1970, 1975, 1980. 1985. 1990, by The Philadelphia College of
`Pharmacy and Science
`.
`
`Ail Rights Reserved
`
`Library of Congress Catalog Card No. 60-53334
`ISBN 0-912734-04-3
`
`The use of structural formulas from USAN and the USP i")ic-tionary of Drug Names is by
`permission of The USP Convention. The Convention is not responsible for any inaccuracy
`contained herein.
`
`NOTICE-.‘—This text is not intended to represent, nor shah‘ it be interpreted to be, the equivalent
`of or a substitute for the officiai United States Pharmacopeia (USP) and/or the Nationai
`Farmuiary (NF).
`In the event of any difference or discrepancy between the current official
`USP or NF standards of strength, qaaiity, purity, pacizaging and labeling for drugs and
`representations of them herein. the context and effect of the official cornpendia shaii
`prevail.
`
`1.
`
`.
`
`Printed in the United States of America by the Mack Printing Company, Enston, Pennsyiuariia
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1021 PAGE 4
`
`

`
`
`
`-
`
`PART 2
`
`Pharmaceutics
`
`Edward G Bippie PhD
`Professor of Phnrmacemlu
`University" of
`nesota
`Mlnneopolls
`55455
`
`MYLAN PHARMS. INC. EXHIBIT 1021 PAGE 5
`
`

`
`no
`
`UHAPI l:H 9
`
`2. The product of the means divided by one extreme
`gives the other extreme.
`3. The product of the extremes divided by one mean
`gives the other mean. Therefore, if any three terms of a
`proportion are known, the fourth can be found by simple
`calculation.
`
`In solving problems involving proportions the following
`procedure may be used.
`
`First—-Let the unknown quantity be represented by X and let it be the
`fourth term.
`
`Second—-Let the third term he that number in the question which
`express the same kind of value (unit) as is expected in the answer.
`Third-—Arrange the remaining two quantities in the same ratio as the
`third term and X. Thus, the first and second terms will express the
`same kind of values (units) and the third and fourth terms will express
`the same kind of values.
`If the answer sought (X) is to be greater than
`the third term, the second term will be larger than the first, and vice
`verso.
`'
`
`Foo:-.rh—To solve for X, divide the product of the means by the known
`extreme. Cancel to simplify. Since the first and second terms form a
`ratio, common factors may be removed without altering the ratio; since
`the first and third terms are actually numerators of equal fractions, they
`can be divided by the same number without changing the proportion.
`
`Example
`
`100 g of a drug cost $1.80. How much will 25 g cost‘?
`
`If the three quantities in the problem, namely 100 g, $1.80 and 25 g are
`considered, it will be seen readily that 100 g bears the same relation to 25
`g as $1.80 does to the unlmown quantity to be calculated.
`In other
`words, the quantities and prices form equal ratios. The following pro-
`portion can be made
`
`100 g:25 g::$1.80:$X
`
`There are three known terms in the statement and X, the unknown term.
`Arithrnetically, the product of the means must equal the product of the
`extremes. Therefore, if one of the extremes is unknown, it may be
`calculated by dividing the product of the means by the known extreme.
`
`X =
`
`100 g
`
`= $945
`
`While the proportion is set down preferably as given above, it may be
`stated in several other ways. These are given below merely to show their
`relationship to the original form. It may be stated as two equal ratios in
`equation form
`
`100 E = $1.80
`25 g
`X
`
`Keeping in mind the basic three rules, it also is possible to place the
`unknown quantity, X, in either the first. second or third position as long
`as the relationship of the three known terms is not altered. Thus, the
`problem may be written as
`
`2. One pound of a chemical cost $7.65. What is the cost
`of sufficient chemical needed to make 10,000 capsules con-
`taining 0.2 g of the chemical?
`See also the preparation of isotonic solutions by propor-
`tion, Chapter 79.
`
`Percentage
`
`Percent, written as %, means per hundred. Fifteen per-
`cent is written 15% and means 15/399, 0.15, or 15 parts in a
`total of 100 parts. Percent is a type of ratio and has no units.
`Thus, 10% of 1500 tablets is “Fm X 1500 tablets = 150
`tablets.
`
`To change percent to a fraction the percent number he-
`comes the numerator and 100 is the denominator. To
`change a fraction to percent, put the fraction in a form
`having 100 as its denominator; multiply by 100 so that the
`numerator becomes the percent.
`
`_5o,
`50
`1i"g"‘fi, Td6X100=50%
`
`12.5
`, _ 12.5_
`fa Tm, T00 X 100
`
`=
`
`12.5%
`
`Calculations involving percentages are encountered contin-
`ually by pharmacists. They must be familiar, not only with
`the arithmetical principles, but also with certain compendial
`interpretations of the different type percentages involving
`solutions and mixtures.
`The USP states
`
`Percentage concentrations of solutions are expressed as follows:
`Percent weight in wer'gh.'.'—-(who) expresses the number of g of a
`constituent in 100 g of solution.
`Percent weight in uolume—-{w/u} expresses the number of g of a
`constituent in 100 1:11.. of solution. and is used regardless of whether
`water or another liquid is the solvent.
`Percent volume in uol'mne—(v/o) expresses the number of mL of a
`constituent in 100 ml. of solution.
`The term percent used without qualification means, formixtures of
`solids, percent weight in weight; for solutions or suspensions of solids in
`liquids, percent weight in volume; for solutions of liquids in liquids,
`percent volume in volume; and for solutions of gases in liquids, percent
`weight in volume. For example. a 1 percent solution is prepared by
`dissolving 1 g of a solid or 1 ml. of a liquid in sufficient of the solvent to
`make 100 mL of the solution.
`In the dispensing of prescription medications, slight changes in vol-
`ume owing to variations in room temperature may be disregarded.
`
`OI‘
`
`Ci!
`
`25 $100 g_::X:$1.80 (Rule 3)
`
`mm;-92 = $0.45
`100 g
`
`$1.80:X::100 g:25 g (Rule 3)
`
`$1.80 X 25 g = 0.45
`100g
`$
`
`X:$1.80::25 g:100 g (Rule 2)
`
`$1.80 x 25 =
`$0.45
`———Emg
`Obviously, the method of ratio and proportion can be used to solve more
`involved problems.
`
`Problems
`
`Ratio Strength
`
`This is another manner of expressing strength. Such
`phrases as “1 in 10” are understood to mean that 1 part by
`volume of a liquid is to be diluted with, or 1 part by weight of
`a solid dissolved in, sufficient of the solution to make the
`finished solution 10 parts by volume. For example, a 1:10
`solution means 1 mL of a liquid or 1 g of a solid ‘dissolved in
`sufficient solvent to make 10 mL of solution.
`It can be
`converted to percent by
`
`1 g:10 mL::X g:100 mL
`
`X = 10 g in 100 mL of solution which is 10%
`The expression “parts per thousand” leg, 1-5000) always
`means parts weight in volume when dealing with solutions of
`solids in liquids and is similar to the above expression. A
`1-5000 solution means 1 g of solute in sufficient solvent to
`make 5000 mL of solution. This can be converted to percent
`by
`
`If a drug costs $3.00/g, how.mudh would 65 mg cost?
`1.
`How much would 5 gr cost?
`
`1 g:5000 mL::X g:100 mL
`
`X = 0.02 g in 100 mL solution which is 0.02%
`
`MYLAN PHARMS. INC. EXHIBIT 1021 PAGE 6
`
`

`
`SOLUTIONS AND PHASE EOUILIBRIA
`
`218
`
`Table IV-—SolubIlItlas of Potassium Iodide and Sodium
`Chloride In Several Alcohols and Acetone‘j.
`g KI!
`g Nacll
`
`100 9 SolventSolvent 100 g Solvent_j
`
`
`
`35.9
`8.3 I20“)
`7.1 I30")
`1.4
`
`.
`
`148
`
`. . .
`
`Water
`Glycerin
`50
`Propylene Glycol
`17
`Methanol
`. .
`2.9
`Acetone
`0.065
`1.38
`Ethanol
`0.0124
`0.44
`I-Propanol
`0.003
`0.18
`2-Propanol
`0.005
`0.20
`1-Butanol
`
`
`0.0891-Pantanol 0.0018.
`' All measurements are at 25°C unless otherwise indicated.
`
`water-structuring. Such an unfavorable entropy change is
`quite significant in the solution process. As an example of
`this effect, the aqueous solubility of a series of alkyl p-
`aminobenzoates shows a ten million-fold decrease in solubil-
`ity in going from the 1-carbon analog to the 12-carbon ana-
`log. These findings demonstrate clearly the considerable
`effect that hydrophobic associations can have.
`Alcohols—Ethonol, as a solvent, is next in importance to
`water. An advantage is that growth of microorganisms does
`not occur in solutions containing alcohol in a reasonable
`concentration.
`
`Resins, volatile oils, alkaloids, glycosides, etc are dissolved
`by alcohol, while many therapeutically inert principles, such
`as gums, albumin and starch, are insoluble, which makes it
`more useful as a “selective” solvent. Mixtures of water and
`alcohol, in proportions varying to suit specific cases, are used
`extensively. They are often referred to as hydroolcoholic
`solvents.
`
`Glycerin is an excellent solvent, although its range is not
`as extensive as that of water or alcohol. In higher concentra-
`tions it has preservative action.
`It dissolves the fixed alka-
`lies, a large number of salts, vegetable acids, pepsin, tannin,
`some active principles of plants, etc, but it also dissolves
`gums, soluble carbohydrates, starch, etc. It is also of special
`value as a simple solvent, as in phenol glycerite, or where the
`major portion of the glycerin simply is added as a preserva-
`tive and stabilizer of solutions that have been prepared with
`other solvents (see Glycerines, Chapter 34).
`Propylene glycol, which has been used widely as a substi-
`tute for glycerin, is miscible with water, acetone or chloro-
`form in all proportions.
`It is soluble in ether and will dis-
`solve many essential oils but is immiscible with fixed oils.
`It
`is claimed to be as effective as ethyl alcohol in its power of
`inhibiting mold growth and fermentation.
`Isopropyl alcohol possesses solvent properties similar to
`those of ethyl alcohol and is used instead of the latter in a
`number of pharmaceutical manufacturing operations.
`It
`has the advantage in that the commonly available product
`contains not over 1% of water, while ethyl alcohol contains
`about 5% water, often a disadvantage.
`lsopropyl alcohol is
`employed in some liniment and lotion formulations. It can-
`not be taken internally.
`General Properties—Low-molecular-weight and polyhy-
`droxy alcohols form associated structures through hydrogen
`bonds just as in water. When the carbon-atom content of an
`alcohol rises above five, generally only monomers then are
`present in the pure solvent. Although alcohols have high
`dielectric constants, compared to other types of solvents,
`they are small compared to water. As has been discussed,
`the solubility of salts in a solvent should be paralleled by its
`dielectric constant. That is, as the dielectric constant of a
`series of solvents increases, the probability of dissolving a
`salt in the solvent increases. This behavior is observed for
`the alcohols. Table IV, taken from I-Iiguchi,‘ shows how the
`solubility of salts follows the dielectric constant of the alco-
`hols.
`
`As mentioned earlier, absolute alcohol rarely is used phar-
`maceutically. However, hydroalcoholic mixtures such as
`elixirs and spirits frequently are encountered. A very useful
`Eeneralization is that the dielectric properties of a mixed
`solvent, such as water and alcohol, can be approximated as
`the weighted average of the properties of the pure compo-
`nents. Thus, a mixture of 60% alcohol (by weight) in water
`should have a dielectric constant approximated by
`
`‘(mama-:3 = 9-Mftaimhalil "' 0-4l‘twau-.nl
`
`r,,,,,,,,,,,, = o.e(2s} + o.4(so) = 47 .
`
`The dielectric constant of 60% alcohol in water is found
`
`experimentally to be 43, which is in close agreement with
`that just calculated. The dielectric constant of glycerin is
`46, close to the 60% alcohol mixture. One would, therefore,
`expect a salt like sodium chloride to have about the same
`solubility in glycerin as in 60% alcohol. The solubility of
`sodium chloride in glycerin is 8.3 g/100 g of solvent and in
`60% alcohol about 6.3 g/100 g of solvent. This agreement
`would be even closer if comparisons were made on a volume
`rather than weight basis. At least qualitatively it can be
`said that the solubility of a salt in a solvent or a mixed
`solvent very closely follows the dielectric constant of the
`medium or, conversely, that the polarity of mixed solvents is
`paralleled by their dielectric constant, based on salt solubili-
`ty.
`
`Although the dielectric constant is useful in interpreting
`the effect of mixed solvents on salt solubility, it cannot be
`applied properly to the effect of mixed solvents on the solu-
`bility of nonelectrolytes.
`It was seen earlier that unfavor-
`able entropic effects can occur upon dissolution of relatively
`nonpolar nonelectrolytes in water. Such an effect due to
`hydrophobic association considerably affects solubility.
`Yalkowskyil studied the ability of cosolvent systems to in-
`crease the solubility of nonelectrolytes in polar solvents
`where the cosolvent system essentially brings about a reduc-
`tion in structuring of solvent. Thus, by increasing, in a
`positive sense, the entropy of solution by using cosolvents, it
`was possible to increase the solubility of the nonpolar mole-
`cule. Using as an example the solubility of alkyl p-amino-
`benzoates in propylene glycol-water systems, Yalkowslry5
`reported that it is possible to increase the solubility of the
`nonelectrolyte by several orders of magnitude by increasing
`the fraction of propylene glycol
`in the aqueous system.
`Sometimes, it is found that, as a good first approximation,
`the logarithm of the solubility is related linearly to the frac-
`tion of propylene glycol added by
`
`log S, = log S,_o 4- cf
`
`where S; is the solubility in the mixed aqueous system con-
`taining the volume fraction f of nonaqueous cosolvent, S;..;
`is the solubility in water and e is a constant (not dielectric
`constant} characteristic of the system under study. Specif-
`cally, when a 50% solution of propylene glycol in water is
`used, there is a 1000-fold increase in solubility of dodecyl p-
`aminobcnzoate, in comparison to pure water.
`In a series of studies, Martin at at‘; have made attempts to
`predict solubility in mixed solvent systems through anes-
`tension of the “regular solution" theory. The equations are
`logarithmic in nature and can reduce in form to the equa-
`tions of Yalkowskyfi
`Acetone and Related Semipolar Mater-ials—Even
`though acetone has a very high dipole moment (2.8 X 10"“
`esu}, as a pure solvent it does not form associated structures.
`
`MYLAN PHARMS. INC. EXHIBIT 1021 PAGE 7
`
`

`
`must possess the ability to keep the solvated, charged ions
`apart with minimal energy. The role of the dielectric con-
`stant in keeping this energy to a minimum has been dis-
`cussed earlier.
`A polar liquid such as water may exhibit solvent action
`also by virtue of its ability to break a covalent bond in the
`solute and bring about ionization of the latter. For example,
`hydrogen chloride dissolves in water and functions as an acid
`as a result of
`
`+ H20 —’ H3O+ + C]-
`
`The ions formed by this preliminary reaction of breaking the
`covalent bond subsequently are maintained in solution by
`the same mechanism as ionic salts.
`Still another mechanism by which a polar liquid may act
`as a solvent is that involved when the solvent and solute are
`capable of being coupled through hydrogen-bond formation.
`The solubility of the low-molecular-weight alcohols in water,
`for example, is attributed to the ability of the alcohol mole-
`cules to become part of a water-alcohol association complex.
`H
`R
`H
`R
`I
`I
`I
`I
`H—o....--H—o-..---H——o».-..H—o
`
`As the molecular weight of the alcohol increases, it becomes
`progressively less polar and less able to compete with water
`molecules for a place in the lattice-like arrangement formed
`through hydrogen bonding; high-molecular-weight alcohols
`are, therefore, poorly soluble or insoluble in water. When
`the number of carbon atoms in a normal alcohol reaches five,
`its solubility in water is reduced materially.
`When the number of hydroxyl groups in the alcohol is
`increased, its solubility in water generally is increased great-
`ly; it is principally, if not entirely, for this reason that such
`high-molecular-weight compounds as sugars, gums, many
`glycosides and synthetic compounds, such as the polyethyl-
`ene glycols, are very soluble in water.
`The solubility of ethers, aldehydes, ketones, acids and
`anhydrides in water, and in other polar solvents, also is
`attributable largely to the formation of an association com-
`plex between solute and solvent by means of the hydrogen
`bond. The molecules of ethers, aldehydes and ketones. un-
`like those of alcohols, are not associated themselves. because
`of the absence of a hydrogen atom which is capable of form-
`ing the characteristic hydrogen bond. Notwithstanding,
`these substances are more or less polar because of the pres-
`ence of a strongly electronegative oxygen atom, which is
`capable of association with water through hydrogen-bond
`formation. Acetone, for example, dissolves in water, in all
`likelihood, principally because of the following type of asso-
`ciation:
`
`H I
`
`The maximum number of carbon atoms which may be
`present per molecule possessing a hydrogen-bondable
`group, while still retaining water solubility, is approximately
`the same as for the alcohols.
`Although nitrogen is less electronegative than oxygen and.
`thus, tends to form weaker hydrogen bonds, it is observed
`that amines are at least as soluble as alcohols containing an
`equivalent chain length. The reason for this is that alcohols
`form two hydrogen bonds with a net interaction of 12 kcal/
`mole. Primary amines can form three hydrogen bonds; two
`amine protons are shared with the oxygens of two water
`molecules, and the nitrogen accepts one water proton. The
`net interaction for the primary amine is between 12 and 13
`kcal/mole and, hence, it shows an equal or greater solubility
`compared with corresponding alcohols.
`'
`
`I‘)
`
`o E
`
`/..>
`CH,
`
`220
`
`CHAPTER 16
`
`H,c
`
`Fig 16-9. The charge separation In acetone.
`
`This is evidenced by its low boiling point (57°) in compari-
`son with the boiling point of the lower-molecular-weight
`water (100°) and ethanol (79°). The reason why it does not
`associate is because the positive charge in its dipole does not
`reside in a hydrogen atom (Fig 16-9), precluding the possi-
`bility of its forming a hydrogen bond. However, if some
`substance which is capable of forming hydrogen bonds, such
`as water or alcohol, is added to acetone, a very strong inter-
`action through hydrogen bonding will occur (see Mechanism
`of Solvent Action below). Some substances which are semi-
`polar and similar to acetone are aldehydes, low-molecular-
`weight esters, other ketones and nitro-containing com-
`pounds.
`Nonpolar Solvent:-3-This class of solvents includes fixed
`oils such as vegetable oil, petroleum ether (ligroin), carbon
`tetrachloride, benzene and chloroform. On a relative basis
`there is a wide range of polarity among these solvents; for
`example, benzene has no dipole moment while that of chlo-
`roform is 1.05 X 10'"3 esu. But even the polarity of these
`compounds normally classified as nonpolar is still in line
`with the dielectric constant of the solvent. The relation
`between these quantities is seen best through a quantity
`called molar refraction. The molar refraction (or refractivi-
`ty), R, of a compound is given by
`
`R =
`
`l'l2—l_M
`n2+2 D
`
`(19)
`
`where n is the refractive index of the liquid, M is its molecu-
`lar weight and D is its density. The similarity between Eq
`19 and Eq 16 is to be noted and, indeed, in refractive index
`measurements using very long wavelengths of light, n2 = 5.
`Thus, molar refraction under these conditions approximates
`total molar polarization. Since. in the more nonpolar sol-
`vents there is generally no dipole moment, u, total molar
`polarization reflects polarization due only to the induced
`dipoles possible. Thus
`
`P =—-.—=—.—=—«Na
`a
`n2 + 2 D
`
`(20)
`
`It is evident from this that the refractive index of a nonpolar
`compound reflects its relative polarity. For example, the
`more-polar benzene (e = 2.2) has a higher refractive index,
`1.501, than the less-polar hexane (e = 1.9), whose refractive
`index is 1.375.
`It should be emphasized again that when a solvent (such
`as chloroform) has highly electronegative halogen atoms at-
`tached to a carbon atom also containing at least one hydro-
`gen atom, such a solvent will be capable of forming strong
`hydrogen bonds with solutes which are polar in character.
`Thus, through the formation of hydrogen bonds such sol-
`vents will dissolve polar solutes. For example, it is possible
`to dissolve alkaloids in chloroform.
`
`Mechanism of Solvent Action
`
`A solvent may function in one, or more, of several ways.
`When an ionic salt is dissolved, eg, by water, the process of
`solution involves separation of the cations and anions of the
`salt with attendant orientation of molecules of the solvent
`about the ions. Such orientation of solvent molecules about
`the ions of the solute——a process called salvation (hydration,
`if the solvent is water)—is possible only when the solvent is
`highly polar, whereby, the dipoles of the solvent are attract-
`ed to and held by the ions of the solute. The solvent also
`
`MYLAN PHARMS. INC. EXHIBIT 1021 PAGE 8
`
`

`
`SOLUTIONS AND PHASE EQUILIBRIA
`
`221
`
`The solvent action of nonpolar liquids involves a some-
`what different mechanism. Because they are unable to form
`dipoles with which to overcome the attractions between ions
`of an ionic salt, or to break a covalent bond to produce an
`ionic compound or form association complexes with a solute.
`nonpolar liquids are incapable of dissolving polar com-
`pounds. They only can dissolve, in general. other nonpolar
`substances in which the bonds between molecules are weak.
`The forces involved usually are of the induced di-
`pole—induced dipole type. Such is the case when one hydro-
`carbon is dissolved in another, or an oil or a fat is dissolved in
`petroleum ether. Sometimes it is observed that a polar
`substance. such as alcohol. will dissolve in a nonpolar liquid,
`such as benzene. This apparent exception to the preceding
`generalization may be explained by the assumption that the
`alcohol molecule induces a temporary dipole in the benzene
`molecule which forms an association complex with the sol-
`vent molecules. A binding force of this kind is referred to as
`a permanent dipole—inducea' dipole force.
`Some Useful Generalizations—The preceding discussion indicates
`that enough is known about the mechanism of solubility to be able to
`formulate some generalizations concerning this important physical
`property of substances. Because of the greater importance of organic
`substances in the field of medicinal chemistry, certain of the more useful
`generalizations with respect to organic chemicals are presented here in
`summary form. It should be remembered, however. that the phenome-
`non of solubility usually involves several variables. and there may be
`exceptions to general rules.
`the greater
`One general maxim which holds true in most instances is:
`the structural similarity between solute and solvent, the greater the
`solubility. As often stated to the student. “like dissolves like." Thus.
`phenol is almost insoluble in petroleum other but is very soluble in
`glycerin.
`Organic compounds containing polar groups capable of forming hy-
`drogen bouds with water are soluble in water, providing that the molecu-
`lar weight of the compound is not too great.
`It is demonstrated easily
`that the polar groups OI-I, CI-IO. COH, Cl-I01-I. CH10H. C001-l. Nflg,
`C0. NH: and S031! tend to increase the solubility of an organic com-
`pound in water. Do the other hand. nonpolar or very weal: polar groups.
`such as the various hydrocarbon radicals. reduce solubility: the greater
`the number of carbon atoms in the radical. the greater the decrease in
`solubility.
`Introduction of halogen atoms into a molecule in general
`
`Table V—DamonsIral|on of Solublllty Rules
`
`
` Chemical Compound Solubility‘
`
`28.6
`Aniline. C.;H.,Nl-lg
`1430
`Benzene. C.;Hg
`275
`Benzoic acid. Cal-l5C00H
`25
`Benzyl l1l(.‘0l'l0l. CsH5CHg0l'l
`12
`1-Butanol, C4Hg0H
`Miscible
`t-Butyl alcohol. {Cl-l3)3COI-I
`2000
`Carbon tetrachloride. CCI4
`200
`Chloroform. Cl-lCl3
`150
`Fumaric acid. trans-butenedioic acid
`14
`Hydroquinone, Cal-I.4(OH)2
`5
`Maleic acid. cis-butenedioic acid
`15
`Phenol. Cal-l5OH
`2.3
`Pyrocstechol. Cal-I4(Ol-l);
`1.7
`Pyrogallol. Cal-l;;(OH}3
`
`Resorcinol, C31-l.(OH)g 0.9
`
`“ The number of ml. of water required to dissolve 1 g of solute.
`
`tends to decrease solubility because of an increased molecular weight
`without a proportionate increase in polarity.
`The greater the number of polar groups contained per molecule. the
`greater the solubility of a compound. provided that the sire of the rest of
`the molecule is not altered; thus. pyrogallol is much more soluble in
`water than phenol. The relative positions of the groups in the molecule
`also influence solubility; thus, in water, resorcinol (tn-dihydroxyberv
`zone} is more soluble than catechol {o-dihydroxybenzene}. and the latter
`is more soluble than hydroquinone (p-dihydroxybenzene).
`Polymers and compounds of high molecular weight generally are insol-
`uble or only very slightly soluble.
`High melting points frequently are indicative of low solubility for
`organic compounds. One reason for high melting points is the associa-
`tion of molecules and this cohesive force tends to prevent dispersion of
`the solute in the solvent.
`The cis form of an isomer is more soluble than the trans form. See
`Table V.
`Salvation, which is evidence of the existence of a strong attractive
`force between solute and solvent, enhances the solubility of the solute.
`provided there is not a marked ordering of the solvent molecules in the
`solution phase.
`'
`Acids. especially strong acids, usually produce water-soluble salts
`when reacted with nitrogen-containing organic bases.
`
`Colligative Properties of Solutions
`Up to this point concern has been with dissolving a olute
`Osmotic-Pressure Elevation
`in a solvent. Having brought about the dissolution, the
`solution. quite naturally. has a number of properties which
`are different from that of the pure solvent. Of very great
`importance are the colligotive properties which a solution
`Possesses.
`
`The colligative properties of a solution are those that
`depend on the number of solute particles in solution. irre-
`spective of whether these are molecules or ions, large or
`Small. Ideally. the effect of a solute particle of one species is
`considered to be the same as that of an entirely different
`kind ofparticle, at least in dilute solution. Practically. there
`may be differences which may become substantial as the
`concentration of the solution is increased.
`The colligative properties which will be considered are:
`
`1- Osmotic pressure.
`2- V3???-liressure lowering.
`3- Bfllllug-point elevation.
`4‘ F“’331l1.E-point depression.
`
`Of these four. all of which are related. osmotic pressure
`hi!” the 8'1'eatest direct importance in the pharmaceutical
`sciences.
`It is the property that largely determines the
`phyamlflgical acceptability of a variety of solutions used for
`therapeutic Purposes.
`
`Diffusion in Liquids—-Although the property of diffu-
`sion is rapid in gaseous systems. it is not limited to such
`systems. That molecules or ions in liquid systems possess
`this same freedom of movement may be demonstrated by
`placing carefully a layer of water on a concentrated aqueous
`solution of any salt.
`In time it will be observed that the
`boundary between solvent and solution widens gradually
`since salt moves into the water layer and water migrates
`from its layer into the salt solution below. Eventually, the
`composition of the new solution will become uniform
`throughout. This experiment indicates that substances
`tend to move or diffuse from regions of higher concentration
`to regions of lower concentrations so that differences in
`concentration eventually disappear.
`0smosis—ln carrying out the experiment just described.
`it is impossible to distinguish between the diffusion of the
`solute and that of the solvent. However, by separating the
`solution and the solvent by means of a membrane that is
`permeable to the solvent. but not to the solute (such a mem-
`brane is referred to as a semipermeable membrane), it is
`possible to demonstrate visibly the diffusion of solvent into
`the concentrated solution, since volume changes will occur.
`In a similar manner. if two solutions of different concentra-
`
`MYLAN PHARMS. INC. EXHIBIT 1021 PAGE 9
`
`

`
`1314
`
`CHAPTER 66
`
`Uses-Contains ester and alcohol functions that impart both
`lyophilic and hydrophilic characteristics to make it useful as a sur-
`factant and emulsifier.
`It is an ingredient of some Waluehsoluble
`ointment and cream bases,
`
`Polysorbates
`
`d‘yl) derive. Monitans (Ives-
`.1_2. th
`(
`Sorbitan esters, pol
`Camerony>;‘§‘3z1ate§xA‘i,'L5.:});weens ucn
`*O(C,H.ol.,
`,..ioc,H.l. 0"
`H
`
`0
`
`¢::(oc,H.),ou
`u,c(oc,HJ.R
`[5“,,., 04 y'g_y. and 2 -I 20.
`R -1 lC.u"::lC°° l
`
`forming sorbitan (a cyclic sorbitol anhydride); (2) partial esterifica.
`tion of the sorbitan with a fatty acid such as oleic or stearic acid
`yielding a hexitan ester known commercially as a Span and (3)
`chemical addition of ethylene oxide yielding a Tween (the polyox.
`yethylene derivative).
`Description—Polysorbate 80: Lemon- to amber-colored, oily liquid-
`faint, characteristic odor; warm, somewhat bitter taste; specific gravity
`1.07 to 1.09; pH (1:20 aqueous solution) 6 to 8.
`Solubility—Polysorbate 80: Very soluble in water, producing an
`odorless and nearly colorless solution; soluble in alcohol, cottonseed oil
`corn oil, ethyl acetate, methanol or toluene; insoluble in mineral oil.
`
`’
`
`Uses——§ec_ause of their hydrophilic and lyophilic characteristics,
`these nomomc surfactants are very useful as emulsifying agents
`forming 0/W emulsions in pharmaceuticals, cosmetics and other
`types of products. Polysorbate 80 is an ingredient in Coal Tar
`Ointment and Solution. See Glycol Ethers (page 1313).
`
`Sorbitan esters, polyoxyethylene derivatives; t'atty_acid esters of
`sorbitol and its anhydrides copolymenzed with a varying number of
`moles of ethylene oxide. The NF recognizes: Polysorbate 20
`(structure given above), a laurate ester; Polysorbate 40, a palmitate
`ester; Polysorbate 60, a mixture of stearate and palmitate esters;
`and Polysorbate so. an oleate ester-
`Prepa,rat,ion—The8e important nonionic surfactants (page 268)
`an mepared awning with sorbitol by (1) elimination of water-
`
`Other Water-Soluble Ointment Base Component
`Polyethylene Glycol 400 Monostearate USP XVI—An ether. alco-
`hol and ester. Semitransparent, whitish. odorless or nearly odorless
`mass; melts from 30 to 34°. Freely soluble in carbon tetrachloride.
`chloroform, ether or petroleum benzin; slightly soluble in alcohol; insolu-
`ble in water. Uses: A nonionic surface-active agent in the preparation
`of creams, lotions, ointments and similar pharmaceutical preparations,
`which are readily soluble in water.
`
`Pharmaceutical Solvents
`
`The remarkable growth of the solvent industry is attested
`by the more than 300 solvents now being produced on an
`industrial scale. Chemically, these include a great variety of
`organic compounds, ranging from hydrocarbons through al-
`cohols, esters, ethers and acids to nitroparaffins. Their
`main applications are in industry and the synthesis of organ-
`ic chemicals. Comparatively few, however, are used as sol-
`vents in pharmacy, because of their toxicity, volatility, insta-
`bility and/or flammability. Those commonly used as phar-
`maceutical solvents are described in this section.
`
`AC9lOfl9
`
`2-Propanone; Dimethyl Ketone
`
`CH3COCH3
`
`Acetone [67-64-1] c,H.,o (58.08).
`Caution—It is very flammable. Do not use where it may be
`ignited.
`Prepar-ation—Formerly obtained exclusively from the destruc-
`tive distillation of wood. The distillate. consisting principally of
`methanol, acetic acid and acetone was neutralized with lime and the
`acetone was separated from the methyl alcohol by fractional distilla-
`tion. Additional quantities were obtained by pyrolysis of the calci-
`um acetate formed in the neutralization of the distillate.
`It now is obtained largely as a by-product of the butyl alcohol
`industry. This alcohol is formed in the fe