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`PDA Journal
`of Pharmaceutical Science and Technology
`
`PDA
`
`Parenteral Drug Association
`
`Solubility Concepts and Their Applications to the Formulation
`of Pharmaceutical Systems Part I Theoretical Foundations
`Gordon L Flynn
`
`PDA J Pharm Sci and Tech 1984 38 202209
`
`Abraxis EX2055
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
`
`

`

`PARENTERAL
`
`FUNDAMENTALS
`
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`Solubility Concepts and Their Applications to the Formulation of
`
`Pharmaceutical Systems
`
`Part I Theoretical Foundations
`
`GORDON L FLYNN
`
`The University of Michigan College of Pharmacy Ann Arbor Michigan
`
`1 Solubility Fundamentals
`
`The subject of solubility is of fundamental
`importance
`to the student and formulating scientist as everyday deci
`the design and use of dosage forms are
`sions concerning
`affected by the ease and extent to which drugs and excipi
`ents dissolve The study of solubility also puts the student
`and formulating scientist in touch with a practical subject
`whose understanding draws deeply from the thermody
`namic wellspring and which provides through pragmatic
`example a working feel for the intermolecular interactions
`which is the basis of all physical behavior No other sub
`ject of comparable utility serves so admirably as an ex
`ercise in the study of these thermodynamic and intermolec
`ular spheres and for this reason alone solubility theory
`interesting to the scientifically
`
`should be profoundly
`minded
`A Solubility and Drug System Performance The sol
`ubility of a chemical
`is more often than not a determining
`
`factor of its ultimate usefulness as a drug or as an excipient
`or even for other purposes A drugs solution behavior rel
`ative to its dose may dictate the type of physical system most
`the drug A drugs
`appropriate for administration of
`aqueous solubility may also influence the choice of ad
`ministration route and even the administration technique
`via that route For example certain poorly water soluble
`drugs such as diazepam and phenytoin are formulated for
`solutions containing
`parenteral purposes in semiaqueous
`high percentages of water miscible organic solvents Such
`systems must be given exclusively by vein and also at very
`slow rates of injection To do otherwise results in precipi
`tation within the injection site even including precipitation
`flowing stream In the latter
`instance
`in the veins fast
`blockage of small blood vessels downstream of the injection
`point occurs with the possibility of serious untoward effects
`like phlebitis There are also situations where limited sol
`ubility may be advantageous Insolubility in water for in
`stance offers the pharmaceutical scientist a ready means
`of prolonging drug release as is done with depotinject
`ables
`
`Some of the ways solubilities of drugs influence formu
`lation and more specifically
`the elementary processes
`governing a drugs biologic availability and interactivity
`should be considered A schematic representation of the fate
`of an administered drug is provided in Figure 1 Generally
`drug dissolution and other mass transfer processes
`involving
`drug passage through actual membranes and drug binding
`involved Under certain cir
`to biological receptors are all
`cumstances any of these processes may be rate limited by
`the solubility of the involved drug
`The rate of solution of a drug administered as a solid mass
`tablet capsule or even an injected depot
`is determined by
`its effective state of subdivision by mixing in the physiologic
`mileau which determines the local biological hydrody
`namics and by the prevailing degree of saturation of the
`drug in the physiologic fluids Equation 1 describes the
`dissolution reaction in terms of the amount of substance
`dM dissolving in a small
`
`increment of time cit 1
`= BA C
`Eq 1
`
`dt
`
`Here B is a mass transfer coefficient or dissolution rate
`coefficient A is the effective surface area C is the drugs
`solubility and also its concentration
`at the interface of the
`solid surface with the dissolving medium and Cb is the bulk
`phase concentration The mixing action of local fluid flow
`the solids surface is the primary factor determining
`over
`the dissolution rate coefficient and the more forceful
`the
`the value of B Therefore
`shearing action is the larger
`vigorous stirring accelerates solution rates However hy
`drodynamics and therefore the dissolution coefficient
`be controlled in vivo The effective state
`normally cannot
`of subdivision of a solid and the nature of the solid surface
`determine the effective surface area for the dissolution re
`action Reducing particle size increases the actual surface
`the particles remain aggregated they may dis
`area but if
`solve as slowly as a single large mass Thus dispersibility of
`particulates as well as size reduction must receive a great
`deal of developmental attention especially for drugs which
`
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`Solid form of drug at point
`of administration
`
`1
`
`dissolution
`
`dissolved state of drug at
`point of administration
`
`2
`
`1
`
`diffusion across
`bOdy
`membranes andor
`into
`living tissues
`the local
`
`drug in local circulation
`blood andor lymph
`
`3 Idistribution
`
`by
`circulating blood or
`
`lymph
`
`drug distributed in bodys
`central compartment
`
`renal
`
`6 N collection
`
`drug excreted
`
`7
`
`metabolism in
`Liver and other
`tissues
`
`drug metabolically
`eliminated
`
`4
`
`diffusion into
`remote organs
`or peripheral
`tissue
`
`drug at
`
`response points
`
`5
`
`I
`
`drug receptor
`interaction
`
`receptor site occupation
`and pharmacological
`response
`
`Figure 1
`
`have solubility related absorption problems by the oral
`route The ultimate limit on the rate of solution however
`is the solubility itself From drug to drug it exhibits the
`the dissolution rate de
`widest extremes in its values of all
`termining parameters For a specified drug it also sets the
`upper limit on the concentration differential Cs CO
`Sometimes the solubility of a given drug can be manipulated
`through physical methods such as the preparation of high
`free energy polymorphic and solvate crystalline forms On
`other occasions solubility may be chemically tailored as
`done through prodrug approaches Since solubility is the
`main factor differentiating compounds with regard to dis
`solution abilities it has an enormous impact on the selection
`of a drug candidate from the many congeners available to
`be developed and marketed
`In the absorption distribution metabolism and elimi
`nation scheme outlined in Figure I the second indicated
`step is absorption In very general descriptive terms this
`involves diffusion from a region of external application to
`another region inside of a tissue where the drug either is
`active local effect or where it gains entrance to the cir
`culatory system No matter whether a discrete membrane
`is involved or not there is a thickness of tissue which acts
`as a barrier to diffusion Once the drug has gained entrance
`to the downstream side of the barrier the rate of the mass
`
`transfer process can be described by 2
`
`Vol 38 No 5 SeptemberOctober
`
`1984
`
`dM
`
`dt
`
`= PA C0
`
`Eq 2
`
`This equation has the same form as the dissolution equation
`but now Midi is the amount of the drug penetrating the
`barrier in an instant of time A is the area of the application
`or the area of the membrane involved and P is another mass
`termed the permeability coefficient The
`transfer coefficient
`value of P is determined by the ease of diffusion of the drug
`in the various phases of the membrane and by the thickness
`of the membrane factors set apart from solubility but it
`is also in part determined by distribution coefficients be
`tween the application and the membranes phases which
`can be viewed as relative solubilities The bracket term Co
`CO is the difference in concentration of the permeant on
`opposite sides of the barrier and is often simply represented
`by AC In many cases Ci represents the systemic concen
`the drug and as such is generally negligibly
`tration of
`small Regardless barring supersaturation ACs magnitude
`is at its maximumwhen Co the concentration of the drug
`at the point of application represents a saturated state
`Eq 3
`
`ACmax = Cs Ci
`
`In this manner solubility directly sets an upper limit on
`absorption rates
`receptors can
`Even the occupation of a set of biological
`be directly related to the saturated state of a solution al
`though this is normally not the case Usually a drugs action
`is remote from the site of administration in which case
`solubility only figures remotely in the eliciting of a response
`There are however some exceptional instances where the
`active sites are more or less directly accessed For example
`the taste buds of the oral cavity are bathed by the fluids of
`orally administered liquids If binding of the solutes in such
`preparations to the taste response provoking sites on the
`taste buds follows Langmuirs sorption isotherm then the
`interaction may
`concentration
`dependency for this receptor
`
`be stated as
`
`F
`
`QC
`1 + QC
`
`Eq 4
`
`where F is the fraction of sites occupied Q is a constant
`describing the microscopic binding equilibrium between
`sites and surrounding medium and C is concentration in
`the medium Up to a point the higher the concentration
`the greater the fractional coverage of the receptors and in
`turn the greater the response It
`is possible for essentially
`full coverage and maximal response to be obtained at a
`solution concentration less than saturation depending on
`the magnitudes of Q and C However when the product of
`QC falls well short of unity all
`the way to the drugs solu
`bility then the maximum site coverage and associated re
`the saturated solution condition in the
`sponse occurs at
`aqueous environment of the receptor Normally as a drug
`is modified chemically and made more hydrophobic the
`magnitude of the binding constant Q is increased How
`ever solubility in an aqueous medium as found in the oral
`is invariably affected in the opposite direction
`environment
`With some irregularity aqueous solubilities of homologs
`tend to be suppressed to an even greater extent
`than receptor
`
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`site binding constants are increased Thus the product Q
`Cs tends to smaller and smaller values as the chain length
`hydrophobicity n lengthens Because of this it
`is possible
`to make long alkyl chain derivatives with little or no ten
`dency to evoke a taste response What
`in effect happens
`is that the solidsolution equilibrium is driven down to a
`below the threshold for a response By such
`concentration
`methods noxiously bitter drugs like chloroamphenicol and
`clindamycin have been made reasonably palatable as pal
`mitate esters extending their use to pediatric patients
`To this point the solubility concerns considered are those
`governing the behavior of drugs during or after their ad
`ministration Earlier problems facing a formulator center
`around the initial preparation of solutions of drugs suitable
`for administration Limited solubility is especially trou
`blesome when injectable solutions are desired Problems here
`that some drugs are plainly poorly sol
`begin with the fact
`the solvent When severe toxicological
`uble no matter
`constraints on solvent choice are taken into account which
`limits physiologically tolerable solvents to water and a Few
`water miscible organics where injectibles are concerned
`formidable
`the task of solution preparation becomes
`Compounding the complexity drugs represent a diversity
`types Strong electrolyte salts weak electrolytes
`of chemical
`and non electrolytes of widely ranging polarity are all well
`in the drug armamentarium Each of these
`represented
`solute types must be approached differently in terms of
`techniques of solu
`solubilization For each
`type general
`bilization have become established mostly through years
`formulating experience The physical phenomena
`of
`underlying these approaches are only now becoming well
`understood Application of these concepts offers the for
`mulator swifter resolution of solubility related problems
`B General Thermodynamics Considerations
`in this review solubility refers specifically to the
`context
`solution equilibrium between a solute generally a solid in
`a defined state of crystallinity and a solvent This defines
`in mind
`the saturated solution condition It should be kept
`that a solute or solvent can technically by any state of
`matter Only those cases where liquid or solid solutes are
`dissolved in Liquid solvents are to be considered here
`forces within the pure solid solute or
`within the solute rich liquid phase where liquid in liquid
`solubility is concerned and within the solution phase de
`termine the position of the solubility equilibrium an un
`derstanding of these is necessary to interpret solubility
`involves an equilibrium the process of forming a
`Since it
`thermody
`saturated solution can also be treated with full
`namic rigor A description of the thermodynamic events
`interpreted in so far as possible in terms of intermolecular
`interactions presently provides the most
`to characterizing solution phenomena
`The second law of thermodynamics provides necessary
`and sufficient criteria for judging whether or not a system
`form the second law
`is at equilibrium In its most general
`the universe naturally tends towards its most
`states that
`random state This means that interacting systems chem
`ical or otherwise overall become increasingly disordered
`in the course of their spontaneous
`change Equilibrium
`within a system is achieved when the maximum possible
`
`In
`
`its
`
`Intermolecular
`
`insightful approach
`
`disorder for a system and its surroundings is attained For
`an isolated system literally one without contact with its
`surroundings equilibrium is attained when the systems
`reaches its attainable maximum Entropy is
`disorder itself
`the quantitative measure of the disorder and the second law
`of thermodynamics can be rephrased to say that in a spon
`taneously occurring process or reaction the entropy of the
`universe increases This is an unconditional statement The
`universe includes a system which is that part of the objec
`tive world isolated for thermodynamic study and the sur
`roundings which in pragmatic terms includes that part of
`the rest of the objective world capable of influencing events
`in the system Thus in an irreversible spontaneous pro
`cess
`
`ASuniverse =ASsystem
`
`ASsurroundings
`
`0 Eq 5
`
`in
`
`While overall entropy increases during spontaneous change
`there is no net change in the entropy of the universe for
`systems in equilibrium including the continuous equilib
`rium of the reversible process
`is usually possible to evaluate changes in the magni
`It
`tudes of critical
`thermodynamic variables state functions
`is not a straightforward
`within a system under study It
`matter however
`thermody
`to characterize concurrent
`namic events
`in the surroundings For this reason derivative
`restatements of Eq 5 were developed long ago which place
`the criteria for nonequilibrium and equilibrium strictly in
`terms of measurements within the system The most fa
`miliar and useful of these are the criteria based on Gibbs
`free energy The Gibbs criteria may only be applied to
`constant pressure isothermal processes in closed systems
`which involve no work but the work of expansion or com
`pression of the system socalled PV work These boundary
`conditions are the prevailing conditions for most laboratory
`investigations as experiments are most often carried out
`the open and at atmospheric pressure at ambient or ex
`perimentally fixed temperature and with conservation of
`a systems mass if not actually in a dosed system
`A systems Gibbs free energy decreases during sponta
`neous change providing the stated boundary conditions of
`temperature pressure and work are met Gibbs free energy
`is given the symbol G It follows for a process under con
`sideration that IAG1Tp only pv work <0 indicates a spon
`taneous irreversible process while AG TP only PV work
`0 indicates either a state of equilibrium or a process which
`can only be affected through the expenditure of work by
`definition a process which cannot proceed spontaneously
`temperature and pressure the Gibbs free energy
`At constant
`states of a system Gn
`change between final and initial
`Gi = AG is related to changes in the systems enthalpy
`heat content and entropy through
`AG = AH
`
`Eq 6
`TAS
`H1 = AH is the quantity of
`The enthalpy change 111
`heat absorbed or evolved by the system during the process
`to maintain its isothermal condition that is AH = qp for
`heat absorbed
`the constant pressure process By convention
`by a system is positive heat The terms AS or more for
`mally Si SI and T in Eq 6 are the entropy change and
`absolute temperature respectively
`
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`Since AG <0 characterizes spontaneous
`change in a
`the Gibbs free energy
`system processes continue until
`reaches its minimum value at which time the system is in
`equilibrium within itself and with its surroundings The
`greater the difference in Gibbs free energy between the
`systems prevailing state and its final equilibrium state the
`larger the possible AG for a process the further a system
`is from equilibrium and therefore the greater
`is the ultimate
`extent of reaction According to Eq 6 negative values of
`Ali and positive values of AS increase the negative mag
`nitude of AG and therefore favor reaction A negative value
`of AH is synonymous with an exothermic reaction con
`that reactions which
`sistent with the general observation
`heat up are spontaneous Absorption of thermal energy
`positive AH and increased system order negative AS
`
`are in the direction of limiting or forbidding self driven
`change These generalities apply to all processes chemical
`and physical
`During any reaction a system goes from some initial state
`to some final state Thus the solution reaction can be written
`as
`
`Solute + Solvent = Solution
`
`Initial State
`
`Final State
`
`Eq 7
`
`tact
`
`Once the solute and solvent reactants are placed in con
`and
`the solution process commences spontaneously
`the ca
`continues until
`there is either total solution or until
`to take up the solute is exhausted that
`pacity of the solvent
`is until a saturated solution is obtained Either way the
`Gibbs free energy change for the solution process may be
`generally described by
`AG = 2Gi Products
`
`2G1 Reactants Eq 8
`
`In the case of a solidsolution equilibrium where there is
`unreacted solute the excess undissolved solid appears as
`both reactant and product and its contribution to the free
`energy change cancels Therefore it need not be considered
`explicitly With this proviso it follows that
`Gsolute + Gsovent Eq 9
`where Gscdute refers only to that amount of solute which has
`actually dissolved In terms of enthalpy and entropy the
`equation becomes
`
`AGsolution
`
`process
`
`= Gsoiutiou
`
`AGsolution
`
`process
`
`= Hsolution
`
`TSsolution
`
`Hsolute + Hsolvent
`Ssolute + Ssolvent Eq 10
`
`thermodynamic reference states for the
`It remains to select
`solute and solvent For liquid solutes and solvents the pure
`liquid state is an especially convenient choice and the ef
`thermodynamic activities of liquid
`fective concentrations
`are taken as the ratios of their existing vapor
`components
`pressures to their neat liquid vapor pressures The standard
`state usually chosen for solid solutes is the melted solid
`cooled without crystallization to the temperature of the
`experiment the socalled super cooled liquid state This
`
`A closed system constant
`temperature and contrast pressure and only
`PV work are assumed in the remainder of the text and the reader should
`lose sight of these necessary boundary conditions
`not
`
`choice of solid reference state allows the solution phases
`formation to be treated simply as the mixing of two liquids
`Fusion and cooling of the solid to form the super cooled melt
`is then dealt with separately and additively which is per
`thermodynamically The free energy
`fectly acceptable
`change accompanying the formation of a solution from a
`solid non electrolyte solute and solvent
`is
`
`AGsolution
`
`process
`
`= solution
`Hsu
`SSCL
`
`TSsolution
`
`+ Hsolvent
`
`Ssol vent1
`
`ECI 11
`
`Here the subscript SCL refers to the super cooled liquid
`state and the subscript f refers to fusion In this equation
`the fusion terms are written with a superscript as techni
`cally they include in addition to the actual enthalpy and
`entropy of fusion changes in enthalpy and entropy ac
`companying the hypothetically separable heating of the
`solid solute to its melting point and cooling the formed melt
`to the experimental temperature A last technicality is that
`when more than one solution phase participates in the final
`equilibrium as with mutually saturated liquids the changes
`in the systems free energy enthalpy and entropy represent
`the summed changes in both distinct phases
`C Intermolecular Forces As mentioned earlier some
`forces which are outlined in
`knowledge of intermolecular
`Table I is also helpful
`in coming to grips with solubility
`phenomena All chemical and physical change except
`that
`involving subatomic particles is the consequence of a rear
`rangement of the chemical bonds holding atoms together
`as molecules and the physical bonds causing molecules
`to associate During reactions some bonds are broken and
`some new ones are formed with change in the internal en
`ergy of a system all of which is commensurate with a re
`arrangement of the participating atoms andor molecules
`At constant pressure the change in internal energy AE
`plus the energy gain or loss associated with the expansion
`or contraction of the system a part of the PV energy of a
`system yields the enthalpy change H The net gain or loss
`
`of atomic or molecular order is the microscopic basis of the
`entropy change AS
`Almost all solubility phenomena rest on the changing
`association of matter through physical bonds or more
`is only when there is
`forces It
`properly intermolecular
`ionization that any form of what we normally regard as
`chemical bonding specifically the energy to separate ions
`of unlike charge becomes a factor Among other things
`
`Intermolecular Forces
`
`TABLE I
`A Van der Wools Forces
`1 London Dispersion Interaction
`2 Debye Interaction
`3 Keesom Force of Dipole Dipole Bonding
`B Hydrogen Bonding
`C Ionic Interaciions
`1 Ion Ion Bonding
`2 Ion Dipole Bonding
`3 Ion Induced Dipole Interaction
`D Repulsive Forces
`
`Vol 38 No 5 SeptemberOctober 1984
`
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`
`for the condensed
`intermolecular
`forces are responsible
`states of most matter metals and salts excepted Like other
`interactive forces in nature they are electrostatic in origin
`they are far weaker in individual bond strength than are
`but
`the strong covalent and ionic bonds which link atoms in the
`molecular and ionic assemblies which exist at ordinary
`temperatures The summation of all
`intermolecular
`forces
`holding matter in a condensed form yields the cohesive
`energy or more formally the internal energy of cohesion
`of that matter This is readily experimentally estimated for
`pure constituents from the internal energies of vaporization
`neat
`liquids or sublimation solids as there is usually
`negligible net attractiveness in the formed gaseous states
`Therefore the net energy change solely represents that of
`molecular separation Cohesive energy on a per unit volume
`basis is referred to as the cohesive energy density When
`interactions between different materials are being consid
`ered cohesion is used to describe the interactions within the
`pure phases between like molecules while adhesion de
`scribes the interspecies attractiveness
`Of all
`interactions Londons
`the possible purely physical
`dispersion force and hydrogen bonding are of the greatest
`importance in solubility and solubilization at least in so far
`as nonelectrolytes are concerned When charged atoms or
`molecules are considered ion dipole interactions are also
`a principal solubility determining factor A listing of the
`types of intermolecular forces is presented in Table I There
`are three distinct categories van der Waals forces hydrogen
`bonding and ionic interactions A complete description of
`there
`these forces is outside of the scope of this review but
`in at least a little
`is reason to discuss aspects of the subject
`in order to correct a few widely held misconcep
`
`detail
`
`tions
`Van der Waals
`forces
`include three distinguishable
`modes of interaction namely the Londons dispersion force
`the Debye force and the Keesom force The first of these
`the London dispersion force or the force sometimes re
`ferred to as the induced dipole induced interaction is the
`most ubiquitous form of physical association of matter It
`the electronic
`through the coordination of
`is generated
`motions of the countless atoms comprising a finite system
`The electron motions of an atom are most correlated with
`those of its nearest neighbors and the induction time frame
`from atom to atom is measurable in terms of the time frame
`of electronic oscillations 1014 seconds The electron
`motions become less and less synchronized as the distance
`between atoms of
`in a condensed phase is in
`reference
`creased and ultimately the interaction passes from attrac
`tion to repulsion retardation Since the interaction be
`tween specific atoms decays rapidly with distance neigh
`boring atom interactions predominate and the net effect
`attraction The correlation length or distance over which
`the electronic fields are at least partially in phase and at
`tractive is related to the optical density of the material
`in
`dense media such as water and the
`question In nonoptically
`myriad organic liquids of the chemistry lab correlation
`lengths are measured in lens of centimeters Also of great
`consequence the electronic motions underlying the London
`accommodate to what are in relative
`force instantaneously
`terms slow translational movements of molecules which
`
`is
`
`is
`
`cause them to reorient
`
`in space Thus this force is inde
`juxtaposition As a result the
`pendent of intermolecular
`London force is relatively temperature insensitive
`A great misconception about Londons attractiveness
`the belief
`that the net attractiveness is exceedingly short
`ranged This is true for two isolated atoms considered as the
`sole interactants But
`in a condensed phase the proper
`summation of the interactions of all atoms over all other
`atoms which involves multiple integrals yields a net at
`tractiveness with long range character approaching that
`found between ions A second misconception
`about Lon
`is relatively weak Again this
`dons attractivenes is that it
`the focus is an isolated pair of atoms But in sum
`is true if
`mation over all atoms in a finite system the net attractive
`ness is hardly insignificant Since there is no preferred
`
`molecular orientation to this force its contribution to the
`cohesive energy per unit volume of semipolar and polar
`substances is with few exceptions far greater than that of
`co existing Debye and Keesom forces which on a single
`bond basis may appear
`far stronger This is readily seen in
`Tables II and III
`In Table II dispersion forces are roughly
`20 of the association energy of water despite its hydrogen
`bonding networks In Table III acetone with its strong di
`pole is seen to have but twice the cohesive energy density
`of alkanes of comparable molecular weight Butyl chlorides
`cohesive energy density is only marginally greater than
`hexanes When hydrogen bonding is possible however
`cohesive energy densities jump to high levels as seen in the
`alkanols polyols and water
`The Debye force involves the perturbation of the elec
`tronic structure of an atom or molecule by the permanent
`dipole of a neighboring molecule the socalled dipolein
`duced dipole interaction The net strength of this interaction
`depends on the strength of the dipole and the polarizability
`of the induced molecule This force is found when there are
`it generally makes a
`is never repulsive it
`
`dipolar molecular species present but
`minor contribution to cohesiveness
`
`It
`
`interaction to
`
`is not considered an orientating force
`The Keesom force arises as the result of interactions of
`two fixed dipoles In order for the individual
`be attractive the positive and negative centers of the two
`participating molecules have to be favorably oriented The
`strength of interaction depends on the dipole movements
`of the molecules and their relative positions in space It takes
`a strong dipole dipole bond to overcome the translation
`energies of molecules so that in most condensed phases of
`there is extensive cancellation of at
`dipolar substances
`tractiveness by pairs of molecules which have attained un
`favorable orientation as the consequence of thermally in
`duced motions Because of the orientational
`requirement
`Keesom forces are highly temperature sensitive
`Hydrogen bonding is a unique interaction in which a
`proton covalently attached to one electronegative
`center
`center The bond is
`shared with a second electronegative
`regarded as partly covalent and partly simple electrostatic
`The strength of the individual bond depends on the elec
`tronegativities of the centers sharing the proton and can be
`as much as 67 Kcalmole for bonds involving oxygen and
`nitrogen atoms fluorine is mentioned widely in hydrogen
`atom of
`bonding discussions
`as another electronegative
`
`is
`
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`TABLE II
`
`Force Contribution
`
`Substance
`
`Dispersion
`
`Ioduction
`
`H20
`NC
`HI
`NaC1
`
`C6I114
`
`215
`402
`618
`30
`696
`
`046
`024
`0027
`
`H bonding
`and
`
`Orientation
`
`869
`079
`0006
`
`Ion Ion
`
`M10
`
`180
`
`Total
`
`Internal
`
`Energy of
`Association
`
`Kw 25°C
`
`1130
`505
`621
`1830
`
`696
`
`Table In Cohesive Energies of Selected Organic Liquids
`
`Class and
`
`Substance
`
`HYDROCARBONS
`
`Propane
`nButane
`n Pentane
`nElexane
`
`Normal
`
`Boiling
`
`Point
`°C
`
`421
`05
`361
`687
`1024
`
`Molecular
`
`Solubility
`
`Parameter
`
`Weight
`
`ealian312
`
`Cohesive
`
`Energy
`
`Density
`calicm3
`
`Liquid
`
`Density
`gmicm3
`
`Molar
`
`Volume
`V
`cm3
`
`441
`
`581
`722
`862
`1002
`1142
`
`1283
`1423
`
`577
`659
`
`702
`727
`750
`754
`764
`774
`
`333
`434
`493
`
`529
`563
`569
`584
`599
`
`0493
`0573
`0622
`0655
`
`0679
`0699
`0714
`0727
`
`895
`1014
`
`1161
`1316
`1476
`1634
`1797
`1957
`
`Molar
`
`Cohesive
`
`Energy
`
`+01
`
`calmole
`
`2980
`4400
`5960
`
`nHeptane
`n Octane
`nNonane
`nDecane
`ALCOHOLS
`Methanol
`
`Ethanol
`
`nPropanol
`
`isoPropanol
`nButanol
`
`isoButanol
`
`nPentanol
`nHexanol
`
`nHeptanol
`nOctanol
`nNonanol
`nDecanol
`nUndecanol
`nDodecanol
`GLYCOLS DIOLS POLYOLS
`Ethylene glycol
`
`Propylene glycol
`13 Propane did
`
`123
`1488
`1725
`
`645
`783
`972
`825
`
`1177
`995
`1380
`1570
`1762
`1952
`2135
`2298
`2444
`2596
`
`1976
`1873
`
`2149
`2901
`Glycerol
`2070
`13 Butane diol
`OTHER MISCELLANEOUS SOLVENTS
`801
`Benzene
`347
`561
`
`Ether
`
`Acetone
`
`Butyraldehyde
`
`ButylchIoride
`
`Chloroform
`Carbon tetrachloride
`Water
`
`748
`784
`621
`765
`1002
`
`Vol 38 No 5 1 September October 1984
`
`3204
`4607
`601
`601
`7412
`7412
`
`8815
`10218
`11620
`13023
`14426
`15829
`
`17231
`18634
`
`6207
`761
`
`761
`9209
`9012
`
`7811
`7412
`5811
`7211
`
`9257
`1194
`1538
`
`1802
`
`1450
`1278
`1218
`
`1144
`1160
`1108
`1112
`1077
`1050
`1030
`1013
`1003
`
`985
`978
`
`1705
`1499
`1611
`1769
`1376
`
`916
`753
`962
`909
`837
`916
`855
`2353
`
`2103
`1633
`1484
`
`1909
`
`135
`
`123
`1237
`1160
`1103
`1061
`1026
`1006
`
`970
`957
`
`2907
`2247
`2595
`3129
`
`189
`
`839
`567
`925
`826
`701
`839
`731
`5537
`
`0787
`0785
`0799
`
`0781
`0806
`0802
`0811
`0815
`0819
`0822
`0825
`0826
`0828
`0830
`
`1110
`1033
`
`1050
`1259
`1004
`
`0874
`0708
`
`0785
`0797
`0881
`1480
`1585
`09971
`
`407
`587
`752
`
`770
`920
`924
`1087
`1253
`1419
`1584
`1750
`1915
`
`2080
`2246
`
`559
`737
`725
`732
`898
`
`894
`1047
`740
`905
`
`1051
`807
`970
`1807
`
`6960
`8310
`9300
`10490
`11730
`
`8560
`9580
`11160
`
`10070
`12420
`11370
`13440
`14540
`15650
`16810
`17950
`19270
`20180
`21480
`
`16270
`
`16550
`18810
`22710
`16970
`
`7500
`5940
`6840
`7480
`7370
`6770
`8090
`10010
`
`207
`
`

`

`Downloaded from journalpdaorg on June 26 2017
`
`consequence While it allows strong hydrogen bonding
`networks
`in hydrogen fluoride one should take note that
`the organic fluorine atom fluorine attached to a carbon
`atom is essentially devoid of hydrogen bonding ability and
`to aqueous solubility Car
`thus is a liability with respect
`boxylic acids on the other hand are capable of interacting
`strongly through a pair of H bonds and they
`exceedingly
`form relatively stable dimers in organic media through
`and glycols
`hydrogen bonding In water and alcohols
`structuring related to hydrogen bonding has a more fleeting
`is nevertheless highly significant within the
`time scale of molecular events Therefore such solvents
`
`nature but
`
`it
`
`exist
`
`in an ordered state relative to apolar solvents In water
`and the other mentioned polar solvents hydrogen bonding
`is the major contributor
`to the internal energy of cohesion
`but not so much so that the net Londons force is made in
`significant Because hydrogen
`bonding involves precise
`is a highly tem
`posturing of its molecular participants it
`perature sensitive interaction and it
`rapidly decays as
`temperature is raised
`The ion ion interaction is a strong and long range force
`is the dominant association
`f