Ion Pair Formation as a Possible Mechanism for the Enhancement Effect of Lauric Acid on the Transdermal Permeation of Ondansetron

PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY

Vol 9 No 3 pp 311ndash320 2004

RESEARCH ARTICLE

Ion Pair Formation as a Possible Mechanism for the Enhancement Effect ofLauric Acid on the Transdermal Permeation of Ondansetron

Dimitrios A Dimas Paraskevas P Dallas and Dimitrios M Rekkas

Division of Pharmaceutical Technology School of Pharmacy

University of Athens Panepistimiopolis Zografou

Athens Greece

ABSTRACT

Transdermal application can be an alternative drug delivery route for ondansetron an

antiemetic drug Previous studies found that fatty acids namely oleic and lauric were

the most effective penetration enhancers The aim of this study was to investigate the

formation of an ion pair between ondansetron and lauric acid as a possible mechanism

of its enhancing action Several techniques were used to reveal the formation of an ion

pair complex Partitioning experiments where the n-octanolwater coefficient was

measured showed an increase in the distribution coefficient in the presence of the

acid possibly as a result of the formation of more lipophilic ion pairs between the

charged molecules of ondansetron and lauric acid Further evidence of complex

formation between ondansetron and lauric acid was gained from the 13C-nuclear

magnetic resonance (13C-NMR) spectra of ondansetron lauric acid and their mixture

(molar ratio 11) The NMR spectra revealed alterations to the magnetic environment

of the carbon atoms adjacent to the ionized group which are the carbonyl group of the

acid and the nitrogen of the imidazole ring of ondansetron This evidence substantiates

the theory of ion pair formation Finally thermal analysis of the binary mixtures of

ondansetron and lauric acid revealed the formation of an additional compound with

different melting point from pure ondansetron and lauric acid which is thermody-

namically favored

Key Words Transdermal Ion pair Penetration enhancer Ondansetron

Correspondence Paraskevas P Dallas PhD Division of Pharmaceutical Technology School of Pharmacy University of Athens

Panepistimiopolis Zografou Athens 157 71 Greece Fax +30-210-7274027 E-mail dallaspharmuoagr

311

DOI 101081PDT-200031449 1083-7450 (Print) 1097-9867 (Online)

Copyright D 2004 by Marcel Dekker Inc wwwdekkercom

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INTRODUCTION

Transdermal application can be an alternative drug

delivery route which might allow administration of

lower doses of a drug and avoidance of first-pass

metabolism It can also provide sustained and constant

plasma levels and improve patient compliance

Despite the obvious advantages of transdermal

drug delivery this route of administration presents

unique challenges The main barrier to the skin per-

meation of a drug is the stratum corneum and its

compact structure It consists of dead flattened cells

filled with keratin which are embedded in a lipid

matrix Lipids in the intercellular spaces are fatty acids

ceramides and cholesterol arranged in bilayers[1] To

overcome the problems arising from skin imperme-

ability various approaches to reversibly alter the

barrier resistance have been proposed Among these

approaches is the use of enhancers Penetration enhanc-

ers are chemical compounds that can partition and in-

teract with the stratum corneum constituents when

incorporated in a formulation Therefore they reduce

the resistance to the diffusion of the drug An ideal

penetration enhancer must be pharmacologically inert

nontoxic non-irritant nonallergenic and chemically and

physically stable Also its action must be reversible[2]

Ondansetron a carbazol antiemetic drug acts as a

competitive highly selective inhibitor of 5-HT3 seroto-

nin receptors It is used for the prevention of nausea and

vomiting associated with cancer chemotherapy and for

postoperative nausea and vomiting[3 ndash 8] It blocks the 5-

HT3 receptors at both peripheral sites in the gastroin-

testinal (GI) tract as well as within the area postrema in

the central nervous system[9] Ondansetron is adminis-

tered by intramuscular or slow intravenous injection as

hydrochloride salt per os as hydrochloride salt or base

or rectally as base Dosing varies according to the

purpose from 8 to 32 mg expressed in terms of the base

In our previous study[10] an experimental design

technique was used to estimate the effect of the type

and the concentration of the enhancer and the effect of

skin from different donors on the permeation of

ondansetron base through human cadaver epidermis

Eight penetration enhancers were studied chosen from

different chemical categories on the basis of their

effectiveness as it has been previously described in

literature[11] It was found[10] that the formulations

containing oleic or lauric acid as enhancer showed the

largest amounts of ondansetron permeated per unit area

(mgcm2) of epidermal membrane after 24 48 and 72 h

(Fig 1) Based on ondansetronrsquos pharmacokinetic data

and the oral dose the desired permeation rate was

calculated Formulations containing oleic or lauric acid

as penetration enhancers could meet the desired

transdermal permeation rate for adults It was sug-

gested that except for the direct effect of the acids on

the skin their enhancing action could also be attributed

to the formation of an ion pair between the drug and

the enhancer

The formation of more lipophilic ion pairs than the

ionized drug is one mechanism by which charged

species can be transported through the skin[1213]

Ondansetron is a weak base (pKa=74) and exists in

acidic solutions protonated as a cation Therefore it is

possible to form ion pairs with oppositely charged ions

which will subsequently partition into the stratum

corneum The chemical structures of ondansetron and

lauric acid are shown in Fig 2

Figure 1 Cumulative amount of ondansetron permeated per unit area (mgcm2) as a function of time from gel containing 5 lauric

acid and from gel without enhancer Each value is the meanplusmnSD (n=5)

312 Dimas Dallas and Rekkas

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In the present study several techniques were used

to reveal the formation of an ion pair complex between

ondansetron and lauric acid In partitioning experi-

ments where the n-octanolwater coefficient was

measured 13C nuclear magnetic resonance spectrosco-

py and thermal analysis of the binary mixtures of

ondansetron and lauric acid were used to investigate

the possibility of the complex formation

MATERIALS AND METHODS

Materials

The materials used were ondansetron hydrochloride

(Cipla lot BX 1088 Bombay India) chloroform-D

(from Merck Darmstadt Germany) lauric acid (Sigma

St Louis MO) methanol acetonitrile (both from Lab-

Scan Dublin Ireland) ammonia 30 n-octanol

sodium chloride (all from Panreac Barcelona Spain)

potassium dihydrogen phosphate (Riedel de Haen

Seelze Germany) and chloroform (Fluka Steinheim

Switzerland) All materials were used as received

Preparation of Ondansetron Free Base

Ondansetron free base was prepared from ondanse-

tron hydrochloride For this purpose 2 g of ondansetron

hydrochloride were dissolved in 500 mL of water and

2 mL of aqueous ammonia were added Ondansetron

free base was filtered under vacuum through a ROBU-

GLAS1 filter por 4 (Andrews Glass Vineland NJ) and

washed with an aqueous solution of 5 ammonia

several times Then it was dissolved with dichloro-

methane methanol 9010 (vv) and the filtrates were

collected in a round-bottomed flask The solvents were

evaporated in a rotary evaporator Buchi rotawapor R-

2000 (Buchi Flawil Switzerland) to receive the ondan-

setron free base To assure complete removal of the

residual organic solvent the flask was left under vacuum

overnight The purity of the base was confirmed by its

melting point and 1HndashNuclear Magnetic Resonance

HPLC Method

The HPLC system consisted of a high pressure

pump (P1000 Spectra Physics Fremont CA) an

autosampler (AS1000 Spectra Physics Fremont CA)

equipped with a Hypersil1 CPS (150 cm46 mm 5 m)

column (ThermoHypersil Bellefonte PA) a variable

wavelength detector (Spectra 100 UVndashVis Spectra

Physics Fremont CA) set at 305 nm[1415] The data

were analyzed using the ChromQuest Chromatography

Data System (ThermoQuest San Jose CA) The

mobile phase consisting of 001 M KH2PO4 (pH=5)

acetonitrile 6040 (vv) was pumped at a flow rate of

2 mLmin The injection volume was 50 mL

Determination ofDistribution Coefficients

The distribution coefficients of ondansetron be-

tween n-octanol and phosphate buffers at 32C were

determined Phosphate buffers were prepared according

to USP 24[14] covering a pH range from 58 to 90 The

ionic strength of each buffer was adjusted to 03 M

with sodium chloride Both n-octanol and phosphate

buffers were presaturated with each other overnight

before use Five milliliters of n-octanol were mixed

with 5 mL of phosphate buffer solution containing the

drug (30 mgmL) for 24 h at 32C After phase sep-

aration by centrifugation the drug concentration in the

buffer was determined using a modified previously

described HPLC method The partitioning experiments

were performed in three different solutions in tripli-

cates making a total of nine determinations of the dis-

tribution coefficient

Because the amount of ondansetron initially used

was known its distribution coefficient (D) was cal-

culated using the following equation

D frac14 Co Caq

Caq

Vaq

Vorg

eth1THORN

where Co and Caq were the concentrations of the drug in

the aqueous phase initially and after partitioning and Vaq

and Vorg were the volumes of the aqueous and organic

phase respectively

Figure 2 Structure of (A) ondansetron (B) lauric acid

Ion Pair Formation for Enhancement Effect of Lauric Acid 313

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The effects of lauric acid on the distribution coef-

ficient were determined by the addition of 01 M of the

fatty acid to the oily phase

13C Nuclear MagneticResonance Spectroscopy

The 13C-NMR spectra of ondansetron lauric acid

and their mixture were examined in chloroform-D The

spectra were recorded on Bruker DRX 400 and Bruker

AC 200 spectrometers [1H (400 and 200 MHz) and 13C

(50 MHz) Chemical shifts were recorded as units

relative to tetramethylsilane as the internal standard

The NMR experiments were performed using standard

Bruker microprograms

Preparation of OndansetronLauricAcid Binary Mixtures

Mixtures of ondansetron and lauric acid covering

the entire range of composition were prepared Both

substances were accurately weighed in amber colored

glass vials and dissolved in chloroform by sonication

to allow intimate mixing of the compounds at a mo-

lecular level The solvent was removed by evaporation

under nitrogen stream at room temperature The mix-

tures were frozen at 20C for at least 48 h to crys-

tallize and equilibrate and stored at 20C

Differential ScanningCalorimetry (DSC)

To avoid mass-related artifacts specific amounts

of the mixtures (25 mg) were accurately weighed in

standard aluminum pans (Type BO 14-6117 Perkin

Elmer Germany) The pans were sealed using a

universal crimper press (Perkin Elmer Germany) to

prevent any evaporative losses and thus the composition

remained constant This means that pressure was an

unknown variable but pressure has little or no effect

on solidliquid transition and so this variable was

neglected[16] DSC measurements were carried out

against an empty pan used as a reference at a heating

rate of 10Cmin under a stream of nitrogen as purging

gas Thermal analysis of the mixtures was performed on

Figure 3 Oilwater distribution coefficient D of ondansetron

into n-octanol (6) and into 01 M lauric acid in n-octanol (~)

Each value is the meanplusmnSD (n=3)

Figure 4 The ratio of distribution coefficients of ondansetron

between 01 M lauric acid in n-octanol by that in n-octanol


Figure 5 The facilitated transport scheme of ondansetron

species between aqueous (W) and oil (O) interface


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a Perkin Elmer 1020 DSC 7 Thermal Analysis System

(Perkin Elmer Germany) and the DSC curves were

recorded and analyzed by the PerkinndashElmer software

The melting characteristics measured were the peak

temperature (Tm) and the enthalpy of fusion (DH)

Enthalpies of fusion were determined from the peak area

divided by the sample weight

Thermal analysis of the mixtures was performed in

triplicates In all cases the repeatability on the deter-

mination of the melting points was 05C

RESULTS AND DISCUSSION

The distribution coefficients of ondansetron between

n-octanol or n-octanol plus 01 M lauric acid and

phosphate buffers at 32C were determined The

partitioning of ondansetron in n-octanol increased as

the pH of the buffer increased (Fig 3) This is in

accordance with the pH-partitioning theory since the

amount of unionized drug increased as pH increased

The incorporation of lauric acid in the oily phase

Figure 6 The 13C-NMR of (A) lauric acid (B) ondansetron (C) mixture of ondansetron and lauric acid (11 molar ratio)


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increased in a statistically significant (plt005) fashion

the distribution coefficient over the whole pH range

58ndash90 (Fig 3) In Fig 4 the ratio of the distribution

coefficient in n-octanol plus lauric acid divided by that in

n-octanol versus pH is shown[1718] As pH increases

over 82 the ratio increases because over this value

ondansetron is unionized It is remarkable though that

the ratio takes its maximum value around pH 66 where

predominates the ionized form of the drug

According to the pH-partition theory only union-

ized molecules can permeate through lipophilic mem-

branes In fact the permeation of charged species

purely by passive diffusion is very slow due to its

unfavorable partitioning into the membrane However

transfer of ionized molecules can be facilitated by the

presence of carrier molecules in the membrane and

formation of more lipophilic ion pairs[19 ndash 23] Ion pairs

are defined as neutral species formed only by electro-

static attraction between oppositely charged ions

which are sufficiently lipophilic to dissolve in lipoidal

medium such as stratum corneum[24]

In a similar manner it was assumed that ondanse-

tron forms ion pairs with lauric acid At pH 66 where

the ratio takes its largest value ion pairing is most

effective as the drug exists predominately in its ionized

form and the fatty acid is also ionized

The facilitated transport scheme is illustrated in

Fig 5 The carrier molecules lauric acid were

incorporated in n-octanol At pH values of the aqueous

donor phase above the pKa of the acid the fatty acid

molecules present at the aqueousoil interface will

ionize Subsequently the carboxylate anions will form

electrically neutral ion pairs in the interfacial region

with the drug cations arriving from the aqueous phase

which can partition into the organic phase[25]

Further evidence of complex formation between

ondansetron and fatty acids could be gained from the

NMR spectra of ondansetron lauric acid and their

mixture (ondansetronlauric acid molar ratio 11) in

CDCl3 The formation of a complex might be expected

to affect the magnetic environment of the carbon atom

of the carbonyl group of lauric acid as well as the

adjacent to this carbon atoms In the same way it is

expected to affect the carbon atoms adjacent to the

nitrogen of the imidazole ring of ondansetron[26] The13C-NMR spectra in CDCl3 of these compounds are

shown in Fig 6 A closer examination of these spectra

indicated a significant change in the chemical shift of

the carbon atoms of lauric acid The peak at 18054 ppm

of the carbon 1 (Fig 2B) of the carbonyl group shifted to

17782 ppm in the mixture (Fig 6) Also a shift from

3410 to 3488 ppm was observed for the carbon atom 2

(Fig 2B) adjacent to the carbonyl group The compar-

ison between the spectra of the ondansetron and the

mixture indicated a shift from 12713 to 12559 ppm for

the carbon atom 4rsquo (Fig 2A) adjacent to the nitrogen of

the imidazole ring of ondansetron Also a shift from

1315 to 1242 ppm was observed for the methylene

carbon on the imidazole ring (Fig 2A) The shifts

observed are tabulated in Table 1

As previously stated the formation of the ion

pair proceeds through the interaction between of the

charged molecules that is between the carbonyl group

of the fatty acid and the nitrogen of the imidazole ring

of ondansetron From the results obtained it is evident

that there are alterations in the magnetic environment

of the carbon atoms adjacent to the ionized groups

This fact empowers the assumption of the interaction

between the two substances and the formation of an

ion pair This is of particular significance for the

penetration mechanism because the ion pair complex is

implicated in the mechanism on the enhanced perme-

ation of ondansetron through human epidermis

Thermal analysis[27] of the mixtures of ondanse-

tron and lauric acid was used to further enlighten the

mode of action of the fatty acid on the transdermal

permeation of ondansetron

Sample DSC traces of the mixtures are shown in

Fig 7 Also the phase diagram of ondansetronndashlauric

acid binary systems is depicted in Fig 8 where tem-

perature was plotted versus the composition of the

mixtures In such diagrams the temperature below

which the system is completely solid is called the

solidus temperature Also the temperature above which

the system is a homogenous liquid is mentioned as the

liquidus temperature Points in the temperaturecompo-

sition phase diagram enclosed by the solidus and

liquidus lines represent two phase systems with the

component in excess as solid in equilibrium with a

homogenous liquid mixture[28]

The melting point of pure ondansetron (Fig 7

peak A) was 21982C it decreased with the addi-

tion of lauric acid and it attained a minimum (Fig 7

peak B) at 17625C Lauric acid also exhibited as

a single sharp endotherm (Fig 7 peak C) at 4331Cand the melting point decreased with the addition of

Table 1 Chemical shifts from 13C-NMR spectra

Compound

Chemical shift (ppm)

Carbon atom (Fig 1)

1 2 4rsquo ndashCH3

Lauric acid 18054 3410 ndash ndash

Ondansetron ndash ndash 12713 1316

Mixture 17782 3488 12559 1242


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ondansetron taking the minimum value (Fig 7 peak

D) at 3950C

The other endothermic peaks that were observed

can be attributed to[29]

1 A phase transition in any one of the pure

components before they melt

2 An eutectic reaction between ondansetron and

lauric acid at this temperature

3 The formation of an additional compound

between ondansetron and lauric acid

Peaks between 43 and 79C vanished after a

heatingcoolingheating cycle and therefore they

can be attributed to metastable phases of lauric acid

On the contrary peak E was present after the same

heatingcoolingheating cycle If the endothermic

peak E corresponded to a eutectic formation the DSC

Figure 7 Sample DSC traces of ondansetronlauric acid binary mixtures The labels represent the percentage (ww) of ondansetron

in each binary mixture Sixty percent (ww) ondansetron is the 11 molar mixture


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traces should have exhibited the characteristic double

peaks of these systems for all compositions except

from the eutectic composition because continuous

dissolution of one of the solid phases would take

place In this case the first endotherm peak would

correspond to the solidus temperature and the second

broad endotherm peak would be the liquidus temper-

ature As it can be concluded from Fig 7 this peak

does not follow the characteristic eutectic pattern

All the above-mentioned conclusions along with

closer examination of the compositiontemperature

phase diagram clearly indicate that thermal event E

represents a solid complex of ondansetron and lauric

acid From the phase diagram it can be concluded that

the complex is too unstable to have its own recognized

melting point and dissociation may occur before this

temperature is reached Such a system is called peri-

tectic[2930] The melting point of the complex is

7981C and has an enthalpy of fusion of 1648

(plusmn023) Jg compared to ondansetron with melting

point 21982C and an enthalpy of fusion of 15356

(plusmn1790) Jg As previously stated a reduction on the

melting point of a substance will have a direct effect

on its solubility in the skin lipids and consequently on

its transdermal permeation[2831]

The enthalpies of fusion of the pure compounds

and the molecular complex can be used to obtain in-

formation about the nature of the interaction[32 ndash 34] If

the system is assumed to be a simple mechanical mixture

of the two components the heat of mixing is calculated

using the mixture using the following equation

DHcalc frac14 Xond DHond thorn Xlauric DHlauric eth2THORN

where X and DH are the mole fraction and the heat of

fusion of ondansetron and lauric acid as shown by the

subscript The calculated and the experimental DH

values are shown in Table 2 The difference between

these values is called heat of mixing DHm and it can give

useful information about the thermal events and the

structure of the system Negative values of DHm indicate

clustering of the molecules in the system and positive

DHm values propose a quasi-eutectic system If DHm

equals zero the formation of a molecular solution is

suggested[32 ndash 34] Table 2 shows that calculated values of

heat of fusion are higher than the experimental values

Thus the negative value of the heat of mixing suggests

clustering of the molecules in the ondansetronlauric

acid system

Furthermore the entropy of fusion (DS) of the pure

components and the complex can be calculated using

the following equation[33]

DS frac14 DH

Teth3THORN

where DH is the enthalpy of fusion and T is the

melting temperature The values of the entropy of

fusion are shown in Table 2 The positive values in

all cases indicate an increase in the randomness of

the binary system after mixing the substances Never-

theless the calculated values for the entropy of fu-

sion of the complex were higher compared to the

experimental value This suggests an ordering in the

complex melting as a result of an interaction be-

tween ondansetron and lauric acid forming the addi-

tional compound

The results show that the enhancing effect of the

fatty acids on the transdermal permeation of ondanse-

tron can be attributed not only to their direct effect on

Table 2 Experimental and calculated heat of fusion and

entropy of fusion data for the ondansetronlauric acid bi-

nary system

Ondansetron

Lauric

acid

Addition

compound

Enthalpy of

fusion (KJ mol1)

Experimental 4505 868 847

Calculated ndash ndash 2551

Heat of mixing ndash ndash 1704

Entropy of

fusion (J mol1K1)



Figure 8 The temperaturecomposition phase diagram of

ondansetronlauric acid binary mixtures as determined by

DSC traces A) Homogenous liquid B) liquid+solid ondanse-

tron C) liquid+solid addition compound D) solid


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the skin structure but also to the formation of an ion

pair between ondansetron and lauric acid

CONCLUSIONS

Lauric acid was effective as a penetration enhancer

for the transdermal delivery of ondansetron The

possibility of the formation of ion pair between the drug

and lauric acid was investigated For this reason the

distribution coefficients of ondansetron in n-octanol

phosphate buffer with the presence of lauric acid were

measured The experimental data suggest that the

distribution coefficient effectively increases and a

possible explanation is the formation of more lipophilic

ion pairs between the charged molecules of ondansetron

and lauric acid Furthermore the 13C Nuclear Magnetic

Resonance spectra revealed alterations to the magnetic

environment of the carbon atoms adjacent to the ionized

group that is the carbonyl group of the fatty acid and the

nitrogen of the imidazole ring of ondansetron This

evidence empowers the theory of ion pair formation

Finally thermal analysis of the binary mixtures of

ondansetron and lauric acid and the construction of

compositiontemperature phase diagrams revealed the

formation of an addition compound This complex has a

different melting point from pure ondansetron and lauric

acid and its formation is thermodynamically favored

It is evident therefore that the enhancing effect of

lauric acid on the transdermal permeation of ondanse-

tron can be attributed not only on its direct effect on


pair between the drug and the enhancer

ACKNOWLEDGMENTS

The authors thank associate professor Dr Kyriakos

Viras from the Division of Physical Chemistry

Department of Chemistry University of Athens for

his contribution on explaining the DSC traces They

also thank lecturer Dr Prokopios Magiatis from the

Division of Pharmacognosy and Natural Products

Chemistry Department of Pharmacy University of

Athens for his help with the identification of

NMR spectra

REFERENCES

1 Elias PM Stratum corneum revisited J Derma-

tol 1999 23 756ndash7582 Pfister WR Hsieh DST Permeation enhancers

compatible with transdermal drug delivery sys-

tems Part I selection and formulation consider-

ations Pharm Technol 1990 14 (9) 132ndash1393 Llacer JM Gallardo V Parera A Ruiz MA

Formation of ondansetron polymorphs Int J

Pharm 1999 177 221ndash2294 Roila F Favero DA Ondansetron clinical

pharmacokinetics Clin Pharmacokinet 1995 29

(2) 95ndash1095 Simpson KH Hicks FM Clinical pharmaco-

kinetics of ondansetron A review J Pharm

Pharmacol 1996 48 774ndash7816 Cothhup PV Felgate CC Palmer JL Scully

NL Determination of ondansetron in plasma and

its pharmacokinetics in the young and elderly J

Pharm Sci 1991 80 (9) 868ndash8717 Llacer JM Ruiz MA Parera A Gallardo V

Adsortionndashdesorption of ondansetron on latex

particles Drug Dev Ind Pharm 2000 26 (3)237ndash242

8 wwwfdagovmedwatchsafety2000dec00htm

(accessed July 2002)

9 Anderson PO Knoben JE Troutman WG

Handbook of Clinical Drug Data Appleton amp

Lange Connecticut 1999 519

10 Dimas DA Dallas PP Rekkas DM Use of an

8132 asymmetrical factorial design for the in vitro

evaluation of ondansetron permeation through

human epidermis Pharm Dev Technol in press

11 Walters KA Hadgraft J Pharmaceutical Skin

Penetration Enhancement Marcel Dekker New

York 1993

12 Quintanar-Guerrero D Allemann E Fessi H

Doelker E Applications of the ion-pair concept

to hydrophilic substances with special emphasis

on peptides Pharm Res 1997 14 (2) 119ndash12713 Lee SJ Kurihara-Bengstrom T Kim SW Ion-

paired drug diffusion through polymer membranes

Int J Pharm 1987 47 59ndash7314 The United States Pharmacopeia 24 United States

Pharmacopeial Convention Rockville MD 2000

1218ndash1220 2231ndash2232

15 Takahashi K Rytting JH Approach to improve

permeation of ondansetron across shed snake skin

as a model membrane J Pharm Pharmacol 200153 789ndash794

16 Stott PW Williams AC Brian BW Mecha-

nistic study into the enhanced transdermal perme-

ation of a model b-blocker propanolol by fatty

acids a melting point depression effect Int J

Pharm 2001 219 161ndash17617 Green PG Hadgraft J Facilitated transfer of

cationic drugs across a lipoidal membrane by oleic


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ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly

acid and lauric acid Int J Pharm 1987 37 251ndash255

18 Green PG Guy RH Hadgraft J In vitro and

in vivo enhancement of skin permeation with

oleic lauric acids Int J Pharm 1988 48 103ndash111

19 Barker N Hadgraft J Facilitated percutaneous

absorption a model system Int J Pharm 1981 8193ndash202

20 Hadgraft J Walters KA Wotton RK Facili-

tated percutaneous absorption a comparison and

evaluation of two in vitro models Int J Pharm

1986 32 257ndash26321 Green PG Hadgraft J Wolff M Physico-

chemical aspects of the transdermal delivery of

bupranolol Int J Pharm 1989 55 259ndash26522 Pardo A Shin Y Cohen S Kinetics of

transdermal penetration of an organic ion pair

physostigmine salicylate J Pharm Sci 1992 81990ndash995

23 Valenta C Siman U Kratzel M Hadgraft J

The dermal delivery of lignocaine influence of ion

pairing Int J Pharm 2000 197 77ndash8524 Hatanaka T Kamon T Morigaki S Katayama

K Koizumi T Ion pair skin transport of a

zwitterionic drug cephalexin J Control Release

2000 66 63ndash7125 Neubert R Ion pair transport across membranes

Pharm Res 1989 6 (9) 743ndash74726 Ogiso T Shintani M Mechanism for the

enhancement effect of fatty acids on the percuta-

neous absorption of propanolol J Pharm Sci

1990 79 (12) 1065ndash107127 Dollimore D Lerdkanchanaporn S Thermal

analysis Anal Chem 1998 70 27Rndash35R28 Stott PW Williams AC Barry BW Trans-

dermal delivery from eutectic systems enhanced

permeation of a model drug ibuprofen J Control

Release 1998 50 297ndash30829 Mahedran KH Nagaraj S Sridharan R

Gnanasekaran T Differential scanning calorimet-

ric studies on the phase diagram of the binary

LiClndashCaCl2 system J Alloys Compd 2001 32578ndash83

30 Ford JA Timmins P Pharmaceutical Thermal

Analysis John Wiley amp Sons Inc New York

1989 25ndash68

31 Touitou E Chow DD Lawter JR Chiral b-

blockers for transdermal delivery Int J Pharm

1994 104 19ndash2832 Rai US George S Thermochemical studies on

the eutectics and addition compounds in the binary

systems of benzidine with p-nitrophenol m-

aminophenol and resorcinol Thermochim Acta

1994 243 17ndash2533 Rai US Shekhar H Some physicochemical

studies on the binary organic eutectics Thermo-

chim Acta 1991 175 215ndash22734 Rai US George S Physicochemical studies on

organic eutectics and the 11 addition compound

benzidinendasha-napthol system J Mater Sci 199227 17ndash25

Received June 13 2003

Accepted September 15 2003


Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly

INTRODUCTION

Transdermal application can be an alternative drug

delivery route which might allow administration of

lower doses of a drug and avoidance of first-pass

metabolism It can also provide sustained and constant

plasma levels and improve patient compliance

Despite the obvious advantages of transdermal

drug delivery this route of administration presents

unique challenges The main barrier to the skin per-

meation of a drug is the stratum corneum and its

compact structure It consists of dead flattened cells

filled with keratin which are embedded in a lipid

matrix Lipids in the intercellular spaces are fatty acids

ceramides and cholesterol arranged in bilayers[1] To

overcome the problems arising from skin imperme-

ability various approaches to reversibly alter the

barrier resistance have been proposed Among these

approaches is the use of enhancers Penetration enhanc-

ers are chemical compounds that can partition and in-

teract with the stratum corneum constituents when

incorporated in a formulation Therefore they reduce

the resistance to the diffusion of the drug An ideal

penetration enhancer must be pharmacologically inert

nontoxic non-irritant nonallergenic and chemically and

physically stable Also its action must be reversible[2]

Ondansetron a carbazol antiemetic drug acts as a

competitive highly selective inhibitor of 5-HT3 seroto-

nin receptors It is used for the prevention of nausea and

vomiting associated with cancer chemotherapy and for

postoperative nausea and vomiting[3 ndash 8] It blocks the 5-

HT3 receptors at both peripheral sites in the gastroin-

testinal (GI) tract as well as within the area postrema in

the central nervous system[9] Ondansetron is adminis-

tered by intramuscular or slow intravenous injection as

hydrochloride salt per os as hydrochloride salt or base

or rectally as base Dosing varies according to the

purpose from 8 to 32 mg expressed in terms of the base

In our previous study[10] an experimental design

technique was used to estimate the effect of the type

and the concentration of the enhancer and the effect of

skin from different donors on the permeation of

ondansetron base through human cadaver epidermis

Eight penetration enhancers were studied chosen from

different chemical categories on the basis of their

effectiveness as it has been previously described in

literature[11] It was found[10] that the formulations

containing oleic or lauric acid as enhancer showed the

largest amounts of ondansetron permeated per unit area

(mgcm2) of epidermal membrane after 24 48 and 72 h

(Fig 1) Based on ondansetronrsquos pharmacokinetic data

and the oral dose the desired permeation rate was

calculated Formulations containing oleic or lauric acid

as penetration enhancers could meet the desired

transdermal permeation rate for adults It was sug-

gested that except for the direct effect of the acids on

the skin their enhancing action could also be attributed

to the formation of an ion pair between the drug and

the enhancer

The formation of more lipophilic ion pairs than the

ionized drug is one mechanism by which charged

species can be transported through the skin[1213]

Ondansetron is a weak base (pKa=74) and exists in

acidic solutions protonated as a cation Therefore it is

possible to form ion pairs with oppositely charged ions

which will subsequently partition into the stratum

corneum The chemical structures of ondansetron and

lauric acid are shown in Fig 2

Figure 1 Cumulative amount of ondansetron permeated per unit area (mgcm2) as a function of time from gel containing 5 lauric

acid and from gel without enhancer Each value is the meanplusmnSD (n=5)


Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly










Materials



























HPLC Method

































D frac14 Co Caq

Caq

Vaq

Vorg

eth1THORN




phase respectively



Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly














































Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly






















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly
































































































Compound


Carbon atom (Fig 1)

1 2 4rsquo ndashCH3



Mixture 17782 3488 12559 1242


Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly


D) at 3950C


















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly















































acid system




DS frac14 DH

Teth3THORN











tional compound






nary system

Ondansetron

Lauric

acid

Addition

compound

Enthalpy of

fusion (KJ mol1)




Entropy of

fusion (J mol1K1)








Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly



CONCLUSIONS




























ACKNOWLEDGMENTS









NMR spectra

REFERENCES




























York 1993








1218ndash1220 2231ndash2232











Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly


































1989 25ndash68















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly










Materials



























HPLC Method

































D frac14 Co Caq

Caq

Vaq

Vorg

eth1THORN




phase respectively



Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly














































Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly






















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly
































































































Compound


Carbon atom (Fig 1)

1 2 4rsquo ndashCH3



Mixture 17782 3488 12559 1242


Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly


D) at 3950C


















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly















































acid system




DS frac14 DH

Teth3THORN











tional compound






nary system

Ondansetron

Lauric

acid

Addition

compound

Enthalpy of

fusion (KJ mol1)




Entropy of

fusion (J mol1K1)








Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly



CONCLUSIONS




























ACKNOWLEDGMENTS









NMR spectra

REFERENCES




























York 1993








1218ndash1220 2231ndash2232











Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly


































1989 25ndash68















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly














































Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly






















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly
































































































Compound


Carbon atom (Fig 1)

1 2 4rsquo ndashCH3



Mixture 17782 3488 12559 1242


Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly


D) at 3950C


















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly















































acid system




DS frac14 DH

Teth3THORN











tional compound






nary system

Ondansetron

Lauric

acid

Addition

compound

Enthalpy of

fusion (KJ mol1)




Entropy of

fusion (J mol1K1)








Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly



CONCLUSIONS




























ACKNOWLEDGMENTS









NMR spectra

REFERENCES




























York 1993








1218ndash1220 2231ndash2232











Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly


































1989 25ndash68















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly






















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly
































































































Compound


Carbon atom (Fig 1)

1 2 4rsquo ndashCH3



Mixture 17782 3488 12559 1242


Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly


D) at 3950C


















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly















































acid system




DS frac14 DH

Teth3THORN











tional compound






nary system

Ondansetron

Lauric

acid

Addition

compound

Enthalpy of

fusion (KJ mol1)




Entropy of

fusion (J mol1K1)








Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly



CONCLUSIONS




























ACKNOWLEDGMENTS









NMR spectra

REFERENCES




























York 1993








1218ndash1220 2231ndash2232











Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly


































1989 25ndash68















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly
































































































Compound


Carbon atom (Fig 1)

1 2 4rsquo ndashCH3



Mixture 17782 3488 12559 1242


Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly


D) at 3950C


















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly















































acid system




DS frac14 DH

Teth3THORN











tional compound






nary system

Ondansetron

Lauric

acid

Addition

compound

Enthalpy of

fusion (KJ mol1)




Entropy of

fusion (J mol1K1)








Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly



CONCLUSIONS




























ACKNOWLEDGMENTS









NMR spectra

REFERENCES




























York 1993








1218ndash1220 2231ndash2232











Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly


































1989 25ndash68















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly


D) at 3950C


















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly















































acid system




DS frac14 DH

Teth3THORN











tional compound






nary system

Ondansetron

Lauric

acid

Addition

compound

Enthalpy of

fusion (KJ mol1)




Entropy of

fusion (J mol1K1)








Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly



CONCLUSIONS




























ACKNOWLEDGMENTS









NMR spectra

REFERENCES




























York 1993








1218ndash1220 2231ndash2232











Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly


































1989 25ndash68















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly















































acid system




DS frac14 DH

Teth3THORN











tional compound






nary system

Ondansetron

Lauric

acid

Addition

compound

Enthalpy of

fusion (KJ mol1)




Entropy of

fusion (J mol1K1)








Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly



CONCLUSIONS




























ACKNOWLEDGMENTS









NMR spectra

REFERENCES




























York 1993








1218ndash1220 2231ndash2232











Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly


































1989 25ndash68















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly



CONCLUSIONS




























ACKNOWLEDGMENTS









NMR spectra

REFERENCES




























York 1993








1218ndash1220 2231ndash2232











Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly


































1989 25ndash68















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly


































1989 25ndash68















Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

rec

om b

y U

nive

rsity

of

Lav

al o

n 07

16

14Fo

r pe

rson

al u

se o

nly

Documents

Ion Pair Formation as a Possible Mechanism for the Enhancement Effect of Lauric Acid on the Transdermal Permeation of Ondansetron