ArticlePDF Available

Preparation and investigation of mefenamic acid - polyethylene glycol - sucrose ester solid dispersions


Abstract and Figures

Mefenamic acid (MA) is a widely used non-steroidal anti-inflammatory (NSAID) drug. The adverse effects typical of NSAIDs are also present in the case of MA, partly due to its low water solubility. The aim of this study was to increase the water solubility of MA in order to influence its absorption and bioavailability. Solid dispersions of MA were prepared by the melting method using polyethylene glycol 6000 and different types (laurate, D-1216; palmitate, P-1670; stearate, S-1670) and amounts of sucrose esters as carriers. The X-ray diffraction results show that MA crystals were not present in the products. Dissolution tests carried out in artificial intestinal juice showed that the product containing 10 % D-1216 increased water solubility about 3 times. The apparent permeability coefficient of MA across human Caco-2 intestinal epithelial cell layers was high and, despite the difference in solubility, there was no further increase in drug penetration in the presence of the applied additives.
Content may be subject to copyright.
Acta Pharm. 65 (2015) 453–462 Origi nal research pap er
DOI: 10.1515/acph-2015-0035
Preparation and investigation of mefenamic acid –
polyethylene glycol – sucrose ester solid dispersions
Mefenamic acid (MA) is a widely used non-steroidal anti-
inammatory (NSAID) drug. The adverse eects typical of
NSAIDs are also present in the case of MA, partly due to its
low water solubility. The aim of this study was to increase
the water solubility of MA in order to inuence its absorp-
tion and bioavailability. Solid dispersions of MA were pre-
pared by the melting method using polyethylene glycol
6000 and dierent types (laurate, D-1216; palmitate, P-1670;
stearate, S-1670) and amounts of sucrose esters as carriers.
The X-ray diraction results show that MA crystals were
not present in the products. Dissolution tests carried out in
articial intestinal juice showed that the product contain-
ing 10 % D-1216 increased water solubility about 3 times.
The apparent permeability coecient of MA across human
Caco-2 intestinal epithelial cell layers was high and, de-
spite the dierence in solubility, there was no further in-
crease in drug penetration in the presence of the applied
Keywords: mefenamic acid, sucrose esters, PEG 6000, solid
dispersion, Caco-2 cells
Mefenamic acid [MA, 2-(2,3-dimethylphenyl)aminobenzoic acid], an anthranilic acid
derivative, is a widely used non-steroidal anti-inammatory (NSAID) drug (1).
Regarding the pharmacokinetics of the drug, MA is absorbed from the small intestine
(2), its bioavailability is about 90 % but is inuenced by the amount of water ingested with
the drug in fasting subjects. The tmax is aained in 2–4 hours, and steady-state concentra-
tion is reached in 2–3 days (2, 3).
Like other NSAIDs, MA can cause serious gastrointestinal adverse eects (bleeding,
ulceration) due to its mechanism of action (4) and acting as an irritant of the gastrointesti-
nal mucosa (5).
MA belongs to class II of the biopharmaceutical classication system (BCS) – drugs
with low solubility and high permeability; therefore, its oral bioavailability is determined
by its dissolution rate in the gastrointestinal uid and, consequently, it has variable absorp-
1University of Medicine and Pharmacy
Tîrgu Mureş, Faculty of Pharmacy
540139, Tîrgu Mureş, Romania
2Institute of Biophysics
Biological Research Centre
Hungarian Academy of Sciences
6726, Szeged, Hungary
3University of Szeged
Faculty of Pharmacy
Department of Pharmaceutical Technology
6720, Szeged, Hungary
Accepted July 14, 2015
* Correspondence; e-mail: croitoru.mircea@um
I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
tion (6, 7). In the literature, there are dierent methods to enhance MA solubility and dis-
solution rate. The most commonly used techniques are the formation of inclusion com-
plexes with several cyclodextrin derivatives (8–10) and preparation of solid dispersions
(SD) with water soluble polymers (polyvinylpyrrolidone, PVP, or polyethylene glycol, PEG)
(11) in binary and ternary systems with a disintegrant and Polysorbate 20, respectively (12).
Solubility increase was achieved in both cases according to literature data, but there is no
information regarding the eect of auxiliary substances on permeability. Auxiliary sub-
stances may negatively aect the permeability (13). The presence of hydroxy-propyl-b-
cyclodextrin decreased the permeability of dexamethasone in a Caco-2 cell model and in
the in situ single-pass rat intestinal perfusion model (14) while Polysorbate 80 decreased
permeability of progesterone across an articial dimethicone membrane (15). Polymers
such as PEG 400 are also able to reduce the permeability of lipophilic drugs (16). PEG with
higher molecular mass increases the permeability coecient (Papp) of indomethacin (17).
The permeability-increasing eect of sucrose esters (SE) on Caco-2 cells was also demon-
strated (18).
The aim of our work was to increase the water solubility of MA in order to reduce its
gastrointestinal adverse eects (19) and the variability of absorption. Modication of the
permeability of MA in dierent solid dispersions was also evaluated (solubility-permea-
bility interplay). Ternary products were prepared with PEG 6000 and sucrose esters as
carriers. Sucrose esters were chosen as ternary components because they can act as pene-
tration enhancers along with their solubility increasing property. Sucrose esters are non-
-ionic surfactants (20, 21) and, due to their thermal behaviour (low melting point), can be
used in preparation of solid dispersions made by the melting technique (21, 22). In this
paper, beside the product preparation method, the solubility and permeability inuencing
properties of the obtained solid dispersions are presented.
Mefenamic acid and all reagents were purchased from Sigma-Aldrich, Hungary, un-
less otherwise indicated. Laurate sucrose ester (D-1216, sucrose laurate) was of pharmaceu-
tical grade, palmitate (P-1670, sucrose palmitate) and stearate (S-1670, sucrose stearate) su-
crose esters were of analytical grade (Mitsubishi Kagaku Foods Co., Japan). PEG 6000 was
supplied by Merck, Germany. All other reagents and solvents were of analytical grade.
Product preparation
Ternary products composed of MA, PEG 6000 and SE were prepared by the melting
method. The SEs were dissolved (D1216) or suspended (P1670 and S1670) in the melted PEG
6000 (80 °C). The temperature was increased to 110 °C, then the accurately weighed MA
powder was added to the blend to dissolve under mixing for 20 minutes. The obtained
mixtures were poured onto a cooled metal plate in a thin layer to cool quickly. The tem-
perature of the cooled plate was contolled by a JULABO cryothermostate model F32 (JU-
LABO model-F32, Labortechnik GmbH, Germany). The mixtures were kept at –20 °C for
24 hours, then scraped o, pulverized in a mortar and passed through a 100-mm sieve. The
products were stored at room temperature until analysis. The composition of the products
I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
Table I. Composition o f the studied products
MA (%) SE (%) PEG (%) Product code
D-1216 5 85 D5
10 80 D10
P-1670 5 85 P5
10 80 P10
S-1670 5 85 S5
10 80 S10
10 0 90 PEG
Characterization of solid dispersions
X-ray diraction analysis. – X-ray diraction (XRPD) analyses were conducted using a
Rigaku MiniFlexTM II X-Ray diractometer (Rigaku Co., Japan), where the tube anode was
Cu with Kα = 1.5405 Ǻ. The data was collected using 30-kV tube voltage and 15-mA tube
current in step scan mode (4 ° min–1). The instrument was calibrated using silicon.
In vitro dissolution studies and kinetic calculations. – Dissolution studies were performed
in articial gastric uid (AGF, pH 1.2) and articial intestinal uid (AIF, pH 6.8) without
enzymes, using the rotating paddle method according to Eur. Ph. – Pharma Test PTW-II,
Germany (23), adapted to 100-mL dissolution medium. Amounts of samples equivalent to
30 mg MA were introduced into hydroxypropyl methylcellulose capsules and immersed
into the dissolution medium at a rotation speed of 100 rpm and temperature of 37 °C. Aliq-
uots of 50 mL were collected periodically and replaced with fresh dissolution medium.
Aer ltration the concentration of MA was determined spectrophotometrically (ATI UNI-
CAM UV-VIS, spectrophotometer, USA) at 352 nm (AGF) and 288 nm (AIF). Measurements
were performed in triplicate. Dissolution tests were conducted under non-sink conditions
in order to evaluate the dierences between the formulations. The mechanism of drug re-
lease was evaluated by dierent mathematical models oered by the DDSolver soware
(24). The best t was chosen based on the adjusted coecient of determination (R2adj) (25).
Cell culture, viability and permeability assays
The cell culture conditions and the methods for toxicity and permeability measure-
ments in the case of MA and its products were described by our group previously (26).
Briey, for the cytotoxicity assays, Caco-2 human intestinal epithelial cells were cultured
in 96-well plates in Dulbecco’s modied Eagle’s medium without phenol red containing
10 % fetal bovine serum (Gibco, Invitrogen, USA). During the treatment period, the plates
were placed on a horizontal shaker at 100 rpm. Tested formulations contained 1, 10, 30, 100,
300, 1000, 3000 mg mL–1 MA as the nal concentration. Cytotoxicity was evaluated by: (i)
measuring the lactate dehydrogenase (LDH) enzyme activity from culture supernatant
is presented in Table I. All products contained 10 % of MA, 5 % or 10 % of sucrose ester
(D1216, P1670 and S167, shortened as D, P and S, respectively) and 85 or 80 % of PEG 6000.
I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
using a LDH detection kit (Roche, Switzerland), (ii) testing cell metabolic activity by meas-
uring MTT dye [3-(4,5-dimethyltiazol-2-yl)-2,5-diphenyltetrazolium bromide] conversion,
reecting the number of viable cells. To study the permeability of MA in solid dispersions,
human Caco-2 cells were cultured on Transwell lter inserts (polycarbonate membrane,
0.4-mm pore size, 1.12 cm2 surface area, Corning Costar Co., USA) for 21 days. The tran-
sepithelial electrical resistance (TEER) of Caco-2 monolayers varied between 450 and 600
W cm–2, indicating good barrier properties. The treatment solutions contained 3 or 100 mg
mL–1 MA dissolved in Ringer-Hepes buer and MA penetration across cell layers was
determined in the apical (donor) to basal (acceptor) direction for 1 hour. The concentrations
of MA were determined both in the basolateral and apical compartments using a Merck
HPLC system (consisting of a quaternary pump L-7100, auto sampler L-7200, column ther-
mostat L-7360, DAD detector L-7455, interface L-7000, solvent degasser L-7612, HSM man-
ager soware) (Merck, Germany). The analysis was carried out at ambient temperature
using a Purospher RP C18e (5 mm, 250 x 4.6 mm, Merck) column. Determinations were
performed by isocratic elution at a ow rate of 1.5 mL min–1. The mobile phase composition
consisted of 55 % 20 mmol L–1 phosphate buer (pH 6.5) and 45 % acetonitrile. Volumes of
100 mL were injected using the loop method; the detection wavelength was set at 281 nm.
Calculations were performed by measurement of peak areas.
The apparent permeability (Papp) was calculated using the formula:
where dQ/dt is the rate of drug permeation across the cells, c0 is the donor compartment
concentration at time zero and A is the area of the cell monolayer (1.12 cm2).
All data presented are means ± standard deviations. The values were compared using
ANOVA followed by Dunnet’s test using (GraphPad Prism 5.0 soware, GraphPad Soware
Inc., USA). The changes were considered statistically signicant at p < 0.05. All experiments
were repeated at least two times, the number of parallel samples varied between 3 and 8.
X-ray diraction analysis
The XRPD paerns of the MA, P1670 and solid dispersions are represented in Fig. 1.
MA exists in two polymorphic forms. Based on our previous DSC thermograms (9) and
the XRPD peaks observed at 6.4, 16.0, 21.5 and 26.3° (2q) (27, 28), the form I polymorph of
MA was identied. The sharp, narrow peaks observed in the case of MA indicate its crys-
talline status. The diractograms of pure PEG 6000 and P1670 showed broad peaks at 19.2,
23.3 and 21.36° (2q), respectively. The peaks related to MA were not present in the case of
solid dispersions and the peaks of PEG 6000 are reduced and shied to higher angles, in-
dicating the amorphous state of the drug. In the case of solid dispersions, the peaks of PEG
6000 are predominantly present. Therefore, it can be conrmed that the active ingredient
is predominantly molecularly dispersed in the carrier or amorphous. The relative degree
of crystallinity (RDC) was calculated at 16.5° using the formula (29):
app =
I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
where RISD is the peak height of the solid dispersion and RIMA is the peak height of MA at
the same angle. The RDC for P10 was 0.012 and 0.014, for D5 suggesting that only partially
crystallized MA molecules are present in the products.
Dissolution studies
MA, a drug with an acidic character, dissolves slightly in AGF, especially its form I
polymorph (27); aer 120 minutes only 0.6 % of MA was dissolved. In the case of ternary
products the dissolution curves showed a peak aer 15–30 minutes, indicating that super-
saturation occured only when chiey molecularly dispersed form was present, followed
by recrystallization of the drug, which entailed a decrease in the amount dissolved. The
best results were obtained with the S5 product, where 3.1 % of MA was dissolved aer 120
In AIF, 9 % of MA was dissolved aer 120 minutes (concentration of 2.70 mg per 100
mL–1 was achieved). The amount of dissolved drug increased about 3 times (28.6 %) 8.58
mg in 100 mL–1) in the product containing 10 % D-1216 compared to pure MA. In the case
of other studied products, the dissolution rate of MA proved to be lower. Solubility de-
creased in the following order: D10 > S10 > P10 > D5 > P5 >S5 > PEG. The dissolution proles
in AIF are represented in Fig. 2.
The mechanism of drug release is described by the Gompertz function:
where Fmax is maximum dissolution, a determines the undissolved portion at time t = 1
(scale factor), and b is the dissolution rate per unit time (shape factor) (30). The coecients
of determination were above 0.95 in all cases.
The Gompertz model is typically used for comparing release proles of drugs with
good solubility and intermediate release rates. This model has a steep increase at the
Fig. 1. XRPD paerns of the studied products (MA – mefenamic acid, P1670, PEG 6000 and solid dis-
persions D5 and P10 see (Table I).
I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
Fig. 2. Dissolution proles of MA alone and in solid dispersions in articial intestinal uid (mean ±
SD, n = 3).
begin ning and converges slowly to the asymptotic maximal dissolution (27). In our case,
aer fast weing of the matrix, a certain amount of MA dissolved fast; aer that, the dis-
solution media became saturated in MA because of the non-sink conditions. Similarly to
data shown in Fig. 2, D10 was the most ecient of the studied products in increasing the
MA dissolution rate according to dissolution prole data (Table II) compared to the Gom-
pertz model.
Eects of mefenamic acid and formulations on the viability of Caco-2 cells
MA was not toxic in concentrations lower than 100 mg mL–1 in both assays (MTT dye
conversion and LDH release assays) but caused cell death at concentration of 1 mg mL–1
(Table III). Formulation containing only PEG 6000 did not change the toxicity paern of the
active ingredient. Among the formulations, those containing S-1670 (S5 and S10) showed
the highest toxicity, which was increased ten times compared to MA and PEG. P-1670-
containing samples (P5 and P10) were less toxic than formulations with S-1670. The non-
toxic concentrations of P-1670 were three times higher than that for S-1670; however, the
concentrations killing cells were the same for samples S5, S10, P5 and P10. The best formu-
lation was the D5 sample containing D-1216, where the non-toxic concentration was 100 mg
mL–1 and the toxic one was 300 mg mL–1.
Eect of formulations on transepithelial electrical resistance in Caco-2 cells
Caco-2 cell layers were treated by dilution of the samples containing 3 mg mL–1 of MA.
Aer 1-hour treatment, the resistance of cell monolayers did not change; it remained in the
range of the original 450–600 W cm–2 values. No signicant dierences were found in the
resistance of cell monolayers treated with the products.
I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
Permeability measurement across Caco-2 cells
The permeability coecient of MA was 49 × 10–6 cm s–1, reecting its high permeabil-
ity rate and lipophilic character (Fig. 3).
PEG 6000 and sucrose esters could not further increase the permeability of MA at the
tested low concentration (3 mg mL–1), when the active ingredient was already completely
solubilized (Fig. 4). The permeability coecient of MA decreased statistically signicantly
in products D5 and P10 (p < 0.05), since the hydrophilic auxiliary substances reduced the
permeability of MA. The analysis was repeated in the case of MA, D5, D10 and PEG prod-
ucts using 100 mg mL–1 MA in the donor compartment. Similarly to the rst set of experi-
ments, D10 and PEG did not cause any signicant change in the permeability of MA, while
D5 drug penetration decreased signicantly (p < 0.05).
Table II. Dissolution kinetics of solid dispersions in AIF
Product Fmax ± SD
(mg per 100 mL–1)
a ± SD
b ± SD
MA 11.17 ± 2.49 223.20 ± 203.28 3.48 ± 1.64 0.9660
PEG 27.06 ± 14.11 88.12 ± 139.25 1.91 ± 1.41 0.9775
D5 21.87 ± 3.49 21.95 ± 20.75 2.28 ± 0.74 0.9514
D10 106.29 ± 36.80 5.98 ± 0.44 0.75 ± 0.08 0.9907
P5 60.32 ± 70.14 11.89 ± 4.96 1.34 ± 0.64 0.9806
P10 89.72 ± 50.31 6.10 ± 0.59 0.82 ± 0.37 0.9884
S5 29.86 ± 30.62 48.47 ± 41.30 2.76 ± 1.85 0.9612
S10 60.55 ± 33.04 8.84 ± 3.67 1.17 ± 0.51 0.9839
Fmax – maximum dissolution; a – undissolved portion at time t = 1 (scale factor); bdissolution rate per unit t ime
(shape factor)
Table III. Toxic eects of MA and its products on Caco-2 human epithelial cells aer 24 hours
MTT dye conversionaLDH release
(mg mL–1)
(mg mL–1)
(mg mL–1)
(mg mL–1)
MA 100 1000 100 1000
PEG 100 1000 100 1000
D5 100 300 100 300
D10 30 300 30 300
P5 30 100 30 100
P10 30 100 10 100
S5 10 100 10 100
S10 10 100 10 100
a TC0 – the highest non-toxic concentration (no toxicity); TC100 – 100 % toxic concentration
I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
Fig. 3. Permeability of mefenamic acid measured on Caco-2 epithelial cell layers aer 1-hour treat-
ments with dierent formulations (Papp – apparent permeability coecient, * statistically signicant
dierences between the MA and the formulations, p < 0.05).
Fig. 4. Relationship between MA solubility and Papp in the case of D-1216 containing products (D5 and
D10) and the binary product (PEG) (the rate of change was calculated by dividing the solubility of the
product by the solubility of MA and the Papp of the products by the Papp of the MA).
The relationship between MA solubility and permeability
The relationship between MA solubility and permeability and its products with
D-1216 is shown in Fig. 4. The solubility rate increased in this order: MA-PEG < D5 < D10.
The rate of change of Papp (at 3 mg mL–1 MA) did not correlate with the solubility increment;
neither ascendant nor descendant tendencies could be observed. This can be explained by
the high permeability of MA and by the dierence in pH values applied in the AIF (pH 6.8)
and permeability (pH 7.4) studies.
The importance of increasing the water solubility of drugs belonging to BCS II class
is well known. In the case of MA, besides increasing the biopharmaceutical properties of
the drug using hydrophilic auxiliary substances, the severe adverse eects can be also
I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
reduced in such formulations. Water-solubility increasing auxiliary substances may mod-
ify the permeability of dierent APIs. In this work, dierent formulations of MA were
tested and the relationship between solubility and permeability was evaluated. MA was
embedded in the PEG 6000 polymer in the presence of sucrose ester surfactants. Based on
the dissolution test results, conrmed by the Gompertz-function parameters, the best re-
sults were obtained in the case of the 10 % D-1216 – containing product. This product also
proved to be one of the best formulations in the cellular toxicity test on Caco-2 cells. The
dissolved amount of MA aer 120 min increased only moderately, but aer 30 minutes a
signicant rise in the solubility of MA can be observed. Therefore, under in vivo conditions
the higher dissolved amount of MA – which is available for absorption – may increase the
absorption rate of MA.
Acknowledgments. – This paper was published under the framework of the European Social
Found, Human Resources Development Operational Programme 2007–2013, Project No. **
1. S. C. Sweetman (Ed.), Martindale: The Complete Drug Reference, 36th ed., Pharmaceutical Press, Lon-
don 2009, p. 80.
2. M. Ba, Non-coeliac at jejunal mucosa, Gut 30 (1989) 67–68.
3. T. Hamaguchi, D. Shinkuma, Y. Yamanaka and N. Mizuno, Bioavailability of mefenamic acid:
inuence of food and water intake, J. Pharm. Sci. 75 (1986) 891–893.
4. J. L. Wallace, Mechanisms, prevention and clinical implications of nonsteroidal anti-inamma-
tory drug-enteropathy, World J. Gastroenterol. 19 (2013) 1861–1876; DOI: 10.3748/wjg.v19.i12.1861.
5. D. V. Derle, M. Bele and N. Kasliwal, In vitro and in vivo evaluation of mefenamic acid and its
complexes with b-cyclodextrin and HP-b-cyclodextrin, Asian J. Pharm. 2 (2008) 30–34; DOI: 10.
6. G. L. Amidon, H. Lennernas, V. P. Shah and J. R. Crison, A theoretical basis for a biopharmaceutic
drug classication: the correlation of in vitro drug product dissolution and in vivo bioavailability,
Pharm. Res. 12 (1995) 413–420.
7. D. Mudit, Y. Bhardwaj, P. K. Keshavarao and P. Selvam, Enhancing solubility and dissolution of
mefenamic acid by freeze drying using b-cyclodextrin, Int. Res. J. Pharm. 2 (2011) 146–150; DOI:
8. U. Domanska, A. Pelczara and A. Pobudowska, Eect of 2-hydroxypropyl-b-cyclodextrin on solu-
bility of sparingly soluble drug derivatives of anthranilic acid, Int. J. Mol. Sci. 12 (2011) 2383–2394;
DOI: 10.3390/ms12042383.
9. I. Fülöp, Á. Gyéresi and Ș. Hobai, Characterisation of the interaction between fenamates and hy-
droxy-propyl-b-cyclodextrin, Bull. Med. Sci. 83 (2010) 58–62.
10. K. R. Rao, M. V. Nagabhushanam and K. P. Chowdary, In vitro dissolution studies on solid disper-
sions of mefenamic acid, Indian J. Pharm. Sci. 73 (2011) 243–247; DOI: 10.4103/0250-474X.91575.
11. G. Owusu-Ababio, N. K. Ebube, R. Reams and M. Habib, Comparative dissolution studies for
mefenamic acid-polyethylene glycol solid dispersion systems and tablets, Pharm. Dev. Technol. 3
(1998) 405–412; DOI: 10.3109/10837459809009868.
12. A. Dahan A and J. M. Miller, The solubility-permeability interplay and its implications in formu-
lation design and development for poorly soluble drugs, A APS J. 14 (2012) 244–251; DOI: 10.1208/
I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
13. A. Beig, R. Agbaria and A. Dahan, Oral delivery of lipophilic drugs: The tradeo between solu-
bility increase and permeability decrease when using cyclodextrin-based formulations, Plos One
8 (2013) e68237; DOI: 10.1371/journal.pone.0068237.
14. G. E. Amidon, W. I. Higuchi and N. F. Ho, Theoretical and experimental studies of transport of
micelle-solubilized solutes, J. Pharm. Sci. 71 (1982) 77–84.
15. J. M. Miller, A. Beig, R. A. Carr, G. K. Webster and A. Dahan, The solubility-permeability interplay
when using cosolvents for solubilization: revising the way we use solubility-enabling formula-
tions, Mol. Pharm. 9 (2012) 581–590; DOI: 10.1021/mp200460u.
16. A. Beiq, J. M. Miller and A. Dahan, Accounting for the solubility-permeability interplay in oral
formulation development for poor water solubility drugs: the eect of PEG-400 on carbamazepine
absorption, Eur. J. Pharm. Biopharm. 81 (2012) 386–391; DOI: 10.1016/j.ejpb.2012.02.012.
17. L. Kiss, E. Hellinger, A. M. Pilbat, A. Kiel, Z. Török, A. Füredi, G. Szakács, S. Veszelka, P. Sipos,
B. Ózsvári, L. G. Puskás, M. Vastag, P. Szabó-Révész and M. A. Deli, Sucrose esters increase drug
penetration, but do not inhibit P-glycoprotein in Caco-2 intestinal epithelial cells, J. Pharm. Sci. 103
(2014) 3107–3119; DOI: 10.1002/jps.24085.
18. A. Szűts and P. Szabó-Révész, Sucrose esters as natural surfactants in drug delivery systems – a
mini-review, Int. J. Pharm. 433 (2012) 1–9; DOI: 10.1016/j.pharm.2012.04.076.
19. T. Hladon, J. Pawlaczyk and B. Szafran, Stability of mefenamic acid in the inclusion complex with
b-cyclodextrin in the solid phase, J. Incl. Phenom. Macrocycl. Chem. 35 (1999) 497–506; DOI: 10.1023/
20. Ryoto Sugar Ester Technical Information, Ryoto Sugar Ester (Food grade)/ Surope™ SE Pharma,
Mitsubishi-Kagaku Foods Corporation; hp://; last access date May 25,
21. A. Szűts, E. Pallagi, G. Regdon, Jr., Z. Aigner and P. Szabó-Révész, Study of thermal behaviour of
sugar esters, Int. J. Pharm. 336 (2007) 199–207; DOI: 10.1016/j.pharm.2006.11.053.
22. A. Szűts, Zs. Makai, R. Rajkó and P. Szabó-Révész, Study of the eects of drugs on the structures
of sucrose esters and the eects of solid-state interactions on drug release, J. Pharm. Biomed. Anal.
48 (2008) 1136–1142; DOI: 10.1016/j.jpba.2008.08.028.
23. European Pharmacopoeia 8th ed., Council of Europe, Strasbourg 2013, pp. 288–295.
24. Y. Zhang, M. Huo, J. Zhou, A. Zou, W. Li, C. Yao and S. Xie, DDSolver: an add-in program for mo-
deling and comparison of drug dissolution proles, AA PS J. 12 (2010) 263–271; DOI: 10.1208/
25. P. Costa and J. M. Sousa Lobo, Modeling and comparison of dissolution proles, Eur. J. Pharm. Sci.
13 (2001) 123–133; DOI: 10.1016/S0928-0987(01)00095-1.
26. I. Fülöp, Á. Gyéresi, M. A. Deli, L. Kiss, M. D. Croitoru, P. Szabó-Révész and Z. Aigner, Ternary
solid dispersions of oxicams: Dissolution and permeability study, Farmacia 63 (2015) 286–295.
27. M. Dixit, A. Kini and P. K. Kulkarni, Enhancing the dissolution of polymorphs I and II of
mefenamic acid by spray drying, Turk. J. Pharm. Sci. 9 (2012) 13–26.
28. S. Romero, B. Escalera and P. Bustamante, Solubility behavior of polymorphs I and II of mefenam-
ic acid in solvent mixtures, Int. J. Pharm. 178 (1999) 193–202.
29. S. G. Vaya Kumar and D. N. Mishra, Preparation, characterization and in vitro dissolution stu-
dies of solid dispersion of meloxicam with PEG 6000, Yakugaku Zasshi (J. Pharm. Sci. Japan) 126
(2006) 657–664.
30. H. Lokhandwala, A. Deshpande and S. Deshpande, Kinetic modelling and dissolution proles
comparison: an overview, Int. J. Pharm. Biol. Sci. 4 (2013) 728–737.
... The chemical name of PL is 2-[2-(2-hydroxyethoxy)propoxy]ethanol (Wong et al., 2006). It is approved as an excipient for human use by FDA (Diniz et Various techniques have been used in the investigation of solid dispersions (SDs) of various weakly soluble drugs and other organic compounds (Moneghini et al., 2008;Aso et al., 2009;Moneghini et al., 2009;Menedez et al., 2010;Maurya et al., 2010;Van Eardenbrugh and Taylor, 2010;Issa et al., 2013;Paudel et al., 2013;Li et al., 2014;Xiqiang et al., 2014;Fulop et al., 2015;Kang et al., 2015;Wang et al., 2015;Altamimi and Neau, 2016). Microwave technology has been investigated rarely in literature in order to enhance solubility, in vitro dissolution, therapeutic efficacy and in vivo bioavailability of such drugs. ...
Full-text available
Apigenin (APG) is a poorly soluble bioactive compound/nutraceutical which shows poor bioavailability upon oral administration. Hence, the objective of this research work was to develop APG solid dispersions (SDs) using different techniques with the expectation to obtain improvement in its in vitro dissolution rate and in vivo bioavailability upon oral administration. Different SDs of APG were prepared by microwave, melted and kneaded technology using pluronicF127 (PL) as a carrier. Prepared SDs were characterized using “thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infra-red (FTIR) spectrometer, powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM)”. After characterization, prepared SDs of APG were studied for in vitro drug release/dissolution profile and in vivo pharmacokinetic studies. The results of TGA, DSC, FTIR, PXRD and SEM indicated successful formation of APG SDs. In vitro dissolution experiments suggested significant release of APG from all SDs (67.39-84.13 %) in comparison with control (32.74 %). Optimized SD of APG from each technology was subjected to in vivo pharmacokinetic study in rats. The results indicated significant improvement in oral absorption of APG from SD prepared using microwave and melted technology in comparison with pure drug and commercial capsule. The enhancement in oral bioavailability of APG from microwave SD (319.19 %) was 3.19 fold as compared with marketed capsule (100.00 %). Significant enhancement in the dissolution rate and oral absorption of APG from SD suggested that developed SD systems can be successfully used for oral drug delivery system of APG.
... Thus their solubility has to be increased to enhance their dissolution rate and consequently to improve their bioavailability. The SDs of MA and FFA have been prepared and evaluated using different techniques and different carriers in order to enhance their solubility, dissolution and bioavailability [26][27][28][29][30][31]. However, the SDs of these drugs have not been investigated using a solvent-free MW technology in literature. ...
Full-text available
The present studies were undertaken to develop solvent-free solid dispersions (SDs) for poorly soluble anti-inflammatory drugs mefenamic acid (MA) and flufenamic acid (FFA) in order to enhance their in vitro dissolution rate and in vivo anti-inflammatory effects. The SDs of MA and FFA were prepared using microwaves irradiation (MW) technique. Different carriers such as Pluronic F127® (PL), Eudragit EPO® (EPO), polyethylene glycol 4000 (PEG 4000) and Gelucire 50/13 (GLU) were used for the preparation of SDs. Prepared MW irradiated SDs were characterized physicochemically using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infra-red (FT-IR) spectroscopy, powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). The physicochemical characteristics and drug release profile of SDs were compared with pure drugs. The results of DSC, TGA, FT-IR, PXRD and SEM showed that SDs were successfully prepared. In vitro dissolution rate of MA and FFA was remarkably enhanced by SDs in comparison with pure MA and FFA. The SDs of MA and FFA prepared using PEG 400 showed higher drug release profile in comparison with those prepared using PL, EPO or GLU. The dissolution efficiency for MA-PEG SD and FFA-PEG SD was obtained as 61.40 and 59.18%, respectively. Optimized SDs were also evaluated for in vivo anti-inflammatory effects in male Wistar rats. The results showed significant % inhibition by MA-PEG (87.74% after 4 h) and FFA-PEG SDs (81.76% after 4 h) in comparison with pure MA (68.09% after 4 h) and pure FFA (55.27% after 4 h) (P<0.05). These results suggested that MW irradiated SDs of MA and FFA could be successfully used for the enhancement of in vitro dissolution rate and in vivo therapeutic efficacy of both drugs.
... Enzymatic degradation of CS during dissolution was achieved by the inclusion of pepsin in SGF (3.2 mg/mL) and trypsin in SIF (0.2 mg/mL). No surfactant was added to the dissolution medium as this would better differentiate between SD preparations (13,14). In addition, CS may act as surfactant due to its highly amphiphilic nature. ...
Full-text available
Due to its unique properties, such as biodegradability, biocompatibility, high amphiphilic property, and micelle formation, casein (CS) has been increasingly studied for drug delivery. We used CS as a drug carrier in solid dispersions (SDs) and evaluated the effect of its degradation by trypsin on drug dissolution from the dispersions. SDs of CS and mefenamic acid (MA) were prepared by physical mixing, kneading, and coprecipitation methods. In comparison to pure MA, the dispersions were evaluated for drug-protein interaction, loss of drug crystalinity, and drug morphology by differential scanning calorimetry, X-ray diffractometry, Fourier transform infrared spectroscopy, and scanning electron microscopy. Drug dissolution from the dispersions was evaluated in simulated intestinal fluid as enzyme free and trypsin-enriched media. Furthermore, in vivo drug absorption of MA from CS-MA coprecipitate was evaluated in rats, in comparison with a reference SD of polyethylene glycol and MA (PEG-MA SD). Relative to other CS preparations, CS-MA coprecipitate showed the highest loss of drug crystallinity, drug micronization, and CS-MA interaction. CS remarkably enhanced the dissolution rate and extent of MA from the physical and kneaded mixtures. However, the highest dissolution enhancement was obtained when MA was coprecipitated with CS. Trypsin that can hydrolyze CS during dissolution resulted in further enhancement of MA dissolution from the physical and kneaded mixtures. However, a corresponding retardation effect was obtained for the coprecipitate. In correlation with in vitro drug release, CS-MA coprecipitate also showed significantly higher MA bioavailability in rats than PEG-MA SD.
Full-text available
One of the applications of Hot-Melt Extrusion (HME) is the stabilization of amorphous drugs through its incorporation into polymeric blends in the form of Amorphous Solid Dispersions (ASDs). In this study, HME was applied to solve a real problem in the development of an ibrutinib product, stabilizing the amorphous form. A systematic approach was followed by combining theoretical calculations, high-throughput screening (HTS) focused on physical stability and Principal Components Analysis (PCA). The HTS enabled the evaluation of 33 formulations for physical stability and the PCA was key to select four promising systems. The low relevance of drug loading on the drug crystallization supported the HME tests with a very high drug load of 50%. Milled extrudates were characterized and demonstrated to be fully amorphous. The thermal analysis detected a glass transition temperature much higher than the predicted values. Along with several weak intermolecular interactions detected in Raman spectroscopy, a dipolar interaction involving the α, β unsaturated ketone was also noticed. The additive effect of these intermolecular interactions changed markedly the performance of the ASDs. The physical strength of the prepared systems was corroborated by stability studies until 6 months at long-term and accelerated conditions.
Mefenamic acid (MA) has been reported as a weakly soluble drug which presents weak in vivo absorption upon oral administration using conventional formulations. Solid dispersions (SDs) have been investigated extensively in literature for enhancing the solubility and bioavailability of weakly-soluble molecules. Hence, the aim of proposed study was to prepare MA novel formulations in the form of SDs using hot-melt extrusion technology in order to enhance its palatability, bioavailability and pharmacodynamics effects/anti-inflammatory efficacy. Various SDs of MA were prepared using hot-melt extrusion technology, characterized physically and investigated for dissolution tests. Optimized SD formulations of MA were being subjected to palatability, pharmacodynamics and pharmacokinetic studies in rats. Optimized SD of MA showed significant rat palatability tastes as compared with pure and marketed MA (P < 0.05). Anti-inflammatory efficacy of 20% SD and 25% SD of MA was found to be 86.44 and 89.83%, respectively in comparison with 74.57 and 78.24% by pure MA and marketed MA, respectively. The anti-inflammatory efficacy of optimized SD was found to be significant as compared with pure and marketed MA (P < 0.05). The oral absorption of MA from optimized 20% SD was also noted as statistically significant as compared with pure MA (P < 0.05). The relative bioavailability of MA from 20 and 25% SDs was 2.97 and 2.24-folds higher than pure MA. The results of this study suggested that SDs prepared using hot-melt extrusion technology are capable to enhance palatability, anti-inflammatory efficacy and oral bioavailability of MA in comparison with pure drug.
A novel multicomponent crystal (MC) of mefenamic acid (MA) and N-methyl-D-glucamine (MG) had been prepared to improve the physicochemical properties of poorly soluble drugs, and was characterized for its physicochemical properties by powder X-ray diffraction analysis, differential scanning calorimetry thermal analysis, FT-IR spectroscopy, in vitro dissolution rate, and physical stability. In addition, the crystal structure was determined by single-crystal X-ray diffraction analysis. The differential scanning calorimetry thermogram of the MA-MG binary system exhibits a single and sharp endothermic peak at 151.20°C, which was attributed to the melting point of a MC of MA-MG. FT-IR spectroscopy analysis showed the occurrence of solid-state interaction by involving proton transfer between MA and MG. The crystal structure analysis confirmed that MA-MG formed 1:1 ratio salt type MC. The formation of a MC of MA with MG significantly improved the dissolution rate of MA in compared to intact MA, and also the crystal demonstrated a good stability under a high relative humidity. These good properties would be attributed to the layer structure of MA and MG in the crystal.
This study aims to produce mefenamic acid-nicotinamide (MEF-NIC) cocrystal using gas anti-solvent (GAS) process in order to improve dissolution rate of MEF. Box-Behnken design was used to investigate the effects of three operating parameters: operating temperature, coformer-to-drug molar ratio and %drug saturation in the starting solution in the ranges of 25-45. °C, 3-5 and 70-90%, respectively. The analysis of experimental design showed that coformer-to-drug molar ratio and %drug saturation are significant parameters affecting the dissolution rate of the cocrystals. At a temperature of 45. °C, a coformer-to-drug ratio of 5 and a %drug saturation of 70% were found to be the optimal conditions for achieving the fastest dissolution time. Additionally, the sieved MEF-NIC cocrystal obtained from the optimal GAS conditions showed an enhanced dissolution rate 38 times greater than that of pure MEF and 1.6 times greater than cocrystal from a traditional slow evaporation method. © 2018 The Korean Society of Industrial and Engineering Chemistry.
Full-text available
Mefenamic acid, an anti-inflammatory drug, exhibits poor water solubility and flow properties, poor dissolution and poor wetting. Consequently, the aim of this study was to improve the dissolution of both the form of mefenamic acid (1 & II). Microspheres containing mefenamic acid (Form 1 & II) were produced by spray drying using isopropyl alcohol and water in the ratio of 40:60 (v/v) as solvent system. The prepared formulations were evaluated for in vitro dissolution and solubility. The prepared drug particles were characterized by scanning electron microscopy (SEM), differential scanning calorimeter (DSC), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR). Dissolution profile of the spray dried microspheres was compared with pure sample and recrystallized sample. Spray dried microspheres of both form of mefenamic acid exhibited decreased crystallinity and improved micromeritic & mechanical properties. The dissolution of the spray dried microspheres (Form 1 & II) were improved compared with recrystallized and pure sample of mefenamic acid. Consequently, it was believed that spray drying of mefenamic acid is a useful tool to improve dissolution, Hence this spray drying technique can be used for formulation of tablets of mefenamic acid by direct compression with directly compressible tablet excipients.
Full-text available
Mefenamic acid, an anti-inflammatory drug, exhibits poor water solubility, dissolution and flow properties. Thus, the aim of the present study was to improve the solubility and dissolution rate of Mefenamic acid by preparing microparticle by Freeze drying technique. Mefenamic acid microparticle containing different ratio of β-cyclodextrin were produced by Freeze drying using water and Isopropyl alcohol as solvent system to enhance solubility and dissolution rate. The prepared formulations containing different ratio of drug and polymer were evaluated for in vitro dissolution and solubility. The prepared formulations were characterized by scanning electron microscopy, differential scanning calorimeter, X-ray diffraction and Fourier transform infrared spectroscopy. Dissolution profile of the Freeze dried microparticle was compared with its physical mixture and pure sample. Freeze dried microparticle exhibited decreased crystallinity and the solubility and dissolution of the microparticle containing different ratio of drug and β-cyclodextrin were significant improved compared with its physical mixture and pure sample of Mefenamic acid. Dissolution of microparticle containing 1:3 w/w (FD 3) showed higher % release i.e. 98.6 % in 60 min compare to other formulation. Consequently, hence, from the above result it can be conclude that Freeze dried microparticle of Mefenamic acid is a useful technique to improve the solubility and dissolution of poorly water soluble drug like Mefenamic acid.
Full-text available
Solid dispersions are efficient means for improving the dissolution rate of hydrophobic drugs. In this study ternary solid dispersions were made by melting method using PEG 6000, three types of sugar esters and three enolic acid derivates used as non-steroidal anti-inflammatory drugs piroxicam, meloxicam and tenoxicam. The prepared solid dispersions were characterized by X-ray diffraction. Dissolution studies, kinetic calculations, and in the case of tenoxicam permeability and toxicity studies on Caco-2 human intestinal epithelial cells were also performed. X-ray diffraction studies showed a significant decrease in the degree of crystallinity due to amorphisation of the active ingredient or formation of a solid solution. The highest amount of drug dissolution in artificial gastric juice was obtained in the presence of 5% sugar esters. In the case of piroxicam and meloxicam the kinetics of dissolution were modified by the studied excipients. PEG 6000 did not change the toxicity of tenoxicam, while stearate and palmitate sucrose esters increased the damage to cultured Caco-2 cells. Laurate sucrose ester was the least toxic. The excipients did not modify the permeability of the lipid soluble tenoxicam across epithelial cells. Sucrose esters significantly increased the dissolution of model drugs, and may reduce the interindividual differences observed in the absorption rate of these drugs, due to their poor solubility. © 2015, Romanian Society for Pharmaceutical Sciences. All rights reserved.
Full-text available
O objetivo do presente estudo foi desenvolver comprimidos liofilizados de olanzapina (FDT). A solubilidade e a taxa de dissolução da olanzapina, fracamente solúvel em água, foram melhoradas com a preparação de comprimidos liofilizados de olanzapina usando a técnica de liofilização. O FDT foi preparado por dispersão do fármaco em solução aquosa de materiais altamente solúveis em água, como gelatina, glicina e sorbitol. A mistura foi colocada em blisters e, então, submetida ao congelamento e liofilização. O FDT foi caracterizado por DSC, Difração de Raios X e microscopia eletrônica de varredura(SEM) e avaliaram-se a solubilidade de saturação e a dissolução. As amostras for5am armazenadas em câmara de estabilidade para investigar a estabilidade física. Os resultados obtidos com DSC e Raios X foram analisados e mostraram a transformação do estado cristalino da olanzepina em FDT no estado amorfo durante a formação do FDT. Os resultados da SEM sugerem a redução do tamanho das partículas de olanzapina. A solubilidade da olanzapina do FDT melhorou significativamente a taxa de dissolução do fármaco comparativamente à mistura física (PM) e ao fármaco puro. Mais do que 90% da olanzepina no FDT dissolveu em 5 minutos, comparativamente aos 19,78% do fármaco puro dissolvido em 60 minutos. No teste de estabilidade, o perfil de liberação da FDT mostrou-se inalterado, quando comparado com o FDT recém-preparado, após 90 dias de armazenamento.
Full-text available
The purpose of this study was to investigate the impact of oral cyclodextrin-based formulation on both the apparent solubility and intestinal permeability of lipophilic drugs. The apparent solubility of the lipophilic drug dexamethasone was measured in the presence of various HPβCD levels. The drug's permeability was measured in the absence vs. presence of HPβCD in the rat intestinal perfusion model, and across Caco-2 cell monolayers. The role of the unstirred water layer (UWL) in dexamethasone's absorption was studied, and a simplified mass-transport analysis was developed to describe the solubility-permeability interplay. The PAMPA permeability of dexamethasone was measured in the presence of various HPβCD levels, and the correlation with the theoretical predictions was evaluated. While the solubility of dexamethasone was greatly enhanced by the presence of HPβCD (K1∶1 = 2311 M(-1)), all experimental models showed that the drug's permeability was significantly reduced following the cyclodextrin complexation. The UWL was found to have no impact on the absorption of dexamethasone. A mass transport analysis was employed to describe the solubility-permeability interplay. The model enabled excellent quantitative prediction of dexamethasone's permeability as a function of the HPβCD level. This work demonstrates that when using cyclodextrins in solubility-enabling formulations, a tradeoff exists between solubility increase and permeability decrease that must not be overlooked. This tradeoff was found to be independent of the unstirred water layer. The transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption.
Full-text available
This article reviews the latest developments in understanding the pathogenesis, detection and treatment of small intestinal damage and bleeding caused by nonsteroidal anti-inflammatory drugs (NSAIDs). With improvements in the detection of NSAID-induced damage in the small intestine, it is now clear that this injury and the associated bleeding occurs more frequently than that occurring in the stomach and duodenum, and can also be regarded as more dangerous. However, there are no proven-effective therapies for NSAID-enteropathy, and detection remains a challenge, particularly because of the poor correlation between tissue injury and symptoms. Moreover, recent studies suggest that commonly used drugs for protecting the upper gastrointestinal tract (i.e., proton pump inhibitors) can significantly worsen NSAID-induced damage in the small intestine. The pathogenesis of NSAID-enteropathy is complex, but studies in animal models are shedding light on the key factors that contribute to ulceration and bleeding, and are providing clues to the development of effective therapies and prevention strategies. Novel NSAIDs that do not cause small intestinal damage in animal models offer hope for a solution to this serious adverse effect of one of the most widely used classes of drugs.
This review shares different mathematical models used to determine the kinetics of drug release from delivery systems. It consists of an overview of applied method for comparison like model dependent, model independent and statistical model. The mathematical modeling can finally help to optimize the design of a therapeutic device to yield a system with programmed release rate characteristics which is now a prerequisite for controlled release drug delivery system. For the ease of application of these models linear forms to plot the graphs were also discussed. This review also consists of various software programs available to describe the release kinetics from therapeutic device.
Sucrose fatty acid esters are increasingly used as excipients in pharmaceutical products, but few data are available on their toxicity profile, mode of action, and efficacy on intestinal epithelial models. Three water-soluble sucrose esters, palmitate (P-1695), myristate (M-1695), laurate (D-1216), and two reference absorption enhancers, Tween 80 and Cremophor RH40, were tested on Caco-2 cells. Caco-2 monolayers formed a good barrier as reflected by high transepithelial resistance and positive immunostaining for junctional proteins claudin-1, ZO-1, and β-catenin. Sucrose esters in nontoxic concentrations significantly reduced resistance and impedance, and increased permeability for atenolol, fluorescein, vinblastine, and rhodamine 123 in Caco-2 monolayers. No visible opening of the tight junctions was induced by sucrose esters assessed by immunohistochemistry and electron microscopy, but some alterations were seen in the structure of filamentous actin microfilaments. Sucrose esters fluidized the plasma membrane and enhanced the accumulation of efflux transporter ligands rhodamine 123 and calcein AM in epithelial cells, but did not inhibit the P-glycoprotein (P-gp)-mediated calcein AM accumulation in MES-SA/Dx5 cell line. These data indicate that in addition to their dissolution-increasing properties sucrose esters can enhance drug permeability through both the transcellular and paracellular routes without inhibiting P-gp. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci
A physical model describing the simultaneous diffusion of free solute and micelle-solubilized solute across the aqueous boundary layer, coupled with partitioning and diffusion of free solute through a lipoidal membrane, is derived. In vitro experiments utilizing progesterone and polysorbate 80 showed excellent agreement between theoretical predictions based on independently determined parameters and experimental results. The physical model predicts that micelles can assist the transport of solubilized solute across the aqueous diffusion layer, resulting in a higher solute concentration at the membrane surface than would be predicted if micelle diffusion is neglected. At high surfactant concentrations, the aqueous diffusion layer resistance can be eliminated and the activity of the solute at the membrane can approach the bulk solute activity. This mechanism could explain observed enhanced absorption rates in vivo when both micelle solubilization occurs and the aqueous diffusion layer is an important transport barrier. The importance of determining and defining the thermodynamic activity of the diffusing solute is emphasized.