Pharmaceutica Acta Helvetiae 73 1999.

237245

In vitro study of the interaction between quinolones and

polyvalent cations
M a Sonia Rodrguez
Cruz, Isabel Gonzalez

Alonso ) , Amparo SanchezNavarro,

a
M Luisa Sayalero Marinero
Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Uniersity of Salamanca, Ada. Campo Charro sr n, 37007, Salamanca,
Spain
Received 3 August 1998; revised 16 September 1998; accepted 30 September 1998

Abstract
The aim of the present study was to evaluate the influence of aluminium and iron on the in vitro dissolution kinetics of ciprofloxacin
and ofloxacin as well as the usefulness of this type of in vitro data to predict modifications in in vivo absorption processes as a
consequence of different factors, such as the widely documented in vivo interaction between quinolones and cations. Fitting of
experimental data to different theoretical in vitro dissolution profiles was performed by non-linear regression methods and the statistical
moments were calculated from raw experimental data. Analysis of residuals applied to dissolution curves as well as statistical comparison
of the estimated parameters were carried out to evaluate the in vitro interaction. The results reveal significative modifications of the
dissolution profiles of these quinolones as a consequence of the presence of cations, especially for Fe 2q which decreases 34.7% the
maximum amount dissolved for ciprofloxacin and 29.1% for ofloxacin. Al 3q also produces a decrease of the total amount of quinolone
dissolved although less relevant than Fe 2q. Analysis of residuals proved to be the best statistical method to evaluate differences between
whole dissolution profiles, at least under the experimental conditions used. q 1999 Published by Elsevier Science B.V. All rights
reserved.
Keywords: Ofloxacin; Ciprofloxacin; Polyvalent cations; Dissolution test; Dissolution kinetics; Interaction

1. Introduction
Despite the considerable body of information in the
literature about the interaction between quinolones and
polyvalent cations Kara et al., 1991; Shiba et al., 1992;
Wayne Frost et al., 1992; Lomaestro and Bailie, 1993;
Maeda et al., 1993; Sanchez
Navarro et al., 1994., many

aspects related to this process remain to be clarified,

including the mechanism or experimental and clinical conditions controlling this interaction.
Several authors Nix et al., 1989; Polk et al., 1989.
have suggested the formation of an insoluble, non-absorbable complex between the quinolone and the corresponding
)
Corresponding author. Tel.: q34-23-294-536; fax: q34-23-294-515;
e-mail: igal@gugu.usal.es

cation; others Ross and Riley, 1990; Ross and Riley,

1992. have proposed the formation of a micellar phase as
a consequence of changes in the net charge of the compound and, recently, Macas
et al. 1994. have
Sanchez

found that ofloxacin with metal cations follows the general

pattern expected, leading to the formation of salts or
coordination compounds, while ciprofloxacin retains the
molecular network and no functional group seems to be
lost or modified after entering into contact with different
polyvalent cations. In contrast, the effect of polyvalent
cations on the oral absorption of ciprofloxacin has been
reported to be higher than the effect observed with
ofloxacin Wolfson and Hooper, 1989; Flor et al., 1990..
Additionally, there are some differences among the results
found by different authors studying quantitative modifications in the oral absorption of quinolones administered

0031-6865r99r$ - see front matter q 1999 Published by Elsevier Science B.V. All rights reserved.
PII: S 0 0 3 1 - 6 8 6 5 9 8 . 0 0 0 2 9 - 6

238

M a S. Rodrguez
Cruz et al.r Pharmaceutica Acta Heletiae 73 (1999) 237245

with drugs or food containing cations Nix et al., 1990;

Martnez-Cabarga
et al., 1991; Pertti et al., 1991..

The conclusion to be drawn from the available information is that some type of interaction takes place between
quinolones and cations which leads to a decrease in the
amount of antibacterial drug absorbed when administered
by the oral route, but the interaction process seems to be
very sensitive to slight changes in factors related to the
experimental andror clinical conditions of the different
assays. This would justify the wide dispersion of the
results reported in the literature.
The present study was therefore carried out to evaluate
the influence of the presence of Al 3q and Fe 2q ions on the
in vitro dissolution profiles of ciprofloxacin and ofloxacin.
Also to analyze the advantages and limitations of different
available statistical methods used to compare in vitro
dissolution curves. Since drug dissolution is the previous
step to drug absorption, the study of the modifications of
the dissolution profiles will provide useful information
about the possible changes in drug absorption as a consequence of interactions.

2. Materials and methods

2.1. Materials and equipment
2.1.1. Drugs and reagents
The quinolone solid dosage formulations assayed were
Baycip w 250 mg Bayer, Barcelona, Spain. and Tarivid w
200 mg Hoescht Farma, Barcelona, Spain..
The cation preparations were: Fero-Gradumet w Abbot
Cientifica, Madrid, Spain. and aluminium hydroxide powder Merck, Darmstadt, Germany..
2.1.2. Equipment
Hanson SR 6-Flask Dissolution test station Hanson
Research, Chatsworth, CA.. U-2000 Spectrophotometer
Hitachi, Tokyo, Japan.. 5000 Liquid Chromatograph
Varian. connected to a Kontron SFM 25 fluorescence
detector.
2.2. Methods
2.2.1. In itro dissolution assay
Dissolution profiles were determined at 37 " 0.58C in
900 ml of phosphate buffer solution, pH s 6. Commercially available dissolution equipment employing the paddle apparatus as described in the USP XXII 1989. was
used. Rotation speed was maintained at 50 r.p.m. The

paddle was positioned to extend to exactly 2.5 cm above

the flask bottom. Samples 2 ml. were taken with a
graduated syringe at the following times.
Ciprofloxacin: 1, 2, 3, 4, 5, 7, 10, 15, 20, 30, 45, 60 and
90 min.
Ofloxacin: 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240,
300 and 360 min.
Each sample was replaced by an equal volume of
dissolution media to keep the total volume constant. A
correction was made to take into account the cumulative
removed volumes when determining the total amount dissolved as a function of time.
All samples were suitably filtered, placing a filter at the
end of the sample probe, and kept at 58C until immediate
analytical determination.
The suitability of the paddle apparatus was checked
using the USP prednisone and salicylic acid calibrators
calibrators for system suitability test of basket and paddle
dissolution apparatus. Hanson, 1992..
One tablet of the corresponding quinolone was placed
in each filled flask 6 tablets per run. when establishing
the dissolution profiles of the quinolones in the absence of
cations. These profiles were considered as reference curves.
To evaluate the influence of the different cations on the
quinolone dissolution kinetics, the corresponding cation
preparation was added to each flask at the same time as the
quinolone formulation. For Al 3q, a sufficient amount of
aluminium hydroxide powder to obtain 2.5 g of Al 3q was
added; when studying the influence of Fe 2q, two 525 mg
FeSO4 tablets were included in the dissolution media. The
amounts of cations were selected based on the usual
clinical doses.
Addition of quinolones or cations do not modifies the
pH of dissolution media for the sampling period.

2.2.2. Analytical techniques

Samples from all assays, except those on Fe 2q, were
analyzed by an UV-spectrophotometric technique at wavelengths of 287 nm and 271 nm for ofloxacin and
ciprofloxacin, respectively.
Standard curves were prepared in phosphate buffer
solution pH s 6. at a concentration range of 0.520.0
mgrl for ofloxacin and 0.510.0 mgrl for ciprofloxacin.
Samples were diluted when necessary to achieve concentrations included within the standard curve range.
The UV technique showed adequate linearity, precision
and accuracy with coefficients of variation of less than 5%
and 2.5% for ofloxacin and ciprofloxacin, respectively.
Samples from the Fe 2q assays were analyzed by an
HPLC technique. A Varian 5.000 Chromatograph connected to a variable wavelength fluorescence detector was

M a S. Rodrguez
Cruz et al.r Pharmaceutica Acta Heletiae 73 (1999) 237245

239

Fig. 1. Dissolution profiles of ciprofloxacin and ofloxacin corresponding to in vitro tests carried out under the following experimental conditions:
phosphate buffer solution, pH s6, T a s 378C. Each curve is the mean of six experiments.

used. The 15 cm-long column 4 mm internal diameter.

was packed with Nucleosil w 120 R-18 5m of particle size.
The mobile phase consisted of acetonitrile and 0.025 M
phosphate buffer solution, pH 3, 9:91 vrv. and the flow
rate was 2 mlrmin. The fluorescence excitation and emission wavelengths were set at 277 nm and 445 nm for
ciprofloxacin and 330 nm and 450 nm for ofloxacin,
respectively. 50 ml of the internal standard each quinolone
was used as the internal standard of the other one. was
added to 200 ml of the sample. The mixture was vigorously shaken for 30 s and 100 ml was injected into the
chromotograph. Standard curves were prepared as indicated for UV detection and samples were also diluted if
necessary.
This HPLC technique also showed adequate linearity,
precision and accuracy with coefficients of variation of
less than 10% and 8% for ofloxacin and ciprofloxacin,
respectively.

Both, UV and HPLC, techniques quantifies free drug in

the dissolution media.

2.2.3. Data analysis

The dissolution pattern, described as the cumulative
amount of drug dissolved, was fitted to different mathematical expressions, commonly related to in vitro dissolution profiles, for immediate release dosage formulations
Abdou, 1989..
These expressions are:
Zero-order kinetics:
dQ
dt

sK0

1.

where: dQrdt s dissolution rate; K o s constant amount

of drug dissolved per unit time

Table 1
Mean dissolution parameters of ofloxacin under standard conditions and in presence of two different cations

Ofloxacin 200 mg
Oflo 200qAl 3q
Oflo 200qFe 2q

MDT min.

CV

Qma x mg.

K d miny1 .

45.20"13.84
98.41"37.67
36.17"11.41

1.20"2.80ey1
1.25"9.42ey2
1.09"1.05ey1

173.60"11.67
152.11"16.89
123.16"3.58

3.04ey2"6.64ey3
1.77ey2"3.33ey3
4.33ey2"7.20ey3

M a S. Rodrguez
Cruz et al.r Pharmaceutica Acta Heletiae 73 (1999) 237245

240

Table 2
Mean dissolution parameters of ciprofloxacin under standard conditions and in presence of two different cations

Ciprofloxacin 250 mg
Cipro 250 mgqAl 3q
Cipro 250 mgqFe 2q

MDT min.

CV

Qma x mg.

K d miny1 .

8.87"1.69
11.32"4.79
17.32"11.66

1.82"3.74ey1
1.85"3.99ey1
1.04"1.06ey1

219.41"7.74
180.16"46.47
143.24"8.39

2.43ey1"6.69ey2
2.32ey1"9.70ey2
4.76ey1"1.12ey1

First-order kinetics:
Q t s Q max 1 y eyK d t .

2.

where: Q t s amount of drug dissolved at time t; Qmax

s maximum amount of drug dissolved; K d s first-order
dissolution rate constant
Weibull distribution function:
Q t s Q max 1 y ey trt d .

3.

where: td s time necessary to achieve 63.2% of total

drug dissolved; b s an adimensional parameter defined
by the shape of the dissolution curve plot related to the
order of the process..
The fitting was carried out using the PCNONLIN 4.0
program Dunne and Stucker, 1992..
The statistical criterion for the selection of the optimum
fitting was the minimum AIC value Test MAICE.
Yamaoka et al., 1977..

In addition to dissolution curve fitting the mean in vitro

dissolution time MDT. and the coefficient of variation
CV. were calculated using trapezoidal integration Purves,
1992.. The MDT is defined as follows:
`

MDT s

H0 t dQrQ

max

4.

where: Q s amount of drug dissolved at time t; Qmax s

maximum amount of drug dissolved.
The CV values, which inform about the dispersion of
the dissolution process Weiss, 1992., were calculated
according to the following expression:
CV s

'VDT
MDT

5.

VDT is the variance of the dissolution times, that is the

moment of second degree, as the dissolution profile may
be considered a distribution function of the residence times

Fig. 2. Dissolution profiles of ofloxacin corresponding to in vitro tests carried out in absence of cations and in presence of Al 3q or Fe 2q. Each curve is the
mean of six experiments.

M a S. Rodrguez
Cruz et al.r Pharmaceutica Acta Heletiae 73 (1999) 237245

241

Fig. 3. Dissolution profiles of ciprofloxacin corresponding to in vitro tests carried out in absence of cations and in presence of Al 3q or Fe 2q. Each curve is
the mean of six experiments.

of each drug molecule in the pharmaceutical formulation.

VDT was calculated by trapezoidal integration as follows:
`

VDT s

H0

2
t y MDT. dQrQmax

6.

2.2.4.2. Estimation of a fit factor F

In order to measure the dissimilarity between the reference
curves and those obtained in presence of cations a fit
factor F was calculated for each added cation. This factor
approximates the percent error between two curves and

2.2.4. Statistical analysis

2.2.4.1. ANOVA
Statistical moments MDT, CV. as well as other dissolution parameters Qmax , K d . were calculated from each
individual dissolution profile and the statistical comparison
of each parameter in presence and absence of cations, for
both quinolones, was carried out using the test ANOVA at
the standard significance level p - 0.05..

Table 3
Modifications of dissolution parameters of ciprofloxacin and ofloxacin
calculated as percentage of change of mean parameter values
OFLOXACINqAl3q
OFLOXACINqFe2q
CIPROFLOXACINqAl3q
CIPROFLOXACINqFe2q

MDT

Qma x

Kd

117.72
x 19.98
27.62
95.26

x 12.38
x 29.06
x 17.89
x 34.72

x 41.78
42.43
x 4.53
95.88

Fig. 4. Differences between dissolution profiles in absence and presence

of each studied cation, quantified by a fit factor value F . calculated from
in vitro individual dissolution curves of ciprofloxacin and ofloxacin.

M a S. Rodrguez
Cruz et al.r Pharmaceutica Acta Heletiae 73 (1999) 237245

242

2.2.4.3. Analysis of the residuals

Considering the dissolution profile of the quinolone in
absence of cations as the reference curve, the weighted
residual was calculated for each sample time and every
dissolution curve, according to the well known expression:
Qr y Qc
Rs
8.
Qr
Analysis of residuals was carried out for each cation by
plotting residuals versus time and examining the scatterplots which inform about the trend in deviations, if they
exist.

3. Results
Fig. 1 shows the mean in vitro dissolution curves of
ciprofloxacin and ofloxacin in phosphate buffer solution

Fig. 5. Scatterplot of residuals for dissolution curves of ofloxacin in

presence of cations using the dissolution curve of the quinolone in
absence of cations as the reference profile.

quantifies, by a single numerical parameter, the total difference between compared profiles.
According to Moore and Flanner 1996. this fit factor is
defined by the following equation:
n

< Qr y Qc <
Fs

is1
n

100

7.

Qr
is1

where: n is the total number of samples; Qr and Qc are the

amount of drug dissolved under standard conditions reference curve. and in presence of the cation, respectively.
According to that, the fit factor F is calculated for each
cation and each quinolone.

Fig. 6. Scatterplot of residuals for dissolution curves of ciprofloxacin in

presence of cations using the dissolution curve of the quinolone in
absence of cations as the reference profile.

M a S. Rodrguez
Cruz et al.r Pharmaceutica Acta Heletiae 73 (1999) 237245

pH s 6.; the corresponding dissolution parameters are

included in Tables 1 and 2.
The maximum dissolved amount of drug, defined by the
asymptote of the fitted curves, are 219.41 " 7.74 mg and
173.60 " 11.67 mg, which represent percentages of 88%
and 87% of the theoretical dose for ciprofloxacin and
ofloxacin, respectively. The first order rate constant show
a value of 2.43e y 1 " 6.69e y 2 miny1 for ciprofloxacin,
significantly higher than the 3.04e y 2 " 6.64e y 3 miny1
corresponding to ofloxacin. In agreement with it, the MDT,
calculated by trapezoidal integration from raw experimental data, show statistically significant differences between
ciprofloxacin 8.87 " 1.69 min. and ofloxacin 45.20 "
13.84 min.. The dispersion of the dissolution times, measured as the CV, is slightly higher for ciprofloxacin 1.82
" 3.74e y 1. than for ofloxacin 1.20 " 2.80e y 1..
Figs. 2 and 3 illustrate the effect of the presence of
different cations on the in vitro dissolution profiles of
ofloxacin and ciprofloxacin, respectively. The cations yield
to a decrease of the maximum amount dissolved for
ciprofloxacin as well as ofloxacin. Modifications of the
first order rate constant are also observed as a consequence
of addition of Fe 2q to the dissolution media.
Table 3 summarizes the modification of the dissolution
parameters caused by presence of each cation; these are
expressed as percentage of change calculated from the
mean parameter values.
Fig. 4 depicts the F values obtained for both quinolones
and each cation. This parameter shows the highest value
for Fe 2q with ciprofloxacin 41.10%., followed by Fe 2q
with ofloxacin 26.24%.. For Al 3q the values of this factor
are similar for both quinolones.
Figs. 5 and 6 illustrate the results of the analysis of the
residuals by means of the corresponding scatterplot.
4. Discussion
Under the same experimental conditions dissolution of
ciprofloxacin showed to be much faster than ofloxacin
from the commercial dosage forms used. Fig. 1 illustrates
these differences which are confirmed by the values of the
parameters related to the dissolution rate. MDT for
ciprofloxacin is 8.87 " 1.69 min, about one fifth of the
corresponding value for ofloxacin 45.20 " 13.84 min..
Comparison of the first order dissolution rate constants
yields to the same conclusion as this parameter shows a
value of 3.04e y 2 " 6.64e y 3 miny1 for ofloxacin and
2.43e y 1 " 6.69e y 2 miny1 for ciprofloxacin.
Both, first order kinetics and Weibull distribution function provide an acceptable data fitting with similar AIC
values and no statistically significant differences between
the estimated dissolution parameters using each function:

243

Q max and K d or td each one calculated as the inverse of

the other; td s 1rK d and K d s 1rtd ..
Parameters included in Tables 1 and 2 correspond to
those values estimated by first order kinetics fitting.
Goodness of fitting was additionally tested by comparison of the values of K d obtained by non-linear regression
and those calculated from the inverse of MDT, as the
relationship K d s 1rMDT comes true for first order kinetic process. Based on it, this relationship can be used as
an additional test to verify the goodness of data fitting.
According to MDT value, the dissolution rate constants
take values of 2.21e y 2 miny1 and 1.13e y 1 miny1 for
ofloxacin and ciprofloxacin, respectively, which differ from
the estimated values by data fitting, especially for
ciprofloxacin 1.13e y 1 miny1 versus 2.43e y 1 miny1 ..
These results point to pseudo or apparent. first order rates
as Wagner states for conditions of variable surface area
Wagner, 1969..
On assessing the influence of polyvalent cations on the
dissolution kinetics of these quinolones, Fe 2q proved to be
the cation which most significantly decreases Qmax value,
followed by Al 3q.
Regarding the dissolution rate parameters such as MDT
and K d , significative modifications in K d are observed for
both quinolones with Fe 2q and also for ofloxacin with
Al 3q, nevertheless the changes observed in these parameters do not follow a fixed pattern, but show increases or
decreases depending on the drug andror the cation. The
interpretation of these results is not easy as the addition of
cations to the dissolution media produces the existence of
two simultaneous processes: drug dissolution and drugcation interaction. The characterization of these two kinetic
processes by a single first rate constant is a simplistic,
non-realistic model, and yields to the estimation of a
hybrid constant without a clear physico-chemical meaning.
The increase or decrease of this hybrid constant can not be
directly associated to changes in the dissolution rate.
A similar situation arises when calculating MDT from
experimental data. In presence of cations the interaction
process takes place and the drug can be in any of the three
following states: non-dissolved drug remaining in the
dosage form, dissolved drug in the media or drugcation
complex. Under these conditions the parameter calculated
using expression number 4 is not the MDT as Q is not the
amount of drug dissolved but the amount of free drug in
the dissolution media Notice that only free drug is determined..
Because of the limitation showed when using rate parameters to compare dissolution profiles under our experimental conditions, a fit factor F proposed by Moore and
Flanner 1996. to quantify the total difference between
curves, was calculated for each cation, using Eq. 7..

244

M a S. Rodrguez
Cruz et al.r Pharmaceutica Acta Heletiae 73 (1999) 237245

According to the results, Fe 2q modifies the dissolution

profile of ciprofloxacin in a 41.1% and only in a 26.24%
for ofloxacin; Al 3q affects, from a quantitative point of
view, similarly to both quinolones.
As a consequence of unweighting the differences between compared profiles, the higher the amount dissolved
the stronger its contribution to the total sum of differences
and therefore to the F value. In other words the fit factor
calculated according to Eq. 7. underestimates the differences when those affect to the early phase of the curve
which corresponds to the lower amounts of drug dissolved.
A weighted fit factor will overcome this problem.
We propose the analysis of the weighted residuals
Gabrielsson and Weiner, 1994. as the most suitable statistical method to compare whole dissolution profiles. This
type of analysis allows one to ponder and evaluate the
modifications from the beginning to the end of the process.
The scatterplot of residuals informs about the distribution
of differences and bias when they exist. Figs. 5 and 6 show
a biased scatterplot of residuals for both quinolones and
the two cations showing interesting differences when comparing ofloxacin to ciprofloxacin. The bias is always observed from the early stages for ofloxacin while it does not
appear at the beginning for ciprofloxacin but increases
with time becoming higher than ofloxacin in the latter
stages. These results point out to a quicker but less intense
drugcations interactions for ofloxacin compared to
ciprofloxacin. Differences between ofloxacin and
ciprofloxacin behaviour in presence of cations, from a
physico-chemical point of view, have already been reported in a previous work as referenced in Section 1.
Analysis of residuals also permits us to establish the
differences between the studied cations. Interaction with
Al 3q takes place the fastest while interaction with Fe 2q
becomes more evident with time and yields to the highest
significative differences in the asymptote of the dissolution
curve.
The conclusion to be drawn, from the commented results, is that comparison of in vitro dissolution curves
provides a useful method to detect factors affecting in vivo
absorption processes such as drugdrug andror fooddrug
interaction. It has been proved for ciprofloxacin and
ofloxacin, whose in vitro dissolution profiles in presence
of cations change in good agreement with the modifications reported for the oral absorption of these quinolones,
administered together with drugs or foods containing Fe 2q
or Al 3q.
Regarding the statistical method used for comparison,
different strategies can be followed, as described and
commented in Sections 2.2 and 4, respectively. All of
them, in spite of their limitations, bring some information
about the changes in dissolution profiles. Nevertheless the

interpretation of changes observed in the fitted parameters

and statistical moments must be cautious. Analysis of
residuals provides, in any case, the most suitable and
recommended method to evaluate the differences between
different in vitro dissolution profiles.
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