Available via license: CC BY
Content may be subject to copyright.
Article Not peer-reviewed version
Incompatibility of Y-Site
Administered Drugs: the Case of
Acyclovir and Ciprofloxacin
Dorine Labrosse , Lugan Flacher , Thomas Bachelart * , Ahcène Boumendjel *
Posted Date: 27 September 2023
doi: 10.20944/preprints202309.1844.v1
Keywords: drugs incompatibility; drugs interactions; acyclovir; ciprofloxacin
Preprints.org is a free multidiscipline platform providing preprint service that
is dedicated to making early versions of research outputs permanently
available and citable. Preprints posted at Preprints.org appear in Web of
Science, Crossref, Google Scholar, Scilit, Europe PMC.
Copyright: This is an open access article distributed under the Creative Commons
Attribution License which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
Article
Incompatibility of Y-Site Administered Drugs: the
Case of Acyclovir and Ciprofloxacin
Dorine Labrosse 1, Lugan Flacher 1, Thomas Bachelart 1,* and Ahcène Boumendjel 2,*
1 DrugOptimal, 29 chemin du Vieux Chêne 38240 Meylan, France
2 Université Grenoble Alpes, INSERM, LRB, 38000 Grenoble, France
* Correspondence: Correspondence: ahcene.boumendjel@univ-grenoble-alpes.fr (A.B.);
thomas.bachelart@drugoptimal.com (T.B.).
Abstract: Multiple drugs administration is a common practice in hospitals and clinics. This is the case when
heavy pathologies are treated. In this context, frequently, antivirals and antibiotics are co-administrated either
simultaneously or sequentially ignoring potential incompatibilities. In this study, we focused on an antiviral
(Acyclovir) and an antibiotic (Ciprofloxacin) compatibility/incompatibility when they co-administrated with
special interest on the effect of drugs ratio, pH and delay. By implementing robust HPLC method, we
determined the main factors leading to potential modification of concentration of one of the two drugs in the
mixture. The results showed that acyclovir is quantitatively recovered in all conditions related to pH,
concentration and time (up to 24 hours). However, ciprofloxacin is strongly altered in acidic and basic
conditions, the quantity of ciprofloxacin and time after mixing the two drugs. The most valuable piece of
information is that the ratio of acyclovir/ciprofloxacin is crucial. The latter should be calculated and managed
to provide at least two fold quantity of acyclovir versus ciprofloxacin in order to maintain the administrated
doses and warrant efficient therapeutic effect.
Keywords: drugs incompatibility; drugs interactions; acyclovir; ciprofloxacin
1. Introduction
Intravenous (IV) drug administration plays a pivotal role in the treatment of severe infections
and heavy pathologies. To ensure effective patient care, healthcare professionals frequently
encounter the need for simultaneous or sequential administration of multiple medications. However,
the co-administration of drugs via IV injection, best known as Y-site administration raises concerns
about incompatibility and the potential for physicochemical interactions (PIC) that may compromise
therapeutic efficacy, patient safety or both [1,2]. It is essential to differentiate a physicochemical
incompatibility from a pharmacological drug interaction. In the case of physicochemical
incompatibility, drugs interact and cancel each other out before reaching their target. On the other
hand, in a pharmacological drug interaction, the drugs reach their biological target and produce their
effects, which are themselves antagonistic or responsible for an increase in toxicity.
In this context, incompatibility studies are essential to assess the physical and chemical stability
of drug combinations and to determine the potential for precipitation, pH changes, drug degradation,
or the formation of byproducts with potential side effects [3-5]. Such investigations provide valuable
insights into the feasibility and safety of co-administration, helping healthcare professionals make
informed decisions regarding IV drug therapy and ensuring optimal patient outcomes [6,7].
The incompatibility issue concerns the major classes of drugs and especially those bearing acidic
and/or basic characters [8].
In this study, we focused our efforts on two major drugs: acyclovir and ciprofloxacin (Figure 1).
Acyclovir, (9-[(2-hydroxyethoxy)methyl]guanine), a nucleoside analogue of the guanosine family, is
a widely used antiviral drug as tablets, topical creams and intravenous injections [9]. Neutral
acyclovir suffers from poor solubility in water (1.2−1.6 mg/mL at 25°C limiting its absorption into the
gastrointestinal tract when taken orally [10,11]. Ciprofloxacin, 1-cyclopropyl-6-fluoro-4-oxo-7-
piperazin-1-ylquinoline-3-carboxylic acid, is a broad-spectrum antibiotic agent in the
Disclaimer/Publisher’s Note: The statements, opinions, and data contained in all publications are solely those of the individual author(s) and
contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting
from any ideas, methods, instructions, or products referred to in the content.
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 27 September 2023 doi:10.20944/preprints202309.1844.v1
© 2023 by the author(s). Distributed under a Creative Commons CC BY license.
2
fluoroquinolone class used to treat bacterial infections [12]. The simultaneous administration of
acyclovir and ciprofloxacin may be necessary in certain clinical scenarios, such as the treatment of
patients with co-existing viral and bacterial infections or the prevention of secondary infections
during viral outbreaks [13]. Therefore, it is crucial to evaluate the incompatibility of acyclovir and
ciprofloxacin solutions when co-administered via IV infusion.
Figure 1. Chemical structures of acyclovir and ciprofloxacin.
Although individual compatibility/incompatibility studies were conducted for acyclovir and
ciprofloxacin with other medications [14,15], limited or even non-existent scientific data regarding
their compatibility when combined in a co-administration therapy (Y-cite administration).
Considering the widespread use of these drugs, the absence of comprehensive compatibility
information recalls significant challenges in clinical practice. Consequently, healthcare professionals
must resort to empirical approaches or rely on anecdotal evidence to guide the co-administration of
these two drugs.
The aim of this study is to investigate the incompatibility of acyclovir and ciprofloxacin solutions
during Y-cite administration. By employing rigorous analytical techniques and monitoring key
physicochemical parameters, we aim to provide evidence-based recommendations regarding the
feasibility and safety of their simultaneous administration.
2. Materials and Methods
2.1. Products, Solvents and Consumables
The following products, solvents and consumables have been used : acyclovir (Mylan) powder
for injectable solution, ciprofloxacin (Fresenius Kabi) 400 mg/200 mL, sodium chloride (Fresenius
Kabi) 0.9% (9g/1000 mL), methanol HPLC Grade (Carl Roth), distilled water, phosphoric acid (Sigma-
Aldrich) 85%, di-sodium hydrogenophosphate (Prolabo), sodium hydroxide tablets (ChemLab),
hydrochloric acid (ChemLab), vials (Thermo Fisher Scientific), Eppendorf and Falcon tubes.
2.2. Instruments and Chromatographic Conditions
Chromatographic analyses were performed using the Agilent 1100 series HPLC system (Agilent
Technologies) equipped with degasser G1322A, binary pump G1312A, autosampler G1329A,
thermostatted column compartment G1316A and MWD UV detector (G1365B). The compounds were
separated on a Select® Peptide CSHTM C18, 150 x 4.6 mm, 2.5 μm, 130 A column at 40 °C. The
injection volume was fixed at 10 μL. Mobile phase, composed of distilled water (containing Na2HPO4,
20 mM and phosphoric acid, pH=3) and methanol (60/40, v/v), was used for isocratic elution at a flow
rate of 0.5 mL/min. The detector monitored the elution at 205, 260 and 273 nm for simultaneous
detection of acyclovir and ciprofloxacin over a period of 10 minutes. The obtained chromatograms
were analyzed using ChemStation B.04.03 software.
2.3. Stock Solutions Preparation
The sampling of adequate volume were realized with 200 μL and 1000 μL micropipettes
(Eppendorf France). Ciprofloxacin stock solution was prepared directly by sampling the commercial
solution 2 mg/mL, concentration currently used in clinical practices [16]. Acyclovir stock solutions
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 27 September 2023 doi:10.20944/preprints202309.1844.v1
3
were prepared by weighting powder with a precision balance (Denver Instrument) and then, by
reconstituting with sodium chloride 0.9% at 2 mg/mL, in a Falcon tube. The solutions were manually
stirred and sonicated for a minute with a Sonicator (Elma). For the screening experiment, stock
solutions were prepared as follows: Ciprofloxacin (2 mg/mL). Acyclovir (500 mg) was dissolved in
NaCl 0.9 % (100 mL) at 5 mg/mL.
2.4. Screening of Solutions Preparation by Visual Inspection
To start our investigation on acyclovir and ciprofloxacin, we performed a series of tests analyzed
by visual inspection to have a glimpse of the behavior of those two drugs when administrated
concomitantly. Acyclovir (concentration, reconstitution solvent) and Ciprofloxacine (concentration,
reconstitution solvent) were prepared at five volume ratios (1/1, 1/2, 2/1, 1/9, 9/1). Samples were
prepared in 0.5 mL Eppendorf tubes (non-sterile), appropriate volume of each drug (to reach desired
ratio) was added with precision pipette. Each sample was made in triplicate. The visual inspections
were performed with the same background and the same light source and physical stability was
assessed by two observers. A second and a third visual inspection was performed at t = 2h (+/- 20
min) and at t = 13h (+/-1h). Each result was described according to the following nomenclature: Q0:
clear solution; Q1: small amount; Q2: important amount; Q3: huge amount. The aspect of the solution
is described as follows: P: particles/precipitate; C: crystals.
2.5. Assays of Stability of Acyclovir and Ciprofloxaxin at Different pH Values
In order to study the behavior of single drug solutions, seven samples containing 1 mL of stock
solution of acyclovir at 2 mg/mL (see stock solutions preparation, Table 1S in supporting information)
were prepared by adjusting the pH with successive additions of 10 μL of hydrochloric acid or sodium
hydroxide solutions at different concentrations (100 μM, 1 mM, 10 mM, 100 mM, 1M, 6M). Tubes
were shaken manually. The same method and conditions were implemented to study the behavior
of ciprofloxacin. Two replicates for each drugs were realized. pH measurements were taken using a
pH-meter (FP20 Mettler Toledo). Once the pH was adjusted, samples were diluted 50 times with
mobile phase (methanol and distilled water, phosphate buffer, pH=3, 50/50, v/v) in Eppendorf tubes
in order to reach a drug concentration in linearity range. To avoid sampling of crystals or precipitates,
volume samplings with micropipettes were made delicately at the top of the Eppendorf tube. After
dilution and agitation of tubes, samples were transferred in vials and visually inspected to check the
absence or presence of precipitate and/or crystals. Then, RP-HPLC analysis was performed at 0, 2, 4
and 24h.
2.6. Compatibility Studies
2.6.1. Drug Mixtures Preparation
From acyclovir and ciprofloxacin stock solutions at 2 mg/mL, drug mixtures were prepared at
different volume ratios (1:1, 2:1, 1:2, 9:1, 1:9) (for details, See Table 1S in supporting information).
Tubes were shaken manually. The ratio 1:2 were prepared in ten replicates, the ratios 1:1 and 2:1 in
five replicates and the ratios 9:1 and 1:9 in triplicate. Before analyses, ratios 1:1, 2:1 and 1:2 were
diluted 50 times and ratios 9:1 and 1:9, 20 times, with mobile phase (methanol and distilled water,
phosphate buffer, pH = 3, 50/50, v/v) in order to obtain drug concentrations in the linearity ranges.
To avoid sampling of crystals, volume sampling were made delicately at the top of the Eppendorf
tube. After dilution and agitation of tubes, samples were transferred in vials and visually inspected
to observe the presence/absence of impurities or crystals.
2.6.2. Preparation of Controls for the Two Drugs
From acyclovir stock solutions, controls were prepared in four replicates for ratios 1:1 and 2:1,
in five replicates for ratio 1:2 and in triplicate for ratios 9:1 and 1:9. From ciprofloxacin stock solution,
controls were prepared in four replicates for ratios 1:1, 2:1 and 1:2 and in triplicate for ratios 9:1 and
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 27 September 2023 doi:10.20944/preprints202309.1844.v1
4
1:9. Mimicking theoretical concentrations, controls were prepared by adding corresponding volume
of mobile phase (methanol and distilled water, phosphate buffer, pH = 3, 50/50, v/v). Then, each
control was diluted 50 times for ratios 1:1, 2:1 and 1:2 and 20 times for ratios 9:1 and 1:9 with the same
scheme as for drug mixtures.
2.6.3. Physical Compatibility Studies
Measurement of pH with indicating pH paper and visual inspection with unaided eye, facing
daylight, as compared control solutions, immediately after mixing and after 2, 4 and 24h of contact,
in order to observe physical changes of solutions (precipitation, color change…) were performed on
each volume ratios.
2.6.4. Chemical Compatibility Studies
RP-HPLC analyses were performed on diluting samples immediately after preparation and
after 2, 4 and 24h of contact. For controls, RP-HPLC analyses were realized only after preparation.
The obtained data concerned peak area and permitted to calculate the mass of each drug in mixtures.
A recovery percentage was defined as the ratio between the measured mass and theoretical mass of
the drug in mixture. Therefore, a chemical incompatibility was characterized by a recovery
percentage less than 90%, i.e. a decrease of 10% (5% in the case of drugs with a narrow therapeutic
margin) of measured concentration compared with the theoretical concentration. The data were
processed using Excel software.
2.7. HPLC Method Validation
Validation of parameters of the HPLC method was assessed in accordance with International
Conference on Harmonization (ICH) guidelines concerning linearity as well as the limits of detection
(LOD) and quantification (LOQ) [17,18].
2.7.1. Standard Solutions Preparation
An external calibration method, useful to quantify the amount of drug remaining in test samples.
For Acyclovir, seven samples were prepared from stock solution (2 mg/mL) in duplicate via
successive dilution (0.2; 0.15; 0.1; 0.05; 0.025; 0.01 and 0.005 mg/mL) with methanol and distilled
water, phosphate buffer, pH=3, 50/50. For ciprofloxacin, five samples were prepared from stock
solution (2 mg/mL) in triplicate via successive dilution (0.2; 0.1; 0.05; 0.005 ad 0.0025 mg/mL) with
methanol and distilled water, phosphate buffer, pH=3, 50/50. After dilution, manual agitation,
transfer in a vial and visual inspection in order to verify the absence of impurities or precipitates were
performed. Then, samples were immediately analyzed by RP-HPLC (isocratic method, 40% methanol
over 10 min).
2.7.2. System suitability
A system suitability testing was carried out by determining the peak retention time and the area,
and by calculating the resolution, the selectivity factor, the number of theoretical plates and the
symmetry factor [17]. This test was performed on five replicates of the ratio 1:1 (v:v), analyzed
immediately after mixing (for more details, see Table 2S in supporting information).
2.7.3. Specificity, Linearity, Range/Limit of Detection and Quantification
Specificity of the method was considered as validated if no peaks other than acyclovir and
ciprofloxacin appeared on the chromatograms. Linearity was established through the construction of
calibration curves using two standard ranges containing seven standard solutions for acyclovir and
three standard ranges containing five standard solutions for ciprofloxacin (See Standard solutions
preparation) [17]. To assert linearity, the coefficient of determination (R2) had to be higher than 0.999
[19]. The detection limit and the quantification limit were determined using the method based on the
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 27 September 2023 doi:10.20944/preprints202309.1844.v1
5
signal-to-noise ratio: LOD = (3*h*m)/(2*H) and LOQ = (10*h*m)/(2*H) (with h = higher fluctuation of
the background noise in the blank, determined over a distance equal to 5 times the width at mid-
height of the peak corresponding to the product concerned and located on either side of the place
where the peak would be observed ; H = height of the peak concerned; m = theoretical drug mass).
3. Results and Discussion
3.1. Screening of Drug Mixtures at Different Ratios
Acyclovir and ciprofloxacin were mixed at five different ratios (volume/volume). The quantity
of each drug is the same in each volume. Visual observation were made at three different time
intervals. A shown in Table 1, as expected at time zero, the solution was limpid and clear indicating
the drugs are more likely to be intact and they are in their expected forms. After two hours, small
amounts of crystals were observed except when the amount of acyclovir is in large excess (ratio 9/1).
Important amount of crystals were observed after 24 hours for ratios 1/1, 1/2 and 1/9. However, no
crystals were observed when acyclovir is prominent (ratios 2/1 and 9/1). These observations were
confirmed by recovery studies using HPLC analyses (see section 4.3).
Table 1. Visual observation of acyclovir/ciprofloxacin combinations.
Ratio 1/1 1/2 2/1 1/9 9/1
Time (h) 0 2 24 0 2 24 0 2 24 0 2 24 0 2 24
Observation 0 1 2 0 1 2 0 1 0 0 1 2 0 0 0
0: clear solution; 1: small amount of crystals; 2: important amount of crystals.
3.2. Influence of pH on Recovery of Acyclovir and Ciprofloxacin
The influence of pH on the recovery of both drugs was studied at eight different pH ranging
from 3 to 11 (Figure 2). For acyclovir, the influence of pH was insignificant as the recovery was
quantitative at different time intervals (Figure 2A). However, the pH and time effects on ciprofloxacin
recovery are more marked compared to acyclovir (Figure 2B).
0
20
40
60
80
100
120
02424
Recovery percentage (%)
Time (h)
2A: Recovery percentage of acyclovir
pH=3 pH=5 pH=6 pH=7 pH=8 pH=9 pH=11
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 27 September 2023 doi:10.20944/preprints202309.1844.v1
6
Figure 2. Recovery percentage of acyclovir at different pH and time.
At near neutral pH values (7.22 and 7.97), the recovery of ciprofloxacin drops strongly even at
time zero. The recovery was dropped below 10% after 24 hours. From the pKa values of ciprofloxacin
(Figure 3) [20,21], at neutral pH and near isoelectric point the carboxyl and the secondary amino
groups are mainly charged but the sum of the charges is close to zero and the molecules as a whole
is neutral resulting in the solubility dropping (Figure 3). At slightly acidic conditions (pH = 5), around
75% of the drug was recovered after 2, 4 and 24 h. The same behavior is observed at slightly basic
conditions (pH = 8.72 and 9.24). At strong acidic or basic conditions, the recovery is almost total. So
as can be expected, ciprofloxacin is an amphoteric drug allowing that at acidic and basic conditions,
the drug is in its ionized form which is compatible with higher solubility.
HN
NN
N
H2N
O
O
OH
Acyclovir
NN
N
FCO2H
O
H
Ciprofloxacin
pKa = 2.27
pKa = 9.25
pKa = 6.09
pKa = 8.74
Figure 3. Acid-base characters of acyclovir and ciprofloxacin.
3.3. Compatibility/Incompatibility Studies by HPLC
3.3.1. Validation of the RP-HPLC Method
In order to asses that the system is working perfectly, we conducted the system suitability testing
regarding the retention time, the resolution and selectivity factor [17] (For more details, see Table 2S
in the supporting information section).
The calibration curves of acyclovir and ciprofloxacin were realized by reverse phase high
performance liquid chromatography and are shown in Figure 3. The calibration curve of acyclovir
indicate a linearity of the peak area from 0.05 to 2 μg (mass concentration of 0.005 to 0.2 mg/mL),
whereas for ciprofloxacin it indicate a linearity of the peak area from 0.025 to 2 μg of ciprofloxacin
(mass concentration of 0.0025 to 0.2 mg/mL). (for more details, see Table 3S in the see supporting
information section). These curves were used to monitor the percentage of acyclovir and
ciprofloxacin in mixtures at different ratios and different times intervals.
0
20
40
60
80
100
120
02424
Recovery percentage (%)
Time (h)
2B: Recovery percentage of ciprofloxacin
pH=3 pH=5 pH=6 pH=7 pH=8 pH=9 pH=11
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 27 September 2023 doi:10.20944/preprints202309.1844.v1
7
Figure 3. Calibration curve of acyclovir and ciprofloxacin. Calibration were realized at 260 nm on two
standard ranges (n=2) for acyclovir and n=3 for ciprofloxacin.
3.3.2. Compatibility/Incompatibility of Acyclovir and Ciprofloxacin Mixture
The recovery of acyclovir and ciprofloxacin was measured by RP-HPLC at five different ratios
(1/1; 2/1; 1/2; 9/1 and 1/9) and time intervals (from 0 to 24 h) (Figure 4). At ratio 1/1, the recovery of
ciprofloxacin is severely dropped after 2 hours of contact. After 24 h, less than 20% of ciprofloxacin
was recovered. At 2/1 ratio, a total recovery of both drugs is measured. When the latter ratio was
inversed (from 2/1 to 1/2), the recovery of acyclovir was total whereas the recovery percentage of
ciprofloxacin was around 35, 30 and 18% after 2, 4 and 24 intervals, respectively. When the acyclovir
is present in large excess (ratio 9/1), the recovery of both drugs is almost quantitative which is in
agreement with what observed with ratio 2/1. The ratio 1/9 gave the same results as ratio 9/1 with
both compounds recovered almost quantitatively.
y = 5,734.15512x
R² = 0.99999
-2000
0
2000
4000
6000
8000
10000
12000
14000
-0.500.511.522.5
Peak area at 260 nm
Amount of acyclovir (µg)
Calibration curve of acyclovir
y = 5,380.6263x
R² = 0.9997
-5000
0
5000
10000
15000
20000
-0.500.511.522.533.54
Peak area mean at 260 nm
Mass of ciprofloxacin (µg)
Calibration curve of ciprofloxacin
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 27 September 2023 doi:10.20944/preprints202309.1844.v1
8
n=4 n=5 n=3 n=5 n=5
n=4 n=5
n=3 n=5
n=5
0
20
40
60
80
100
120
Control 0 2 4 24
Recovery percentage (%)
Time (h)
Recovery percentage of acyclovir and ciprofloxacin at volume
ratio 1:1 as a function of time
Acyclovir Ciprofloxacin
n=4 n=5 n=3 n=5 n=5
n=4 n=5 n=3 n=5 n=5
0
20
40
60
80
100
120
Control 0 2 4 24
Recovery percentage (%)
Time (h)
Recovery percentage of acyclovir and ciprofloxacin at volume
ratio 2:1 as a function of time
Acyclovir Ciprofloxacin
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 27 September 2023 doi:10.20944/preprints202309.1844.v1
9
n=5 n=10 n=8 n=10 n=10
n=4 n=10
n=8
n=10 n=10
0
20
40
60
80
100
120
Control 0 2 4 24
Recovery percentage (%)
Time (h)
Recovery percentage of acyclovir and ciprofloxacin at volume
ratio 1:2 as a function of time
Acyclovir Ciprofloxacin
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 27 September 2023 doi:10.20944/preprints202309.1844.v1
10
Figure 4. Recovery of acyclovir and ciprofloxacin at different ratios and time intervals.
The consequences of IPCs can be multiple. First of all, an IPC can result in a loss of
active ingredient (following precipitation or degradation) and therefore an incorrect dose
delivered to the patient. Catheters could become clogged due to the formation of a precipitate
in them, preventing the medication from being administered to the patient. In addition, the
precipitates can cause embolism if they reach the general circulation, crystals could be
deposited in the organs and cause inflammation. Following gas release, gas bubbles could
reach the patient's systemic circulation, thereby creating a risk of gas embolism. Finally, the
secondary derivatives that can be produced can turn out to be toxic. All of these problems are
likely to lead to a reduction in the effectiveness of medications, therapeutic failure or even
jeopardize the patient's vital prognosis.
Interactions between acyclovir and ciprofloxacin is not documented. However, this does not
necessarily mean that no interactions exists. Our study highlight clearly that caution should be taken
when these drugs are concomitantly taken, via Y-site administration. Particularly, two parameters
n=3 n=3 n=3 n=3 n=3
n=3 n=3 n=3 n=3 n=3
0
20
40
60
80
100
120
Control02424
Recovery percentage (%)
Time (h)
Recovery percentage of acyclovir and ciprofloxacin at volume
ratio 9:1 as a function of time
Acyclovir Ciprofloxacin
n=3 n=3 n=3 n=3 n=3
n=3 n=3 n=3 n=3 n=3
0
20
40
60
80
100
120
Control 0 2 4 24
Recovery percentage (%)
Time (h)
Recovery percentage of acyclovir and ciprofloxacin at volume
ratio 1:9 as a function of time
Acyclovir Ciprofloxacin
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 27 September 2023 doi:10.20944/preprints202309.1844.v1
11
must be monitored, the pH and the ratio of the two drugs. These tow parameters are tightly linked
to the amphoteric characters of drugs.
4. Conclusions
This study intends to fill the existing knowledge gap and contribute to the optimization of IV
drug therapy, enhancing patient care and promoting rational prescribing practices. By systematically
evaluating the compatibility of these commonly used medications, we can ensure safer and more
effective treatment options, thereby improving patient outcomes and advancing the field of
pharmacotherapy. The most striking information deals with the ratio acyclovir/ciprofloxacin used for
Y-site IV administration. An equal ratio leads to bad recovery of ciprofloxacin. Excess of acyclovir
versus ciprofloxacin (ratio 2/1 and higher) leads to almost full recovery of both drugs. When one of
the drugs is present in large excess (ratios 1/9 and 9/1), a full recovery of both drugs was observed.
The results obtained from this investigation provide valuable insights for healthcare
professionals, empowering them to make informed decisions about the co-administration of
acyclovir and ciprofloxacin via IV infusion.
Supplementary Materials. The following supporting information can be downloaded at the website of this
paper posted on Preprints.org, Volumes of stock solutions used to prepare the mixtures; System suitability
testing for RP-HPLC method; Regression analysis; Compatibility data for acyclovir and ciprofloxacin
Author Contributions: D.L. performed the experiments. T.B. performed a part of the experiments, supervised
the HPLC studies, participated in the project conceptualization and participated in the manuscript writing. L.F.
Participated in the project conceptualization. A.B. Supervised the study and wrote the original draft of the
manuscript.
Funding: This study was equally funded by University Grenoble Alpes and DrugOptimal to whom authors are
thankful.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: All the data generated within this study were provided in Supplementary
Materials
Acknowledgments: Authors are thankful to Dr. Edwige NICOLLE (Faculty of Pharmacy of Grenoble) for the
instructive discussion.
Conflicts of Interest: The authors declare no conflict of interest.
References
1. Castells, L.G.; Rodríguez, R.M.; Roura, T.J.; Prat, D.M.; Soy, M.D. López, C.C. Compatibility of drugs
administered as Y-site infusion in intensive care units: A systematic review. Med. Intensiva (Engl Ed). 2020,
44, 80-87. doi: 10.1016/j.medin.2018.08.004.
2. Oduyale, M.S.; Patel, N.; Borthwick, M.; Claus, S. Co-administration of multiple intravenous medicines:
Intensive care nurses' views and perspectives. Nurs. Crit. Care 2020, 25, 156-164. doi: 10.1111/nicc.12497.
3. Allwood, M.C.; Kearney, M.C. Compatibility and stability of additives in parenteral nutrition admixtures.
Nutrition 1998, 14, 697-706. doi: 10.1016/s0899-9007(98)00063-x
4. Trissel, L.A. Handbook on injectable drugs. 20th ed. 2018, Bethesda, MD: American Society of Health-
System Pharmacists.
5. Begum, S.G.; Reddy, Y.D.; Divya, B.S.; Kiranmai, S.Y.; Sushmitha, P.K.K.; Ruksar, S. Pharmaceutical
incompatibilites: a review. Asian J. Pharm. Res. Devel (AJPRD). 2018, 6, 56-61.
6. Wagner, L.A.F.; Neininger, M.P.; Hensen, J.; Zube, O.; Bertsche, T. Avoiding incompatible drug pairs in
central-venous catheters of patients receiving critical care: an algorithm-based analysis and a staff survey.
Eur. J. Clin. Pharmacol. 2023, 79, 1081-1089. doi: 10.1007/s00228-023-03509-0.
7. Maiguy-Foinard, A.; Genay, S.; Lannoy, D.; Barthélémy, C.; Lebuffe, G.; Debaene, B.; Odou, P.; Décaudin,
B. Criteria for choosing an intravenous infusion line intended for multidrug infusion in anaesthesia and
intensive care units. Anaesth. Crit. Care Pain Med. 2017, 36, 53-63. doi: 10.1016/j.accpm.2016.02.007.
8. Manallack, D.T.; Prankerd, R.J.; Yuriev, E.; Oprea, T.I.; Chalmers, D.K. The Significance of acid/base
properties in drug discovery. Chem. Soc. Rev. 2013, 42, 485–496. doi:10.1039/c2cs35348b.
9. Elion, G.B.; Furman, P.A.; Fyfe, J.A.; De Miranda, P.; Beauchamp, L.; Schaeffer, H.J. Selectivity of action of
an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine. Proc. Natl. Acad. Sci. U.S.A. 1977, 74, 5716−5720.
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 27 September 2023 doi:10.20944/preprints202309.1844.v1
12
10. Kristl, A. Estimation of aqueous solubility for some guanine derivatives using partition coefficient and
melting temperature. J. Pharm. Sci. 1999, 88, 109−110. doi: 10.1021/js980180z
11. Bergström, C.A.S; Norinder, U.; Luthman, K.; Artursson, P. Experimental and computational screening
models for prediction of aqueous drug solubility. Pharm. Res. 2002, 19, 182−188. doi:
10.1023/a:1014224900524.
12. Khan, M.Y.; Gruninger, R.P.; Nelson, S.M.; Klicker, R.E. Comparative in vitro activity of norfloxacin (MK-
0366) and ten other oral antimicrobial agents against urinary bacterial isolate. Antimicrob. Agents Chemother.
1982, 21, 848–851. doi: 10.1128/aac.21.5.848.
13. Garcia, A.; Grundmann, O. The utilization and development of viral vectors in vaccines as a prophylactic
treatment against Ebola virus as an emerging and zoonotic infectious disease. Mini Rev. Med. Chem. 2023,
doi: 10.2174/1389557523666230725115324.
14. Wilder, A.J.; Foushee, J.A.; Fox, L.M.; Navalle, J.; Wright, A.M.; Greer, M.A. Physical compatibility of
medications used in critically Ill patients with balanced fluid solutions. Int. J. Pharm. Compd. 2020, 24, 238-
241.
15. Kim, L.K.; Compatibility of ciprofloxacin lactate with other drugs. during simulated Y-site administration.
Am. J. Health-Syst. Pharm. 1999, 56, 1730-1733. doi: 10.1177/106002809302700604
16. Lefeuvre, S.; Bois-Maublanc, J.; Hocqueloux, L.; Bret, L.; Francia, T.; Eleout-Da Violante, C.; Billaud, E.M.;
Barbier, F.; Got, L. A simple ultra-high-performance liquid chromatography-high resolution mass
spectrometry assay for the simultaneous quantification of 15 antibiotics in plasma. J. Chromatogr. B Analyt.
Technol. Biomed. Life Sci. 2017, 1065-1066, 50-58. doi: 10.1016/j.jchromb.2017.09.014.
17. Sanogo, S., Silimbani, P.; Gaggeri R.; Rossi, R.; Elviri, L.; Maltoni, M.; Masini, C. Validation of RP-HPLC
method to assess the compatibility of metoclopramide and midazolam intravenous mixture used in
patients with cancer. Eur. J. Hosp. Pharm. 2019, 26, 323-328. doi: 10.1136/ejhpharm-2018-001544.
18. Tietje, C.; Brouder, A. « International conference on harmonisation of technical requirements for
registration of pharmaceuticals for human use », in Handbook of Transnational Economic Governance Regimes,
Brill | Nijhoff, 2010, 1041-1053. doi: 10.1163/ej.9789004163300.i-1081.897.
19. Yuwono, M.; Indrayanto, G. « Validation of chromatographic methods of analysis », in Profiles of Drug
Substances, Excipients and Related Methodology, Elsevier, 2005, 243-259. doi: 10.1016/S0099-5428(05)32009-0.
20. Shamshina, J.L.; Cojocaru, O.A.; Kelley, S.P.; Bica, K.; Wallace, S.P.; Gurau, G.; Rogers, R.D. Acyclovir as an
ionic liquid cation or anion can improve aqueous solubility. ACS Omega 2017, 2, 3483-3493. doi:
10.1021/acsomega
21. Babic, S.; Horavt, A.J.M.; Pavolvic, D.M.; Kastelan-Macan, M. Determination of pKa values of active
pharmaceutical ingredients. Trends Anal. Chem. 2007, 26, 1043-1061.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those
of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s)
disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or
products referred to in the content.
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 27 September 2023 doi:10.20944/preprints202309.1844.v1
