The oral route of administration is the most popular
due to the advantages afforded to patients for self-administration. However, aqueous
solubility of a drug can be a critical limitation to its oral absorption.
Lipophilic drugs show poor or fluctuated aqueous solubility and hence cause
serious delivery problems due to erratic drug absorption. Many techniques have
been used to improve the drug aqueous solubility. Among these techniques: conversion
of poorly water-soluble drugs into amorphous state in order to improve the
biopharmaceutical properties of solid dosage forms , application of
liquisolid technique , using solid dispersion preparations ;  or
formulation of nanoparticles ; microcrystals  and spray dried particles . In this study, naproxen (Nap) was selected as a
model poorly water soluble drug. Nap is a non-steroidal anti-inflammatory drug
with analgesic and antipyretic properties whose efficiency is offset by its low
solubility and slow dissolution while orally administered.
Cyclodextrins (CDs) are cyclic oligosaccharides that
widely used in the pharmaceutical industry for their capabilities to modify
physical, chemical and biological properties of a number of hydrophobic drug
molecules through the formation of inclusion complexes ; . These
inclusion complexes in addition to improving the drug solubility, they can
enhance drug stability; prevent drug/excipient interactions or mask the drug
unpleasant taste. Literatures describing the complexation of NAP with cyclodextrins
and enhancing its dissolution properties are available (See for example: .
However, using combinations of cyclodextrins and poloxamers and/or sorbitol
have not been studied before. Accordingly, the aim of the present study was to
investigate and compare the effect of using ß-CD with and without
adjuvant additives (Pluronic F-127 and sorbitol) on dissolution of NAP in
physically mixed and freeze dried forms. Pluronics are polyethylene oxide
(PEO)-polypropylene oxide (PPO)- polyethylene oxide (PEO) copolymers, also
known as Poloxamers. Poloxamer consists of a hydrophilic corona (ethylene
oxide, EO) and hydrophobic core (polypropylene oxide, PO) blocks arranged in a
triblock structure resulting in an amphiphilic structure. They are non-ionic
surfactants that have been extensively used as wetting and solubilizing agents.
Poloxamers were first introduced by late 50th and since then they
have been proposed to diverse pharmaceutical applications such as emulsifiers,
solubilizing agents, suspension stabilizers and wetting agents . Their
ability to self-aggregate, thereby forming micelles and liquid crystalline
phases, and greater hydrophilicity is another advantage for the solubilization
of poorly water-soluble drugs ; ; ; . These amphiphilic
co-polymers are available in different grades as poloxamer 188 and poloxamer
407. Sorbitol is a type of sugar which has been reported to improve the
solubility of some poorly water-soluble drugs ; . The influences of
different drug to carrier ratio and the adopted technique on the physicochemical
characterization of NAP formulations were performed.
MATERIALS AND METHODS
Naproxin (Nap) was
obtained from F. Hoffman-La Roche Ltd. (Mexico), ß-cyclodextrin (ß-CD),
sorbitol (Sorb), and Poloxamer 407 (PluronicTM F-127; PLX) were
purchased from Sigma-Aldrich (USA). Other reagents were of analytical grade and
used as received.
1. Preparation of drug-carrier Physical mixture
Nap/carrier systems were prepared from the
previously sieved (38-63µm) individual components. Binary physical mixtures (PM)
at 1:1and 1:4 (w/w) drug-to-carrier (PLX, ß-CD or Sorb)
ratios were prepared. A ternary system Nap/ß–CD /PLX and Nap/ß–CD /Sorb were
prepared at 1:2:2 (w/w ratio). Drug and carrier(s) PMs were prepared by simple
blending of the powders by turbula mixer (Type T2C, Glen Creston Ltd, UK) for
10 min at 31 rpm.
2. Preparation of drug-carrier freeze-dried (FD) systems:
The calculated amounts of
drug and carrier were dissolved in ethanol/water (40%v/v) mixture, aided by sonication for
15 minutes. For CD formulations, heating up to 70°C was necessary to aid the
solubility and the formation of drug-CD inclusion complexes, then the solutions
were frozen at -85°C for 5 hours before the freeze drying process using the VirTis
freeze dryer (Biopharma, USA).
3. Drug content uniformity:
Drug content for the
prepared PM and FD formulations were
determined by dissolving an exact amount of the prepared powders in 20 ml of ethanol and analyzing the samples,
after suitable dilution, spectrophotometrically at 271nm
using UV/VIS spectrophotometer (Model M501, Camspec Ltd., Cambridge, UK).
The dissolution studies
of Nap and its formulations (PM and FD) were performed under sink conditions
using United State Pharmacopoeia type II dissolution test apparatus (Erweka DT
6, Heusenstamm, Germany). Test samples
of each formulation containing drug equivalent to 12 mg were placed in
900 ml of distilled water at 37 °C
(paddle method at 100 rpm). At appropriate time interval, aliquots of 10
ml were withdrawn with a filter-syringe and drug content was assayed spectrophotometrically.
The withdrawn aliquots were replaced by a fresh dissolution medium to keep the
- Differential Scanning Calorimetry
The changes, if any, in the thermal characteristics of Nap, carriers and
Nap formulations were studied using DSC (DSC Q1000, TA instrument,
England). Samples equivalent to about 3-6 mg of the powder, in
hermetically sealed aluminium pans, were scanned from 20-300°C/min at 10°C/min.
The instrument was calibrated with sapphire and indium before running the
samples. The percentage crystallinity for the preparations was
calculated using the following equation :
crystallinity = (? HmTP / ? HmNap × W) × 100
? HmTP = the melting enthalpy of tested
? HmNap = the melting enthalpy
of naproxen (Jg-1)
W = the weight fraction of naproxen in the
6. Fourier-Transform Infrared (FT-IR) Spectroscopic Analysis
Infrared spectra for individual components as well as
different formulations were obtained using
Perkin-Elmer FT-IR system Spectrum BX (Beaconsfield, Buckinghamshire,
UK). The samples were scanned over the wave number
range from 4000 to 550 cm-1 at 4 cm-1. The technique used
very small amount of each sample which directly loaded into the system.
Spectrum BX series software version 2.19 was used to determine peak positions.
The student t-test was applied, results are quoted
as statistically significant when P < 0.05.
RESULTS AND DISCUSSION
1. Content uniformity:
Monitoring drug content
uniformity in the early stages of the formulation is an important issue in the
pharmaceutical field as it required for the control of drug quality and
sturdiness of the process. Also the
information obtained from drug content uniformity can be quite helpful in
relation to possible segregation as well as other process issues . All
of the Nap/PLX and Nap/ ß–CD binary systems (PM and FD) showed reasonable drug
content uniformity (97- 101%), indicating a homogeneous distribution of the
drug in the prepared formulations. On the other hand, formulations with Sorb showed
lower drug content uniformity ranging from 92 to 95%.
2. Dissolution study:
dissolutions of Nap from various binary and ternary physical mixtures as well
as freeze dried systems are presented as percentage of drug released versus
time curves (Figures 1 and 2). The time
necessary for dissolution of 50% of the drug (t50) was calculated
for each system and is presented in Table 1. To elucidate the effect of carrier
type and the method of preparation on drug dissolution, the relative
dissolution efficiencies (RDE) after 5 min were calculated as the ratio of drug
released from each formulation to that of the pure drug at that time (Table 1).
Table (1): Time required for dissolution of 50% of drug (t50)
and relative dissolution efficiency (RDE) from Nap/carrier physical mixture
(PM) and freeze dried (FD) systems.
Drug/carrier ratio (w/w)
Nap/ CD /PLX PM
Nap/ CD /Sorb PM
Nap/ CD FD
5.0 (±0.6, 3)
5.0 (±0.5, 3)
30.0 (±2.1, 3)
2.7 (±0.3, 3)
5.0 (±0.8, 3)
3.0 (±0.6, 3)
2.0 (±0.3, 3)
3.5 (±0.4, 3)
3.5 (±0.5, 3)
- a Ratio between the percentage
drug released from Nap/carrier system and that of drug alone at 5 min.
Numbers between brackets are standard deviation and number of
2.1. Dissolution of Nap from binary and ternary physical mixture (PM):
For binary Nap/PLX PMs,
the percentage drug released was significantly (P<0.05) higher than
that of the pure drug at the two drug/carrier ratios (Figure 1A). This could be
due to the solubilizing effect of the carrier as a result of improving in the
wetting of the hydrophobic Nap. At low concentration,
PLXs like other surfactants form monomolecular micelles by change in
configuration in solution. PLX at the lower concentration of 1:1 drug:carrier
ratio showed a better (P<0.05) dissolution data regarding t50 and
RDE, compared to that with higher carrier concentration (Table 1). However, after
about 40 min both formulations showed a similar dissolution pattern.
In a trial to explain such results, the thermoreversible
gelation behavior of the copolymer could be considered, which is well known
properties of PLX. The gel formation capability of the copolymer based on both
critical micelle temperature (CMT) and micellar packing. CMT is the temperature
where micelles are formed, and is reported to be about 24°C (Lin and Alexandridis, 2002). Above the critical micelle
concentration, self assembled micellar structure is obtained. The liquid-phase
micelles formed by PLXs undergo transition into liquid crystal gel phases in
response to increased temperature (Wanka,
1994). It was reported that PLX 407 forms gel
above a certain concentration of about 15% w/v ; .
In this study, though the temperature of the dissolution medium was above CMT,
but the concentration of the copolymer was too small to form the gel structure.
But deep at the microenvironment level around the copolymer specifically in the
diffusion layer, the concentration may be at the saturation level. This may resulted
in the formation of a gel microenvironment that would slow down drug movement
through it, and consequently drug dissolution. This may explain why higher PLX
concentration showed less drug release compared to the lower concentration. This
would signify the use of a small amount of PLX during the preparation of PM of
the drug instead of the larger amount of 1:4 ratio to obtain a reasonable
weight of the drug dose that is easily administered.
For binary Nap/ß-CD PMs,
there was a significant difference (P<0.05) in terms of percentage of
Nap released compared to the drug alone (Figure 1B). This indicates that ß-CD
was effective in enhancing Nap dissolution by simple mixing. Drug release was
better than that obtained using PLX as carrier. The improvement of the initial
dissolution rate obtained with PMs can be attributed to both improved drug
particle wettability, due to the surfactant-like properties of the carrier, and
“in situ” formation of readily soluble complexes in the dissolution medium ;
. There was no significant difference
(P>0.05) in terms of t50 and
RDE in the two drug:carrier ratios; 1:1,and 1:4 (Table 1). This would indicate that the
concentration of ß-CD in 1:1 (w/w) system was enough to entrap and accommodate
Nap molecules in the same efficiency as the higher carrier concentration (1:4
w/w ratio). This result is useful as it eliminates the use of large amount of
ß-CD, as it can cause toxicity at such high concentrations . For Sorb combinations, Nap/Sorb 1:1 PM
did not significantly (P>0.05) improved drug dissolution compared to
control (Figure 1C). Moreover, t50 was not reached till the end of
the experiment time (Table 1). Increasing Sorb concentration in the PM to 1:4
Nap/Sorb resulted in slight improvement in drug dissolution with a t50
of 30 minutes. Using Sorb, with the known dose of Nap of about 250 mg at low
doses, such high ratio will increase the bulkiness of the dose that would be
non-convenient for patients. Accordingly, sorbitol is not a good choice of
carriers to enhance naproxen dissolution. On the other hand, PLX and ß-CD gave
about 7- and 8-fold, respectively, enhancement in RDE with the lower ratio of
1:1 Nap/carrier that would reduce their workable
amount in pharmaceutical formulations, that would be more suitable from
the economic and administration point of view.
Figure 1: Percentage
drug released from pure drug and its binary physical mixture with poloxamer 407
(A), ß-cyclodextrin (B), sorbitol (C) and ternary drug/ ß- cyclodextrin/poloxamer
and drug/ ß-cyclodextrin sorbitol mixture (D).
The overall results for
the binary drug/carrier PMs indicated the superiority of ß-CD in improving Nap
dissolution over the other two carriers. However,
the use of CDs in the pharmaceutical area is hindered by problems such as high
cost, relatively low water solubility, and potential toxicity . Increasing
the complexation and solubilization efficacy of CDs is a possible means to
reduce their workable amount. Among the strategies suggested towards this aim is
the addition of a suitable auxiliary substance so as to increase and strengthen
the CD solubilizing capacity , . It
was reported that the addition of an auxiliary substance can significantly
increase CD solubilizing and complexing effect by synergistic multi-component
complex formulation. The addition of a suitable water-soluble polymer to drug/ß-CD
system has been proven to enhance solubilizing efficiencies of ß-CD , . Therefore, in this study PLX and Sorb were added separately
to Nap/ß–CD PM at the ratio of 1:2:2 w/w Nap:ß–CD:((PLX or Sorb). The
percentage drug released versus time plots are illustrated in Figure 1D. For
Nap/ß-CD/Sorb PM, the data revealed that addition of Sorb did not significantly
(P>0.05) improve drug dissolution compared to that for Nap/ß-CD PM
regarding dissolution parameters (Table 1). It could be assumed that Sorb in this
amount was not enough to elucidate a noticeable enhancing power. On the other hand, ternary Nap/ß-CD/PLX mixture
showed a marked improvement in drug dissolution with a burst drug release showing
a t50 of about 2.5 ±0.3 min compared to about 5.0 min for
Nap/ß–CD system. Regarding the
dissolution efficiency, ternary PLX mixture showed 14- and 2-fold enhancement
in dissolution compared to pure drug and binary Nap/ß-CD, respectively,
indicating the augmenting effect of PLX to CD in enhancing the drug
dissolution. Consequently, it is possible to suggest that this behavior may be
due to having Nap/ß-CD complex in a more close dispersed state within the triblock
polymer (PLX) matrix via interactions between the exterior of the complex and PLX,
this suggestion is supported by Moore et al . In addition, being
amphiphilic, PLX would increase the solubility of the free, un-complexed drug. The
better performance of this ternary complex will allow further reduction in the
amount of ß-CD needed to solubilize a given amount of drug. Besides, it could
be suitably utilized to formulate a fast-dissolving Nap solid dosage form as
evidenced from the dissolution profile.
2.2 Dissolution of Nap from freeze
dried (FD) formulations:
For the FD formulations, Figure
(2) shows the dissolution profiles of FD formulations. Freeze
dried (FD) preparations are shown in Figure 2A. FD drug showed a significant
(P< 0.05) increase in drug dissolution compared to control untreated drug. After 5 min the amount of drug dissolved was around 11%
for freeze-dried naproxen compared to only 6% for the control untreated drug,
in a good agreement with previous findings . The FD Nap:PLX binary systems markedly
improved drug dissolution with a burst drug release of about 75 and 83% after 5
min with RDE of 11 and 12 for 1:1 and 1:4 Nap/PLX, respectively. A complete
drug dissolution was obtained in about 15 min from 1:4 Nap:PLX formulation.
Comparing those results with drug dissolution from Nap/ß-CD FD formulations;
there was a marked increase in the drug dissolution. Figure (2B) shows that,
similar to some extent to PLX combinations, there is a burst release of Nap
with a percentage drug release after 5 minutes of about 58 ±1.7 and 76± 0.9% for 1:1and 1:4 ratios,
respectively, compared to only 7.0 ±1.1% of the pure drug. The lower Nap/ß-CD
ratio showed less enhancement compared to the CD higher concentration (see
Table 1). The better performance of FD
formulations in the early time of dissolution process compared to PM (P
< 0.05) can be attributed to: (i) the effect of processing, freeze drying, and
(ii) a higher solubility of Nap as a consequence of its in-depth interaction
and more effective complexation with ß–CD, as well as to the high energetic
amorphous state reduction of drug crystallinity following complexation as will be explained by the DSC data. The results are in
agreement with a study by Lin and Kao .
Figure 2: Percentage drug
released from pure untreated drug (Nap) and freeze dried drug (FD Nap) and
binary formulations with poloxamer 407 (A) and ß-cyclodextrin (B).
To compare between all Nap
formulations prepared by PM to that by FD, ternary Nap/ß–CD/PLX PM showed the highest
dissolution parameters of all tested formulations. This would indicate that
simple blending of the drug with the two carriers is enough to give dissolution
performance that is better than freeze drying technology of the binary Nap/ß–CD.
This is more economically favored and easier for possible scale-up and
industrial applications compared to FD technique.
From this study, the overall results would
strongly recommend the use of PLX as in combination with ß–CD. This would boost
the safety issues of the administered formulation as we can reduce CD amount,
as in the ternary PM. Furthermore, it has been reported that PLX 407 is the least toxic of commercially
available copolymers (32).
3. Solid state characterization of the binary
and ternary Nap systems
To understand the possible mechanism of improved
dissolution, differential scanning calorimetry (DSC) and Fourier transform infrared
(FTIR) were used for solid state
characterization of binary (PM and FD) and ternary systems. The DSC
thermograms for Nap, PLX, ß–CD alone or in combinations are presented in Figure
(3). The calculated parameters for the melting transitions (Tpeak and
% crystallinity) were determined and are presented in Table 2. The sharper the
peak obtained in the DSC thermogram, the higher the melting point, and the
higher the degree of crystallinity of the structure .
For pure Nap, the DSC
curve was typical of a crystalline anhydrous substance showed a sharp
endothermic peak at 158.9°C
and fusion enthalpy of 139 ±3.8 Jg-1, this is in agreement with previous
findings . For pure PLX, a single endothermic peak was obtained at about
55°C, with regard to the drug PM, thermograms indicated a marked change in the
drug endothermic behavior. For 1:1 ratio, there was a shift in Tpeak
to a lower value with reduction in peak sharpness, fusion enthalpy and percent
crystallinity (Table 2). For the higher carrier concentration, the drug
endothermic peak was completely eliminated, with only PLX peak shifted to a
lower temperature. Such results can be explained on the basis that if a polymer
having a low meting point compared to that of the drug and if the drug is
soluble in the molten polymer, then the drug and polymer might form eutectic
system ; ; ; as PLX has a low melting point than Nap, then during
the heating stage of the DSC measurement Nap may have dissolved in the melt and
formed the eutectic mixture.
Pure NAP Nap/CD Nap/CD Nap/CD/PLX Nap/PLX Nap/CD Nap/CD
1:4 PM 1:1 PM 1:2:2 FD 1:4 FD 1:4 FD 1:1
Figure 3: DSC thermograms of
Table 2: Effect of physical mixing (PM) and freeze drying (FD) of Nap/carrier
systems on the peak temperature (Tpeak) and percent crystallinity.
Drug/carrier ratio (w/w)
Tpeak (°C )
Nap/ ß–CD /PLX
119.4 (± 1.6)
After complete melting of
the eutectic, the remaining solid drug suspended in the liquid melt (which
might have exceeded the eutectic concentration) would have resulted in the
second endotherm at 123°C. In the case of 1:4 ratio, PLX constituted the major
phase with the possibility of complete dissolution of the drug in the copolymer
melt, this would explain the complete disappearance of the drug endotherm and
highly reduced percent crystallinity of 11% and 7% for 1:1 and 1:4 Nap/carrier
ratio, respectively. The presence of a small amount of the drug as impurities
might have resulted in the shortening of PLX peak to a lower melting point. The
same principle is applicable to the thermograms of freeze dried PLX formulations,
with the complete disappearance of the drug peak even at the low copolymer
concentration and a similar percent crystallinity to those of physically mixed
formulations (see Table 2).
The DSC curve of ß-CD
shows a broad endotherm in the range of 75°C to 85°C, which can be attributed
to desolvation. For Nap/ß-CD physical mixing preparations there was only a
trend of reduced Tpeak of the drug (P>0.05), however reduced
peak sharpness was observed probably due to greater disorder in the crystal
structure. However, when the percentage crystallinity was calculated, the
results showed 45% and 20% of crystallinity for 1:1 and 1:4 Nap/carrier ratio,
respectively, in comparison to the pure drug (100% crystallinity). This would explain
the improvement in dissolution properties of Nap, as the structure had become less
crystalline or the drug crystal lattice was disrupted compared to the pure
naproxen. Regarding freeze dried combinations (Figure 3), there was a trend (P>0.05)
of reduced Tpeak by about 2°C. However, there was a marked decrease
in peak sharpness with reduced enthalpy and consequently % crystallinity down
to 13% at 1:4 ratio (Table 2). This would indicate a more amorphous preparation
with better drug disolution.
For the ternary Nap/ ß-CD/PLX PM, only one
broad endotherm at 146°C (Figure 3), with the disappearance of the melting
endotherm of the two carriers. This suggests the theory of solid dispersion formation
due to dissolution of the drug in the molten PLX. The % crystallinity suggests
a reduced crystallinity (22% crystallinity) that would explain the obtained high
dissolution results (See Figure 1D).
Figure 4: FT-IR spectra of naproxen formulations
In FTIR analysis (Figure 4), Nap showed the characteristic quartet
of bands for carbonyl stretching at frequencies of 1724, 1678, 1629 and 1602 cm-1
. The spectra of binary and ternary physical mixture did not show a
significant difference from that of pure drug in the area of the main Nap
absorption bands. The IR spectrum of PLX is characterized by principal
absorption bands at 2891 cm–1 (C-H stretch aliphatic), 1343 cm–1
(in-plane O-H bend) and 1111 cm–1 (C-O strech).
In the case of FD
preparations, the band at frequency of 1678 cm-1, is broader (1:1
w/w Nap/ ß-CD) or almost disappeared (1:4 w/w Nap/ ß-CD), indicating a possible
interaction occurred between the drug and ß-CD due to the change taken place
around the bond. This can be explained by the dissociation of the
intermolecular hydrogen bonds of Nap through strong interaction between the
components through inclusion complex ; , e.g. formation of hydrogen
bonding between carboxylic group of the drug and hydroxyl group of ß-CD. These
data are in accordance with solubility and dissolution studies.
In the present investigation,
poloxamer 407 has improved significantly the dissolution of Nap either by
physical mixing or freeze drying techniques. ß-cyclodextrin was more effective than
polomaxer in the physically mixed formulation, but less in the freeze drying
ones. Among the ratios used both two carriers were effective in the lower
drug/carrier ratio of 1:1, alleviating the need for the use of higher excipient
concentration. This indicated that an increase in
the mass fraction of polymer could not offer any advantage for dissolution
enhancement. The incorporation of the two carriers together in a ternary
drug physical mixture augmented drug release that was even comparable to those
of the freeze dried formulations. Therefore, it could
be concluded that solid oral dosage forms of Nap with ß-cyclodextrin and
poloxamer 407 physically mixed together could be
formulated with a high dissolution, faster onset of action, expected to improve
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