Arch Pharm Res Vol 35, No 7, 1159-1168, 2012
DOI 10.1007/s12272-012-0706-6
The Synthesis and Characterization of Fatty Acid Salts of Chitosan as
Novel Matrices for Prolonged Intragastric Drug Delivery
Ahmad Bani-Jaber, Imad Hamdan, and Mahmoud Alkawareek
Faculty of Pharmacy, The University of Jordan, Amman, Jordan
(Received October 12, 2010/Revised March 13, 2011/Accepted April 6, 2011)
The aim of this study was to prepare fatty acid salts of chitosan (CS) and to evaluate the salts
as matrices for sustained drug release and prolonged gastric retention. CS-laurate and CSpalmitate were formed by mixing saturated CS solution and aqueous solutions of sodium laurate and sodium palmitate, respectively, and collected by centrifugation. They were characterized using Fourier-transform infrared spectroscopy and differential scanning calorimetry.
Different matrices as effervescent tablets were prepared using each of these CS-salts, CS and
the corresponding physical mixtures of CS and the fatty acids. Sodium bicarbonate as an effervescent agent and ranitidine HCl as a model drug were incorporated into these matrices. In
vitro buoyancy and drug dissolution were studied for the matrices in 0.1 M HCl. Tablets with
fatty acid salts of CS showed both rapid and prolonged buoyancy (> 8 h). Comparatively, CS
tablets exhibited a short floatation period (< 2 h) and tablets were completely disintegrated
within 1 h of soaking. In addition, slow and prolonged drug release was achieved from tablets
of fatty acid salts of CS with average drug release of 80.1 and 71.8% for CS-laurate and CSpalmitate, respectively. Rapid drug release (> 80% at 1 h) was exhibited by tablets with CS or
the physical mixtures.
Key words: Chitosan, Chitosan-laurate, Chitosan-palmitate, Floating tablet, Sustained release
INTRODUCTION
Retention of drug delivery systems in the stomach
prolongs overall gastrointestinal time and improves
the oral bioavailability of drugs that undergo sitespecific absorption from the stomach or upper part of
the small intestine. In addition, stomach retention
improves the local activity of the drug, such as improving the efficacy of amoxicillin against Helicobacter
pylori.
Several approaches are used to prolong gastric
retention time. These include polymeric bioadhesive
systems (Santus et al., 1997; Liu et al., 2011), swelling
and expanding systems (Deshpande et al., 1996, 1997;
Avachat et al., 2011), and floating drug delivery systems
(Menon et al., 1994; Whitehead et al., 1998; Tadros,
2010). Buoyant preparations offer a simple and practiCorrespondence to: Ahmad Bani-Jaber, Faculty of Pharmacy,
The University of Jordan, Amman, Jordan
Tel.: (962-6) 5355000 Ext.: 23329; Fax: (962-6) 5339649
E-mail: [email protected]
cal approach to achieve increased gastric residence
time for the dosage form and sustained drug release
(Gambhire et al., 2007). In addition, it offers greater
safety than some other approaches for clinical uses (Li
et al., 2001). To achieve an intragastric floating system,
low-density additives (e.g., fatty acids and fatty alcohols)
and gas-generating agents (effervescent type) are used
(Xu et al., 2001; Jain and Gupta, 2009). The effervescent
type consists of a polymeric matrix containing effervescent components such as sodium bicarbonate. The matrices are fabricated so that, upon arrival in the stomach,
carbon dioxide is liberated by the acidity of the gastric
contents and is entrapped in a gelling hydrocolloid.
This produces an upward motion of the dosage form
and maintains its buoyancy (Singh and Kim, 2000).
Chitosan (CS) is a natural derivative of chitin produced by partial N-deacetylation under alkaline conditions. It has interesting biological properties, including biocompatibility (Patashnik et al., 1974; Felt et al.
1999; Song et al. 2001), biodegradability (Lehr et al.,
1992), and mucoadhesivity (He et al., 1998). CS exhibits
pH-sensitive behavior as a weak polybase due to the
1159
1160
large quantities of amino groups on its chain. CS dissolves easily at low pH while it is insoluble at higher
pH ranges. The mechanism of pH-sensitive swelling
involves the protonation of amine groups of CS under
low pH conditions. This protonation leads to chain repulsion, diffusion of proton and counter ions together
with water inside the gel and dissociation of secondary interactions (Yao et al., 1994). This property has
helped it to be used in the delivery of chemical drugs
to the stomach and it has been widely investigated as
a delivery matrix. However, the high aqueous solubility of CS restricts polymer utility for gastric drug delivery due to its fast dissolution in the acidic environment
of the stomach (Portero et al., 2002; Phaechamud and
Ritthidej, 2007), and drug release from CS matrices is
greater in acidic solution than in basic solution, probably due to the swelling properties of the matrices at
acidic pH (Miyazaki et al., 1998; Gupta and Kumar,
2000). Covalent cross-linking with aldehydes has been
a common approach to overcome this problem. This
method has its own limitations, since the introduction
of aldehydes induces toxicity and depresses bioadhesion
and biodegradability (Genta et al. 1998). An alternative
strategy that is useful for reducing CS solubility and
improving the controlled drug release capacity is reacetylation with acetic anhydride (Portero et al., 2002).
CS is a polycation and is able to form salts with a wide
variety of acids. This property has been used extensively to prepare ionically cross-linked hydrogels
(Cerchiara et al. 2002; Orienti et al. 2002; Cerchiara
et al. 2003a, 2003b; Berger et al. 2004). Ionic crosslinking is a simple procedure that, in contrast to covalent cross-linking, does not require potentially toxic
molecules, such as catalyst. Moreover, the chemical
nature and length of the bridging units of the crosslinker influence the hydrogel properties, such as water
uptake and drug release (Bigucci et al., 2008). Aspartic,
glutamic, hydrochloric, lactic and citric acids (Orienti
et al., 2002), in addition to succinic, adipic and suberic
acids (Bigucci et al., 2008), are among the cross-linkers
or salt formers used.
Fatty acids or their salts have been used to enhance
drug absorption from various sites of the gastrointestinal tract (Ishizawa et al., 1987; Lindmark et al.,
1995; Higaki et al., 2001), to coat microbubbles as ultrasonic contrast agents (Soetanto and Chan, 2000), to
control drug release from pH-sensitive gels (Eeckman
et al., 2001), and to prepare fatty drug salt as an alternative to sustained-release polymeric formulations
(Aungst and Hussain, 1992).
In this paper, we propose to use fatty acids to prepare hydrophobic salts of CS and to use such salts as
matrices for prolonged intragastric drug delivery.
A. Bani-Jaber et al.
These salts may have lower solubility and undergo less
erosion in the gastric fluid than the parent polymer,
which will allow more controlled and prolonged drug
release from their tablets. The fatty acid salts were
synthesized, characterized and used to prepare effervescent tablets. Floating, swelling, and drug release
behavior were evaluated for the tablets, in comparison
to corresponding tablets with unmodified CS.
MATERIALS AND METHODS
Materials
High molecular weight CS (600,000) with more than
75% of deacetylation (Brookfield viscosity 800,000 cps
in 1% solution with 1% acetic acid), lauric acid (LA)
and palmitic acid (PA) were purchased from SigmaAldrich. Ranitidine HCl was a gift from the Jordanian
Pharmaceutical Company. For all experiments, distilled
water was used and all other chemicals were of pure
laboratory grade.
Methods
Optimization of CS/fatty-acid interaction
Excess solid CS was added to acetic acid (0.18% in
water) and mixed using a magnetic stirrer for 24 h.
Clear saturated CS solution (pH 5.91 ± 0.03) was
obtained by centrifugation, and the concentration of
the dissolved polymer was measured (9.8 mg/mL ±
0.30) by the drying method. Three unsaturated solutions of CS (7.4, 4.9, and 2.5 mg/mL) were also prepared by proper dilution of the saturated solution with
0.1 M HCl. The pH values of the diluted CS solutions
were 3.65 ± 0.15, 1.50 ± 0.02, and 1.19 ± 0.02, respectively. Sodium laurate and sodium palmitate solutions
were prepared by equimolar reactions of LA and PA
with NaOH in water at 1.5% fatty acid and NaOH
concentrations of 0.2996 and 0.2340%, respectively. To
20 mL of each CS solution, sodium laurate solution (10
mL) was added and a precipitate formed immediately
after each addition. The precipitates were isolated by
centrifugation, washed twice using distilled water,
allowed to dry in glass petri-dishes at room temperature,
and ground into powders using a mortar and pestle.
The dried powders were analyzed by Fourier transforminfrared (FT-IR) spectroscopy using Shimadzu FT-IR
spectrometer as described later for the characterization of CS/fatty acid salts. For comparative purposes,
FT-IR analysis was also performed for pure LA, pure
CS and physical mixtures of the pure substances.
Different volumes of sodium laurate and sodium
palmitate solutions ranging from 0-15 mL were combined with a fixed volume (30 mL) of the saturated CS
solution, and then fixed volumes (50 mL) were reached
Fatty Acid Salts of Chitosan for Drug Delivery
1161
by adding distilled water. For 2 h, the mixtures contained sodium laurate were fixed on a shaker and mixed
at room temperature, and those containing sodiumpalmitate were incubated in water-bath shaker at
60oC. After shaking, all mixtures precipitated and
were centrifuged to give clear supernatants, the viscosity of which was measured using Physica MCR
Rheometer 301.
salt. From each mixture, powder quantities equivalent
to 100 mg of the drug were directly compressed into
tablets in a 10-mm die using a manual tableting hydraulic press at a compression force of 50 kN. Punches
used for compression were flat with beveled edges and
pressure was released immediately after compression.
The prepared tablets were used for buoyancy and/or
dissolution studies.
Preparation of CS/fatty-acid salts
Saturated CS solutions in 0.18% acetic acid (400
mL) were combined with sodium laurate and sodium
palmitate solutions equivalent to 1.5% fatty acid (200
mL) and 400 mL distilled water. The mixtures were
incubated and shaken as described in the previous
section, with subsequent filtration and two distilled
water washes of the obtained precipitates. The precipitates were left to dry at room temperature in glass
petri-dishes, and then ground into powders using a
mortar and pestle and passed through a 250-µm sieve.
Swelling studies
Different polymeric tablets (200 mg each) of CS, CSlaurate and CS-palmitate were prepared as described
in the previous section. The tablets were initially
weighed (Wi) and then soaked in 900 mL of 0.1 M HCl
using USP Type-II dissolution apparatus at a temperature of 37.0 ± 0.1oC and a paddle speed of 100
rpm. At suitable time intervals, stirring was stopped
to allow for the removal of tablets by a spatula. The
removed tablets were rolled on a filter paper to remove
any liquid on the surface and then weighed to give the
wet weight (Ww). The swelling ratio was calculated as
(Ww × Wi)/Wi.
Characterization of CS/fatty-acid salts
The powders of CS/fatty acid salts were analyzed by
FT-IR spectroscopy using Shimadzu FT-IR spectrometer (Japan) and compared to pure CS, pure fatty
acid and physical mixtures of the pure substances. A
total of 1% (w/w) of sample was mixed with dry KBr.
The mixture was ground into a fine powder using an
agate mortar before compression into a KBr disk that
was scanned at 10 mm/s at a resolution of 4 cm−1. DSC
thermograms were obtained using a differential scanning calorimeter (Mettler, Toledo DSC823e) configured
to a Mettler® Star software system (STARe Default
DBV9.00). The equipment was calibrated with indium.
Five mg of sample were weighed into a standard aluminum pan with a pierced cover and heated from
ambient temperature to 300oC at a heating rate of 10
o
C/min under constant purging of nitrogen atmosphere
at 80 mL/min.
Tablet preparation
Non-effervescent physical mixtures were prepared
by mixing each CS/fatty acid salt and ranitidine HCl
as a model drug in a mortar and pestle at drug/polymer ratio (w/w) of 1:2. Effervescent mixtures with the
same drug-polymer composition were prepared by
including sodium bicarbonate at 40 mg per 100 mg of
the polymer with no ingredient replacement. Mixing
time was 5 min. Corresponding mixtures were prepared by replacing CS/fatty acid salt with the equivalent weight of CS or a physical mixture of CS/fatty
acid having the same ratio (w/w) of CS/fatty acid that
was used to prepare the corresponding CS/fatty acid
In vitro buoyancy
The dissolution and buoyancy studies were conducted in triplicate using USP Type-II dissolution apparatus (Vankel dissolution tester). Dissolution medium
was 0.1 M HCl, and the stirring rate and temperature
were adjusted to 100 rpm and 37 ± 0.1oC, respectively.
For buoyancy, the tablets were observed over 8 h
during which the time required for the tablets to rise
to the surface and float was determined as the floating
lag-time (T-lag) and the floating tablets were then
observed for the duration of floating (floating time).
Drug release studies
The dissolution studies were performed in triplicate
using USP type II (paddle method) dissolution apparatus (Vankel dissolution tester). Tablets were placed
in 0.1 M HCl dissolution medium and then stirred at
a rate of 100 rpm and temperature of 37 ± 0.1oC.
Samples (10 mL) were drawn at predetermined time
intervals and assayed for drug content using UV
spectrophotometery at 310 nm. To maintain a constant
volume of dissolution medium, drawn samples were
replaced with equal volumes of dissolution medium.
RESULTS AND DISCUSSION
Optimization of CS/fatty acid reaction
The spectrum of CS (Fig. 1A) exhibited the following
characteristics bands: broad band between 3000 and
3700 cm−1 due to OH and NH stretching; at 2885 cm−1
1162
Fig. 1. FT-IR spectra of CS (A), LA (B), and CS-LA
physical mixture (C).
due to CH stretching; at 1651 cm−1 due to amide I; and
at 1589 cm−1 due to NH bending from amine and amide
II. In the spectrum of LA (Fig. 1B), C-H stretching
vibration bands in the region from 2800 to 3000 cm−1
and a high intensity band at ~1700 cm−1, ascribed to
C=O stretching, were also observed. The spectrum of
A. Bani-Jaber et al.
the physical mixture (Fig. 1C) displayed the bands
shown for the single components. The spectrum of the
precipitate obtained by mixing saturated CS solution
(pH = 5.91) and sodium laurate solution (Fig. 2A)
differed from that of the physical mixture in the region
from 1500 to 1800 cm−1. The former spectrum did not
show the strong carbonyl absorption band shown for
LA at ~1700 cm−1, and instead new absorption bands
appeared at lower wavelengths (1651 and 1558 cm−1)
in this spectrum. However, in the region from 2500 to
3500 cm−1, the precipitate showed bands similar to
those shown for the physical mixture: C-H stretching
vibration of LA in the region 2840 to 3000 cm−1 and a
broad band between 3000 and 3700 cm−1 due to OH
and NH stretching of CS. The previous observations
indicated that the precipitate was an ion pair of CS
and LA. Ion pairing was likely a result of a protonated
form of CS and an ionized form of LA interacting
through ionized amino and carboxy groups in the form
of CS-laurate. Similar observations can be found from
the corresponding comparisons for the precipitate
obtained by mixing unsaturated solution of CS (7.4
mg/mL, pH = 3.65) and sodium laurate solution. However, an extra peak at ~1700 cm−1 was also observed,
which matches the carbonyl absorption band of LA,
Fig. 2. FT-IR spectra of precipitates obtained by mixing Na-laurate solution (1.5 %) with saturated CS solution (9.8 mg/
mL, A), and unsaturated CS solutions at concentrations 7.4 mg/mL (B), 4.9 mg/mL (C) and 2.5 mg/mL (D).
Fatty Acid Salts of Chitosan for Drug Delivery
but with a high reduction in intensity. Mixing this
unsaturated solution of CS with sodium laurate led to
the formation of CS-laurate and free LA, which coprecipitated as a heterogeneous solid mixture. The
formation of LA in this mixture was due to the protonation of some of the added sodium laurate. Spectra
C and D (Fig. 2) matched that of LA (Fig. 1A), and thus
we concluded that using highly acidic unsaturated CS
solutions (pH < 2) with CS concentration ≤ 4.9 mg/mL
led to the precipitation of most of the added sodium
laurate as LA due to protonation and insignificant CSlaurate formation. The previous effects of the acidity
of CS solution on the nature of the precipitate obtained
can be explained based on the fact that as the polymer
solution was more acidic (more unsaturated), the
sodium salt of lauric acid was more protonated and
precipitated as free LA. This is likely because as the
pH is reduced more protons are available to neutralize
more sodium laurate, leading to less ionized fatty acid
to react with the ionized polymer, thus keeping CS in
solution and precipitating sodium laurate as a free
acid.
1163
this point. The optimum fatty acid concentration for
the highest CS/fatty acid salt formation was found
when the average viscosity did not change significantly (p-value < 0.05 by t-test), and was 0.015 and
0.012 mmol/mL for LA and PA, respectively. Based on
these values and the total number of moles of amino
groups in the added CS, the percentage of the free
amino groups in the precipitates was estimated to be
56.7 and 66.2% for CS-laurate and CS-palmitate,
respectively.
Viscosity measurements
Fig. 3 shows how the supernatant viscosity changed
when the concentration of sodium salts of the fatty
acids changed in the final mixtures obtained by mixing
fixed volumes of CS saturated solution and different
volumes of the salts. The viscosity progressively decreased with the increase in added sodium laurate or
sodium palmitate until reaching a critical point, after
which the viscosity did not significantly decrease. The
critical point was reached when CS completely reacted
with the added fatty acid and precipitated; supernatant viscosity close to that of water (1) was obtained at
Characterization of CS/fatty acid salts
Salt formation and the absence of free fatty acids in
the prepared CS/fatty acid salt powders were confirmed by FT-IR and DSC analyses. The spectrum of CSlaurate matched that in Fig. 2, as discussed for the
comparison between the latter spectrum and that of
CS-LA physical mixture. The spectra of CS-palmitate
along with those of CS, PA and CS-PA physical mixture
are reported in Fig. 4. The involvement of both CS and
PA in the formation of CS-palmitate was indicated in
the spectrum of CS-palmitate by a broad absorption
band between 3000 and 3700 cm−1 corresponding to
OH and NH stretching of CS and C-H stretching
vibration bands of PA between 2800 and 3000 cm−1.
However, in this spectrum, the carbonyl absorption
band of PA, observed in the physical mixture at ~1700
cm−1, disappeared, indicating salt formation between
CS and PA. Further evidence for CS-FA salt formation was given by DSC thermograms for CS-laurate,
CS, LA and CS-LA physical mixture (Fig. 5). The
melting peak of LA, also found in the physical-mixture
at ~47oC, was not observed in CS-laurate. In addition,
CS both as a single component and as a physical mixture with LA showed thermal degradation starting at
Fig. 3. Variation of viscosity values of supernatants from
CS/fatty acid mixtures as a function of fatty acid concentration. Each value is the mean ± S.D. of n = 3.
Fig. 4. FT-IR spectra of CS (A), PA (B), CS-PA physical
mixture (C), and CS-palmitate (D).
1164
A. Bani-Jaber et al.
Fig. 5. DCS thermograms of LA (A), CS (B), CS-LA physical mixture (C), and CS-laurate (D).
~280oC, while this degradation initiated at ~260oC for
CS-laurate. The likely explanation for the different
thermal behavior of CS-laurate from that of the physical mixture is the molecular dispersion by ionic interaction of LA among CS polymeric chains in the form of
CS-laurate. This led to amorphization of LA, disappearance of the LA melting peak, and a change in the
thermal stability of CS. Similar results were obtained for
CS-palmitate (thermograms not shown). The properties
of the fatty acid salts of CS are summarized in Table I.
between 1-3 h and tablet disappearance after 3 h. At 3
h, the wet weight of the tablets was lower than the
initial tablet weight and thus a negative swelling ratio
was calculated. Relative to CS tablets, the tablets of
CS/fatty acid salts showed greater and progressive
increase in swelling over 6 h. At 6 h, the tablets made
of CS-laurate and CS-palmitate showed almost 11and 14-fold increases in tablet weight as a result of
Swelling studies
The swelling results are plotted and reported in Fig.
6. CS tablets showed a maximum of almost two-fold
swelling at 1 h due to polymer ionization and gelling.
Afterward swelling decreased rapidly likely because of
leaching of the dissolved polymer out of the tablets,
indicated as a progressive decrease in tablet wet weight
Table I. Properties of CS/fatty acid salts
Property
Finding (s)
Interaction type
Ion pairing
Solubility (0.1 M HCl)
Insoluble but swellable
Free amino groups (%)
56.7% (CS-Laurate)
66.2% (CS-Palmitate)
Solid state
Amorphous
Fig. 6. Swelling of tablets made of different CS forms in
0.1 M HCl.
Fatty Acid Salts of Chitosan for Drug Delivery
1165
release in 0.1 M HCl from effervescent CS matrices
was rapid with an average drug release of 84% at 1 h,
which could be attributed to the high solubility of CS
and the drug in the acidic medium. Faster drug release
was obtained when CS was combined physically with
LA or PA in the effervescent tablets, which was
illustrated at 0.5 h by an average drug release of more
than 90% for the physical mixtures versus 25% for CS.
The interference of insoluble fatty acids with CS gel
formation could explain the previous comparison.
Relative to the previous matrices, those with fatty
acid salts of CS showed remarkably slower and prolonged drug release as 70-80% of the loaded drug was
released slowly over 8 h. Since CS is in the ionized
form but complexed to an ionized fatty acid in these
matrices, it gels and highly swells as shown by the
swelling studies. However, because the fatty acid salts
of CS are less soluble in 0.1 M HCl than the parent
polymer, leaching of CS out of the matrices was minimized, leading to more stable gel formation. As the gel
formed, solvent penetration into the tablets and drug
diffusion out of the tablets were controlled.
The dissolution data were fitted to various models:
swelling, respectively. The fact that fatty acid salts of
CS are polyelectrolytic in nature, since both the polymer and the fatty acid are already in the ionized state,
and the low leaching of the polymer out of tablets likely
due to low solubility of the fatty polymer in the swelling
medium could explain these high swelling values.
In vitro buoyancy
All of the matrices with no sodium bicarbonate
incorporated were non-floating (Table II). However,
inclusion of 40 mg of sodium bicarbonate per tablet
caused the matrices to float but at different times (Tlag range: 0.5-25 min) as a result of CO2 generation
and entrapment inside the matrices, which decreased
the density of the tablets. As the density of tablets fell
below 1, the tablets became buoyant. As this entrapment was relatively stable, longer floating was obtained.
Effervescent tablets having CS as matrix former floated
within 24 min. However, these tablets gradually decreased in size while floating and completely disappeared
within 2 h of the acidic soaking. This could be explained by the fact that CS is soluble in 0.1 M HCl
and thus leached out of the tablets during floating.
Effervescent matrices containing a physical mixture of
CS and LA or PA floated within 15 min but rapidly
disintegrated within 1 h of soaking. This rapid disintegration could be attributed to the insoluble fatty
acids, which likely decreased the continuity of the CS
gel structure such that the matrices could not withstand the bursting effect of CO2. Effervescent matrices
made of CS-palmitate or CS-laurate were the best
floating systems with rapid floating (T-lag < 1 min)
and prolonged floating time (> 8 h). In these matrices,
CS was ionized and complexed to an ionized fatty
acid, which likely prevented leaching of the polymer
out of the matrices, thus providing good gelling and
matrix integrity to entrap CO2 and to withstand the
effervescent bursting effect of the gas. The floating
results were also consistent with the results of the
swelling study as more swelling was achieved for tablets
made of CS fatty acid salts than for those made of CS.
Fig. 7. Ranitidine release in 0.1 M HCl from different
effervescent matrices. Each value is the mean ± S.D. of n
= 3.
Drug release studies
The dissolution profiles are given in Fig. 7. Ranitidine
Table II. Floating parameters in 0.1 M HCl of different matrices as a function of sodium bicarbonate level (mg/tablet)
Matrix-type
Sodium bicarbonate level
CS-PA
CS-LA
(Physical mixture) (Physical mixture)
CS
0
T-lag (s)
N.F.*
Floating time (h)
N.F.*
40
0
40
0
40
CS-palmitate
CS-laurate
0
0
40
40
1440.0 ± 216.3 N.F.* 557.3 ± 81.7 N.F.* 106.0 ± 38.1 N.F.* 45.0 ± 0.0 N.F.* 34.0 ± 2.8
1.3 ± 0.1
*
N.F.*
C. D.**
**
N.F.*
C. D.**
N.F.*
>8
Each value is the mean ± S.D. of n = 3; No floatation observed; Complete disintegration within 1 h
N.F.*
>8
1166
A. Bani-Jaber et al.
Qt/Q = Ktn
zero-order release kinetics Eq. (1), first-order release
kinetics (Gibaldi and Feldman, 1967; Wagner, 1969)
Eq. (2), Higuchi’s square root of time equation (Higuchi,
1963) Eq. 3, and Hixson-Crowell’s cube root of time
equation (Hixson and Crowell, 1931) Eq. (4). The goodness of fit was evaluated using r (correlation coefficient) values.
Qt = Q0 + K0t
where Qt is the amount of drug dissolved in time t, Q
is the amount of drug dissolved in time (the drug
loaded in the formulation), Qt/Q is the fractional
release of the drug in time t, K is a constant incorporating structural and geometric characteristics of
the dosage form, n is the release (diffusional) exponent that depends on the release mechanism and the
shape of the matrix tested, and t is release time. For
tablets, when n < 0.45, drug release is controlled by
diffusion and, when n > 0.98, drug release is controlled
by matrix erosion. Values of n between 0.45 and 0.98
can be regarded as an indicator of the superposition of
both phenomena. The mean n values were 0.753 ±
0.182 and 0.603 ± 0.076 for CS-laurate and CS-palmitate, respectively, suggesting that drug release was
controlled by the superposition of diffusion and erosion. The time for 50% drug release was calculated
according to the previous model and was 4.10 ± 0.70
and 5.44 ± 1.70 h for CS-laurate and CS-palmitate,
respectively. In addition, the similarity factor (f2) for
comparison between the corresponding dissolution
profiles was calculated and found to be 48.6. A test
batch is considered similar to that of a reference batch
if the f2 value of their profiles is between 50 and 100.
The last two calculations indicated that drug release
was slower from CS-palmitate matrices than from CSlaurate matrices, which could be attributed to the
higher alkyl chain-length of PA, which likely led to
more control of solvent penetration and drug diffusion.
In conclusion, salt formation between CS and fatty
acids was achieved by mixing saturated CS solution
and aqueous solution of sodium laurate or palmitate.
Tablets made of CS-laurate or CS-palmitate exhibited
greater swelling in 0.1 M HCl than those made of CS,
which reflected changes in polymer solubility and gelling in the acidic medium as a result of salt formation
between CS and the fatty acids. Effervescent tablets
made of these CS/fatty acid salts achieved better floating parameters and much more controlled and prolonged
drug release in 0.1 M HCl than those made of CS or
physical mixtures of CS and fatty acids. Fatty acid
salts of CS are therefore considered good candidates
for prolonged intragastric drug delivery, particularly
(1)
Where Qt is the fractional amount of drug dissolved
in time t, Q0 is the initial amount of drug in the solution (most times, Q0 = 0), K0 is the zero order release
constant and t is release time.
Qt = Q0 e1−Kt
(2)
Where Qt is the fractional amount of drug dissolved
in time t, Q0 is the initial amount of drug in the
solution, K1 is the first order release constant and t is
release time.
Qt = KH ÷ t
(3)
Where Qt is the fractional amount of drug dissolved
in time t, KH is the Higuchi dissolution constant and t
is release time.
(Q0)1/3 − (Qt)1/3 = Kst
(5)
(4)
Where Q0 is the initial amount of drug in the pharmaceutical dosage form, Qt is the remaining amount of
drug in pharmaceutical dosage form at time t, Ks is a
constant incorporating the surface-volume relation
and t is release time.
Both CS-laurate and CS-palmitate matrices followed
the Higuchi matrix model, which had the highest correlation coefficient values (Table III). This indicated
that drug release at early times was rapid, likely due
to release of drug at the tablet surface; the release
then progressively slowed down, likely as a result of
formation of a gel-layer that controlled solvent penetration and drug diffusion.
In order to evaluate the drug release mechanism from
these matrices, the dissolution data were further fitted
to Korsmeyer-Peppas’ power law equation (Korsmeyer
et al., 1983; Peppas, 1985) Eq. (5).
Table III. Fitting of drug release data of floating controlled-release matrices to various mathematical models
Matrix type
Zero order
K0
First order
r0
K1
Higuchi matrix
r1
KH
rH
Hixson-Crowell
Ks
rs
CS-laurate
0.112 ± 0.011 0.902 ± 0.043 0.234 ± 0.005 0.857 ± 0.022 0.280 ± 0.004 0.942 ± 0.020 0.056 ± 0.001 0.903 ± 0.015
CS-palmitate 0.093 ± 0.023 0.866 ± 0.055 0.190 ± 0.017 0.918 ± 0.019 0.233 ± 0.040 0.964 ± 0.016 0.045 ± 0.006 0.950 ± 0.010
Each value is the mean ± S.D. of n = 3.
Fatty Acid Salts of Chitosan for Drug Delivery
when CS fails to sustain the drug release.
ACKNOWLEDGEMENTS
This work was funded by a grant from the Deanship
of Academic Research, The University of Jordan,
Amman, Jordan.
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