Date post: | 12-Apr-2018 |
Category: |
Documents |
Upload: | handriko-ds |
View: | 271 times |
Download: | 11 times |
7/21/2019 jurnal internasional biofarmasetika
http://slidepdf.com/reader/full/jurnal-internasional-biofarmasetika 1/9
63Amal A . Ammar.et al . / I nternational Journal of Biopharmaceutics. 2011; 2(2): 63-71.
ISSN 0976 - 1047
2229 - 7499
International Journal of Biopharmaceutics
Journal homepage: www.ijbonline.com
FORMULATION, CHARACTERIZATION AND
BIOPHARMACEUTICAL EVALUATION OF ALLOPURINOL
TABLETS
Amal A. Ammar*1, Ahmed M. Samy
2, Maha A. Marzouk
3, Maha k. Ahmed
4
1, 3 & 4Department of Pharmaceutics, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt2 Department of Pharmaceutics, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
ABSTRACT
Allopurinol is a poorly water-soluble drug so the solubility is the main constraint for its oral bioavailability. Solid
dispersions consisting of Allopurinol with different types of polymers were prepared by melting or solvent evaporation
technique. Three formulations exhibited highest drug release after 45 min were incorporated into tablet matrix. Fourier
transform Infrared spectroscopy (FTIR) and differential scanning calorimeter (DSC) were performed to identify any
physicochemical interactions between Allopurinol and the used tablet excipients. Tablet formulations were also subjected to
stability studies. FT1 and FT2 contained solid dispersions with urea and mannitol respectively showed the highest shelf stability
t90 (year) 2.29, 7.11 respectively. On the basis of the in-vitro release profile and stability data both FT1 and FT2 were subjected
to bioavailability studies in human, and were compared with commercial tablets. Tablets containing solid dispersion showed
higher AUC compared to the commercial tablets. These results suggest that the Allopurinol solid dispersion loaded tablets can be utilized to improve its bioavailability.
Keywords: Allopurinol tablets; Bioavailability; Dissolution enhancement; Pharmacokinetics; Xanthine oxidase inhibitor.
INTRODUCTIONAllopurinol is an inhibitor of the enzyme
commonly known as xanthine oxidase. Allopurinol is an
analogue of hypoxanthine. It is effective for the treatment
of both primary hyperuricemia of gout and secondary
hyperuricemia related to hematological disorders or anti-
neoplastic therapy (Clark‟s, 2004; Derek and Da-peng
wang, 1999). It is a very weak acid with a dissociation
constant (pka) of 9.4 and is therefore essentially unionized
at all physiological pH values (Benzra and Bennett, 1978).Its lipid solubility is quite low as is indicated by its
octanol: water partition coefficient of 0.28 (Day et al.,
2007). Allopurinol is a polar compound with strong
Corresponing Author
Amal A. Ammar
E-mail: [email protected]
intermolecular hydrogen bonding and limited solubility in
both polar and non polar media (Samy et al ., 2000; Ammar
and El-Nahhas, 1995; Hamza and Kata, 1989 ).
Oral bioavailability of a drug depends on its
solubility and or dissolution rate, therefore efforts to
increase dissolution of drugs with limited solubility is often
needed. Solid dispersion techniques have been widely used
to improve the dissolution properties and bioavailability of
poorly water soluble drugs (Jagdale et al., 2010). Soliddispersion refers to a group of solid products consisting of
at least two different components, generally a hydrophilic
matrix and a hydrophobic drug. The matrix can be either
crystalline or amorphous. The drug can be dispersed
molecularly, in amorphous particles (clusters) or in
crystalline particles. It is also defined as being a „product
formed by converting a fluid drug-carrier combination to
the solid state‟ (Aggarwal et al., 2010).
IJB
7/21/2019 jurnal internasional biofarmasetika
http://slidepdf.com/reader/full/jurnal-internasional-biofarmasetika 2/9
64Amal A . Ammar.et al . / I nternational Journal of Biopharmaceutics. 2011; 2(2): 63-71.
Several carrier systems have been used in the
preparation of fast release solid dispersions. The technique
provides a disposition of the drug on the surface of certain
materials that can alter the dissolution properties of the
drug. Once the solid dispersion is exposed to aqueous
media and the carrier is dissolved, the drug is released as
very fine colloidal particles (Zedong et al., 2008; Devi,
2003; Vippagunta et al., 2002). This results in a greatly
enhanced surface area, thus prompting expectations of a
high dissolution rate and level of bioavailability for poorly
water-soluble drugs (Goldberg, 1966).
The aim of the present study was to formulate
tablets of Allopurinol solid dispersions in order to improve
dissolution and aqueous solubility and to facilitate faster
onset of action. In a previous study (Samy AM et al ., 2010)
several carriers were used in the preparation of solid
dispersions, including urea, mannitol and PVP K30. In the
current work we choose the three formulations which
exhibited highest drug release after 45 min and
incorporated them into compressed tablets. The prepared
tablets were also evaluated for their uniformity of weight,thickness, hardness, friability, disintegration time and drug
content uniformity. The shelf storage stability testing at
room temperature for one year was carried out on the
formulated Allopurinol tablets. Formulations showed
improved dissolution and higher stability data were chosen
for in-vivo absorption study in comparison with
commercial product.
MATERIALS & METHODS
Materials
Allopurinol (Allo) powder was kindly provided
by Alexandria Company for pharmaceutical industries,
(Alexandria, Egypt); Urea, Sodium chloride, Lactose ,Anhydrous sodium acetate, salicylic acid , acetic acid, di-
sodium hydrogen phosphate, potassium di-hydrogen ortho
phosphate, ethyl alcohol (absolute) and Hydrochloric acid
were supplied from El-Nasr Pharmaceutical chemicals Co.,
(Egypt); Mannitol, Magnesium stearate,
Polyvinylpyrrolidone (PVP) K30 and Polyethylene glycol
(PEG) 4000 were kindly provided by Amoun Company for
pharmaceutical industries, (Cairo, Egypt); Avicel PH101,
Fluka AG, CH – 9470 Buchs., Mittler Teilchengrosse
(Switzerland); Acetonitrile and methanol (HPLC grade),
Scharlau chemie S.A., European Union. (Zyloric® 100 mg
tablet), Glaxo smithkline, Egypt.
METHODS
Study of Physicochemical interaction of Allopurinol
with tablet excipients
Differential scanning calorimetric (DSC) studies
Possible interaction of Allopurinol with the tablet
excipients was investigated using DSC. Approximately 5
mg of samples were weighed and hermetically sealed in
the aluminium pans. Samples of drug alone, each excipient
alone, physical mixtures of Allopurinol with the
investigated excipients (1:1 W/W) were measured with
Shimadzu, (model DSC-50, Japan) thermal analyzer. The
DSC thermogram were obtained over a temperature range
of 25 – 400 ºC with a thermal analyzer equipped with an
advanced computer software program at a scanning rate of
10ºC / min and nitrogen gas purge of 40 ml/ min. The
instrument was calibrated with pure indium as a reference.
Fourier Transforms Infrared Spectroscopy (FTIR) Samples of 1-2 mg of drug alone, each excipient
alone, physical mixtures of Allopurinol with the
investigated excipients (1:1 W/W) prepared by simple and
perfect mixing and solid dispersion (1:1 W/W) were mixed
with KBr (IR grade) compressed into discs in the
compression unit under vacuum and were scanned from
4000 – 400 cm-1 with an empty pellet holder as a reference.
The spectrophotometer was Perkin-Elmer, FTS-1710,
Beaconsfield (UK).
Formulation of Allopurinol tablets. Allopurinol solid dispersions with different
carriers like (urea, mannitol and PVP K30) in different
ratios prepared by melting or solvent evaporation
techniques were incorporated into tablet formulations.
Tablet compression machine with flat-faced single punch,
first medicine machinery, factory of Donghai branch,
(China, Shanghai) was used for the manufacturing of the
directly compressed Allopurinol tablets. Additives used in
preparation of tablets (Avicel PH101, magnesium stearate
and lactose) were incorporated by the ratio showed in table
(1).
Quality control study of the prepared tablets The prepared tablets from each formulation were
subjected to the tablets quality control tests as drug
content, weight uniformity, tablets thickness, disintegration
time, hardness and friability.
Drug release was assessed using a USP type II
dissolution apparatus at 75 rpm in 900 mL 0.1N HCl
maintained at 37ºC ± 0.5ºC (Abd-Elazeem, 2001). Sample
of 5ml was withdrawn at regular intervals and replaced
with the same volume of prewarmed (37ºC ± 0.5ºC) fresh
dissolution medium. The samples withdrawn were filtered
through Whatman filter paper (No. 1, Whatman,
Maidstone, UK) and drug content in each sample was
analyzed after suitable dilution, the amount of Allopurinoldissolved was determined spectrophotometrically at 250
nm. Plain Allopurinol tablets were used as a control.
Shelf Stability study of Allopurinol tablets
Stability studies were conducted on Allopurinol
tablets containing its solid dispersions to assess their shelf
stability with respect to their drug content, after storing
them at room temperature for one year.
7/21/2019 jurnal internasional biofarmasetika
http://slidepdf.com/reader/full/jurnal-internasional-biofarmasetika 3/9
65Amal A . Ammar.et al . / I nternational Journal of Biopharmaceutics. 2011; 2(2): 63-71.
Bioavailability study The selected tablet formulations with the highest
dissolution profile (FT1, FT2) and commercial tablets
(Zyloric® 100mg tablets, Glaxo-Wellcome) were
subjected to a single dose relative pharmacokinetic study.
The study was performed following standard protocol in 6
healthy male volunteers, weighing 60 to 85 kg and of 22 to
30 years old in a cross-over design with two weeks wash
out period in accordance with all applicable regulations.
The study was reviewed and approved by the Ethical and
Institutional Review Committee of the Pharmaceutical
Analytical Unit Faculty of Pharmacy, (Boys), Al-Azhar
University, Nasr City, Cairo, Egypt. Before initiating the
study, informed consent was obtained from volunteers after
the nature and possible consequences of the study were
explained. All the subjects were in good health on the basis
of their medical history and complete physical
examination. The volunteers did not smoke and were not
on any kind of medication before or during the experiment.
Venous blood samples were collected pre-dose (0hours)
and at0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4 and 8 h post-dosing.The blood samples were centrifuged at 5,000 rpm for 10
min, and the plasma obtained were stored at -80°C until
analysis. To compare the rate and extent of absorption of
Allopurinol, the following pharmacokinetic variables were
calculated for each volunteer using actual blood sampling
times. The maximum plasma concentration (Cmax) and the
time required to reach this concentration (Tmax) were read
directly from the arithmetic plot of time vs. plasma
concentration for Allopurinol. The overall elimination rate
constant (ke) was calculated from the slope of the terminal
elimination phase of a semilogarithmic plot of
concentration vs. time after subjecting it to linear
regression analysis. The elimination half life (t1/2) wasobtained by dividing 0.693 by ke. The absorption rate
constant (ka) was calculated using the method of residuals
(Gibaldi and Perrier, 1990). The area under the plasma
Allopurinol concentration vs. time curve (AUC0-8) was
determined by means of the trapezoidal rule. The relative
bioavailability of Allopurinol from matrix tablets in
comparison to reference formulation (Zyloric® 100mg
tablets, Glaxo-Wellcome) commercial tablets was
calculated by dividing its AUC0-8 by that of the commercial
tablet dosage form.
Validation of the HPLC method
Allopurinol was subjected to analytical validationin human plasma using an HPLC method according to USP
guidelines, from which the recovery of the prepared tablets
can be calculated.
Preparation of standard solutions
Stock solution of Allopurinol was prepared by
dissolving 10 mg of Allopurinol in 100 ml methanol. This
solution was used to prepare working standard solutions
daily for different concentrations by dilution with
methanol. The internal standard solution was prepared by
dissolving 10 mg salicylic acid in 100 ml methanol. The
working internal standard was prepared by taking 3 ml
from this solution in 10 ml methanol (30µg/ml).
Linearity
The linearity of the method was evaluated using a
calibration curve in the range of 0.5-8 µg/ml Allopurinol.
Thirty μL injections were made in triplicate for each
concentration and chromatographed on a C18 column
using a freshly prepared mobile phase consisted of 2.72 gm
of sodium acetate per liter distilled water adjusted to pH
4.5 with a mixture of acetic acid: acetonitrile (96:4). The
mobile phase was degassed and filtered through a 0.45 µm
filter (Millipore, Sainet-Quentin, Y-velines). The flow rate
was 1 ml/minute. The detection wave length was 254 nm.
The run time was 20 minutes. The calibration curve was
obtained by plotting the peak area as a function of drug
concentration and the regression parameters were
determined.
Intra-day and inter-day reproducibility of Allopurinol
The intra-day and inter-day reproducibility were
determined by replicate analysis of three sets of samples
spiked with different concentrations of Allopurinol (0.5, 1,
2, 4, 6, and 8 μg/mL) within one day or on three
consecutive days.
RecoveryAbsolute recovery of Allopurinol was determined
in triplicate, using blank human plasma samples spiked
with Allopurinol; the mean peak area was compared to that
obtained from the standard drug with the same
concentration.
RESULTS AND DISCUSSION
Study of physicochemical interaction of Allopurinol
with tablet excipients
DSC studies
DSC thermogram of Allopurinol and the tablet
excipients presents in figure (1) in which Allopurinol is
characterized by a sharp endothermic peak at 386°
corresponding to its melting point. Magnesium stearate and
anhydrous lactose had sharp peaks at 117.08 and 245.11°C,
respectively while Avicel PH101 had a broad peak at
134.1°C. On the other hand, thermogram for all physical
mixtures indicate that there was no appreciable shift in themelting peak of Allopurinol with all excipients. This
indicates the absence of possible interactions between the
components.
FTIR spectroscopy
Figure (2) shows FTIR spectra for Allopurinol
alone and each tablet excipient alone and Allopurinol with
tablet excipients in physical mixtures. FTIR spectrum of
pure Allopurinol characterized by the absorption bands
7/21/2019 jurnal internasional biofarmasetika
http://slidepdf.com/reader/full/jurnal-internasional-biofarmasetika 4/9
66Amal A . Ammar.et al . / I nternational Journal of Biopharmaceutics. 2011; 2(2): 63-71.
at 3167 cm-1 at high frequency, most probably attributed
to N-H stretching band of secondary amine group, at 3034
cm-1 denoting C-H stretching vibration of pyrimidine ring.
At low frequencies the band at 1693 cm-1 indicating C=O
stretching vibration of the keno form of 4-hydroxy
tautomer. Also the bands at (1581-1469.96) cm-1 are
attributed predominantly to C-N stretching and C-C ring
stretching respectively. Bands at 1234.55-698.29 cm-1
denote CH in plane deformation. An IR spectrum of
Magnesium stearate alone exhibited a major bands at
3541.62 cm-1 for O-H stretching bands of COOH acid
group, also bands at 2856.83, 2640.79 and 2328.29cm-1
were for C-H aliphatic bands. While at 1541 cm-1 for C=O
of carboxylic acid group. The spectra of Allopurinol and
Magnesium stearate physical mixture show the same bands
of both Allopurinol and magnesium stearate at the same
position. Anhydrous lactose spectrum is dominated firstly
by the strong primary alcohol (OH) stretching vibration
showing peaks at 3466.39, 3364.16, 3300.50 and 3248.42
cm-1. These (OH) groups in lactose are hydrogen bonded to
each other; free hydroxyl groups would manifestthemselves at higher frequency at 3852.19, 3765.39 and
3630.36 cm-1. At low frequencies, C-O stretching present
in primary and secondary alcohols respectively, R-CH2-
OH and R-CH-OH-R dominates and shows strong
absorption band at 1431.31 and 1089.88 respectively. The
spectra of Allopurinol and anhydrous lactose physical
mixture show the absorption bands of both Allopurinol and
lactose at the same position. An IR spectra of Avicel
PH101 which characterized by a peak at 3460.61, 3408.52,
3234.92 and 3140.40 cm-1 corresponding to the strong
primary alcohol (OH) stretching vibration. These (OH)
groups in Avicel PH101 are hydrogen bonded to each
other; free hydroxyl groups would manifest themselves athigher frequency at 3805.9, 3759.6 and 3674.73 cm -1.
Bands at 1375.37 and 1039.73 cm-1 corresponding to that
of C-O stretching present in primary and secondary
alcohols respectively. While bands at 2846.83, 2717.95,
2526.98, 2332.15 and 2264.63cm-1 were corresponding to
C-H group. The IR spectra of the physical mixture of
Allopurinol and Avicel PH101 seemed to be only the
summation of drug and Avicel PH101 spectra. This result
suggested that there was no interaction between drug and
Avicel PH101 in the physical mixture. It was clear that all
characteristic bands of Allopurinol and tablet excipients
(magnesium stearate, anhydrous lactose and Avicel PH101
were appeared in the same regions and at the same rangesand there was no new bands appeared, although the shape
of the functional group regions in the spectrum of the drug
and the excipients used was not identical with that of pure
drug alone. This might be indicative of absence of
interaction between Allopurinol and excipients.
Quality control of the prepared tablets
Physical Properties
The results of the uniformity of weight, hardness,
drug content, thickness, and friability of the tablets are
given in Table 2. All the samples of the test product
complied with the official requirements of uniformity of
weight. The drug content ranged from 95.4 to 105.4% of
the label claim for Allopurinol in all formulations. The low
friability values (0.023%±0.0015 to 0.33%±0.004) indicate
that the matrix tablets are compact and hard.
In-vitro dissolution of Allopurinol from tablets The in-vitro release of Allopurinol from tablets
prepared as a solid dispersion compared with control
tablets in 0.1 N HCl at 37°C ± 0.5°C are represented in
Figure (3). It was found that the release of Allopurinol
according to their percent mean released at 45 minutes
were 102±0.23 % for FT1; 103.7±0.5% for FT2 and
15±0.7% for FT3. One way analysis of variance (ANOVA)
of Allopurinol tablets with respect to their % released at 45
minute followed by Tukey- Kramer multiple comparisons
test, showed significant difference at p < 0.05.
Kinetic treatment for the in-vitro release of Allopurinol
tablets
It was found that the in-vitro release of Allopurinol
followed different kinetic orders and no definite kinetic
order could express the drug release from different tablet
formulations (table 3).
Stability study Allopurinol tablets stability study according to the
calculated t90 after one year shelf storage was as follows:
FT2 Allopurinol tablets containing mannitol (drug:carrier)
1:1> FT1 Allopurinol tablets containing urea (drug:carrier)
1:1> FT3 Allopurinol tablets containing PVP K30(drug:carrier) 1:1 with t90 7.11 , 2.29 and 1.61 year
respectively. So, FT1 and FT2 were selected for the in-
vivo study compared with commercial tablet (zyloric® 100
mg).
Validation of the HPLC method
Optimization of chromatographic conditions
Different chromatographic conditions affecting the
separation process were studied and optimized. Different
compositions of the mobile phase, flow rates, and
wavelengths were tried. Allopurinol's peak was resolved by
using a reversed-phase Nucleosil C18 column (particle
size: 5 μm, 250 mm × 4.6 mm), a mobile phase consistedof 2.72 gm of sodium acetate per liter distilled water
adjusted to pH 4.5 with a mixture of acetic acid:
acetonitrile (96:4). The mobile phase was degassed and
filtered through a 0.45 µm filter (Millipore, Sainet-
Quentin, Y-velines). The flow rate was 1 ml/minute. The
detection wave length was 254nm. Allopurinol and
salicylic acid were resolved and the retention times were
6.2 and 17.5 minutes, respectively. No
7/21/2019 jurnal internasional biofarmasetika
http://slidepdf.com/reader/full/jurnal-internasional-biofarmasetika 5/9
67Amal A . Ammar.et al . / I nternational Journal of Biopharmaceutics. 2011; 2(2): 63-71.
interfering peaks were observed in the chromatogram of
the blank human plasma. Salicylic acid is a good choice as
internal standard due to its similar spectral properties to
Allopurinol.
Linearity
According to peak area-response at 254 nm, Beer's
law was obeyed over the range of 0.5-8 μg/mL of
Allopurinol, with a high correlation coefficient (0.9997).
The equation of linear regression was Y = 0.182X – 0.023.
Intra-day and inter-day reproducibility of Allopurinol
assay
Intra- and iner-day of Allopurinol assay were
calculated. The average correlation coefficient was 0.996
and 0.996, respectively as shown in table 4. These results
confirmed excellent linearity of the calibration lines and
high reproducibility of the assay.
Absolute recovery Using the proposed HPLC method, absolute recovery of
the drug was 94.5359.
Bioavailability studies The mean Allopurinol plasma concentration vs. time
profiles is shown in Figure 4. The mean pharmacokinetic
parameters calculated from individual plasma Allopurinol
concentrations vs. time profiles are summarized in Table 5.
Based on statistical data, pharmacokinetic parameters of
the two preparations indicated bioequivalence. The relative
bioavailability of Allopurinol tablet containing urea in
(drug: carrier ratio 1:1) and Allopurinol tablets containing
mannitol in (drug : carrier ratio 1:1) was found to be 118
and 54 % respectively.
Figure 1. DSC thermograms of allopurinol and various tablet excipients Allo, allopurinol; PM, physical mixture; Mag . St., Magnesium stearate and Anhy. Lact. Anhydrous lactose.
7/21/2019 jurnal internasional biofarmasetika
http://slidepdf.com/reader/full/jurnal-internasional-biofarmasetika 6/9
68Amal A . Ammar.et al . / I nternational Journal of Biopharmaceutics. 2011; 2(2): 63-71.
Figure 2. FTIR spectrum of Allo, various tablet excipients and the physical mixturesAllo, Allopurinol; PM, physical mixture; Mag.St., Magnesium stearate and Anhy.Lact., Anhydrous lactose
Figure 3. Percent drug released from tablets formulation compared to plain drug (c) and commercial tablet (Zyloric
100)
Figure 4. Allopurinol mean plasma concentration-time curve after oral administration
7/21/2019 jurnal internasional biofarmasetika
http://slidepdf.com/reader/full/jurnal-internasional-biofarmasetika 7/9
69Amal A . Ammar.et al . / I nternational Journal of Biopharmaceutics. 2011; 2(2): 63-71.
Table 1. Composition of Allopurinol tablets
Table 2. Quality control data of Allopurinol tablets
Table 3. Kinetic treatments for the in-vitro release of Allopurinol tablets
Z1(Zyloric® 100mg Galaxo-Wellcome)
Table 4. Intra-day and inter-day reproducibility of Allopurinol in human plasma by high-performance liquid
chromatography
Spiked Conc. (μg/ml)
Peak area ratio
Intra-day
Inter-day
Mean ± S.D Mean ± S.D
0.00 0.00 ± 0.00 0.00 ± 0.00
0.5 0.077 ± 0.07 0.077 ± 0.005
1 0.150 ± 0.15 0.153 ± 0.003
2 0.338 ± 0.33 0.348 ± 0.019
4 0.740 ± 0.74 0.732 ± 0.017
6 1.0008 ± 0.04
1.043 ± 0.04
8 1.459 ± 0.10 1.513 ± 0.02
Slope 0.177 ± 0.01 0.188 ± 0.003
Correlation coefficient(r) 0.9964 ± 0.004 0.996 ± 0.001
S.D. = Standard deviation
Components (mg)
Tablet code SD tecnique Allo. Urea MannitolPVP
K30
Avicel
PH101
Anhydrous
lactose
Magnesium
stearate
FT1 melting 100 100 ------ --------- 30 67 3
FT2 melting 100 ----- 100 -------- 30 67 3FT3
Solvent
evaporation100 ------ ---------- 100
30 67 3
Control (C) 100 ------ --------- ----------- 15 39 1.5
Formula
Quality control tests FT1 FT2 FT3
Weight variation (mg) ± S.D. 297.80 ±1.06 299.13 ±1.29 299.03 ± 2.28
Thickness (mm) ± S.D. 3.6811±0.01 3.528 ± 0.02 3.73 ±0.01
Hardness (Kg) ± S.D. 5.2 ± 0.141 4.793 ± 0.147 4.99 ± 0.43
Friability (% Loss) ± S.D. 0.023 ± 0.015 0.333 ± 0.004 0.07 ± 0.0141
Disintegration time (minutes) ± S.D. 9.66 ± 0.288 2.5 ± 0.502 50.00 ± 1.414
Drug content (%) ± S.D. 96.224 ± 0.89 95.63 ± 0.945 102.42 ± 1.55
Formula A
Correlation coeff icient (r)
Zero-order First-order Second-order Higuchi-diffusion
model
Hixson-Crowel
cube root law
Baker-lonsdale
equation
FT1
0.947
-0.950 0.9176 0.979 0.996 0.994
FT2 0.853 -0.986 0.917 0.9103 0.982 0.981
FT3 0.966 -0.696 0.624 0.923 0.817 0.743
Z1
0.837 -0.997 0.919 0.896 0.963 0.919
7/21/2019 jurnal internasional biofarmasetika
http://slidepdf.com/reader/full/jurnal-internasional-biofarmasetika 8/9
70Amal A . Ammar.et al . / I nternational Journal of Biopharmaceutics. 2011; 2(2): 63-71.
Table 5. Pharmacokinetic parameters of different Allopurinol treatments administered orally to human volunteers
Pharmacokinetic parametersVolunteers orally administered
TF1 TF2 Commercial tablets
Cmax (μg/ml) 1.883 1.752 1.467
tmax (hr) 1 1.208 1
t½ ab (hr) -1.558 -0.979 -2.121t½ el (hr) 1.096 0.584 1.474
K ab (hr-1
) -0.445 -0.708 -0.327
K el (hr-
) 0.666 1.247 0.475
AUC0-8 (μg.hr/ml) 3.976 1.874 1
AUC0-∞ (μg.hr/ml) 4.463 2.040 1.467
RB % 118 54 -------
CONCLUSION
Allopurinol tablet (FT1) which contains urea in (drug
: carrier ratio 1:1) at dose of 100 mg has a best relative
bioavailability, highest Cmax and AUC 0-∞ and
reasonable k ab and k el.
ACKNOWLEDGMENTS
The authors would like to thank Alexandria Company
for pharmaceutical industries, (Alexandria, Egypt) for their
donation of Allopurinol and Amoun Company for
pharmaceutical industries, (Cairo, Egypt) for providing the
other used polymers.
REFERENCES
Abd-Elazeem M, Khattab I, samy E, Tous S, Joachim J and Reynier J. Improvement availability of Allopurinol from
pharmaceutical dosage forms: II- capsules and tablets. Az. J. Pharm. Sci. 2001; 27: 387-399.
Aggarwal S, Gupta G D and Chaudhary S. Solid dispersion as an eminent strategic approach in solubility enhancement of
poorly soluble drugs, I.J.P.S.R 2010, 1(8).
Ammar HO and El-Nahhas SA. Improvement of some pharmaceutical properties of drugs by cyclodextrin complexation.
Pharmazie. 1995; 50: 49-50.
Benzra SA and Bennett TR. (1978) in “Analytical profiles of drug substances and excipients”, Academic press, Inc, 7, pp.1-
18.
Clark‟s analysis of drugs and poisons in pharmaceutical body fluids and postmartum materials (2004), 3 rd Ed., Pharmaceutical
press, London, pp. 601-603.Day RO, Grham GG, Hicks M, Mclchlan AJ, Stocker SL and Williams KM. Clinical pharmacokinetics and pharmacodynamics
of Allopurinol. Clin. Pharmacokinet . 2007; 46: 623-644.
Derek K and Da-peng wang TL. Formulation development of Allopurinol suppositories and injectables. Drug Dev Ind Pharm.
1999; 25: 1205-1208.
Devi VK, Vijayalakhmi P and Avinash M. Preformulation studies on celecoxib with a view to improve bioavailability. Indian J
Pharm Sci. 2003; 65:542-545.
Gibaldi M, Perrier D. Pharmacokinetics. New York, NY: Marcel Dekker; 1990.
Goldberg AH, Galbaldi M and Kanig KL. Increasing dissolution rates and gastrointestinal absorption of drugs via solid
solutions and eutectic mixtures III. Experimental evaluation of griseofulvin-succinic acid solution. J Pharm Sci. 1966;
55:487-492.
Hamza YE and Kata M. Influence of certain non-ionic surfactants on solubiliziton and in-vitro availability of Allopurinol.
Pharm Ind 1989; 51: 1441-1444.
Jagdale SC, Kuchekar BS, Chabukswar AR, Musale VP and Jadhao MA. Preparation and in vitro evaluation of Allopurinol-
Gelucire 50/13 solid dispersions. Int J. Advances in Pharm. Sci. 2010; 1: 60-67.Kramer, W.G. and Feldman, S. High performance liquid chromatographic assay for allopurinol and oxipurinol in human
plasma, J. Chromatogr . 1979; 162, 94-97
Reinders, M.K.; Nijdam, L.C.; VanRoon, E.N.; Movig, K.L.L.; Jansen, T.L.Th.A.; Van de Laar, M. A.F.J. and Brouwers,
J.R.B.J. A simple method for quantification of Alloprinol and oxipurinol in human serum by high performance liquid
chromatograghy with UV-detection, J. Pharm. Biomed. Anal . 2007; 45, 312-317.
Samy AM, Marzouk MA, Ammar AA, Ahmed MK . Enhancement of the dissolution profile of allopurinol by a solid dispersion
technique. Drug Discov Ther . 2010; 4(2):77-84.
7/21/2019 jurnal internasional biofarmasetika
http://slidepdf.com/reader/full/jurnal-internasional-biofarmasetika 9/9
71Amal A . Ammar.et al . / I nternational Journal of Biopharmaceutics. 2011; 2(2): 63-71.
Samy EM, Hassan MA, Tous SS and Rhodes CT. Improvement of availability of Allopurinol from pharmaceutical dosage
forms I: suppositories. Eu J Pharm. Biopharm. 2000; 49: 119-127.
Tada, H.; Fujisaki, A. and Itoh, K. Facile and rapid high performance liquid chromatography method for simultaneous
determination of allopurinol in human serum, J. Clin. Pharm. 2003; 28, 229-243.
Vippagunta SR, Maul KA, Tallavajhala S and Grant DJW. Solid-state characterization of nifedipine solid dispersions. Int J
Pharm. 2002; 236:111-123.
Zedong D, Ashish C, Harpreet S, Duk SC, Hitesh C and Navnit S. Evaluation of solid state properties of solid dispersions
prepared by hot-melt extrusion and solvent co-precipitation. Int J Pharm. 2008; 355:141-149.