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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

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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.




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




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




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.




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




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




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.

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