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Formulation Development and Optimization of Cefuroxime Axetil tablets by

Direct Compression Method and its Stability Studies

Article  in  LATIN AMERICAN JOURNAL OF PHARMACY · March 2012

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 Latin American Journal of Pharmacy Regular Article
(formerly Acta Farmacéutica Bonaerense) Received: February 3, 2012
Revised version: March 21, 2012
Lat. Am. J. Pharm. 31 (2): 271-8 (2012) Accepted: March 22, 2011

Formulation Development and Optimization of Cefuroxime Axetil

tablets by Direct Compression Method and its Stability Studies
Iyad N. MUHAMMAD, Muhammad H. SHOAIB, Rabia I. YOUSUF,
Muhammad HANIF, Sabahat JABEEN & Tariq ALI

Department of Pharmaceutics, Faculty of Pharmacy, University of Karachi,

Karachi - Sind - 75270 - Pakistan

SUMMARY. Cefuroxime axetil (CA) immediate release (IR) tablets were developed and optimized by di-
rect compression method. Ten formulations were designed and optimized using central composite design
with two main variables, microcrystalline cellulose PH 102 and croscarmellose. Pharmaceutical evaluation
of the formulations was conducted emphasizing on dissolution profile of the drug by USP dissolution test
using apparatus II in 0.07 N HCl and in medium of pH 1.2, 4.5 and 6.8 to determine the dissolution pat-
tern of the low soluble drug. Test formulations were compared against reference brand using f2 similarity
factor. Test formulations were assayed by a validated HPLC method, with acetonitrile and 10 mM ammo-
nium acetate solution (pH = 5.2) in a ratio of 15:85 as mobile phase. Stability studies under stress were
conducted on selected formulations according to ICH guidelines. It was conclusive that stable CA formula-
tions could be developed by direct compression method.

INTRODUCTION
Cefuroxime axetil (CA) is a prodrug which is
hydrolyzed by esterases of the gut mucosa, re-
leasing the active cefuroxime base. After oral
administration, the absorption of CA is carried
out from the gastrointestinal tract 1,2. Cefuroxime
axetil has in vitro microbial activity same as the
parent cefuroxime 3-5. Cefuroxime is a poorly
water soluble drug with BCS class II characters,
low solubility but high permeability 6. Depend-
ing on the physical state of the drug powder
some also includes it in BCS class IV drug 7. It is
a well known fact that CA forms a gel like mass
which hinders the absorption of the drug in vivo
8. The bioavailability and kinetics of the drug
has been observed to vary depending on the
physical form from crystalline to amorphous,
with a better absorption of the later one 9 and
having more stability in dosage forms 10. Several
reports conforms improving the bioavailability
of the drug by using different excipients with
optimization process and improvising the per-
meability issues of the drug. The release pattern
of cefuroxime axetil has been observed to be
improved by the use of superdisintegrant and
amorphous form of CA 8,11,12.
Optimization techniques have been widely
used in pharmaceutical industries on different
pharmaceutical dosage forms for the last many
years specially using statistical design of experi-
ments 13. These includes to observe the physical
properties of tablets, like disintegration time for
a directly compressed tablets 14 or to evaluate
the release properties and bio-adhesiveness of
newly developed drug delivering formulations.
Since recent past the trend to substitute the
tablet process has overwhelmingly inclined to-
wards direct compression due to its convenience
and productivity 15, the present study was fo-
cused on developing tablet formulations contain-
ing CA by direct compression method that pre-
sents the best responses after being optimized
showing the effects of superdisintegrant and sol-
ublisers in providing appropriate release pattern
of the drug in different dissolution media.

KEY WORDS: Cefuroxime axetil, Centre composite design, Formulation development, Formulation optimiza-
tion, Similarity factor f2, Stability under stress conditions.
* Author to whom correspondence should be addressed. E-mail: harrisshoaib2000@yahoo.com

ISSN 0326-2383 271

MUHAMMAD I.N., SHOAIB M.H., YOUSUF R.I., HANIF M., JABEEN S. & ALI T.

MATERIAL AND METHODS
Design of Experiments for optimization
Formulations were developed applying a
central composite response surface method with
two independent variables, i.e the directly com-
pressible diluent binder microcrystalline cellu-
lose (Avicel PH-102®), and super disintegrant
croscarmellose (AC-Di-sol) and observing the
response variables that included tablet weight
variation, hardness, thickness, friability, disinte-
gration time, and dissolution as mentioned in
Tables 1 and 2. A total of 10 formulations, in-
cluding the centre formulation, in duplicate,
were developed and optimized according to 2nd
order center composite response surface
method.
Active and Excipients
Amorphous CA compacted powder; obtained
with gratitude from Medicaid Pharma, Karachi.
Microcrystalline cellulose (Avicel® PH 102), and
croscarmellose Sodium (Ac-Di-Sol), were of
FMC Corporation, USA, Sodium Lauryl Sulphate,
SLS and magnesium stearate were of Fisher Sci-
entific, UK.
Process of Tablet manufacturing by direct
compression method
Formulations were designed with varying
percentages of excipients keeping the API con-
stant and adding fixed quantities of SLS and
magnesium stearate summarized in Table 2. All
the ingredients were accurately weighed,
screened through 40 mesh sieve and geometri-
cally mixed in a polyethylene bag for 10 min.
Ac-Di-Sol was then added to the polyethylene
bag’s content and again mixed for the next 5
min, finally magnesium stearate was added at
this stage and the content was mixed for anoth-
er 5 min. The content was pressed in single
punch tablet machine (Korsch, Erweka, Ger-
many); at an appropriate pressure that produced
caplet shaped tablets having hardness ranging
between 6 to 10 kg.
Pharmaceutical evaluation: in vitro
comparative tests with reference product
The developed tablet formulations were
evaluated through different pharmacopeial and
non-pharmacopeial pharmaceutical tests against
Zinnat® as reference product of cefuroxime ax-
etil to evaluate the pharmaceutical quality.
Tablet Characteristics
Different tablet attributes were observed as
response variables. Weight variation is a direct
indicative to the dosage form uniformity 16, so
the tablet weight variation was carried out in 20
tablets randomLy selected from each formula-
tion and weighing it carefully on a type 1 ana-

Levels (% content)
Factors % Content per tablet
-1.414 -1 0 +1 +1.414

Cefuroxime axetil (equivalent to 250 mg)

Avicel® PH 102 (X1) 20-50 22.93 25 30 35 38
Ac-Di-Sol® (X2) 1-5 1.59 2 3 4 4.41

Table 1. A two factor central composite response surface Design of Experiments.

Coded factors Factors amount Factors amount

Formulation Amount % mg Total wt. Total wt.
Run
Code of Tab rounded up
X1 X2 X1 X2 X1 X2

1 Test 1 -1 -1 25.00 2.00 115.00 9.00 432.00 435

2 Test 2 1 -1 35.00 2.00 160.00 9.00 477.00 480
3 Test 3 -1 1 25.00 4.00 115.00 18.00 441.00 440
4 Test 4 1 1 35.00 4.00 160.00 18.00 486.00 490
5 Test 5 -1.414 0 22.93 3.00 105.68 13.50 427.18 430
6 Test 6 1.414 0 37.07 3.00 169.32 13.50 490.82 490
7 Test 7 0 -1.414 30.00 1.59 137.50 7.14 452.64 455
8 Test 8 0 1.414 30.00 4.41 137.50 19.86 465.36 465
9 Test 9 0 0 30.00 3.00 137.50 13.50 459.00 460
10 Test 10 0 0 30.00 3.00 137.50 13.50 459.00 460
Table 2. Second-order Central Composite Design: 2 Factors 10 Runs with center in duplicate.

272

lytical balance (Mettler Toledo, Germany).
Tablet friability was carried out using (H Jurgens
friabilator GmbH & Co. D-2800 Bremann, Ger-
many), after being carefully dedusted and accu-
rately weighed, and rotated at a speed of 100
rotations in 4 min followed by re-dedusting and
weighing 17. The disintegration test was ob-
served to ensure the dispersibility of the tablet
content in purified water at a temperature of 37
± 2 °C within an appropriate time interval.
Tablets were placed in each tube of the basket
rack assembly of disintegrator (Erweka disinte-
gration tester, ZT2, Heusenstamm, Germany),
and oscillated in water and the time of complete
disintegration noted.
Dissolution Release Profile Comparison
Preparation of dissolution medium
The dissolution medium pH 1.2 medium was
a 0.1 M solution of HCl, while pH 4.5 phosphate
buffer was 0.68 w/v solution of potassium dihy-
drogen phosphate monobasic hydrogen phos-
phate (KH2PO4) pH adjusted with HCl. For pH
6.8 buffer solution, a 0.2 M solution each of
potassium dihydrogen phosphate (2.74 % w/v)
and sodium hydroxide (0.8 % w/v) was mixed
with water in a ratio of 50:22:28 and pH adjust-
ed with sodium hydroxide 18.
Method
United States Pharmacopeial dissolution test
1 for cefuroxime axetil tablets with USP appara-
tus II was applied to observe the drug release in
900 mL of 0.07 N Hydrochloric acid as dissolu-
tion medium, 5 mL samples were withdrawn at
prescribed time interval of 5, 10, 15, 30, 45, 60,
90 and 120 mins. and was replaced by fresh
medium 19. Cefuroxime axetil was determined at
278 nm using double beam UV-Vis spectropho-
tometer (1800, Shimadzu, Kyoto, Japan). The
dissolution profile was also established in pH
1.2, 4.5 and 6.8 buffer solutions as dissolution
medium to observe the release of the drug in
the developed formulations.
Assay method
The test formulations were assayed and uni-
formity of dosage form units was determined by
a modified and validated high performance liq-
uid chromatographic (HPLC) method reported
by Darouiche & Hamill 20. The mobile phase
was composed of 15 % v/v acetonitrile and 85 %
v/v 10 mM ammonium acetate solution (pH =
5.2) with a flow rate of 1.0 mL/min and a detec-
tion wavelength of 254 nm and injection volume
100 µL. The liquid chromatography system con-
sisted of a pump LC- 10 ADVP, Communication
Latin American Journal of Pharmacy - 31 (2) - 2012
Bus Module CBM 102, and a UV detector SPD
10-AVP (Shimadzu Corp, Tokyo, Japan). The data
were processed using HPLC Software Class GC
10 ver. 2.0 (1993-2000), Shimadzu Corp., Kyoto,
Japan. The separation of drug was done by Su-
pelcosil® column LC-18-DB 250 x 4.6 mm, 5 µm
(Supelco, Bellefonte, PA, USA). The proposed
method was validated according to International
Conference on Harmonization guidelines for re-
coveries, accuracy and reproducibility 21.
Assay test method
Twenty tablets were accurately weighed and
crushed in porcelain mortar; powder, weighing
averagely for one tablet was taken and dis-
solved in mobile phase and diluted till 0.025 %
and filtered through 0.45µ Millipore filter. Sam-
ples of the solution were injected and the same
procedure was carried out for reference stan-
dard solution of CA. Area under the curve was
measured using standard reference peak area.
Accelerated Stability studies under stress
The best formulation observed (Test 8, Test
9 and TEST 10 ) were kept in stability chamber
NuAire, USA for accelerated stability studies ac-
cording to ICH guidelines at 40 ± 1 °C and RH
of 75 ± 1 % for 1, 3, and 6 months during which
the formulations were tested physically and
chemically for quality attributes.
RESULTS AND DISCUSSION
Design expert® software was used for the
development of immediate release tablets con-
taining CA. The levels of independent variables
are mentioned in Table 1 and the coded and ac-
tual quantities for individual ingredients in Table
2. The tablets were compressed conveniently by
direct compression using compacted drug pow-
der, directly compressible ingredients and single
punch machine. The formulations were evaluat-
ed for pharmaceutical attributes. All the formula-
tions were manufactured having thickness under
the prescribed range of ± 5 %. Variation in tablet
thickness is often governed by the flowability of
the tablet content and filling of the dye 22. Avicel
PH102 has been observed to acquire better
flowability with promising tables binding capa-
bilitites and this indicates the binding properties
of the binders 23. The hardness of the ten pre-
pared tablet formulations were found to have a
range between 6.05 and 10.34 kg.N with a mean
value 7.98 kg.N. The hardness is a direct indica-
tive of the binding charectrstics of the filler
273
MUHAMMAD I.N., SHOAIB M.H., YOUSUF R.I., HANIF M., JABEEN S. & ALI T.

binder and the compressional force with which
the tablet content has been compressed 24. The
results of the present study explains well about
the compaction tendency of Avicel® PH102 and
its role in tablet hardness and thickness as was
previously reported 25. The developed formula-
tions has shown a consistency in weight varia-
tion and the tablet weight lied under the accept-
able range. A direct relationship between the
tablets content with that of pharmaceutical at-
tributes was observed, the summary of the phar-
maceutical attributes are mentioned in Table 3.
In the present study a modified, more sim-
ple, precise and less tedious method was ap-
plied that could be used for the formulations
and biological fluids. The method was having
linearity over a range of 50 µg/mL to 0.39
µg/mL with r2 value of 0.9849 and retention
time between 4-6 min the accuracy for LLOQ
was 90 % with CV% of 1.88 % as precision. The
within day (n = 5) accuracy for the concentra-
tions was ranging from 94.35 to 98.58 with a
precision of 0.8-4.27. The between day accuracy
and precision (n = 3) for the same set of con-

Thickness Hardness Weight variation Friability

Formulations
(mm) (kg) (mg) (%)

REF coated 5.10 ± 0.06 NA 460.99 ± 0.53 NA

Test 1 4.12 ± 0.07 6.29 ± 0.17 436.80 ± 2.27 1.09
Test 2 5.19 ± 0.07 6.08 ± 0.15 482.43 ± 3.38 0.80
Test 3 4.15 ± 0.04 7.11 ± 0.15 442.95 ± 6.28 1.06
Test 4 5.25 ± 0.07 6.73 ± 0.33 489.86 ± 4.53 1.80
Test 5 4.04 ± 0.07 6.05 ± 0.21 433.02 ± 2.50 1.03
Test 6 5.23 ± 0.10 6.99 ± 0.23 489.68 ± 5.19 1.00
Test 7 4.32 ± 0.11 9.88 ± 0.41 455.01 ± 4.10 1.27
Test 8 4.76 ± 0.14 10.22 ± 0.06 465.68 ± 4.80 0.65
Test 9 4.77 ± 0.06 10.34 ± 0.09 462.89 ± 4.23 0.91
Test 10 4.74 ± 0.06 10.10 ± 0.13 462.67 ± 2.07 0.65
Table 3. Relationship between tablets content and pharmaceutical attributes.

Conc. range for Linearity µg/mL 50 - 0.2604

Coefficient r2 0.9849
LLOQ/Sensitivity 0.39
LLOD 0.2604

Conc. µg/mL After 4 h After 7 h After 9 h

25 98.46 97.64 96.48

Within -Day Accuracy
6.25 98.58 97.24 95.74
3.125 98.04 94.72 95.62
0.781 96.78 97.85 94.35

25 4.27 0.23 0.64

6.25 0.80 2.79 3.76
Within - Day Precision
3.125 0.83 1.25 2.73
0.781 1.67 2.72 2.34
Day 1 Day 2 Day 3

25 97.43 97.47 97.83

Between - Day Accuracy
6.25 101.25 97.82 96.82
3.125 97.88 97.74 96.35
0.781 97.24 93.83 96.36

25 2.07 2.14 3.12

6.25 2.55 2.75 1.47
Between - Day Precision
3.125 2.47 3.82 4.84
0.781 2.82 2.78 2.18
Table 4. Validation parameters.

274
 Latin American Journal of Pharmacy - 31 (2) - 2012

centrations within three days were ranging from
93.83 to 101.25 and 1.47-4.84. The validation
summary is mentioned in Table 4. The assay re-
sult showed the pharmacopeial requirement for
the developed formulations i.e. 90-110 %. There
are some other works that has proposed some
modified methods for the determination of CA
by other techniques 26-29, an assay method in
plasma was developed by Szlagowska et al. 30,
in which a modified and validated method was
presented for the determination of CA in plas-
ma.
The conventional release oral solid dosge
form needs to be disintegrated from its intact
form, and get dissolved to show its release pat-
tern. In any such case where the disintegration
is retarding or is slow, the dissolution is affected
drastically by the disintegration, hence it be-
comes the rate limiting step in release pattern.
The formulation composition of the immedite
release dosage form hence should be fabricated
such that it assures the disintegration and simul-
taneous dissolution in the upper gastrointestinal
tract 31. According to the Food and Drug Admin-

Figure 1. Release pattern of developed formulations in different dissolution media.

Formulations 0.07 N HCl pH 1.2 pH 4.5 pH 6.8

TEST 1 38.23 31.33 30.47 41.27

TEST 2 43.30 42.20 41.41 41.81
TEST 3 46.12 36.14 38.77 48.80
TEST 4 43.37 46.02 45.64 40.33
TEST 5 29.58 29.87 30.11 34.41
TEST 6 48.71 47.40 46.06 48.25
TEST 7 46.83 34.22 37.94 41.07
TEST 8 49.36 49.66 49.12 48.27
TEST 9 49.77 46.67 41.50 49.97
TEST 10 49.70 46.61 40.74 46.31
Table 5. Drug Release at different dissolution medium f 2 Similarity.

275
MUHAMMAD I.N., SHOAIB M.H., YOUSUF R.I., HANIF M., JABEEN S. & ALI T.

Formulation
Study Period Tests
T8 T9 T 10

Physical Hardness Kg.N 10.22 10.34 10.10

Friability % 00.65 00.91 00.65
0 month Pharmaceutical Two point Dissolution at 15 min 75.12 75.89 75.12
0.07 N HCl % Drug Release 45 min 86.64 86.95 87.41

Assay % 94.12 90.46 93.27

Physical Hardness Kg.N 10.17 09.97 09.76

Friability % 00.72 00.98 00.77

1 month Pharmaceutical Two point Dissolution 15 min 68.23 69.34 73.54

at 0.07 N HCl 45 min 82.65 82.43 85.98

Assay % 89.12 89.83 89.78

Physical Hardness Kg.N 09.65 09.72 08.54

Friability % 00.71 01.01 00.98
3 month Pharmaceutical Two point Dissolution at 0.07 N HCl 15 min 67.45 67.24 72.54
45 min 80.13 78.378 84.23

Assay % 86.33 88.76 88.43

Physical Hardness Kg.N 09.64 08.76 08.52

Friability % 00.85 01.12 01.08
6 month Pharmaceutical Two point Dissolution at 0.07 N HCl 15 min 68.34 62.77 67.43
45 min 79.34 77.33 77.43

Assay % 87.43 87.35 86.32

Table 6. Stability studies of selected cefuroxime axetil 250 mg formulations.

istration, US, the dissolution profiles of a tablet
formulation should be obtained in at least three
dissolution media having pH values i.e 1.2, 4.5,
and 6.8. In the present study, the in vitro release
pattern of the drug was observed in pharma-
copeial dissolution medium and was compared
using f 2 similarity factor with the reference drug
formulation. The drug release in the present
study was observed in pH 1.2 dissolution medi-
um, and pH 4.5 and 6.8 phosphate buffer solu-
tions. As amorphous form of CA was reportedly
having better solubility and permeability than
the crystalline form, the same was established in
the current study. It is reported in the literature
that the dissolution and pH-solubility data of
both prodrugs and drugs could be relevant 32,33
and the FDA and ICH recommends f 2 similarity
factor to be adopted for comparing the dissolu-
tion data profile 34. The comparison of the de-
veloped formulations based on f 2 similarity fac-
tor showed formulation TEST 8, TEST 9 and
TEST 10 among all the developed formulations
that had good similarity in vitro in pharma-
copeial dissolution medium. As the drug is a
weak alkaline in nature the dissolution at pH
6.8 showed a little hindered release, but has
demonstrated similarity in release with an f 2 val-
ue of 49.9 as compared to reference formula-
tion. The summary of the release pattern is
mentioned in Table 5, while Figure 1 represents
the release pattern graphically.
As for the optimization, the response surface
method graph (Fig. 2) represents the best possi-
ble combination of avicel and crosscarmellose
that would show the desired similarity factor.
The possible test designs that were predic-
tive to be optimized are mentioned in Figure 3.
Formulation TEST 8 was the closest formulation
and declared as the optimized and stable formu-
lation of CA with sufficient dissolution pattern.
The stability studies on the test formulations
(Table 6) has shown TEST-8 and center point
formulations TEST 9 and TEST-10 to be the sta-
ble ones of which TEST 8 has shown a stability
till six months of storage.
Although the stability of the formulations
were observed for the uncoated tablets, under
stressed conditions, amorphous form of CA has

276

Figure 2. RSM optimization graphical representation
based on f 2 similarity for the developed formulations.
been reported to obey the first order reversible
degradation reaction 35 which was rapid in pres-
ence of high humidity and temperatures 36 and
similar results were also observed in tablet
dosage form 37. The use of uncoated tablet in
the present study was to observe the stability of
unprotected directly compressed tablets which
was suggestive that the stability could be im-
proved by the addition of stabilizers and coat-
ing.
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