INTRODUCTION:
The goal of any drug delivery system is to
provide a therapeutic amount of drug to
proper site in the body to achieve promptly and then to maintain the
desired drug concentration. That is, the drug delivery system should deliver
drug at a rate dedicated by the
needs of the body over a specified period of treatment. Immediate-Release
[IR] Preparations are primarily intended to achieve faster onset of action for
drugs such as analgesics, antipyretics, and coronary vasodilators. Other
advantages include enhanced oral bioavailability through transmucosal
delivery and pregastric absorption, convenience in
drug administration to dysphasic patients, especially the elderly and
bedridden, and new business opportunities.
Capecitabine is orally administred
chemotherapeutic agent used in the treatment of metastatic breast cancer and metastatic
colorectal cancer. It is an oral systemic prodrug that is enzymatically
converted to 5-fluorouracil (5-FU). Healthy and tumor cells metabolize 5-FU to
5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate
(FUTP). These metabolites cause cell injury by two different mechanisms. First,
they inhibit the formation of thymidine triphosphate, which is essential for the synthesis of DNA.
Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP during
the synthesis of RNA.
This metabolic error can
interfere with RNA processing and protein synthesis. Presently, CPC is marketed as immediate
release (IR) tablets (150, 500mg) which are at high cost. The present study is
to formulate cost efficient product which is bioequivalent to innovator
product.
MATERIALS AND METHODS:
Capecitabine (Natco Pharma
Ltd, Hyderabad), Micro crystalline cellulose (FMC Bio polymers, New York), HPMC
E5 (DMV Fonterra excipients, Ireland), Croscarmellouse sodium (Ferro corporation, Ireland),
Lactose anhydrous (Rich Pharma
Chem, Mumbai), Purified water (Natco Pharma Ltd, Hyderabad). All other solvents and chemicals were of
analytical-reagent grade.
Pre Formulation studies:
The physical
properties such as organoleptic properties,
solubility, melting point, water content (Karl fisher method) and flow properties such as angle of repose, bulk density,
tapped density, Compressibility Index (Carr’s Consolidation Index) and Hausner’s Ratio were been evaluated1 - 6.
Drug – Excipient Compatibility Studies:
API and excipients are taken in different
ratios and mixed together in a polybag for 5 min as
shown in table no- 1. Each mixture is allotted sample code for identification.
4 sets of samples were allocated where each sample mixture is divided in to 1gm
in to its corresponding glass vial (USP Type I) at different conditions. All
vials are properly sealed and loaded at respective conditions. The samples are
to be checked for its description, related substance and water content by KF.
The prepared drug
and excipient mixtures were evaluated at various
intervals for related substances by HPLC as per the following conditions and
time intervals: initial, 14 days (550C ± 20C), 14 days
(40 ± 20C and 75 ± 5% RH) and 28 days (40 ± 20C and 75 ± 5%
RH)7.
Formulation of Capecitabine
(IR) tablets:
Capecitabine, avicel PH 101, croscarmellose
sodium are weighed passed through 40 # mesh mixed for 5 min. HPMC E5 are
weighed added to the required quantity
of water stir for 10 min by using mechanical stirrer to get a clear solution .The solution are
added to the drug mix to get a wet mass
. The wet mass was passed through 12 # mesh kept in tray dried at 55°C.
The
dried granules are passed through 18 # mesh. Croscarmellose sodium, lactose anhydrous are
weighed, passed through 40 # mesh added to the above dried granules and mixed for 3 minutes. Magnesium stearate are weighed passed through 40 # mesh added to the
above blend lubricated for 2 minutes the lubricated granules are compressed
with the 16
×8.5 mm
oval shaped punches8 - 10. The composition of each
formulation is given in table 1.
Evaluation of Capecitabine
(IR) tablets:
Tablets were
evaluated for hardness, weight variation, thickness, friability, drug content
and disintegrating time,. The Pfizer hardness tester (serve well instruments and equipments
pvt.ltd, Bangalore) and Roche friabilator (Campbell, Mumbai) were used to test hardness and friability loss respectively. In weight
variation test, ten tablets were selected at random and average weight was
determined using electronic balance (Oreintal,Switzerland). Thickness of tablets is determined by
using Verniear calliperus (Mitutoyo, Japan).
To determine drug content of tablets, twenty tablets were weighed and
powdered, an amount equivalent to 60mg of Capecitabine
tablet powder was taken in 100 ml volumetric flask containing 60 ml medium, sonicate for 30 minutes with occasional stirring and keep on orbitary
shaker for 15 minutes, cool to room temperature and diluted to volume with
diluents and mixed well, filter the solution through 0.45µl membrane and
transfer 3ml of filtrate into 25 ml volumetric flask and make up to the
volume with diluents and inject 10µl of
the standard preparation (60mg/100ml) and sample preparation into the
chromatographic system and record the chromatogram. Disintegrating time was determined using USP tablet disintegrating test
apparatus (Electrolab, Japan) using 900 ml of medium at 37oc (11
-17).
Dissolution
studies:
In- vitro drug release studies of all the
formulations were carried out using tablet dissolution test apparatus (Electrolab TDT8 dissolution tester USP) at 50rpm. Water (deareated) was used as the dissolution media with
temperature maintained at 37±0.5ºC. Samples were withdrawn at different time
intervals and analyzed at 426nm for percentage drug release using UV-Visible
spectrophotometer (Schimadzu, Japan). The sample
after each withdrawal was replaced with same volume of fresh media (18,
19).
Data analysis:
To analyze the
mechanism of release and release rate kinetics of the dosage form, the data
obtained were fitted into Zero order, First order, Higuchi matrix, and Peppas. Based on the R-value, the best-fit model was
selected.
Similarity and dissimilarity
factor
The similarity factor (f2) was defined by
CDER, FDA, and EMEA as the “logarithmic reciprocal square root transformation
of one plus the mean squared difference in percent dissolved between the test
and reference release profiles”.
Dissimilarity or difference factor (f1)
describes the relative error between two dissolution profiles. It approximates
the percent error between the curves. The percent error is zero when the test
and reference release profiles are identical and increases proportionally with
the dissimilarity between the two profiles.
There are several methods for dissolution
profile comparison. f2 is the simplest among those methods. Moore and Flanner
proposed a model independent mathematical approach to compare the dissolution
profile using two factors f1 and f2.
f1 = { [ å t=1 n½Rt – Tt
½ ] / [ å t=1 n Rt
] } . 100
f2 = 50. log { [1 + (
1/n) å t=1 n (Rt - Tt
) 2 ] –0.5 . 100}
Where 'Rt'
and ‘Tt' are the cumulative percentage
dissolved at each of the selected n time point of the reference and test
product respectively.
The factor f1 is proportional to the
average difference between the two profiles, where as factor f2 is inversely
proportional to the averaged squared difference between the two profiles, with
emphasis on the larger difference among all the time points. The similarity
factor f2 and its significance are shown as:
Similarity factor
(f2) Significance
<50 Test and reference profiles are dissimilar
50 -100 Test
and reference profiles are similar
100 Test
and reference profiles are identical
>100 The
equation yields a negative value
Stability Studies:
Stability
studies were carried out at 40oC ± 2oC / 75% RH ± 5% RH
for a period of 3 months. The tablets were stored in High density Polyethylene
(HDPE) containers and evaluated at 30 days interval and evaluated for change in
in-vitro drug release pattern, physical appearance and drug content.
RESULTS AND DISCUSSION:
The physical
characteristics of drug are as follows: Appearance looks like white to
yellowish powder with characteristic odour,
practically insoluble in cold water, slightly soluble in ethanol and soluble in
PEG 400, water content is 0.04% and melting point is 110- 120oc. The angle of repose was found to be in the range of 25.590
to 38.630, which indicates good - passable flow. Bulk density and
tapped density varied from 0.382 gm/cc to 0.447 gm/cc and 0.535 gm/cc to 0.568
gm/cc respectively. The percentage compressibility is within the range of
20.89% to 26.62% and the Hausner’s ratio is within the range of 1.24 to 1.35,
which indicates flow of powder is passable - poor in flow. The drug- excipient compatibility studies concluded that there was no
characteristic change in the colour of the mixture
and no additional degradation was observed and they are stable and compatible
with the active ingredient but impurity specifications reveled that an increase
in impurities (Impurity A: 4-(2-(N-methyl carbonyl)-4-pyrydyloxy) aniline,
Impurity B: 1, 3-Bis (4-chloro-3-di floro phenyl) phenyl urea, Impurity C: 4(4-
((((2-chloro-3-tri floro methyl) phenyl) amino)
carbonyl) amino)-phenyl)-N-methyl-2-pyridine carboxamide
tosylate) at the initial stage is found in Povidone and Cross Povidone, so
these are incompatible with active ingredient . The average hardness of all the
batches is in the range of 7.3 to 8.4Kg/cm2 and possesses sufficient
hardness. As the % weight variation was within the limits of ± 5% USP in range
from 650 to 658 mg. The thickness for all formulations is within the limits.
The % friability is in the range of 0.79 % to 0.95 %, which was found to be in
limit. The drug content is in the range of 98.1 to 100.3 %. The disintegrating
time is in the range of 10.40 to 14.30 min. The results were shown in the table
2.
Tablets of all formulations achieved 100%
drug release with in 60 min and met the requirements of in vitro dissolution expect F1. But the
rate of release of drug is equal in formulation F4 comparable to innovator, the
results can be seen in table 3 and figures 1, 2 and 3. Data analysis for
optimized (F4) formulation was performed and found that it follows zero order
release as shown in table 4 and figures
4, 5, 6 and 7. The similarity factor f2 for F4 formulation and innovator was
91.59, which indicate both the profiles are similar; the results are shown in
table 5. The stability studies for F4 formulation had shown no
magnificent change in the evaluation parameters for 3 months at 30 day interval
(40oC ± 2oC / 75% RH ± 5% RH). The results of stability
studies were shown in table 6.
Figure:1.Dissolution profile for innovator, F1, F2, F3, F4
formulations
Figure: 2.Dissolution profile for innovator, F5, F6, F7
formulations
Figure: 3.
Dissolution profile for innovator, F4 formulations
Figure: 4. Zero
order for F4 formulation
Figure: 5. First
order for F4 formulation
Figure: 6. Higuchi
for F4 formulation
Figure: 7. Peppas for F4 formulation
CONCLUSION:
The
present study was carried out to develop IR tablets of Capecitabine
by wet granulation technique using HPMC E5 as binding agent. The formulation F4
containing HPMC E5 (20mg) as binder and Avicel PH 101
(97.5mg) as filler showed good flow
properties, mechanical properties and good initial burst release of drug (26.5%) and maintained integrity of the
tablet and standard the release of drug over a period of 60min (100.8%). Drug
release kinetics of the optimized formulation F4 followed zero order kinetics.
The Significant factor for innovator and F4 formulation was 91.59. From present
study it was concluded that formulation F4 is Bioequivalent with innovator
product.
REFERENCES
1.
Howard C. Ansel`s Introduction to
Pharmaceutical dosage forms 4th edition. 87-91.
2.
Herbert A. Liberman, Leon Lachman, Joseph L. Kanic. The
Theory and Practice of Industrial Pharmacy. 3rd Edition. 171-191
3. Application to Preformulation Studies AAPS'TharmSciTech,
Vol. 10, No. 2, DOI: 10.1208/s 12249-009-9248-8.
4. Indian Pharmacopeia-2007; Vol-1;
142-162: 135-137: 477-480: 574-575.
5.
United States
pharmacopoeia. 2002; 2045.
6.
United States
pharmacopoeia. 2002; 2082-2083.
7. Indian Pharmacopeia.2007; vol-1;
107: 112
8. M.E. Aulton.
Pharmaceutics: The science of dosage form design. 2nd Edition.
133-136: 156-165.
9. Nansri Saha Ghosh
et.al. (2011) Formulation of immediate release dosage form of Ranitidine
HCl tablets using HPMC and starch acetate film former
Journal of Chemical and Pharmaceutical
Research 147-157.
10. Prakash K et.al (2005) Formulation
development and dissolution enhancement of metronidazole,
Asian Journal of Biomedical and Pharm. Sciences, vol-1 no.2.
11.
R. Natarajan, Rohit Vaishnani and NN. Rajendran. Formulation and Evaluation of Immediate Release
Tablets of Paroxetine HCl
Using Different Superdisintegrants. Int. Journal of
Pharmaceutical Research. Sep 2011; 1095.
12.
Jigar A patel, Jitendra S. Patel,
Arjun Sony, Hemangi J
Patel. Formulation and Evaluation of Immediate Release Tablets of Azithromycin Using Superdisintegrants. American journal of pharmtech
research. 2011; 1(4): 211-218.
13. Indian Pharmacopeia. 2007;
vol-1; 182-186.
14. Herbert A. Liberman,
Leon lachman, Joseph L.Kanic.
The Theory and Practice of Industrial Pharmacy. 3rd Edition.
296-297.
15.
Erande Ritesh, T. Regupati, Shaikhsurfraj.
Formulation and evaluation of Fast Dissolution Tablet Loperamide
HCl. Indo American Journal of Pharmaceutical
Research. 2011; 1(1): 84-91.
16. United States Pharmacopoeia.2002; 2010-2013:
2082-2083: 2159-2161.
17. Alfred Martin. Physical
Pharmacy: Oral Dosage Forms. 6th Edition.300:318.
18. FDA guidance on “Dissolution Testing of Immediate Release
Solid Oral Dosage Forms”. (www.fda.gov.com).
19.
Mohico, L., Dumant., 1997. Probability of passing
dissolution acceptance criteria for an immediate release tablet, Int J Pharm.,97:119-13.
