Pasqualoto K. F. M., Teófilo R. F., Guterres M., Pereira F. S., Ferreira M. M. C., "A study of physicochemical and biopharmaceutical properties of Amoxicillin formulations developed by direct compression using full factorial design with multiple responses". Águas de Lindóia, SP, Brazil, 10-15/09/2006: 10th International Conference on Chemometrics in Analytical Chemistry (CAC-2006, CAC-X), Book of Abstracts (2006) P074. Poster 074.
10th International Conference on Chemometrics in Analytical Chemistry P074
A study of physicochemical
and biopharmaceutical properties
of Amoxicillin formulations
developed by direct compression
using full factorial
design with multiple responses
Kerly F. M. Pasqualoto*,
Reinaldo F. Teófilo, Marco Guterres, Flávia S. Pereira, Márcia
M. C. Ferreira
kerlyfmp@iqm.unicamp.br
Theoretical and Applied Chemometrics
Laboratory, Department of Physical Chemistry, Institute of
Chemistry, The State University
of Campinas, Campinas, SP, Brazil
Keywords: factorial design,
direct compression, physicochemical properties
_____________________________________________________________________________________
Direct
compression technique presents an economic
advantage in time, costs and
energy, when
compared to the
traditional granulation methods.1
The variables that influence the tablets obtained
by
direct compression
method deserve to be studied to
minimize formulation costs and to improve
the
physicochemical
and biopharmaceutical properties
of the resulting compacts.
Amoxicillin 500 mg
formulations were
previously developed by direct compression,2
and the adjuvants investigated were
microcrystalline cellulose,
spray-dried lactose, and croscarmellose sodium,
which is a superdisintegrant
agent. In this
study, the purpose was to explore the
adjuvants (independent variables) effects on
the
resulting
amoxicillin tablet formulations
considering multiple responses
(physicochemical and
biopharmaceutical properties
- dependent variables), as well as to indicate
the most suitable formulation
composition.
A full
23 factorial design3
was built to eight different amoxicillin formulations,
each one containing three
replicate batches, and eight
responses were obtained. Each independent variable
was investigated at two
levels: the
microcrystalline cellulose (MCC) type Avicel®
PH-102 (low) or PH-200 (high), the absence
(low) or presence
(high) of spray-dried lactocese (LAC), and
the absence (low) or presence (high) of
properties as
average weight, thickness and diameter,
hardness, friability, amoxicillin concentration
(iodometric assay),
disintegration time, and dissolution profile.2
The responses more relevant to the
distinct formulations
for the experimental design were hardness,
friability, and the amount of amoxicillin
dissolved during
the first hour. Three models
were built for each response,
using multiple linear
regression (MLR).
The coefficients were considered as independent variables, and the responses
obtained
to this new set was
the optimum response for each original variable. A
new model was constructed, and
its respective coefficients
indicate that the level of each variable should be fixed to
obtain better responses.
A criterious
statistical evaluation considering each
response individually, was also performed.
The
comparison between
the best levels from simultaneous and
individual response evaluation was carried
out.
Regarding
each response individually, the MCC
and DIS levels were significant and
negative for
hardness (see
the side table). The variables LAC
and DIS presented an interaction for
the friability
response. The presence
of LAC and the absence of DIS increased the
friability. The MCC type Avicel®
PH-200 also contributed
to increase of that physicochemical property. Tablet
formulations presenting high
_____________________________________________________________
friability values are
not
recommended. The amount of
Hardness
Friability Amount Amox. Dissolv.
Multiple Response drug disolved presented
two
________________________________________________
interactions, one between the
Coeff. p
Coeff. p
Coeff. p
Variables Levels
MCC and DIS levels, and
________________________________________________
another between the LAC and
Mean
107.13 0.000
0.20 0.000
3.62 0.000
MCC
0 DIS
levels. The combination
MCC
-6.46 0.021
0.03 0.004
-0.20 0.032
LAC -1.33
of MCC low level (Avicel®
PH-
LAC
-2.92 0.263
0.05 0.000
-0.31 0.002
DIS 6.03
102), LAC low level (absence),
DIS
-6.13 0.027
0.00 0.895
0.07 0.394
and DIS high level (presence)
MCCxLAC
0.00 1.000
0.20 0.058
0.00 0.973
simultaneously increases the
MCCxDIS
-1.63 0.527
0.02 0.081
-0.22 0.020
amount of drug
dissolved,
LACxDIS
-3.92 0.139
0.03 0.006
-0.23 0.014
considering the plot of marginal
_____________________________________________________________
means analysis. The individual
response evaluation
indicated that the most suitable
amoxicillin table formulation should present
the
microcrystalline cellulose
Avicel® PH-102 and
the superdisintegrant agent, croscarmellose sodium,
in its
composition.
The simultaenous and individual response
analysis generated similar results (table above),
except to the MCC
level. The multiple response analysis did not allow taking
any information related to the
type of MCC (level
0) in the most suitable amoxicillin table formulation.
Acknowledgment. CNPq
and FAPESP for financial support.
_____________________________________________________________________________________
References
1 Shangraw, R.F.
(1989) Pharmaceutical Dosage Forms: Tablets, v. 1, New York: Marcel
Dekker Inc.
2 Pasqualoto,
K.F.M., Funck, J.A.B., da Silva, F.E.B., Kratz, C.P. Acta Pharm. Bonaerense
2005,
24,
39-47.
3 Teófilo,
R.F., Ferreira, M.M.C. Quim. Nova 2006, 29, 338-350.