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Polymer International 45 (1998) 211�6
Polysiloxanes as Matrix Materials for
Slow Release of 2-Pyridine Aldoxime
Chloride
Dinesh C. Gupta,* Gajjala Sumana & Seema Agarwal
Defence Research and Development Establishment, Gwalior-474002, India
(Received 23 April 1997 ; revised version received 2 July 1997 ; accepted 26 July 1997)
Abstract : The efficacy of polysiloxanes and copolysiloxanes as matrix materials
for the slow release of 2-pyridine aldoxime chloride (2-PAM-Cl) was investigated
by in vitro studies using both slabs and microcapsules. The release rate of
2-PAM-Cl was determined in pH 7�phosphate bu?er at 37. Transport
parameters such as the Fickian coefficient, di?usion coefficient, and the polymer�
2-PAM-Cl interaction parameter were calculated. The order of release and the
time taken for 80% release were also calculated. ( 1998 SCI.
Polym. Int. 45, 211�6 (1998)
Key words : polysiloxanes ; copolysiloxanes ; in vitro release ; 2-pyridine aldoxime
chloride ; transport parameters ; order of release
block the receptors on the receiving side of cholinergic
synapses. When the atropine is bound to receptors no
signal is given, unlike the situation with acetylcholine.
The e?ects of atropine are restricted to certain parts of
the cholinergic system. It is inactive with respect to
striped (voluntary) muscles and cannot for this reason
relieve cramps and paralysis of the skeletal musculature.
PAM-Cl acts as an enzyme reactivator, which restores
the inhibited enzyme to its normal functions. Further, it
reacts directly with a nerve agent and subsequently
degrades into non-poisonous products. 2-PAM-Cl has
been reported to be excreted rapidly from the body and
has a short biological half life.3 As a result, 2-PAM-Cl
has to be administered repeatedly to counteract nerveagent intoxication. Alternatively, instead of taking
PAM-Cl in multiple doses, a slow release formulation of
this antidote can be substituted. Siloxane polymers are
known to be biocompatible and physiologically inert.
They are already in use as matrix materials for controlled or sustained release of a variety of drugs.4h9
Therefore, the present studies were carried out on the
release rate of PAM-Cl using siloxane polymers as
matrix materials.
INTRODUCTION
The cholinergic system is the primary target of intoxication by organophosphorous compounds (nerve
agents). Nerve agents inhibit acetylcholine esterase at
vital cholinergic, muscarinic and nicotinic sites, thereby
causing toxic symptoms. Nerve agents (Soman, Sarin,
Tubun, etc.) inhaled as vapours or aerosols rapidly
enter the systematic circulation, resulting in nervous
system breakdown e.g. conjunctival congestion, nasal
discharge, respiratory problems, sweating, hypertension,
paralysis, coma.1 Toxic symptom appear after 5 s to
5 min of inhalation. The toxic e?ects of speci衏
organophosphorus compounds vary according to the
route of absorption, distribution and the rate of reaction with choline esterase and the stability of the
product. In all cases, treatment involves prevention of
further exposure, blockage of the e?ect of excess acetylcholine and maintenance of adequate respiration. Atropine sulphate with 2-PAM-Cl is the standard treatment
for organophosphorus poisoning.2 Atropine is able to
* To whom all correspondence should be addressed.
211
( 1998 SCI. Polymer International 0959�03/98/$17.50
Printed in Great Britain
212
D. C. Gupta, G. Sumana, S. Agarwal
EXPERIMENTAL
Drug incorporation in the polymer matrix
Chemicals
required
for
the
present
study
(dimethyldichlorosilane, vinylmethyldichlorosilane and
diethyldichlorosilane, tetraethoxysilane and dibutyltin
dilaurate) were procured from M/S Fluka, Switzerland,
and were used as received. PAM-Cl was synthesized as
per a reported procedure.10
2-PAM-Cl was incorporated into each polysiloxane
matrix by the bulk method,12 i.e. addition of PAM-Cl
before addition of curing agents. 20% of PAM-Cl was
blended with each of the polysiloxanes and mixed thoroughly. The mixture was cured at room temperature in
the presence of 2% TES ] DBTL catalyst mixture.
Synthesis of polysiloxanes
PAM -Cl incorporation by microencapsulation 13
Linear polysiloxane diols were prepared by controlled
hydrolysis of dialkyldichlorosilanes, or mixtures of
dichlorosilanes, using a saturated solution of sodium
chloride in water in 1 : 2 ratio (v/v) at 0� over a
period of 2 h. The reaction mixture was kept at room
temperature for about 13� h, extracted with ether and
dried over anhydrous sodium sulphate. Polysiloxanes,
i.e. polydimethylsiloxane (PDMS), polymethylvinylsiloxane (PMVS), poly(dimethyl-methyl vinyl)siloxane
(P(DM-MV)S),
poly(methyl
vinyl-diethyl)siloxane
(P(MV-DE)S and poly(dimethyl diethyl)siloxane
(P(DM-DE)S) were synthesised for the present study.
These polysiloxanes were characterised by viscosity and
infrared spectroscopy. The intrinsic viscosity of the
polysiloxanes was determined in toluene at 30 ^ 1
using an Ubbelohde viscometer. IR spectra were recorded in the range 400�00 cm~1 using a Perkin-Elmer
infrared spectrometer.
Microcapsules of PAM-Cl in a polysiloxane matrix
were also prepared in the present study. An aqueous
solution of PAM-Cl (30%) was added to the solution of
polydimethyl siloxane having [g] \ 0� in ether in the
presence of Tween-20 (polyoxyethylene 20 sorbiton
monolaurate) emulsi衑r at a stirring speed of
4000 rev min~1. Gelatin was used as stabilizer. Ether
was removed under reduced pressure and hard capsule
walls were formed. Microcapsules produced in this
manner were isolated by centrifuging the emulsion and
were dried in air at room temperature. The size of the
microcapsules was studied by SEM and found to be
20 km.
Curing of polysiloxanes 11
A mixture of tetraethoxysilane (TES) and dibutyltin
dilaurate (DBTL) in a ratio of 3 : 1 was prepared by
weighing and mixing these chemicals thoroughly. 10 g of
un衛led polysiloxane was weighed out and 2� catalyst mixture (TES ] DBTL) was added.
The curing environment was room air over a 20� h
period. The polysiloxanes were converted to crosslinked
and infusible membranes.
Hydrolytic degradation
Crosslinked polysiloxanes were subjected to hydrolytic
degradation under physiological conditions. Rectangular slabs of polydialkyl siloxanes of suitable dimensions
(20 ] 20 ] 0�mm3) and weighing about 0�5 g
were cut by a sharp knife from the cured polysiloxane
strips and placed in 250 ml of 0� (w/v) saline which is
equivalent to the NaCl concentration in the body 製id.
Polydialkyl siloxane strips were also immersed in
250 ml of pH 7�phosphate bu?er at 37 under
unstirred conditions. The uptake of saline and phosphate bu?er at 37 were measured at di?erent time
intervals over a period of 4 weeks.
In-vitro drug (PAM -Cl ) release
For the study of in vitro drug release12h14 under physiological conditions the drug-loaded polysiloxane system
was placed in 250 ml of pH 7�phosphate bu?er at
37 under unstirred conditions. The release of the drug
in the medium was determined by taking out an aliquot
(0�ml) at suitable time intervals and measuring its
absorbance at j
(336 nm) after suitable dilution in
max
0�N NaOH, using a Shimadzu UV spectrometer.
RESULTS AND DISCUSSION
The polysiloxanes synthesized and their intrinsic viscosities in toluene at 30 are given in Table 1. Polydimethylsiloxanes of di?erent intrinsic viscosities
[g] \ 0�4 dl/g~1 were also prepared by change in
equilibration time after hydrolysis of dichlorosilanes.
The polysiloxanes were characterized by IR spectrophotometry. The IR spectra show a strong peak at
1060�00 cm~1 due to SiwOwSi bonds, indicating
the formation of siloxane polymers. No peak was
observed at 666 cm~1, con衦ming the absence of SiwCl
bonds in these polymers. Thus we have assumed that all
the dichlorosilane was hydrolysed during the process
and converted to SiwOH and 衝ally SiwOwSl bonds.
Peaks at 1240�60 cm~1 and at 1410 cm~1 may be
due to SiwC bonds.15
POLYMER INTERNATIONAL VOL. 45, NO. 2, 1998
Slow release of 2-pyridine aldoxime chloride by polysiloxanes
213
TABLE 1. Polysiloxanes synthesized for the present study
Polymer
Composition
Equilibrium time (h)
蚷� (dl g�
PDMS
PDMS
PDMS
PVMS
P(DM-MV)S
P(DM-MV)S
P(DM-DE)S
P(MV-DE)S
?
?
?
?
75 : 25
25 : 75
75 : 25
75 : 25
25
19
13
25
25
25
25
25
0�
0�
0�0�
0�
0�
0�
0�
These IR observations led us to the conclusion that
siloxane polymers were formed by hydrolysis of
dichlorodiorganosilanes.
Effect of saline and pH 7 �phosphate buffer
The polyorganosiloxanes synthesized were immersed in
0� (w/v) saline for about 4 weeks at room temperature (37). No change in weight was observed,
indicating that the siloxane polymers do not react with
saline and do not degrade in this medium. Similarly,
there was no change in weight of polysiloxane strips
immersed in phosphate bu?er at pH 7�and 37. The
UV spectra of polysiloxanes in phosphate bu?er before
and after immersion were recorded. There was no
change in UV spectra indicating that these samples
were physiologically inert. Polysiloxane slabs also
retained their shape and physical integrity after immersion in saline and phosphate bu?er.
In vitro PAM -Cl release
The in vitro release pattern of a drug from a polymer
matrix gives an indication of its ability to function as a
sustained and controlled release delivery system and its
knowledge is a prerequisite for studying its in vivo performance. Hence the release of PAM-Cl, an antidote for
organophosphorous poisoning, was investigated using
polysiloxanes as matrix material.
Release of PAM-Cl from a polydimethylsiloxane
matrix was measured in pH 7�phosphate bu?er at
37 (Table 2). It was observed that polydimethylsiloxane of [g] \ 0� dl g~1, did not release PAM-Cl,
whereas PDMS of [g] \ 0� dl g~1 released PAM-Cl
very quickly (95% release in 1 h). Assuming that there
was a similar level of crosslinks in the systems, release of
PAM-Cl from a PDMS matrix is viscosity dependent ;
hence we selected an intermediate viscosity of
[g] \ 0� dl g~1. Keeping this parameter constant,
other polysiloxane matrices of similar viscosities were
examined for PAM-Cl release. Release of PAM-Cl at
di?erent time intervals using various polysiloxane
matrices are given in Table 3. The amounts of PAM-Cl
released versus time were plotted for di?erent polyPOLYMER INTERNATIONAL VOL. 45, NO. 2, 1998
siloxane matrices in Figs 1 and 2). Release of PAM-Cl
was very high in the 衦st hour ([35%) indicating an
outpouring in all polysiloxane萈AM-Cl systems. It was
slightly lower in the case of P(DM-MV)S (27%). The
outpouring observed in these systems may be due to a
storage e?ect (delay between sample preparation and
the release measurement) as reported in the literature.16
Release of PAM-Cl decreases with increase of time. The
time taken for 80% release of PAM-Cl from the various
polysiloxane matrices is given in Table 4. Polydimethylsiloxane releases 80% of the drug in 14 h, whereas the
other polysiloxane matrices release 80% PAM-Cl in 5�
10 h. After 80% release of PAM-Cl, release of the drug
becomes extremely slow and cannot be followed. Total
drug release was over in approximately 30� h. There
was no erosion of the matrix during the release rate
measurement in pH 7�phosphate bu?er at 37. It
retained its shape and physical integrity for more than 4
weeks. Thus it appears that drug release occurs purely
by a di?usion process. The P(DM-MV)S matrix releases
TABLE 2. Release rate studies of PAM-2-Cl
through PDMS matrix having [ g ] = 0.18 dl g?1a,b
Time (h)
Amount of PAM-Cl released through
PDMS matrix (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
34
42
48
53
57
60
63
66
69
72
74
76
78
80
a When 蚷� � 0�, the drug is not released from the siloxane matrix.
b When 蚷� � 0� the release is over within 1 h.
D. C. Gupta, G. Sumana, S. Agarwal
214
TABLE 3. Release rate studies of PAM-Cl through polysiloxane matrices
Time (h)
0�1
2
3
4
5
6
7
8
9
10
PAM-2-Cl released (%)a
PDMS
PVMS
P(DM-VM)Sb
P(DM-DE)Sc
P(VM-DE)Sd
27
34
42
48
53
57
60
63
66
69
71
26
35
45
54
60
66
72
77
82
?
?
21
27
35
40
45
51
58
62
67
72
78
29
38
49
58
66
71
75
?
?
?
?
30
39
51
62
71
80
84
?
?
?
?
a For membranes of average 蚷� � 0� dl g�
b P(DM-MV)S � 75 : 25.
c P(DM-DE)S � 75 : 25.
d P(MV-DE)S � 75 : 25.
80% drug in 10 h, which is acceptable for a slow release
formulation. Polydimethylsiloxane, being a hydrophobic and non-polar polymer and having a high crosslink
density, took 14 h to release 80% of the drug. However,
by introduction of methyl vinyl siloxane and diethyl
siloxane chains into the PDMS matrix, some loosening
Fig. 2. Release of PAM-Cl from polysiloxane copolymers.
TABLE 4. Release time of PAM-Cl from polysiloxane matrices
Sample no.
Polymer
Time for 80% release
1
2
3
4
5
PDMS
PVMS
P(DM-MV)S
P(DM-DE)S
P(MV-DE)S
14
7
10
6
5
Fig. 1. Release of PAM-Cl from polydimethylsiloxane.
POLYMER INTERNATIONAL VOL. 45, NO. 2, 1998
Slow release of 2-pyridine aldoxime chloride by polysiloxanes
215
TABLE 5. Transport parameters of PAM-Cl?polysiloxane systems
Polymer
M1 a
c
K
n
D (cm2 s�
PDMS
PVMS
P(DM-MV)S
P(DM-DE)S
P(MV-DE)S
1427
3284
2764
4379
6385
0�
0�5
0�5
0�
0�
0�
0�2
0�
0�
0�
5�� 10�
8�� 10�
4�� 10�
5�� 10�1� � 10�
a M1 � Mol. wt. between crosslinks.
c
and increase of 裡xibility is shown by their respective
M1 (molecular weight between crosslink) values (Table
c
5). That is why P(DM-MV)S releases PAM-Cl in a relatively shorter time (10 h) compared with PDMS (14 h).
Introduction of ethyl groups into the PDMS matrix
further increases the 裡xibility of the system and
reduces the release rate time of PAM-Cl to (5�h)
(Table 4).
The relative amounts of PAM-Cl released were
plotted against t1@2. These plots result in straight lines,
indicating that the rate of release of PAM-Cl from polysiloxanes follows t1@2 behaviour.
Release of PAM-Cl from siloxane matrices is based
purely on a di?usion process and 衪s well with the generalized equation :16
M /M \ Ktn
t a
where M is the amount of drug released at time t, M is
t
a
the amount of drug released after reaching equilibrium,
K is a constant characteristic of the polymer萻olute
(drug) system, and n is a di?usion characteristic of the
release mechanism. From this equation, values of K and
n were calculated by plotting log M /M versus log t.
t a
Values of n and K are given in Table 5. Values of n were
found to be 0�9. This value of n \ 0�indicates
that release of PAM-Cl is Fickian di?usion controlled.
Di?usion coefficients were calculated using the equation :16
M /M \ 4(Dt/nl2)1@2
t a
for 0 O M /M O 0�where D is the di?usion coefficient
t 0
of PAM-Cl through polysiloxane matrices, t is time and
l the thickness of the slab.
Di?usion coefficient values for various PAM-Cl polysiloxane matrix systems have been calculated from the
slope of M /M versus t and are given in Table 5. The
t a
value
of
D
for
the
PDMS
system
is
5�] 10~11 cm2 s~1.
This
value
changes
to
4�] 10~10 cm2 s~1 in the case of P(DM-MV)S. This
indicates that introduction of methyl vinyl siloxane
units into PDMS increases the 裡xibility of the system,
and therefore the D value increases along with the
release rate. The value of D is 8�] 10~10 cm2 s~1 in
the case of PVMS. Higher values of D, i.e. 5�] 10~9
and 1�] 10~9 cm2 s~1 for P(DM-DE)S and P(MVPOLYMER INTERNATIONAL VOL. 45, NO. 2, 1998
DE)S systems, respectively, may be due to an increase in
裡xibility of these systems.
In vitro release rate of microcapsules
Similarly to our earlier studies, release rates of microcapsules of PDMS in pH 7�phosphate bu?er at 37
were also measured by UV spectrophotometry. As
shown in Fig. 1, 20% of PAM-Cl is released the 衦st
hour, whereafter the release rate was constant for 4 h.
The release rate versus time plot indicates that there is a
lower initial outpouring compared with slabs, and the
order of release is found to be zero.
Microcapsules of PDMS were only studied because
of the long time taken to release PAM-Cl from slabs.
The shorter time taken in microcapsules may be due to
reduction in wall thickness and in crosslink density due
to the presence of emulsi衑rs and stabilizers, which
hinder the process of crosslinking in PDMS.17 This
work is preliminary in nature.
CONCLUSIONS
1.
2.
3.
4.
5.
6.
All polysiloxane systems show an initial outpouring e?ect in release of PAM-Cl, particularly
in slab form.
Poly(dimethylmethylvinyl)siloxane
copolymer
(75 : 25) is found to be a suitable system for the
slow release of PAM-Cl.
The release of PAM-Cl from polysiloxane
matrices follows a t1@2 order for the slab form.
Values of di?usion coefficients have been calculated for PAM-Cl萷olysiloxane systems.
The initial outpouring e?ect is considerably
reduced in the case of microcapsules.
The release of PAM-Cl from microcapsules is
zero-order.
ACKNOWLEDGEMENT
The authors are grateful to Dr. R. V. Swamy, Director,
DRDE, Gwalior, for permission to publish the manuscript. Thanks are also due to Dr. D. K. Jaiswal, Joint
Director for his constant encouragement and suggestions.
216
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D. C. Gupta, G. Sumana, S. Agarwal
11 Bajaj, P., Babu, G. N., Khanna, D. N. & Varshney, S. K., J. Appl.
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12 Pramanik, D., Biswas, D., Ray, T. T. & Bakr, Md. A., J. Polym.
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