European Journal of Pharmaceutical Sciences 10 (2000) 225–235

www.elsevier.nl / locate / ejps

Influence of neutron activation factors on matrix tablets for site specific

delivery to the colon
Sayeh F. Ahrabi a , *, Jyrki Heinamaki
¨ ¨ b , Sverre A. Sande a , Christina Graffner c
a
Department of Pharmaceutics, School of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, N-0316 Oslo, Norway
b
Department of Pharmacy, University of Helsinki, Helsinki, Finland
c
Medical Products Agency, Uppsala, Sweden
Received 30 August 1999; received in revised form 3 January 2000; accepted 12 January 2000

Abstract

The impact of the neutron activation procedure, i.e. incorporation of samarium oxide (Sm 2 O 3 ) and neutron irradiation, on the
compression properties (including the crushing strength) and in vitro dissolution of potential colonic delivery systems based on matrix
tablets of amidated pectin (Am.P) or two types of hydroxypropyl methylcellulose (HPMC) was investigated. The neutron activation
factors did not influence the compression properties of the tablets. Replacement of magnesium stearate with samarium stearate in directly
compressed Am.P tablets to achieve both radiolabelling and lubrication resulted in a greater extent of concentration-dependent reduction
of the crushing strength. Dissolution tests demonstrated that irradiation increased the release of the model drug ropivacaine from the
tablets. The extent of this increase was unexpectedly low considering the previously observed degradation of the polymer expressed as an
irradiation-induced viscosity reduction in solutions prepared from the polymers. Delayed-release coating with Eudragit  L 100 protected
the HPMC tablets against the release-increasing effect of irradiation until the late phases of release. Sm 2 O 3 retarded the release to a
varying extent depending on particle characteristics. Incorporation of Sm 2 O 3 in the coating layer did not influence the release. However,
one-third of the radioactivity leached from the coating within 60 min in 0.1 M HCl.  2000 Elsevier Science B.V. All rights reserved.

Keywords: Neutron activation; Matrix tablets; Colonic delivery; Delayed-release coating; Dissolution; Samarium salts

1. Introduction (or other lanthanide oxides) can result in a concentration-

dependent increase of the hardness and disintegration time
During the development of a product for controlled of immediate-release tablets (Parr and Jay, 1987), alter the
release in the colon, it is of importance to determine the size and density of microspheres for oral use and reduce
actual site of release of the active drug. g-Scintigraphy the release rate of the drug from these systems (Watts et
provides the possibility for the non-invasive observation of al., 1993b) and cause a marked reduction in the dissolution
the site of drug dissolution and the degree of spreading. rate of the drug from lipophilic suppositories (Ahrabi et al.,
This technique involves the detection of g-rays emitted 1999a). Also, the neutron irradiation procedure alone
from the dosage system with an external gamma camera. generally increases the release of the drug from the
One method of radiolabelling the formulation with a g- formulations (Watts et al., 1993a; Ahrabi et al., 1999a).
emitting radioactive isotope is to incorporate a lanthanide However, in tablets and pellets coated with Eudragit  L 30
salt (usually samarium oxide, Sm 2 O 3 ) into the dosage form D-55, it was shown that the amount released was reduced
and perform a subsequent irradiation with thermal neu- as a result of comparatively higher neutron irradiation
trons. There are several advantages in utilising the neutron doses (Waaler et al., 1999).
activation method compared to other radiolabelling tech- Lanthanide oxides have the general characteristics of a
niques (Digenis and Sandefer, 1991). However, both the high degree of crystallinity, a high specific gravity, and
incorporation of the lanthanide salt and the neutron irradia- poor flowability. In product development, such properties
tion process might influence the in vitro and in vivo could be potential sources of problems. In order to
performance of the formulation. The addition of Sm 2 O 3 overcome some of the problems related to the oxides, the
utilisation of stearate salts has been suggested (Esposito et
*Corresponding author. Tel.: 147-22-857-905; fax: 147-22-854-402. al., 1994). Samarium stearate has been proposed to replace
E-mail address: s.f.ahrabi@farmasi.uio.no (S.F. Ahrabi) magnesium stearate as a lubricant in formulations. This

0928-0987 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved.
PII: S0928-0987( 00 )00070-1
226 S.F. Ahrabi et al. / European Journal of Pharmaceutical Sciences 10 (2000) 225 – 235

gives the unique possibility of radiolabelling the finished the aqueous latex dispersion. Eudragit L 100 was selected
product instead of a product developed only for clinical because of the suitable dissolution pH (.6) and the
studies. structural similarity to Eudragit S 100.
The overall aim of the present study was to investigate The more detailed objectives of this investigation were:
the influence of neutron activation factors on the properties (a) to compare the previously observed physico-chemical
of some colon specific drug delivery systems based on changes as a result of neutron irradiation of the plain
various mechanisms. One investigated system is based on excipients with the effects of irradiation on tablets made of
a combination of time-controlled and pH-dependent mech- those materials; (b) to study the influence of an admixture
anisms. Controlled-release cores of hydroxypropyl methyl- of a lanthanide salt (Sm 2 O 3 or samarium stearate) on the
celluloses (HPMCs) coated with a pH-dependent film were properties of the tablets; and (c) to study the effect of the
used (Steed et al., 1994). Another release-controlling addition of a lanthanide salt to the coating compared to the
mechanism is based on a material that undergoes degra- tablet core.
dation by bacterial enzymes in the colon, e.g. pectin Furthermore, it was necessary to perform preliminary
(Holloway et al., 1983). Pectins are plant polysaccharides investigations on the effects of neutron irradiation on the
that have been studied extensively as potential colonic solubility of a compressed model drug (ropivacaine hydro-
delivery systems (Ashford and Fell, 1994). chloride) and the mechanical properties of free films
In a previous investigation (Ahrabi et al., 1999b) we prepared from an organic dispersion of Eudragit L 100.
demonstrated that the degradation of pectins and HPMCs Table 1 gives an overview of the studies performed in the
is a function of the neutron radiation dose. The extent of present work.
degradation was dependent on the type of polymer.
Amidated pectin (Am.P) proved to be the most promising
pectin type, both in terms of resistance towards thermal 2. Materials and methods
neutron irradiation, and for colonic delivery (Ahrabi et al.,
1999b,c). In the case of HPMCs, Metolose  60SH and 2.1. Materials
90SH were chosen because of their good tableting prop-
erties, different structures and comparative different resist- Amidated pectin type 920, Am.P (Citrus Colloids, UK),
ance towards the neutron irradiation dose. We also showed HPMCs USP types 2910 and 2208 (Metolose 60SH-4000
that films produced from an aqueous dispersion of Eudragit ¨
and 90SH-4000, Shin-Etsu, Japan), Eudragit L 100 (Rohm,
S 100 were more resistant towards irradiation than those Germany), microcrystalline cellulose (Emcocel 90M, Men-
produced from Eudragit L 100-55. However, in the present dell, USA), samarium oxide 99.999% REO, Sm 2 O 3 (Batch
study, an organic solution of pH-dependent poly- 1, E2806; and Batch 2, 290698, Johnson & Matthey Alfa,
methacrylates was chosen because Sm 2 O 3 or samarium Germany), samarium stearate (Vectorpharma, Italy), mag-
stearate was to be admixed with the coating layer in some nesium stearate (NMD, Norway), Pectinex Ultra SP-L,
preparations. An organic solution would withstand such activity 26,000 PG / ml in pH 3.5 (Novo Nordic, Denmark),
treatment, whereas alkaline earth metal compounds and and ropivacaine hydrochloride monohydrate, Rop.HCl
magnesium stearate are reported to cause coagulation of (Astra AB, Sweden) were obtained from the indicated

Table 1
Overview of the investigations performed in the present work
1. Preliminary studies on some materials a Effects of different doses of neutron
irradiation on the:
Compressed Rop.HCl discs Diffusion-controlled dissolution
and the enthalpy of dissolution
Free films of Eudragit L 100 Mechanical properties
2. Formulations Effects of neutron activation factors on the:
Compression Dissolution
properties properties
Am.P tablets
Directly compressed 1b 2
Prepared by wet granulation 1 1
HPMC tablets (directly compressed)
Sm 2 O 3 in the core 1 1
Sm 2 O 3 in the coating 2c 1
a
The rest of the materials were studied in an earlier investigation (Ahrabi et al., 1999b).
b
Comparison of the addition of Sm 2 O 3 , samarium stearate and magnesium stearate.
c
Crushing strength only.
 S.F. Ahrabi et al. / European Journal of Pharmaceutical Sciences 10 (2000) 225 – 235 227

sources. All other reagents were of analytical or pharma- Tablets were produced using an instrumented single-
ceutical grade. punch Korsch EK-0 (Korsch, Germany). The instrumen-
The physico-chemical properties of Am.P, 60SH and tation software was designed by Puuman Oy (Kuopio,
90SH are presented elsewhere in detail (Ahrabi et al., Finland). Compression was performed at 30 rpm. The
1999b). A sieve analysis performed on the polymers directly compressed formulations were made one by one.
indicated that Am.P had the largest particles and 60SH the Thirteen millimetre flat-faced (Am.P tablets) or double
smallest. Details of the analysis were concave (HPMC tablets) punches with a compression force
of 25 and 17 kN, respectively, were used.
60SH (90SH): . 149 mm, 10%; Force-displacement data were used for the calculation of
149–75 mm, 30% (50%); 75–53 mm, 30% (40%); different factors. The total work (Wtot , Paronen and Julsin,
, 53 mm, 30% (10%) 1982), the work of friction (Wf ) and the work of ejection
(We ) were measured by the software. A Schleuniger Tablet
Am.P: . 149 mm, 15%; . 75 mm, 60–80% Tester 6D was used for testing the crushing strength of the
tablets.
Eudragit L 100 is a methacrylic acid copolymer type A For direct compression studies, tablets consisting of the
USP/ NF (methacrylic acid / methyl methacrylate, 1:1) with basic Am.P formulation with the addition of (a) 0.5%
an average MW of 135,000. magnesium stearate, (b) 0.5% magnesium stearate and 5
The comparative physico-chemical characteristics of mg Sm 2 O 3 , (c) 0.5% samarium stearate, or (d) 2.6%
Sm 2 O 3 and samarium stearate are presented in Table 2. samarium stearate, were produced. These blends were only
tested for compression properties and the crushing strength
2.2. Formulations, tablet compression and coating of the tablets immediately after preparation, since they
were not strong enough to resist further handling.
The tablets consisted of 50 mg of the model drug, For the delayed-release coating of the tablets, an organic
Rop.HCl, and 500 mg excipients (Am.P or HPMC alone or solution of Eudragit L 100 in isopropanol and acetone
in combination with Sm 2 O 3 ). To enhance the flowability (1:1.5) was used to achieve approximately 20 mg polymer
of the HPMC blends, 0.3% colloidal silica was added. per tablet. PEG 6000 (8% of dry polymer in the dispersion)
Powders were mixed for 15 min in a Turbula mixer type was used as plasticiser and magnesium stearate (26% of
T2F (Basel, Switzerland). Preliminary studies showed that dry polymer) was added to reduce the tackiness of the
direct compression of Am.P produced tablets that lacked tablets. Details of the coating process were the same as
the minimum required mechanical strength. Thus an reported earlier (Ahrabi et al., 1999c).
amount of the mixed powder mass was separated for
investigation of the compression properties of directly
compressed Am.P as a result of the admixture of lantha- 2.3. Scanning electron microscopy ( SEM)
nide salts (see below in this section) and the rest of the
blend was granulated. Granules were prepared by spraying Investigation of the particle size and surface structure of
water onto the powder bulk followed by effective manual the lanthanide salts and magnesium stearate samples was
mixing. It was passed through a 1.6 mm screen using an performed by coating the samples with gold–palladium for
oscillating granulator and dried overnight at 208C. The dry 6 min at 20 mA (E 5000 SEM coating unit, Polaron, UK)
granules were screened through 1.0 mm. Magnesium or and using a scanning electron microscope type JSM-6400
samarium stearate was added to powders or granules (Jeol, Japan) at 5 kV. Prior to sample preparation, the
through a 0.15 mm screen and mixed for 2 min in the agglomerates of batch 2 of Sm 2 O 3 were broken gently
Turbula mixer immediately before compression. between two layers of paper.

Table 2
Some physico-chemical characteristics of the lanthanide salts
Type MW Density Solubility (mg / ml) Particle size
(g / ml) pH 1.2 Other
7.52 b 8.35 c 5.4310 24 b,d
Samarium oxide 348.7 Soluble 90% ,16 mm f
Samarium stearate a 1000.8 1.24 0.067 ,10 23 e ¯10–100 mm g
a
Dobetti et al., 1994.
b
Digenis and Sandefer, 1991.
c
Merck Index, 1989.
d
In water.
e
In pH 5.5 and 7.5.
f
Ahrabi et al., 1999a.
g
SEM analysis (Fig. 2).
228 S.F. Ahrabi et al. / European Journal of Pharmaceutical Sciences 10 (2000) 225 – 235

2.4. Preparation and mechanical properties of the free content of this material, i.e. seven tablets that were
films irradiated in the same ‘rabbit’ were analysed for their
relative 153 Sm activity using a HPGe detector connected to
Free films were prepared utilising a previously described a multi-channel analyser (EG&G Ortec Spectrum ACE)
method with small adjustments (Ahrabi et al., 1999b). via a spectroscopy amplifier (Canberra 2026). The analyser
Seventy grams of the solution was sprayed to obtain films was interfaced to a PC, and the areas under the photo-
with a thickness of 200–300 mm. Films of acceptable peaks were calculated.
thickness and appearance were stored at room temperature
(25638C) in 60% relative humidity and protected from 2.7. Radiolabel in the coating layer
light until irradiation. The tensile strength of the films was
tested using the same method as described previously Two extra batches of tablets based on 60SH were
(Ahrabi et al., 1999b). produced and coated with a dispersion of similar com-
position as mentioned above except that half the amount of
2.5. Experimental designs magnesium stearate was replaced with Sm 2 O 3 . The
amount of Sm 2 O 3 incorporated in the coating layer was
Table 3 shows the experimental factors and their levels measured for seven tablets from each of the two batches
for the D-optimal and the 2 4 factorial designs utilised in using the following method. A precise volume of a
the study. Modde 4.0 (Umetri, Sweden) was used to create standard solution of Sm 2 O 3 in 0.5 M HNO 3 was pippetted
the designs, which are presented in detail in Tables 5 and onto a preweighed piece of paper with approximately the
6. All batches were produced independently and in a same surface dimensions as the tablets. This sample was
randomised order. used as the standard and was irradiated in the same rabbit
as the tablets. The 153 Sm g-activities of the tablets were
2.6. Radiolabelling and uniformity of the content of determined using the HPGe detector. This activity was
Sm2 O3 in the cores thereafter correlated to the g-activity of the standard
sample and the original amount of Sm 2 O 3 in the coating
Samples were irradiated at the JEEP II reactor, Institute layer was calculated.
for Energy Technology, Norway, using thermal neutrons The leaching of incorporated Sm 2 O 3 from the coating
with a nominal flux of 1.1310 13 n cm 22 s 21 (temperature was measured using the following method. Three beakers
approx. 578C). Seven tablets from each batch were packed each containing 250 ml 0.1 M HCl solution were placed in
into each polyethylene ampoule before the ampoules were a water bath at 378C. One irradiated and still radioactive
placed in the transport system (the ‘rabbit’), shipped to the tablet was placed in each beaker. The beakers were stirred
reactor, and irradiated for predetermined times. Our previ- manually every 5 min and immediately before sample
ous study (Ahrabi et al., 1999b) showed that the reactor withdrawal. Samples of 10 ml were withdrawn after 15, 30
heat alone did not have any impact on the physico- and 60 min and their 153 Sm g-activity was measured
chemical properties of pectins or HPMCs. against an irradiated samarium standard using the HPGe
Certain formulations containing the lowest or the highest detector. The total amount of samarium released was
amounts of Sm 2 O 3 were examined for the uniformity of calculated.

Table 3
Experimental levels for the independent variables in the two designs
Variable Experimental level
Variable type Sum levels a Low values High values Centre points
b
Pectin
Sm 2 O 3 (mg) Continuous 4 0 5 2.5
N.I.c (min) Continuous 4 0 2 1
HPMC d
Type Category 2 60SH 90SH 60SH
Coating Category 2 2 1 1
Sm 2 O 3 (mg) Continuous 2 0 5 2.5
N.I. (min) Continuous 2 0 2 1
a
Excluding the centre points.
b
D-Optimal design, tablets produced by wet granulation.
c
N.I., neutron irradiation.
d 4
2 factorial design, directly compressed tablets.
 S.F. Ahrabi et al. / European Journal of Pharmaceutical Sciences 10 (2000) 225 – 235 229

2.8. Dissolution (62S.E.), where S.E. is the standard error (model error)
based on the predicted versus measured values calculated
2.8.1. Dissolution of compressed Rop.HCl for each time point. This confidence limit was used to
Compressed discs of Rop.HCl were prepared and sub- illustrate the entire area of the predicted release curves,
sequently irradiated. Diffusion-controlled dissolution rates which was not significantly affected by the investigated
(D) and the enthalpy of dissolution (DH ) for non-irradiated variables.
and irradiated discs were determined in water at 378C PCA was used to illustrate the collective trends and
according to the method of Nicklasson and Magnusson properties of a group.
(1985).

2.8.2. Dissolution tests for tablets 3. Results

A Flow-Through apparatus (Ph.Eur. 3rd edition, 1997)
with a 22.6 mm cell and a flow rate of 8 ml / min (if not 3.1. Preliminary studies of the materials
stated otherwise) was used utilising the sequential dissolu-
tion liquids described previously (Ahrabi et al., 1999c). 3.1.1. Effects of neutron irradiation on the solubility of
The tablets were exposed to Simulated Gastric Fluid (SGF) Rop.HCl compressed discs
for 60 min, followed by 3 or 6 h (Am.P or HPMC tablets, D was determined to be 9.9(60.6)310 26 cm 2 / s for
respectively) exposure to Simulated Small Intestinal Fluid non-irradiated Rop.HCl in water at 378C. This value did
(SSIF). Am.P tablets were then exposed to Simulated not change significantly after up to 2 min of neutron
Cecal Fluid (SCF) for another 3–4 h, to evaluate their irradiation. Three minutes of radiation, though, resulted in
potential ability to undergo bacterial degradation in the a statistically significant (P , 0.05) decrease in the value
colon. All adjustments were made by adding concentrated
of D to 8.4(60.7)310 26 cm 2 / s. DH (33.965.8 kJ / mol)
solutions to the original dissolution medium under vigor-
did not change following neutron irradiation.
ous stirring without interrupting the test.
These results suggest that, despite the slight increase in
For the HPMC formulations, samples of 4 ml were
the solubility of Rop.HCl powder as a function of the
taken at predetermined time intervals, without buffer
neutron irradiation dose (Ahrabi et al., 1999a), the dif-
replacement. The amount of Rop.HCl released was de-
fusion-controlled dissolution rate and the enthalpy of
termined spectrophotometrically at 204 nm. In the case of
dissolution of compressed Rop.HCl were not altered after
Am.P tablets, aliquots of 500 ml were withdrawn and the
2 min of neutron irradiation under the conditions applied in
amount of Rop.HCl released was determined using a
this study.
previously described HPLC method (Ahrabi et al., 1999c).

2.9. Multivariate analysis and model development for 3.1.2. Effects of neutron irradiation on the mechanical
the dissolution studies properties of the free films
One minute of neutron irradiation did not affect the
Principal Component Analysis (PCA) and Partial Least average value of the fracture stress for the films, whereas 2
Square Projection to the Latent Structures (PLS) were used min irradiation resulted in a 30% reduction in this parame-
to build up models to simplify and explain the observed ter (2.9 MPa for the non-irradiated films to 2 MPa for the 2
effects (Esbensen et al., 1994), employing Unscrambler min irradiated films). This difference was statistically
(Camo AS, Norway). significant (t-test at 95% confidence level). The films were
For the evaluation of the effects of varying parameters rigid and brittle (fracture strain ,0.2 mm), probably due to
on the release profiles, it is desirable to have models the small amount of plasticiser compared to the amount of
covering the entire dissolution curve instead of two to solids in the dispersion.
three chosen time points (Abuzarur-Aloul et al., 1998),
especially when a complicated and specific profile is 3.2. Effects of the addition of lanthanide salts on the
observed. To exclude any variance in the data due to compression properties and crushing strength of the
unexplained experimental variation (e.g., manual granula- tablets
tion, HPLC analysis, etc.), we developed a PLS2 model
(PLS with more than one response) including main factors, 3.2.1. Am.P tablets
two-factor interactions and the quadratic terms. All mea- Table 4 shows the results of the compression studies for
sured points of the dissolution curves were incorporated in the directly compressed Am.P tablets and their crushing
each model. The predicted values for the amount released strength. The effects of the addition of Sm 2 O 3 or 0.5%
at the corresponding time points were calculated by the samarium stearate on the various tableting parameters was
program and were used to plot the predicted dissolution negligible, although samarium stearate induced a marked
profiles. The 95% confidence limit was defined as reduction in the crushing strength of the tablets. Increasing
230 S.F. Ahrabi et al. / European Journal of Pharmaceutical Sciences 10 (2000) 225 – 235

Table 4 Table 5
Effects of the addition of samarium stearate and samarium oxide on the D-Optimal design and the effects of neutron activation factors on some
compression properties and crushing strength of directly compressed selected responses for pectin-based tablets made by wet granulation
Am.P matrix tablets a (average of six tablets)
Wtot Wf We Crushing Experiment Experimental Response
(Nm) (Nm) (Nm) strength (N) variable
Crush.str.b C60 c C240 C285
MgS 0.5% 23.9 2.47 0.79 26 Sm 2 O 3 N.I.a (N) (%) (%) (%)
(0.5) (0.06) (0.01) (2) (mg) (min)
Sm 2 O 3 5 mg1 23.4 2.38* 0.82* 26
1 0 0 58 24 58 80
MgS 0.5% (0.5) (0.06) (0.02) (5)
2 5 0 66 22 52 68
SmS 0.5% 23.3* 2.63* 0.76* 21*
3 0 2 53 24 67 82
(0.4) (0.04) (0.02) (1)
4 5 2 60 24 61 85
SmS 2.6% b 21.2* 2.40 0.60*
5 0 1.333 61 22 65 88
(0.4) (0.06) (0.2) –c
6 5 0.667 62 22 55 90
a
MgS, magnesium stearate; SmS, samarium stearate. The results are 7 3.333 0 56 24 57 73
the average of six measurements (S.D.). 8 1.667 2 54 23 67 89
b
Average of two different batches, each consisting of six measure- 9 2.5 1 59 23 55 84
ments. 10 2.5 1 62 23 57 85
c
Too soft, not measurable. 11 2.5 1 65 21 54 86
*Significantly different from MgS 0.5% (two-tailed Student’s t-test at a
N.I., neutron irradiation.
the 95% confidence level). b
Crush.str., crushing strength of the tablets.
c
C60, C240, C285 represent the percentage of drug released (during
the amount of samarium stearate to 2.6% caused a the dissolution test) at, respectively, 60, 240 and 285 min.
significant reduction in We and Wtot . Also, the produced
tablets were too soft to allow any measurement of their particle size distribution and flaky structure, whereas the
crushing strength. samarium stearate particles were round and almost 10
In order to explain the observed compression results, times larger. The figure also demonstrates the similarity
particles of magnesium stearate, samarium stearate and the between the primary particles of the two different batches
two batches of Sm 2 O 3 were studied by SEM (Fig. 1). A of Sm 2 O 3 .
comparison of magnesium and samarium stearates indi- Table 5 shows the average values of the crushing
cates a total lack of similarity in the structure and size of strength of the Am.P tablets made by granulation. Incorpo-
the particles. Magnesium stearate shows a typical fine ration of Sm 2 O 3 did not affect the compression properties

Fig. 1. SEM pictures of particles of (a) magnesium stearate (calibration bar 10 mm), (b) samarium stearate (calibration bar 100 mm), and (c,d) Sm 2 O 3
batches 1 and 2, respectively (calibration bars 1 mm).
 S.F. Ahrabi et al. / European Journal of Pharmaceutical Sciences 10 (2000) 225 – 235 231

Table 6
The 2 4 factorial design for the HPMC tablets and the average values of some selected responses (n 5 4)
Experiment Experimental variable Response
a
Type Coating Sm 2 O 3 N.I. Crush.str.b C60 c C240 C420
(mg) (min) (N) (%) (%) (%)
A 60SH 2 0 0 101 12 35 46
B 60SH 2 5 0 93 10 28 39
C 60SH 2 0 2 97 12 35 47
D 60SH 2 5 2 83 13 38 52
E 60SH 1 0 0 99 3 17 31
F 60SH 1 5 0 134 2 16 30
G 60SH 1 0 2 128 2 19 34
H 60SH 1 5 2 106 3 21 38
I 90SH 2 0 0 78 11 32 37
J 90SH 2 5 0 82 12 34 45
K 90SH 2 0 2 71 11 36 49
L 90SH 2 5 2 103 12 38 52
M 90SH 1 0 0 95 2 19 32
N 90SH 1 5 0 98 3 20 36
O 90SH 1 0 2 107 3 20 38
P 90SH 1 5 2 106 3 20 38
S1 60SH 1 2.5 1 105 4 20 36
S2 60SH 1 2.5 1 87 3 18 32
S3 60SH 1 2.5 1 130 3 20 35
a
N.I., neutron irradiation.
b
Crush.str., crushing strength of the tablets (n 5 6).
c
C60, C240, C420 represent the percentage of drug released (during the dissolution test) at, respectively, 60, 240 and 420 min.

of these tablets, nor did any of the two neutron activation variables on the crushing strength of these tablets (see
factors influence their crushing strength. Table 6 for average values). Three principal components
were identified explaining 76% (36, 20 and 20%) of the
3.2.2. HPMC tablets variance within the data. The loadings (Fig. 2) indicate that
The addition of Sm 2 O 3 did not impose any significant none of the neutron activation factors had any effect on the
effect on the compression properties of HPMC tablets. A crushing strength of the tablets. 60SH produced harder
PCA model was applied to illustrate the effects of the tablets due to its smaller particle size compared to 90SH

Fig. 2. Plot of X-loadings from PCA on the effects of the type of HPMC (Type), coating (Coat), addition of Sm 2 O 3 (Sm2O3) and neutron irradiation
(N.I.) on the crushing strength (Hardness) of the HPMC tablets. The effects are visualised by projection: a diagonal line (DL) is drawn from the response
(Hardness) through the origin (in the present case, the line would be the same as the PC1 line). Thereafter, a perpendicular line from each of the variables is
drawn to the DL. The variables that hit the DL on the same side of the origin as the investigated response have a positive impact, and the variables on the
opposite side of the origin have a negative effect, on that response. Variables that hit the line in the vicinity of the origin do not have an effect on the
response.
232 S.F. Ahrabi et al. / European Journal of Pharmaceutical Sciences 10 (2000) 225 – 235

and the coating also had a positive impact on this 3.4.2. HPMC tablets
parameter. Table 6 gives the average amounts of drug released from
The incorporation of Sm 2 O 3 in the coating layer of the the HPMC tablets at selected time points. The predicted
tablets did not affect the crushing strength. release profiles for the various formulations are shown in
Fig. 4a–d. Two minutes of neutron irradiation significantly
increased the release of the drug from the uncoated tablets.
3.3. Uniformity of content of Sm2 O3 in the tablets This effect was strengthened by the presence of 5 mg
Sm 2 O 3 in the case of tablets composed of 90SH, and also
The uniformity of content for Sm 2 O 3 in the Am.P for the coated tablets. Coated formulations of 60SH were
tablets was within 65% of the average for all tablets, not influenced by neutron irradiation, until the last mea-
which complies with the requirements of the Ph.Eur. The sured point.
variation in the content of Sm 2 O 3 was found to be larger The addition of Sm 2 O 3 did not influence the release
in HPMC tablets than in Am.P tablets. This difference was from the 90SH tablets. In both coated and uncoated 60SH
not observed when Sm 2 O 3 was added to the coating layer tablets, the addition of 5 mg Sm 2 O 3 induced a reduction in
of the HPMC tablets. In all the tablets, however, the the average amount of drug released from the tablets, even
uniformity of the content of this salt remained within 65% though the effect was not statistically significant. The
of the average. average weight of the coating layer in the different batches
of tablets was 22.4 (64.9) mg / tablet. Although the
3.4. Effects of neutron activation factors on the in vitro variation was relatively large, no correlation was observed
dissolution of the tablets between the amount of coating and the crushing strength or
the dissolution properties of the tablets (employing PLS2).

3.4.1. Am.P tablets made by granulation

3.4.3. HPMC tablets coated with Sm2 O3 -containing
Table 5 presents the average amounts of drug released
Eudragit L 100
from Am.P tablets at selected time points. Fig. 3 shows the
The average amount of samarium in the coating layer of
predicted release profiles of formulations 1–4. Two min-
the Sm 2 O 3 -containing Eudragit L 100 coated tablets for
utes neutron irradiation significantly increased the release
two independently produced batches was 1.9 and 1.97 mg
in SSIF and the early phases of SCF. However, incorpora-
per tablet (approximately 90 mg / g coating). This corre-
tion of 5 mg Sm 2 O 3 reduced release both in SGF and
sponds to a g-activity of approximately 0.8 MBq, 72 h
SSIF. The interesting observation is that the combination
after 2 min neutron irradiation.
of both of these factors seems to counteract the effects of
The in vitro dissolution of the tablets coated with the
each other and the release profile of formulation 4 was
Sm 2 O 3 -containing Eudragit L100 dispersion did not differ
similar to that corresponding to the untreated tablets.
from the tablets coated with the standard dispersion.
The in vitro dissolution of formulations 1–4 was also
Irradiation did not have any different impact on these
studied with a flow rate of 16 ml / min. The results show
tablets either.
similar effects of the neutron activation factors, although
Fig. 5 indicates that the released amount of Sm 2 O 3 in
the amount released in all three media was higher.
0.1 M HCl from the coating layer followed a linear pattern
after an initial burst effect.

4. Discussion

4.1. Lanthanide salts and compression properties

Both Sm 2 O 3 and samarium stearate were examined as

radiolabelling agents. The former did not have any signifi-
cant influence on the compression properties of the formu-
lations or the crushing strength of the tablets. Samarium
stearate was examined because of the possibility of benefit-
ting from its combined lubrication and radiolabelling
properties, and thereby its potential to replace magnesium
Fig. 3. Predicted release profiles for Am.P tablets. (———) (rich line stearate and Sm 2 O 3 (Esposito et al., 1994). In order to
without point markers) No treatment (reference), (s) 5 mg Sm 2 O 3 , (n) 2
min neutron irradiation, (3) 5 mg Sm 2 O 3 and 2 min neutron irradiation. achieve the same amount of 153 Sm g-activity as in 5 mg
Error bars indicate 62S.E. The vertical stippled lines denote the change Sm 2 O 3 , though, a larger amount was required (14.3 mg or
of dissolution medium. 2.6% of the tablet weight in the present study) because of
 S.F. Ahrabi et al. / European Journal of Pharmaceutical Sciences 10 (2000) 225 – 235 233

Fig. 5. Leaching of radioactivity from the tablet coating as a function of

dissolution time in 0.1 M HCl at 378C. Error bars denote 6max / min
values (n 5 3).

the larger molecular weight of samarium stearate (Table 2)

and the number of samarium per molecule.
Early investigations reported that the specific area of
stearate salts and their laminar structure are directly related
to a reduction in mechanical strength (Lerk et al., 1977)
due to film formation of stearates around the other particles
(Bolhuis et al., 1975). A later study (Johansson, 1985)
demonstrated that a strong or thick film of the lubricant is
not a prerequisite for good lubrication since it was possible
to achieve efficient die wall lubrication from coarse
particles of magnesium stearate, without imposing a severe
negative impact on the tablet strength. We demonstrated
that samarium stearate, applied at the same concentration
as magnesium stearate, exhibited similar lubrication prop-
erties despite its large and round particles (Fig. 1).
However, the produced tablets had a significantly lower
crushing strength compared to those incorporating mag-
nesium stearate (Table 4). The reason for this is not clear
at this point.
When 2.6% samarium stearate was added to the powder
blend, it was not possible to produce acceptable compacts.
Similar results were observed by Esposito et al. (1994),
who reported a significant linear reduction in the hardness
of immediate-release tablets as a function of increased
concentration of samarium stearate. In our study, since the
original crushing strength of the tablets was quite low, the
effect of the addition of large amounts of samarium
stearate was dramatic.

4.2. Neutron activation factors and in vitro dissolution

Neutron irradiation increased the dissolution rate of the

drug from the tablets. The difference in release from the
irradiated tablets became larger as a function of dissolution
time. This effect might be explained by polymer degra-
dation. Whereas the diffusion of the drug through a
Fig. 4. Predicted release profiles for HPMC tablets. (a) 60SH, (b) 90SH, hydrated hydrophilic matrix is independent of the molecu-
(c) coated 60SH, (d) coated 90SH. Legend and error bars as for Fig. 1. lar weight of the polymer, the erosion process is inversely
The vertical stippled lines denote a change of dissolution medium. related to the polymer’s molecular weight (Reynolds et al.,
234 S.F. Ahrabi et al. / European Journal of Pharmaceutical Sciences 10 (2000) 225 – 235

1998). The erosion of the polymer becomes more domi- dissolution results would thus suggest that the process did
nant in the late phases of release and thus the effect of a not affect the dosage system, which is only partly true,
decrease in the molecular weight will be visible in time. meaning that the final effect is a combination of two
However, the effect of irradiation on dissolution from the opposite effects.
tablets was unexpectedly small considering the extent of Different results were obtained for both coated and
polymer degradation observed in our previous study uncoated HPMC tablets. In 60SH, the effect of 2 min
(Ahrabi et al., 1999b). For HPMC matrices, it has been neutron irradiation was not influenced by the addition of 5
shown that the viscosity of the polymer does not influence mg Sm 2 O 3 , whereas in 90SH tablets the release-increasing
the release of the drug to a large extent (Nixon, 1996). Our effect of irradiation was further enhanced. This observation
results are also in agreement with the investigation of might be explained by the exposure of samarium to
Waaler et al. (1999), who reported a slight increase in the neutrons causing energy emission by the radioactive
release of a drug from tablets with similar composition and isotope to the surroundings and accentuation of the effects
coating following 2 min neutron irradiation. of neutron irradiation alone. This phenomenon occurs in
The pattern of release of the model drug from the coated all the dosage systems, but only in those lacking the
tablets as a result of irradiation was the same as that retarding effect of Sm 2 O 3 (e.g., 90SH) is the effect
observed for the corresponding uncoated tablets (Fig. 4a– observed as an interaction.
d), despite the sensitivity of the mechanical strength of the
free films prepared from the coating dispersion to the same 4.3. Radiolabel in the coating layer
irradiation dose. Therefore, under the conditions applied in
the present study, a direct correlation between the me- The possibility of using solubilised Sm 2 O 3 or erbium
chanical resistance of the free films and their release oxide embedded in cellulose-based enteric polymers in-
properties was not possible. stead of the core of the tablets has been addressed in the
The incorporation of Sm 2 O 3 caused a statistically literature (Digenis and Sandefer, 1991). This is an attrac-
significant release-retarding effect for Am.P tablets in the tive approach because product developments based on
SSIF and early stages of SCF. The mechanism behind this coatings for site-specific delivery to the GI tract are
is still not known. However, there is evidence in the increasing (Leopold, 1999).
literature that the presence of a non-soluble drug in During the coating process with the Sm 2 O 3 -containing
swelling matrices contributes to the formation of an dispersion, the Sm 2 O 3 particles showed a tendency for
undissolved front of drug particles. This might suppress rapid sedimentation due to their high density. This problem
the relaxation of the polymer close to the swelling front can be solved by a higher rate of stirring of the dispersion.
(Colombo et al., 1995) and thereby reduce the rate of Nevertheless, sedimentation of the suspended particles in
diffusion and dissolution. It is possible that Sm 2 O 3 with its the tube connecting the liquid container via the pump to
high density and hydrophobic nature might exhibit a the spray nozzle was also observed, making it necessary to
similar mechanism. This effect was not significant in the shake the tube continuously during the coating process.
HPMC tablets. This is most probably due to the different However, the major drawback of incorporating Sm 2 O 3
quality of the batch of Sm 2 O 3 used to prepare these in the coating is that this salt is readily soluble in dilute
tablets. Although SEM demonstrated that the primary inorganic acids, which might lead to premature leaching of
shape and size of the particles were similar in both Sm 2 O 3 the radioactivity in the stomach during a g-scintigraphic
batches, the particles of batch 2 (used in HPMC tablets) study. We found that approximately one-third of the
were clustered into rather hard agglomerates. Since the incorporated amount of Sm 2 O 3 was released within 60 min
Sm 2 O 3 powder was not sieved before admixing in any of at 378C. Samarium stearate, on the other hand, is practical-
the cases, batch 1 had a better possibility of a more even ly insoluble in the pH range of interest. This, together with
distribution around the polymer particles. This may also be its low density, makes it a more attractive candidate for
an explanation for the larger variation in the content of such an application. An attempt to produce free films using
Sm 2 O 3 in the HPMC tablets. Batch 2 was also the one this salt was not successful, most probably due to its large
added to the coating dispersion. In this case, however, the particle size.
agglomerates were broken and the particles were finely
dispersed by the high rate of stirring during preparation,
and hence caused a negligible variation in the content of 5. Conclusions
Sm 2 O 3 in the tablets.
When the two neutron activation factors were combined, It is possible to use the neutron activation technique for
the dissolution behaviour was observed to be different. The the radiolabelling of oral colon-delivery systems based on
profiles for Am.P tablets were similar to that from un- a polysaccharide matrix of Am.P or of a HPMC matrix
labelled tablets, which indicates that the retarding effect of surrounded by a delayed-release coating of Eudragit L 100.
the incorporation of 5 mg Sm 2 O 3 counteracts the increas- The incorporation of Sm 2 O 3 did not have any impact on
ing effect of 2 min neutron irradiation. The in vitro the compression properties of matrix tablets based on these
 S.F. Ahrabi et al. / European Journal of Pharmaceutical Sciences 10 (2000) 225 – 235 235

polymers. The replacement of magnesium stearate with Ahrabi, S.F., Sande, S.A., Waaler, T., Graffner, C., 1999a. Influence of
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Colombo, P., Bettini, R., Massimo, G., Catellani, P.L., Santi, P., Peppas,
Delayed-release coating protected the HPMC tablets N., 1995. Drug diffusion front movement is important in drug release
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It was possible to incorporate a reproducible amount of activation techniques in the in vivo assessment of orally administered
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University of Oslo, is gratefully acknowledged. We would activation: effects on in vitro performance. Pharm. Res. 4, 524–526.
also like to thank Shin-Etsu (Japan), Donsmark Process Reynolds, T.D., Gehrke, S.H., Hussain, A.S., Shenouda, L., 1998.
Technology (the agent of Rohm ¨ GmbH, Germany, in Polymer erosion and drug release characterization of hydroxypropyl
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materials. One of the authors (S.F.A.) would like to vivo behaviour of a colonic delivery system: a pilot study in man. Int.
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the stability towards degradation by neutron irradiation. Validation of
the travel grant, respectively.
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