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TUGAS MANDIRI

TEKNOLOGI SEDIAAN SOLIDA

Oleh :

Nama : Dindha Pratiwi Setyaningrum

NIM : 152210101010

Kelas : A

Dosen : Lusia Oktora Ruma K.S, S.Farm., M.Sc.,Apt

FAKULTAS FARMASI
UNIVERSITAS JEMBER
2017
TUGAS MANDIRI
Mencari sebuah jurnal internasional tentang soft capsule. Dan gunakan jurnal tersebut untuk
menjawab pertanyaan yang diberikan, meliputi :
1. Mengapa bentuk sediaan soft capsule dipilih untuk zat aktif tersebut ?
2. Sebutkan bahan-bahan penyusun soft capsule dalam penelitian tersebut dan jelaskan
alasan pemilihan bahan-bahan tersebut !
3. Tuliskan metode pembuatan soft capsule dalam jurnal penelitian !
4. Evaluasi apa saja yang dilakukan terhadap soft capsule !

Physical and enteric properties of soft gelatin capsules coated with Eudragit L 30 D-55

Soft Gelatin Capsule (SGC) dengan polimer enterik yang mengandung ibuprofen baik
dalam PEG 400 atau Miglyol dan efek dari plastisizer, yaitu trietil sitrat (TEC) dan tributil
sitrat (TBC), pada sifat fisik dan enterik kapsul lunak gelatin yang dilapisi dengan Eudragit L
30 D-55 diteliti. Tujuan dari penelitian yang telah dilakukan adalah untuk menyelidiki pengaruh
plastisizer dan cairan pengisi pada sifat fisik dan enterik kapsul gelatin lunak yang dilapisi
dengan Eudragit L 30 D-55.
Formulasi obat ke dalam soft gelatin capsule yaitu untuk mengatasi banyak masalah yang
terkait dengan sediaan tablet, termasuk pemadatan yang buruk, kurangnya kandungan atau
keseragaman bobot, atau masalah pencampuran. Bentuk sediaan soft gelatin capsule dipilih
karena penggunaannya akan meningkatkan stabilitas, terutama dengan obat-obatan yang sangat
rentan terhadap oksidasi dan hidrolisis. Penggunaan soft gelatin capsule juga akan meningkatkan
bioavailabilitas obat yang sifatnya hidrofobik. Pada penelitian ini dibuat soft gelatin capsule
enterik yang memungkinkan formulasi obat yang sesuai dengan pH rendah dan untuk zat aktif
yang rentan terhadap degradasi di lambung karena adanya enzim atau media asam. Lapisan
polimer enterik juga telah digunakan untuk mengurangi kejadian iritasi lambung dari obat-obatan
dan mengantarkan obat ke usus.
Soft gelatin capsule diperoleh dari RP Scherer (Detroit, MI). Bahan-bahan penyusunnya
terdiri dari ibuprofen 400 mg yang dilarutkan dalam polietilen glikol (PEG 400) atau Miglyol
812. Enteric kapsul yaitu Eudragit L 30 D-55 yang disumbangkan oleh Rohm Tech (Maiden,
MA). Dan plastisizer, yakni trietil sitrat (TEC) dan tributil sitrat (TBC). Alasan pemilihan bahan-
bahan penyusun soft gelatin capsule, diantaranya adalah ibuprofen dipilih karena ibuprofen
hampir tidak larut dalam media asam pada lambung. Kemudian penambahan PEG 400 ke
formulasi untuk memperbaiki adhesi polimer ke kulit gelatin. Lapisan Eudragit L 30 D
digunakan untuk menunjukkan stabilitas yang baik dari sediaan soft gelatin capsule tanpa
perubahan sifat disolusi dari waktu ke waktu. Dan penambahan plasticizer dalam sistem film
polimer diperlukan untuk pembentukan film halus yang bebas retak, memperbaiki aliran,
memberikan fleksibilitas, meningkatkan kekuatan, dan ketahanan sobek dari lapisan film.
Metode yang digunakan dalam pembuatan soft gelatin capsule yaiu coating. Metode
coating merupakan metode penyalutan atau enkapsulasi pada suatu sediaan yang bertujuan untuk
melindungi sediaan dari asam lambung, mencegah pelepasan obat pada lambung yang dapat
mengiritasi lambung, mencegah pelepasan obat pada lambung yang dapat menyebabkan efek
samping berupa gangguan GIT dan memperpanjang durasi pelepasan obat untuk obat-obat yang
efek farmakologinya diharapkan cukup lama. Pada tahapan persiapan coating, suspensi pelapis
akrilik dibuat dengan menambahkan air ke dispersi polimer Eudragit L 30 D-55 yang tersedia
untuk mengurangi kandungan padatan. Kira-kira 15%-20% plasticizer (berdasarkan berat
polimer kering) ditambahkan, dan suspensi diaduk selama kurang lebih 30 menit untuk dispersi
yang mengandung plasticizer terlarut dalam air (TEC), dan kurang lebih 48 jam untuk suspensi
yang mengandung plasticizer yang tidak larut air (TBC). 2% larutan hidroksipropil metilselulosa
(HPMC) dibuat dengan menambahkan Opadry ke air yang dimurnikan. Selanjutnya prosedur
coating dilakukan dengan cara; soft gelatin capsule yang mengandung larutan ibuprofen dilapisi
dengan model Hi-Coater Mini HCT-20. Sebanyak 300 g ditempatkan di Hi-Coater dan
dipanaskan terlebih dahulu selama 30-60 menit sebelum dilakukan inisiasi pelapisan. Suhu diatur
antara 30 dan 34 C. Kecepatan putaran diatur pada 35 rpm. Batch yang dilapisi dengan HPMC
diatur laju penyemprotannya 2,2 g / menit dan tekanan udara adalah 1 kg / cm2. Densitas
Eudragit L 30 D-55 diatur pada kecepatan 2,1 g / menit dan tekanan udara adalah 1 kg / cm2.
Untuk mengetahui koalesensi lebih lanjut dari film polimer dan memastikan distribusi plasticizer
bersifat homogen, semua kapsul diseimbangkan kira-kira selama 16 jam pada suhu 35 C
setelah lapisan akrilik digunakan.
Evaluasi yang dilakukan terhadap soft gelatin capsule yang dilapisi dengan Eudragit L
30 D-55 meliputi; uji disintegrasi, merupakan uji yang dilakukan untuk mengetahui larutnya atau
hancurnya kapsul dalam larutan. Karena ibuprofen hampir tidak larut dalam media asam, dan
gelatin akan larut dalam hitungan menit dalam 0,1 N HC1, pengujian disintegrasi dilakukan
dengan Bio-Dis II untuk menentukan apakah proteksi enterik telah dicapai atau tidak. Bio-Dis II
diprogram untuk beroperasi pada 20 tetes per menit dalam 250 ml 0,1 N HCI pada suhu 37 C.
Tiga kapsul dari masing-masing lot diuji ketahanan enteriknya.
Yang kedua adalah analisis kelembaban. Kelembaban di dinding kapsul ditentukan dengan
teknik Karl Fischer. Modifikasi metode Karl Fischer digunakan, dimana gelatin ditempatkan
dalam aseton dan dibiarkan seimbang selama 12 jam sebelum sampel ditempatkan di peralatan.
Untuk menentukan kehilangan pengeringan, kapsul gelatin lunak dari masing-masing lot
dipotong secara longitudinal di sepanjang jahitan. Cairan pengisi dilepaskan dengan hati-hati dan
kapsul dikeringkan. Kerang kapsul ditimbang, ditempatkan dalam oven 40 C selama 4 hari,
kemudian dilepas. Penurunan berat dan persen penurunan berat bada kemudian dihitung.
Dan evaluasi yang terakhir adalah analisis fisik. Sifat mekanik soft gelatin capsule diukur dengan
menggunakan alat uji universal Instron, Model 4201. Kapsul yang akan diuji ditempatkan pada
platform stasioner bawah, dan pelat atas disesuaikan sampai bersentuhan dengan kapsul. Bagian
atas kemudian diaktifkan untuk menurunkan dan mengkompres kapsul dengan kecepatan 5 mm /
menit. Kekuatan beban diukur dalam kg, dan jarak pelat atas yang ditempuh dalam mm dan titik
kegagalan kapsul gelatin lunak dicatat.
Hasil penelitian menunjukkan bahwa soft gelatin capsule (SGC) dengan lapisan enteric
berupa Eudragit L 30 D-55 dengan TEC (sebagai plastiziser) memberikan perlindungan enterik
yang baik tanpa cairan pengisi daripada TBC. Studi awal ini menyarankan kemungkinan
perpindahan plasticizer dari film akrilik ke dalam cangkang gelatin, dan penelitian lebih lanjut
sedang dalam proses untuk menyelidiki kinetika difusi dari plasticizer.
international
journal of
ELSEVIER International Journal of Pharmaceutics 113 (1995) 17-24
pharmaceutics

Physical and enteric properties of soft gelatin capsules coated


with Eudragit L 30 D-55
L.A. Felton a,,, M.M. Haase a, N.H. Shah b G. Zhang b, M.H. Infeld b, A.W. Malick b,
J.W. McGinity a

a College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA


b Hoffman-La Roche, Inc., Nutley, NJ 07110, USA
Received 23 December 1993; modified version received 13 May 1994; accepted 26 May 1994

Abstract

The enteric coating of soft gelatin capsules (SGC) containing ibuprofen in either PEG 400 or Miglyol was
investigated. The effects of two plasticizers, triethyl citrate (TEC) and tributyl citrate (TBC), on the physical and
enteric properties of SGC coated with Eudragit L 30 D-55 were studied. The water soluble plasticizer TEC was
found to be a good plasticizing agent for the Eudragit L 30 D-55 irrespective of the fill liquid, while the TBC
provided satisfactory results only for capsules containing the hydrophobic fill liquid, Miglyol . The combination of
TEC and TBC provided effective plasticization for the acrylic coating regardless of the fill liquid. A subcoat of
HPMC showed no effect on the enteric protection of either Miglyol - and PEG-containing capsules that were stored
at room temperature and zero percent relative humidity. The moisture content of the gelatin shell of the film coated
SGC stored at room temperature and at 0 or 96% relative humidity was followed as a function of time. The load
strength of the capsules was measured during 3 months of storage using an Instron universal testing apparatus, and
the physical-mechanical properties of the capsules were correlated with the moisture content of the SGC. As the
moisture content of the gelatin decreased, all formulations exhibited an increase in load strength.

Keywords: Soft gelatin capsule; Enteric coating; Eudragit L copolymer; Plasticizer; PEG 400; Miglyol; Mechanical
properties

1. Introduction of an enteric polymer. Enteric polymeric coatings


have also b e e n e m p l o y e d to decrease the inci-
F o r drugs that are susceptible to d e g r a d a t i o n dence of gastric irritation from drugs such as
in the stomach due to the p r e s e n c e of enzymes or aspirin (Petroski, 1989) and to deliver drugs to
acidic media, protection of the dosage form has the small intestine (Sherif et al., 1969). Such
generally b e e n achieved t h r o u g h the application polymers include the acrylates, cellulosic deriva-
tives, and shellac. These polymers have b e e n used
previously for enteric coating of tablets (Porter et
al., 1982; L e h m a n n , 1986) and pellets ( M e h t a et
* Corresponding author. al., 1986)).

0378-5173/95/$09.50 1995 Elsevier Science B.V. All rights reserved


SSDI 0378-5173(94)00169-6
18 L.A. Felton et al. / International Journal of Pharmaceutics 113 (1995) 17-24

Few studies, however, have reported on the hydrophobic drugs (Mallis et al., 1975; Johnson et
coating of gelatin capsules with enteric polymers. al., 1976). Coating SGC with enteric polymers
Murthy and co-workers (1986) conducted a com- would allow formulations of drugs which are sen-
parative evaluation of the aqueous enteric poly- sitive to low pH or gastric enzymes to benefit
mers, Eudragit L 30 D, Aquateric , and from the advantages that SGC offer. However,
Coateric , coated on hard gelatin capsules the inherent flexibility of the gelatin shell pre-
(HGC). Higher levels of enteric coatings were sents significant challenges to the pharmaceutical
needed to prevent agglomeration of capsules scientist when film coating soft gelatin capsules
stored at high temperatures and humidity. No with enteric polymers. The objectives of the pre-
significant difference in release rates or enteric sent study were to investigate the effects of plasti-
protection was found between the two plasticiz- cizers and the fill liquid on the physical and
ers, diethyl phthalate (DEP) and triethyl citrate enteric properties of soft gelatin capsules that
(TEC), in the Eudragit coatings. The Eudragit were coated with Eudragit L 30 D-55 (known as
L 30 D showed excellent stability with no change Eudragit L 30 D prior to 1 July 1993). The
in dissolution
/
properties over time. Murthy and stability of the enteric coated SGC and the mois-
co-workers (1988) also investigated the effect of ture content of the gelatin were also studied
hydroxypropyl cellulose (HPC) subcoats and over- during storage as a function of humidity.
coats on organic and aqueous-based enteric poly-
mers. Eudragit L 30 D was found to provide a
smooth homogeneous film with and without the 2. Materials and methods
HPC subcoat with no difference noted in enteric
protection. 2.1. Materials
Thoma and Bechtold (1986) reported that
problems which occur during the enteric coating The soft gelatin capsules were obtained from
of hard gelatin capsules were generally due to the R.P. Scherer (Detroit, MI) and contained ibupro-
physical properties of the gelatin. Film coating fen 400 mg dissolved in either polyethylene glycol
HGC with aqueous spray formulations caused the (PEG 400, Union Carbide, Houston, TX) or
capsule shell to soften and become sticky due to Miglyol 812 (Dynamit-Nobel, Troisdorf, Ger-
solubilization of the gelatin. The application of many). The soft gelatin capsules were size 6 ob-
HPC or HPMC (hydroxypropyl methylcellulose) long (II). The final weight of the uncoated cap-
as a subcoat was found to eliminate the problem, sules containing PEG was approx. 0.721 g. Un-
though an increase in brittleness of the gelatin coated capsules containing the Miglyol weighed
capsule due to water evaporation and drying was on average 0.643 g. The Eudragit L 30 D-55 was
reported. The addition of PEG 400 and PEG donated by Rohm Tech (Maiden, MA) and
6000 to the coating formulation was found to Opadry was donated by Colorcon, Inc. (West
provide improved adhesion of the polymer to the Point, PA). The two plasticizers, triethyl citrate
gelatin shell. and tributyl citrate, were donated by Morflex Inc.
The formulation of drugs into soft gelatin cap- (Greensboro, NC).
sules (SGC) has been reported to solve many
problems associated with tableting, including poor 2.2. Methods
compaction, lack of content or weight uniformity,
and other powder flow or mixing problems (Sea- 2.2.1. Coating preparation
ger, 1985). Improved stability has been achieved The acrylic coating suspensions were prepared
through the use of soft gelatin capsules, most by adding water to the commercially available
notably with drugs which are highly susceptible to Eudragit L 30 D-55 polymeric dispersion to
oxidation and hydrolysis (Ebert, 1977; Ma- decrease the solids content to approx. 15%. 20%
conachie, 1977). However, the greatest advantage plasticizer (based on dry polymer weight) was
that SGC offer is the increased bioavailability of added, and the suspensions were agitated for at
L.A. Felton et al. / International Journal of Pharmaceutics 113 (1995) 17-24 19

least 30 min for dispersions containing the water on drying, soft gelatin capsules from each lot
soluble plasticizer (TEC), and for a minimum of were cut longitudinally along the seam. The fill
48 h for the suspensions containing the non-water liquid was carefully removed and the capsules
soluble plasticizer (TBC). were dried with a laboratory wipe. The capsule
A 2% solution of hydroxypropyl methylcellu- shells were weighed, placed in a 40C oven for 4
lose (HPMC) was prepared by adding the days, then reweighed. Weight loss and percent
Opadry to purified water. A clear solution was weight loss were then calculated (n = 4). Since
obtained following agitation for approx. 2 h. there was less than a 1% difference in the results
from both methods, and the Karl Fischer method
2.2.2. Coating procedure took considerably more time to perform, the
Soft gelatin capsules containing ibuprofen so- moisture content was determined using the loss
lutions were coated in a Mini Hi-Coater Model on drying method.
HCT-20, Fruend Company, Tokyo, Japan. A 300
g batch was placed in the Hi-Coater and pre- 2.2.5. Physical analysis
warmed for 30-60 min before coating was initi- The mechanical properties of the SGC were
ated. Outlet bed temperatures were held between measured using an Instron, Model 4201 universal
30 and 34C. The rotational speed was set at 35 testing apparatus. The capsule to be tested was
rpm. Batches which were subcoated with HPMC placed on the lower stationary platform, and the
were coated at a sprayed rate of 2.2 g / m i n and upper platen was adjusted until it was in contact
the air pressure was 1 k g / c m 2. The plasticized with the capsule. The upper platen was then
Eudragit L 30 D-55 dispersion was applied at a activated to lower and compress the capsule at a
rate of 2.1 g / m i n and the air pressure was 1 rate of 5 mm/min. The load strength was mea-
kg/ c m 2. To promote further coalescence of the sured in kg, and the distance the upper platen
polymeric film and to ensure the distribution of traveled in mm at the failure point of the soft
plasticizer was homogeneous, all capsules were gelatin capsule was recorded.
equilibrated for approx. 16 h at 35C after the
acrylic coating was applied (Goodhart et al., 1984;
Lippold et al., 1989). 3. Results and discussion

2.2.3. Disintegration test Previous reports in the literature have ad-


Since ibuprofen is virtually insoluble in acidic dressed some of the problems concerning the film
media, and gelatin will dissolve within minutes in coating of hard gelatin capsules that are unique
0.1 N HC1, disintegration testing with a Bio-Dis II to that dosage form. The two-piece design of the
(VanKel Industries, Edison, N J) was used to de- HGC has caused problems in the film coating
termine whether or not enteric protection had process, due mainly to the separation of the HGC
been achieved. The Bio-Dis II was programmed during the coating process, resulting in the poly-
to operate at 20 dips per min in 250 ml 0.1 N HCI meric dispersion gaining entrance to the fill pow-
at 37C. Three capsules from each lot were tested der. Thoma and Bechtold (1986) suggested a
for enteric resistance. number of procedures to minimize these prob-
lems. Soft gelatin capsules generally contain the
2.2.4. Moisture analysis medicament dissolved or dispersed in oils or hy-
The residual moisture in the capsules walls drophilic liquids, which may present unique prob-
was determined with the Karl Fischer technique lems in the application of enteric polymers. In
and from moisture loss on drying. A modification our study, the soft gelatin capsules were placed in
of the Karl Fischer method was used, in which the Hi-Coater and prewarmed before coating was
the gelatin was placed in acetone and allowed to initiated. Without this prewarming, the SGC were
equilibrate for a 12 h period before the sample very cold to the touch after completion of the
was placed in the apparatus. To determine loss coating process and the outer layers of the coat-
20 L.A. Felton et al. / International Journal of Pharmaceutics 113 (1995) 17-24

ing dried faster than the inner coating layers, distribution for water insoluble plasticizing agents,
causing bubble formation in the film. Prewarming such as TBC, required greater than 24 h. Gutier-
the capsules increased the temperature of the fill rez-Rocca (1993) also reported rapid partitioning
liquid to that of the bed temperature, and al- of the water soluble plasticizers, TEC and tri-
lowed the coating to dry more uniformly, result- acetin, with Eudragit L 30 D. Adsorption stud-
ing in a smooth, homogenous film. ies carried out to 72 h did not demonstrate any
The addition of a plasticizer in the polymeric increase in the adsorption of these plasticizers to
film system was also necessary for the formation the polymers. Long equilibrium times of 36 h
of smooth films that were free of cracks and were reported for the insoluble plasticizers, TBC
other defects. Physical characteristics of the film and acetyl tributyl citrate, to allow for the parti-
such as tensile strength and elasticity will change tioning of the plasticizers into the acrylic poly-
with the addition of a plasticizer. Plasticizers are mer. If insufficient time is allowed for the plasti-
especially necessary components to reduce brit- cizer to partition into the polymer phase, the
tleness, improve flow, impart flexibility, and in- unincorporated plasticizer droplets, as well as the
crease toughness, strength, and tear resistance of plasticized polymer particles, are sprayed on to
the film coat (Banker, 1966). The plasticizer must the substrates during the coating process. Uneven
be distributed evenly between the polymer chains plasticizer distribution within the film could re-
in order to disrupt the intermolecular forces sult and potentially cause changes in the physical
holding the chains in a rigid pattern. Disruption mechanical properties of the film during aging.
of the polymer-polymer bonds generally results in To allow for the plasticizer to partition from the
a decrease in tensile strength, a lowering of glass aqueous phase to the polymer phase, the TEC
transition temperature, and an increase in elon- was mixed with the polymeric dispersion for at
gation and flexibility of the films. Use of a plasti- least 30 min. For the water insoluble TBC, mixing
cizer has been found to be imperative when work- times were extended to 48 h to ensure that plasti-
ing with polymeric films, such as acrylic polymers, cization of the polymer had occurred.
that are generally considered to be brittle in The effects of the plasticizers and the two fill
nature. liquids on the disintegration times of SGC coated
Two alkyl esters of citric acid, TEC and TBC, with Eudragit L 30 D-55 in 0.1N HCI solution
were used as plasticizers in the film coating for-
mulations. The three butyl groups on the TBC
caused this plasticizer to be inherently more hy- Table 1
drophobic than TEC. The method of plasticizer Initial disintegration times of SGC coated with Eudragit L
incorporation into an aqueous polymeric disper- 30 D-55 in 0.1 N HC1

sion has been shown to be a crucial factor in Fill liquid % L 30 D Plasticizer Enteric
protection
determining the physical-mechanical properties
of the final film coating (Iyer, 1990). When plasti- PEG 400 uncoated none 3 min
PEG 400 5% 20% T E C > 4h
cization occurs by a mechanical process, the plas-
PEG 400 10% 20% T E C > 4h
ticizer must partition from the aqueous phase to PEG 400 15% 20% T E C > 4h
the polymer phase and subsequently diffuse PEG 400 5% 20% T B C 0.5 h
throughout the polymer. The rate and extent of PEG 400 10% 20% T B C 0.5 h
this partitioning for an aqueous dispersion is de- PEG 400 10% 10% T E C / > 4h
10% T B C
pendent on the solubility of the plasticizer in
P E G 400 10% + 2% H P M C 20% T E C > 4h
water and its affinity toward the polymer phase. Miglyol uncoated none 3 min
Bodmeier and Paeratakul (1994) found the equi- Miglyol 10% 20% T E C > 4h
librium of plasticizer distribution in an aqueous Miglyol 10% 20% T B C 3h
dispersion of ethyl cellulose for water soluble Miglyol 10% 10% T E C / > 4h
10% T B C
plasticizers, such as TEC, occurred rapidly
Miglyol 10% + 2% H P M C 20% T E C > 4h
whereas the time needed to achieve equilibrium
L.A. Felton et al. / International Journal of Pharmaceutics 113 (1995) 17-24 21

are listed in Table 1. Uncoated SGC ruptured 47


and released the fill liquid within 3 min regard-
less of the fill liquid. Complete dissolution of the 3

SGC occurred within 7 min in the acidic media. Initial


Protection from disintegration of the SGC was 2 [] 0%RladRT(2 weeks)
seen for both fill liquids when TEC was the ~i 96%RH/RT(2 weeks)
I~1 RT (6 Months)
plasticizing agent. The films containing the water 1-
insoluble plasticizer, TBC, did not provide en-
teric protection to capsules containing PEG 400, 0
Storage Condiffon Over Time
a hydrophilic fill liquid. However, film coatings
containing the TBC alone in capsules containing Fig. 1. Enteric protection of SGC containing Miglyol coated
with Eudragit L 30 D-55 plasticized with TBC during stor-
the hydrophobic fill liquid, Miglyol, showed age.
much improved enteric protection. Film coatings
containing the TBC in combination with TEC
provided enteric protection for both Miglyol were unable to be tested, as shown in Table 2. A
and PEG containing capsules. Enteric protection 5% level of Eudragit L 30 D-55 was not suffi-
was also achieved for capsules which received a cient to protect the capsules containing PEG
2% HPMC subcoat prior to the acrylic coating, from agglomeration at 96% relative humidity and
regardless of the fill liquid. room temperature (96% R H / R T ) . At 10 and
Capsules were stored in open containers at 15% coating levels, better protection from the
room temperature and at either 0 or 96% relative environment was achieved. These findings are in
humidity while capsules stored under ambient agreement with those of Murthy and co-workers
conditions were placed in glass containers with (1986, 1987) who reported a higher level of poly-
screw-top lids. Enteric protection was followed meric film was required to protect the HGC from
over a 3 month period. No change in enteric agglomeration under conditions of high humidity.
protection was noted in capsules that initially Capsules containing the HPMC subcoat also
exhibited enteric protection for at least 4 h, with agglomerated during storage at 96% R H / R T ,
the exception of the lots that agglomerated and regardless of fill liquid. Gutierrez-Rocca and

Table 2
Disintegration times of SGC coated with Eudragit L30D-55 during storage as a function of relative humidity
% L 30D-55 % plasticizer 0% R H / R T 96% R H / R T
1 month 3 months 1 month 3 months
PEG
5% 20% TEC > 4h > 4h a
10% 20% TEC >4h >4h >4h >4h
15% 20% TEC >4h >4h >4h >4h
10% 10% TEC >4h >4h >4h >4h
10% TBC
10% and
2% H P M C 20% T E C >4h >4h >4h

Miglyol
a
10% 20% T E C >4h >4h >4h
10% 10% T E C / >4h >4h >4h >4h
10% T B C
10% and
2% H P M C 20% T E C >4h >4h a
a Capsules agglomerated - unable to be tested.
22 L~4. F elton et al. / International Journal of Pharmaceutics 113 (1995) 17-24

McGinity (1994) reported that the glass transition film. Further studies are needed to investigate
temperature (Tg) of the acrylic polymer decreased this plasticizer migration more fully.
during storage at high humidity due to the ad- In agreement with the findings of Murthy and
sorbed water acting as a plasticizer and breaking co-workers (1986) with hard gelatin capsules, no
the intermolecular hydrogen bonds of the poly- discernible difference in the enteric protection of
mer which resulted in a stickier film coating. In the SGC was observed between capsules that had
the present study, the H P M C subcoat acted as a a protective subcoat of H P M C and those without
barrier to slow moisture penetration. More water a subcoat, regardless of the fill liquid, during
remained in the acrylic film, resulting in a lower- storage at 0% relative humidity and room tem-
ing of the Tg and causing the product to agglom- perature (0% R H / R T ) . The H P M C subcoat was
erate. Without the H P M C subcoat, the Miglyol found to adhere to the gelatin shell wall initially,
capsules coated with the acrylic polymer contain- but adherence was impaired over time and sepa-
ing T E C as the plasticizer also agglomerated at ration of the film from the gelatin shell occurred
high humidity probably due to the hydrophobic during storage. With hard gelatin capsules, Thoma
properties of the fill liquid, causing more mois- and Bechtold (1986) had reported improved ad-
ture to remain in the film and lower the Tg. hesion of an enteric polymer to the shell of the
Enteric protection of Miglyol containing cap- H G C when a subcoat of H P M C was initially
sules coated with Eudragit L 30 D-55 with TBC applied.
as the plasticizer was found to decrease during The moisture content of the soft gelatin cap-
storage, as shown in Fig. 1. Initially, the coated sules was investigated due to the potential effects
capsules could withstand 3 h in acidic media. that moisture may exert on the physical proper-
After 2 weeks storage at 0% R H / R T , enteric ties of the film and the gelatin shell. The coated
protection decreased to 2 h while enteric protec- capsules containing P E G initially possessed a sig-
tion decreased to 1 h in the capsules stored at nificantly higher moisture content than those
96% R H / R T . The disintegration times were also containing Miglyol , as shown in Table 3. During
found to drop after 6 months storage under ambi- storage at 0% R H / R T , the moisture content of
ent conditions. This result could be due to the the gelatin decreased in both Miglyol - and
partitioning of the TBC from the film into the PEG-containing SGC. Previous reports in the lit-
hydrophobic fill liquid. Schulze and McGinity erature discuss the migration of water from the
(1993) found the Eudragit L polymers were very gelatin shell of H G C (Bond et al., 1970; Bell et
brittle. With the migration of plasticizer from the al., 1973). The present study found that the mois-
film into the fill liquid, the film will become more ture content increased during storage at 96%
brittle and crack, resulting in failure of the acrylic R H / R T , regardless of the fill liquid. However,

Table 3
Moisture content of SGC coated with Eudragit L 30 D-55 during storage as a function of relative humidity
Storage Fill Plasticizer Initial 1 month 2 months 3 months
0% RH/RT PEG TEC 4.96% 2.73% 1.81% 1.36%
PEG TEC/TBC 4.78% 2.56% 1.79% 1.12%
Miglyol TEC 1.15% 0.00% 0.00% 0.00%
Miglyol TEC/TBC 2.46% 0.00% 0.00% 0.00%
96% RH/RT PEG TEC 4.96% 6.58% 9.35% 9.18%
PEG TEC/TBC 4.78% 7.47% 9.03% 8.90%
Miglyol TEC 1.15% 13.11% 11.21% a
Miglyol TEC/TBC 2.46% 13.62% 11.06% 11.60%
a Capsules agglomerated - unable to test.
L.A. Felton et al. / International Journal of Pharmaceutics 113 (1995) 17-24 23

the gelatin shell of the capsules containing 12 ' "5


Miglyol gained more moisture than PEG cap- ~l,
~-~ 10' o
sules, probably due to the hydrophobic nature of 4
the Miglyol. Under high humidity, water mi-
,- 8-
grated through the acrylic coating into the gelatin 3 --~
shell. The water continued to migrate into the 6-

hydrophilic PEG liquid, whereas the hydrophobic


properties of the Miglyol prevented water mi- ~O 4 ~:
~
gration into the fill liquid. The water remained in
the gelatin which resulted in an increased mois- 2 , 1
0 1 2 3
ture content of the gelatin shell. This explanation Time (Months)
is in agreement with Strickland and co-workers Fig. 2. C o m p a r i s o n of load s t r e n g t h a n d m o i s t u r e c o n t e n t of
(1962) who found the direction of water transfer c o a t e d S G C c o n t a i n i n g P E G ( m o i s t u r e c o n t e n t , n = 4; load
was determined by the relative hygroscopicity of s t r e n g t h , n = 3): m o i s t u r e c o n t e n t ( ) ; load s t r e n g t h ([]).

the gelatin capsule and the fill contents and Sera-


juddin and co-workers (1986) who reported the
content of the gelatin shell remained constant
extent of the migration of water into the fill
after the first month. Capsules coated with
material of the SGC depended on the nature of
Eudragit L 30 D-55 containing the TEC plasti-
the solvent used in the fill liquid.
cizer exhibited this phenomenon as well as the
The moisture content of the gelatin shell af-
capsules coated with films containing the
fects the mechanical properties of the gelatin
T E C / T B C combination. One possible explana-
capsules. Kontny and Mulski (1989) related rela-
tion for this surprising result could be due to the
tive humidity to capsule brittleness and found
migration of the plasticizer from the acrylic film
that below forty percent relative humidity, HGC
into the gelatin shell thus making the shell more
became brittle. Liebowitz and co-workers (1990)
flexible and able to withstand higher pressures.
found increased brittleness occurred when HGC
In conclusion, a method for the application of
were exposed to high temperatures and low rela-
an aqueous dispersion of an acrylic polymer to
tive humidities. Because SGC contain a high level
soft gelatin capsules was developed. The results
of moisture and a plasticizer which imparts char-
of this study demonstrated that the film coating
acteristic flexibility to the gelatin, the moisture
of SGC with Eudragit L 30 D-55 plasticized
content was correlated to the physical strength of
with TEC provided good enteric protection, re-
the coated SGC. Using an Instron universal test-
ing apparatus, the load strength of the coated
capsules was measured. During storage at 0% 8' '1.2
R H / R T , the strength of the capsules was ex- Z
pected to decrease, as the moisture content of 7' ~1.0 "~
0

the capsules decreased. Shah and co-workers 6" "0.8


(1992) had found SGC containing PEG 400 as the =
5" "0.6
fill material became brittle upon aging and ex- 0
plained the result as possibly due to water and "O 4 "0.4
plasticizer migration from the shell into the fill O
3 "0.2
liquid. In this study, however, the strength of the
PEG capsules coated with Eudragit L 30 D-55 2 T T o.o ~
and stored at 0% R H / R T was found to increase 0 1 2
Time (Months)
as the moisture levels of the gelatin shell de-
Fig. 3. C o m p a r i s o n of load s t r e n g t h a n d m o i s t u r e c o n t e n t of
creased (Fig. 2). The load strength of the Miglyol c o a t e d S G C c o n t a i n i n g Miglyol ( m o i s t u r e content, n = 4;
capsules also increased over the three month load s t r e n g t h , n = 3): m o i s t u r e c o n t e n t ( m ) ; load s t r e n g t h
period, as shown in Fig. 3, although the moisture (D).
24 L~4. Felton et al. / International Journal of Pharmaceutics 113 (1995) 17-24

gardless of the fill liquid. The properties of the Kontny, M.J. and Mulski, C.A., Gelatin capsule brittleness as
fill liquid, however, in conjunction with the hy- a function of relative humidity at room temperature. Int. J.
Pharm., 54 (1989) 79-85.
drophobic plasticizer TBC, were found to influ- Lehmann, K., Acrylic latices from redispersible powders for
ence the degree of enteric protection. Changes in peroral and transdermal drug formulations. Drug Dev.
the enteric protection of the Miglyol capsules Ind. Pharm., 12 (1986) 265-287.
coated with Eudragit L 30 D-55 containing TBC Liebowitz, S.M., Vadino, W.A. and Ambrosio, T.J., Determi-
as the plasticizing agent occurred during storage, nation of hard gelatin capsule brittleness using a motor-
ized compression test stand. Drug Dev. Ind. Pharm., 16,
possibly due to plasticizer migration from the (1990) 995-1010.
acrylic film into the gelatin, resulting in an in- Lippold, B.H., Sutter, B.K. and Lippold, B.C., Parameters
creased brittleness in the films and ultimately controlling drug release from pellets coated with aqueous
crack formation and film failure. An increase in ethyl cellulose dispersions. Int. J. Pharm., 54 (1989) 15-25.
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Manuf Chem., 48 (1977) 33-39.
formulations, possibly attributed to the migration Mallis, G.I., Schmidt, D.H. and Lindenbaum, J., Superior
of the plasticizer into the gelatin. While this bioavailability of digoxin solution in capsules. Clin. Phar-
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Tech., 10 (1986) 46-56.
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comparative evaluation of aqueous enteric polymers in
capsule coatings. Pharm. Tech., 10 (1986) 36-46.
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