Abstract

Recently, hydroxypropyl methylcellulose (HPMC) has been made available
as an alternative to gelatin for the manufacture of two-piece hard capsules. Hard
Capsules manufactured from HPMC with carrageenan as a gelling agent have
demonstrated rapid and comparable in-vivo disintegration times to gelatin and
overcome some of the disadvantages gelatin capsules present. Gelatin
becomes brittle when stored at low humidity and shell dehydration may occur
with hygroscopic fillings. In addition, the presence of aldehyde groups in the
filling material can reduce the solubility of the gelatin capsule shell by crosslinking.
HPMC capsule shells demonstrate lack of brittleness even at moisture
levels below 2%, no cross-linking and improved chemical stability, however
there is a lack of information relating to the physico- chemical properties of
HPMC capsule shells and their dissolution behaviour. The aims of this work
were to develop and use different techniques to investigate the physicochemical
properties of HPMC and gelatin hard capsule shells and to study the
possible interactions between the capsule shell (after different storage
conditions) and dissolution media (composition, pH and ionic strength) with and
without filling materials.
Thermal analysis was undertaken using MDSC to determine and compare the
glass transition temperatures of gelatin and three batches of HPMC, which gave
an insight into their fundamental physico-chemical properties. Rheological
studies were undertaken using DMA, which is a novel method that has not been
used previously on capsule shells, to investigate and compare the different
viscoelastic properties of the capsules. These included: static scans to study the
elastic modulus, linear creep to determine the behaviour of the capsule shells
under stress, and dynamic scans to determine the storage modulus and
viscosity. The influence of storage RH and time (35% and 53% RH for 24 hours
and 3 days), dissolution media composition, ionic strength and pH on the shell
dissolution time, and drug release properties of the capsules (using theophylline
as the model drug) was also investigated.
The findings show that the gelatin capsules became brittle at low moisture
content and show some degree of aging upon storage, this was not seen for
HPMC. Capsules made form HPMC were more elastic than gelatin and
gelatin/Polyethylene glycol, with a greater degree of recovery to an applied
stress (e.g. the Young’s Modulus for New HPMC and gelatin capsules was
0.728 MPa vs 1.092 MPa respectively after storage at 53%RH/3 days, and % JR
for both capsules was 99.26% vs 98.47% respectively after storage at
35%RH/24 hr). It was also found that storage conditions showed no significant
effect on the capsule shell dissolution time, and pH had minimal effect on shell
dissolution time of the HPMC capsules. The Changes seen with change in pH
were attributed to dissolution media composition, salt concentration and ionic
strength of the different dissolution media. For HPMC shells, dissolution time in
Sörensen phosphate buffer decreased by 13 – 22 % as pH increased from 5 to
8, however, in citro-phosphate buffer there was a 19 – 36 % increase in
dissolution time from pH 5 to 7, In acetate buffer, HPMC shells did not dissolve
in pH 6, whereas gelatin dissolution time increased from 2.0 to 3.5 mins as pH
increased. Drug dissolution rate was highest from HPMC capsules in all 0.1 M
3
dissolution media compared with gelatin and was affected by the presence of
high concentrations of K+ and Na+ ions, whereas gelatin capsules were
influenced mostly by the presence of Na+ ions. For example in 0.1 M potassium
phosphate buffer (KPB) 100% drug release from HPMC capsules occurred after
35 mins, however, this occurred after 180 mins for gelatin capsules, and in 0.1
M sodium phosphate buffer (NaPB) 100% drug release from HPMC and gelatin
capsules occurred after 27 mins and 120 mins respectively. After 5 hours, < 4 %
and 10 % drug release was obtained in 0.5 M KPB and NaPB respectively. The
mechanism of drug release from gelatin capsules was found to be different in
both basic and acidic media. This was constant for the HPMC capsules,
showing that the change in pH did not affect the release mechanism.
These investigations support work that has been previously reported concerning
the properties of the HPMC capsules, and provide new information In terms of
their viscoelasticity, interactions with various ions present in different dissolution
media, drug dissolution behaviour before and after storage for prolonged
periods, and the mechanisms of drug release.