Materials and methods
Two case studies were designed to investigate the influence of material attributes: the percent HP substitution, viscosity,
and particle size on the functional performance of hydrophilic matrix-tablet formulations (2–3).
The rate-controlling polymer in the model formulations was Methocel K15M Premium CR (USP substitution type 2208). The designation of "15M" describes a relatively high-viscosity material, and the "CR" grade is designed
for controlled-release applications.
Polymer concentration can be an important factor for matrix robustness. Two polymer concentrations, therefore, were evaluated:
30% w/w, which has been shown to produce robust formulations, and 15% w/w, which was considered relatively low and could result
in performance differences of the hydrophilic matrix tablet associated with variability in the material attributes.
Table I: Physiochemical properties of hypromellose (Methocel K 15 Premium CR , Dow Chemical) batches.
|
For these case studies, Methocel K15M Premium CR batches were carefully selected. Six of the batches were selected on the
basis of having two out of three material attributes (percent HP, particle size, and apparent viscosity) within the nominal
manufacturer sales-specification values, with the third property at the "high" or the "low" extremes of the normal sales-specification
range. In addition, one batch had all three properties close to the nominal specification values, denoted as "center point"
(see Table I). A total of 14 matrix formulations (seven each for 15% and 30% w/w polymer concentration) were prepared. The Methocel K15M
Premium CR batches used in these studies will be referred to by the "batch name" listed in Table I.
The methoxyl substitution content could be considered another material attribute for Methocel that may affect the robustness
of the formulation. Prior assessment of the methoxyl content variation (from the manufacturer's sales-specification) showed
this to be precisely controlled, and therefore, it was not considered to be a significant variable and was excluded from the
study.
Propranolol hydrochloride ER model formulations
Table II: Extended-release model formulation containing propranolol hydrochloride as the active ingredient.
|
For the first study, the model API was propranolol HCl (soluble drug, 50 mg/mL, 160-mg dose). The formulation is detailed
in Table II.
Tablet preparation procedure. Propranolol HCl, hypromellose, and microcrystalline cellulose were passed through an ASTM #30 mesh (600 µm) screen and mixed
in a four-quart V blender (Model B Lab Blender, Patterson–Kelley) at 26 rpm for 10 min. Magnesium stearate was screened through
an ASTM #40 mesh (400 µm) screen and added to the powder mixture, followed by blending for an additional 3 min. The final
powder mixtures were compressed at 5–20 kN (compaction pressure of 70–280 MPa) using an instrumented 10-station rotary tablet
press (Piccola, RIVA) at 20 rpm using standard round 9.52-mm concave tooling and a tablet weight of 350 mg.
The formulated powder blends were analyzed for bulk and tapped densities using a VanKel density tester (Model 10705, Varian),
flowability using a flow tester (Sotax FT 300, Sotax), and loss on drying (LOD) using an infrared (IR) moisture balance (Model
IR-200, Denver Instrument). Tablet weight, breaking force, diameter, and thickness were measured with an automated tablet
tester (Multicheck V, Erweka). Tablet friability was measured using a VanKel friabilator (Varian) at 100 revolutions and
25 rpm. A dissolution study was performed using an USP Apparatus II, 100 rpm, with sinkers, and 1000 mL of a pH 6.8 phosphate buffer. Propranolol release was detected at a wavelength
of 289 nm using a ultraviolet (UV)-visible spectrophotometer (Agilent 8453, Agilent Technologies) fitted with quartz flow
cells of a 2-mm path length.
The similarity factor (f
2
), which is a measurement of the similarity in the percentage of dissolution between two curves, was calculated by comparing
the high versus the low end of the selected physicochemical property. Two dissolution profiles are considered similar when
the f
2
value is > 50. In addition, the release exponent (n) and release-rate constant (k) were calculated by fitting the dissolution data to the Power Law equation (M
t
/M
inf
) = k t
n
, where M
t
is the amount of drug released at time t; M
inf
is the amount of drug released over a very long time, which corresponds in principle to the initial loading; k is the kinetic constant; and n is the release exponent (12).
Theophylline ER model formulations
Table III: Extended-release model formulation containing theophylline as the active ingredient.
|
In the second study, the model API was theophylline anhydrous (slightly soluble drug, 8.3 mg/mL, 160-mg dose). The formulation
is detailed in Table III.
Tablet-preparation procedure. Theophylline, hypromellose, lactose, and fumed silica (Cab-O-Sil, Cabot) were passed through an ASTM #30 mesh (600 µm) screen
and mixed in a four-quart V blender (Patterson-Kelley) at 26 rpm for 10 min. Magnesium stearate was screened through an ASTM
#40 mesh (400 µm) screen, added to the powder mixture, followed by blending for a further 3 min. The final powder blends were
compressed at 15 kN (210 MPa) using an instrumented 10-station rotary tablet press (Piccola, RIVA) at 20 rpm using a standard
round 9.52-mm concave tooling and a tablet weight of 350 mg.
All blends were analyzed for bulk and tapped density using a VanKel density tester (Varian) and LOD (Model IR-200, Denver
Instrument). Tablets were examined for physical properties, including weight variation, thickness, and hardness as well as
friability. Drug release was measured using an USP Apparatus II (VK 7000, Varian) at 100 rpm with sinkers and 1000 mL of deionized water at 37 ± 0.5 °C. Theophylline release
was detected at a wavelength of 272 nm using a UV-visible spectrophotometer (Agilent 8453, Agilent Technologies) fitted with
quartz flow cells of a 2-mm path length. The similarity factor (f
2
) was calculated by comparing the high versus the low end of the selected physicochemical property. In addition, the release
exponent (n) and release-rate constant (k) were calculated by fitting the dissolution data to the Power Law equation (11).
|
