Materials and methods
Table II: Polyethylene oxide extended-release formulations used in the study.
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Formulation and preparation of PEO ER matrices.
The influence of hydro-alcoholic media on formulations of practically water insoluble gliclazide and freely water soluble
metformin HCl was investigated. Two 12-h release PEO matrix formulations were developed containing gliclazide or metformin
HCl, PEO (i.e., Polyox 1105 or 301) as a matrix former, microcrystalline cellulose (MCC) as a filler, fumed silica as a flow
aid, and magnesium stearate as a lubricant (see Table II). Table III shows the solubility of the drugs, polymer, and filler
in water and alcohol.
Table III: Solubility of the drugs, polymer and filler used in the study, in water and alcohol (14, 33–37).
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Both formulations, batch size 400 g, were blended in a shaker-mixer (Turbula, Bachofen). Microcrystalline cellulose and fumed
silica were first screened through a 500 μm (35 mesh) sieve to homogenize the powder. The rest of the ingredients, except
the lubricant, were added and blended for 10 min at 64 rpm. Magnesium stearate was then added and the formulations were mixed
for an additional one minute.
Tablets were manufactured using an instrumented 10-station rotary tablet press (Piccola, Riva) operating at 20 rpm. Gliclazide
tablets with a target weight of 200 mg were produced using 7 mm normal concave tooling at 20 kN (255 MPa). Metformin HCl matrices
with a target weight of 1000 mg were manufactured using 7 × 18 mm concave caplet tooling at 20 kN (79 MPa).
Dissolution studies.
Dissolution tests were conducted in a USP compliant dissolution bath (Sotax) using Apparatus II (i.e., paddles) with 8-mesh (2.38 mm) quadrangular baskets (QLA) in
1000 mL purified water, 5% or 40% w/v ethanol (USP/BP Hayman) solutions at 100 rpm and 37.0 ± 0.5 °C. Tablets were subjected
to the hydro-alcoholic media for duration of 12 h, or 1 h followed by 11-h dissolution in water.
Absorbance was measured with a dual-beam UV–vis spectrophotometer (PerkinElmer) using 5 mm quartz cells at a wavelength of
228 nm and 0.1 mm cells at 233 nm for gliclazide and metformin HCl, respectively. Tablets were analyzed in triplicates using
an automated sampling device, and mean with standard deviation values were reported.
The drug release profiles in hydro-alcoholic media were compared to those in purified water using the f
2 factor. An f
2 value between 50 and 100 indicates that the two dissolution profiles are similar (7, 38).
To investigate the mechanism of drug release in various media, the release data between 5 and 60% were fitted to the following
equation (16, 39–40):
where Q is the percentage drug released at time t, k is a kinetic constant incorporating structural and geometric characteristics of the tablet and n is the diffusion exponent that indicates the drug release mechanism (39–40).
For matrix tablets, an n value close to 0.5 indicates predominantly diffusion control of drug release. An n value around 1.0 indicates erosion or
relaxation control mechanism of drug release (41–42). Intermediate values suggest that both diffusion and erosion contribute
to the overall release mechanism (18).
The values of n and k are inversely related, such that a decrease in n value results in a k value increase. A high k value may suggest a burst drug release from the matrix (43–44).
Preparation and testing of PEO compacts.
Three viscosity grades of PEO were tested (i.e., Polyox 1105, 301, and Coagulant). PEO compacts with a target weight of 300
mg were manufactured using hydraulic automatic press (Auto T8, Atlas, Specac) and 10 mm flat-faced tooling at a compression
force of 20 kN (255 MPa).
Compacts were tested in a USP-compliant AT7 Sotax dissolution bath using Apparatus II (i.e., paddles) with large (15 × 31 mm) sinkers (Sotax), in 900 mL
of 0:100, 25:75 and 50:50 w/v ethanol:purified water mixtures at 100 rpm and 37 ± 0.5 °C.
The swelling properties of the compacts in various media were determined using a modified version of the method described
by Tahara et al. and Kavanagh and Corrigan by measuring the wet weight of the hydrated PEO compacts at 15, 30, 60 and 120
mins (45, 46). Each compact was placed into a preweighed plastic container; the excess media was drained and blotted from
around the tablet without touching it. The compact and the container were weighed, and the wet weight of each tablet was established.
Every determination at each time point was performed in triplicate, and average and standard deviation values were calculated.
The ratio of the wet weight (W
w
) to the initial weight (W
i
) of the compacts was calculated, as an indication of the extent of matrix relative swelling, similar to the Panomsuk et al.
approach, as described in the following equation (47):
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