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The process of extrusion/spheronization used to produce spherical granules frequently relies on formulations containing microcrystalline cellulose (MCC). This excipient can hold water, even when pressure is applied, and form "pastes" that have suitable rheological properties, which allow both extrusion and subsequent spheronization to produce uniform spherical granules. This article describes a new approach to providing paste systems with appropriate characteristics. This can be achieved by incorporating glyceryl monostearate (GMS) into the formulation. It was found that the inclusion of GMS in formulations provides a useful alternative to MCC as an effective excipient to aid the preparation of spherical granules, allowing the incorporation of drug loads as high as 90%.
The process of preparing spherical granules of approximately 1 mm in diameter by extrusion/ spheronization was introduced during the late 1960s. It involves forming the powder into a wet mass, which is forced through a restricted area (extrusion) to form strands of extrudate that are broken into short lengths and rounded by placement on a rotating plate within a cylinder.1 The sequence associated with the rounding of the extrudate have been described by Chapman.2 The exact consistency required to ensure that a wet mass can be processed into pellets is difficult to define. Raines et al. used the approach of Benbow et al. to establish a relationship between measurable rheological parameters obtained by utilization of a ram extruder and the quality of the surface of extrudate.3,4 Chohan and Newton have demonstrated that the same formulations also show the presence of extensional flow and elasticity.5 Recently, MacRitchie et al. have demonstrated that measurements of the storage and loss modulus values of formulations may provide an insight into the evaluation of the rheological properties of wet powder masses that can be processed to form acceptable round pellets.6 Certainly, simple shear rate/shear stress graphs cannot adequately define the rheolgical properties of the paste that can be successfully processed, but simple extrusion force measurements provide a guide to formulation suitability.
Most formulations used in the pharmaceutical industry contain microcrystalline cellulose (MCC), which is capable of holding water rather like a sponge and restricting the separation of water from the solid that can occur during extrusion and spheronization.
There are literature claims that other excipients can be used to replace MCC. These claims are often over optimistic and are based on a less than objective assessment of the quality of the pellets. For example, a recent paper claims that pectinic acid is "well suited as an excipient for pelletization by extrusion/spheronization."
The results clearly show that pellets can be prepared from a range of contents of pectinic acid and lactose, but the quality of the pellets formed must be questioned as none of the so-called optimum formulations form pellets that can be described as spherical. Even by the insensitive method of describing "roundness," namely the aspect ratio, none of the formulations reported has a value for the aspect ratio of less than 1.10, which is far from a spherical pellet.
Several of the so-called "optimum" formulations have an aspect ratio of approximately 1.20, the value shown by Chopra et al. to be the limiting value for satisfactory filling of pellets into capsules.10 In addition to the lack of roundness, extrusion/spheronization is such that as the pellets become less round, there can also be an increase in shape variation. For example, if the results of Chopra are considered, for pellets that were intentionally made with different shapes, the variation coefficient of the aspect ratio (1.06) for the "spheronized" pellets was 3.37%, whereas that for the "long dumbbells" (aspect ratio, 1.59) was 10.69%.10 Thus, as a general principle, as pellets become less round, there is the tendency to become more variable in shape.
There are circumstances when the presence of MCC can be detrimental to a formulation. Basit et al. found that, for a specific formulation containing the drug ranitidine, the decomposition of the drug could be restricted to acceptable levels if the quantity of MCC was reduced and glyceryl monostearate (GMS) was added to the formulation.11 The aim of this work was to determine if this was just a solution to a specific problem and whether it was possible to totally remove MCC from formulations.
Barium sulfate (batch 5/093/3) was supplied by Sachtleben Chemie GmbH (Germany), grade XRHN with a particle size grade of 10 μm. GMS (batch 209215, mean Feret's number diameter 59.l μm), was provided by Huls (UK) as
. Diclofenac sodium (batch 0703, mean Feret's number diameter 20.0 μm) was purchased from Profarma Nobel (Sweden). The MCC (mean Feret's number diameter of 54.8 μm) was
Avicel PH 101
(batch 6521, FMC International [Ireland]). The compositions of the formulations tested are presented in Table I. The quantity of water required was obtained by trial and error to provide a formulation which, generally, could be extruded and spheronized to give pellets of uniform size and shape.
Table I Composition of formulations.
To produce the pellets, the powders were dry blended for 5 min in a planetary mixer (Kenwood Chef, UK). The required amount of water, which was obtained by initial ranging experiments, was added and the mixing continued for a further 10 min with occasional scraping of the sides of the bowl. The weight mass was packed into a ram extruder, which was fitted with a die of diameter 1.5 and length 6 mm.12 The ram of the extruder was driven downwards within the barrel at 200 mm/min by a mechanical press (MRX; Lloyds, UK). The force resisting flow/piston displacement graph was recorded using a computer; the type of flow and, where appropriate, the value of the steady state flow has recorded (3 determinations). The extrudate (100 g) was spheronized on a 12.5 cm diameter spheronizer fitted with a crosshatch plate (Caleva, UK) rotating at 1800 rpm for 10 min. The pellets were dried in a hot air oven (Pickstone Equipment, UK) at 40 °C for 12 h.
The particle size distribution of the pellets was determined by sieve analysis using a set of British Standard Sieves (BSS 450) and an agitator (Endecotts, UK). From a cumulative percentage undersize graph, the median size and the inter quartile range were estimated. The shape of the pellets (sample size, 100 pellets) in the most frequently occurring size fraction was assessed as a two-dimensional shape factor eR,13 with an image analyser (Seescan Solitaire 512; Sonata, UK) connected to a black and white camera (CCD-4 miniature video camera module; Rengo Co. Ltd, Japan) and zoom lens (18-108/2.3; Olympus, Germany). The magnification was set so that one pixel was less than 26 μm for each formulation measured. The apparent density of the pellets taken from the median size fraction was determined (3 replicate determinations) with an air comparison pycnometer (Model 930; Beckman Irwin, USA). The porosity was obtained as 1 minus the ratio of the apparent pellet density to the apparent powder density of the constituents of the pellets.
Dissolution of the pellets containing diclofenac sodium was undertaken with the USP XXXI dissolution apparatus II or paddle method (Pharmatest Dissolution tester, Type PTWS, Germany), with a paddle speed of 100 rpm in 900 mL of simulated intestinal fluid, without pancreatin. A pH of 7.5 was achieved with a buffer containing, 0.05 M monobasic potassium phosphate and 0.038 M sodium hydroxide, with a total ionic strength of 0.088 M. The quantity of pellets, from the modal size fraction, was chosen to ensure that sink conditions were maintained. The quantity of drug present in the samples automatically taken at known time intervals was analysed by UV spectrophotometry (UV-Vis spectrophotometer Model 554; Bodenseewerk Perkin-Elmer & Co. GmbH, Germany). Six beakers were used for each formulation.
The two model materials tested represent drugs with a very low solubility 0.0025 g/L (barium sulfate) and one with low solubility 9 g/L (diclofenac sodium). The formulations incorporated as much as 90% of the two model drugs. That it was possible to prepare pellets from the formulations listed in Table I illustrates the potential of GMS as an excipient, which can provide the possibility of preparing spherical granules for different materials. To compare the performance of the GMS, one formulation of each of the model drugs was prepared with MCC. It is clearly noticeable that the quantity of water required to be able to prepare the formulations containing MCC is approximately double that required to prepare pellets with GMS.
Within the GMS formulations, the amount of water required decreased as the quantity of GMS increased when diclofenac was the model compound. The quantity of water was slightly reduced in the case of the barium sulfate when the level of GMS increased. This shows that the components of the formulation have an important influence on the level of water needed to allow the process to be successful. The formulations all required similar levels of steady state extrusion force and these represent the levels often encountered with conventional formulations containing MCC (Table II). At less than 4 kN, the extrudate is often too soft and tends to agglomerate when placed on the spheronizer plate, and at more than 20 kN the extrudate fails to round even after prolonged spheronization. All the extrudates had a smooth surface and there was no evidence of surface irregularities of the type reported by Harrison et al.14
Table II Characteristics of the extrusion process.
Diameter. The pellets containing GMS tend to have a median diameter larger than the die diameter (1.5 mm), whereas those containing MCC are slightly smaller (Table III). For diclofenac, the diameter increases as the quantity of drug increases. If the process described by Chapman forms the spherical granules, the final diameter can be greater than the extrudate diameter if, prior to spheronization, the extrudate breaks into sections that are considerably longer than its diameter.
Table III Characteristics of the pellets produced by the formulations.
The degree of consolidation, which occurs during the process, is clearly shown by the final porosity of the pellets. The very low levels of porosity obtained with pellets containing high levels of GMS and diclofenac (0.04-0.09) contrast with those that contain the high levels of barium sulfate (0.25-0.30). A comparison of the formulations containing GMS and MCC shows that for barium sulphate formulations, the porosity is lower with MCC, whereas it is the reverse for the diclofenac formulations. There is clearly a difference in structure of the granules despite the apparent similarity of processing.
Shape. The shape of pellets prepared from diclofenac is nearly round because the value of eR for ball bearings of this diameter is 0.7. The values for eR of the highest levels of barium sulfate are not quite as satisfactory as the other pellets, but an eR of 0.523 presents pellets that are nearly spherical. The aspect ratios of all the pellets are well within the acceptability limiting value for capsule filling suggested by Chopra.10 If anything, the pellets containing GMS have slightly higher values for roundness measure.
Dissolution. Pellet dissolution results (Figure 1) were analysed by the statistical moment theory.15 The drug release for two formulations containing 10% of drug was faster from the formulation prepared with MCC. In fact the formulation containing 90% GMS had the highest value for the mean dissolution time (MDT). This is perhaps not too surprising in view of the hydrophobic nature of GMS. The 1.04 h value of MDT does not make this a controlled release formulation. As the level of drug increases and that of GMS decreases, the value of the MDT fluctuates, but even at a 50% drug load, the formulation has a value of MDT comparable with preparations that contain 20% and 50% drug.
Figure 1 In vitro dissolution of diclofenac pellet formulations.
The 10% and 40% drug containing formulations, show a release mechanism represented by the square root law; that is, diffusion controlled release. The 10% and 40% are two of the slowest releasing formulations. A further factor involved with the release mechanism is the pellets' dimensions. For pellets containing 10, 20 and 30% of drug the model size fraction used in the test was 1700-2000 μm; for 40% the pellets were 2000-2360 μm; and for 50% the size fraction was 2360-2800 μm. The dimensions involved in the penetration of fluid into the pellet and the transfer of the drug out of the pellets differed, altering the mechanism of drug release observed.
The work has demonstrated that it is possible to prepare spherical granules by extrusion/spheronization without MCC. This can be achieved by adding GMS at levels ranging from 10-90%. The granules have a larger diameter than the dimensions used to produce the extrudate, but in all cases were acceptably spherical. The structure of the granules as represented by the porosity is dependent on the quantity of GMS present and the properties of the additional material. For high concentrations of GMS porosity levels less than 10% can be achieved.
Table IV Dissolution performance of pellets in the modal size fraction: as area under the dissolution time profile (AUC), mean dissolution time (MDT), relative dispersion (RD) of the dissolution time (VR) and the release model (RM).
When compared with formulations containing the same quantities of model drug and MCC, those containing GMS required less than half the quantity of water, yet had similar extrusion force/displacement profiles. The pellets from the GMS formulations always produced pellets that were larger. The drug release from GMS formulations was at a slightly reduced rate than those containing MCC, but as the drug content of the pellets increased, the release rate generally increased. The release rates from GMS formulations were nearer to an immediate release formulation than an extended release formulation. Thus, GMS can be considered as a spheronization enhancer rather than a controlled release additive.
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