The effect of filler, active ingredient and Kollidon® VA64 sollubility on the release profile of the active ingredient from wet granulation tablet formulations
Claassen, Petrus Jacobus
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There are mainly two manufacturing processes used in the pharmaceutical industry, namely direct compression and granulation of which granulation can be subdivided into wet granulation and dry granulation. Wet granulation is a process still widely used in the pharmaceutical industry and provides better control of drug content uniformity and compactibility at low drug concentrations. Lactose monohydrate and microcrystalline cellulose (MCC) were used as fillers in this study. Both these fillers possess unacceptable powder flow properties and the use of wet granulation may improve this property. One of the advantages of lactose monohydrate over MCC is that it is partially water soluble. A fractional factorial design was used in this study. Twelve tablet formulations were formulated containing different combinations of active ingredients (furosemide or pyridoxine hydrochloride), fillers (lactose monohydrate or MCC) and a binder (Kollidon® VA64) in three different concentrations (0.75, 1.5 or 3.0% w/w). The binder was used to produce granules by means of wet granulation, using ethanol as granulating fluid. The granules were dried in an oven and screened through different sized sieves to produce the final granulated powder formulations ready for tableting. A disintegrant (Ac-di-sol®) and lubricant (magnesium stearate) were incorporated into the granulated powder formulations extra-granular (0.5% w/w) and were kept as a constant in this study throughout all the formulations. A Turbula® mixer was used to mix the granulated powder formulations for a constant 5 minutes. During the first phase of the study, tablets were compressed using 2 compression settings (22 and 24). These compression settings were used to determine what effect different external pressures would have on the different tablet properties. Tablet weight for all the formulations was kept constant at 250 mg, although the volume of the matrix differed for each tablet formulation. The physical properties of the tablets were evaluated with regard to weight variation, mechanical strength (crushing strength and friability) and disintegration. Tablet formulation 12 yielded unsatisfactory tablets, due to poor powder flow into the die. Tablet formulations that contained the highest binder concentration (3.0% w/w) and were compressed at the highest compression setting (24) (formulations 4 and 9), exhibited the highest mechanical strength. The disintegration results revealed that the tablet formulations containing MCC as filler disintegrated faster compared to those containing lactose monohydrate. The increase in binder concentration caused an increase in mechanical strength, possibly decreasing tablet porosity, therefore prolonging disintegration time due to impeded water penetration into the tablet matrix. During the final phase of the study, dissolution studies were conducted on the different tablet formulations in 0.1 M HCl for 120 minutes. In terms of dissolution results, the initial dissolution rate (DRi) and extent of dissolution (AUC) were compared. It was found that the tablet formulations containing pyridoxine hydrochloride as active pharmaceutical ingredient (API) exhibited faster drug dissolution (higher DRi and AUC-values) compared to those tablet formulations containing furosemide. The faster dissolution exhibited by the pyridoxine hydro- chloride containing formulations can possibly be attributed to the fact that pyridoxine hydrochloride is good water soluble whereas furosemide is practically insoluble in water. The effect of the filler depended on the aqueous solubility of the filler and the concentration of the binder (Kollidon VA64) employed. An increase in binder concentration led to a decrease in the initial rate of dissolution as well as the extent of drug dissolution. In the case of the pyridoxine hydrochloride containing formulations, formulation 9 exhibited the slowest DRi and lowest extent of drug dissolution (1.40 ± 0.03 µg.cm-3.min-1 and 2396.52 ± 26.43 µg.cm-3.min respectively). In the case of the furosemide containing formulations, formulation 4 exhibited the slowest DRi and lowest extent of drug dissolution (0.22 ± 0.07 µg.cm-3.min-1 and 1018.62 ± 59.74 µg.cm-3 min respectively). In both cases, the formulations contained Kollidon VA64 in a concentration of 3% w/w and were compressed at compression setting 24. The disintegration process of tablets goes hand in hand with the dissolution process and results have shown that by establishing rapid contact between drug particles and the surrounding medium proves to be a necessity for rapid drug dissolution. Disintegration does not assure drug dissolution, but when prolonged, slower dissolution rates can be obtained, implying a slow rate and low extent of drug dissolution. The disintegrant in this study was incorporated extra-granular ensuring rapid tablet disintegration. However, due to binder concentration of 3% w/w, granule disintegration was probably negatively affected resulting in a lower drug surface area exposed to the surrounding dissolution medium, leading to a slower initial rate and extent of drug dissolution. From the results obtained during this study it was evident that formulation variables such as the type of filler, the concentration of the binder and compression setting employed during tablet manufacturing can have a ronounced effect on the pharmaceutical availability of the active ingredient. However, the extent of the effect was dependent on the aqueous solubility of the active ingredient.
- Health Sciences