FACTORS AFFECTING DRUG DISTRIBUTION IN GRANULES

FACTORS AFFECTING DRUG DISTRIBUTION IN GRANULES

Abstract:

The formulation and processing variables affecting the distribution of a low dose drug in granules prepared by the massing and screening method have been investigated. Five granule formulations were used to elucidate the effect of the “relative solubilities” on the drug distribution in granules. These were borax/lactose, sodium salicylate/ lactose, sulphadimidine/lactose, sodium salicylate/dibasic calcium orthophosphate (d.c.o.) and sulphadimidine/d.c.o. Water was used as the binder for the formulation containing lactose diluent and PVP binder for d.c.o. Relative dissolution ratio R was derived. This was found to govern drug distribution in granules. The effect of dose variation for a soluble drug was shown to affect R which also explained why dosage uniformity in granules was more problematic in micro-dose than high dose drugs. The effect of the massing action on dosage uniformity throughout the granule sizes has been elucidated. A higher R value in the granule formulation was found to cause some solute dissolution including the drug in the initially overwetted region. The binder distribution from this region now containing dissolved components enriched the drier area of the mix with the solutes. This action was found to be further enhanced by solute migration during drying. Thus the peak, drug concentration was obtained in the intermediate sized granules. For an appreciably high R value as in sodium salicylate/lactose formulation, a snow-balling action was envisaged to counteract the massing action to a certain extent. This allowed a further low drug concentration in the fines. The d.c.o. diluent which showed a lesser degree of surface wetness was found to reduce this snow-balling action. Massing a dry mix with a binder, of constant composition throughout the massing period, e.g. a solution simultaneously saturated with part of the drug and diluent, led to a directly related drug concentration with the granule size. Also massing sulphadimidine/d.c.o. dry mix with PVP binder caused a constant PVP binder composition during the massing as both components are poorly soluble. This led to an inverse relationship between the drug concentration and the granule size on account of the dilution effect of the directly related binder content with granule size. A formulation containing a drug with an R value lower than unity but a markedly higher diluent relative solubility, as in sulphadimidine/lactose granulation, produced the most uniform drug distribution in the granules. Although the lactose solubility is appreciable, its R value is still low due to its presence as a high dose, 987o w/w, diluent. A formulation was designed to make R value equal to 1. This was, as expected, found to lead to a uniform drug distribution irrespective of granule size or granule bed depth. Other variables which were studied were drying temperature, binder concentration and binder type, intermediate granule screening during drying, excessive massing time, granule packing density during drying, granule bed thickness or height, particle size of both components and drying method. The action of initial larger drug particle sizes for a moderately or poorly soluble drug was due to lack of ease of wetting for bonding to the initially overwetted mass and slower dissolution rate as in borax. The former action led to a lower concentration in the larger granules in the batch but the latter a higher concentration. For a readily wettable drug e.g. sodium salicylate the rate of dissolution with particle size was found to be sufficiently rapid to cause a non-rate determining step. Intermediate screening of borax/lactose produced granules with a high borax concentration in the larger granules depending on the moisture content remaining as well as the sieve mesh used in the rescreening process. This was apportioned to abrasion and bonding of the wet fines to granules. The action of excessive (60 minute) massing time was found to produce the same effect as the increase in the binder volume. This was a further decrease in borax concentration in larger granules with a shift of the peak concentration in finergranules. A comparative study of the drying method showed that the highest borax concentration was obtained in the larger granules dried by freeze drying, then vacuum drying, hot air oven and fluidised drying. The freeze dried granules further substantiates the distribution of the borax rich binder from the overwetted to the drier region of the wet mass during massing. It also showed that solute migration in a batch of granules dried on the tray caused a further depletion of borax from the larger to the intermediate granules. The effect in the granules dried by fluidisation was an abrasive action while that of the other drying methods was due to solute migration during drying. All the factors affecting drug distribution during the drying in the hot air oven were found to be connected with the degree of solute migration. A denser packing of granules increased solute migration; a higher drying temperature decreased the migration; an increase in the height of granule bed increased the migration and led to a direct relationship between borax concentration and the mean granule size. An increase in the particle size of the diluent increased the effective volume of the binder in the pores available to increase the quantity of the dissolved drug and increase the solute migration of the drug. The larger pores in larger granules entrapped a higher quantity of the drug in the larger granules. The concentration of drug in granules is therefore the net effect of the massing action and solute migration during drying.

FACTORS AFFECTING DRUG DISTRIBUTION IN GRANULES