FACTORS AFFECTING DRUG DISTRIBUTION IN GRANULES
FACTORS AFFECTING DRUG DISTRIBUTION IN GRANULES
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Date
1980-12
Authors
OJILE, JOSEPH ELUGBE
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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.
Description
A Dissertation submitted to the
Council for National Academic
Awards as part fulfillment of
the requirements for the Degree
of
DOCTOR OF PHILOSOPHY
Keywords
FACTORS,, AFFECTING,, DRUG,, DISTRIBUTION,, GRANULES