III. Discussion
The assay results on the drug content showed that there are
some substandard drugs on Rwandan market. Before stability testing 1
acetylsalicylic acid was found substandard. After stability testing, 1
acetylsalicylic acid more, 1 cotrimoxazole, 1 paracetamol, 1 quinine were found
substandard. In total about 23.8 % (5/21) of the sampled drugs were found
substandard.
This result is similar to those obtained by Shakoor et al.
(1997) on pharmaceuticals from Nigerian and Thai markets and to those obtained
by Kibwage et al. (1992) on drugs from the Kenyan market, except that no fake
drug was found in this study.
Among those that passed the drug content test, 1
acetylsalicylic acid, 2 cotrimoxazole, 1 sulfadoxine / pyrimethamine failed the
initial dissolution test. After stability testing, 2 acetylsalicylic acid, 1
metronidazole and 1 quinine failed the dissolution test. In total about 38 %
(8/21) of the sampled drugs failed the dissolution test. The findings are
similar to those obtained by Risha et al. (2002) on the in vitro evaluation of
the quality of essential drugs on the Tanzanian market, where 29% of the
samples that passed the assay test, failed the initial dissolution test.
Dramatic changes in the dissolution behaviour of some
formulations have been observed after storage at high temperature and high
relative humidity. However it was not possible to determine the exact cause of
the failure, as the composition of the formulation was not known.
These failures can not be attributed to a single manufacturer
and it was observed that different drug formulations from the same manufacturer
had different characteristics for drug content as well as for dissolution rate:
acetylsalicylic acid tablets from S&R Pharmaceuticals did not disintegrate,
while paracetamol tablets released more than 80% within 10 minutes.
Cotrimoxazole tablets from Labophar failed the dissolution requirements for
sulfamethoxazole, while metronidazole and quinine formulations complied with
the pharmacopoeia.
The above observations might be the results of the fact that
the manufacturers do not practice the Good Manufacturing Practices (GMP)
principles. The ingredients used may be of inferior quality or they do not
validate their manufacturing process.
Dissolution stability can be influenced by several factors.
Important among them are the manufacturing process, formulation variables (e.g.
physiochemical properties of the active and inactive ingredients), storage
conditions and packaging.
Any one of the above factors acting alone or in combination
may alter the characteristics of the product. Based on literature data one can
speculate about the possible causes of the changes in dissolution rate seen
after stability testing.
For example the solubility, hygroscopicity and thermal
characteristics of the active component and excipients (including coating
materials) are critical parameters that influence dissolution profiles, hence
its stability. During storage under high humidity conditions, the active drug
may dissolve and recrystallize and in the processes alter the release
characteristics of the tablet. A tablet can absorb moisture, in such
circumstances the original interparticulate bonds formed in the compact will be
replaced by the new bonds, possibly resulting in a tablet having a different
porosity and pore structure and, hence, having a different in vitro release
pattern compared with the original. Some manufacturers such as Labophar and
S&R Pharmaceuticals did not include a desiccant into the packaging
containers, while it is known that desiccants absorb the moisture and reduce
the humidity in the container, thus contribute to the dissolution stability of
the product.
The initial moisture level of the finished product also
impacts the dissolution. The tablets with a higher moisture level are more apt
to change during aging than those prepared from compounds containing low
moisture.
Fillers or diluents in the formulation are usually viewed as
inert excipients. Whereas this is true for the most part, some fillers by their
hygroscopic nature, provide the necessary moisture for reaction to occur and
thereby promote chemical or physical changes in the product. Others act as
adsorbents that interfere with the liberation of the drug from the dosage form
(Murthy et al., 1993).
Specific interactions between the active ingredient and a
component of formulation have been reported to result in slower dissolution
under accelerated storage conditions. When phenylbutazone was prepared by
direct compression with lactose and microcrystalline cellulose as diluents and
the tablets were stored in paper bags at 40°C and 90% RH for 14 weeks, a
significant reduction in the dissolution rates of phenylbutazone was observed.
This was attributed to the reaction between lactose and the drug based on the
appearance of a new endothermic peak at 220°C that was not related to the
melting point of lactose and phenylbutazone, which are 200 and 107°C,
respectively (Murthy et al., 1993).
During dissolution experiments involving immediate release
products, gum-type binders may form a viscous gel barrier in and around the
tablet, thereby inhibiting disintegration of the dosage form and causing
subsequent delay in drug release (Murthy et al., 1993).
The swelling capacity of the disintegrant is an important
property that determines the outcome of the dissolution after storage. For
example maize starch looses its capacity to swell on aging or after exposure to
high humidity and temperature (Risha et al. (2002). Dissolution behavior of
tablets manufactured with this type of starch will decrease progressively with
aging or during accelerated stability testing.
The dissolution rate of Quinine sugar-coated tablets
manufactured by Elys Chemicals (Kenya) decreased dramatically; probably the
cause is the coating material. Several examples cited in literature suggest
that enteric- and sugar-coated products are more sensitive to the effect of
humidity than uncoated products.(Murthy et al., 1993).
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