Introduction with their medicines4. The packaging allows

 

Introduction

Multi-compartment
compliance aids (MCA’s) are being increasingly used in both primary and
secondary care settings to assist patients with medicine compliance, in both a
safe and effective manner. The devices not only help patients to remember to
take their medication, but also acts as a visual prompt for carers enabling
them to see whether their patients have had their required doses1.   Additionally, these aids are an indispensable
tool in polypharmacy2, with the potential to reduce wastage3.
MCA’s are particularly useful
for the elderly population and the visually impaired who may have difficulty managing
complex drug regimens and are looking to promote independence with their medicines4.
The packaging allows days of the week to be incorporated, allowing patients to
follow a specific drug regime, organised by dosing intervals. Hence, minimising
errors associated with administrating incorrect doses at incorrect times. The pharmacist
may arrange the aids, placing different medications in the same compartment;
allowing them to keep track of the medication the patient is receiving every
day, ensuring it is taken at the desired time.

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However,
MCA’s pose a concern regarding product stability as medicines are removed from
their manufacturers original packaging, and has even prompted pharmacists to
establish a database on product stability5. Repackaging
may even be warranted as unlicensed use of the product and may invalidate the stated
expiry date2. The
original packaging has been designed with the appropriate pharmacopoeial and
quality standards in mind1, and dosage forms are required to meet
British Pharmacopoeial requirements including content uniformity. Other factors
which are considered during drug design are the effects of humidity,
temperature and oxygen. MCA’s cannot guarantee the same level
of protection, and the pharmacist must use their clinical judgment to prepare
one or not. The compliance aids are not air tight and provide less moisture
protection than original packaging. This may lead to chemical and physical
deterioration, reducing efficacy and compromising patient safety.  Often systems are re-used without cleaning posing
the risk of chemical and microbiological contamination. Also,
specific medication formulations cannot be repackaged (e.g. those which require
refrigeration, dispersible tablets, significantly hygroscopic preparations and
solid dose cytotoxic preparations including methotrexate). The Royal Pharmaceutical Society also includes medicines
with variable dosing and a narrow therapeutic index such as warfarin6.

 

Aim

The aim of
this investigation was to assess the chemical and physical stability of
dispersible aspirin 75mg tablets, before and after repackaging into
multi-compartment compliance aids (blister
packs) after 5 weeks of storage.  Any
alterations in aspirin content or physical parameters were determined through
several chemical and physical tests.

 Discussion

The stability
tests revealed that the physio-chemical properties of the dispersible 75mg
aspirin tablets weren’t maintained after repackaging into multi compartment
compliance aids over 5 the week period.

A weight
uniformity test was conducted to ensure an accurate and consistent dosage
form.  It was shown that there was a
change in the mean weight of the tablets from 148.29 ± 0.0094 mg to 149.54 ±
0.0169 mg, with a 0.84% increase. The masses complied with the British
Pharmacopoeial standards as they were between 80 and 250mg with a coefficient
variance of less than 7.5%.8 Despite the requirements being met,
this small but significant weight increase may be indicative of an uptake of
humidity from the environment and a permeation of moisture through the compliance
aid. Aspirin is hygroscopic9 and is rapidly hydrolysed to salicylic
acid, its degradant on exposure to moisture. According to the British
Pharmacopeia (BP), the limit of salicylic acid (SA) content within a
dispersible formulation is 3%10. Hydrolysis may cause product
degradation, hence compromising bioavailability and reducing efficacy. The
pharmacist must consider whether the degradation of the active pharmaceutical
ingredient (API) will result in sub-therapeutic or toxic affect, with
potentially serious implications for the patient. It is the responsible
pharmacists’ duty to guarantee the safe supply of medicines.

A chemical titration
was used determine the content of aspirin. Before repackaging the amount of aspirin
was found to be 69.48mg which then decreased to 69.22mg. In both batches the
aspirin content failed to meet BP requirements as they weren’t within 95% -105%
of the labelled amount of 75mg11. Again, this could be due to
moisture uptake and hydrolysis, resulting in a reduction of the API and reduced
therapeutic efficacy. This may compromise patient safety, resulting in sub
therapeutic dosing. However, the values may not be accurate due to poor
titration technique and human error whilst reading the titre values. Although salicylic
acid content wasn’t tested, when weight gain is linked to water absorption the
physiochemical properties may be altered and the concentration of degradant may
increase12. A study on aspirin 300mg dispersible tablets repackaged
as whole and split tablets, demonstrated significant changes in the SA content.
When comparing with original packaging, a greater percentage of SA was present
in the tablets stored under accelerated conditions. The tablets had swollen,
become discoloured and disintegrated easily, highlighting that both temperature
and moisture accelerate degradation13. Physical appearances are
important as alteration may discourage patients from administration, leading to compliance issues which may
compromise safety. In future, SA and aspirin content could be analysed using high
pressure liquid chromatography (HPLC) for increased precision and accuracy14.
 Regarding weights, the variances may be down
to error of the balance. It may also be caused by the non-uniformity in the particle size
distribution and bulk densities of the tablets in their compression during
manufacture18.

For crushing
strength batch 1 was found to have a mean strength of 37.5± 4.7668N and batch 2
36.2± 4.5277N. The reduction in strength is due to decreased compression force and
less condensed particles, requiring less force to overcome the intermolecular forces.
If the tablet is too hard it may not disintegrate in the requisite time, and if
it too soft, it may not withstand patient handling or packaging. However,
generally dispersible tablets have less physical resistance than regular
tablets. It may be possible that moisture uptake may have affected excipients
such as the binder allowing it to be crushed more easily. A study conducted on
dispersible lamotrigine tablets repackaged into compliance aids also
demonstrated a reduction in hardness and 60 days into the study, a 21.9%
reduction had been reported. Variations in hardness is common with friability
and such changes are likely to alter the dissolution profile and
bioavailability of aspirin, affecting its efficacy and performance12.
 Friability should be measured if the
study was to be repeated, to determine tablets ease of chipping and breaking.

The time
taken for the tablet to disintegrate decreased from 20 to 12 seconds. Rapid
disintegration leads to rapid dissolution which can potentially affect
performance and bioavailability of a drug, hence impacting its shelf life.
Common disintegrants which are chemically stable in original packaging can be hugely affected by moisture. A study conducted on asprin,
atenolol and lansoprazole showed a decline in stability profiles when
repackaged into MCA’s for 8 weeks, particularly their disintegration times. A
faster time was observed for aspirin and atenolol, however both complied with
BP standards10.  It has been demonstrated that moisture uptake
associated with disintegrants can result in micro-cracks due to the disintegrant
swelling, causing it to disintegrate quicker, affecting the medications
performance15.  According to BP, dispersible
tablets disintegrate within 15 minutes, using water at 37° C7. Thus,
the tablets complied with the requirements.

In future dissolution
can be tested to measure the rate of drug release, providing an indication of
the bio-availability of aspirin. A study on Sodium valproate 100mg tablets
after repackaging and storage under various conditions showed variable
dissolution compared to controls, with the most pronounced differences being
demonstrated at 40°C/75% RH16. Many dissolution profiles indicated
slower, and in certain cases incomplete, absorption of the drug, therefore
affecting the bioavailability.

The study was
limited as environmental factors such as temperature and humidity weren’t accounted
for, nor controlled. Tablets should be tested at differing temperatures and various
humidity. These factors were not monitored and therefore we cannot account for
any fluctuations that may have occurred. This may be measured using a
hygrometer or a digital thermometer in the future. Factors such as patient or
pharmacist handling weren’t considered, therefore the results aren’t a reliable
representation as different situations a patient may experience weren’t simulated,
such as storage in a humid bathroom.  Also, measurements were taken at week 5 and not
varying time intervals, for example t = 3 weeks. The study period for which the
tablets were stored was too short to observe major changes and greater degradation
may have been apparent after 5 weeks. The safety of the use in polypharmacy was
not tested as we didn’t combine other medications. A study stored dispersible
aspirin tablets alongside 5 other medications for 5 weeks17. Although, no degradation was detected in these quantitative HPLC
methods, this parameter should be tested in the future.

 

Conclusion

To conclude, the physiochemical stability of the tablets was
not maintained throughout storage, although certain BP requirements were met.
Based on the outcome of the study, the tablets are not recommended for
repackaging into MCA’s, supporting manufacturer’s instructions that tablets should not be removed from
their original packaging. Although changes in the results weren’t numerically large, they were of critical
value. It was indicated there was a small degree of degradation and a reduction
in the API, thus the efficacy and performance of the medication. This may
compromise patient safety and result in toxic or subtherapeutic dosing. Tablets
were tested at only 5 weeks, and realistic conditions weren’t replicated considering
factors such as humidity, temperature, light and patient handling.
Investigational data was lacking as not enough quality control tests were
conducted such as dissolution or friability. There has not enough research and
data collated on the stability of medicines after packaging into compliance
aids, particularly dispersible formulations and therefore careful consideration
be taken when considering preparing one.

 

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