IntroductionMulti 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 that patients have taken 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.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 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. AimThe 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.
MethodPreparation of tablet samplesIn the preparation of the tablet samples, weights were recorded to 0.0001g. The balance was tared, and a weighing boat was placed on the balance, noting the weight.
20 tablets were transferred onto the boat and weighed, calculating an average. The tablets were placed in a mortar and pestle and ground into a fine powder7.Chemical Assay-titrimetric determination of aspirin contentThe balance was tared, and a weighing boat was placed on the balance, measuring the weight of the boat. A quantity of the powdered aspirin tablets containing 0.
5g of aspirin was added to the boat and the weight was recorded. The powder was carefully tipped from the boat into a 100ml conical flask, ensuring no product was lost. The boat was reweighed, and the weight was noted. The powder was added to two further flasks, clearly marking three flasks as A, B and C. Using a bulb pipette, 25.0 ml of 0.5 M sodium hydroxide solution was added to each of the three flasks containing the tablet powder. The flasks were swirled gently to disperse the powder.
A blank was produced by adding 25.0 ml of 0.5 M sodium hydroxide solution to a fourth, empty flask. The four flasks were then boiled gently for 10 minutes, ensuring any powder adhering to the neck of the flasks were washed down into the sodium hydroxide solution.
The flasks were then left to cool, then 3 drops of phenol red solution was added to each flask. The excess of alkali in each flask was titrated with 0.5 M hydrochloric acid, where care was taken with the blank as the titre should have been approximately 25.0 ml. Sample A was used as a rough titration, but more care was taken with the titration of the remaining two flasks as these were used for the calculation. The difference between the titre for the blank flask and the sample flasks represented the amount of sodium hydroxide consumed during boiling. Each ml of 0.
5 M sodium hydroxide was equivalent to 45.04 mg of aspirin. Using the titre difference, the sample weight and the average tablet weight, the amount of aspirin per tablet was calculated. Also, the average, standard deviation and relative standard deviation was calculated7.Physical testsWeight uniformity- the balance was tared, and a weighing boat was placed on the balance and the weight was noted. 10 individual tablets from each batch were then transferred onto the boat and the weight noted. Mean, standard deviation and co-efficient of variance were calculated.Crushing strength- 10 individual tablets from each batch were crushed using the Pharmatron tester, recording the results in Newtons (N).
Mean and standard deviation were calculated.Disintegration- 6 individual tablets from each batch were placed in water at 37°C and the disintegration time was measured, using the Manesty tablet disintegration unit MK4 tester.36 individual tablets were repackaged into multi-compartment blister packs (Venalink single-fold, cold-seal), and placed in the cupboard for 5 weeks under room conditions. The tablets were then retested using the same tests as above and any alterations in aspirin content or physical parameters were determined7.DiscussionThe stability tests revealed that the physio-chemical properties of the dispersible 75mg aspirin tablets weren’t maintained after repackaging into multi dose compliance aids over 5 the week period.A weight uniformity test was conducted to ensure 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 250 mg 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 different conditions. The tablets had swelled, 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 be a safety issue. 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 manufacturing18.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 and in turn rapid dissolution 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.