Abstract
Background
As per regulations, drugs have to be used within their shelf life and must be discarded after their expiry date. The present study was conducted in commonly used analgesic agents to investigate the change in the physical, chemical, and efficacy parameters of the drugs over a period of two years after their expiry date.
Methods
The drugs studied were Tab Ibuprofen, Tab Diclofenac, Tab Piroxicam, Inj Diclofenac, and Inj Piroxicam. The parameters investigated were chemical potency, physical stability, and analgesic efficacy. Testing for these parameters was carried out once before expiry to establish the baseline followed by at expiry, and then every six months for two years post expiry date.
Results
The active ingredient in all the drugs were within the accepted range as per IP during the study period indicating that they retained their potency up to a period of two years post expiry. The analgesic efficacy as determined by the “Radiant Heat Tail flick” and “Acetic acid-induced writhing” model also showed no significant difference in the Maximum Possible Efficacy and Percent protection, indicating that the drugs retained their efficacy. There was a slight difference in the dissolution times at expiry as compared to different time periods in the case of Ibuprofen and Diclofenac, while there are was no statistical difference in the disintegration times during the study period.
Conclusion
The analgesic drugs in our study retained their chemical potency, physical stability and analgesic efficacy up to a period of two years after expiry. The expiry date of a drug, as estimated currently, is not an accurate reflection of its actual shelf life.
Keywords: Expiry date, Shelf life, Expired drug
Introduction
Regulations require pharmaceutical manufacturers to place expiry dates on their products before marketing.1 The expiry date of a drug is the final day that the manufacturer guarantees the full potency and safety of a given drug. Drug products typically have a shelf life that extends from 12 to 60 months from the time of manufacture.2 Shelf life and expiry date of a given pharmaceutical preparation is estimated by various Real-time and Accelerated stability tests, which monitor the product over a period of time under varying storage conditions of temperature and humidity.3 The degradation pattern and estimation of the degradation rate are modeled and utilized as a part of the process for assessing shelf life. The input thus derived is used to extrapolate and arrive at the shelf life of the product.4
As per regulations, a drug has to be used within its shelf life and has to be discarded post its expiry date.4 However, there are a few studies in the literature that indicate that drugs can retain their physical stability and chemical potency many years after their expiry date, and the actual shelf life of the drug may be much longer.5 This suggests that the drugs may retain their efficacy even beyond their expiry date.6,7 This aspect holds tremendous significance, not only for the patients but also the health care professionals, and can lead to a paradigm shift in the way drugs are used. Any research into how drugs behave after the end of their shelf life would also be of considerable importance to regulatory agencies that are responsible for framing guidelines for the shelf life of the pharmaceutical products.
To our knowledge, very few such studies on drugs past their expiry date have been conducted. Moreover, majority of these studies have involved investigating the physical stability and chemical potency of expired drugs, and no study has attempted to confirm their efficacy. There is hence, a felt need to perform studies that not only investigate the physical stability and chemical potency but also check the efficacy of drugs over a period of time during and after expiry.
The present study was undertaken to study the relevant parameters in oral and parenteral formulations of analgesic drugs for two years after their expiry to investigate how these parameters change/deteriorate over a period of time. The aim was to try and answer the question; What happens to drugs after expiry? To this extent, this study not only investigated the physical and chemical parameters but also studied their efficacy (in animal models) after the expiry of these pharmaceutical products.
Materials and methods
The study drugs viz Tab Ibuprofen 200 mg, Tab Diclofenac 50 mg, Tab Piroxicam 20 mg, Inj Diclofenac 25 mg/ml, and Inj Piroxicam 20 mg/ml were procured within the last 3–4 months of their shelf life. The drug samples belonged to one single batch/lot to ensure uniformity. It was ensured that these drugs were stored in a cool, dry place at room temperature as per the manufacturer’s recommended conditions and conforming to Indian Pharmacopoeia as per IP guidelines.8 Each drug was taken and studied for various parameters, including chemical potency, physical stability, and efficacy. The timing for assessing these parameters was within the last three months of their shelf life, immediately after their expiry date, and every six months till two years after the expiry date of each drug. For minimizing any adverse environmental impact due to expired drugs, it was ensured that the number of each study drug was restricted to only that which were to be used in the study, and no excess quantity was procured.
Chemical potency
The study drugs were subjected to analytical assays to estimate the active ingredient in the pharmaceutical preparations. The estimation of chemical potency was performed as per IP by Auriga Research Ltd, a NABL certified laboratory using the High-Performance Liquid Chromatography (HPLC) method. Ten samples of each study drug were tested, initially during the shelf life, then once immediately after the expiry, followed by every six months beyond the expiry date.The chemical potency was considered acceptable if the test results were within the acceptable ranges (lower and upper) as per Indian Pharmacopoeia (IP).8
Physical stability
The tests of physical stability viz disintegration time and dissolution time are well accepted and validated tests to estimate the changes in physical parameters, which are crucial for the absorption and bioavailability of an oral pharmaceutical formulation9,10 The disintegration time was estimated using the Digital Tablet disintegration test-apparatus, Model VTD-DVP, Make: VEEGO. Six tablets of each formulation were tested as per IP. The tablets were considered to have passed the test if they disintegrate within 30 min. The dissolution time was tested using the Digital tablet dissolution rate test apparatus, Model: 3 TEST AUTO-LIFTING make: LABLINE designed as per USP/IP standards. The tablets were kept in the inner fine mesh basket, which was rotated at a defined RPM, and the time taken for the entire tablet to pass through the inner basket and disappear into the beaker was taken as the surrogate marker for 100% dissolution of that tablet. This method was resorted to due to the lack of facilities for repeatedly estimating the chemical concentration of the drug in the dissolved medium.
Analgesic efficacy
Analgesic efficacy was analyzed in two animal models, viz tail-flick method and acetic acid-induced writhing method. Six albino mice of either sex were used to estimate analgesic efficacy for each drug initially before expiry and subsequently every six months, till two years after the expiry date. The drug administration was done as oral suspensions for oral formulations, and the parenteral formulations were administered as intraperitoneal injections. The recommended dose ranges for analgesic efficacy in mice were identified from the literature.11, 12, 13, 14, 15 Accordingly, the drugs were administered in the dosages, Diclofenac 20 mg/kg orally and 10 mg/kg IP, Piroxicam 10 mg/kg both in case of oral and IP route and Tab Ibuprofen 50 mg/kg orally.
Tail-flick method
In this method, the painful stimulus is given in the form of radiant heat, and the threshold for flicking of the tail by the animal is a good estimate of the analgesic activity of a given drug.16 The equipment used was Digital Tail-flick analgesiometer (Model No: PP-150, Make: INCO). The tail-flick latency was obtained thrice before drug administration, and the mean was used as Basal latency (BL). A cutoff time of 10 s as maximum latency (ML) was observed to prevent any tissue damage to the animal. The animal that failed to withdraw its tail in 3–5 s was rejected from the study. The reaction times were tested at regular time periods at 30 min, 60 min, 90 min, and 120 min after the administration of the drug. The change in the reaction time was used as the parameter of percentage analgesic activity and denoted as Maximum Possible Efficacy, and calculated as depicted in Fig. 1.17
Fig. 1.
Calculation of Analgesic efficacy in Tail-flick and Writhing models of pain.
Writhing test
Analgesic activity was assessed by the acetic acid-induced writhing test, a chemical visceral pain model.18 Writhing was induced in mice by intraperitoneal administration of 0.06% acetic acid. Mice were injected i.p. with 0.1 ml/10 gm of 1% acetic acid solution 30 min after the i.p. administration of the drugs. Writhing was defined as a stretch, tension to one side, extension of hind legs, contraction of the abdomen, turning of the trunk (twist). The number of writhes in a 20 min period was counted, starting 5 min after the administration The percentage protection against acetic acid was calculated, as depicted in Fig. 1.18
Statistical analysis
Satistical analysis was performed using SPSS (Windows version 22.0). One-Way ANOVA test was used for analysis and a p-value of less than 0.05 was considered significant.
Results
As can be seen from Table1, the chemical potency of all the study drugs was within the acceptable lower/upper ranges (as per IP) during their shelf life and up to a period of two years after their expiry date indicating that the active ingredient had not degraded during this time.
Table 1.
Mean Chemical Potency of the active ingredient in the formulations during the study period.
| Time of testing | Mean Chemical Potency of the active ingredient in the drug formulations (n = 10) |
||||
|---|---|---|---|---|---|
| Tab Piroxicam (20 mg) | Tab Diclofenac (50 mg) | Tab Ibuprofen (200 mg) | Inj Piroxicam (20 mg/ml) | Inj Diclofenac (25 mg/ml) | |
| Before expiry | 20.41 ± 0.28 | 50.44 ± 0.31 | 197.83 ± 0.58 | 19.52 ± 0.21 | 24.97 ± 0.26 |
| At expiry | 20.22 ± 0.19 | 49.07 ± 0.25 | 198.37 ± 0.63 | 19.38 ± 0.07 | 24.00 ± 0.70 |
| 6 months after expiry | 20.35 ± 0.31 | 51.87 ± 0.38 | 196.97 ± 0.58 | 19.63 ± 0.16 | 25.31 ± 0.11 |
| 12 months after expiry | 19.73 ± 0.22 | 51.71 ± 0.19 | 198.53 ± 0.79 | 19.91 ± 0.16 | 25.12 ± 0.32 |
| 18 months after expiry | 20.17 ± 0.25 | 51.60 ± 0.36 | 204.04 ± 3.06 | 20.09 ± 0.10 | 24.86 ± 0.31 |
| 2 years after expiry | 19.84 ± 0.15 | 49.75 ± 0.20 | 201.69 ± 1.90 | 20.19 ± 0.24 | 25.35 ± 0.27 |
| Acceptable range of active ingredient in the tested formulation as per IP (mg) | 18.5 mg–21.5 mg (92.5%–107.5%) | 45 mg–55 mg (90%–110%) | 190 mg–210 mg (95%–105%) | 18 mg/ml–22 mg/ml (90%–110%) | 23.75 mg/ml-26.25 mg/ml (95%–105%) |
The mean active ingredient estimated for the samples throughout the period of study was as folows :Tab Piroxicam (20 mg) between 19.73 mg and 20.41 mg, Tab Diclofenac (50 mg) between 49.07 mg and 51.87 mg, Tab Ibuprofen (200 mg) between 196.53 mg–204 mg, Inj Piroxicam (20 mg/ml) between 19.38 mg/ml–20.19 mg/ml and Inj Diclofenac (25 mg/ml) between 24 mg/ml–25.35 mg/ml. As is evident, at every time period during the shelf life and after expiry, the active ingredient of these drug formulations was within the acceptable range as prescribed in IP. Moreover, not only was the mean active ingredient of the pharmaceutical preparations within the accepted maximum and minimal range, but each and every tested sample of the oral formulations and parenteral formulations was also within the permissible range as per IP.
Secondly, as can be seen from Table 2, all the tested tablets passed the disintegration test as per the specified time given in the IP, which is 3 min for dispersible tablet, 30 min for film-coated tablet, and 60 min for enteric-coated tablets.
Table 2.
Mean disintegration time of the tested oral formulations during the study period.
| Time of testing | Mean disintegration time of the tested oral formulations (n = 6) |
||
|---|---|---|---|
| Tab Ibuprofen (mins) | Tab Diclofenac (mins) | Tab Piroxicam dispersible (sec) | |
| Before expiry | 6.94 ± 1.56 | 17.25 ± 3.43 | 49.83 ± 11.34 |
| At expiry | 5.41 ± 1.91 | 20.04 ± 4.36 | 44.67 ± 9.24 |
| 6 months after expiry | 5.94 ± 1.69 | 16.11 ± 3.79 | 49.17 ± 8.16 |
| 12 months after expiry | 6.17 ± 2.07 | 15.42 ± 4.79 | 41.67 ± 9.81 |
| 18 months after expiry | 7.21 ± 1.27 | 13.66 ± 3.47 | 50.83 ± 10.17 |
| 2 years after expiry | 8.26 ± 1.90 | 14.62 ± 2.71 | 46.33 ± 7.12 |
| Reference range as per IP | 30 min | 60 min | 3 min |
As seen from Table 3, there was a statistical difference (one-way ANOVA) in the dissolution times of both Ibuprofen (F = 2.78, P < 0.05) and Diclofenac (F = 2.54, P < 0.05). The results were further analyzed with Fishers’ LSD post hoc test. For Ibuprofen there was a statistical difference in the dissolution times at 6, 12, 18, and 24 months when compared to at expiry. The dissolution time between all other time periods showed no significant difference. For Tab Diclofenac, there was a statistically significant difference in the dissolution times of the drug at expiry and 12 months post expiry and between 12 months and 18/24 months post expiry.
Table 3.
Mean dissolution time of the tested oral formulations.
| Time of testing | Mean dissolution time of the tested oral formulations (n = 6) |
|
|---|---|---|
| Tab Ibuprofen (min) | Tab Diclofenac (min) | |
| Before expiry | 18.99 ± 6.43 | 38.34 ± 6.33 |
| At expiry | 14.71 ± 6.17 | 28.25 ± 10.63 |
| 6 months after expiry | 28.99 ± 7.97 | 32.80 ± 7.90 |
| 12 months after expiry | 24.84 ± 7.90 | 42.18 ± 9.34 |
| 18 months after expiry | 26.92 ± 6.83 | 28.27 ± 7.75 |
| 2 years after expiry | 28.57 ± 13.31 | 30.02 ± 10.34 |
| One-way ANOVA df (5,30) | F = 2.78 P < 0.05 |
F = 2.54 P < 0.05 |
The mean Maximum Possible Efficacy (MPE) of the tested drugs during the study period was Inj Diclofenac (60.03%–69.70%), Tab Ibuprofen (60.02%–65.73%), Inj Piroxicam (55.59%–62.76), Tab Diclofenac (51.34%–58.75%), and Tab Piroxicam (44.72%–55.11%). There was no statistically significant difference in analgesic efficacy (MPE) of the drugs during the shelf life and subsequently at periodic intervals after the expiry date (P > 0.05 for all the study drugs). This signifies that the efficacy of the drugs did not come down even up to two years past the expiry date ( Table 4).
Table 4.
Evaluation of Analgesic activity - Maximum Possible Efficacy (MPE %) of the study drugs with Tail-Flick model of Pain.
| Time of testing | Mean Maximum Possible Efficacy (%) of the tested formulations in radiant heat tail-flick model in mice (n = 6) |
||||
|---|---|---|---|---|---|
| Tab Piroxicam |
Tab Diclofenac |
Tab Ibuprofen |
Inj Piroxicam |
Inj Diclofenac |
|
| Before expiry | 44.72 ± 8.24 | 57.56 ± 6.53 | 64.86 ± 4.52 | 58.54 ± 5.87 | 68.67 ± 9.02 |
| At expiry | 51.63 ± 5.30 | 52.41 ± 5.54 | 60.02 ± 5.26 | 55.59 ± 6.88 | 64.13 ± 9.24 |
| 6 months after expiry | 53.69 ± 8.46 | 55.52 ± 4.27 | 65.05 ± 6.94 | 62.76 ± 10.04 | 69.70 ± 8.95 |
| 12 months after expiry | 55.11 ± 14.07 | 58.75 ± 5.20 | 65.73 ± 6.16 | 57.43 ± 7.82 | 65.68 ± 6.67 |
| 18 months after expiry | 48.84 ± 9.05 | 51.34 ± 6.84 | 63.65 ± 5.47 | 56.10 ± 7.70 | 60.03 ± 9.58 |
| 2 years after expiry | 50.08 ± 3.18 | 53.98 ± 4.61 | 61.24 ± 4.44 | 59.38 ± 6.60 | 63.43 ± 3.74 |
| One-way ANOVA df (5,30) | F = 1.082 p = 0.38 | F-1.60 p = 0.18 | F = 1.03 p = 0.41 | F = 0.70 p = 0.62 | F = 1.18 p = 0.34 |
(P > 0.05 for all the drugs during the entire study period).
The mean percent protection of the tested drugs as seen from Table 5 was as follows: Tab Ibuprofen (57.48%–61.76%), Inj Diclofenac (56.73%–61.50%), Tab Diclofenac (49.88%–54.81%), Inj Piroxicam (39.20%–46.56%) and Tab Piroxicam (37.46%–45.51%). Further, as can be seen from the table, for each drug tested, there was no statistical difference in percent protection during the shelf life and at periodic intervals after the expiry date (P > 0.05 for all the study drugs). This signifies that the drugs retained their efficacy even up to two years past the expiry date.
Table 5.
Evaluation of Analgesic activity – Mean Percentage protection (%) of the study drugs in Acetic acid-Induced writhing model of pain.
| Time of testing | Mean Percentage protection (%) of the tested formulations in acetic acid-induced writhing in mice (n = 6) |
||||
|---|---|---|---|---|---|
| Tab Piroxicam |
Tab Diclofenac |
Tab Ibuprofen |
Inj Piroxicam |
Inj Diclofenac |
|
| Before expiry | 37.46 ± 5.92 | 54.81 ± 7.51 | 58.31 ± 6.75 | 46.56 ± 5.80 | 59.70 ± 4.74 |
| At expiry | 38.02 ± 9.32 | 50.67 ± 3.59 | 57.48 ± 3.47 | 45.76 ± 8.81 | 60.20 ± 2.88 |
| 6 months after expiry | 45.36 ± 8.50 | 49.88 ± 6.82 | 60.03 ± 6.35 | 40.69 ± 8.41 | 58.52 ± 4.26 |
| 12 months after expiry | 45.51 ± 9.41 | 53.77 ± 3.57 | 59.03 ± 3.70 | 39.20 ± 6.93 | 61.50 ± 2.42 |
| 18 months after expiry | 38.81 ± 7.25 | 51.40 ± 2.19 | 57.482 ± 0.27 | 39.60 ± 9.05 | 59.57 ± 2.98 |
| 2 years after expiry | 39.17 ± 6.52 | 54.30 ± 1.95 | 61.76 ± 4.10 | 39.35 ± 8.52 | 56.73 ± 3.83 |
| One-way ANOVA df(5,30) | F = 1.30 p = 0.29 | F = 1.13 p = 0.16 | F = 0.94 p = 0.46 | F = 1.07 p = 0.39 | F = 1.04 p = 0.41 |
(P > 0.05 for all the drugs during the entire study period).
Discussion
There are a few anecdotal and observational reports in the literature that suggest that drugs may still retain potency long after their expiry date.19, 20, 21, 22, 23 One of the earlier such studies was by Stark et al, wherein they investigated the drug content of four products (captopril tablets, flucloxacillin capsules, cefoxitin injection, and theophylline tablets) and found that at least 98% of label claim was still found 18 months to 14 years past the labeled expiration dates. There is another study by Cantrell et al, who discovered long expired medications in a retail pharmacy in their original, unopened containers and found that 12 of the 14 tested drugs had at least 90% of the labeled amount 28–40 yrs after their expiry.7 Shelf-Life Extension Program (SLEP) of the US Army is one of the biggest projects, which checked the long-term stability of federal drug stockpiles, and showed that in the majority of the drugs tested, the active ingredient remained within the accepted range. In this study, 3005 lots after the expiry date belonging to 122 drugs were tested, out of which 2650 (88%) lots still contained the recommended active ingredient.5,23
To this end, our observations are in agreement with the above studies. The chemical potency of all the tested drugs in our study was within the acceptable ranges during their shelf life and up to a period of two years after their expiry date. This indicates that the active ingredient had not degraded during this entire period. Moreover, in our study, multiple samples (Ten) of each drug were analyzed at each point in time, and both the mean and individual values of each and every tested sample were within the permissible range. This is significant because many of the prior studies on this aspect had tested one or a very limited number of samples.
In our study, all the oral formulations tested at different periods after the expiry date passed the disintegration time test, and there was no statistically significant difference in the disintegration times of all the preparations at any point during the shelf life or after expiry. However, our study showed a statistical difference in the dissolution times at expiry as compared to 12, 18, and 24 months post expiry for Ibuprofen and Expiry and 12 months and also between 12 months and 18 and 24 months post expiry for Diclofenac. There was no statistical difference in the dissolution times at other times during the testing period. This could be because, in our study, the time taken for the entire tablet to completely pass from the inner fine basket into the dissolution medium was taken as a surrogate endpoint for 100% dissolution and may not be an accurate reflection of the dissolution time. This is because the dissolution time of the tablets is not purely a physical parameter, but chemical transformation and ionization/unionization also play an important part, which might not have been taken into consideration with the surrogate endpoint employed by us in the study.
For measuring the analgesic activity of the NSAIDs, we employed two animal models. Radiant heat tail-flick model was used to estimate the measure of central analgesic activity and Acetic acid-induced Writhing Model for efficacy against visceral pain. There was no statistical difference in the analgesic efficacy of the study drugs during the shelf life and at varying time intervals after the expiry. Notably, unlike some earlier studies, which suggested that NSAIDs may be less effective in tail-flick (reflective of central effect) as compared to writhing (model of visceral pain), in our study, the NSAIDs tested were able to elicit antinociception in both the models of pain.
The results of our study, taken together, indicate that the NSAIDs have retained their chemical potency, physical stability, and efficacy even up to two years after expiry. This suggests that the determination of expiry date as done currently may not be the best reflection of the actual shelf life of the drugs. The expiry date of a pharmaceutical product is normally estimated using two types of stability testing: real-time stability tests and accelerated stability tests.3 However, as real-time stability tests can take years, drug manufacturers employ the accelerated stability tests that involve exposing the pharmaceutical products and testing their stability under rigorous conditions at relatively high temperature and humidity, and data from these is extrapolated to estimate the expiry date and determine shelf life. Further, the current regulations require the manufacturers to put a date till when they can guarantee the full safety and potency of a drug; However, these regulations do not require them to determine how long medications remain potent after that, allowing manufacturers to arbitrarily establish expiration dates without determining actual long-term drug stability.24
As mentioned earlier, Shelf-Life Extension Program (SLEP) also showed that a majority of the medicines remained potent after the expiry date, with the FDA declaring them useable and extending their expiry dates by more than one year, with an average extension of 66 months and a maximum extension of 278 months.5
The results of our study also suggest that such expired drugs may still be effective, and a case could be made to consider them for use, especially when no suitable alternative is available provided they are stored in their original unopened packaging in recommended storage conditions. This should not be construed as a recommendation to use drugs beyond their expiry date, as patient safety and efficacy are of supreme importance. Very importantly, and to put things into perspective, except renal tubular damage that has been reported with the use of expired tetracycline, there are no published reports of human toxicity due to ingestion of any of the currently approved drugs after their expiry date.25
Hence, based on the results of the study, we propose that the procedure of setting up the expiry date be revisited to reflect more accurately the real shelf life of a drug. There could be a case to argue in favor of establishing a formal extension program in which an independent organization, regularly tests the drugs at a designated point of time during the shelf before the expiry date and then consider extending the shelf life depending upon the results of these testing programs.26
There has been increasing concern over the shortage of medicines, with the problem more critical in developing countries where a large section of the population does not have access to even basic medicines.27 The current standards for assigning a shelf life to drugs and discarding them after the purported expiry dates seem particularly disconcerting when these populations are considered. Further, in times of any crisis, humanitarian medical help may not reach in time to affected populations due to infrastructural barriers in resource-limited countries,28 but a donated drug that reaches these regions after expiry has to be discarded even if no suitable replacement exists; ultimately harming the interests of the patients.29
Finally, it is possible that extending shelf lives could have a positive environmental effect as disposing of expired drugs has been found to lead to contamination posing a significant ecological risk.30 Despite guidelines on safe disposal, most of the expired drugs are generally discarded in landfills, burnt, dumped in trash cans, or even flushed down the sink.31 If medications get an extension and longer shelf life, it could reduce medication disposal and decrease the deleterious effects on the environment.
Conclusion
The NSAIDs in our study retained their chemical potency, physical stability, and analgesic efficacy up to a period of two years after expiry. The expiry date of a drug as is being estimated currently is not an accurate reflection of its actual shelf life. Appropriate extension of shelf lives of medications could play a role in decreasing medication shortages. Furthermore, if shelf-life extensions are applied more broadly, it might be possible not only to reduce national health care costs and but also to help provide medications to populations who would otherwise be unable to afford them.
Ethical clearance
The study was conducted after due clearance from the Institute Animal Ethics Committee (IAEC) of AFMC Pune vide approval no: IAEC/AFMC/05/2015 dated May 23, 2015.
Disclosure of competing interest
The authors have none to declare.
Acknowledgements
This paper is based on Armed Forces Medical Research Committee Project No. 4626/2015 granted and funded by the office of the Directorate General Armed Forces Medical Services and Defence Research Development Organization, Government of India.
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