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Open-Label Study of the Stability of Sublingual Nitroglycerin Tablets in Simulated Real-Life Conditions
ARTICLE IN PRESS Open-Label Study of the Stability of Sublingual Nitroglycerin Tablets in Simulated Real-Life Conditions James J. Nawarskas, PharmDa,*, Jason Koury, PharmDb, David A. Lauber, BSa, and Linda A. Felton, PhDa Contemporary practice favors refilling sublingual nitroglycerin (SL NTG) every 3 to 6 months. This recommendation is based on antiquated data that does not consider the reformulated tablet and the improved manufacturing process. Our objective was to investigate the stability of SL NTG over time using simulated real-life scenarios in comparison to controlled storage conditions. This was an open-label study of 100- and 25-count commercial SL NTG bottles stored in either controlled temperature and relative humidity conditions, or carried in a pocket or purse. SL NTG potency (chemical stability) was assessed using high performance liquid chromatography and physical stability was assessed by changes in tablet weights over time through the labeled expiration date. Both chemical and physical stability of SL NTG were affected by environmental and physical factors. High temperature storage resulted in the most rapid loss of potency. Tablets carried in a pant pocket lost potency faster than those carried in a purse. Potency was also dependent on headspace of the bottle. Tablets stored in the original bottle in a temperate environment could be expected to maintained potency for more than 2 years when carried in a purse, irrespective of package size. When carried in a pant pocket, potency of a 25-count bottle was maintained for 2 years, whereas potency of a 100-count bottle fell below acceptable limits at 12 months. In conclusion, since potency is dependent on temperature, headspace, and carrying practices, frequency of SL NTG refills should be based on individual patient behavior. © 2018 Elsevier Inc. All rights reserved. (Am J Cardiol 2018;00:1−6)
Sublingual (SL) nitroglycerin (NTG) is a mainstay for treating ischemic heart disease.1−3 Due to its volatility, SL NTG must be stored in amber glass vials with metal screw top caps.4−8 Early studies suggested that SL NTG tablets rapidly lose potency, leading to recommendations that patients replace SL NTG every 3 to 6 months.5,6,9,10 However, this may not apply to contemporary practice due to improved tablet manufacturing processes and more diligence by the health care community in ensuring patients adhere to medicine storage and handling recommendations. Unpublished data suggest that once opened, SL NTG tablets maintain potency until the labeled expiration date.11 However, whether this holds true under conditions of normal patient use is unknown. The objective of this study was to investigate the stability of SL NTG using simulated real-life scenarios and controlled storage conditions. Methods SL NTG 0.4 mg tablets (Nitrostat, Pfizer/ParkeDavis, NYC, New York) of identical lot number were kept in the original manufacturer’s packaging and subjected to 5 different storage conditions: (1) 25˚C/60% a University of New Mexico College of Pharmacy, Albuquerque, New Mexico; and bUniversity of New Mexico Hospitals, Albuquerque, New Mexico. Manuscript received June 1, 2018; revised manuscript received and accepted August 24, 2018. *Corresponding author: Tel: 505-272-0584; fax: 505-272-9749. E-mail address: [email protected] (J.J. Nawarskas).
0002-9149/© 2018 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjcard.2018.08.048
relative humidity (RH); (2) 40˚C/75% RH; (3) ambient (laboratory shelf); (4) “pocket”; and (5) “purse” conditions. In addition, 25 tablets were placed into 30-ounce plastic amber prescription vials with flip-top lids (hereafter referred to as pop-tops) for additional analyses. Due to the volatility of NTG, the influence of headspace (unfilled bottle volume) on drug stability was assessed by removing 50 tablets from 100-count bottles (designated as the headspace samples). The pocket condition involved a study team member placing 3 bottles (25-count, 100-count, and headspace sample) in his front pant pocket; the purse condition consisted of an assistant placing 3 bottles in her everyday carrying purse. For both pocket and purse conditions, 100-count bottles (full and headspace) were opened an average of once weekly and the 25-count bottles were opened once a month for several seconds (to mimic the amount of time to remove 1 tablet). After removal, tablets were returned to the bottle to ensure sufficient tablets were available for analysis. Bottles stored at ambient, 25˚C/60%, and 40˚C/75% conditions were only opened on testing days. To assess physical tablet stability, 2 additional 100count bottles of SL NTG were carried in the pocket of a third study team member. One bottle remained full whereas the other had 75 tablets removed to replicate a scenario in which a patient had been using the tablets over time, thereby leading to a smaller quantity with more room for tablet movement within the bottle. Whole and/or intact tablets from each bottle were weighed at various time points (described below). www.ajconline.org
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At 0, 1, 2, 3, 6, 12, 18, 24, 30 months, and at the expiration date stated on the bottles (33 months for 100-count, 34 months for 25-count), 3 tablets from each storage condition and/or package were assayed by high performance liquid chromatography (HPLC) to quantify drug content. The 30month sampling point was omitted for the 25-count bottles as there were not enough tablets for analysis. Individual tablets were placed in 10 ml volumetric flasks and brought to volume with a 60:40 water:methanol solution. The flasks were sonicated for 7 to 9 minutes and the fluid was then passed through a 0.45 mm filter (Chromafil PET -45/25 polyester disposable syringe filter). Drug concentrations were determined by an Agilent 1260 Infinity series HPLC equipped with an Econosphere C18 150 mm x 4.6 mm, 5 um column. The mobile phase consisted of 60:40 HPLC grade water:methanol and the injection volume was 20 mL. The wavelength of detection was set at 220 nm. Nitroglycerin United States Pharmacopeia (USP) reference standard was used to prepare standards. The percent of labeled drug for each sample was determined from the standard curve and the average and standard deviation were then calculated. The initial headspace of the 3 packaging configurations (100-count, 25-count, and headspace) was determined as follows: empty 100 count and 25 count bottles were filled with water which was then transferred to a graduated cylinder to determine the total bottle volume. Next, 100 tablets and 25 tablets were placed in graduated cylinders and the volume occupied was determined. Three measurements were made for each sample (n = 3) and headspace calculated as the difference between the total bottle volume and the volume of the tablets.
Results Chemical stability data are shown in Figures 1−3. The USP monograph for SL NTG sets the potency limits at 90% to 115% of labeled amount and thus 90% was used as the lowest acceptable level for this study.12 Overall, tablets stored at 25˚C/60% RH and ambient conditions (data not shown) were considered the most stable, with drug content (potency) meeting the USP specification through the expiration date stated on the label, irrespective of package size. In contrast, potency declined rapidly in tablets stored in the 40˚C/75% RH condition, falling below the 90% threshold within 2 to 6 months. These results are in agreement with previous research which showed that SL NTG volatilization was dependent on storage temperature.7 The observed decrease in potency occurred faster in the 25-count and headspace samples in comparison to the 100-count package, which is also consistent with previous research.7 Headspace was considered a variable that would likely impact SL NTG stability. The instability of SL NTG tablets has been shown to be due to physical volatilization rather than chemical degradation.4 In this study, tablets placed in the pop-top vials lost potency very rapidly, nearly 50% at 1 month when stored at 40˚C/75% RH (Figure 3). This loss in potency can be attributed to the drug’s continual volatilization, never reaching saturation of the volatilized NTG in the headspace since these vials do not provide a hermetic seal. Moreover, these vials are made from plastic and NTG has been shown to adsorb to such materials.13,14 For the tablets stored in the original manufacturer’s glass vials, the sample designated as “headspace” had the largest headspace whereas the 25-count bottle had the smallest
Figure 1. Chemical stability of 100-count bottles of sublingual nitroglycerin tablets. United States Pharmacopeia (USP) potency specification is between 90% and 115% of the labeled amount. The dashed line indicates the lowest acceptable potency per USP. RH = relative humidity.
ARTICLE IN PRESS Cardiovascular Pharmacology/Sublingual Nitroglycerin Stability
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Figure 2. Chemical stability of 25-count bottles of sublingual nitroglycerin tablets. United States Pharmacopeia (USP) potency specification is between 90% and 115% of the labeled amount. The dashed line indicates the lowest acceptable potency per USP. RH = relative humidity.
initial headspace (Table 1). However, the loss of NTG potency was similar for the 2 samples and seemed to occur faster than with the 100-count bottle (Figures 1−3). To help explain this seemingly contradictory finding, the headspace volumes were normalized by dividing the initial
volume by the number of tablets in the container (Table 1). The normalized headspace for the “headspace” and 25count bottles was about 2 to 2.5 times higher than that of the 100-count bottle, which then correlated well with the observed potency data.
Figure 3. Chemical stability of half-filled 100-count bottles of sublingual nitroglycerin tablets (i.e., headspace samples) and pharmaceutical-grade plastic amber prescription vials with easily removable flip-top lids (i.e., pop-top samples). United States Pharmacopeia (USP) potency specification is between 90% and 115% of the labeled amount. The dashed line indicates the lowest acceptable potency per USP. RH = relative humidity.
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Table 1 Initial headspace of the sublingual nitroglycerin container configurations Package size
Headspace
Normalized headspace (volume per tablet)
100 count bottle Headspace (100 count bottle with 50 tablets removed) 25 count bottle
9.1 cc 11.6 cc
0.09 cc/tablet 0.23 cc/tablet
4.0 cc
0.16 cc/tablet
Tablets stored in the purse retained potency above the 90% acceptability threshold longer than tablets carried in the pocket. These findings may be attributed to the higher body heat that tablets were exposed to while in the pocket as well as to the added physical collisions of the tablets created by patient movement. These results are in agreement with the findings from the temperature and/or RH-controlled conditions (discussed earlier) as well as previously published reports that NTG volatilization is temperature dependent.7 With the exception of the tablets stored at elevated temperature and RH, the tablets in the 100-count bottles maintained potency throughout the majority of the study period and became subpotent only near the expiration date for the pocket and purse conditions (Figure 1). At nearly every time point, the potency of tablets stored at 25˚C/60% RH was slightly higher than that of tablets stored in the purse, and the potency of tablets in the purse was slightly higher than that of tablets carried in the pocket (Figures 1−3). Similar to the 100-count bottles, tablets in the 25-count bottles maintained potency throughout the majority of the study with the exception of the tablets stored at 40˚C/75% RH (Figure 2). However, by the expiration date, the potency of tablets from the 25-count bottle stored in the pocket was noticeably below that of tablets stored in either the purse or the 25˚C/60% RH condition, and was also below the 90% USP potency threshold (Figure 2). Tablets from the headspace bottles showed a similar trend (Figure 3), with those stored at 25˚C/60% RH maintaining potency throughout, whereas those stored in the purse fell below the potency limit only at the end of the study. In contrast, headspace tablets stored in the pocket failed to meet potency specifications at 12 months. These results can again be correlated with normalized headspace: the normalized headspace of the “headspace” bottle was approximately 50% times greater than that of the 25-count bottle. To simulate real-life scenarios, the 100-count bottles (including headspace samples) were opened once per week and the 25-count bottles were opened once per month. This was meant to mimic a patient who would take SL NTG roughly once per week or once per month, respectively. Patients requiring infrequent use of SL NTG may be more likely to receive 25-count bottles whereas those with more frequent usage may opt for 100-count bottles. To determine the effects of tablet removal, we compared the 100-count bottles to the headspace bottles, as this would most closely replicate the increasing headspace seen with periodic tablet removal. In this scenario, a more rapid loss in potency occurred with simulated frequent tablet removal (“headspace” bottles) compared with infrequent removal
(100-count bottles), which was exacerbated when carried in the pocket (1 and 3). These results may again be attributed to differences in headspace, where the normalized headspace for the “headspace” bottles was about 2.5 times that of the full 100 count bottles (Table 1). Tablets retained good physical stability over the first 12 months of the study and then became more fragile as the study progressed, most notably in the 100-count bottle in which 75 tablets were removed (Figure 4). The investigative team also observed that tablets began to lose their sharp, flat edges with more loose powder deposits settling in the bottle after 12 months (Figure 5). By the end of the study, tablet weights were approximately 78% and 92% of starting weights for the 100-count bottles containing 25 and 100 tablets, respectively. Discussion The results of this study put into question the contemporary practice of having patients replace their SL NTG tablets every 3 to 6 months. Our results demonstrate that when stored at temperate environmental conditions and subject to normal patient activity, SL NTG tablets maintain their potency anywhere from about 12 months after opening up until the labeled expiration date, depending on how they are carried and how frequently they are used. Our results also indicate that higher tablet stress, both physical (movement of tablets) and environmental (temperature and humidity), results in more rapid loss of potency. Early published studies demonstrated that SL NTG potency was an issue for a significant number of patients.15−18 However, all these studies were published in the 1980s, and do not account for advances made since then with regards to tablet manufacturing processes and patient education. More recent unpublished research suggests that contemporary manufacturing of SL NTG in reformulated stabilized compressed tablets (versus the older, molded tablets) and patient counseling on proper drug storage may circumvent the need to replace SL NTG before the product expiration date, even with frequent opening.11 At the time of this study, Nitrostat was the only SL NTG tablet available in the United States. Our study shows that by following manufacturer’s recommendations (keep tablets sealed in the original bottle; do no expose to temperatures over 25˚C), a 100-count bottle should stay potent for at least 2 years if carried in a purse and for 6 to 12 months if carried in a pocket, even with periodic bottle openings. The 25-count bottle should stay potent until the expiration date on the label if carried in a purse and for 2 years if carried in a pocket. Patients should therefore be queried as to how they carry their SL NTG to help guide refill frequency recommendations. The temperature and humidity at which the product is stored must also be considered. Our results showed that storage at 25˚C preserved tablet stability in comparison to an environment of more extreme heat and humidity (i.e., 40˚C/75% RH). This is consistent with prior research and manufacturer recommendations.7,8 Patients who live in hot and humid climate may therefore experience a more rapid decline in SL NTG potency compared with patients living
Cardiovascular Pharmacology/Sublingual Nitroglycerin Stability
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Figure 4. Physical stability of full and 1=4 full bottles (100 count size) of sublingual nitroglycerin tablets.
in cooler or more temperate environments and these patients should consider refilling their SL NTG more frequently than recommended above until more research can be done in this area. From a practical standpoint, patients who need SL NTG once per month or less should be prescribed a 25count bottle, with the 100-count bottle reserved for those using SL NTG more frequently. For the 100-count bottle, the method of storage and the effects of headspace become more of a concern. Our results demonstrate good potency beyond 2 years with a 100-count bottle stored in a purse when the bottle is opened and the product used regularly (i.e., once per week). However, when the bottle is carried in a pocket where tablet collisions are more common and the immediate environment is warmer, loss of potency becomes evident by 12 months. For these patients, a 25-count bottle may be more appropriate, or the 100-count bottle refilled every
Figure 5. Representative 0.4 mg sublingual nitroglycerin tablets from a fresh bottle (left) and a bottle that had been carried in a front pant pocket for 33 months (right).
6 to 9 months. Regardless, our results do not support universally instructing patients to either use SL NTG until the labeled expiration date or replace it every 6 months. The convenience and economics of less frequent product replacement could be appreciated by patients. For example, if 25 tablets cost $30 (our purchase cost), refilling every 12 to 24 months would save $30 to $90 versus refilling every 6 months, with even more savings for patients purchasing the more expensive 100-count bottles. However, there may be some patients (e.g., those living in hot and humid environments and those carrying half-full 100-count bottles in their pockets), for whom replacing SL NTG every 6 months may still be sage advice. Our study is limited by the fact that we are a single site located in the southwestern United States, a region with very low RH. In addition, our sample size was small with the results of each chemical assay based on only 3 tablets. We also studied only 1 SL NTG tablet preparation (Nitrostat; the only SL NTG product commercially available at the time) and it is probable that SL NTG from other manufacturers will eventually become available. However, we believe our study results will also apply to SL NTG tablets from other manufacturers due to commonalities in standard tablet manufacturing processes. Lastly, the personnel who carried the SL NTG were not cardiac patients and may have behaved differently (i.e., were more active) than patients with heart disease. If that was the case, however, then our results may actually have underestimated the physical stability of the product by exposing it to more physical stress. Our study results demonstrate that several factors influence SL NTG stability. Storage conditions (temperature and humidity), headspace of the bottle, and method of carrying all impact how long SL NTG maintains its potency.
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Temperate conditions involving low physical tablet movement in the bottle results in much longer product stability compared with warmer, more humid conditions or conditions with greater tablet movement. A reduction in tablet potency also occurs as tablets are removed from the bottle and headspace increases over time. Accordingly, SL NTG may maintain potency for a few months or up until the labeled expiration date depending on the situation. Each patient should be regularly queried regarding how he and/ or she carry his and/or her SL NTG to help guide prescribing and refill frequency recommendations.
1. Amsterdam EA, Wenger NK, Brindis RG, Casey D.E. Jr, Ganiats TG, Holmes D.R. Jr, Jaffe AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Peterson ED, Sabatine MS, Smalling RW, Zieman SJ. 2014 AHA/ACC guideline for the management of patients with non-st-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;130:2354–2394. 2. Murrell W. Nitro-glycerine as a remedy for angina pectoris. Lancet Lond Engl 1879;113:80–81. 3. O’Gara PT, Kushner FG, Ascheim DD, Casey D.E. Jr, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX. 2013 ACCF/AHA guideline for the management of st-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;127:e362–e425. 4. Yacobi A, Amann AH, Baaske DM. Pharmaceutical considerations of nitroglycerin. Drug Intell Clin Pharm 1983;17:255–263.
5. Lagas M, Duchateau AM. Sublingual nitroglycerin. II. In vitro and in vivo availability of Nitrostat and Nitrobaat tablets. Pharm Weekbl Sci 1988;10:254–258. 6. Mayer GA. Instability of nitroglycerin tablets. Can Med Assoc J 1974;110:788–789. 7. Lagas M, Duchateau AM. Sublingual nitroglycerin. I. Comparative evaluation of the physical stability of commercially available tablets. Pharm Weekbl Sci 1988;10:246–253. 8. Nitrostat prescribing information. Available at: http://labeling.pfizer. com/ShowLabeling.aspx?id=663. Accessed on August 17, 2018. 9. Nitroglycerin - Medicinenet.com. Available at: https://www.medicinenet.com/nitroglycerin/article.htm#what_is_nitroglycerin? Accessed on August 17, 2018. 10. Patient education: Medications for angina (Beyond the Basics) UpToDate. Available at: https://www.uptodate.com/contents/medications-for-angina-beyond-the-basics. Accessed on August 17, 2018. 11. Rinkor LJ. Sublingual nitroglycerin and stability. Pharm Lett 2003;19: Detail-Document 190608. 12. USP Monographs: Nitroglycerin Sublingual Tablets. Available at: http:// www.pharmacopeia.cn/v29240/usp29nf24s0_m56980a.html. Accessed on August 17, 2018. 13. Pikal MJ, Bibler DA, Rutherford B. Polymer sorption of nitroglycerin and stability of molded nitroglycerin tablets in unit-dose packaging. J Pharm Sci 1977;66:1293–1297. 14. Banes D. Deterioration of nitroglycerin tablets. J Pharm Sci 1968;57:893–894. 15. O’Hanrahan M, McGarry K, Kelly JG, Horgan J, O’Malley K. Diminished activity of glyceryl trinitrate. Br Med J Clin Res Ed 1982;284:1183–1184. 16. Marty J, Shaw J, Hunt D. The stability of glyceryl trinitrate tablets during patient use. Aust N Z J Med 1983;13:147–150. 17. DeVine AM, Johnson CE. Sublingual nitroglycerin: tablet potency and patient education. Am Pharm 1982;22:40–43. NS. 18. Curry SH, Mehta K, Shavlik TA, Felt R. Survey of sublingual nitroglycerin-tablet potency under conditions of patient use. Int Med Spec 1987;8:63–71.
Sublingual (SL) nitroglycerin (NTG) is a mainstay for treating ischemic heart disease.1−3 Due to its volatility, SL NTG must be stored in amber glass vials with metal screw top caps.4−8 Early studies suggested that SL NTG tablets rapidly lose potency, leading to recommendations that patients replace SL NTG every 3 to 6 months.5,6,9,10 However, this may not apply to contemporary practice due to improved tablet manufacturing processes and more diligence by the health care community in ensuring patients adhere to medicine storage and handling recommendations. Unpublished data suggest that once opened, SL NTG tablets maintain potency until the labeled expiration date.11 However, whether this holds true under conditions of normal patient use is unknown. The objective of this study was to investigate the stability of SL NTG using simulated real-life scenarios and controlled storage conditions. Methods SL NTG 0.4 mg tablets (Nitrostat, Pfizer/ParkeDavis, NYC, New York) of identical lot number were kept in the original manufacturer’s packaging and subjected to 5 different storage conditions: (1) 25˚C/60% a University of New Mexico College of Pharmacy, Albuquerque, New Mexico; and bUniversity of New Mexico Hospitals, Albuquerque, New Mexico. Manuscript received June 1, 2018; revised manuscript received and accepted August 24, 2018. *Corresponding author: Tel: 505-272-0584; fax: 505-272-9749. E-mail address: [email protected] (J.J. Nawarskas).
0002-9149/© 2018 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjcard.2018.08.048
relative humidity (RH); (2) 40˚C/75% RH; (3) ambient (laboratory shelf); (4) “pocket”; and (5) “purse” conditions. In addition, 25 tablets were placed into 30-ounce plastic amber prescription vials with flip-top lids (hereafter referred to as pop-tops) for additional analyses. Due to the volatility of NTG, the influence of headspace (unfilled bottle volume) on drug stability was assessed by removing 50 tablets from 100-count bottles (designated as the headspace samples). The pocket condition involved a study team member placing 3 bottles (25-count, 100-count, and headspace sample) in his front pant pocket; the purse condition consisted of an assistant placing 3 bottles in her everyday carrying purse. For both pocket and purse conditions, 100-count bottles (full and headspace) were opened an average of once weekly and the 25-count bottles were opened once a month for several seconds (to mimic the amount of time to remove 1 tablet). After removal, tablets were returned to the bottle to ensure sufficient tablets were available for analysis. Bottles stored at ambient, 25˚C/60%, and 40˚C/75% conditions were only opened on testing days. To assess physical tablet stability, 2 additional 100count bottles of SL NTG were carried in the pocket of a third study team member. One bottle remained full whereas the other had 75 tablets removed to replicate a scenario in which a patient had been using the tablets over time, thereby leading to a smaller quantity with more room for tablet movement within the bottle. Whole and/or intact tablets from each bottle were weighed at various time points (described below). www.ajconline.org
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At 0, 1, 2, 3, 6, 12, 18, 24, 30 months, and at the expiration date stated on the bottles (33 months for 100-count, 34 months for 25-count), 3 tablets from each storage condition and/or package were assayed by high performance liquid chromatography (HPLC) to quantify drug content. The 30month sampling point was omitted for the 25-count bottles as there were not enough tablets for analysis. Individual tablets were placed in 10 ml volumetric flasks and brought to volume with a 60:40 water:methanol solution. The flasks were sonicated for 7 to 9 minutes and the fluid was then passed through a 0.45 mm filter (Chromafil PET -45/25 polyester disposable syringe filter). Drug concentrations were determined by an Agilent 1260 Infinity series HPLC equipped with an Econosphere C18 150 mm x 4.6 mm, 5 um column. The mobile phase consisted of 60:40 HPLC grade water:methanol and the injection volume was 20 mL. The wavelength of detection was set at 220 nm. Nitroglycerin United States Pharmacopeia (USP) reference standard was used to prepare standards. The percent of labeled drug for each sample was determined from the standard curve and the average and standard deviation were then calculated. The initial headspace of the 3 packaging configurations (100-count, 25-count, and headspace) was determined as follows: empty 100 count and 25 count bottles were filled with water which was then transferred to a graduated cylinder to determine the total bottle volume. Next, 100 tablets and 25 tablets were placed in graduated cylinders and the volume occupied was determined. Three measurements were made for each sample (n = 3) and headspace calculated as the difference between the total bottle volume and the volume of the tablets.
Results Chemical stability data are shown in Figures 1−3. The USP monograph for SL NTG sets the potency limits at 90% to 115% of labeled amount and thus 90% was used as the lowest acceptable level for this study.12 Overall, tablets stored at 25˚C/60% RH and ambient conditions (data not shown) were considered the most stable, with drug content (potency) meeting the USP specification through the expiration date stated on the label, irrespective of package size. In contrast, potency declined rapidly in tablets stored in the 40˚C/75% RH condition, falling below the 90% threshold within 2 to 6 months. These results are in agreement with previous research which showed that SL NTG volatilization was dependent on storage temperature.7 The observed decrease in potency occurred faster in the 25-count and headspace samples in comparison to the 100-count package, which is also consistent with previous research.7 Headspace was considered a variable that would likely impact SL NTG stability. The instability of SL NTG tablets has been shown to be due to physical volatilization rather than chemical degradation.4 In this study, tablets placed in the pop-top vials lost potency very rapidly, nearly 50% at 1 month when stored at 40˚C/75% RH (Figure 3). This loss in potency can be attributed to the drug’s continual volatilization, never reaching saturation of the volatilized NTG in the headspace since these vials do not provide a hermetic seal. Moreover, these vials are made from plastic and NTG has been shown to adsorb to such materials.13,14 For the tablets stored in the original manufacturer’s glass vials, the sample designated as “headspace” had the largest headspace whereas the 25-count bottle had the smallest
Figure 1. Chemical stability of 100-count bottles of sublingual nitroglycerin tablets. United States Pharmacopeia (USP) potency specification is between 90% and 115% of the labeled amount. The dashed line indicates the lowest acceptable potency per USP. RH = relative humidity.
ARTICLE IN PRESS Cardiovascular Pharmacology/Sublingual Nitroglycerin Stability
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Figure 2. Chemical stability of 25-count bottles of sublingual nitroglycerin tablets. United States Pharmacopeia (USP) potency specification is between 90% and 115% of the labeled amount. The dashed line indicates the lowest acceptable potency per USP. RH = relative humidity.
initial headspace (Table 1). However, the loss of NTG potency was similar for the 2 samples and seemed to occur faster than with the 100-count bottle (Figures 1−3). To help explain this seemingly contradictory finding, the headspace volumes were normalized by dividing the initial
volume by the number of tablets in the container (Table 1). The normalized headspace for the “headspace” and 25count bottles was about 2 to 2.5 times higher than that of the 100-count bottle, which then correlated well with the observed potency data.
Figure 3. Chemical stability of half-filled 100-count bottles of sublingual nitroglycerin tablets (i.e., headspace samples) and pharmaceutical-grade plastic amber prescription vials with easily removable flip-top lids (i.e., pop-top samples). United States Pharmacopeia (USP) potency specification is between 90% and 115% of the labeled amount. The dashed line indicates the lowest acceptable potency per USP. RH = relative humidity.
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Table 1 Initial headspace of the sublingual nitroglycerin container configurations Package size
Headspace
Normalized headspace (volume per tablet)
100 count bottle Headspace (100 count bottle with 50 tablets removed) 25 count bottle
9.1 cc 11.6 cc
0.09 cc/tablet 0.23 cc/tablet
4.0 cc
0.16 cc/tablet
Tablets stored in the purse retained potency above the 90% acceptability threshold longer than tablets carried in the pocket. These findings may be attributed to the higher body heat that tablets were exposed to while in the pocket as well as to the added physical collisions of the tablets created by patient movement. These results are in agreement with the findings from the temperature and/or RH-controlled conditions (discussed earlier) as well as previously published reports that NTG volatilization is temperature dependent.7 With the exception of the tablets stored at elevated temperature and RH, the tablets in the 100-count bottles maintained potency throughout the majority of the study period and became subpotent only near the expiration date for the pocket and purse conditions (Figure 1). At nearly every time point, the potency of tablets stored at 25˚C/60% RH was slightly higher than that of tablets stored in the purse, and the potency of tablets in the purse was slightly higher than that of tablets carried in the pocket (Figures 1−3). Similar to the 100-count bottles, tablets in the 25-count bottles maintained potency throughout the majority of the study with the exception of the tablets stored at 40˚C/75% RH (Figure 2). However, by the expiration date, the potency of tablets from the 25-count bottle stored in the pocket was noticeably below that of tablets stored in either the purse or the 25˚C/60% RH condition, and was also below the 90% USP potency threshold (Figure 2). Tablets from the headspace bottles showed a similar trend (Figure 3), with those stored at 25˚C/60% RH maintaining potency throughout, whereas those stored in the purse fell below the potency limit only at the end of the study. In contrast, headspace tablets stored in the pocket failed to meet potency specifications at 12 months. These results can again be correlated with normalized headspace: the normalized headspace of the “headspace” bottle was approximately 50% times greater than that of the 25-count bottle. To simulate real-life scenarios, the 100-count bottles (including headspace samples) were opened once per week and the 25-count bottles were opened once per month. This was meant to mimic a patient who would take SL NTG roughly once per week or once per month, respectively. Patients requiring infrequent use of SL NTG may be more likely to receive 25-count bottles whereas those with more frequent usage may opt for 100-count bottles. To determine the effects of tablet removal, we compared the 100-count bottles to the headspace bottles, as this would most closely replicate the increasing headspace seen with periodic tablet removal. In this scenario, a more rapid loss in potency occurred with simulated frequent tablet removal (“headspace” bottles) compared with infrequent removal
(100-count bottles), which was exacerbated when carried in the pocket (1 and 3). These results may again be attributed to differences in headspace, where the normalized headspace for the “headspace” bottles was about 2.5 times that of the full 100 count bottles (Table 1). Tablets retained good physical stability over the first 12 months of the study and then became more fragile as the study progressed, most notably in the 100-count bottle in which 75 tablets were removed (Figure 4). The investigative team also observed that tablets began to lose their sharp, flat edges with more loose powder deposits settling in the bottle after 12 months (Figure 5). By the end of the study, tablet weights were approximately 78% and 92% of starting weights for the 100-count bottles containing 25 and 100 tablets, respectively. Discussion The results of this study put into question the contemporary practice of having patients replace their SL NTG tablets every 3 to 6 months. Our results demonstrate that when stored at temperate environmental conditions and subject to normal patient activity, SL NTG tablets maintain their potency anywhere from about 12 months after opening up until the labeled expiration date, depending on how they are carried and how frequently they are used. Our results also indicate that higher tablet stress, both physical (movement of tablets) and environmental (temperature and humidity), results in more rapid loss of potency. Early published studies demonstrated that SL NTG potency was an issue for a significant number of patients.15−18 However, all these studies were published in the 1980s, and do not account for advances made since then with regards to tablet manufacturing processes and patient education. More recent unpublished research suggests that contemporary manufacturing of SL NTG in reformulated stabilized compressed tablets (versus the older, molded tablets) and patient counseling on proper drug storage may circumvent the need to replace SL NTG before the product expiration date, even with frequent opening.11 At the time of this study, Nitrostat was the only SL NTG tablet available in the United States. Our study shows that by following manufacturer’s recommendations (keep tablets sealed in the original bottle; do no expose to temperatures over 25˚C), a 100-count bottle should stay potent for at least 2 years if carried in a purse and for 6 to 12 months if carried in a pocket, even with periodic bottle openings. The 25-count bottle should stay potent until the expiration date on the label if carried in a purse and for 2 years if carried in a pocket. Patients should therefore be queried as to how they carry their SL NTG to help guide refill frequency recommendations. The temperature and humidity at which the product is stored must also be considered. Our results showed that storage at 25˚C preserved tablet stability in comparison to an environment of more extreme heat and humidity (i.e., 40˚C/75% RH). This is consistent with prior research and manufacturer recommendations.7,8 Patients who live in hot and humid climate may therefore experience a more rapid decline in SL NTG potency compared with patients living
Cardiovascular Pharmacology/Sublingual Nitroglycerin Stability
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Figure 4. Physical stability of full and 1=4 full bottles (100 count size) of sublingual nitroglycerin tablets.
in cooler or more temperate environments and these patients should consider refilling their SL NTG more frequently than recommended above until more research can be done in this area. From a practical standpoint, patients who need SL NTG once per month or less should be prescribed a 25count bottle, with the 100-count bottle reserved for those using SL NTG more frequently. For the 100-count bottle, the method of storage and the effects of headspace become more of a concern. Our results demonstrate good potency beyond 2 years with a 100-count bottle stored in a purse when the bottle is opened and the product used regularly (i.e., once per week). However, when the bottle is carried in a pocket where tablet collisions are more common and the immediate environment is warmer, loss of potency becomes evident by 12 months. For these patients, a 25-count bottle may be more appropriate, or the 100-count bottle refilled every
Figure 5. Representative 0.4 mg sublingual nitroglycerin tablets from a fresh bottle (left) and a bottle that had been carried in a front pant pocket for 33 months (right).
6 to 9 months. Regardless, our results do not support universally instructing patients to either use SL NTG until the labeled expiration date or replace it every 6 months. The convenience and economics of less frequent product replacement could be appreciated by patients. For example, if 25 tablets cost $30 (our purchase cost), refilling every 12 to 24 months would save $30 to $90 versus refilling every 6 months, with even more savings for patients purchasing the more expensive 100-count bottles. However, there may be some patients (e.g., those living in hot and humid environments and those carrying half-full 100-count bottles in their pockets), for whom replacing SL NTG every 6 months may still be sage advice. Our study is limited by the fact that we are a single site located in the southwestern United States, a region with very low RH. In addition, our sample size was small with the results of each chemical assay based on only 3 tablets. We also studied only 1 SL NTG tablet preparation (Nitrostat; the only SL NTG product commercially available at the time) and it is probable that SL NTG from other manufacturers will eventually become available. However, we believe our study results will also apply to SL NTG tablets from other manufacturers due to commonalities in standard tablet manufacturing processes. Lastly, the personnel who carried the SL NTG were not cardiac patients and may have behaved differently (i.e., were more active) than patients with heart disease. If that was the case, however, then our results may actually have underestimated the physical stability of the product by exposing it to more physical stress. Our study results demonstrate that several factors influence SL NTG stability. Storage conditions (temperature and humidity), headspace of the bottle, and method of carrying all impact how long SL NTG maintains its potency.
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The American Journal of Cardiology (www.ajconline.org)
Temperate conditions involving low physical tablet movement in the bottle results in much longer product stability compared with warmer, more humid conditions or conditions with greater tablet movement. A reduction in tablet potency also occurs as tablets are removed from the bottle and headspace increases over time. Accordingly, SL NTG may maintain potency for a few months or up until the labeled expiration date depending on the situation. Each patient should be regularly queried regarding how he and/ or she carry his and/or her SL NTG to help guide prescribing and refill frequency recommendations.
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