STEM TODAY April 2017, No.19
STEM TODAY April 2017 , No.19
CONTENTS Pharm02: We do not know how long medications may be safe and effective beyond their expiration dates The long足term stability of medications, possibly even beyond their labeled shelf足 lives, is largely unknown, and the issue has been operationally avoided by continuous replenishment of supplies. In order to continue safe and effective pharmaceutical treatments in the absence or interruption of re足supply, additional information is required on how each medication changes during long足 duration storage.
Editorial Editor: Mr. Abhishek Kumar Sinha Editor / Technical Advisor: Mr. Martin Cabaniss
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Cover Page S102-S-008 S102-S-008 (8 March 2001) — The Space Shuttle Discovery blasts off from Launch Pad 39B at dawn on mission STS-102. Liftoff occurred at 6:42:09 (EST) for this eighth shuttle flight to the International Space Station. Image Credit: NASA
Back Cover New Full-hemisphere Views of Earth at Night NASA scientists are releasing new global maps of Earth at night, providing the clearest yet composite view of the patterns of human settlement across our planet. This composite image, one of three new full-hemisphere views, provides a view of the Americas at night. The clouds and sun glint - added here for aesthetic effect - are derived from MODIS instrument land surface and cloud cover products. Image Credit: Image Credit: NASA Earth Observatory image by Joshua Stevens, using Suomi NPP VIIRS data from Miguel Román, NASA’s Goddard Space Flight Center
STEM Today , April 2017
Editorial Dear Reader
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All young people should be prepared to think deeply and to think well so that they have the chance to become the innovators, educators, researchers, and leaders who can solve the most pressing challenges facing our world, both today and tomorrow. But, right now, not enough of our youth have access to quality STEM learning opportunities and too few students see these disciplines as springboards for their careers. According to Marillyn Hewson, "Our children - the elementary, middle and high school students of today - make up a generation that will change our universe forever. This is the generation that will walk on Mars, explore deep space and unlock mysteries that we can’t yet imagine". "They won’t get there alone. It is our job to prepare, inspire and equip them to build the future - and that’s exactly what Generation Beyond is designed to do." STEM Today will inspire and educate people about Spaceflight and effects of Spaceflight on Astronauts. Editor Mr. Abhishek Kumar Sinha
Editorial Dear Reader The Science, Technology, Engineering and Math (STEM) program is designed to inspire the next generation of innovators, explorers, inventors and pioneers to pursue STEM careers. According to former President Barack Obama, " Science is more than a school subject, or the periodic table, or the properties of waves. It is an approach to the world, a critical way to understand and explore and engage with the world, and then have the capacity to change that world..." STEM Today addresses the inadequate number of teachers skilled to educate in Human Spaceflight. It will prepare , inspire and educate teachers about Spaceflight. STEM Today will focus on NASA’S Human Research Roadmap. It will research on long duration spaceflight and put together latest research in Human Spaceflight in its monthly newsletter. Editor / Technical Advisor Mr. Martin Cabaniss
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Exploration Medical Capability (ExMC) Pharm02: We do not know how long medications may be safe and e ective beyond their expiration dates
The long-term stability of medications, possibly even beyond their labeled shelf-lives, is largely unknown, and the issue has been operationally avoided by continuous replenishment of supplies. In order to continue safe and e ective pharmaceutical treatments in the absence or interruption of re-supply, additional information is required on how each medication changes during long-duration storage. Ultimately, this information will be used to best match medications chosen for a particular space ight mission with duration of that mission, reducing or even obviating interim resupply.
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Physical and Chemical Changes in Pharmaceuticals Flown on Space Missions
Efficacious pharmaceuticals with adequate shelf life are essential for successful space medical operations. Therefore, stability of pharmaceuticals is of paramount importance to ensure health and wellness of astronauts on future space exploration missions. Unique physical and environmental factors of space missions such as radiation, excessive vibration, microgravity, and an enclosed and CO2 -rich environment, in addition to humidity and temperature variations, may contribute to instability of pharmaceutical dosage forms.
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Degradation of pharmaceuticals can result in inadequate efficacy and untoward toxic effects that could compromise astronaut safety and health. Over the life of NASA’s human spaceflight program, duration of missions has increased, resulting in a concomitant increase in demand for pharmaceuticals during flights. The use of pharmaceuticals during space shuttle missions is common with crews taking more than 500 individual doses of 31 different medications during the first 33 flights.
Primarily, medications taken during shuttle flights have been orally administered, although ocular, topical, rectal, and parenteral formulations are included in the onboard operational medical kits. Stability characteristics and industry standards for shelf life are well established for terrestrial environments. For example, photolytic degradation of drugs by exposure to the low energy of visible light and fluorescent light is a well-documented phenomenon. Light is destructive to many drug classes, making amber bottles standard for dispensing most pharmaceuticals. Although amber-colored bottles are effective in protecting drugs from destructive exposure to components of visible light, they do not protect drugs from other forms of radiation that may affect drug stability in space. This study aims to evaluate the effect of prolonged exposure to the spacecraft environment on the stability of pharmaceuticals. The objective was to identify differences in variables that indicate physical and chemical
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stability of medications between ground controls and spaceflight; chemical degradation profiles of formulations and relevant environmental variables of temperature, humidity, and cumulative radiation dose were compared for the two conditions. Medications in this study represent 18% of the formulary flown on spaceflights and include those commonly used by astronauts during flight, candidates from therapeutic classes contained in the ISS and shuttle medical kits, different dosage forms, and formulations in unique commercial dispensers. A sufficient quantity of each medication from the same lot was purchased from a local pharmacy vendor and packed in these specially designed identical kits that were used as ground control and flight medication payload kits. All kits were equipped with passive radiation dosimeters (provided by the NASA Space Radiation Analysis Group) and with temperature and relative humidity (RH) recorders.
Results
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No changes in physical appearance were observed in ground control samples of formulations from payloads 1-3 while physical changes in some of the solid and semisolid formulations after flight were observed with samples from all the four payloads. However, discoloration of amoxicillin/clavulanate (Augmentin r) tablets and liquefaction of ciprofloxacin ophthalmic ointment were noticed also in control samples from payload 4.
A list of formulations with physical changes in flight samples is presented in Table II. While the most frequently observed physical change in flight samples was discoloration, samples of clotrimazole cream and mupirocin ointment from payload 4 exhibited phase separation. Ciprofloxacin ophthalmic ointment was the only semisolid formulation with liquefaction in both control and flight samples from payload 4; however, the storage period for this payload (880 days) was beyond the labeled expiration date for this formulation. An interesting observation is that the number of formulations with physical changes was higher in flight samples from all payloads than in controls but variable between payloads. Six formulations from payload 2 flight samples had discoloration, and the number but not the formulations were the same in later payloads as well (3 and 4). All of the six formulations were within labeled expiration date during payload 2 time period while five of them expired by the time of the return of payload 4.
The data presented in Table III suggest that the number of formulations that did not meet content requirement of active pharmaceutical ingredient (API) was higher in flight kits compared to the corresponding control kits from all four payloads. This difference in the number of unstable formulations between flight and control
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increased with the length of storage time in space and consistently fewer formulations from the flight kit met acceptance criteria for API content than from the respective control kit at the end of each payload period.
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After 880 days of storage in flight (payload 4), only 27% of solid formulations met the acceptance criteria for content. After 596 days (payload 3) in flight, fewer than half of the solid dosage forms in the flight payload kit met content acceptance criteria. A list of medications from control and flight payload kits with percentage of chemical content less than the USP requirement or less than 10% of the label claim . Of these formulations listed, acyclovir, the only antiviral formulation in this study and metronidazole, an antibiotic, had expiration dates beyond the study period; the other seven formulations were stable, both on the ground and in space, beyond their expiration date.
The percent content of amoxicillin and clavulanate after each payload period, presented in Fig. 3, shows a faster degradation of clavulanate on the ground than in flight. These data indicate that clavulanate may be inherently unstable and is more susceptible to environmental factors on the ground. Degradation profiles for ciprofloxacin and promethazine (PMZ), the two medications that were flown in three different formulations, are presented in Fig. 4. The API content for the formulations of both medications is comparable between flight and ground. Ciprofloxacin ophthalmic solution from flight and control kits had acceptable API content beyond labeled expiration date while PMZ injection degraded faster during flight, reaching less than acceptable potency before the expiration date. The potency of PMZ tablets from both control and flight was below acceptable limit by payload 2 period onwards prior to expiration date. Degradation profiles for other antibiotic tablet formulations are presented in Fig. 5. Clavulanate in amoxicillin/clavulanate (Augmentin r) was the most unstable API. The rates of degradation of clavulanate on the ground and in spaceflight were 0.1005% and 0.0936%/100 days, with a predicted loss of potency close to 50% occurring by 489 and 534 days, respectively, much sooner than the expiration date. In general, while degradation was faster in space than on the ground for most of the APIs, loss of API content was <20% of label claim except for levothyroxine and trimethoprim which were 28% and 21%, respectively. The mean temperature and relative humidity data for control and flight for all four payloads are presented in Fig. 6. Temperature and humidity were similar for ground and flight conditions, and they remained within the USP recommended range. Although the average percent humidity for all payloads remained well within the USP-defined range during flight, there were isolated incidents of RH values falling below the recommended minimal level (30%). As expected, the cumulative radiation dose for control conditions for all four payloads (5.45 mGy) was negligible and substantially lower than the cumulative radiation dose during flight (110.7 mGy), and the accumulation rate appears to be linear (Fig. 7).
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Results of this investigation constitute a preliminary but a systematic evaluation for the first time, of changes in physical and chemical variables of pharmaceuticals stored on space missions. In general, a number of formulations tested had a lower potency or percent content of API after storage in space with a consistently higher number of formulations failing USP potency requirement after each storage period interval in space than on Earth (Table III). This reduction in potency of flight samples occurred sooner than the labeled expiration date for many formulations suggesting that storage conditions unique to the spacecraft environment may influence stability of pharmaceuticals in space. On Earth, drug potency is known to vary with storage conditions, especially temperature and humidity. Many drugs stored under standard conditions retain 90% of their potency for at least 5 years after the expiration date on the label and sometimes for even longer periods. However, most stability studies and guidance pertain to pharmaceutical products dispensed in original commercial containers in contrast to the ones used in this study
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which are special custom-manufactured polypropylene containers that match those used for dispensing solid dosage forms in operational medical kits; such off-nominal packaging may compromise stability of formulations.
Certain APIs such as levothyroxine, dextroamphetamine, promethazine, trimethoprim, sulfamethoxazole, and clavulanate appear to be more susceptible to spaceflight environmental conditions than others in the study. Levothyroxine was the only API that fell below potency level in flight samples from all four payloads while remained stable on ground until after the first two payload intervals (332 days). Additionally, levothyroxine had a higher percent degradation than others with more than 20% loss of API after 880 days of storage in space. Levothyroxine formulation is known to be unstable on the ground,and these results suggest that this formulation may not be suitable for spaceflight. Promethazine and dextroamphetamine, the two lightsensitive stereoisomer compounds, also appear to be more
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susceptible to spaceflight conditions failing potency requirement after storage for 353 days in space which was earlier than expiration date. Similarly, ciprofloxacin, another light-sensitive compound also appears to have degraded faster in space than on the ground (Fig. 3) suggesting that the rate of degradation for light-sensitive pharmaceuticals may be accelerated during spaceflight.
Interestingly, the degradation rate of promethazine liquid in flight samples was more than 200% faster than in controls. A contributing factor for the observed faster degradation in flight with light-sensitive APIs could come from the radiation-rich environment of the spacecraft.
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In contrast to the results with light-sensitive APIs, the percentage of degradation of clavulanate was higher on the ground than in spaceflight, probably resulting from the higher RH (36-44%) recorded on the ground than in flight (23-25%) since clavulanate is very sensitive to RH differences. Amoxicillin, the other API in this combination antibiotic formulation was stable with acceptable potency on the ground and in space for over 353 days, consistent with reports of lower susceptibility of this compound to environmental conditions. To assess relative susceptibility of dosage forms to spaceflights environment, solid, semisolid, and liquid formulations of PMZ and ciprofloxacin, included in the ISS medical kits, were examined. The rate of degradation for all three formulations for both drugs was slightly faster in flight than on the ground as indicated by the difference in degradation profiles of API between the two conditions; this difference was greater with PMZ than with ciprofloxacin. Interestingly, the liquid formulation of ciprofloxacin in sealed commercial vials, remained potent beyond its expiration date in contrast to PMZ which degraded faster during flight. It is noteworthy that for light-sensitive APIs like promethazine, commercial dispensers may not provide adequate protection against radiation-rich spacecraft environment and might warrant the need for the development of spacehardy dispensing technologies. However, consistent with the general consensus on the ground that stability issues are less frequent with solid than with liquid or semisolid formulations, seven of nine formulations that remained potent by the end of the study period (880 days) were solid dosages in spite of being repackaged in flight dispensers, and the other two stable formulations, triamcinolone cream and ciprofloxacin ointment, were flown in commercial dispensers. 13 anti-infectives consisting of ten antibiotic, two antifungal, and one antiviral compounds were included in the study, and ten of the formulations were solid dosage forms. The two combination antibiotic formulations, sulfamethoxazole/trimethoprim and amoxicillin/clavulanate degraded faster in space than on the ground with amoxicillin/clavulanate combination being the least stable preparation both on the ground and in space. Imipenem/cilastatin, another combination antibiotic, was flown in its original commercial vial and appeared to be relatively stable both on the ground and in flight. Two formulations, metronidazole and acyclovir antiviral formulation were stable in space, concurrent with reports of their sustained stability on the ground. In a related ground-based study conducted by the FDA under the Shelf Life Extension Program (SLEP), stability of medications stored in their original containers under ideal storage conditions (cool, dry, and dark conditions) beyond their label expiration date was examined in an attempt to extend shelf life of expensive formulations such as the antibiotics. Results of this study indicated that ciprofloxacin stored unopened in commercial containers was stable for more than 10 years, with a shelf life extension up to 13 years. Results also indicated that 88% of the 3,005 lots of 122 medications tested were stable and remained potent for an average 66 months after their expiration date. However, while the SLEP study aims to extend shelf life of stock pharmaceuticals in sealed commercial containers, in the present investigation; we examined potency of repackaged antibiotics exposed to the unique environmental conditions of spaceflight
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At present, medication lots contained in the ISS operational formulary that are within 6 months of labeled expiration date are replaced as needed in compliance with FDA guidelines.
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Chemical Potency and Degradation Products of Medications Stored Over 550 Days
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Results from an Du et al. multi-year medication stability study on the ISS showed that most spaceflight-aged medications fail to meet United States Pharmacopeia (USP) guidelines for active pharmaceutical ingredient (API) content around the time of their expiration dates. There were six exceptions that failed earlier than their expiration dates: the antimicrobials amoxicillin/clavulanate, levofloxacin, and trimethoprim/sulfamethoxazole; the diuretic furosemide; and the synthetic hormone levothyroxine. Du and colleagues reported analysis of only a single sample of each drug, so it is not possible to assign statistical significance to their results, but their results indicate that at least some drugs in the flight medical kit merit further attention.
Also, Du et al. measured only the content of the active ingredient from each sample; no screening for appearance (or toxicity) of breakdown products was performed. The study described in this current report was conducted to expand upon their earlier results. Authors took advantage of unused medical supplies as a source
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of additional ISS-aged samples that could be used to test the hypothesis that medication degradation on the ISS does not differ from what is typically seen on Earth. Nine medications were available for study (Supplemental Table I). The medications included several of those most heavily used by US crewmembers: two sleep aids, an antihistamine, a decongestant, three pain relievers, an antidiarrheal, and an alertness medication. Each medication was available at a single time point; typical stability study protocol (analysis of the same medication at multiple time points) was not possible. Because the samples examined in this study were obtained opportunistically from medical supplies, no control samples (that is, samples aged for a similar period on the ground) were available. All medications were solid dosage forms.
Results
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To assess potency and purity, nine aged medications were analyzed with respect to active pharmaceutical ingredient (API) and degradant amounts (Table I). Results were compared to the USP requirements for API and the content of degradants and impurities . For medications having USP-specified criteria for impurities or related substances, known impurities and degradation products were investigated and assessed against USP criteria.
Aspirin samples 9 months beyond the original manufacturer expiration date were found to contain active in-
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gredient well within USP guidelines (96.5% of the label claim of 325 mg per tablet; Table I). Free salicylic acid was found at less than 0.05% in each sample; the USP limit for this impurity is no more than (NMT) 0.3% (Fig. 1a). Acetaminophen samples that were analyzed 5 months after their original manufacturer expiration date were found to contain active ingredient at 97.0% of the label claim of 325 mg per tablet, well within 2012 USP guidelines (Table I). Two additional peaks were observed (Fig. 1b), 0.17 and 0.25% (by peak area). The USP monograph for acetaminophen has been updated; these samples do not meet current requirements for API content (98-102% of label). Ibuprofen samples analyzed 3 months before their original expiration date also met USP criteria, with the active ingredient at 99.9% of the label claim of 400 mg per tablet (Table I). USP has identified and determined limits for an impurity in ibuprofen called ibuprofen-related compound C. Ibuprofenrelated compound C was found at less than 0.001% in each sample; the USP limit for this impurity is 0.25% (Fig. 1c). The USP monograph for ibuprofen has been updated; these samples meet current requirements for API content (97-103% of label).
Antihistamine loratadine samples were found to contain active ingredient well within USP guidelines at 8 months beyond the manufacturer expiration date, 99.9% of the label claim of 10 mg per tablet (Table I). Three additional peaks, one of which had a retention-time match for loratadine-related compound B, were each ob-
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served at ≤0.03% with a total of ≤0.07% (Fig. 2). Identification or other analysis of these additional peaks was not possible due to the small amount of material. USP guidelines limit individual impurities to ≤0.1% and total impurities to 0.1% (Table II). Total impurities in these samples were within, but close to, the USP limits.
Samples of loperamide, an opioid compound with little central nervous system activity used to treat diarrhea, were analyzed 2 months before the manufacturer expiration date. They contained active ingredient at 96.3% of the label claim of 2 mg per tablet (Table I). Additional, unidentified peaks were observed bracketing the main peak at ≤0.1 and ≤0.8%, respectively (Fig. 3), the second of which (at 0.8%), exceeds the new limits of 0.1%. The USP-identified impurity 4-(8-chloro-11-fluoro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2- b]pyridine-11yl)-1-piperidinecarboxylate ethyl (RRT 0.79) was not detected. Pseudoephedrine samples were analyzed 9 months after the manufacturer expiration date and found to contain active ingredient at 99.0% of the label claim of 120 mg per tablet (Table I). The melatonin samples in this study were 11 months beyond the manufacturer expiration date, the oldest samples in this study. They were found to contain API at 89.2% of the label claim of 10 mg per tablet and thus failed to meet USP standards for API content. Ten additional peaks were observed at ≤0.16% with a total of ≤0.96% (Table II and Fig. 4). USP guidelines limit individual impurities to ≤0.1% and total impurities to 1.0% (Table II). Although total impurities in these samples were within (but very close to) limits, the individual impurity limits were exceeded in multiple samples for five of the 10 impurities detected. Samples of this sleep supplement thus failed to meet USP criteria for both impurities and API. Zolpidem samples that were 9 months beyond their expiration date were found to contain active ingredient at 100.6% of the label claim of 10 mg per tablet, well within USP guidelines. Seven impurities were detected, totaling 0.29% by peak area and 0.24 by peak height. This is less than the USP limit of 0.5%. The most abundant was zolpidem-related compound B (0.12% by peak area and 0.10% by peak height). Three of the impurities were unspecified degradation products, the most abundant at 0.02% by peak area and by peak height (Table II).
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Samples of modafinil, an alertness medication, were analyzed 2 months before the original manufacturer expiration date and found to contain active ingredient at 100.6% of the label claim of 200 mg per tablet, well within USP guidelines (Table I). Five impurities were detected, totaling 0.17%, about 10% of the USP standard of 1.5%. The most abundant was modafinil sulfate (0.14%), for which the USP specifies a limit of 0.5%. Three of the impurities were unspecified products that totaled 0.01%.
The Shelf Life Extension Program (SLEP), a > 20 years cooperative study of the Department of Defense and the Food and Drug Administration, has clearly shown medication stability is dependent on manufacturer and formulation and can even vary from one manufacturing lot to another. Although it is tempting to conclude from the current results, each based on a single time point, that aspirin, pseudoephedrine, and zolpidem remain safe and effective for more than 6 months after expiration, other studies have made it clear that limited results like these cannot be extrapolated to other time points, brands, or even lots of the same medication. These limitations notwithstanding, five of the nine medications tested (56%) met 2012 USP requirements for API and degradants and impurities at least 5 months past their expiration dates (Fig. 5). Four of the nine (44% of those tested) medications tested met 2012 USP requirements up to 8 months post expiration. Another three medications (33% of those tested) met USP guidelines 2 to 3 months before expiration. Some common degradation products with specific USP guidelines were noted in aspirin, ibuprofen, loratadine, and zolpidem. Other degradation products were noted in other samples, at amounts too small for further analysis with USP methods and, with the exception of melatonin, within 2012 USP guidelines for total impurities for those medications. It is worth noting that the samples in this study had been repackaged into bags to reduce the overall volume of the ISS medication kit, whereas the samples from the Cantrell and SLEP studies were stored in their unopened original manufacturerâ&#x20AC;&#x2122;s packaging. Packaging is a critical factor in long-term stability of medications; aspirin lost 7% of its active ingredient after 1 week in a dosette box in accelerated aging conditions (40â&#x2014;Ś C, 75% relative humidity). Even an enteric coating on a tablet may improve product stability.
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Stability of vitamin B complex in multivitamin and multimineral supplement tablets after space flight
The effect of storage in space on the stability of vitamin B complex in two commercial vitamin tablets was examined. Reference standards (1 g) of thiamine hydrochloride, riboflavin, nicotinic acid, and pyridoxine hydrochloride (products of Supelco), as well as methylparaben, methanol, acetonitrile, glacial acetic acid, hydrochloric
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acid (36.5-38%) and sodium 1-hexanesulfonate were purchased from VWR (Bridgeport, NJ). Centrum Silverr Multivitamin/ Multimineral Supplements (Wyeth, designated as Brand #1) and OneADay Womenâ&#x20AC;&#x2122;s r (Bayer, Brand #2) were purchased from local pharmacies to serve as our laboratory controls (GL). Brand #1 and Brand #2 multivitamin/multimineral supplements retrieved from one space shuttle flight and three ISS expeditions were provided by NASA-JSC. The space shuttle flight group (Payload I) tablets flew on a space shuttle for a short 14-20 day short space journey. The two ISS groups (Payloads II and III) were the tablets taken to the ISS by a space shuttle flight, which remained on the ISS for approximately 12 and 19 months before returning to Earth. The Ground controls (G0 ) groups were the vitamins purchased simultaneously with the space samples (same product lot) by NASA-JSC, but stored in a controlled laboratory on earth for the same time duration as the group flown on a space shuttle or an ISS mission. The lab also purchased Brand #1 and Brand #2 vitamins from different local pharmacies as another ground control group (GL). In addition, three positive controls were provided by NASA-JSC.
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These were vitamin tablets (1) stored in the Orbital Environmental Simulator (OES) for the same time duration under similar temperature and humidity conditions but not the radiations of space flight, (2) retrieved from Kennedy Space Center (KSC), and (3) Brand #2 irradiated in the Space Radiation Laboratory at Brookhaven National Laboratory(NSRL) . The samples were shipped to our lab by FedEx without being X-rayed to avoid additional irradiation.
Results
The four vitamin B retention times are reported in Fig. 1. The peak shape of niacin (vitamin B3 ) was asymmetric when its reference standard was dissolved in 0.1 M HCl, but was symmetric when it was dissolved in diluting solution or deionized water (Fig. 1). The percent of vitamin B1 , B2 , B3 and B6 present in the multivitamin and multimineral supplements retrieved from the spacecrafts (shuttle and ISS), and the positive control groups (OES and KSC) were not significantly different from what was indicated in the USP and on the package labels (90% to 150%), except the vitamin B1 from the Brand #2 tablets retrieved from one ISS expedition was 74.9Âą11.5% (Table 2). The percent of vitamins B1 , B2 , B3 and B6 present in all groups of Brand #1 were found not significantly different from those of the controls. And all were within but all in 90-150% window. Deionized water was not a good dissolution medium for vitamin B2 (riboflavin) due to its low solubility, while 0.1 M HCl caused chemical changes in vitamin B3 (niacin). Brand #1 disintegrated and dissolved 15 min faster than Brand #2 in either medium. There was no significant difference among the averaged release profiles of all experimental groups and control groups, although large variation among individual profiles was observed. Due to complexity in numerous experimental groups with similar results, only one payload of Brand #2 is listed in Table 3 to show the similarity in release performance. As aforementioned, only Brand #2 vitamin tablets were irradiated in the NSRL under eight different source conditions to mimic the potential irradiation exposure and potential dose levels in outer space (Table 1). The in vitro released profiles (n = 2) using deionized water as dissolution medium and our laboratory tablets as the negative control were found similar among these eight groups (Table 4). The ingredient loading allowance for vitamin B complex can be as much as its 150% of the label claims based on USP/NF 2010. The unused portion of this water soluble vitamin complex may be excreted easily by healthy individuals. Among the four water soluble vitamin B ingredients, vitamin B2 (riboflavin) is least water soluble (Table 4), but it was released completely when 0.1 M HCl was used as the dissolution medium (Table 4). The dilution solution (water-acetonitrile-glacial acetic acid, 94:5:1, v/v/v) recommended in the USP/NF does not represent a physiological medium. It was used only for retrieving content, but not for in vitro dissolution, because acetonitrile may escape into the air by the required agitation. Water is not the ideal in vitro dissolution medium for two reasons. First, vitamin B2 is not soluble in water. Second, water is not a typical disintegrating or dissolution medium when an immediate release tablet is administered by mouth into the stomach. 0.1 M HCl may be used to study vitamin B1 , B2 , and B6 , but preferably
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not for vitamin B3 (niacin) due to the appearance of asymmetry observed in the chromatographic peak shape. Therefore, more than one dissolution medium should be used for vitamin B analysis.
The two negative control groups,GL and G0 of both Brand #1 and Brand #2 from difference sources were comparable in the study. The chromatographic peak apex of vitamin B3 (niacin) of all six Brand #2 tablets retrieved from an ISS expedition flight were noted different from those in the ground control group by having a notch (Fig. 2a-c). Two out of six Orbital Environmental Simulator tablets in the same payload also started to lose their symmetry (Fig. 2d). A reason for this instability could come from the active pharmaceutical ingredient (API) itself, formulation matrix, API-excipient interaction or the packaging container. Polymer plastic containers are probably better suited for withstanding vibration forces experienced during ascent and decent spacecraft to Earth by being lighter than glass and metal ones and less breakable.
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Results indicate that vitamin B3 in one of the brands tested (#2) may be subject to marginal degradation after storage on ISS for 4 months as indicated by the chromatograms for all six tablets showing a split peak appearing as a notch at the peak tip. Chromatograms were not different for ground and flight samples for Brand #1 suggesting that this may be more suitable for use in space. Numerous physical and environmental factors unique to the space flight environment have been shown to affect the stability and shelf-life of medications flown on the Space Shuttle and the International Space Station (ISS).
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Shelf Life Extension Program (SLEP)
The Shelf Life Extension Program (SLEP) is a joint program of the United States Department of Defense and the Food and Drug Administration which aims to reduce the cost to the military of maintaining stockpiles of certain pharmaceuticals. Under SLEP, medications are tested for safety and stability for extended periods of time in controlled storage conditions. In many cases, medications remain effective for years past their printed expiry dates.
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