International Journal of Pharmaceutics 396 (2010) 105–110

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International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

The most appropriate storage method in unit-dose package and correlation

between color change and decomposition rate of aspirin tablets
Noriko Yamazaki, Kumiko Taya, Ken-ichi Shimokawa, Fumiyoshi Ishii ∗
Department of Health Care and Sciences, Faculty of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose, Tokyo 204-8588, Japan

a r t i c l e i n f o a b s t r a c t

Article history: The most appropriate method to preserve Bufferin 81-mg tablets dispensed for unit-dose packaging in
Received 24 March 2010 the hospital pharmacy was examined. The surface color change of the tablets was investigated over time
Received in revised form 29 May 2010 by spectrophotometry, and the decomposition rate of aspirin was measured by high-performance liquid
Accepted 18 June 2010
chromatography (HPLC). To overcome these, it was found that we can effectively prevent color changes
Available online 25 June 2010
and preserve the quality by maintaining the humidity as 55% or less, storage with drying agent in a plastic
or aluminum pack. It was revealed that the color changes became greater and the decomposition rate
Keywords:
became higher as time passed. Color changes markedly affect the patients’ compliance, and are found
Aspirin tablet
Color change
to be a very important factor. It was considered that the clarity of the correlation between the color
Decomposition rate change and decomposition rate may contribute to a decrease in the number of tablets discarded before
Discard the expiration date.
Storage method © 2010 Elsevier B.V. All rights reserved.

1. Introduction (TIA), cerebral infarction) and inhibition of thrombus/embolus

formation after coronary aortic bypass graft (CABG) or percuta-
Since “Bufferin 81-mg tablets” (The proprietary name was neous transluminal coronary angioplasty (PTCA)”. In particular, the
changed to “Bufferin combination tablets A81” in September 2009.), frequency of elderly persons taking this preparation is high, and
as an anti-platelet agent, were manufactured/sold by LION Co., compliance as prophylactic administration requiring regular once-
Ltd. (Tokyo; Japan) in 2000, they have been routinely employed a-day dosing may be important.
in clinical practice as 2-layer, light orange tablets containing 81 mg The principal component of Bufferin 81-mg tablets, aspirin
of aspirin and 33 mg of dialuminate (aluminum glycinate: 11 mg, (acetylsalicylic acid), is known to gradually decompose into sali-
magnesium carbonate: 22 mg) in respective layers. In addition, cylic and acetic acids in the presence of moist air. In the package
Corn Starch, Saccharin, Sodium Saccharin, Talc, d-Mannitol and inserts of Bufferin 81-mg tablets, it is also described that this prod-
Gelatin, as the excipients or additives, are included in these tablets. uct is decomposed via moistening, and should be handed to patients
However, actually, “Bufferin 81-mg tablets” became commercially with its aluminum-sheet package remaining intact, as “Precautions
available as “Children’s bufferin” in 1963. After Weiss et al. reported for handling”. However, in clinical practice, Bufferin 81-mg tablets
the anti-platelet actions of aspirin in 1967 (Mann and Plummer, may be taken out of the aluminum sheet, dispensed for unit-dose
1994), “Children’s bufferin” was also selected as an anti-platelet packaging, and delivered to patients in some hospitals/drugstores,
agent beyond its approved indications from the 1970s in Japan considering compliance, difficulty in SP-sheet opening (Owaki et al.,
(Hirasawa, 2001). In 1999, it was approved as an anti-platelet 2004), and availability in nursing facilities. In the interview form
agent to eliminate its extra-indication use. In 2000, it was man- (IF) (Lion Co., Ltd., 2003) of Bufferin 81-mg tablets, the standard
ufactured/sold with a modified name. free salicylic acid content is established as 3% or less of the aspirin
In the “Indications” column of Bufferin 81-mg tablets, the fol- content. The stability of these tablets after unit-dose packaging has
lowing contents are described: “ inhibition of thrombus/embolus been reported. However, the relationship between color changes
formation related to the following disorders: angina pectoris and the decomposition rate remains to be clarified.
(chronic stable angina, unstable angina), myocardial infarction, Target pharmacists working in hospitals/drugstores, we con-
and ischemic cerebrovascular disorder (transient ischemic attack ducted a questionnaire survey regarding the presence or absence of
Bufferin 81-mg tablet dispensing for unit-dose packaging, changes
in the color of tablets taken out of the aluminum sheet, and guid-
ance for patients regarding storage methods. Based on the results,
∗ Corresponding author. Tel.: +81 42 495 8468; fax: +81 42 495 8468. we examined the most appropriate storage method to reduce the
E-mail address: fi[email protected] (F. Ishii). rate of aspirin decomposition, as the principal component of re-

0378-5173/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.ijpharm.2010.06.031
106 N. Yamazaki et al. / International Journal of Pharmaceutics 396 (2010) 105–110

packaged Bufferin 81-mg tablets, to 3% or less, as well as the Table 1

Questionnaire regarding Bufferin 81-mg tablets (LION Co., Ltd.).
correlation between color changes and the rate of aspirin decom-
position, and evaluated whether the rate of decomposition can be Workplace: Hospital, Drugstore, Others
estimated based on color changes. Question 1. Have you ever taken Bufferin 81-mg tablets from their
aluminum-sheet package for unit-dose packaging?
→ Yes, No → Persons who selected “No” please skip to Questions 5 and 6.
2. Materials and methods Persons who selected “Yes”: Is a Bufferin 81-mg cassette installed?
→ Yes, No
2.1. Materials Question 2. Have you ever prepared preliminary unit-dose packages
before the date of scheduled patient consultation (visit)?
Bufferin® 81-mg tablets manufactured/sold by Lion Co., Ltd. → Yes, No
Persons who selected “Yes”: How were the preliminary unit-dose
(Tokyo), which were for 33–36 months before the expira- packages stored?
tion date were used. Powder packaging paper used machine, →Uncovered, Unipack, Unipack + a drying agent, Aluminum bag,
which was E Ueda Cello-Poly® (polyethylene (PE) 0.04 mm thick) Others ( )
obtained from Meg Co. (Tokyo), plastic pack (Uni-pack® I-4: Question 3. Have you ever discarded tablets taken out of their aluminum
sheet due to color changes before administration? (before the
0.04 mm × 200 mm × 280 mm, PE) and aluminum pack (Lami-zip®
expiration date)
AL-22: 0.134 mm × 220 mm × 300 mm + gusset 64 mm, polyethy- → Yes, No
lene terephthalate (PET)/aluminum (AL)/PE) supplied from Seisan- Persons who selected “Yes”: How about the condition?
nipponsha, Ltd. (Tokyo), Silica gel S-5 (5 g, 60 mm × 50 mm) → In a cassette for unit-dose package, Preliminarily prepared products, In a
purchased from TachibanaYa Shouji Inc. (Kouchi, Japan), and Unipack,
Others ( )
raw lime drying agent S237270H (20 g, 7 cm × 9 cm) obtained
from Sakamotosekkai Co., Ltd. (Kumamoto, Japan) were used. Question 4. Did you instruct patients on storage methods?
Columns used HPLC was Inertsil® ODS-3 (5 ␮m, 150 mm × 4.6 mm → No special instruction, Use of a Unipack, Use of an empty can, Use of a
drying agent, Others ( )
I.D.) manufactured by GL Sciences Inc. (Tokyo). Membrane fil-
ter (OmniporeTM : 0.2-␮m JG) used Millipore Co. (MA, USA). The Question 5. Have you ever been consulted about color changes by
patients?
reagents used were all of special class grade available on the mar-
→ Yes, No
ket. Persons who selected “Yes”: How did you answer (evaluate)?
→ Evaluate whether or not tablets should be discarded based on the color
(self-assessment, others)
2.2. Questionnaire survey
Evaluate based on the administration period
Evaluate based on the expiration date
A questionnaire survey regarding Bufferin 81-mg tablets Others ( )
by inquiry was conducted involving hospital/drugstore phar-
Question 6. What color leads to you discarding the tablet?
macists who attended the North Tama North-Medical-Area
Medical/Pharmaceutical Study Meeting (Yamazaki et al., 2008), or higher, or higher, or higher
which was held in Meiji Pharmaceutical University on February 14,
2008, and consented to cooperate. The question items are shown in
Table 1. Concerning color changes in comparison with that imme- 2.4. Experiment [II]
diately after opening, photographs of Bufferin 81-mg tablets with
slight, appreciable, and much changes, which could be Temperature/humidity: When storing tablets, the temperature
evaluated under direct vision, were presented, and the following and humidity in the thermohygrostat were maintained at 27 ◦ C and
question was addressed: “What color leads to you discarding the 55%, respectively, as it is described that the rate of aspirin decom-
tablet?”(refer to Photo 1). position on pulverization decreases at a humidity of 56% or less, in
the IF of Bufferin 81-mg tablets.
2.3. Experiment [I] Packaging method: Of the above 7 types, 4 ((B), (D), (E), and (G))
were selected.
Temperature/humidity: Tablets were simultaneously stored in
a thermohygrostat (Enviros KCL-2000W: Tokyo Rikakikai Co., 2.5. Quantification of aspirin and salicylic acid
Ltd., Tokyo), while maintaining the temperature and humidity at
27 ◦ C and 65%, respectively, with reference to the mean tempera- Aspirin was quantified using high-performance liquid chro-
ture/humidity in hospital pharmacies in which optimal conditions matography (HPLC, HPLC JASCO 2000-Plus system, Japan Spec-
may be maintained for medicinal storage (Japanese Society of troscopic Co., Ltd.). The column temperature was 40 ◦ C, and the
Hospital Pharmacists, 2005). flow rate was 1.2 mL/min. As a mobile phase, monobasic potas-
Packaging method: Based on the results of this questionnaire sium phosphate/methanol solution (3:2) (pH 2.0) was used at a
survey, tablets were taken out of the aluminum sheet, and the fol- measurement wavelength of 295 nm.
lowing 7 types ((A)–(G)) of packaging form were employed with Four Bufferin 81-mg tablets were ground, and 0.5 g of powder
reference to routine methods after unit-dose packaging. When was accurately weighed as a sample. The sample was mixed with
storing unit-dose-packaged products in a plastic pack, can, or alu- 10 mL of dehydrated ethanol, agitated, and filtered using a 0.2-
minum pack, 84 packages per lot were simultaneously stored, ␮m membrane filter. The filtrate was mixed with purified water
considering the maximum interval of 12 weeks measured in to accurately prepare a volume of 50 mL. It was used as sample
this study: (A) uncovered tablets, (B) unit-dose-packaged prod- solution.
ucts alone, (C) unit-dose-packaged products stored in a can, (D) The peak area per 10 ␮L of sample/standard solution was mea-
unit-dose-packaged products stored in a plastic pack, (E) unit-dose- sured using HPLC, and the levels of aspirin and salicylic acid were
packaged products stored with silica gel (drying agent) in a plastic calculated based on the assay lines for the two prepared from
pack, (F) unit-dose-packaged products stored with a raw lime dry- standard solution. Furthermore, the sample aspirin decomposi-
ing agent in a plastic pack, and (G) unit-dose-packaged products tion rate was calculated using the following formula by converting
stored in an aluminum pack. the sample level of salicylic acid to the aspirin level (converted
 N. Yamazaki et al. / International Journal of Pharmaceutics 396 (2010) 105–110 107

Fig. 1. Experiment [I]: the aspirin decomposition rate in tablets with each package form stored in a thermohygrostat (temperature: 27 ◦ C, humidity: 65%): at the start of
measurement, the decomposition rate was 1.3%.

aspirin level): 3. Results

Aspirin decomposition rate (%) 3.1. Results of the questionnaire survey

Converted aspirin level
= × 100 Twenty-four pharmacists (16 hospital and 8 drugstore pharma-
Actual aspirin level + converted aspirin level
cists) responded to the “Questionnaire regarding Bufferin 81-mg
Tablets” presented in Table 1. Of these, 14 (58.3%) reported that
Measurement was performed immediately after tablet removal
Bufferin 81-mg tablets were taken out of the aluminum-sheet
from the aluminum sheet (at the start of the experiment) and 1, 2, 4,
package for unit-dose packaging. Of the 14 pharmacists, 8 (57.1%)
8, and 12 weeks after unit-dose packaging, establishing a maximum
indicated the preparation of preliminary packages before drug
interval as 3 months, which may be indicated in prescriptions.
delivery to patients. Only 2 (14.3%) reported guidance for patients
In all experiments, these substances were quantified 3 times per
regarding the storage of unit-dose-packaged Bufferin. Furthermore,
lot using 3 different lots of Bufferin 81-mg tablets. The mean of 9
12 (85.7%) had discarded tablets taken out of the aluminum sheet
measurements was employed.
due to color changes before the expiration date. Question 6, “What
color leads to you discarding the tablet?”, was raised, while pre-
2.6. Color changes senting a photograph of Bufferin 81-mg tablets with color changes
(Photograph 1). Ten pharmacists (41.7%) selected grade 1 or higher
In Experiment I, Bufferin 81-mg tablets were taken out of the tablets, 12 (50.0%) selected grade 2 or higher tablets, and 2 (8.3%)
aluminum sheet, separately packaged by unit-dose, and stored in selected grade 3 tablets.
a thermohygrostat (temperature: 27 ◦ C, humidity: 65%). Apparent
changes on the tablet surface were investigated using photography
and spectrophotometry at the start of this experiment and after 2, 3.2. Rate of aspirin decomposition
4, 8, and 12 weeks, as described below. At each point, 4 tablets
per lot (total: 12 tablets) were evaluated. The bilateral sides were 3.2.1. Experiment [I]
assessed using a spectrophotometer, and the mean was employed. The serial changes in the aspirin decomposition rate in tablets
The aspirin decomposition rate at each point was calculated, as with each package form stored in a thermohygrostat (temperature:
described above (Section 4). 27 ◦ C, humidity: 65%) are shown in Fig. 1. At the start of measure-
Photography ment, the decomposition rate was 1.3%. In uncovered tablets, the
Photographs were taken using a digital steel camera (Cyber-Shot decomposition rate exceeded 3% 2 weeks after unit-dose packag-
DSC-T9: Sony Co., Ltd.) under an illuminance of 20,000 lx. ing; the tablets did not meet the standards. In unit-dose-packaged
Spectrophotometer products alone/unit-dose-packaged products stored in a can, a sim-
The color of tablets was measured through the L*a*b* color- ilar tendency was noted 4 weeks after unit-dose packaging. In
ing system using a spectrophotometer (CM-2002: Konica Minolta unit-dose-packaged products stored in a plastic pack, the decom-
Co., Ltd.). Color differences related to serial changes of the tablet position rate was less than 3% 4 weeks after unit-dose packaging,
(E*ab) were calculated employing the following formula: but exceeded 4.7% after 8 weeks; the tablets did not meet the stan-
 dards. In unit-dose-packaged products stored with a drying agent
2 2 2
E ∗ ab = (L∗ ) + (a∗ ) + (b∗ ) (silica gel/raw lime) in a plastic pack, the decomposition rate was
approximately 2% after 8 weeks, although it exceeded 3% after 12
In this formula, L* and (a*; b*) indicate differences in weeks. On the other hand, in unit-dose-packaged products stored
brightness and color (a*: red-green direction; b*: yellow-blue in an aluminum pack, the decomposition rate was approximately
direction), respectively. 2% or less after 12 weeks.
108 N. Yamazaki et al. / International Journal of Pharmaceutics 396 (2010) 105–110

Fig. 2. Experiment [II]: the aspirin decomposition rate in tablets with each package form stored in a thermohygrostat (temperature: 27 ◦ C, humidity: 55%): at the start of
measurement, the decomposition rate was 1.3%.

3.2.2. Experiment [II] established by the National Bureau of Standards (NBS unit), and
As it is described that the rate of aspirin decomposition on pul- decomposition rate is shown in Fig. 3. The color difference and
verization decreases at a humidity of 56% or less, in the IF of Bufferin decomposition rate serially increased. According to the NBS cri-
81-mg tablets, this experiment was conducted, while maintaining teria, the color of tablets was evaluated as “noticeably different”
the thermohygrostat temperature and humidity at 27 ◦ C and 55%, after 2 weeks and “appreciable different” after 4, 8, and 12 weeks.
respectively. For storage, 4 package forms ((B), (D), (E), and (G)) The decomposition rate reached 3% more than 2 weeks after the
were employed. The serial changes in the decomposition rate for start of the experiment; the tablets did not meet the standards.
each package form in comparison with that for the (B) package
form obtained at a temperature and humidity of 27 ◦ C and 65%,
4. Discussion
respectively, in Experiment I are shown in Fig. 2.
Concerning the (B) package form, the results were compared
In clinical practice, Bayaspirin® 100-mg (Bayer Schering Pharma
between 2 different humidity conditions: 65 and 55%. At a humidity
Co., Ltd. 2008), which exhibit the same effects as Bufferin 81-
of 65%, the decomposition rate was 3.8% 4 weeks after unit-dose
mg tablets, are commercially available. These are enteric-coated
packaging, as described above. However, it was 2.4% at a humidity
tablets, and non-sealed tablets are also commercially available
of 55%. Concerning the (D) package form, the decomposition rate
as a preparation that can be utilized for unit-dose packaging.
after 8 weeks was 4.7% at a humidity of 65%, whereas it was 3% at
When packaging tablets by unit-dose, the stability may be main-
a humidity of 55%. Concerning the (E) and (G) package forms, the
tained by selecting coated tablets, because their hygroscopic
decomposition rates after 12 weeks were approximately 3% or less.
property is lower. However, actually, Bufferin 81-mg tablets, which
These results confirmed that the aspirin decomposition rate at a
show a marked hygroscopic property, are separately packaged by
humidity of 55% was lower than at a humidity of 65% regardless of
unit-dose in some hospitals, as indicated by the results of this
the presence or absence of pulverization.
questionnaire survey. This may be because prescribing physicians
are accustomed to Bufferin 81-mg tablets, with a 40-year history
3.2.3. Color changes from 1963, and because even elderly persons with reduced vision
The changes in the appearance/color of unit-dose-packaged can distinguish light orange tablets. However, based on the results
Bufferin 81-mg tablets at the start of the experiment and after a spe- of this questionnaire survey, there are limitations: Bufferin 81-
cific period (2, 4, 8, and 12 weeks) of storage in a thermohygrostat mg tablets are dispensed for unit-dose packaging, although it is
(temperature: 27 ◦ C, humidity: 65%) are shown in Photo 2. described that this product should be handed to patients with its
The color of tablets immediately after being taken out of the aluminum-sheet package remaining intact, in the package inserts
aluminum sheet (at the start of the experiment) was light orange. of this agent; and color changes related to unit-dose packaging
The white color of the dialuminate-containing layer was slightly require discarding before administration in some cases. To over-
more marked. At this point, the decomposition rate was 1.3%. After come these limitations, an optimal storage method at the mean
2 weeks, the circumference became slightly dark orange, show- temperature/humidity in hospital pharmacies should be reviewed,
ing a change in the appearance. However, the decomposition rate and patients should be instructed on storage at home so that the
was 2.8%. After 4 weeks, the sides and circumference became dark conditions may be maintained.
orange, and the decomposition rate was 3.8%; the tablets did not In this study, the rate of aspirin decomposition for each
meet the standards. After 8 weeks, a portion of the center became packaging form was measured under Experiment I (mean tempera-
dark orange in addition to the sides and circumference, with a ture/humidity in hospital pharmacies: 27 ◦ C and 65%, respectively)
decomposition rate of 5.5%. In addition, after 12 weeks, dark orange and Experiment II (27 ◦ C and 55%, respectively, in accordance with
spots extending at the center were observed, and the corner was a humidity of 56% or less at which the rate of aspirin decompo-
affected in some tablets. The decomposition rate was 7.1%. sition decreases) conditions. The results of Experiment II showed
The relationship among the color difference (E*ab) mea- that the aspirin decomposition rate in Bufferin 81-mg tablets was
sured using a spectrophotometer, criteria for color differences inhibited when the humidity on storage was established as 55%
 N. Yamazaki et al. / International Journal of Pharmaceutics 396 (2010) 105–110 109

Fig. 3. The relationship among the color difference (E*ab) measured using a spectrophotometer, criteria for color differences established by the National Bureau of Standards
(NBS unit), and aspirin decomposition rate.

or less. Briefly, aspirin decomposition depends on humidity; an therefore, it should be positively introduced, although it is expen-
environmental humidity maintained at 55% or less during the stor- sive.
age period may be useful for inhibiting decomposition. Based on Concerning color changes, this experiment confirmed that both
these results, it is important to maintain the humidity in hospital the color difference (E*ab) on the tablet surface and aspirin
pharmacies at 55% or less. However, the mean hospital pharmacy decomposition rate serially increased. A spectrophotometer may
temperature and humidity in June were reported to be 27 ◦ C and not be installed in clinical practice; color differences may be visually
65% (Japanese Society of Hospital Pharmacists, 2005), respectively, assessed.
by the Japanese Society of Hospital Pharmacists. During specific Based on the results of this questionnaire survey, 41.7% of the
hours or in some areas, the mean humidity was 70% or more. pharmacists reported that tablets with “slight changes ” in color
Considering this, an optimal storage method under the Experi- were discarded (Photograph 1). The slight changes were evalu-
ment I conditions was reviewed. After Bufferin 81-mg tablets were ated as color differences ranging from 0.5 to 1.5 according to the
taken out of the aluminum sheet, the rate of aspirin decompo- NBS criteria. As shown in Fig. 3, the aspirin decomposition rate
sition rapidly increased, as shown in Fig. 1. In addition, there was 2% or less, meeting the standards. With this color, the phar-
were no marked differences in the decomposition rate among sev- macists discarded tablets, possibly because they considered that
eral storage methods: unit-dose-packaged tablets, those stored in even slight color changes showed an elevated aspirin decomposi-
a plastic pack, and those stored in a can. Briefly, the 0.04-mm tion rate beyond the standards, or because they paid attention to
thick plastic pack employed in this study did not exhibit any anti- the tablet’s color at the time of drug delivery to patients to prevent
hygroscopic effects even when sealed with a zipper, and the aspirin the reduction of compliance related to post-delivery color changes,
decomposition rate was similar to that in unit-dose-packaged or considering the humidity level on storage at home.
uncovered tablets. However, as shown in Fig. 1, the decomposition A review of the relationship between color changes and the
rate was markedly inhibited when a drying agent was placed in the decomposition rate obtained in this experiment may contribute
plastic pack. When employing an aluminum pack, it was further to a decrease in the number of tablets discarded before the
inhibited. The introduction of these storage methods in each hos- expiration date (Fig. 3). Briefly, when color differences are trace
pital/drugstore may make it possible to maintain the stability of or slight, the decomposition rate may be 3% or less, meeting
this preparation over a longer period even if Bufferin 81-mg tablets the standards. When they are appreciable, it may exceed 3%.
are taken out of their sealed packaging. However, when administering aspirin for the secondary pre-
In this experiment, silica gel and raw lime were used as vention of myocardial infarction, the dose ranges from 50 to
drying agents. The volume of these drying agents required to 162 mg (Japanese Circulation Society, 2006); its anti-platelet
maintain their effects for 12 weeks was calculated using a for- actions may not be markedly reduced even if the decomposi-
mula (JIS Z0301) regarding anti-hygroscopic packaging methods. tion rate exceeds 3%. However, to prevent Bufferin 81-mg tablets’
Products immediately after arrival from the manufacturers were deviation from the standards and maintain patient compliance,
employed. However, in clinical practice, storage conditions may tablets should be dispensed for unit-dose packaging immedi-
vary: an insufficient volume of drying agents, and the use of dry- ately before administration. When preparing preliminary unit-dose
ing agents absorbing moisture to some degree. In such cases, packages for specific reasons, storage methods are important.
the rate of aspirin decomposition may be higher than in this Quality control with the above storage methods at an optimal
experiment. Silica gel must be dried using a microwave oven, humidity and guidance regarding appropriate storage at home
and used at a sufficient volume. Furthermore, an aluminum pack after drug delivery may prevent color changes, maintaining com-
inhibits the decomposition rate in the absence of drying agents; pliance.
110 N. Yamazaki et al. / International Journal of Pharmaceutics 396 (2010) 105–110

These results may provide information useful for health care Japanese Circulation Society, 2006. Guidelines for Secondary Prevention of Myocar-
professionals and patients, improving future medicinal manage- dial Infarction, pp. 12–16 http://www.netjcs.or.jp/.
Japanese Society of Hospital Pharmacists, 2005. Stability Date in Uncovered Tablets
ment. and Capsules. Iyaku (Medicine and Drug) Joumal Co., Ltd, ISBN 475322130X.
Lion Co., Ltd., 2003. Interview Form “Bufferin® 81-mg Tablets”.
Appendix A. Supplementary data Mann, C.C., Plummer, M.L., 1994. The Aspirin Wars: Money, Medicine, and 100 Years
of Rampant Competition. Diamond. Co, ISBN 4478860092.
Owaki, N., Mase, S., Shibata, Y., Ushida, M., Masuda, S., Shibata, Y., Kammati, A.,
Supplementary data associated with this article can be found, in Ogawa, K., Kumagai, M., Yokota, M., Hayakawa, T., 2004. A multi-center study
the online version, at doi:10.1016/j.ijpharm.2010.06.031. on convenience of removing tablets and capsules from heat-sealed packages.
Jpn. J. Pharm. Health Care Sci. 30, 312–320.
Yamazaki, A., Osawa, K., Kuramoto, H., Honda, K., Tajima, M., Yokoyama, H., Yoshi-
References nari, J., Hiranuka, I., Baba, T., Nonaka, A., Ishibashi, Y., Hino, F., Yamazaki, N.,
Shimokawa, K., Ishii, F., 2008. Activity report about the North Tama North-
Bayer Schering Pharma. Co., Ltd., 2008. Ethical Drug Package Insert Medical-Area Medical/Pharmaceutical Study Meeting. In: The128th Annual
“Bayaspirin® 100mg”. Meeting of the Pharmaceutical Society of Japan, vol. 2, p. 218.
Hirasawa, M., 2001. Super Drug Aspirin: A Way to the Super Drug. Heibonsha Limited
Publishers, ISBN 458285107.