XML Template (2009) [5.9.2009–2:48pm] [1–4]
{TANDF_FPP}CMO/CMO_A_365060(NEW).3d (CMO) [First Proof]
Current Medical Research and Opinion
C213
Volume 25, Number 2 2008
The major risk factors for ‘pill-induced esophagitis’
6,7
evaluated 26 generics of alendronate sodium tablets
are: patient age-related impairment of esophageal motility (70mg) currently available in Canada, Germany, the
and the characteristics of the dosage form, including size, Netherlands and the United Kingdom. The measurements
shape and coating
8–10
. As the population ages, the pro- of in vitro disintegration showed that six of the products
blems of osteoporosis and impaired esophageal peristalsis had a disintegration time530s, which is comparable to
both increase. Impaired esophageal peristalsis in elderly that of tablets designed for oral disintegration
12
. Since
subjects increases the likelihood that solid oral dosage then, at the time this study was conducted the Food and
forms (mainly tablets and capsules) will lodge in the eso- Drug Administration approved three generic alendronate
phagus with impaired clearance or reflux back from the sodium tablets (70mg) for use in the United States.
stomach into the esophagus with a consequential pro- The purpose of this study was to expand the evaluation
longed contact time with the esophageal mucosa. of in vitro disintegration times to include these newly
Generic versions of alendronate sodium tablets are cur- approved generics alendronate sodium tablets.
rently availableintheUnitedStates. IntheUnited States,
if a drug substance and a drug product monograph exist in
the US Pharmacopeia (USP), the generic version is
Methods
expected to conform to these established quality specifica-
tions. The generic version is also required to use the same Disintegration times were determined on six tablets per
saltformoftheactiveingredient,asthesaltformcanaffect product by the USP disintegration method in water at
the inherent solubility and subsequent absorption of the 37
C14
C using the basket-rack apparatus without disks
13
.
active ingredient. The pharmaceutical dosage form has to The USP definition of disintegration is defined as ‘that
be equivalent and in the case of alendronate sodium the state in which any residue of the unit, except fragments
generic form must also be a pharmaceutical tablet with the of insoluble coatings or capsule shell remaining on the
sodium salt form. There is currently a USP monograph for screen of the test apparatus is a soft mass having no palp-
alendronate sodium (drug substance) and for alendronic ably firm core.’ The mean time at which the onset of dis-
acid tablets
11
and unless stated otherwise the generic integration was observed visually was recorded for each
form should conform to these standards. tablet in addition to the mean time for complete disinte-
It is also expected that the generic product will demon- gration. In cases of extremely rapid disintegration an onset
strate bioequivalence with the branded product, as in most timeof1or2sarelikelynodifferent,howeverthetimewas
cases matching the systemic exposure should ensure com- recorded as accurately as possible given this limitation.
parable safety and efficacy. However, a single-dose bioa- The onset of disintegration is not described in the USP,
vailability study in healthy subjects does not evaluate as the intent of the USP disintegration test is to measure
disintegration characteristics. For the weekly alendronate the time for complete disintegration, as this is critical from
sodium tablets, the dissolution tolerance is not less than adrugabsorptionperspective.Detailsofthegenerictablets
75% (Q) of the labeled amount of alendronic acid dis- used in the study and the branded reference product are
solvedin15min
11
.Thereisnodisintegrationspecification listed in Table 1.
for alendronic acid tablets, as disintegration in general has
been replaced over the last 30 years with dissolution test-
ing. For routine batch control, the generic manufacturer,
Results
as well as the manufacturer of the branded product, will
conduct in vitro dissolution to ensure that the drug As shown in Table 2, the onset of disintegration for all
dissolvesfrom thetabletsinanacceptable andaconsistent productswassimilar(approximately1s),howeverthetime
fashion. tocompletedisintegrationshowedawiderange.Themean
A potential concern is that the pharmaceutical disintegration time of the Barr 70-mg lots was rapid and
attributes of the various generic alendronate sodium for- consistent among lots. Barr lot A tablets disintegrated in
mulations may affect the potential for local irritation and 10s and Barr lots B and C both disintegrated in 9s. The
tolerability, especially in the upper gastrointestinal tract. mean disintegration time of Teva lot A tablets was 60s,
Bisphosphonates as a class have the potential to cause Teva lot B tablets disintegrated in 27s and Teva lot C
upper gastrointestinal irritation, and demonstrating bioe- tablets disintegrated in 72s. The mean disintegration
quivalenceinasmallsetofhealthysubjectsmaynotensure time of the branded tablets was approximately 1min
comparable esophageal exposure to that of the innovator which was consistent with the disintegration time of
product. three lots reported in the original study (43, 52 and
In a study that evaluated in vitro disintegration and 78s)
12
. The mean disintegration time of the Watson
dissolution of once-weekly generic alendronate sodium 70-mg tablets (branded generic) was approximately
tablets (70mg), Dansereau et al.
12
, found six products 108s. The results show that Teva lot B and all three Barr
with very rapid disintegration rates. This original research lots have in vitro disintegration times that were less than
2
In vitro disintegration studies of weekly generic alendronate sodium Dansereau et al.
www.cmrojournal.com
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2009 Informa UK Ltd
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