EXCIPIENTS
`
`MAIZE STARCH AND SUPERDISINTEGRANTS
`IN A DIRECT-COMPRESSION FORMULATION
`
`THIS ARTICLE DESCRIBES A STUDY OF THE DISINTEGRATION PROPERTIES OF A PARTIALLY PREGELA(cid:173)
`TINISED MAIZE STARCH AND COMPARES ITS EFFECTIVENESS WITH VARIOUS SUPERDISINTEGRANTS IN A
`DIRECT COMPACTION HYDROCHLOROTHIAZIDE FORMULATION.
`
`Maize starch has a long
`
`history of use as a disin(cid:173)
`tegrant in oral solid dosage
`forms. Physical modifications
`of maize starch, through par(cid:173)
`tial pregelatinisation, have
`increased the functional bene(cid:173)
`fit of maize starch in terms of
`flowability
`and
`solubility,
`while retaining disintegrant
`capability and moisture stabil(cid:173)
`ity.
`While newer superdisinte(cid:173)
`grants have demonstrated
`improved disintegration and
`dissolution functionality over
`traditional
`starch
`disinte(cid:173)
`grants, they can also be asso(cid:173)
`ciated with
`tablet stability
`problems related to moisture
`uptake.
`Superdisintegrants
`function primarily by drawing
`large amounts of water into
`the tablet and simultaneously
`swelling. It is this great affin(cid:173)
`ity for water that can impact
`the stability of moisture-sen(cid:173)
`sitive materials under acceler(cid:173)
`ated storage conditions.
`These materials have also
`been implicated in poor film
`coating quality when used at
`higher-than-recommended
`levels in the formulation. The
`rapid uptake of water by
`superdisintegrant particles on
`the surface of the tablet core
`can cause premature swelling
`of the particles during the
`aqueous film-coating process.
`These rapidly swelling parti-
`
`cles result in the formation of
`craters in the tablet surface
`that impact the visual and
`mechanical quality of
`the
`applied film. In addition to
`core surface erosion, it was
`shown by Peck et al., 1 that
`moisture penetration was not
`limited to the tablet surface
`alone but was drawn through
`the core by capillary forces
`and intra- and interparticulate
`wicking of the superdisinte(cid:173)
`grant particles.
`Although a partially pregela(cid:173)
`tinised starch may have to be
`used at a higher level in a for(cid:173)
`mulation to obtain the compa(cid:173)
`rable
`disintegration
`time,
`additional benefits such as
`improvements in powder flow,
`compactibility, moisture sta(cid:173)
`bility and reduced formulation
`cost may be realised. 1t has
`also
`been
`reported
`by
`Shangraw et aJ.2 that the disin(cid:173)
`tegrant characteristics of par(cid:173)
`tially pregelatinised maize
`starch are unaffected by pH,
`while the swelling characteris(cid:173)
`tics of anionic crosslinked
`starches and celluloses may
`be altered in acidic media. It
`was further shown by Brzecko
`and Augsburger' that the dis(cid:173)
`integrant performance of par(cid:173)
`tially pregelatinised maize
`starch
`in a hydrochloroth(cid:173)
`iazide
`tablet was generally
`unaffected at accelerated stor(cid:173)
`age conditions up to 50 weeks.
`
`TABLE 1. FORMULATIONS USED IN THE DISINTEGRATION COMPARISONS.
`
`1
`
`"
`
`25.0
`37375
`37375
`
`2
`
`"
`
`250
`36375
`38.375
`20
`
`3
`
`"'
`
`25.0
`36375
`36.375
`
`2.0
`
`Sodium starch glyCOiatB
`
`~stearate
`
`025
`1000
`
`0.25
`100.0
`
`0.25
`1000
`
`4
`
`"
`
`25.0
`36.375
`36.375
`
`2.0
`
`0.25
`100.0
`
`8
`
`"
`
`I
`
`"'
`
`250
`36.375
`36375
`
`2.0
`0.25
`100.0
`
`0.25
`100.0
`
`PH ARM AC E UTIC A L MAN UFACTURI N G
`
`EJCM
`
`R E VI E W
`
`DE C EM BE R 1881
`
`Supplied by the British Library 21 Feb 201 7, 17:15 (GMT)
`
`A FIG 1 TABLET HARDNESS AESUL TS
`
`PREGELATINISED STARCH
`COMPARED WITH
`SUPERDISINTEGRANTS
`The aim of this work was to
`study the disintegration prop(cid:173)
`erties of a partially pregela(cid:173)
`tinised maize
`starch
`and
`compare its effectiveness with
`various superdisintegrants in a
`direct
`compaction
`hydrochlorothiazide
`formula(cid:173)
`tion.
`Hydrochlorothiazide
`(from Abbott Laboratories)
`was chosen as the model drug
`due to its relative insolubility
`in water and its poor dissolu(cid:173)
`tion characteristics. It has also
`been cited in many publica-
`
`tions on dissolution and disin(cid:173)
`tegration. The propensity for
`moisture uptake of each of the
`disintegrants was examined,
`both as individual powders as
`well as their contribution to
`moisture uptake in the final
`tablet sample. Included in the
`study was the examination of
`other tablet quality attributes
`such as the effect of the disin(cid:173)
`tegrants on tablet hardness,
`friability and dissolution. A
`further goal was to determine
`at what level in the formula(cid:173)
`tion would the partially prege(cid:173)
`latinised maize starch provide
`the equivalent disintegrant
`times as the other disinte(cid:173)
`grants.
`
`EVALUATION METHODS FOR
`THE COMPARISON
`Six direct-compression formu(cid:173)
`Lations were prepared for the
`study. The disintegrants eval(cid:173)
`uated were partially pregela(cid:173)
`tinised maize starch (Starch
`1500®, Colorcon),
`sodium
`starch glycolate (Explotab®,
`Mendell),
`crospovidone
`(Polyplasdone® XL,
`ISP
`Technologies) and crosslinked
`CMC (Ac-Di-Sol®, FMC).
`was
`Hydrochlorothiazide
`present at 25.0% (w/w) of all
`formulations. Each of the four
`disintegrants was added to a
`formulation at a 2.0% level
`
`Par Pharm., Inc.
`Exhibit 1058
`Page 001
`
`

`

`EXCI PIEN TS
`
`tion with 2.0% Starch 1500
`produced the hardest tablets
`at 11.4kp (Fig 1).
`Tablets of comparable hard(cid:173)
`ness (7-8kp) were selected for
`disintegration, dissolution and
`moisture-uptake testing. The
`time in 3JDC
`disintegration
`water for the control batch
`with no disintegrant was 170.8
`minutes. The tablets contain(cid:173)
`ing 2.0~ Starch 1500 disinte(cid:173)
`grated in 2.5 minutes, and the
`tablets containing crosslinked
`CMC and crospovidone had
`disintegration
`limes of less
`than 1 minute. The tablets
`containing 2.0% sodium starch
`glycolate and 10% Starch 1500
`disintegrated
`in about 1.0
`minute (Fig 2).
`Dissolution for the control
`batch with no disintegrant was
`very slow with only 20~
`released in 35 minutes. At the
`5-minute
`time point,
`the
`tablets with 2.0~ Starch 1500
`released 30q. of the drug com(cid:173)
`pared with 40 to 50% released
`for the tablets containing the
`other disintegrants. At 10
`minutes,
`batches
`released
`between 70 and 78%, includ(cid:173)
`ing the batch with 2.0~ Starch
`1500. D1ssolution was fastest
`for the batch with lO<k Starch
`1500 with a T60% of 7.0 min(cid:173)
`utes. Ail other batches met a
`T609f in less than 10 minutes.
`Moisture uptake isotherm
`data
`showed
`significantly
`higher moisture uptake for the
`superdisintegrant powders in
`comparison with the starch.
`Isotherms on the mdividuai
`tablets also showed significant
`differences, even though the
`d1smtegrants were only pre(cid:173)
`sent at a 2.0~ level. The
`tablet
`contammg
`2.0/l
`crosslinked CMC showed 2.5
`times
`the weight
`increase
`compared to the batch wtth
`2.0t:'f Starch 1500.
`
`PREGELATINIZED STARCH
`PERFORMED AS EFFECTIVELY
`AS THE SUPERDISINTEGRANTS
`In
`this wrect-compression
`hydrochlorothiazide
`formula(cid:173)
`tion, the use of partially prege(cid:173)
`Iatinised starch performed as
`effectively as the superdisinte(cid:173)
`grants, and due to its low
`propensity
`for moisture
`uptake may afford superior
`moisture stability to similar
`formulations. Although
`the
`use of superdisintegrants may
`be necessary in some formula(cid:173)
`tions, the inclusion of Starch
`1500 may allow for a reduction
`in
`superwsintegrant
`levels
`while avoiding potential stabil(cid:173)
`ity problems. Additionally, the
`improved flow and tabletting
`characteristics
`of partially
`pregelatinised
`starch
`can
`impart further bcnefir to the
`formulation in terms of aque(cid:173)
`ous film-coating quality.
`
`REFERENCES
`1. Peck et al. Pharmauutical
`Production
`Ttch
`Sourct,
`October 1999.
`2. Shangraw, R.F., Mitrevej,
`A.
`and
`Shah,
`M.
`Phannaceutical
`Tuhnology,
`4{10), 49 (1980)
`3. Brzecko and Augsburger,
`AAPS 2nd National Mcetmg,
`Boston, USA, june 1987.
`READER SERVICE INFORMATION NO 11109
`
`17Iis article is by Charles R.
`Cunningham, Global Technical
`Mtmager, Excipimts, Colorcon,
`West Point, PA, USA. For fur(cid:173)
`mfonnation
`contact
`thn
`Deborah ]. Taylor, Product
`Group Manager,
`Coloram
`Lim1ted, Flagship House, Victory
`Way, Crossways, Dartford, Kmt
`DA2 6QD, UK TeL· Int+44-
`(0)1322-293000. Fax: /n/+·14-
`Webs1te:
`(0)1322-627200.
`wu1w.colorcon.com
`
`• FIG 2 DISINTEGRATION RFSULTS
`
`with the exception of the con(cid:173)
`trol formulation which had no
`disintegram. An
`additional
`batch was prepared with
`10.~ Starch 1500. Dicalcium
`phosphate
`dihydrate
`(Emcompress®, Mendell) and
`spray dried lactose monohy(cid:173)
`drate (Foremost) made up the
`remainder of the formulation
`at
`a
`50:50
`ratio
`(qs).
`Magnesium stearate at 0.25%
`was present in each formula(cid:173)
`tion as the lubricant (Table 1).
`Moisture uptake isotherms
`were conducted on each of the
`disintegrant powders using a
`VTI Corporation SGA-100
`Symmetncal
`Gravimetric
`Analyzer. This is a continuous
`gas flow adsorption mstrument
`for obtaining water vapour
`temperatures
`isotherms at
`ranging from 0 to 80 C at
`ambient pressure. The mstru(cid:173)
`ment was controlled at 25 C
`for this study. In adwtion to
`the disintegrant powder test(cid:173)
`ing, this instrument was used
`to test the final tablet samples
`
`from each formulation.
`Each blend was also tested
`for density and powder flow
`characteristics. Tablets were
`compressed to 200mg total
`weight at 6, 8, 10, 12, 14 and
`16 kN compaction force on a
`station
`Piccola
`(Riva)-10
`mstrumented
`rotary
`tablet
`press. The tooling used was
`5/16 inch flat-faced beveled
`edge. Tablet samples at each
`compaction force were tested
`for hardness, weight variation,
`thickness, disintegration time,
`and USP Z3 dissolution for
`hydrochlorothiazide.
`
`DISSOLUTION AND MOISTURE(cid:173)
`UPTAKE TESTING
`The tablet hardness at each
`compaction force was mea(cid:173)
`sured using a Schleuniger
`tablet hardness tester. No sig(cid:173)
`nificant differences
`in
`the
`compactibility of the inwvidual
`blends were seen. At 16kN of
`compaction force, the tablet
`hardness values ranged from
`10.4 to 11.4kp. The formula-,
`
`Reader Reply No. M9
`
`.,.
`
`I'HARIIACEUTICAL
`
`IIANUFACTIIII1118
`
`IIEVIEW D£C:£MIEII 1111
`
`Supplied by the British Library 21 Feb 2017. 17:15 (GMT)
`
`Par Pharm., Inc.
`Exhibit 1058
`Page 002
`
`