Poster Reprint
`
`American Association of
`Pharmaceutical Scientists
`
`October, 1999
`
`Evaluation of a Partially Pregelatinized Starch in Comparison with Superdisintegrants in
`a Direct-Compression Hydrochlorothiazide Formulation
`Charles R. Cunningham, Laura K. Scattergood
`Colorcon, West Point, PA
`
`ECTIVES
`Objectives
`Corn starch has long been used as a disintegrant in oral solid dosage forms. Physical modifications of corn starch, through
`partial pregelatinization, have added functional benefits in terms of flowability and partial solubility, while retaining its
`disintegrant capability and moisture stability. The goal of this study was to compare the tablet disintegration and drug
`dissolution effectiveness of a partially pregelatinized starch (Starch 1500®) in comparison with various superdisintegrants in a
`poorly soluble, hydrochlorothiazide direct compaction applications.
`METHODS
`Methods
`Materials - Disintegrants
`Partially pregelatinized corn starch
`Sodium starch glycolate
`(cid:127) Crospovidone
`(cid:127) Crosslinked CMC
`
`–Starch 1500 ®, Colorcon
`–Explotab ®, Mendell
`–Polyplasdone® XL, ISP Technologies
`–Ac-Di-Sol ®, FMC
`
`Materials - Primary Excipients
`(cid:127) Dicalcium phosphate dihydrate, unmille
`(cid:127) Lactose monohydrate spray drie
`
`–Emcompress ®, Mendell
`–Fast Flo ®, Foremost
`
`Materials - Active
`(cid:127) Hydrochlorothiazide USP
`
`– Abbott Laboratories
`
`Formulations
`Six direct compression tablet formulations were prepared :
`
`INGREDIENT
`
`HCTZ
`
`Dicalcium phosphate
`FF Lactose
`
`Starch 1500
`Crosslinked CMC
`Crospovidone
`
`Sodium starch glycolate
`Mg Stearate
`
`1
`%
`25.000
`
`37.375
`37.375
`
`2
`%
`25.000
`
`36.375
`36.375
`
`2.000
`
`3
`%
`25.000
`
`36.375
`36.375
`
`2.000
`
`4
`%
`25.000
`
`36.375
`36.375
`
`2.000
`
`0.250
`
`0.250
`
`0.250
`
`0.250
`
`5
`%
`25.000
`
`36.375
`36.375
`
`6
`%
`25.000
`
`32.375
`32.375
`
`10.000
`
`2.000
`0.250
`
`0.250
`
`Total %
`
`100.0
`
`100.0
`
`100.0
`
`100.0
`
`100.0
`
`100.0
`
`For each batch, all ingredients except magnesium stearate were blended together in a twin-shell
`blender for 15 minutes. The magnesium stearate was then added and blended for an additional 5 minutes.
`
`Par Pharm., Inc.
`Exhibit 1030
`Page 001
`
`(cid:127)
`(cid:127)
`

`

`Compaction
`The tablets were compressed using a 10 station instrumented Piccola rotary tablet press using size B, 5/16"
`flat-faced beveled edge tooling.
`The target tablet weight was 200mg (50mg hydrochlorothiazide).
`
`Moisture-Uptake Isotherms
`Moisture-uptake isotherms were conducted on each of the disintegrant powders using a VTI Corporation SGA-
`100 Symmetrical Gravimetric Analyzer. This is a continuous gas flow adsorption instrument for obtaining water
`vapor isotherms at temperatures ranging from 0o to 80o C at ambient pressure. The instrument temperature was
`controlled at 25oC for this study. In addition to the disintegrant powder testing, this instrument was used to test
`final tablet samples from each of the formulations with 2.0% disintegrant.
`
`RESULTS
`
`Compaction
`
`14
`
`compaction force (kp)
`Tablet hardness at 16kN
`
`0
`
`No
`Disintegrant
`
`2% Starch
`1500
`
`2%
`Crosslinked
`CMC
`
`2% Cros-
`povido ne
`
`2% Sodium
`starch
`glycolate
`
`10% Starch
`1500
`
`Tablet hardness (kN)
`
`11.2
`
`11.4
`
`11
`
`10.8
`
`11.2
`
`10.4
`
`The tablet hardness at each compaction force was measured using a Schleuniger tablet hardness tester. No
`significant differences in the compactibility of the individual blends were seen.
`
`2
`
`12
`
`10
`
`8
`
`6
`
`4
`
`2
`
`compaction force (kN)
`Tablet hardness at 16kN
`
`Par Pharm., Inc.
`Exhibit 1030
`Page 002
`
`

`

`Ejection Force Profiles
`
`0.35
`
`0.30
`
`0.25
`
`0.20
`
`0.15
`
`0.10
`
`Ejection force (kN
`
`0.05
`
`5
`
`7
`
`9
`
`11
`Compaction force (kN)
`
`13
`
`15
`
`17
`
`No Disintegrant
`
`2.0% Starch 1500
`
`2.0% Crosslinked CMC
`
`2.0% Crospovidone
`
`2.0% Sodium starch gl ycolete
`
`10.0% Starch 1500
`
`The control formulation with no disintegrant exhibited the highest ejection force profile. All other disintegrants at a
`2.0% usage level provided a similar lowering of ejection force values while the batch containing 10.0% Starch
`1500 provided a substantial decrease in ejection forces when compared to the control batch.
`
`Moisture-Uptake Isotherms - Powders
`
`Crospovidone
`
`Sodium starch glycolate
`
`Crosslinked CMC
`
`Starch 1500
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`% Weight Change
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`90
`
`% Relative Humidity at 25 deg.C
`
`Moisture-uptake isotherm data showed significantly higher moisture uptake for the superdisintegrant
`powders in comparison with the Starch 1500.
`
`3
`
`Par Pharm., Inc.
`Exhibit 1030
`Page 003
`
`

`

`Moisture-Uptake Isotherms - Tablets
`
`2.0% Crosslinked CMC
`
`2.0% Sodium starch glycolate
`
`2.0% Crospovidone
`
`2.0% Starch 1500
`
`No Disintegrant
`
`2.5
`
`2.0
`
`1.5
`
`1.0
`
`0.5
`
`0.0
`
`% Weight Change
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`90
`
`% Relative Humidity at 25 deg.C
`
`Isotherm data for the individual tablets also show significant differences even though the disintegrants
`were only present at a 2.0% level. The tablet containing 2.0% crosslinked CMC showed 2.5 times the
`weight increase compared to the tablets with 2.0% Starch 1500.
`
`Disintegration Results
`
`7.1 kp
`
`7.7 kp
`
`6.6 kp
`
`6.8 kp
`
`8.1 kp
`
`7.9 kp
`
`180
`
`160
`
`140
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Disintegration Time (minutes
`
`No
`Disintegrant
`
`2.0% Starch
`1500
`
`Series1
`
`170.89
`
`2.5
`
`2.0%
`Crosslinked
`CMC
`0.28
`
`2.0% Cros-
`povidone
`
`0.38
`
`2.0% Sodium
`starch
`glycolate
`1.05
`
`10.0% Starch
`1500
`
`1.19
`
`*Tablet hardness values
`
`Tablets of comparable hardness (7-8 kp) were selected for disintegration testing. The effect of all the
`disintegrants was substantial. The disintegration time in 37oC DI water for the control batch with no
`disintegrant was 170.8 minutes compared to all other tablets disintegrating in 2.5 minutes or less.
`
`4
`
`Par Pharm., Inc.
`Exhibit 1030
`Page 004
`
`

`

`Dissolution Results
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`% Released
`
`0
`
`0
`
`5
`
`10
`
`20
`15
`Time (min)
`
`25
`
`30
`
`35
`
`No Disintegrant
`2.0% Crosslinked CMC
`2.0% Sodium Starch Glycolate
`
`2.0% Starch 1500
`2.0% Crospovidone
`10.0% Starch 1500
`
`Dissolution for the control batch with no disintegrant was very slow with only 20% drug released in 35
`minutes. At the 5-minute time point, the tablets with 2.0% Starch 1500 released 30% of the drug
`compared with 40 to 50 % released for the tablets containing the other disintegrants. At 10 minutes,
`batches released between 70 and 78% including the batch with 2.0% Starch 1500.
`
`Dissolution T-60% Released
`
`2.0%
`Starch 1500
`
`2.0%
`Crosslinke
`d CMC
`
`2.0%
`Crospovidone
`
`2.0% Sodium
`starch glycolate
`
`10.0%
`Starch 1500
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`T-60% (minutes)
`
`The USP requirement for hydrochlorothiazide tablets is that not less than 60% drug be released in 60 minutes. All
`tablet samples with disintegrant met T-60% in less than 10 minutes. Dissolution was fastest for the batch with 10%
`Starch 1500 with a T-60% of 7.0 minutes. All other batches met a T-60% in under 10 minutes.
`
`The control batch was not charted as it only released 30% drug in 60 minutes.
`
`5
`
`Par Pharm., Inc.
`Exhibit 1030
`Page 005
`
`

`

`Conclusions
`Although superdisintegrants have demonstrated improved disintegration and dissolution functionality over traditional
`starch disintegrants, they can also be associated with tablet stability problems related to moisture uptake.
`Superdisintegrants function primarily by drawing large amounts of water into the tablet and simultaneously swell-
`ing. It is this great affinity for water that can impact the stability of moisture-sensitive materials under accelerated
`storage conditions.
`
`In this direct-compression hydrochlorothiazide formulation, partially pregelatinized starch performed as effectively
`as the superdisintegrants, and due to its low propensity for moisture uptake may afford superior moisture stability.
`Although the use of superdisintegrants may be necessary in some formulations, the inclusion of Starch 1500 may
`allow for a reduction in superdisintegrant levels while avoiding potential stability problems.
`
`Additionally, the improved flow and lubricity characteristics of partially pregelatinized starch can impart further
`benefit to the formulation in a very cost-effective manner.
`
`Acknowledgments
`The authors are grateful to Dr. Agustin Venero and Mr. John Bullis of VTI Corporation for their time and effort in
`conducting the numerous moisture uptake tests. The authors would also like to acknowledge Ms. Melanie
`Hartman of West Chester University for her help in preparing and testing tablet samples.
`
`The information contained herein, to the best of our knowledge, is true and accurate. Any recommendations or
`suggestions are made without warranty or guarantee, since the conditions of use are beyond our control. Any
`information contained herein is intended as a recommendation for use of our products so as not to infringe on
`any patent.
`
`6
`
`Par Pharm., Inc.
`Exhibit 1030
`Page 006
`
`