Nonionic superdisintegrant for improved dissolution of cationic drugs

INTER
Pharmaceuticals
Polyplasdone® Crospovidone
Nonionic superdisintegrant
for improved dissolution of
cationic drugs
The superior dissolution performance
of Polyplasdone® crospovidone
The dissolution rate of a drug plays an important role in its bioavailability.
Thus, it is frequently necessary to formulate with a disintegrant that
produces the fastest rate of drug dissolution. When working with
cationic drugs, however, anionic disintegrants like croscarmellose sodium
(CCS) and sodium starch glycolate (SSG) may interact with the active and
actually retard dissolution. Unlike anionic disintegrants, Polyplasdone
crospovidones are nonionic and will not complex with cationic drug
actives to delay drug dissolution.
Chemically inert. And other reasons why
Polyplasdone crospovidone is better
Polyplasdone crospovidone is nonionic (Figure 1). Other superdisintegrants
such as CCS and SSG are anionic in nature (Figures 2 and 3).
It has been proposed that any weakly basic (cationic) drug, when
present in an environment where the pH is >2 and near or below the
pKa of the cationic drug, should be expected to interact with ionized
polymers like CCS and SSG (1). Thus, it is not surprising that with eight
of eight cationic drug actives evaluated, tablets with Polyplasdone
crospovidone provided the fastest rate of dissolution compared to
tablets with CCS and SSG.
Figure 1: Chemical structure of Polyplasdone crospovidone
Benefits
Nonionic - will not interact with cationic drug actives
Superior dissolution performance with both soluble and poorly
soluble cationic actives
Compatible with most pharmaceutical formulation ingredients
Available as free-flowing, white powders in a range of particle sizes
Figure 2: Croscarmellose sodium structure
O
CH 2OCH 2COONa
O
OH
OH
O
OH
OH
O
O
CH 2OCH 2COONa
n
CH 2
CH n
N O
Figure 3: Sodium starch glycolate structure
CH2COONa
CH2OH
CH2OH
CH2OH
O
O
O
OH
OH
OH
O
O
O
OH
OH
OH
n

Pharmaceuticals
Not all disintegrants perform the same with cationic drugs
To directly compare the effect of disintegrants on the rate of drug
dissolution, Polyplasdone XL and XL-10 crospovidones, CCS and
and SSG were evaluated at 2% w/w according to the model tablet
formulation listed in Table 1. To compare disintegrant performance,
the drug active level and those of the other excipients
were held constant. For a given drug studied, all of the tablets
with the various superdisintegrants studied were compressed to
equal breaking force and exhibited similar disintegration properties.
Both soluble and poorly soluble drugs were selected (Table
2) to determine if the observed trend differed based on drug
solubility. For the dissolution media, the media recommended
by the United States Pharmacopeia (USP) or by the U.S. Food and
Drug Administration (FDA) for each drug was used.
Table 1: Direct compression tablet formulation
Ingredient Amount (%) Amount (mg)
Drug Active 18.0 99.0
Disintegrant 2.0 11.0
Talc 0.5 2.75
Magnesium Stearate 0.5 2.75
Microcrystaline Cellulose 79.0 434.5
Total 100.0 550.0
The time required to achieve 80% drug release for all drugs
studied with each superdisintegrant in the recommended media
is shown in Table 3. With all eight cationic drugs tested, tablets
containing Polyplasdone disintegrants provided the fastest drug
release compared to the other disintegrants. By comparison,
the anionic disintegrants – CCS and SSG – imparted the slowest
rate of drug release with cationic actives. The dissolution profiles
are shown in Figures 4 through 11. Thus, when formulating with
cationic drugs, Polyplasdone crospovidones are the preferred
disintegrants – continued proof that the technology is a problem
solver for formulators of oral solid dosage forms.
Figure 4: Polyplasdone disintegrants provided the fastest tablet
dissolution with venlafaxine HCI
Tablet breaking force = 178 N + /- 5%
The dissolution medium is water as specified by U.S. FDA,
Dissolution Methods for Drug Products
% Drug Dissolved
100
80
60
40
20
Table 2: Cationic drug actives evaluated
0
0
10
20
30
40
50
60
Time (in minutes)
Active
Aqueous Solubility*
Polyplasdone XL
Polyplasdone XL-10
Croscarmellose Sodium
Sodium Starch Glycolate
Chlorpromazine HCl
Ranitidine HCl
Cetirizine HCl
Venlafaxine HCl
Ciprofloxacin HCl
Freely Soluble
Freely Soluble
Freely Soluble
Freely Soluble
Slightly Soluble
Figure 5: Polyplasdone XL provides the fastest
dissolution with ciprofloxacin HCI
Tablet breaking force = 184 N + /- 5%
The dissolution medium is 0.1N HCI as specified by USP
100
Fexofenadine HCl
Slightly Soluble
80
Terbinafine HCI
Clopidogrel Bisulfate
Slightly Soluble
Practically Insoluble
% Drug Dissolved
60
40
* The aqueous solubility of each drug is based on definitions for solubility
provided in the European Pharmacopeia. Freely soluble is defined as a
compound requiring 1 to 10 ml of water to dissolve 1 gram of drug at
15-25ºC. A soluble compound requires 10 to 30 ml of water to dissolve 1
gram of drug. Slightly soluble and very slightly soluble require 100-1,000
ml and 1,000-10,000 ml of water to dissolve a gram of drug, respectively. A
practically insoluble compound requires more than 10,000 ml of water to
dissolve 1 gram of drug.
20
0
0
Polyplasdone XL
10 20 30 40 50 60
Time (in minutes)
Polyplasdone XL-10 Croscarmellose Sodium Sodium Starch Glycolate

Pharmaceuticals
Table 3: Polyplasdone crospovidone shows the fastest drug release with cationic drug actives
Drug
Dissolution
Media
Polyplasdone XL
Polyplasdone
XL-10
T 80 (minutes)
Croscarmellose
Sodium
Starch Glycolate
Sodium
Chlorpromazine HCl 0.1 N HCl 25 29 33 42
Ranitidine HCl water 8 21 34 38
Cetirizine HCl water 13 15 59 24
Venlafaxine HCl water 7 6 21 10
Ciprofloxacin HCl 0.1N HCl 21 27 33 25
Fexofenadine HCl 0.001 N HCl 14 24 29 24
Terbinafine HCl
Clopidogrel Bisulfate
n/a = Not Achieved
Citrate buffer, pH
3.0 adjusted with 33 n/a n/a n/a
HCl, 500 ml
Hydochloric acid
buffer, pH 2, 10 9 10 15
1000 ml
Figure 6: Polyplasdone crospovidone provided the fastest
dissolution with chlorpromazine HCI
Figure 7: Polyplasdone crospovidone provided the fastest
dissolution with terbinafine HCI tablets
Tablet breaking force = 157 N + /- 5%
The dissolution medium is 0.1N HCI as specified by USP
Tablet breaking force = 157 N + /- 5%
The dissolution medium is citrate buffer, pH 3.0, adjusted with HCl, 500 ml, as
specified by FDA, Dissolution Methods for Drug Products
100
100
80
80
% Drug Dissolved
60
40
% Drug Dissolved
60
40
20
20
0
0
10
20
30
Time (in minutes)
40
50
60
0
0
10
20
30
Time (in minutes)
40
50
60
Polyplasdone XL
Polyplasdone XL-10
Croscarmellose Sodium
Sodium Starch Glycolate
Polyplasdone XL
Polyplasdone XL-10
Croscarmellose Sodium
Sodium Starch Glycolate

Pharmaceuticals
Figure 8: Polyplasdone disintegrants provided the fastest tablet
dissolution with ranitidine HCI
Figure 10: Polyplasdone crospovidone provided the fastest
dissolution with clopidogrel bisulfate tablets
Tablet breaking force = 182 N + /- 5%
The dissolution medium is water as specified in USP
Tablet breaking force = 158 N + /- 5%
The dissolution medium is hydrochloric acid buffer, pH 2, 1000 ml, as specified
by USP
100
100
80
80
% Drug Dissolved
60
40
% Drug Dissolved
60
40
20
20
0
0
10
20
30
40
50
60
0
0
10
20
30
40
50
60
Time (in minutes)
Time (in minutes)
Polyplasdone XL
Polyplasdone XL-10
Croscarmellose Sodium
Sodium Starch Glycolate
Polyplasdone XL
Polyplasdone XL-10
Croscarmellose Sodium
Sodium Starch Glycolate
Figure 9: Polyplasdone disintegrants provided the fastest tablet
dissolution with cetrizine HCI
Figure 11: Polyplasdone crospovidone provided the fastest
dissolution with fexofenadine HCI tablets
Tablet breaking force = 180 N + /- 5%
The dissolution medium is water
Tablet breaking force = 181 N + /- 5%
The dissolution medium is 0.001N HCl as specified by FDA, Dissolution
Methods for Drug Products
100
100
80
80
% Drug Dissolved
60
40
% Drug Dissolved
60
40
20
20
0
0
10
20
30
Time (in minutes)
40
50
60
0
0
10
20
30
Time (in minutes)
40
50
60
Polyplasdone XL
Polyplasdone XL-10
Croscarmellose Sodium
Sodium Starch Glycolate
Polyplasdone XL
Polyplasdone XL-10
Croscarmellose Sodium
Sodium Starch Glycolate
References:
1. R. G. Hollenbeck, K. T. Mitrevej, A.C. Fan, “Estimation of the extent of drug – excipient interactions involving croscarmellose sodium,” J. Pharm. Sci., 72, 325–327, (1983).
Further Reading:
J. Balasubramaniam, K. Bindu, V.U. Rao, D. Ray, R. Haldar, and A.W. Brzeczko, “Effect of Superdisintegrants on Dissolution of Cationic Drugs,” Dissolution Technologies,
15 (2), 18-25 (2008).
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Product Code: PH5285-I2-07/2009
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