Utility of Polyplasdone™ Crospovidone in Orally Disintegrating

PHARMACEUTICAL TECHNOLOGY REPORT
Ashland Specialty Ingredients
ashland.com
Page 1 of 6
PTR-098
Utility of Polyplasdone™ crospovidone in Orally
Disintegrating Tablet Formulations
Quyen Schwing, Marvin Davis, Divya Tewari, Thomas Dürig
Ashland Specialty Ingredients, Wilmington, Delaware 19808, USA
Introduction
The goal of this study was to evaluate the effect of several superdisintegrants on disintegration time, breaking force,
and drug release of different orally disintegrating tablet (ODT) formulations. Acetaminophen (APAP) and fenofibrate
were used as model drugs for wet granulation methods. The superdisintegrants tested were as follows:





Polyplasdone crospovidone
Competitive crospovidone
Croscamellose sodium
Sodium starch glycolate
L-HPC
Because the XL and Ultra grades of Polyplasdone crospovidone have the same physical and chemical properties (the
only difference being in the level of impurities) these grades are used interchangeably in this study. The competitive
CL and CL-F grades of crospovidone vary only in particle size and are also used interchangeably. It was found that
orally disintegrating tablets made with Polyplasdone XL and Ultra crospovidones have shorter disintegration times,
lower friability, and faster drug release than tablets made with other polymers.
Methods
Preparation of 650 mg Acetaminophen (APAP) ODT by Wet Granulation. Passed the intragranular ingredients
(Table 1) through a 14 mesh screen, Placed the screened materials into the Collete high-shear mixer/granulator and
mixed for 2 minutes, then started spraying purified water at 50 g/min, with the impeller at 295 RPM and chopper at
3554 RPM, until a suitable endpoint was achieved. The granulation was placed in the oven with the temperature set
at 65°C, and dried to NMT 2% moisture. Then the granulation was milled in the FitzMill with a 0.065" screen, knives
forward, at medium speed. The milled APAP granulation and each superdisintegrant was screened through mesh 18
and blended for 10 minutes. Passed the magnesium stearate through a 35 mesh screen, added to the blend, and
blended for 3 minutes. Collected the final blend and compressed on a Manesty Betapress using 7/16” FFBE tooling,
to a tablet weight of 650 mg.
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representation, express or implied, for which Ashland assumes legal responsibility. ®Registered trademark, Ashland or its subsidiaries, registered in various countries. ™Trademark, Ashland or its subsidiaries, registered in various
countries. *Trademark owned by a third party. © 2014, Ashland.
Rev. 02-2014
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Table 1. Acetaminophen ODT formulation
Tablet formulation
(%w/w)
Ingredients
Tablet weight
(mg)
Intragranular
Acetaminophen (dense powder)
50
325
Lactose, regular, NF
18.3
118.6
Calcium sulfate hydrous, NF
18.3
118.6
3
19.5
Superdisintegrant
10
65
Magnesium stearate
0.5
3.3
Total
100
650
Klucel™ EXF hydroxypropylcellulose
Extragranular
For each tablet formulation we tested hardness, thickness, friability, and disintegration time.
Dissolution of APAP ODT Formulation. Dissolution (n = 3) was conducted in 900 ml pH 5.8 phosphate buffer media
at 37°C using USP apparatus II at 50 rpm paddle speed (Distek Dissolution System, Model 5100). The amount of
acetaminophen dissolved was monitored using a UV spectrophotometer (Agilent 8453) at 220 nm. Samples were
taken at 7.5, 15, 30, and 45 minutes.
Preparation of 348 mg Fenofibrate ODT by Wet Granulation. Dissolved Plasdone™ K29/32 povidone (Table 2)
into a quantity of DI water calculated to be 15% of batch size, then dissolved sodium lauryl sulfate (SLS) completely in
the povidone solution. The remaining intra-granular ingredients were passed through a 14 mesh screen. The
screened materials were placed into the Collete high-shear mixer/granulator and mixed for 2 minutes, then the
povidone-SLS solution was sprayed in at 50 g/min, with the impeller at 295 RPM and chopper at 3554 RPM, until a
suitable endpoint was achieved. The granulation was placed in the oven set to 65°C, and dried to NMT 2% moisture.
The dried granulation was passed through the FitzMill with a 0.065" screen, knives forward and medium speed.
The milled fenofibrate granulation, each superdisintegrant and peppermint flavor were passed through an 18 mesh
screen, and blended for 10 minutes. Magnesium stearate and silicon dioxide were passed through a 35 mesh screen,
added to the fenofibrate blend, and blended for 3 minutes. The final blend was compressed on a Manesty Betapress
using 3/8” FFBE tooling, to a tablet weight of 348 mg.
Table 2. Fenofibrate ODT tablet formulation
Ingredients
Tablet Formulation
(% w/w)
Tablet Weight
(mg)
Intragranular
Fenofibrate
15.5
54
Mannitol
35
121.94
Microcrystalline cellulose
24
83.61
Sodium lauryl sulfate (SLS)
1.5
5.23
3
10.45
Plasdone™ K29/32 povidone
Extragranular
Peppermint flavor
0.2
0.7
Superdisintegrant
20
69.68
Silicon dioxide
0.4
1.39
Magnesium stearate
0.4
1.39
Total
100
348.39
For each tablet formulation we tested hardness, thickness, friability, and disintegration time.
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Dissolution of Fenofibrate ODT Formulations. Dissolution was carried out in 0.05M SLS, USP Apparatus II at 75
rpm for 60 minutes. Samples were withdrawn at 15, 30, 45, and 60 minutes and immediately diluted with methanol to
prevent supersaturation solubility of the API in SLS solution. The diluted samples were filtered through a 0.45 μm
nylon membrane and quantitated by HPLC with UV detection at 286 nm. Column: Synergi 4 µm Hydro-RP 80 Å, 250
× 4.6 mm.
Results and Discussion
Orally Disintegrating Acetaminophen Tablets, Figures 1 and 2 show that both Polyplasdone™ crospovidone and
L-HPC yielded harder tablets with lower friability than other polymers; Figure 3 shows that tablets made with
Polyplasdone XL crospovidone had the shortest disintegration time. The prolonged disintegration time in tablets made
with L-HPC and croscamellose sodium can be related to their fibrous structure, which forms a gel-like mass upon
hydration. The behavior of sodium starch glycolate tablets can be related to the main characteristics of starch,
swelling and gelling. The dissolution profiles in Figure 4 show that all tablet formulations with superdisintegrants have
similar percent drug release in phosphate pH 5.8 medium. However, tablets made with sodium starch glycolate gave
the fastest drug release, due to the soft tablets breaking apart in ionic solution faster.
20
Polyplasdone™ XL crospovidone
18
L-HPC
16
Competitive CL crospovidone
Croscamellose sodium
Hardness (kP)
14
Sodium starch glycolate
12
10
8
6
4
2
5
10
15
20
Main compression force (kN)
25
30
Figure 1. Effect of compression force on hardness of acetaminophen ODTs
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5
Sodium starch glycolate
Croscamellose sodium
4
Competitive CL crospovidone
Polyplasdone™ XL crospovidone
L-HPC
Friability (%)
3
2
1
0
5
10
15
20
Main compression force (kN)
25
30
Figure 2. Effect of compression force on friability of acetaminophen ODTs
100
90
Disintegration time (sec)
80
70
Polyplasdone™ XL crospovidone
L-HPC
Competitive CL crospovidone
Croscamellose sodium
Sodium starch glycolate
60
50
40
30
20
10
0
10
15
20
Main compression force (kN)
25
Figure 3. Effect of compression force on disintegration time of acetaminophen ODTs
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100
% Acetaminophen released
90
80
70
Polyplasdone XL crospovidone
60
Croscamellose sodium
Competitive CL crospovidone
50
Sodium starch glycolate
L-HPC
40
Acetaminophen only
30
20
10
0
0
10
20
30
Time (min)
40
50
60
Figure 4. Dissolution profile of acetaminophen ODT in pH 5.8 phosphate buffer
Orally Disintegrating Fenofibrate Tablets. Figure 5 shows that fenofibrate ODTs made with Polyplasdone Ultra
crospovidone have the highest breaking force. In addition, tablets made with croscamellose sodium and sodium
starch glycolate had the longest disintegration times in DI water (Figure 6). These results may be related to the high
level of free carboxylic groups within the disintegrants, which results in the formation of a gel layer, preventing further
penetration of water into deeper parts of the tablets. Both Polyplasdone crospovidone and the competitive
crospovidone showed much shorter disintegration times due to their wicking and swelling properties, which maintain
the multiparticulate structure with a high surface area. Tablets made with Polyplasdone Ultra crospovidone had the
shortest disintegration time.
12
Polyplasdone™ Ultra crospovidone
Croscamellose sodium
10
Hardness (kP)
Competitive crospovidone
8
Sodium starch glycolate
6
4
2
0
0
5
10
15
20
25
Main Compression Forces (kN)
Figure 5. Effect of compression force on hardness of fenofibrate ODTs
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350
Polyplasdone™ Ultra
crospovidone
Disintegration time (sec)
300
Croscarmellose
sodium
250
Sodium starch
glycolate
200
Competitive equivalent
crospovidone
150
100
50
0
5
10
Main compression force (kN)
15
Figure 6. Effect of compression force on disintegration time of fenofibrate ODTs
The dissolution profiles of fenofibrate tablets show the tablets made with Polyplasdone Ultra crospovidone had the
fastest drug release, when compared with the other tablets (Figure 7). Both sodium starch Glycolate and
Croscamellose Sodium tablets showed slower drug release, which may be correlated with the prolonged
disintegration time discussed above.
100
90
80
Tolerance (Q) Line
% Fenofibrate Released
70
60
50
Polyplasdone™ Ultra crospovidone
40
Competitive equivalent CL crospovidone
Croscarmellose sodium
30
Sodium starch glycolate
No Superdisintegrant
20
10
0
0
10
20
30
40
Time (min)
50
60
70
Figure 1. Dissolution profile of fenofibrate tablets (at initial time) in 0.025M SLS medium
Conclusions
From the results discussed above, and due to the physical and chemical properties of the various polymers, it was
found that orally-disintegrating tablets of formulations made with Polyplasdone XL and Ultra crospovidones had
shorter disintegration times and better friability than tablets made with other polymers.

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