Prevention of Dose Dumping in

PVA-Based Directly Compressed

Sustained-Release Matrix Tablets
G. Moddelmog*, G. Birk, T. Wedel, D. Lubda, F. Bauer 1

Introduction
Tablets showing prolonged API release are often
based on swellable and erodible hydrophilic polymer
matrices. Avoiding pH-dependent or alcohol-induced
Tablet Tests and Dissolution Influence of the pH of the Dissolution Medium on API
Tablet characteristics were measured using an Erweka Release
Multicheck 5.1 (n=20) for each compression force, and
110
friability was measured on an Erweka TA 420 (both devices
100
from Erweka GmbH, Heusenstamm, Germany) according
90
to the Ph. Eur./USP test method. The in-vitro diltiazem

% of Diltiazem HCl dissolved

80
release behavior was tested using an apparatus 2 (USP) at
in-vitro dose dumping effects in such highly dosed, 70
50 rpm in different release media containing 900 mL over a
long-acting oral dosage forms is a prerequisite to 60
12-hour release time. Diltiazem detection was carried out
ensure in-vivo success. 50
at 237 nm in a flow-through cell spectrometer. To simulate
40
possible dose-dumping effects due to pH changes in the
The aim of this study was to investigate the influence 30
GI tract or because of alcohol consumption, the in-vitro
of a directly compressible polyvinyl alcohol (PVA) 20
dissolution tests were performed in different release media:
tablet matrix on the in-vitro drug release that occurs 10

in media of various pH values or alcohol concentrations. 0

HCl 0.1 M, HCl buffer pH 1.2 (Ph. Eur.), phosphate buffer 0 1 2 3 4 5 6 7 8 9 10 11 12
Diltiazem HCl was used as a model API. Time [h]
pH 7.2 (USP) and the pH change method (acc. Ph. Eur. Parteck SRP 80 Parteck SRP 80 Parteck SRP 80 Parteck SRP 80
Method A) HCl 0.1 M HCl Buffer pH 1.2 Phosphate Buffer pH 7.2 HCl 0.1M (2h)
>
Phosphate Buffer pH 7.2

Mixtures of 0.1 M HCl with 5, 10, 20 and 40% (v/v) ethanol Figure 4: Diltiazem HCl release from Parteck SRP 80-based matrix tablets (30 kN) in
different release media.

Methods
A special PVA 40-88 grade (Parteck SRP 80) marketed by
MilliporeSigma with a mean particle size of 88 m (mea-
sured by laser diffraction, Dv50) was first blended (1:1) with
microcrystalline cellulose MCC (Vivapur 102, JRS Pharma
GmbH & Co.KG) in a Turbula mixer (Willy A. Bachofen) for
10 minutes. Afterwards, diltiazem HCl (Selectchemie AG) and
0.50% of a highly dispersed silicon dioxide (MilliporeSigma)
were then added to the Parteck SRP 80- MCC-premix and
blended for another 10 minutes. The mixture was then put
The in-vitro API release of Parteck SRP 80-based diltiazem
matrix tablets is ostensibly independent of the pH of the
dissolution medium used.
Figure 1: Swelling and erosion of Parteck SRP 80-based sustained-release tablets after
contact with dissolution medium (after 1 hour in a disintegration tester Ph. Eur.; at 37 C).
Influence of the Alcohol Content of the Dissolution
Medium on API Release
Results and Discussion
120

110
through an 800 m sieve. Following, 0.50% magnesium Influence of Compression Force on Tablet Hardness
100
stearate (Parteck LUB MST, MilliporeSigma) was added to and Ejection Force
% of Diltiazem HCl dissolved

90
the sieved contents. Finally, the mixture was blended again 80

for 5 minutes and then directly compressed on a Korsch 300

269
600 Parteck SRP 80, 70
Tablet Hardness [N]
EK 0-DMS single punch instrumented tablet press (11 mm, Parteck SRP 80, 60
Tablet Hardness [N]

Ejection Force [N]

211
Ejection Force [N]
flat, facetted) at compression forces of 5, 10, 20 and 30 kN 200 400 50

into tablets weighing 400 mg each. 108

40

100 200 30

44
20

10
Viscosity (40 g/L, water, 20 C) 34.046.0 mPas 0
5 10 20 30
0

Compression Force [kN] 0

Degree of hydrolysis (USP) 8589 % 0 1 2 3 4 5 6
Time [h]
7 8 9 10 11 12

Bulk density 0.510.58 g/mL Figure 2: Compressibility and ejection forces.

Parteck SRP 80, Parteck SRP 80, Parteck SRP 80, Parteck SRP 80, Parteck SRP 80,

Tapped density 0.700.77 g/mL HCl 0.1 M HCl 0.1 M / Ethanol

95 / 5 % v/v
HCl 0.1 M / Ethanol
90 / 10 % v/v
HCl 0.1 M / Ethanol
80 / 20 % v/v
HCl 0.1 M / Ethanol
60 / 40 % v/v

Angle of repose 3237

Figure 5: Diltiazem HCl release from Parteck SRP 80-based matrix tablets (30 kN) in
Mean particle size 60100 m Parteck SRP 80 is suitable for direct compression (DC)

release media with different alcohol content.
(laser diffraction Dv50) (target: ~ 80 m) processes and displays high compressibility and low ejection
BET surface area force over a vast range of compression forces.
0.30.5 m/g
(nitrogen adsorption)
BET pore volume There are evidently no in-vitro dose-dumping effects visible
not detectable
(nitrogen adsorption) over a 12-hour release time, even in a 40% (v/v) alcohol
Influence of Compression Force and Tablet Hardness
Loss on drying (3 h, 105 C) 5.0 % release medium the release behavior is identical to the
on API Release
release behavior that took place in 0.1 M HCl medium under
Table 1: Material characteristics of the PVA 40-88 used.
110 the same conditions.
100

90
% of Diltiazem HCl dissolved

80
Matrix Tablet Formulation 70

Diltiazem HCl,
60
Conclusion
90.00 mg 22.50% (w/w) 50
Selectchemie AG 40

Parteck SRP 80, Parteck SRP 80 is well-suited for the direct compres-
153.00 mg 38.25% (w/w) 30

MilliporeSigma 20 sion of prolonged release diltiazem HCl tablets that

Microcrystalline 10
have a strong tablet hardness and an accumulated
153.00 mg 38.25% (w/w)
cellulose, JRS 0
first-order API release ranging from 80 to 100% for
0 1 2 3 4 5 6 7 8 9 10 11 12
Highly dispersed silicon
2.00 mg 0.50% (w/w)
Time [h]
up to 12 hours. Furthermore, these tablets produce
dioxide, MilliporeSigma
practically identical behavioral results in the in-vitro
Parteck SRP 80 Parteck SRP 80 Parteck SRP 80
Compression Force 10 kN Compression Force 20 kN Compression Force 30 kN
Magnesium stearate, Tablet Hardness 108 N Tablet Hardness 211 N Tablet Hardness 269 N

MilliporeSigma
2.00 mg 0.50% (w/w) dissolution curve progression independent of pH
Figure 3: Diltiazem HCl release from Parteck SRP 80-based matrix tablets with
different hardnesses (at pH 7.2).
or alcohol content in the test media. The constant
Table 2: Composition of a diltiazem HCl sustained-release matrix tablet based on PVA. in-vitro diltiazem release over a broad compression
force, tablet hardness and pH range and also in alcohol-
containing dissolution media are prerequisites in the
The accumulated API release over 12 hours is independent
prevention of possible in-vivo dose-dumping risks.
of the compression force used (10 to 30 kN) and remains
constant over a broad range of tablet hardnesses (108 to
269 N).

1
Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany
*Corresponding author: guenter.moddelmog@emdgroup.com

The life science business of Merck KGaA, Darmstadt, Germany operates as
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All other trademarks are the property of their respective owners.
Copyright 2017 EMD Millipore Corporation. All Rights Reserved. 03/2017
References
1. Beltrami, V.; Doelker, E and Gurny, R. Le poly (alcool de vinyle) dans les forms liberation
prolonge destines la voie orale. Pharm. Acta Helv. 65, 130-143 (1990).
2. Danki, S.; Hiremath, S.; Salger, S. and Sayeed, A. Preparation and evaluation of sustained
release matrix tablets of propranolol hydrochloride. Int J Pharm. Bio. Sci., 4, 227-241 (2010).
3. J edinger, N., Khinast, J. and Roblegg, E. The design of controlled-release formulations resistant
to alcohol- induced dose dumping A review. Eur. J. Pharm. Biopharm., 87, 217-226 (2014).
The typical technical data above serve to generally characterize the excipient. These values are not meant
as specifications and they do not have binding character. The product specification is available separately
at: www.emdmillipore.com
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