Aim: This diploma thesis focused on the study of the influence of two types of high-shear mixers as well as the effect of poly(meth)acrylate concentrations on the properties of prepared granules and consequently matrix tablets. Methods: Caffeine was employed as the model drug and matrix tablets were prepared via the wet granulation process using two different high-shear mixers either Stephan UMC5 or Rotolab mixer. Eudragit® NM 30D was used in various concentrations as a wet granulation agent for time controlled drug release with low permeability and pH independent swelling. In addition, lactose monohydrate was added as indifferent soluble filler, magnesium stearate served as the antiadhesive excipient and colloidal silica was added for flowability improvement. Matrix tablets were evaluated for mass, content and dosage uniformity, uniformity of dosage units, friability, hardness and dissolution according to Ph. Eur. Results - Conclusions: All prepared tablets exhibited sustained drug release. The employment of different mixers for sustained matrix tablets preparation did not significantly influence the release profile of caffeine (Eudragit® NM concentrations 9- 14%), except when the lower Eudragit® NM concentration (7%) was used for granulation. Furthermore, Eudragit® NM concentrations (7 – 14% per tablet) did not significantly affect the release profile of caffeine from matrix tablets, neither in the Stephan UMC5 nor the Rotolab mixer.

1. University of Veterinary and Pharmaceutical Sciences Brno
Faculty of Pharmacy
Department of Pharmaceutics
Nikolaos Chalkidis
Supervisor: Assoc. Prof. PharmDr. Kateřina Kubová, Ph.D
Brno, 2015
Diploma Thesis Presentation
“Eudragit NM use in matrix tablets technology”

2. MATRIX TABLETS
In matrix systems a drug is dissolved or dispersed into an excipient or
mixture of excipients which are able to form a matrix structure
• These excipients are the matrix formers or matrix carriers and are
usually of polymer origin.
• Drug release from matrix tablets is achieved by water penetration
into the matrix, which is followed by either the diffusion of the drug
into the surrounding medium, or the erosion of the matrix, or even a
combination of both.
Hydrophilic matrix systems diffusion
and erosion
Hydrophobic or inert matrix systems
diffusion

3. • Sustained release characterizes dosage forms that exhibit a slower
release than that of an immediate release dosage form. Drug
delivery systems that are designed to achieve or extend therapeutic
effect by continuously releasing medication over an extended period
of time after administration of a single dose.
• These formulations are also known as prolonged release, modified
release, extended release or depot formulations.
• As a result sustained release formulations reduce the frequency of
the dosing or increase the drug effectiveness by localization at the
site of action
SUSTAINED RELEASE

4. Eudragit®
• Synthetic acrylic copolymers derived
from esters of acrylic and
methacrylic acid, by free radical
polymerization
• Physicochemical properties are
determined by their functional
groups
• Categories:
soluble or insoluble
pH dependent or independent
EUDRAGIT®

5. Wet granulation process:
• Caffeine: model drug
• Eudragit® NM 30D: wet granulation agent
• Lactose monohydrate: indifferent soluble filler suitable for wet granulation
process
• Magnesium stearate: antiadhesive excipient
• Colloidal silica unhydrica: excipient for improved flowability
AIM OF DIPLOMA THESIS
Preparation of sustained release matrix tablets and determination of:
• the influence of two types of high-shear mixers
• the effect of poly(meth)acrylate concentrations on matrix tablets.

6. Two types of high shear mixers were used
1. Stephan UMC5 high shear mixer
2. Rotolab mixer
HIGH SHEAR MIXERS

7. EUDRAGIT® NM
Physical properties: milky-white liquid, low
viscosity, faint characteristic odour
Product Form: Aqueous Dispersion 30%
Dissolution:
• Insoluble
• Low permeability
• pH independent swelling
Characteristics:
• No plasticizer required
• Highly flexible
Concentrations used:
1. 7%
2. 9%
3. 12%
4. 14%
Ethyl acrylate Methyl methacrylate

8. GRANULE PREPARATION
Wet granulation
• granules were prepared in Stephan UMC 5 (A) electronic high-shear mixer or
in high-shear mixer Rotolab (B)
• granulation liquid (30% water dispersion of Eudragit® polymers) was manually added for
the first 60 seconds, then the mixture was granulated for 240 s, by 1200 rpm
• the wet mass was passed through a 1.25-mm (A) or 1.5-mm (B) mesh sieve, granules were
dried for 24 hours at 40 °C in a cabinet dryer. After drying, the granules were again
passed through the sieve
multistep granulation process, in the first step the granules containing only 24 % of Eudragit® dispersion were prepared,
then another 5 % of water dispersion was added until the desired concentration of Eudragit® was achieved
Composition of granules
Sample Caffeine Eudragit® NM 30D (g) No. of granulation
steps(g) (g) (%)
1 150 47.0 24.0 1
2 150 62.6 29.4 2
3 150 83.4 35.7 3
4 150 101.3 40.3 4

9. GRANULE EVALUATION
Particle size
Lactose Caffeine
Average particle size (μm) 18.47 48.94
Standard Deviation(μm) 4.4 18.13
Minimum (μm) 10 18.32
Maximum (μm) 30.86 105.95
Powder mixtures were evaluated according to
European Pharmacopoeia tests

10. # sample Flowability (s) Hausner ratio
Compressibility
index (%)
Evaluation
1A 3.69 1.18 15.1
Good/Fair
SD 0.04 0.02 1.56
1B 3.48 1.17 14.2
Good
SD 0.06 0.01 0.9
3A 3.19 1.11 10.0
Excellent
SD 0.07 0 0
4A 3.20 1.10 8.5
Excellent
SD 0.08 0.01 1.1
1B 1.01 1.13 11.2
Good
SD 0.01 0.01 1.1
2B 0.94 1.11 10.1
Excellent
SD 0.01 0.02 1.9
3B 0.90 1.09 8.0
Excellent
SD 0.01 0.02 1.9
4B 0.86 1.08 7.2
Excellent
Compressibility Index (%) Flow Character
≤10 Excellent
11-15 Good
16-20 Fair
21-25 Passable
26-31 Poor
32-37 Very poor
≥38 Very, very poor
Flowability
Compressibility
Hausner’s ratio
Hausner Ratio
1.00-1.11
1.12-1.18
1.19-1.25
1.26-1.34
1.35-1.45
1.46-1.59
>1.60
• Better evaluation marks
for granules prepared in
Rotolab
• Improved flowability with
increasing concentrations
of Eudragit® NM
• Hausner‘s ratio < 1.25 all
granules suitable for
matrix tablet preparation

11. Mass uniformity Sample
1A 2A 3A 4A 1B 2B 3B 4B
Tablet weight (g)
Average (g) 0.1325 0.1356 0.1467 0.1490 0.1415 0.1384 0.1441 0.1484
SD (g) 0.0010 0.0012 0.0011 0.0009 0.0015 0.0006 0.0015 0.0010
Accepted limit ± 7,5 % (g) accepted accepted accepted accepted accepted accepted accepted accepted
MATRIX TABLET EVALUATION
The prepared granules were compressed using 7 mm
diameter flat-faced punches
• All prepared matrix tablets comply with the mass uniformity
test limits (±7.5%) according to Ph. Eur. 2013

12. MATRIX TABLET EVALUATION
Content and dosage unit uniformity
Sample
Theoretical
content [%]
Uniformity of dosage units
Acceptance value
L1
value
Average
content ± SD (%)
Accepted limit (%) Evaluation
1A 100 3.99 15 98.75 ± 1.14 85.0 - 115.0 accepted
2A 100 1.00 15 100.26 ± 0.31 85.0 - 115.0 accepted
3A 100 3.39 15 100.53 ± 1.19 85.0 - 115.0 accepted
4A 100 3.46 15 103.90 ± 0.44 85.0 - 115.0 accepted
1B 100 12.98 15 109.13 ± 2.23 85.0 - 115.0 accepted
2B 100 1.55 15 100.23 ± 0.55 85.0 - 115.0 accepted
3B 100 1.75 15 102.03 ± 0.51 85.0 - 115.0 accepted
4B 100 6.65 15 105.03 ± 1.30 85.0 - 115.0 accepted
• All prepared matrix tablets comply with the content
uniformity limits (±15%), as well as dosage unit limits (<L1)
according to Ph. Eur. 2013

13. Sample
Number of
tablets
Weight of tablets before
friability test (g)
Weight of tablets after
friability test (g)
Friability
[%]
Accepted
limit (%)
1A 49 6.4899 6.4683 0.33 1,0
2A 48 6.4903 6.4753 0.23 1,0
3A 44 6.4504 6.4490 0.02 1,0
4A 43 6.4950 6.4353 0.92 1,0
1B 46 6.5030 6.4842 0.29 1,0
2B 47 6.5255 6.4993 0.40 1,0
3B 45 6.5020 6.4870 0.23 1,0
4B 44 6.5794 6.5375 0.64 1,0
Friability
MATRIX TABLET EVALUATION
• All prepared matrix tablets comply with the friability limits
1%), according to Ph. Eur. 2013
• Higher concentrations of Eudragit® NM seem to result in
decreased mechanical resistance

14. MATRIX TABLET EVALUATION
Sample 1A 2A 3A 4A 1B 2B 3B 4B
Hardness of prepared matrix tablets [N]
Average
value [N]
124.1 97.5 55.4 70.5 106.8 108.3 92.8 100.0
SD [N] 3.87 4.06 4.29 4.01 4.06 5.95 7.00 3.64
Maximum
hardness [N]
129.8 102.3 62.5 75.8 113.9 116.4 103.2 106.0
Minimum
hardness [N]
118.0 87.2 49.4 64.2 101.5 97.9 79.7 95.8
Hardness
• High Hardness values reflect excellent mechanical properties
• Higher amounts of Eudragit® polymers seem to result, in
some cases, in reduced hardness

15. Dissolution test pH 6.8
MATRIX TABLET EVALUATION
Similarity factor f2 =47.64
T50%=156 min, T50%=120 min
7% Eudragit® NM
Similarity factor f2 =70.23
T50%=138 min, T50%=138 min
9% Eudragit® NM
Similarity factor f2 =84.36
T50%=170 min, T50%=170 min
12% Eudragit® NM
Similarity factor f2 =79.28
T50%=162 min, T50%=144 min
14% Eudragit® NM
Burst Effect
Stephan 18.53 - 21.54%
Rotolab: 16.28 - 19.00%

16. Compared samples of
matrix tablets
Similarity f2factor Observed influence
1A to 1B 47.64
Type of laboratory mixer
Stephan vs. Rotalab
2A to 2B 70.23
3A to 3B 84.36
4A to 4B 79.28
1A to 2A 73.38
Change of Eudragit® NM
concentration in tablets prepared in
Stephan mixer
2A to 3A 69.65
3A to 4A 70.98
4A to 1A 62.60
1B to 2B 61.61
Change of Eudragit® NM
concentration in tablets prepared in
Rotolab mixer
2B to 3B 62.63
3B to 4B 67.64
4B to 1B 58.45
Similarity f2 factor
MATRIX TABLET EVALUATION
• Mixer effect only for 7%
formulations
• No effect of Eudragit ®
concentration

17. • All tablet samples containing the slightly soluble model drug
caffeine, the poly(meth)acrylate Eudragit® NM (9-14 %) and lactose
as a soluble filler exhibited sustained drug release.
• The employment of different high-shear mixers for sustained matrix
tablets preparation did not significantly influence the release profile
of caffeine, except when the lower Eudragit® NM concentration
(7%) was used for granulation. However, this finding could be
attributed to uneven distribution.
• Eudragit® NM concentrations (7 – 14% per tablet) did not
significantly affect the release of caffeine from matrix tablets, neither
in the Stephan UMC5 nor the Rotolab mixer.
CONCLUSIONS

18. Thank you for your attention!!!