Post on 26-Jan-2017
University of Veterinary and Pharmaceutical Sciences Brno
Faculty of PharmacyDepartment of Pharmaceutics
Nikolaos Chalkidis
Supervisor: Assoc. Prof. PharmDr. Kateřina Kubová, Ph.D
Brno, 2015
Diploma Thesis Presentation
“Eudragit NM use in matrix tablets technology”
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
• 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
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 insolublepH dependent or
independent
EUDRAGIT®
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.
Two types of high shear mixers were used
1. Stephan UMC5 high shear mixer2. Rotolab mixer
HIGH SHEAR MIXERS
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
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
SampleCaffein
e Eudragit® NM
30D (g)No. of
granulation steps (g) (g) (%)
1 150 47.0 24.0 12 150 62.6 29.4 23 150 83.4 35.7 34 150 101.3 40.3 4
GRANULE EVALUATION
Particle size
Lactose Caffeine
Average particle size (μm) 18.47 48.94Standard 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
# sample Flowability (s) Hausner ratioCompressibility
index (%)Evaluation
1A 3.69 1.18 15.1 Good/FairSD 0.04 0.02 1.56
1B 3.48 1.17 14.2 GoodSD 0.06 0.01 0.9
3A 3.19 1.11 10.0 ExcellentSD 0.07 0 0
4A 3.20 1.10 8.5 ExcellentSD 0.08 0.01 1.1
1B 1.01 1.13 11.2 GoodSD 0.01 0.01 1.1
2B 0.94 1.11 10.1 ExcellentSD 0.01 0.02 1.9
3B 0.90 1.09 8.0 ExcellentSD 0.01 0.02 1.9
4B 0.86 1.08 7.2 ExcellentSD 0.03 0.01 1.1
Compressibility Index (%) Flow Character
≤10 Excellent
11-15 Good
16-20 Fair
21-25 Passable26-31 Poor32-37 Very poor≥38 Very, very poor
FlowabilityCompressibilityHausner’s ratio
Hausner Ratio
1.00-1.11
1.12-1.18
1.19-1.25
1.26-1.341.35-1.451.46-1.59
>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
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 0.1484SD (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
MATRIX TABLET EVALUATION
Content and dosage unit uniformity
SampleTheoretical
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
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
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
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
min9% 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
min14% Eudragit® NM
Burst Effect Stephan 18.53 - 21.54% Rotolab: 16.28 - 19.00%
Compared samples of
matrix tabletsSimilarity 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 73.38Change 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 61.61Change 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
• 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
Thank you for your attention!!!