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!!!