Download 1.5.2. Uniformity of tablets content

KAUNAS UNIVERSITY OF MEDICINE
FACULTY OF PHARMACY
DEPARTMENT OF DRUGS TECHNOLOGY AND SOCIAL PHARMACY
Rasa Kalėdaitė
PREPARATION AND DISSOLUTION CHARACTERISTICS OF MATRIX
TABLETS BASED ON EUDRAGIT® NM 30 D
Master Thesis of Pharmacy
Thesis supervisors:
Vitalis Briedis, MD PhD, Professor
PharmDr. Kateřina Dvořáčková PhD
Kaunas 2010
1
SUMMARY
The aim of this study was to evaluate the suitability of Eudragit® NM as a matrix
forming material for model drugs with different solubility.
Methods. Two drugs were selected as the model drugs: freely soluble in water diltiazem
hydrochloride and sparingly soluble in water caffeine. Matrix forming agent was chosen
Eudragit® NM polymer. Granules obtained by wet granulation were tested according to Ph. Eur.
(flowability test, flow test, sieve test and determination of density). Quality parameters of tablets
were tested according to Ph. Eur. (mass and content uniformity, hardness, friability and
dissolution test).
Results. Less than 10 % amount Eudragit® of NM 30 D aqueous dispersion did not
ensure the formation of granules, because the amount of binder was not enough. The granulation
with more than 30 % amount of aqueous polymer dispersion was made by several steps to avoid
forming of wet mass which can not be meshed through the sieve. The flowability time of DH or
C granules is small (less than 3,5 s). The flow character of DH and C granules varied from
passable to excellent, mostly depending on polymer amount. Higher amount of polymer led to
formation of bigger granules and better flow properties. Mass and content uniformity of DH and
C tablets were in the limits of Ph. Eur. The friability was very small less than 0,2 %. Hardness of
DH and C matrix tablets was more than 100 N, high amounts of polymer led to form a viscous
tablets, which deviation of average was high (20 %). Dissolution test was performed 12 hours at
pH 6,8. Dissolution profile for 12 hours of DH tablets which contains high amount of MCC and
Eudragit®
NM was most gradual (4D, 5D) at pH 6.8. Almost all samples of C tablets
disintegrated during first hours and did not show almost any retardation of drug release, except
14C sample (25 mg of MCC and 16,68 mg of Eudragit® NM 30 D). Continual dissolution test
showed, that the release profile is to fast at pH 1.2, so tablets are recommended to coat
acidoresistant coating (Eudragit® L 30 D)
2
SANTRAUKA
Tyrimo tikslas yra nustatyti ar Eudragit® NM yra tinkamas naudoti kaip matricą
formuojanti medžiaga vaistinėms medžiagoms, pasižyminčiomis skirtingomis fizikocheminėmis
savybėmis.
Metodai. Vaistų modeliais buvo pasirinktos 2 medžiagos: lengvai tirpus vandenyje
diltiazemo hidrochloridas ir ribotai vandenyje tirpus kofeinas. Eudragit® NM polimeras
pasirinktas kaip matricą formuojanti medžiaga. Drėgno granuliavimo būdu gautos granulės
ištirtos remiantis Europos farmakopėjos metodais (birumo ir takumo testai, sietų analizė bei
tankio nustatymas). Tablečių kokybės parametrai buvo ištirti remiantis Europos farmakopėja
(masės ir turinio vienodumo testai, tvirtumas, dilumas bei tirpimo testas) .
Rezultatai. Mažesnis nei 10 % vandeninės Eudragit® NM 30 D dispersijos kiekis
neužtikrino granulių susiformavimo, dėl nepakankamo rišančiosios medžiagos kiekio.
Granuliavimas naudojant daugiau nei 30 % vandeninės polimero dispersijos kiekį buvo atliktas
keletu etapų, norint išvengti drėgnos masės susiformavimo, kurią sunku pertrinti per sietą. DH ir
C granulių birumo laikas buvo mažas (mažiau nei 3,5 s). DH ir C granulių takumo pobūdis kito
nuo priimtino iki puikaus, priklausomai nuo polimero kiekio. Didesnis polimero kiekis užtikrino
didesnių granulių susiformavimą ir geresnes takumo savybes. DH ir C masės ir turinio
vienodumas testų rezultatai buvo Europos Farmakopėjos nustatytose ribose. Dilumas buvo labai
mažas (mažiau nei 0,2 %). DH ir C matricos tablečių tvirtumas buvo daugiau nei 100 N, didelis
polimero kiekis paskatino susiformuoti atsparias deformacijai tabletes, kurių nuokrypis nuo
vidurkio buvo aukštas (20 %). Tirpumo testas buvo atlikinėjamas 12 val pH reikšmė 6.8.
Tirpumo profilis DH tablečių, kurios turi didelį kiekį MCC ir Eudragit® NM (4D, 5D) buvo
tolygiausias. Beveik visi C tablečių pavyzdžiai suiro per pirmąsias valandas ir beveik neparodė
jokio vaisto išsiskyrimo sulėtinimo, išskyrus 14C mėginį (25 mg MCC, 16,68 mg Eudragit®
NM). Nuolatinis tirpimo testas parodė, jog tirpumo profilis yra per greitas pH reikšmėje 1,2, taigi
rekomenduojama tabletes padengti rūgščiai atsparia danga (Eudragit® L 30 D).
3
ACKNOWLEDMENT
I would like to thank Vitalis Briedis, MD PhD, Professor for the opportunity to
accomplish research work abroad in University of Veterinary and Pharmaceutical Sciences Brno,
Czech Republic. I owe my deepest gratitude to my supervisor, PharmDr. Kateřina Dvořáčková
PhD, whose encouragement, guidance and support during research made this thesis possible. I
am also grateful to PharmDr. Tereza Bautzová for the assistance during experiments.
4
LIST OF ABBREVIATIONS
AGJ - Artificial gastric juice
C – Caffeine
CSD - Colloidal Silicon Dioxide
DH - Diltiazem Hydrochloride
Ph. Eur. – European Pharmacopoeia
GIT - Gastrointestinal tract
MCC - Microcrystalline Cellulose
MgS – Magnesium Stearate
SD – Standard deviation
5
Table of Contents
INTRODUCTION .........................................................................................................................................9
THE AIM AND TASKS OF STUDY ........................................................................................................ 10
1. REVIEW OF LITERATURE ................................................................................................................. 11
1.1. Basic characteristics of Eudragit® types .......................................................................................... 11
1.1.1. pH-dependent types ...................................................................................................................... 11
1.1.1.1. Eudragit®L and S ....................................................................................................................... 12
1.1.1.2. Eudragit® FS .............................................................................................................................. 13
1.1.2. Time-dependent types .................................................................................................................. 13
1.1.2.1. Eudragit® RL and RS................................................................................................................. 14
1.1.2.2. Eudragit® NE ............................................................................................................................. 14
1.1.2.3. Eudragit® NM ............................................................................................................................ 15
1.2. Applications of Eudragit®................................................................................................................ 15
1.2.1. Enteric coatings ............................................................................................................................ 16
1.2.2. Colon and ileum coatings ............................................................................................................. 17
1.2.3. Sustained release .......................................................................................................................... 18
1.2.4. Matrix formulation ....................................................................................................................... 21
1.3. Definition of tablets ......................................................................................................................... 23
1.4. Powder and granules characterization ............................................................................................. 24
1.4.1. Particle size .................................................................................................................................. 24
1.4.1.1. Optical microscopy.................................................................................................................... 25
1.4.1.2. Sieve analysis ............................................................................................................................ 25
1.4.2. Flowing properties........................................................................................................................ 26
1.4.2.1. Flowability ................................................................................................................................ 26
1.4.2.2. Flow (Compressibility index or Hausner ratio) ......................................................................... 27
1.4.3. Measurement of density ............................................................................................................... 29
1.5. Tablets characterization ................................................................................................................... 29
1.5.1. Uniformity of tablets mass ........................................................................................................... 29
1.5.2. Uniformity of tablets content ....................................................................................................... 29
1.5.3. Friability of uncoated tablets ........................................................................................................ 30
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1.5.4. Resistance to crushing of tablets .................................................................................................. 30
1.5.5. Dissolution test for tablets ............................................................................................................ 31
1.6. Model Drugs .................................................................................................................................... 32
1.6.1. Caffeine ........................................................................................................................................ 32
1.6.2. Diltiazem Hydrochloride .............................................................................................................. 33
1.7. Excipients ........................................................................................................................................ 34
1.7.1. Microcrystalline Cellulose ........................................................................................................... 34
1.7.2. Magnesium Stearate ..................................................................................................................... 34
1.7.3. Colloidal Silicon Dioxide ............................................................................................................. 35
2. EXPERIMENTAL PART ...................................................................................................................... 36
2.1. Drugs and excipients ....................................................................................................................... 36
2.2. Laboratory equipment ..................................................................................................................... 36
2.3. Preparation of granules .................................................................................................................... 37
2.3.1. The measurement of particle size ................................................................................................. 37
2.3.2. Preparation of granules ................................................................................................................. 37
2.4. Evaluation of granules quality parameters ...................................................................................... 39
2.4.1. Determination of granules flowability.......................................................................................... 39
2.4.2. Determination of granules flow (Compressibility index and Hausner ratio) ............................... 39
2.4.3. Determination of density using helium-pycnometer .................................................................... 40
2.4.4. Determination of granules size using sieve analysis .................................................................... 40
2.5. Preparation of matrix tablets ........................................................................................................... 40
2.5.1. Preparation of granules for compressing ...................................................................................... 40
2.5.2. Compression of matrix tablets ...................................................................................................... 41
2.6. Evaluation of quality parameters of matrix tablets (Ph. Eur.) ......................................................... 42
2.6.1. Uniformity of tablet mass ............................................................................................................. 42
2.6.2. Uniformity of tablet content ......................................................................................................... 42
2.6.3. Friability of tablets ....................................................................................................................... 43
2.6.4. Resistance to crushing of tablets (Hardness of tablets) ................................................................ 43
2.6.5. Determination of released drug from matrix tablet ...................................................................... 43
3. RESULTS AND DISCUSSION ............................................................................................................ 45
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3.1. Preparation of granules .................................................................................................................... 45
3.2. Results of granules evaluation ......................................................................................................... 46
3.3. Results of tablets evaluation ............................................................................................................ 47
CONCLUSIONS ........................................................................................................................................ 49
REFERENCES ........................................................................................................................................... 50
ADDITION Nr. 1 ....................................................................................................................................... 55
ADDITION Nr. 2 ....................................................................................................................................... 58
ADDITION Nr. 3 ....................................................................................................................................... 66
ADDITION Nr. 4 ....................................................................................................................................... 70
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INTRODUCTION
Eudragit® is the product line which includes pharmaceutical copolymers from esters of
acrylic or methacrylic acid whose properties are determined by functional group. The individual
grades differ in their proportion of neutral, alkaline or acid groups and thus in terms of their
physicochemical properties. Depending on the pH, these polymers act as polyelectrolytes which
make them suitable for different purposes, from gastric or intestinal soluble drug formulations to
insoluble but swellable delivery forms (matrix formulations), regulated by percentage of charged
and nonionized (ether) groups in the structure of these copolymers. [2] Anionic Eudragit® L,
S and FS types dissolve in neutral or alkaline fluids. Insoluble Eudragit® RL/RS types have
hydrophilic quaternary ammonium groups as hydrochlorides, providing different permeability,
whereas the insoluble Eudragit® NE/NM types include no functional groups. These insoluble
polymers absorb water from physiological fluids and swell in a pH-independent way to create
diffusional barriers for time-controlled drug release. [1] In order to control chronic diseases
(arterial hypertension, ischemic heart disease, arthritis) is important to maintain permanent drug
concentration in blood or tissues, sustained release drug forms are suitable to solve this problem.
Eudragit® NM is a new time-dependent polymethacrylate polymer, which is suitable for
sustained release formulations. Reviewing of the various sources of scientific literature found
that there is little information about Eudragit® NM. There are done just little researches with
water dispersion of Eudragit® NM (30% water dispersion) a matrix forming agent, so it was
topical to make a research with Eudragit® NM as the drug release modifier.
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THE AIM AND TASKS OF STUDY
The aim of study is to evaluate Eudragit® NM suitability as a matrix forming agent for
model drugs with different solubility.
Tasks of study:
1. To prepare granules from two materials with different solubility (DH and C), using
different quantity of MCC and Eudragit® NM 30 D by wet granulation method.
2. To evaluate of prepared DH and C granules physical properties and suitability for tablets
manufacturing by Ph. Eur.
3. To press matrix tablets of DH and C and to assess their quality parameters by Ph. Eur.
4. To determine the most appropriate amount of MCC and Eudragit® NM in matrix tablets
of DH and C which provides prolonged drug release for 12 hours at pH 6,8.
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1. REVIEW OF LITERATURE
1.1. Basic characteristics of Eudragit® types
1.1.1. pH-dependent types
The main structural element of the synthetic methacrylate copolymers is an acidic
function (phthalate or methacrylic acid), which is responsible for the pH-dependent dissolution.
[15] The carboxylic groups are transformed to carboxylate groups in the pH range of 5 – 7 by
salt formation with alkali or amines. Their dissolution pH depends primarily on their content of
carboxylic groups. Methacrylic acid – methyl methacrylate copolymer 1:1 (Eudragit® L 100)
dissolves at pH 6, methacrylic acid – methyl methacrylate copolymer 1:2 (Eudragit® S 100) –
above pH 7. When the ester component is more hydrophilic ethyl acrylate, the films prepared
from methacrylic acid – ethyl acrylate copolymer 1:1 (Eudragit® L 30D or redispersed powder L
100-55) dissolves above pH 5.5. [1]
Table 1. pH – dependent Eudragits® [3, 16, 18]
Eudragit® Polymer
Availability
L 30 D-55
30 % Aqueous Dispersion
L 100-55
Powder
L 100
Powder
L 12,5
12,5 % Organic Solution
S 100
Powder
S 12,5
12,5 % Organic Solution
FS 30 D
30 % Aqueous Dispersion
Dissolution Properties
Dissolution above pH 5,5
Dissolution above pH 6,0
Dissolution above pH 7,0
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1.1.1.1. Eudragit®L and S
Figure 1. Eudragit® L 30 D-55 [4]
Eudragit® L 30 D-55 (methacrylic acid – ethyl acrylate copolymer 1:1 dispersion 30 per
cent Ph. Eur.) is the aqueous dispersion with 30% of dry substance of an anionic copolymer
based on methacrylic acid and ethyl acetate. The dispersion contains 0.7 % sodium laurilsulfate
and 2.3 % polysorbate 80 on solid substance, as emulsifiers. The ratio of the free carboxyl
groups to the ester groups is approx. 1:1. A molecular mass is about 250 000. [4, 17]
Eudragit® 100-55 (methacrylic acid – ethyl acrylate copolymer 1:1, type A Ph. Eur.) is a
solid substance. The product contains 0.7 % sodium laurilsulfate and 2.3 % polysorbate 80 on
solid substance, as emulsifiers. [5]
Figure 2. Eudragit® L, resp. Eudragit® S [6]
Eudragit® L 100 (methacrylic acid – methyl methacrylate copolymer 1:1 Ph. Eur.) and
Eudragit® S 100 (methacrylic acid – methyl methacrylate copolymer 1:2 Ph. Eur.) are solid
substances. The ratio of free carboxyl groups to the esters is about 1:1 in Eudragit® L 100 and
1:2 in Eudragit® S 100. The relative molecular mass is about 135 000. [6, 17]
Eudragit® L 12,5 (methacrylic acid – methyl methacrylate copolymer 1:1 Ph. Eur.) and
Eudragit® S 12,5 (methacrylic acid – methyl methacrylate copolymer 1:2 Ph. Eur.) is a solution
of Eudragit® L 100 (Eudragit® S 100 Ph. Eur.) with 12.5 % dry substance in aqueous isopropyl
alcohol. [7]
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1.1.1.2. Eudragit® FS
Figure 3. Eudragit® FS. [8]
Eudragit® FS 30 D is the aqueous dispersion of an anionic copolymer based on methyl
acrylate, methyl methacrylate and methacrylic acid. The dispersion contains 0.3 % sodium
laurilsulfate and 1.2 % polysorbate 80 on solid substances, as emulsifiers. The ratio of the free
carboxyl groups to the ester groups is 1:10. The average molecular weight is about 220 000. [8]
1.1.2. Time-dependent types
After contact with gastrointestinal fluids, the film coatings swell, independently of pH,
and release the active substance by a diffusion-controlled mechanism. [1]
Table 2. Time-dependent Eudragits® [3,22]
Eudragit® Polymer
Availability
Dissolution Properties
RL 100
Granules
RL PO
Powder
RL 30 D
30 % Aqueous Dispersion
RL 12,5
12,5 % Organic Solution
RS 100
Granules
RS PO
Powder
Low permeability
RS 30 D
30 % Aqueous Dispersion
pH-independent swelling
RS 12,5
12,5 % Organic Solution
NE 30 D
30 % Aqueous Dispersion
Insoluble, low permeability
NE 40 D
40 % Aqueous Dispersion
pH-independent swelling
NM 30 D
30 % Aqueous Dispersion
No plasticizer required
Insoluble
High permeability
pH-independent swelling
Insoluble
Highly flexible
13
1.1.2.1. Eudragit® RL and RS
Figure 4. Eudragit® RL and RS. [9]
Eudragit® RL 100 (ammonio methacrylate copolymer type A Ph. Eur.) and Eudragit® RS
100 (ammonio methacrylate copolymer type B Ph. Eur.) are solid substances; Eudragit® RL PO
and Eudragit® RS PO are solid substances obtained from Eudragit® RL 100 or Eudragit® RS 100.
They are copolymers of ethyl acrylate, methyl methacrylate and low content of methacrylic acid
ester quaternary ammonium groups (trimethylammonioethyl chloride). The ammonium groups
are present as salts and make the polymers permeable. The average molecular weight is 150 00.
[9]
Eudragit® RL 30 D and Eudragit® RS 30 D are aqueous dispersions of Eudragit® RL 100
or Eudragit® RS 100 with 30 % dry substance. The dispersions contain 0.25 % sorbic acid as a
preservative and 0.1 % sodium hydroxide as an alkalizing agent. [10]
Eudragit® RL 12,5 and Eudragit® RS 12,5 are solutions of Eudragit® RL 100 or
Eudragit® RS 100 with 12.5 % (w/w) dry substance in a mixture of 60 % (w/w) isopropyl
alcohol Ph. Eur. and 40 % (w/w) acetone. [11]
1.1.2.2. Eudragit® NE
Figure 5. Eudragit® NE. [12]
Eudragit® NE 30 D (polyacrylate dispersion 30 per cent Ph. Eur.) is the aqueous
dispersion with 30 % dry substance of a neutral copolymer based on ethyl acrylate and methyl
methacrylate. The dispersion contains 1.5 % nonoxynol as an emulsifier. The average molecular
weight is 800 000. [12]
14
Eudragit® NE 40 D is identical to Eudragit® NE 30 D with 40 % dry substance instead of
30 % dry substance. The dispersion contains 2.0 % nonoxynol as an emulsifier. [13]
1.1.2.3. Eudragit® NM
Figure 6. Eudragit® NM. [14]
Eudragit® NM 30 D (polyacrylate dispersion 30 per cent Ph. Eur.) is an aqueous
dispersion with 30 % dry substance of a neutral copolymer based on ethyl acrylate and methyl
methacrylate. The dispersion contains 0.7 % macrogol stearyl ether Ph. Eur. as an emulsifier.
The aqueous dispersion is miscible with water in any proportion, the milky-white appearance
being retained. When 1 part NM 30 D is mixed with 5 parts acetone, a clear to slightly cloudy,
viscous solution is obtained. The same occurs when mixed with ethanol or isopropyl alcohol;
initially the polymer is precipitated, but then dissolves again in the excess organic solvent. When
mixed with 1 N sodium hydroxide in a ratio of 1:2, the dispersion does not dissolve. The milkywhite appearance is retained. The average molecular weight is 600 000. [14]
1.2. Applications of Eudragit®
Generally in technology of solid dosage forms, Eudragits® can be used as the coating
materials (coated tablets, capsules, pellets, microparticles) and matrix formers (matrix tablets,
pellets, microparticles). As the coating materials Eudragits® are able to ensure on one hand site
specific delivery of active ingredient (enteric, ileic, colonic) because of their pH-dependent
solubility and on the other hand pH-independent types are of use in sustained drug release. The
other Eudragits® application is their incorporation into matrix systems where effectively slow
down the drug release in time.
15
Figure 7. Eudragit® polymers used for oral solid dosage formulations. [35]
1.2.1. Enteric coatings
Enteric-coated formulations are suitable to modify the release of the active substance that
it would be released at the proximal part of small intestine. The intended use includes drug
stabilization within the stomach passage; protection against stomach irritation and release
directed to defined segments in the digestive tract. [15] The small intestine can be targeted with
polymers having solubility at pH in the range between 5.0 – 6.0, the distal part requires polymers
having solubility at pH in the range between 7.0 – 7.5. The pH sensitive material is insoluble or
almost impermeable in dissolution liquids of low pH but can dissolve in those liquids which pH
is from 5 to 7. The approach depends on the GIT transit time, which differs in individuals. [20]
Polymers can be used also to create the drug form with pulsatile release. Fan et al. investigated
the pulsatile release tablets with ethylcellulose and Eudragit® L as film coating materials. The
purpose of study was to develop new pulsatile release tablets, which can suppress drug release in
stomach and release drug rapidly after a lag time period in intestine. Dissolution of Eudragit® L
causes pores in the film, so it was selected as the coating material for this purpose. The lag time
16
can be controlled by the thickness of the coating film. Water penetrates through the coating film
and causes the water uptake and expansion of swelling material until the internal forces on the
film causes the tablet to burst and for that reason the drug is released. The burst of thicker film
needs more powerful forces and leads to longer lag time than thinner film. [19]
1.2.2. Colon and ileum coatings
Colon-specific targeting is used for the topical treatment of local disorders. [18] The
second approach is to use a material which dissolves above pH 7. It is suitable for the colonic
delivery system and for this purpose are used Eudragit® S and FS. Many commercial drug
formulations for the oral treatment of inflammatory diseases (such as Asacolitin®, Claversal®,
Salofalk® or Budenofalk®) are coated with pH-sensitive colon coating polymers such as
Eudragit® L or S® (see Table 3) [38]. The solubility in pH 7 can limit the drug release in the
proximal part of the GIT, but there is a possibility that no drug will be released in the colon if the
film is too thick. The release rate of drug coated with Eudragit® S100 depends not only the pH
but also on the ion concentrations of the in vitro solutions. The faster release of the drug is due to
to a higher concentration of ions, because the carboxylic groups in the Eudragit ® S100 are
reacting with bases in the liquid and it causes the increased film solubility rate. [20] Ibekwe et al.
were investigating the in vitro dissolution characteristics of pH-dependent poly(meth)acrylate
polymers in a different simulated fluids. Tablets coated with Eudragit ® S aqueous dispersion
showed a faster dissolution rate comparing to Eudragit® S organic solution, because of the partial
neutralization of the methacrylic acid units which are responsible for the pH-dependent
solubility, during the re-dispersion process. The dissolution of Eudragit® S aqueous coated
tablets begins in the proximal part of the ileo-colonic region. Low permeability of formulations
containing Eudragit FS to water vapor is due to a low hydrophilic character of this polymer.
Tablets coated with Eudragit® FS are suited for delivery to the ileo-colonic region, but polymer
was observed to exhibit a pH-dependent permeability to aqueous media, with some degree of
moisture uptake across the entire pH range used in the dissolution tests (6.8 – 7.4) and swelling
around the tablet core prior to presumable drug release at pH more than 7. [21, 23]
17
Table 3. Coated dosage forms for the treatment of ulcerative colitis in the German market. [38]
Drug
Coating polymers
®
Dissolution pH
Trade name
®
Mesalazine
Eudragit L
6.0
Claversal
Mesalazine
Eudragit® S
7.0
Asacolitin®
Mesalazine
Eudragit® L
6.0
Salofalk®
Sulfasalazine
Eudragit® L 100-55
5.5
Colo-Pleon®
Budenoside
Eudragit® L 100- 5.5
55, ethylcellulose
Eudragit® S
6.0
Budenoside
Entocort®
Budenofalk®
Manufacturer
SmithKline
Beecham
Pharmaceuticals Munich
Henning Berlin GmbH &
Co., Berlin
Dr Falk Pharma GmbH,
Freiburg
Henning Berlin GmbH &
Co., Berlin
ASTRA GmbH, Wedel
Dr Falk Pharma GmbH,
Freiburg
1.2.3. Sustained release
Sustained release polymeric film coating is based upon a generic reservoir design in
which the release of a concentrated drug core is controlled by a semi-permeable membrane. The
membrane controls the fluid permeation into the drug core, thereby controlling the dissolution
and subsequent outward diffusion of the active substance. The primary benefit of sustained
release dosage forms is the reduction of the daily dosing to a twice or once-daily schedule. By
reducing of the required daily doses number, the drug therapy is improved by better patient
compliance and often reduced cost. A sustained release dosage form can stabilize the systemic
drug concentration by providing a constant rate of drug release and absorption. This is very
important for certain applications, for example a pain therapy, that patient could rest throughout
the night without suffering the pain. [22] There are some drugs, which have a narrow therapeutic
index, for example theophylline. It is a xanthine derivative, which is used in the treatment of
bronchial asthma and bronchospastic diseases. So, it requires suitable formulation to maintain
the drug concentration in the serum within the therapeutic range and sustained-release oral
formulation is the best solution. [27]
The polymethacrylates that are used for sustained-release film coatings are Eudragit® RL
(highly permeable), Eudragit® RS (low permeable), Eudragit® NE (permeable), Eudragit® NM
(permeable). These systems are composed of polymers that are water insoluble, but swellable
over the range of physiological pH, and they are suitable for sustained release film coating
applications. [1, 21] Eudragit RL and RS have quaternary ammonium groups which are in the
chloride salt form. The dissociation of these groups in aqueous media is responsible for the
hydration and swelling of the polymers films. [22] Eudragit® RL 100 includes a greater
18
concentration of quaternary ammonium groups and the coatings made from this polymer are
more permeable than those which are made from Eudragit® RS 100. So, the drug release through
Eudragit® RL 100 membranes is bigger than from Eudragit® RS 100. The sustained-release
Eudragit® polymer are used of coating materials for pellets [22], tablets [19], capsules [20],
microspheres [22].
The drug release from dosage forms coated by these polymers could be modified by
addition of wide range other excipients. To increase the permeability of film layers such
substances can be added like: sucrose, lactose and other saccharides; starch, micronized
cellulose, soluble cellulose ethers; poly(vinylpyrrolidone), polyethylene glycol or its derivatives
and fumed or precipitated silica. But water-soluble cellulose ethers have limited compatibility,
because they stimulate slow agglomeration and coagulation within few hours or days [1]. For
instance, the coating permeability from low permeable Eudragit® RS can be increased with
addition of inulin to the film. Inulin is a naturally occurring polysaccharide which is not
significantly hydrolyzed by gastric or intestinal enzymes. The increased swelling ratio is due to
the presence of inulinase enzyme in the dissolution media (simulated colonic fluid) which can
diffuse into the polymeric chains, hydrolyze the fructose backbone of inulin, reduce the network
density and increase the swelling ratio. Colonic bacteria (specifically Bifidobacteria) can degrade
this polysaccharide and this increases the permeability of the film [23]. Eudragit® RL 100 and
RS 100 coating systems have been used in a different sustained release coating applications. [1,
21, 23]. Often, Eudragit® RS and (or) RL are used like coating materials to create sustained
release drug forms from such active substances like ibuprofen, indomethacin, nitrendipine,
diltiazem and others [22].
Eudragit® RL and RS could be combined with other Eudragit® polymer to achieve the
desirable dissolution profile. Eudragit® RL 30 D and RL 30 D in combination with Eudragit® FS
30 D were used as coating materials to produce sustained release pellets of 5-aminosalicylic acid
(5-ASA) for the colon targeting. Pellets were prepared by powder layering of 5-ASA on
nonpareils (0.5-0.6 mm) in a conventional coating pan. Then pellets were coated with an inner
layer of Eudragit® RL and RS (8:2) and a outer layer of Eudragit® FS (different amounts). The
release profile of 5-ASA was sustained for more than 12 h in phosphate buffer after simulated
gastric pre-soak for 2 h. (see Figure 8). [22, 37]
19
Figure 8. Dissolution of 5-ASA pellets for the first 2 h at pH 1.2 followed by pH 7.0 phosphate
buffer. [37]
Different ratios of Eudragit® NE 30 D and Eudragit® L 30D-55 were tested as the coating
materials for drug-layered beads. These were prepared by spraying of Eudragit ® RS 30D
dispersion containing verapamil-hydrochloride as the model drug. It was found that suitable
ratios of polymers were 75:25 and 80:20. In 60% coating level these combinations were suitable
as a functional film coating material for use in delayed drug release applications. For 75:25
polymer ratio the lag time was approx. 3 hours. The longer lag time approx. 5 hours was
observed in the case of 80:20 polymer one. Generally, the lag time increased and drug release
decreased with increasing amount of Eudragit® NE 30 D in the polymer blend (see Figure 9).
[24]
20
Figure 9. Dissolution profiles of uncoated beads and beads coated with NE 30D, L30D and
blends thereof at ratios 75:25 and 80:20 at 60% weight gain. [24]
1.2.4. Matrix formulation
Matrices are monolithic systems constituted of active substance dispersed and entrapped
in a continuum of excipient (adjuvant) – the “matrix forming” substance. The special matrix
advantage is the non-immediate disintegration of the monolith in contact with a dissolution
liquid. The other advantages are simplicity of preparation and low product costs. The usual
appearance of the matrix is the tablet. The matrix keeps a structure for the time needed to release
the dispersed or dissolved drug. The dissolution is slowed down by the typical release
mechanism. There are three types of matrices, which can be constructed and their release
kinetics changing according to the category – inert, erodible and swellable matrices. Inert
matrices leave residual skeletons, erodible matrices slowly disintegrate and the swellable
matrices forms gel layer. [25]
The swellable matrix undergoes erosion during its release time, but the drug release can
proceed together or in the different time with the matrix erosion or dissolution. It depends on the
combination of hydrophilic polymers used for the making the matrix. The swellable matrices are
typical moving boundary release systems. The drug release is controlled by continuously
changing dimension of the diffusive barrier. This barrier is the layer thickness externally formed
on the matrix that controls active substance transport through it. In swellable matrices the barrier
is called gel layer. The hydrophilic polymer fraction in the matrix is the most important
parameter for determining drug release profile. Drug solubility is important also for the release
kinetics. Highly soluble drugs act as pore formers leading to a fast drug release by diffusion
21
process. Poorly soluble drugs will be released mainly by matrix erosion. Many drugs are released
from matrix in the combination of two processes – the diffusion and the erosion. [25] The whole
process consists from: diffusion of the liquid through the Eudragit® polymer matrix and into
branched polymer, reaction between the branched polymer and the liquid, dissolution of the drug
in the liquid, diffusion of the drug through the liquid located in the branched polymer and the
polymer matrix. [26]
Matrices are easily manufactured by direct compression and compression of granules
which are obtained by dry, wet (high shear mixer or fluidized bed) or melt granulation. [28]
Eudragit® is attractive like a matrix forming materials, due to their high chemical stability, good
compatibility properties and large variety of products with different physicochemical
characteristics present on the market. A swellable matrix can be formed from some Eudragit ®
polymers. Ceballos et al prepared extended-release theophylline matrix tablets by a direct
compression of drug and different pH-dependent (Eudragit® L 100, S 100 AND L 100-55) and
time-dependent (Eudragit® RL PO and RS PO) polymer combinations. Matrix tablets based on L
100/RL PO and L 100/RS PO mixtures gave the best results, displaying the highest percent of
theophylline released and the matrix formulation allowed to obtain the more regular release
profiles, with the best equilibrium between the values of drug releases amount at the gastric and
intestinal pH. This was made by the combination of the good erodible properties of L100 with
the swelling properties of RLPO and RSPO polymers. The use of a mixture of Eudragit L100
and RLPO in the 0.7:0.3 w/w ratio enabled a highly reproducible drug release profile to be
achieved, with an almost zero-order kinetic. [27] Colo et al. reported that compressed matrix
tablets based on pH-sensitive polyethylene oxide and Eudragit® L100 compounds ensure a
complete release of the active substance during the transit from stomach to jejunum. A ionization
of the Eudragit® L carboxyls by the anions is the main step of the release from the matrices to the
intestinal fluids. [16]
Inert matrix tablets of carteolol hydrochloride can be prepared from Eudragit ® RS as a
supporting material with different fillers and wetting liquids. Carteolol has a potent β-adrenergic
blocking action. Use of lactose does not allow to form an inert matrix, because this formulation
shows a disintegration process depending on its hydrophilic nature. Mannitol, polyethylene
glycol 6000 and Emcompress® (calcium hydrogen phosphate dihydrate and dibasic calcium
phosphate) are suitable as fillers. The use of Eudragit ® L12.5 as a wetting liquid allows to obtain
two phase release profile. The first phase may represent the release of a drug on the surface of a
tablet and the particles of the drug which are not completely surrounded by the Eudragit ®. The
second phase is the release of drug contained in a inert matrix. [29] Shanawany was investigating
22
sustained release granules of nitrofurantoin from inert wax matrices. Nitrofurantoin is used to
treat urinary tract infection. The problem is that the drug did not achieve therapeutical
concentration because it rapidly eliminated. The long term treatment produces side effect in the
gastrointestinal tract. In order to minimize the side effect and to maintain the blood level within
therapeutic range it was decided to formulate the drug as a sustained release preparation using an
inert wax matrix. The release of a drug from an inert wax matrix involves leaching by the
dissolution media that contacts the embedded drug. The fluid can enter the core through pore
channels and cracks. Several materials have been used as channeling or pore forming agents to
improve the release of the drug from wax matrices: colloidal silicone dioxide, microcrystalline
cellulose, dibasic calcium phosphate hydrate. The release of the drug was significantly increased
with increase of channeling agents. The granules were prepared by fusion, solvent evaporation or
melt granulation methods. Granules prepared by the fusion method and containing equal
quantities of stearic acid and glyceryl monostearate showed the best sustained release properties.
[28]
In erodible matrix systems the mechanism of the drug release occurs by erosion. The
difference of these systems from inert matrices is that the polymer in the inert systems remains
unchanged with time and the drug is released by diffusion and the polymer phase in erodible
systems decreases with time. The erosion mode of these delivery systems is one of the factors
controlling drug release. There are two different modes of erosion: surface (heterogeneous) and
bulk (homogeneous). In bulk-degrading systems, degradation occurs homogeneously throughout
the bulk of the system. In surface-degrading systems, degradation is confined to the outer surface
of the system. The rate of the drug release from a surface-eroding device is proportional to the
surface area of the delivery system. [30] An erodible matrix can be made from
hydroxypropylmethylcellulose. Karasulu et al reported that even a geometrical shape of the
tablets affect the release rate of the active substance (theophylline) in erodible hydrogel matrix
system. Three geometrical shapes were investigated. The highest release rate had triangular
tablets, then – half-spherical and the lowest rate had cylindrical tablets. [31]
1.3. Definition of tablets
Tablets are solid preparations each of which contains a single dose of one or more active
substance. They are obtained by compressing uniform volumes of particles, and they are almost
always intended for oral administration. Compressing pharmaceutical tablets is the most efficient
process for producing a single dose for medication. [32] Some are swallowed whole, some after
23
being chewed, some are dissolved or dispersed in water before being administered and some are
retained in the mouth where the active substance is liberated. The particles consist of one or
more active substances with or without excipients such as diluents, binders, disintegrating
agents, glidants, lubricants, substances capable of modifying the behavior of the preparation in
the digestive tract, coloring matter authorized by the competent authority and flavoring
substances. Tablets are usually right, circular solid cylinders, the end surfaces of which are flat
or convex and the edges of which may be beveled. They may have lines or break-marks and may
bear a symbol or other markings. Tablets may be coated. [17] Tablet drug delivery systems can
range from relatively simple immediate-release formulations to complex extended- or modifiedrelease dosage forms. The most important role of tablet is to achieve the drug delivery to the site
of action in sufficient amount and at the appropriate rate, but it must also meet a number of other
essential criteria. These include physical and chemical stability, ability to be economically mass
produced in a manner that assures the proper amount of drug in each and every dosage unit and
in each batch produced, and, as far as possible, patient acceptability (reasonable size and shape,
taste, color, etc. to encourage patients to take the drug and thus comply with the prescribed
dosing regimen). [33] The compressed tablet is by far most widely used dosage form, because
they are easily administrated and simple to use. The tablet is the most popular dosage form
because it provides advantages for all concerned in the production and consumption of medicinal
products. For the manufacturer it is considerable, because the tablets can be produced at a much
higher rate than any other dosage form. The tablet is a dry dosage, so it promotes stability and
they have a long shelf lives measured in years. Tablets are also convenient to transport in bulk.
From the viewpoint of the pharmacist, tablets are easy to dispense, while the patient receives a
concentrated and readily consumed dosage form. The appropriate coating can mask unpleasant
tastes and improve patient acceptance. [32]
1.4. Powder and granules characterization
1.4.1. Particle size
A powder is characterized by its particle size, which is important to achieve optimum
qualities of tablets. This parameter influences the dissolution rate of the drug in vivo, which in
turn influences absorption rate and therapeutic activity. Particle size is important during the
production of solid dosage forms like tablets and capsules. The manufacture of tablets is based
by a volumetric method. Powders with different particle sizes have different flow and packing
properties, which influences the volume of powders during manufacture process. Any
24
interference with the uniformity of fill volumes may alter the mass of the drug incorporated into
the tablet and reduce the content uniformity. To avoid such problems, the particle size should be
defined during formulation and must be as uniform as possible. [33]
There are many different methods available for particle size analysis. The most common
techniques used in tablet production and raw material processing include sieving, optical
microscopy in conjunction with image analysis, electron microscopy, laser diffractometers and
etc. The particle size measurement method depends on the approximate particle size range. [36]
1.4.1.1. Optical microscopy
Direct measurement of particle dimensions is possible from enlarged photographic or
electronic images of microscopes. There are three types of microscopes commonly used – the
optical microscope, the scanning electron microscope and the transmission electron microscope.
The optical microscope is used to measure particles from 1 µm to about 150 µm. The other
microscopes make use of electron beams and can be used for particles 0.01 µm to 5 µm. They
are especially useful for revealing the surface morphology of extremely small particles. Particles
to be imaged in an optical microscope are usually dispersed in a drop of viscous fluid in which
they are not soluble on a glass slide. [40] A solid particle is often characterized by a diameter.
The measurement is based on a hypothetical sphere that represents only an approximation to the
true shape of the particle. [33] The microscopic measurement technique is most suitable for
particles relatively uniform in size and granular in shape, because a large number of particles,
between 300 to 500, need to be measured to minimize statistical error. [40]
1.4.1.2. Sieve analysis
The most commonly used method for classifying powders (especially granules) is to
sieve the particles through a series of screens with standardized mesh size by sifting, swirling,
shaking or vibrating. Sieve analysis does not provide the information for the largest and the
smallest particle sizes. This analysis also does not differentiate the particle shape. The result of
sieve analysis is also dependent on the time of sieving action, the particle loading on the sieve
and sieve blinding.
Method. A weighed sample is poured into the top sieve which has the largest screen
meshes. Each lower sieve has smaller meshes than the above one. At the base is a round pan,
called receiver. A sample is shaken for a fixed time period at a given amplitude and pulse
frequency. After the shaking the material on each sieve is weighed.
25
Results. The weight of powder on each sieve can then be calculated and the particle size
distribution obtained. A mean sieved diameter is calculated. Because the weight of particles on
each sieve is determined, the mean sieved diameter represents a mass distribution. The results
are expressed by the percentage of each portion from the total amount. The sieve analysis gives a
result of an approximate value for the mean particle size. [40, 41]
1.4.2. Flowing properties
During many pharmaceutical production processes, it is necessary to transfer large
quantities of powder from one location to another in a controlled manner. For example, in
powder blending, powder filling into the dies of a tablet press, powder flow into capsules and
etc. For this reason, the powders for pharmaceuticals use must have sufficient properties of
flowing. [41] The fluidity of powder is influenced by various properties of the particles, such as
particle size and its distribution, shape and surface roughness of the particles, moisture and the
interparticle forces. The fluidity of a powder can be improved by changing its physical
properties, such as moisture content and particle size and shape, by drying, grinding,
classification and granulation. [33]
1.4.2.1. Flowability
Flowability is the ability of powder (granules) to flow in a desired manner is a specific
piece of equipment. [41] The test for flowability is intended to determine the ability of divided
solids (for example, powders and granules) to flow vertically under defined conditions.
Apparatus. According to the flow properties of the material to be tested, funnels with or
without stem, with different angles and orifice diameters are used (see Table 4). Typical
apparatuses are shown in Figure 10. The funnel is maintained upright by a suitable device. The
assembly must be protected from vibrations.
Method. Into a dry funnel, whose bottom opening has been blocked by suitable means,
introduce without compacting a test sample weighed with 0.5 per cent accuracy. The amount of
the sample depends on the apparent volume and the apparatus used. Unblock the bottom opening
of the funnel and measure the time needed for the entire sample to flow out of the funnel. Carry
out three determinations.
Results. The flowability is expressed in seconds and tenths of seconds, related to 100 g
of sample. [17]
26
Figure 10. Typical apparatus for the test of powder (granules) flowability. [17]
Table 4. The sizes of nozzles, which can be used for the flowability test. [17]
Nozzle
Diameter of the outflow opening (mm)
1
10 ± 0.01
2
15 ± 0.01
3
25 ± 0.01
1.4.2.2. Flow (Compressibility index or Hausner ratio)
The widespread use of powders in the pharmaceutical industry has generated a variety of
methods for characterizing powder flow. Four commonly reported methods for testing powder
flow are:
1. Angle of repose,
2. Compressibility index or Hausner ratio,
3. Flow rate through an orifice,
4. Shear cell.
The development of such a variety of test methods was inevitable; powder behavior is
multifaceted and thus complicates the effort to characterize powder flow. [17] In recent years the
compressibility index and the closely related Hausner ratio have become the simple, fast, and
popular methods of predicting powder flow characteristics. The compressibility index has been
proposed as an indirect measure of bulk density, size and shape, surface area, moisture content,
and cohesiveness of materials, because all of these can influence the observed compressibility
27
index. [17] Bulk or tapped density is a measure of the degree of packing or, conversely, the
amount of space between the particles in the powder. Bulk density is determined by placing a
sample of powder (granules) of known weight in a graduated cylinder. Tapped density is
determined by tapping the powder in the graduated cylinder until it no longer settles. [41] The
compressibility index and the Hausner ratio are determined by measuring both the bulk volume
and tapped volume of a powder.
Method. The basic procedure is to measure the unsettled apparent volume, (V0), and the
final tapped volume, (Vf), of the powder after tapping the material until no further volume
changes occur. The bulk and tapped densities; compressibility index and the Hausner ratio are
calculated as follows:
(1)
(2)
(3)
(4)
Results. For the compressibility index and the Hausner ratio, the generally accepted scale
of flowability is given in Table 5. [17]
Table 5. Scale of powder (granules) flowability. [17]
Compressibility index (%)
Flow character
Hausner ratio
1-10
Excellent
1.00-1.11
1-15
Good
1.12-1.18
16-20
Fair
1.19-1.25
21-25
Passable
1.26-1.34
26-31
Poor
1.35-1.45
32-37
Very poor
1.46-1.59
> 38
Very, very poor
> 1.60
28
1.4.3. Measurement of density
Density is mass per unit volume; it is expressed in grams per cm3. Density can be
measured by pycnometer. Pycnometers are used for research and quality control in such
industries as ceramics, fibers, minerals, pharmaceuticals and others. Helium-pycnometry is a
technique to obtain information on the true density of solids. Since helium, which can enter even
the smallest voids or pores and is the least adsorptive, is used to measure, the final result is often
referred to as skeletal density. [45]
Method. Turn on the helium pycnometer and open helium gas faucet. Wait till
temperature will be 20° C. Weigh a dry clean metal vessel. Add approximately 10 g of powder
(granules). Weigh a vessel with material again. Put the vessel with material into a measurement
place and close it. Enter the values of weight of empty vessel and loaded vessel. Start the
measurement.
Results. It is expressed in grams per cm3.
1.5. Tablets characterization
1.5.1. Uniformity of tablets mass
Weigh individually 20 tablets taken at random and determine the average mass. Not more
than 2 of the individual masses deviate from the average mass by more than the percentage
deviation shown in Table 6 and none deviates by more than twice that percentage.
Table 6. Tablet deviation of mass. [17]
Pharmaceutical form
Average Mass
Percentage Deviation
Tablets (uncoated and
80 mg or less
10
film-coated)
More than 80 mg and less than 250 mg
7.5
250 mg or more
5
1.5.2. Uniformity of tablets content
The test for uniformity of content of tablets is based on the assay of the individual
contents of active substance(s) of a number of single-dose units to determine whether the
individual contents are within limits set with reference to the average content of the sample.
29
Method. Using a suitable analytical method, determine the individual contents of active
substance(s) of 10 tablets taken at random.
Results. The preparation complies with the test if each individual content is between
85 % and 115 % of the average content. The preparation fails to comply with the test if more
than one individual content is outside these limits or if one individual content is outside the
limits of 75 % to 125 % of the average content. If one individual content is outside the limits of
85 % to 115 % but within the limits of 75 % to 125 %, determine the individual contents of
another 20 tablets taken at random. The preparation complies with the test if not more than one
of the individual contents of the 30 units is outside 85 % to 115 % of the average content and
none is outside the limits of 75 % to 125 % of the average content.
1.5.3. Friability of uncoated tablets
This test is for the friability determination of compressed, uncoated tablets. Measurement
of tablet friability supplements other physical strength measurements, such as tablet breaking
force.
Method. Use a drum, with an internal diameter between 283-291 mm and a depth
between 36-40 mm, of transparent synthetic polymer with polished internal surfaces, and subject
to minimum static build-up (see Figure 16). For tablets with a unit mass equal to or less than
650 mg, take a sample of whole tablets corresponding as near as possible to 6.5 g. The tablets are
carefully dedusted prior to testing. Accurately weigh the tablet sample, and place the tablets in
the drum. Rotate the drum 100 times, and remove the tablets. Remove any loose dust from the
tablets as before, and accurately weigh. Generally, the test is run once. If obviously cracked,
cleaved, or broken tablets are present in the tablet sample after tumbling, the sample fails the
test. If the results are difficult to interpret or if the weight loss is greater than the targeted value,
the test is repeated twice and the mean of the 3 tests determined.
Results. A maximum loss of mass (obtained from a single test or from the mean of 3
tests) not greater than 1.0 % is considered acceptable for most products. [17]
1.5.4. Resistance to crushing of tablets
This test is intended to determine, under defined conditions, the resistance to crushing of
tablets, measured by the force needed to disrupt them by crushing.
Apparatus. The apparatus consists of 2 jaws facing each other, one of which moves
towards the other. The flat surfaces of the jaws are perpendicular to the direction of movement.
30
The crushing surfaces of the jaws are flat and larger than the zone of contact with the tablet. The
apparatus is calibrated using a system with a precision of 1 Newton.
Method. Place the tablet between the jaws, taking into account, where applicable, the
shape, the break-mark and the inscription; for each measurement orient the tablet in the same
way with respect to the direction of application of the force. Carry out the measurement on
10 tablets, taking care that all fragments of tablets have been removed before each determination.
Expression of results. Express the results as the mean, minimum and maximum values
of the forces measured, all expressed in Newton’s. [17]
1.5.5. Dissolution test for tablets
The test is used to determine the dissolution rate of the active ingredients of tablets.
Paddle apparatus consists of:
1. a cylindrical vessel of borosilicate glass or other suitable transparent material with a
hemispherical bottom and a nominal capacity of 1000 ml ; a cover is fitted to retard
evaporation; the cover has a central hole to accommodate the shaft of the stirrer and other
holes for the thermometer and the devices used to withdraw liquid;
2. a stirrer consisting of a vertical shaft to the lower end of which is attached a blade having
the form of that part of a circle subtended by 2 parallel chords; the blade passes through
the diameter of the shaft so that the bottom of the blade is flush with the bottom of the
shaft ; the shaft is placed so that its axis is within 2 mm of the axis of the vessel and the
bottom of the blade is 25 ± 2 mm from the inner bottom of the vessel ; the upper part of
the shaft is connected to a motor provided with a speed regulator; the stirrer rotates
smoothly without significant wobble;
3. a water-bath that will maintain the dissolution medium at 37 ± 0.5 °C.
Method. Place the prescribed volume of dissolution medium in the vessel, assemble the
apparatus, warm the dissolution medium to 37 ± 0.5 °C and remove the thermometer. Place one
unit of the preparation to be examined in the apparatus. Start the rotation of the apparatus
immediately at the prescribed rate (± 4 %).
Sampling and evaluation. Withdraw at the prescribed time, or at the prescribed intervals
or continuously, the prescribed volume or volumes from a position midway between the surface
of the dissolution medium and the top of the basket or blade and not less than 10 mm from the
vessel wall. Except where continuous measurement is used with the paddle or basket method (the
liquid removed being returned to the vessel) or where a single portion of liquid is removed, add a
volume of dissolution medium equal to the volume of liquid removed or compensate by
31
calculation. Filter the liquid removed using an inert filter of appropriate pore size that does not
cause significant adsorption of the active ingredient from the solution and does not contain
substances extractable by the dissolution medium that would interfere with the prescribed
analytical method. Proceed with analysis of the filtrate as prescribed. The quantity of the active
ingredient dissolved in a specified time is expressed as a percentage of the content stated on the
label. [17]
1.6. Model Drugs
1.6.1. Caffeine
Coffeinum (Ph. Eur.)
Figure 11. Formula of Caffeine. [17]
Description. Caffeine contains not less than 98.5 % and not more than the equivalent of
101.5 % of 1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione, calculated with reference to the
dried substance. A white, crystalline powder or silky, white crystals, sublimes readily, sparingly
soluble in water, freely soluble in boiling water, slightly soluble in ethanol. It dissolves in
concentrated solutions of alkali benzoates or salicylates. [17]
Indications: drowsiness, fatigue, neonatal apnea.
Mechanism. The most excepted explanation for caffeine‘s acute effects now is adenosine
hypothesis. Adenosine is an inhibitory neurotransmitter. Caffeine and other methylxanthines
occupy adenosine receptors and block the action.
Effects. Primary action is stimulation of central nervous system activity. But there are
actions outside the CNS: contraction of striated muscle, including the heart; relaxation of smooth
muscle, especially the coronary arteries, uterus and bronchi; stimulation of gastric acid; diuretic
effect; at higher doses, a stimulating effect on respiration; elevation of basal metabolism.
Pharmacokinetics. Caffeine is rapidly absorbed from the GIT. The drug quickly reaches
the brain because it can pass through the blood-brain barrier. The half-life of caffeine in the
blood varies among people from 2.5 to 7.5 hours. Peak levels of caffeine occur 15 – 45 minutes
after the drug is taken. Caffeine is equally distributed in total body water, so the concentration of
32
the drug is similar. It is metabolized primarily in the liver and is almost entirely excreted in the
urine. [43]
1.6.2. Diltiazem Hydrochloride
Diltiazemi hydrochloridum (Ph. Eur.)
Figure 12. Formula of Diltiazem Hydrochloride. [17]
Description. DH contains not less than 98.5 % and not more than the equivalent of 101.0
%
of
(2S,3S)-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-
benzothiazepin-3-yl acetate hydrochloride, calculated with reference to the dried substance.
It is a white, crystalline powder, freely soluble in water, in methanol and in methylene chloride,
slightly soluble in ethanol. It melts at about 213 °C with decomposition. [17]
Indications: hypertension; prophylactic therapy for effort and vasospastic angina;
supraventricular tachycardia.
Mechanism. DH is a benzothiazepine calcium channel antagonist with proved
antianginal and antihypertensive efficacy. Calcium channel-blocking agents produce a blockade
of L-type (slow) calcium channels, which decreases contractile force and oxygen requirements.
DH cause coronary vasodilatation and relief of spasm; it also dilate peripheral vasculature and
decrease cardiac afterload. DH reduces the rate and contractility of the heart. Because it blocks
calcium-dependent conduction in the atrioventricular node, DH can be used to treat
atrioventricular nodal arrhythmias.
Pharmacokinetics. DH is well-absorbed orally and undergoes hepatic oxidative
metabolism. It is predominantly deacetylated into minimally active metabolite, which is then
eliminated via the biliary tract. The half-life in plasma is approximately 3.0 – 4.5 h. [44]
33
1.7. Excipients
1.7.1. Microcrystalline Cellulose
Cellulosum microcrystallinum (Ph. Eur.)
Synonyms: Avicel PH; Celex; cellulose gel; Emcocel; Tabulose and etc.
Description. MCC is purified, partially depolymerized cellulose that occurs as a white,
odorless, tasteless, crystalline powder composed of porous particles. It is practically insoluble in
water, in acetone, in ethanol, in toluene and in dilute acids. It is commercially available in
different particle sizes, moisture, flow and other physical properties. The nominal mean size of
Avicel PH-101 particle is 50 µm and moisture content is less than 5 %.
Applications. MCC is used in pharmaceuticals, first as a binder (diluent) in tablet
formulations where it is used in direct compression and wet granulation processes. MCC has also
some lubricant properties. [17, 42]
1.7.2. Magnesium Stearate
Magnesii stearas (Ph. Eur.)
Synonyms: Magnesium octadecanoate; octadecanoic acid, magnesium salt; stearic acid,
magnesium salt.
Description. MgS is a mixture of magnesium salts of different fatty acids consisting
mainly of stearic acid [(C17H35COO)2Mg; Mr 591.3] and palmitic acid [(C15H31COO)2 Mg; Mr
535.1] with minor proportions of other fatty acids. It contains not less than 4.0 % and not more
than 5.0 % of Mg (Ar 24.30), calculated with reference to the dried substance. The fatty acid
fraction contains not less than 40.0 % of stearic acid and the sum of stearic acid and palmitic acid
is not less than 90.0 %. MgS is very fine, light white, precipitated or milled, impalpable powder
of low density. It is practically insoluble in water and in ethanol. The powder is greasy to touch
and readily adheres to skin.
Applications. MgS is used as a lubricant in tablet manufacture at concentrations between
0.25 % and 5.0 %.
Comments. MgS is hydrophobic and may retard the dissolution of a drug from a tablet;
the lowest possible concentration is therefore used in manufacturing. Tablet dissolution rate and
crushing strength decreases as the time of blending increases; and MgS may also increase tablet
friability. Therefore the blending time with MgS should be controlled. [17, 42]
34
1.7.3. Colloidal Silicon Dioxide
Silica colloidalis anhydrica (Ph. Eur.)
Synonyms: Aerosil; fumed silica, Cb-O-Sil, colloidal silica and etc.
Description. Colloidal Silicon Dioxide contains not less than 99.0 % and not more than
the equivalent of 100.5 % of SiO2, determined on the ignited substance. CSD is a
submicroscopic fumed silica with a particle size of about 15 nm. It is a light, loose, bluish-white
colored, odorless, tasteless, nongritty amorphous powder. It is practically insoluble in water and
in mineral acids except hydrofluoric acid. It dissolves in hot solutions of alkali hydroxides.
Applications. Small particle size and large specific surface area give it desirable flow
characteristics that are exploited to improve the flow properties of dry powders. [17, 42]
35
2. EXPERIMENTAL PART
2.1. Drugs and excipients
Diltiazem hydrochloride, Zentiva, a.s., Czech Republic.
Caffeine, Jilin Province Shulan Synthetic Pharmaceutical Co., Ltd, China.
Avicel® PH 101 (Cellulosum microcrystalline), FMC Biopolymers, United States of America.
Eudragit® NM 30 D, Evonik Röhm GmbH, Germany.
Colloidal Silicon Dioxide, Degussa, Vicenza, Italy.
Magnesium stearate, Peter Greven, Germany
2.2. Laboratory equipment
Balance KERN 440-47, KERN & Sohn GmbH, Germany
Analytical balance KERN 870-13, KERN & Sohn GmbH, Germany
Optical microscope DN 25 Lambda, Intarcho-micro, Czech Republic
CCD camera Alphaphot-2, Nikon, Japan
Lamp Euromex Fiber Optic Light Source EK-1, Euromex Microscopes, Netherlands
High shear mixer ROTOLAB machine, Zanchetta, Italy
Drying oven Horo 048B, Dr. Ing. Hofman, Germany
Equipment for sieve analysis Retsch AS 200 basic, RETSCH GmbH & Co., Germany
Equipment to measure the flow ERWEKA SVM 102, ERWEKA GmbH, Germany
Equipment for test of flowability MEDIPO, Czech Republic
Mixer TURBULA T2C, Willy A. Bachofen, Switzerland
Helium pycnometer Pycnomatic ATC, Porotec Vertrieb von Wissenschaflichen geräten GmbH,
Germany
Tablet press KORSCH EK 0, Korsch, Germany
Tablet hardness tester C50 tablet Hardness & Compression tester, Engineering System (Notth)
United Kingdom
Friability tester ERWEKA TAR 10, ERWEKA GmbH, Germany
Dissolution paddle apparatus SOTAX AT 7 Smart, SOTAX, Switzerland
Spectrophotometer UV/VIS spectrophotometer, Perkin Elmer instruments, United States of
America.
36
2.3. Preparation of granules
2.3.1. The measurement of particle size
0.01 g of diltiazem hydrochloride were spread on a glass slide. The diameter of 100 particles was
measured using optical microscope connected with CCD camera. The same was done with
caffeine and Avicel® PH 101. The obtained data were treated statistically by means of Microsoft
Office Excel 2007 program. It was calculated the average value, the maximum and minimum
values and standard deviation.
2.3.2. Preparation of granules
It was weighted the necessary amount of model drugs, Avicel® PH 101 and 30 % aqueous
dispersion of Eudragit® NM 30 D (see Table 7 and Table 8).
Table 7. The composition of powder mixtures with diltiazem hydrochloride for granulates
preparation
Name of sample
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Diltiazem
hydrochloride (g)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
Avicel® PH 101 (g)
100
100
100
100
100
100
100
100
100
100
50
50
50
50
50
50
25
25
25
25
25
Eudragit® NM 30 D
aqueous dispersion (g)
10.5
22.2
35.3
50
66.6
85.7
107.7
107.9
130.1
152.3
7.9
16.7
26.5
37.5
50
64.3
6.6
13.9
22.1
31.25
41.7
37
Table 8. The composition of powder mixtures with caffeine for granulates preparation
Name of sample
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
Caffeine (g)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
Avicel® PH 101 (g)
100
100
100
100
100
100
100
50
50
50
50
50
50
50
25
25
25
25
25
25
25
25
25
25
Eudragit® NM 30 D
aqueous dispersion (g)
10.5
22.2
35.3
50
66.6
85.7
107.9
7.9
16.7
26.5
37.5
50
64.3
81
6.6
13.9
22.1
31.25
41.7
53.6
55.6
67.5
81.4
95.3
Granulates were prepared in high-shear mixer ROTOLAB (see Figure 13). The highshear mixer been set like this: impeller pause time – 0 sec, impeller working time – 300 s, cycle
time – 300 s, impeller speed – 1200 Rpm. Diltiazem hydrochloride and Avicel PH 101 was
mixed for first 30 sec without polymer, then other 30 seconds the binder liquid was added
manually and the mixture was blended for 240 s. The mixture was passed through 1.25 mm mesh
sieve and granules were dried for 24 h at 40° C in a drying oven. After drying granules were
passed trough 1.25 mm sieve again. The granulation of batches with Eudragit® NM 30 D
(aqueous dispersion) amount till 30 % from the mass of granulation (in case of 1-7, 11-21, 22-27,
29-34 samples) or 25 % (in case of 36-40 samples) was made by one step. The granulation with
higher amount of Eudragit® NM 30 D (8-10, 28, 35, 41-45 samples) was made by several steps.
First step it was adding 25 % (or 30 %) of Eudragit® NM 30 D, passing through the sieve,
drying. The second step it was adding next 10 % portion of Eudragit® NM 30 D to the granules,
passing through the sieve, drying. If it was necessary third and fourth granulation step (next 10
% portion of Eudragit® NM 30 D) was made till desired concentration of Eudragit® NM 30 D.
38
The granulation by steps helps to avoid to over wet of granules. The obtained granules were
tested to determine their suitability for tablet compression process.
Figure 13. High-shear mixer ROTOLAB.
2.4. Evaluation of granules quality parameters
2.4.1. Determination of granules flowability
100 g of sample was introduced without compacting into a dry funnel, whose bottom
opening blocked by suitable means. Nozzle Nr. 3 (25 mm) was used. The bottom opening was
unblocked and the time needed for the entire sample to flow was measured. Test of flowabilty
was repeated three times. Results were expressed in seconds and tenths of seconds. The samples,
which were not flowing at all, were not tested by other tests.
2.4.2. Determination of granules flow (Compressibility index and Hausner ratio)
This test is intended to determine under defined conditions the apparent volumes, before
and after settling, the ability to settle and the apparent densities of granules. [17] Samples of
granules which did not had the necessary flowability were not tested.
Into the dry 100 ml cylinder it was introduced without compacting approximately 35 g of
sample. The unsettled apparent volume (V0) was read to the nearest milliliter. 1250 taps was
39
made by ERWEKA apparatus and the final tapped volume was read to the nearest milliliter. This
test was repeated three times to avoid inaccuracy.
The results were calculated and expressed as the average of bulk density, tapped density,
compressibility index and Hausner ratio and standard deviation according to 1, 2, 3, 4 formula
(see Page 28).
2.4.3. Determination of density using helium-pycnometer
It was determined the real density of granules samples which had necessary flowability.
The helium-pycnometer POROTEC was turned on. A dry metal vessel was weighted accurately
using the analytical balance. It was filled approximately 10.0 g of sample and it was weighted
again accurately. The vessel with sample was placed into a chamber. The helium gauge was
opened. The weight of empty and loaded vessel were entered to the helium-pycnometer. When
the temperature was 20° C, the measurement was started. Results were expressed as density
(g/cm3) and it was calculated standard deviation.
2.4.4. Determination of granules size using sieve analysis
Sieve analysis was used to determine the percentage of size distribution of granules
particles. Batches of granules which did not had necessary flowability were not tested. 100 g of
sample were sieved for 10 min and 60 amplitude on a set of sieves with meshes sizes from 1.25,
1.00, 0.8, 0.5, 0.25, 0.125 and 0.08 mm using a vibrating sieving equipment. The results were
expressed as percents of granules portions.
2.5. Preparation of matrix tablets
2.5.1. Preparation of granules for compressing
After tests to determine the suitability of granules for compressing were selected samples
which have necessary properties for preparing tablets. After sieve test the granules were not
homogenous, so they were mixed for 2 min in TURBULA. Then it was added 0.5 % MgS and
0.5 % CSD from the weight of granules to each sample (see Table 9 and 10). CSD was passed
through 1.25 mm sieve, because the powder was not homogenous, it had some agglomerates.
Granules with excipients were blended for 5 min in TURBULA.
40
2.5.2. Compression of matrix tablets
The samples were pressed into a matrix tablets using eccentric tablet press KORSCH, it
was used 10 mm punches. Tablets were made like that, that each tablet would contain 100 mg
model drug. The composition of matrix tablets is shown in Table 12 and Table 13.
Table 9. The composition of matrix tablets with diltiazem hydrochloride.
Sample
Diltiazem
hydrochloride (mg)
Avicel® PH
101 (mg)
Eudragit® NM
(mg)
Magnesium
Stearate (mg)
Colloidal
Silicon Dioxide
1D
2D
3D
4D
5D
6D
7D
8D
9D
10D
11D
12D
13D
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
50
50
50
50
25
25
25
15
19,98
25,71
32,37
39,03
45,69
7,95
11,25
15
19,29
6,63
9,375
12,51
1,085
1,11
1,14
1,17
1,21
1,24
0,8
0,8
0,83
0,86
0,66
0,68
0,7
1,085
1,11
1,14
1,17
1,21
1,24
0,8
0,8
0,83
0,86
0,66
0,68
0,7
(mg)
Table 10. The composition of matrix tablets with caffeine
Sample
1C
2C
3C
4C
5C
6C
7C
8C
9C
10C
11C
12C
13C
14C
15C
16C
17C
Caffeine
(mg)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
Avicel® PH
101 (mg)
100
100
100
100
50
50
50
50
50
25
25
25
25
25
25
25
25
Eudragit® NM
(mg)
15
19,98
25,71
32,37
7,95
11,25
15
19,29
24,3
6,63
9,375
12,51
16,08
16,68
20,25
24,42
28,59
Magnesium
Stearate (mg)
1,085
1,11
1,14
1,17
0,8
0,8
0,83
0,86
0,88
0,66
0,68
0,7
0,71
0,72
0,73
0,75
0,78
Colloidal
Silicon Dioxide
(mg)
1,085
1,11
1,14
1,17
0,8
0,8
0,83
0,86
0,88
0,66
0,68
0,7
0,71
0,72
0,73
0,75
0,78
41
2.6. Evaluation of quality parameters of matrix tablets (Ph. Eur.)
2.6.1. Uniformity of tablet mass
It was weighted individually 20 tablets taken at random from each tablet set by the
analytical balance. It was determined the average mass value expressed by milligrams, the
deviation of ±7.5 % from average mass and standard deviation.
2.6.2. Uniformity of tablet content
The uniformity of tablet content was determined by spectrophotometric method
measuring the absorbance of sample. UV/UVIS spectrophotometer Perkin Elmer instruments
was used for the measurement. The wavelength to measure the absorbance was 237 nm for
samples with diltiazem hydrochloride and 275 nm for samples with caffeine. It was taken 10
tablets by random from each sample. Each tablet was crushed and approx. 50 mg of the powder
was quantitatively transferred into 100 ml flask and it was filled with distilled water till the line.
After 24 hours 1 ml of solution was taken and transferred into other 100 ml flask and filled with
distilled water till the line again and the solution was mixed. The concentration of solution was
0.0001 g/l. The sample was filtrated and then the absorbance was measured. 100 mg model drug
(diltiazem hydrochloride or caffeine) was taken to prepare the standard solution. It was dissolved
in 100 ml distilled water. After 24 hours 1 ml of solution was transferred into 100 ml flask and it
was filled with distilled water till 100 ml. The concentration of standard was 0.0001 g/l. The
standard solution was filtrated before measurement.
The content of model drug in tablets was calculated according to the formula 5:
X
Asa  mtbl  mst  d sa
Ast  msa  d st
(5)
where:
X – drug amount in tablet (g),
Asa – absorbance of studied solution,
Ast – absorbance of standard solution,
mtbl – mass of tablet (g)
dsa – dilution of tested sample
dst – dilution of standard sample
msa – mass of tested sample (g)
42
mst – mass of tested sample (g)
The average content of model drug from in each sample was calculated of 10
measurement values and the deviation of ±15 % from the each average content. The results were
expressed by the average value and standard deviation.
2.6.3. Friability of tablets
The sample for test was taken by random from each tablet set. The tablets were
accurately degusted before weighting. The sample weight was near as possible to 6.5 g. The
sample was placed into a friability apparatus ERWEKA drum. The drum was rotated 100 times
for 4 minutes (25 rotations per minute). The tablets were removed from the drum; sample was
cleaned from the dust as before and accurately weighted by the analytical balance. Test for each
sample was made once. The sample mass was expressed in milligrams. Abrasion of tablets was
expressed as the percentage loss from the initial mass of sample.
2.6.4. Resistance to crushing of tablets (Hardness of tablets)
It was taken 10 tablets by random from each sample. Tablets hardness was measured
using C50 Tablet & Compression Tester. Tablet was placed in the radial direction between jaws
of apparatus for automatic measurement. After measurement all fragments of tablet is removed
by brush. Results were expressed as the average, minimum and maximum values in Newton of
the used force.
2.6.5. Determination of released drug from matrix tablet
The dissolution test was proceeded in paddle apparatus SOTAX AT7 Smart, which is the
part of automatic dissolution line. The dissolution medium was selected phosphate buffer
solution pH 6.8 R1 (Ph. Eur.). It consists from 51.0 ml of a 27.2 g/l solution of potassium
dihydrogen phosphate and 49 ml of a 71.6 solution of disodium hydrogen phosphate.
It was measured 1000 ml of dissolution medium in each cylindrical vessel, which were
placed into a water-bath that is maintaining the temperature of dissolution medium at 37 ± 0.5
°C. Individual tablets automatically fell to the bottom of vessel. The speed of stirrer was 100
rounds per minute. The sample of dissolution medium with released model drug was taken
automatically at the time intervals 30, 60, 120, 180, 240, 300, 360, 420, 480, 540, 600, 660 and
720 minutes. The amount of released model drug was measured by UV/UVIS spectrophotometer
Perkin Elmer instruments. The amount of released drug in the prescribed time interval was
expressed by percents.
43
The dissolution test with continual pH change was performed at 37±0.5 ◦C in 900 ml of
buffer with pH 1.2 (artificial gastric juice – AGJ) for 2 hours. Sodium triphosphate was used as
the pH increasing agent. After 2 hours interval, the pH value was changed to 6.8 by adding of
18.7 g of sodium triphosphate for following 10 hours. The stirring rate was of 100 rpm.
44
3. RESULTS AND DISCUSSION
3.1. Preparation of granules
Two drugs were selected as the model drugs: freely soluble in water diltiazem
hydrochloride and sparingly soluble in water caffeine. Microcrystalline cellulose was used as the
insoluble diluent. DH, C and MCC particle size were evaluated by image analysis (optical
microscope connected to CCD camera). The particle size distribution of model drugs and MCC
are shown in Figures 15, 17, 19 and their stereomicroscopic photographs in Figures 14, 16, 18.
The main fraction (66.5 %) of DH particles size was between 41 and 80 µm, 18 % of particles
were smaller than 40 µm, 15 % of particles were between 81 and 120 µm and less than 1% of
particles were bigger than 121 µm. Differences of DH particle size and its distribution were more
significant than C or MCC particles. The main fraction (53 %) of C particles size was between
41 and 80 µm, 15.5 % of particles were smaller than 40 µm, 23 % of particles are 81-120 µm and
10.5 % of particles were bigger than 121 µm. The size distribution of C and MCC particles was
more uniform in all intervals in comparison with DH particles size distribution. The size
distribution of C particles differed from MCC one in amount particles bigger than 121 µm. The
uniformity of particles size distribution (between DH and MCC or C and MCC) ensured
tantamount mixing during the technological processes.
It was prepared three DH sets which differed by the ratio of model drug and MCC, the
ratio between DH and MCC was 1:1, 2:1 and 4:1. Sets of C were made according to the same
ratio. Wet granulation was performed in high shear mixer by adding of different amount of
Eudragit® NM 30 D (for composition see Tables 7 and 8). Less than 10 % amount Eudragit® of
NM 30 D aqueous dispersion did not ensure the formation of DH and MCC or C and MCC
granules, because the amount of binder was too low. The granulation with more than 30 %
amount of Eudragit® NM 30 D was made by several steps to avoid forming of wet mass which
can not be meshed through the sieve. By first step of study, maximal amount of polymer was 30
% (aqueous dispersion) in granules of all sets DH and C. Granules were evaluated, then matrix
tablets were pressed, evaluated by test of Ph. Eur., but drug release was too fast. Trend between
the amount of drug and MCC and polymer was observed and one set with DH and one set with C
have been extended with adding higher amount of Eudragit® NM 30 D. Total it was made 21 DH
and 24 C different granulates.
45
3.2. Results of granules evaluation
The flowability time of DH or C granules is relatively small, so it provides good filling of
dies during tablet manufacturing. The flowability of DH different granules is quite similar. The
flowability of samples, which ratio between DH and MCC was 1:1 (1D – 6D, see Figure 20),
differed less than 1 second. The same time differences were found between samples with ratio
DH and MCC 2:1 (7D – 10D see Figure 21) or 4:1 (11D – 13D see Figure 22). Increasing
amount of Eudragit® NM in granules did not provide the significant change of flowability time
but low decrease of flowability time was observed as the trend. The amount of MCC was not
significant parameter for flowability. Almost the same difference of flowability time (less than
1.5 second) of C granules batches with different amount of MCC, so the amount of MCC did not
influence time. Higher amount of Eudragit® NM in C granules did not provide significant
changes too. The flowability time was observed to be slightly lower with increasing
concentration of Eudragit® NM.
The flow character of DH granules sets varied from passable to excellent. In all DH sets
of samples flow character reached “excellent” rating, so the ratio between DH and MCC is not
most important parameter (see Table 13). The main influence had the amount of Eudragit® NM.
Samples having low concentration of Eudragit® NM had higher compressibility index than
samples with high concentration. Probably this is due to the bigger size of prepared granules and
physicochemical properties of DH. It is well known that the higher proportion of a binder used
for granulation process leads to the enlargement of granulate particle diameter [46]. Large
granules possess better flow properties and it ensures good die filling during tablet manufacture.
The flow character of C granules sets varied not much (see Table 14). In first set of C granules
(ratio between C and MCC is 1:1) flow character is passable, in second set (ratio of C and MCC
is 2:1) flow character changed from passable till fair and in the third set (ratio of C and MCC is
4:1) flow character changes from passable till fair. Probably compressibility index was
influenced by the amount of Eudragit® NM and physicochemical properties of C. Higher amount
of polymer improve flow character of C granules [34]. Different physicochemical properties of
DH and C lead to a different Hausner ratio of these drugs granules, when the amount of MCC
and Eudragit® NM is the same in granules. DH granules possess better flow character than C
granules. This fact could be caused by very poor flow properties of starting material – caffeine.
A flow rate is lower than 10 mg/s. [46] For this reason, granules of C possess worse flow
properties than DH granules.
46
Pycnometric density of DH granules decreased in all sets of samples. Amount of polymer
influence and MCC influence this. Density decrease was probably due to higher amount of
Eudragit® NM which led to bigger and thicker granules formation with higher air amount.
Granules having lower quantity of MCC possessed lower density than samples with higher
amount of MCC. The same trend was observed between the amount of polymer and MCC and
density of C. Pycnometric density of all C granules was higher than DH ones. For results of
pycnometric density see Table 15 for DH granules and Table 16 for C granules.
Size of DH granules was influenced by amount of Eudragit® NM. Samples with small
concentration of polymer had bigger amount of small size granules (from 0,125 mm and smaller)
and samples with higher amount of Eudragit® NM had little amount of small size granules.
Higher amount of polymer led to formation of bigger granules. The same trend was observed in
the case of C granules (see Table 17 and 18). Results of granules evaluation could be considered
as similar between DH and C.
3.3. Results of tablets evaluation
The weights of all DH and C matrix tablets were in accordance with the European
Pharmacopoeia limits (see Table 19 and 20). This is due to good flowing properties of granules.
The model drugs content in matrix tablets were between limits of European
Pharmacopoeia (see Table 19 and 20) with maximal SD 5.87.
All matrix formulations were compliant with official friability limit. The friability was
very small, it was less than 0,1 % for DH matrix tablets (see Table 21) and less than 0,2 % for C
tablets (see Table 22). No significant differences between samples friability were observed.
Hardness of DH matrix tablets were from 107,27 N (11D) to 161,13 N (6D). Lower
amount of polymer in tablets led to similar hardness of tablets in a set and small deviation from
average value. Higher amount of Eudragit® NM in tablet composition resulted in improving of
tablet mechanical properties (see Figure 26). Tablet with high percentage of polymer was
resistance to crushing, first it deformed and when the crushing force became critical tablet
cracks. For this reason the deviation from average value was high among samples of set.
Hardness of C matrix tablets were from 107,71 N (1C) to 134,46 (15C) - see Figure 27. Higher
amount of Eudragit® NM led to higher standard deviation values of hardness average mean
between samples of set. C matrix tablets are not so plastic as DH matrix tablets and this is due to
different physicochemical properties of drug.
47
Compression force of DH tablets (see Figure 28) was various depending from drug and
MCC ratio. Sets with lower amount of MCC needed higher compression force to produce tablets
with similar hardness in comparison with samples with higher amount of MCC, for example the
compression force of 1D is 10,53 kN and average of tablet hardness is 108,11 N, compression
force of 11D is 31,59 kN and average of tablet hardness is 107,27 N. The amounts of polymer in
tablets and their hardnesses were similar, but compression forces were different. So the ratio
between drug and MCC is crucial parameter for compression force. There is the same trend
observed with compression force of C tablets (see Figure 29). Higher compression force was
necessary to be used to achieve similar hardness of tablets with low amount of MCC comparing
with samples having higher amount of MCC. This is due to good compressibility properties of
MCC, which reduces the total compression force. In general, compression force of C tablets is
lower than compression of DH tablets.
Results of tablet evaluation are similar between DH and C matrix tablets.
The dissolution profile of DH matrix tablets was various depending from amount of
MCC and Eudragit® NM (see Figure 30, 31, 32, 33). The dissolution rate of samples with low
amount of polymer is fast, due to insufficient layer thickness of matrix. Increasing amount of
Eudragit® NM in matrix tablet showed more satisfactory retardation of drug release. Ratio
between DH and MCC is also important parameter for matrix formulation. When ratio was 1:1
dissolution profile was more gradual. Burst effect defined as the faster drug release from tablet
surface in the beginning of dissolution [39], was high in all samples (about 30 %), so it would be
recommended to coat these tablets to make dissolution profile more gradual.
The dissolution profile of C matrix tablets was unexpected, because almost all samples of
tablets disintegrated during first hours and did not show almost any retardation of drug release
(see Figure 34, 35, 36, 37, 39). This is probably due to physicochemical properties of drug
components. C is slightly soluble in water, MCC is almost insoluble in water and Eudragit® NM
is insoluble too, so it can cause disintegration of tablets. One sample (14C) showed retardation of
C release. The same sample of 14C tablet was prepared twice using the same components to
avoid mistakes. Both samples of 14C demonstrated similar dissolution profile. So it is optimal
amount of polymer and MCC for C matrix tablet. In future study, it could be recommended to
use other diluent not MCC. Samples which showed optimal release profile (4D, 5D and 14C)
were tested with dissolution test with continual pH change for 2 hours at pH 1.2 and later at pH
6.8 (see Figure 39, 40). The release profile was to fast at pH 1.2, so tablets are recommended to
coat acidoresistant coating (Eudragit® L 30 D).
48
CONCLUSIONS
1. Wet granulation method using high-shear mixer and Eudragit® NM 30 D is suitable to
produce DH and C granules.
2. It was found, that minimal amount of polymer has to be 5 %, which ensures forming of
granules possessing suitable properties for tablets manufacturing.
3. Eudragit® NM is suitable for manufacturing of DH and C matrix tablets, which are in
accordance with limits of tablet test of Ph. Eur.
4. It was found optimal amount of MCC and polymer in tablets, which leads to gradual
release of drug for 12 hours at pH 6.8. In case of DH, the ratio between drug and MCC
has to be 1:1 and contain 13 – 16 % of polymer in tablet. In case of C, the ratio has to be
4:1 and contain 12 % of Eudragit® NM in tablet.
49
REFERENCES
1. McGinity JW, Felton LA. Aqueous polymeric coatings for pharmaceutical dosage forms.
3rd ed. New York: Informa Healthcare USA; 2008. 109, 238, 258, 267
2. Moustafine RI, Kabanova TV, Kemenova VA, Mooter GV. Characteristics of
interpolyelectrolyte complexes of Eudragit E100 with Eudragit L100. J. of Control.
Release 103 (2005) 191-198.
3. Eudragit® product brochure. Available at:
http://www.pharma-polymers.com/NR/rdonlyres/3D19A053-7628-41B1-BC52123763B75566/0/090821FinalEUDRAGIT_online.pdf
4. Specifications and test methods for Eudragit® L 30 D-55. Available at:
http://www.pharmapolymers.com/pharmapolymers/MCMSbase/Pages/ProvideResource.a
spx?respath=/NR/rdonlyres/63F690A0E7834936B2D0676A82FD102B/0/INFO705_E_L
30D55.pdf
5. Specifications and test methods for Eudragit® 100-55. Available at:
http://www.pharmapolymers.com/pharmapolymers/MCMSbase/Pages/ProvideResource.
aspx?respath=/NR/rdonlyres/A6B556A563D141D4BF73CD75DD83955C/0/INFO704_
E_L10055.pdf
6. Specifications and test methods for Eudragit® L 100 and Eudragit® S 100. Available at:
http://www.pharmapolymers.com/pharmapolymers/MCMSbase/Pages/ProvideResource.
aspx?respath=/NR/rdonlyres/E90B3F4073254E2283D3285B42CC601B/0/INFO703_E_
L100_S100.pdf
7. Specifications and test methods for Eudragit® L 12,5 and Eudragit® S 12,5. Available at:
http://www.pharmapolymers.com/pharmapolymers/MCMSbase/Pages/ProvideResource.a
spx?respath=/NR/rdonlyres/A2C6A670873F45BAA5A85C2109A731DB/0/INFO708_E
_RL125_RS125.pdf
8. Specifications and test methods for Eudragit® FS 30 D. Available at:
http://www.pharmapolymers.com/pharmapolymers/MCMSbase/Pages/ProvideResource.
aspx?respath=/NR/rdonlyres/EA96FF4EBB7441488E29631B73E3B6F0/0/Specification
FS30D_xeri21B86.pdf
9. Specifications and test methods for Eudragit® RL 100 and Eudragit® RL PO, Eudragit®
RS 100 and Eudragit® RS PO. Available at: http://www.pharmapolymers.com/pharmapolymers/MCMSbase/Pages/ProvideResource.aspx?respath=/Rdo
50
nlyres/6B60AAA0CD0D49D69FCFB4F6CC2F736D/0/INFO707_E_RL100_RLPO_RS
100_RSPO.pdf
10. Specifications and test methods for Eudragit® RL 30 D and Eudragit® RS 30 D.
Available at:
http://www.pharmapolymers.com/pharmapolymers/MCMSbase/Pages/ProvideResource.
aspx?respath=/NR/rdonlyres/AAF66925A5854D20836BD9D99F1EDC9A/0/INFO709_
E_RL30D_RS30D.pdf
11. Specifications and test methods for Eudragit® RL 12,5 and Eudragit® RS 12,5.
Available at:
http://www.pharmapolymers.com/pharmapolymers/MCMSbase/Pages/ProvideResource.
aspx?respath=/NR/rdonlyres/A2C6A670873F45BAA5A85C2109A731DB/0/INFO708_
E_RL125_RS125.pdf
12. Specifications and test methods for Eudragit® NE 30 D. Available at:
http://www.pharmapolymers.com/pharmapolymers/MCMSbase/Pages/ProvideResource.
aspx?respath=/NR/rdonlyres/343EEF663DDC4C29BDFD31600B26A183/0/INFO706_
E_NE30D.pdf
13. Specifications and test methods for Eudragit® NE 40 D. Available at:
http://www.pharmapolymers.com/pharmapolymers/MCMSbase/Pages/ProvideResource.
aspx?respath=/NR/rdonlyres/94E67D3937304BC58F642692B0939495/0/INFO71_E_N
E40D.pdf
14. Specifications and test methods for Eudragit® NM 30 D. Available at:
http://www.pharmapolymers.com/pharmapolymers/MCMSbase/Pages/ProvideResource.
aspx?respath=/NR/rdonlyres/348C25416BFD4A17AA66A389111FCEA4/0/INFO714_
E_NM30D.pdf
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targeting technology. New York: Marcel Dekker; 2001. 1,6
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evaluation of higly pH-responsive acrylic microparticles for targeted gastrointestinal
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19. Fan TY, Wei SL, Yan WW, Chen DB, Li J. An investigation of pulsatile release tablets
with ethylcellulose and Eudragit L as film coating materials and cross-linked
polyvinylpyrrolidone in the core tablets. J. of Control. Release 77 (2001) 245; 245-251
20. Chan WA, Boswell CD, Zhang Z. Comparison of the release profiles of a water soluble
drug carried by Eudragit-coated capsules in different in-vitro dissolution liquids. Powder
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21. Ibekwe VC, Fadda HM, Parsons GE, Basit AW. A comparative in vitro assessment of
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swelling studies on free films containing inulin in combination with different
polymethacrylates aimed for colonic drug delivery. European Journal of Pharmaceutical
Sciences 28 (2006) 307-314.
24. El-Malah Y, Nazzal S. Novel use of Eudragit® NE 30 D/Eudragit® L 30D-55 blends as
functional coating materials in time-delayed drug release applications. International
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35. Eudragit® 3-Day Workshop. Hot Melt Extrusion & Modified Release Applications.
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http://www.pharmapolymers.com/pharmapolymers/MCMSbase/Pages/ProvideResource.
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pgs8x11forEmailFallWorkshops.pdf
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Candidate Drug Selection to Commercial Dosage form. Boca Raton; CRC Press; 2004.
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54
ADDITION Nr. 1
Figure 14. Stereomicroscopic photographs of diltiazem hydrochloride particles.
Figure 15. The particle size distribution of diltiazem hydrochloride.
55
Figure 16. Stereomicroscopic photographs of caffeine particles.
Figure 17. The particle size distribution of caffeine.
56
Figure 18. Stereomicroscopic photographs of Avicel® PH 101.
Figure 19. The particle size distribution of Avicel® PH 101 particles.
57
ADDITION Nr. 2
Figure 20. Flowability of granule’s mixture consisting of DH and MCC in ratio 1:1 and different
amounts of NM 30D.
Figure 21. Flowability of granule’s mixture consisting of DH and MCC in ratio 2:1 and different
amounts of NM 30
3
2,5
Time (s)
2
1,5
1
0,5
0
7D
8D
9D
10D
Sample
58
Figure 22. Flowability of granule’s mixture consisting of DH and MCC in ratio 4:1 and different
amounts of NM 30D.
3
2,5
Time (s)
2
1,5
1
0,5
0
11D
12D
13D
Sample
Table 11. Standard deviation of flowability test accomplished with mixture of granules consisting
DH, MCC and NM 30 D.
Sample SD (s)
0,04
1D
0,04
2D
0,01
3D
0,01
4D
0,02
5D
0,01
6D
0,06
7D
0,03
8D
0,02
9D
0,02
10D
0,02
11D
0,02
12D
0,01
13D
59
Figure 23. Flowability of granule’s mixture consisting of C and MCC in ratio 1:1 and different
amounts of NM 30D.
3,5
3
2,5
Time (s)
2
1,5
1
0,5
0
1C
2C
3C
4C
Sample
Figure 24. Flowability of granule’s mixture consisting C and MCC in ratio 2:1 and different
amounts of NM 30D.
3,5
3
Time (s)
2,5
2
1,5
1
0,5
0
5C
6C
7C
8C
9C
Sample
60
Figure 25. Flowability of granule’s mixture consisting C and MCC in ratio 4:1 and different
amounts of NM 30D.
3,5
3
Time (s)
2,5
2
1,5
1
0,5
0
10C
11C
12C
13C
14C
15C
16C
17C
Sample
Table 12. Standard deviation of flowability test accomplished with mixture of granules consisting
C, MCC and NM 30 D.
Sample
1C
2C
3C
4C
5C
6C
7C
8C
9C
10C
11C
12C
13C
14C
15C
16C
17C
SD (s)
0,08
0,02
0,02
0,02
0,03
0,01
0,03
0,03
0,02
0,03
0,02
0,02
0,02
0,01
0,01
0,01
0,02
61
Table 13. Flow test results: Hausner ratio and compressibility index calculations of prepared
granules with diltiazem hydrochloride.
Sample
m
(g)
V0
(ml)
Vf
(ml)
ρbulk
(g/ml)
ρtapped
(g/ml)
1D
34,9
93
75,3
0,375
0,463
1,23
18,99
SD
0
1
0,6
0,004
0,004
0,01
0,46
2D
34,9
93
80
0,376
0,437
1,16
13,97
Hausner Compressibility
ratio
index (%)
SD
0,1
1
1
0,004
0,006
0,02
1,72
3D
35
92
80,7
0,38
0,434
1,14
12,32
SD
0
1
1,5
0,004
0,008
0,01
0,75
4D
35
82
72,3
0,427
0,484
1,13
11,78
SD
0,1
1
0,6
0,004
0,004
0,02
1,28
5D
35,3
81,3
70,7
0,435
0,5
1,15
13,11
SD
0,1
0,6
0,6
0,004
0,004
0,01
0,67
6D
35,1
79
71,3
0,444
0,492
1,11
9,7
SD
0,2
1
1,5
0,005
0,008
0,02
1,89
7D
34,3
77,3
59
0,444
0,581
1,31
23,68
SD
0,7
2,3
1
0,008
0,002
0,02
1,32
8D
37,8
95
80,3
0,398
0,471
1,18
15,43
SD
0,2
1
0,6
0,003
0,004
0,02
1,07
9D
34,1
90,3
80,7
0,378
0,423
1,12
10,7
SD
0,1
0,6
0,6
0,002
0,003
0,01
0,61
10D
33,8
92
85,7
0,368
0,395
1,07
6,862
SD
0,3
2
1,5
0,009
0,01
0,02
2,19
11D
34,1
81,7
68,3
0,417
0,499
1,2
16,3
SD
0,4
2,1
0,6
0,006
0,003
0,02
1,45
12D
34,9
88,3
79,3
0,395
0,439
1,11
10,19
SD
0,3
0,6
0,6
0,003
0,003
0
0,07
13D
34,4
88,3
83,3
0,39
0,413
1,06
5,66
SD
0,3
2,1
2,1
0,005
0,006
0
0,13
Flow
character
Fair
Good
Good
Good
Good
Excellent
Passable
Fair
Good
Excellent
Fair
Good
Excellent
62
Table 14. Flow test results: Hausner ratio and compressibility index calculations of prepared
granules with caffeine.
Sample
m
(g)
V0
(ml)
Vf
(ml)
ρbulk ρtapped Hausner Compressibility
(g/ml) (g/ml)
ratio
index (%)
1C
36,4
80,7
61,3
0,451
0,593
1,32
23,97
SD
0,2
0,6
0,6
0,002
0,004
0,01
0,65
2C
36,6
84,3
66,3
0,434
0,552
1,27
21,34
SD
0,2
0,6
0,6
0,001
0,003
0
0,15
3C
36,9
89,3
70,3
0,413
0,525
1,27
21,26
SD
0,2
1,2
0,6
0,004
0,002
0,01
0,89
4C
35,4
79,7
63,3
0,445
0,559
1,26
20,5
SD
0,2
1,2
0,6
0,005
0,003
0,01
0,42
5C
35,7
77,7
59
0,46
0,605
1,32
24,03
SD
0,1
1,2
1
0,006
0,009
0,01
0,65
6C
37,4
85
66
0,44
0,567
1,29
22,36
SD
0,2
1
1
0,003
0,006
0
0,26
7C
35,5
81,7
64,7
0,434
0,548
1,26
20,82
SD
0,2
0,6
0,6
0,002
0,004
0
0,15
8C
36,6
84
67,3
0,435
0,543
1,25
19,84
SD
0,1
1
0,6
0,006
0,005
0,01
0,5
9C
36,2
80,3
66,7
0,451
0,544
1,21
17,02
SD
0,1
0,6
1,2
0,003
0,009
0,01
0,84
10C
36,6
77,3
60
0,474
0,611
1,29
22,39
SD
0,2
1,5
0
0,007
0,003
0,03
1,52
11C
37,1
81
64,3
0,458
0,577
1,26
20,57
SD
0,2
1
0,6
0,004
0,003
0,01
0,51
12C
36,1
77,7
63,3
0,464
0,569
1,23
18,45
SD
0,2
1,2
0,6
0,006
0,004
0,01
0,47
13C
40,1
86
76,3
0,467
0,526
1,13
11,25
SD
0,5
1,7
2,1
0,004
0,008
0,01
0,81
14C
37,3
80
68,3
0,466
0,545
1,17
14,57
SD
0,2
1
0,6
0,004
0,005
0,02
1,28
15C
38,7
79,7
68
0,485
0,569
1,17
14,65
SD
0,3
0,6
1
0,003
0,004
0,01
0,78
16C
39,4
81
70,7
0,486
0,557
1,15
12,75
SD
0,8
1,7
1,2
0,003
0,004
0,01
0,43
17C
38,9
84
74,7
0,463
0,521
1,12
11,11
SD
0,4
1
0,6
0,002
0,004
0,01
0,57
Flow
character
Passable
Passable
Passable
Passable
Passable
Passable
Passable
Fair
Fair
Passable
Passable
Fair
Good
Good
Good
Good
Good
63
Table 15. Pycnometric density of granules consisting of DH, MCC and NM 30D.
Sample
1D
2D
3D
4D
5D
6D
7D
8D
9D
10D
11D
12D
13D
Density
g/cm3
1,4126
1,4099
1,3918
1,3911
1,3786
1,3727
1,3634
1,3633
1,3630
1,3539
1,3424
1,3384
1,3318
SD
g/cm3
0,0002
0,003
0,0016
0,0016
0,0012
0,0015
0,0772
0,0229
0,0011
0,0003
0,0012
0,0011
0,0015
Table 16. Pycnometric density of granules consisting of C, MCC and NM 30D.
Sample
1C
2C
3C
4C
5C
6C
7C
8C
9C
10C
11C
12C
13C
14C
15C
16C
17C
Density
g/cm3
1,4684
1,4624
1,4454
1,4357
1,4582
1,4507
1,4481
1,4345
1,4241
1,4347
1,4328
1,4266
1,4351
1,4229
1,4285
1,4192
1,4210
SD
g/cm3
0,0026
0,0030
0,0013
0,0008
0,0013
0,0025
0,0016
0,0019
0,0024
0,0009
0,0037
0,0003
0,0015
0,21
0,0028
0,0030
0,038
64
Table 17. Granules consisting of DH, MCC and NM 30D size distribution.
Sample
1D
2D
3D
4D
5D
6D
7D
8D
9D
10D
11D
12D
13D
> 1,25
mm
0
0,1
0
0,1
0
0
0
0
0
0,1
0
0,1
0
1,25 1,0 mm
2,7
2,9
2,3
5,7
2,7
4,2
1,7
3,4
3,7
6,4
3,4
8,8
5,5
Size distribution of granules %
1,0 0,8 0,5 0,25 0,8 mm
0,5 mm 0,25 mm 0,125 mm
9
14,5
13,3
23,4
9,4
16,8
15,9
26,6
7,6
16,9
22
30,8
14,9
32,1
33,7
7,6
9,6
19
22,3
35,3
11,7
21,3
23,7
31
8,6
15,7
15,1
17,4
10,3
16,9
17,6
25,6
12
22,2
29,8
26,6
14,6
30,6
3,4
8,9
9,6
17,7
17,2
28,5
17,7
31,5
30
7,4
12,3
23
28,7
22,5
0,125 0,08 mm
17,8
17,9
14,8
5,3
8,8
6,6
26,6
19,4
4,1
4,7
19,7
4
6,9
< 0,08
mm
19,3
10,4
5,6
0,6
2,3
1,5
14,9
6,8
1,6
0,7
3,9
0,5
1,1
Table 18. Granules consisting of C, MCC and NM 30D size distribution.
Sample
1C
2C
3C
4C
5C
6C
7C
8C
9C
10C
11C
12C
13C
14C
15C
16C
17C
> 1,25
mm
0
0
0
0
0
0
0
0
0,1
0
0
0
0,1
0
0
0
0
1,25 1,0 mm
4,4
4,2
0,7
4,2
3
5,6
4,9
1,3
3,5
2,6
2,4
3,1
3,9
4,3
4,9
3,6
2,8
1,0 0,8 mm
8,8
9,2
5,7
8,1
6,8
7,8
8,9
7,2
7,9
6,3
8,2
9,4
11
11
11,3
14,5
11,9
Size of sieves mm
0,8 0,5 0,5 mm
0,25 mm
14,7
19
16,6
21,1
10,3
25,3
18,4
24,9
13,3
23,4
15,8
37,3
17,2
29,9
18,8
32,1
18,5
32,4
14,8
40
16,8
23,9
19,3
30,5
23,4
41,3
23,7
41
25,3
38,1
28
38,6
28,7
42,9
0,25 0,125 mm
33,6
32,7
29,7
27,6
46,8
29,7
35,1
32,5
27,5
29,3
27,9
27,4
18
18,1
18,7
14,5
13,1
0,125 0,08 mm
16,7
11,4
11,6
11,4
5,7
3,2
3,4
7,4
8,3
6,3
13,3
6,8
1,3
1,1
1
0,5
0,4
< 0,08
mm
2,8
4,8
7,7
5,4
1
0,6
0,6
0,7
1,8
0,7
7,6
3,5
0,9
0,8
0,7
0,3
0,2
65
ADDITION Nr. 3
Table 19. Mass and content uniformity of DH matrix tablet - minimal and maximal weight of
tablets, allowed limits of weight deviation by Ph. Eur., average values of drug content.
Sample
1D
2D
3D
4D
5D
6D
7D
8D
9D
10D
11D
12D
13D
Minimal
weight (mg)
211,23
215,16
216,51
233,78
241,97
247,38
159,79
164,48
167,38
172,96
126,62
134,88
138,68
Maximal
weight (mg)
222,37
222,5
233,48
237,61
245,86
251,32
165,54
169,98
172,38
177,94
134,04
138,59
143,35
Limits of
weight (mg)
200,88 - 233,46
205,54 - 238,87
210,89 - 245,09
217,11 - 252,31
223,34 - 259,56
229,56 - 266,78
147,58 - 171,52
150,64 - 175,06
154,16 - 179,16
158,18 - 183,84
122,98 - 142,92
125,56 - 145,92
128,50 - 149,34
Average DH
content (mg)
111,03
109,17
105,27
102,3
103,54
102,4
95,12
96,21
98,42
98,42
100,4
98,04
101,94
SD (mg)
1,79
2,94
3,2
5,01
4,41
0,72
2,71
1,32
2,81
2,81
3,21
3,26
2,08
Table 20. Mass and content uniformity of C matrix tablet - minimal and maximal weight of
tablets, allowed limits of weight deviation by Ph. Eur., average values of drug content.
Sample
1C
2C
3C
4C
5C
6C
7C
8C
9C
10C
11C
12C
13C
14C
15C
16C
17C
Minimal
weight (mg)
214,8
220,8
226,8
234
159,5
161,7
165,7
170,8
175,2
132,9
134,3
138,4
141
143,7
148,1
150
155
Maximal
weight (mg)
223,42
225,46
229,4
237,61
162,8
167,35
171,14
174,55
181,41
136,14
137,35
142,07
144,86
147,59
152,53
152,69
158,84
Limits of
weight (mg)
201,37 - 234,03
205,54 - 238,87
210,89 - 245,09
217,11 - 252,31
147,58 - 171,52
150,64 - 175,06
154,16 - 179,16
158,18 - 183,84
162,86 - 189,26
122,98 - 142,92
125,56 - 145,92
128,49 - 149,33
131,81 - 153,19
132,39 - 153,85
135,71 - 157,71
139,60 - 162,24
143,52 - 166,79
Average C
content (mg)
104,16
102,95
103,62
104,24
101,98
101,4
105,24
103,14
101,24
102,05
101,54
105,57
104,62
103,89
104,23
103,03
108,14
SD (mg)
3,55
3,06
4,58
1,12
1,67
3,66
3,17
2,68
1,93
3,4
3,02
2,94
4,41
3,88
5,87
2,22
5,09
66
Table 21. Friability of DH matrix tablets.
Sample
1D
2D
3D
4D
5D
6D
7D
8D
9D
10D
11D
12D
13D
Friability (%)
0,033
0,031
0,025
0,033
0,049
0,045
0,065
0,066
0,049
0,040
0,114
0,096
0,074
Table 22. Friability of C matrix tablets.
Sample
1C
2C
3C
4C
5C
6C
7C
8C
9C
10C
11C
12C
13C
14C
15C
16C
17C
Friability (%)
0,1
0,119
0,086
0,059
0,139
0,125
0,116
0,088
0,179
0,159
0,145
0,126
0,113
0,081
0,078
0,04
0,035
67
Figure 26. Hardness of DH matrix tablets
180
160
140
Hardness (N)
120
100
80
60
40
20
0
1D
2D
3D
4D
5D
6D
7D
8D
9D
10D
11D
12D
13D
Sample
Figure 27. Hardness of C matrix tablets.
160
140
Harness (N)
120
100
80
60
40
20
0
1C
2C
3C
4C
5C
6C
7C
8C
9C 10C 11C 12C 13C 14C 15C 16C 17C
Sample
68
Figure 28. Press force used within preparation process of DH matrix tablets.
35
30
Force (kN)
25
20
15
10
5
0
1D
2D
3D
4D
5D
6D
7D
8D
9D
10D
11D
12D
13D
Sample
Figure 29. Press force used within preparation process of C matrix tablets.
25
Force (kN)
20
15
10
5
0
1C
2C
3C
4C
5C
6C
7C
8C
9C 10C 11C 12C 13C 14C 15C 16C 17C
Sample
69
ADDITION Nr. 4
Figure 30. Dissolution profile of samples 1D, 2D and 3D in phosphate buffer of pH 6.8.
120
110
DH released amount (%)
100
90
80
70
60
Sample 1D
50
Sample 2D
40
Sample 3D
30
20
10
0
0
30 60 120 180 240 300 360 420 480 540 600 660 720
Time (min)
Figure 31. Dissolution profile of samples 4D, 5D and 6D in phosphate buffer of pH 6.8.
100
90
DH released amount (%)
80
70
60
50
Sample 4D
40
Sample 5D
30
Sample 6D
20
10
0
0
30 60 120 180 240 300 360 420 480 540 600 660 720
Time (min)
70
Figure 32. Dissolution profile of samples 7D, 8D, 9D and 10D in phosphate buffer of pH 6.8.
110
DH released amount (%)
100
90
80
70
60
Sample 7D
50
Sample 8D
40
Sample 9D
30
Sample 10D
20
10
0
0
30 60 120 180 240 300 360 420 480 540 600 660 720
Time (min)
Figure 33. Dissolution profile of samples 11D, 12D and 13D in phosphate buffer of pH 6.8.
100
90
DH released drug (%)
80
70
60
50
Sample 11D
40
Sample 12D
30
Sample 13D
20
10
0
0
30 60 120 180 240 300 360 420 480 540 600 660 720
Time (min)
71
Table 23. Standard deviation values of DH released amount from all samples within dissolution
test.
Standard deviation values of DH released amount within dissolution test (%)
1D
2D
3D
4D
5D
6D
7D
8D
9D 10D 11D 12D
0,00 0,00 0,00 0,00 0,00 0,00 0,00 0,00 0,00 0,00
0,00 0,00
10,74 0,96 1,06 2,35 2,59 1,30 2,67 1,84 0,96 1,28
9,04 1,02
14,47 0,91 1,07 2,76 3,42 1,92 2,35 1,52 1,26 1,38 10,94 6,51
11,56 1,93 2,22 1,73 1,08 3,32 2,97 5,57 0,14 4,23
5,24 3,23
3,98 2,43 3,75 0,74 2,16 4,59 2,31 13,54 0,59 4,92
0,76 3,83
5,23 0,94 4,43 0,41 3,97 5,15 1,32 13,34 1,32 5,02
0,79 3,66
4,46 1,97 4,58 2,67 5,86 5,45 1,34 12,56 1,47 4,88
0,85 3,69
3,95 2,12 4,85 3,21 4,81 5,61 1,54 11,50 1,43 4,70
0,84 3,76
3,76 3,10 5,05 3,2 5,23 5,70 1,54 10,40 1,57 4,47
0,78 3,73
3,65 3,39 5,35 3,16 4,48 5,71 1,38 9,18 1,67 4,22
0,65 3,38
3,45 3,66 5,66 3,05 4,95 5,78 1,32 8,01 1,88 3,97
0,61 2,83
3,26 3,82 6,25 2,94 5,86 5,77 1,18 6,78 1,99 3,73
0,53 2,17
3,08 3,85 6,77 2,71 5,55 5,79 1,02 5,65 2,17 3,43
0,44 1,60
3,05 3,93 6,97 2,42 6,29 5,67 0,95 4,52 2,17 3,17
0,37 1,14
Time
(min)
0
30
60
120
180
240
300
360
420
480
540
600
660
720
13D
0,00
5,30
8,10
9,50
10,20
10,10
9,90
9,40
9,10
8,90
8,70
8,50
8,30
7,90
Figure 34. Dissolution profile of samples 1C, 2C, 3C and 4C in phosphate buffer of pH 6.8.
110
100
C released amount (%)
90
80
70
60
Sample 1C
50
Sample 2C
40
Sample 3C
30
Sample 4C
20
10
0
0
30
60
120 180 240 300 360 420 480 540 600 660 720
Time (min)
72
Figure 35. Dissolution profile of samples 5C, 6C and 7C in phosphate buffer of pH 6.8.
110
100
C released amount (%)
90
80
70
60
Sample 5C
50
Sample 6C
40
Sample 7C
30
20
10
0
0
30
60
120 180 240 300 360 420 480 540 600 660 720
Time (min)
Figure 36. Dissolution profile of samples 8C and 9C in phosphate buffer of pH 6,8.
110
100
90
C released amount (%)
80
70
60
50
Sample 8C
40
Sample 9C
30
20
10
0
0
30
60
120 180 240 300 360 420 480 540 600 660 720
Time (min)
73
Figure 37. Dissolution profile of samples 10C, 11C, 12C and 13C in phosphate buffer of pH 6,8.
110
100
90
C released amout (%)
80
70
60
Sample 10C
50
Sample 11C
40
Sample 12C
30
Sample 13C
20
10
0
0
30
60 120 180 240 300 360 420 480 540 600 660 720
Time (min)
Figure 38. Dissolution profile of samples 14C, 15C, 16C and 17C in phosphate buffer of pH 6,8.
110
100
90
C released amount (%)
80
70
60
Sample 14C
50
Sample 15C
40
Sample 16C
Sample 17C
30
20
10
0
0
30
60
120 180 240 300 360 420 480 540 600 660 720
Time (min)
74
Table 23. Standard deviation values of C released amount from all samples within dissolution
Standard deviation values of C released amount within
dissolution test (%)
test.
Sample
1C
2C
3C
4C
5C
6C
7C
8C
9C
10C
11C
12C
13C
14C
15C
16C
17C
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
30
1,15
2,07
1,59
0,22
1,61
2,59
1,33
3,48
2,3
6,15
14,3
2,75
0,71
2,31
6,24
0,63
4,45
60
1,2
0,27
1,14
0,27
0,75
1,23
0,14
2,37
1,62
2,41
9,83
3,51
0,69
2,82
0,85
0,52
11,5
120
1,24
0,25
1,11
0,66
0,71
0,69
0,05
0,92
0,58
0,85
2,83
4,38
0,78
2,32
0,87
0,53
1,29
180
1,22
0,28
1,15
1,47
0,79
0,75
0,03
0,91
1,51
0,84
2,61
3,22
0,81
1,44
0,85
0,58
1,31
240
1,25
0,35
1,21
1,64
0,7
0,77
0,07
0,86
1,75
0,86
2,74
1,41
0,87
1,59
0,82
0,57
1,34
Time (min)
300 360
1,29 1,28
0,4 0,23
1,32 1,12
1,38 1,15
0,76 0,71
0,86 0,9
0,07 0,1
0,93 0,99
1,77 1,8
0,91 0,97
2,74 2,31
1,04 1,09
0,87 0,86
1,13 1,92
0,85 0,83
0,54 0,57
1,39 1,47
420
1,32
0,25
1,31
1,15
0,71
0,94
0,07
1,01
1,8
0,96
2,47
0,91
0,88
1,75
0,86
0,58
1,5
480
1,35
0,3
1,01
0,91
0,72
1,04
0,04
1
1,82
1,02
2,89
1,16
0,88
1,92
0,81
0,6
1,56
540
1,39
0,15
1,18
0,69
0,56
1,09
0,05
1,08
3,68
1,05
2,19
1,65
0,87
1,82
0,79
0,6
1,64
600
1,37
0,2
0,97
0,69
0,55
1,13
0,08
1,05
1,84
1,1
2,54
1,79
0,91
1,81
0,8
0,62
1,63
660
1,39
0,51
1,42
0,54
0,57
1,21
0,14
1,08
1,89
1,12
2,31
1,54
0,92
2,42
0,81
0,6
1,72
720
1,44
0,42
1,14
0,64
0,53
1,53
0,13
1,12
1,93
1,15
2,45
1,72
0,9
2,18
0,85
0,62
1,74
Figure 39. Dissolution profile of 14C matrix tablet within dissolution test with continual pH
change (the first 2 h at pH 1.2 followed by 10 hours at pH 6,8).
100
90
C released amount (%)
80
70
60
50
40
30
20
10
0
0
30
60
120
180
240
300
360
420
480
540
600
660
720
Time (min)
75
Figure 40. Dissolution profile of 4D and 5D matrix tablets within dissolution test with continual
pH change (the first 2 h at pH 1.2 followed by 10 hours at pH 6,8).
100
90
C released amount (%)
80
70
60
50
Sample 4D
40
Sample 5D
30
20
10
0
0
30
60
90 120 150 180 210 240 300 360 420 480 540 600 660 720
Time (min)
Table 25. Standard deviation values of drug released amount from samples 4D, 5D and 14C
within dissolution test with continual pH change.
Time
(min)
0
30
60
120
180
240
300
360
420
480
540
600
660
720
Standard deviation values of drug released amount
within continual dissolution test (%)
4D
5D
14C
0,00
0,00
0,00
0,61
0,79
4,32
0,65
1,32
4,87
1,18
3,42
5,67
1,10
0,47
4,90
0,94
0,29
1,67
0,98
0,24
0,53
1,01
0,22
1,10
0,96
0,22
1,12
0,98
0,20
1,10
0,96
0,22
1,15
1,00
0,19
1,09
1,01
0,21
1,09
1,00
0,22
1,11
76
77