KAUNAS UNIVERSITY OF MEDICINE FACULTY OF PHARMACY DEPARTMENT OF DRUGS TECHNOLOGY AND SOCIAL PHARMACY

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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

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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)

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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).

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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.

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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

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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

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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 Dissolution Properties

L 30 D-55 30 % Aqueous Dispersion Dissolution above pH 5,5 L 100-55 Powder L 100 Powder Dissolution above pH 6,0 L 12,5 12,5 % Organic Solution S 100 Powder Dissolution above pH 7,0 S 12,5 12,5 % Organic Solution FS 30 D 30 % Aqueous Dispersion

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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 Insoluble High permeability pH-independent swelling RL PO Powder RL 30 D 30 % Aqueous Dispersion RL 12,5 12,5 % Organic Solution RS 100 Granules Insoluble Low permeability pH-independent swelling RS PO Powder RS 30 D 30 % Aqueous Dispersion RS 12,5 12,5 % Organic Solution

NE 30 D 30 % Aqueous Dispersion Insoluble, low permeability pH-independent swelling No plasticizer required Highly flexible

NE 40 D 40 % Aqueous Dispersion NM 30 D 30 % Aqueous Dispersion

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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]

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15 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 milky-white 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.

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16 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

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17 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]

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18 Table 3. Coated dosage forms for the treatment of ulcerative colitis in the German market. [38]

Drug Coating polymers Dissolution pH Trade name Manufacturer Mesalazine Eudragit® L 6.0 Claversal® SmithKline Beecham

Pharmaceuticals Munich Mesalazine Eudragit® S 7.0 Asacolitin® Henning Berlin GmbH &

Co., Berlin

Mesalazine Eudragit® L 6.0 Salofalk® Dr Falk Pharma GmbH, Freiburg

Sulfasalazine Eudragit® L 100-55 5.5 Colo-Pleon® Henning Berlin GmbH & Co., Berlin

Budenoside Eudragit® L 100-55, ethylcellulose

5.5 Entocort® ASTRA GmbH, Wedel

Budenoside Eudragit® S 6.0 Budenofalk® 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

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19 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 glycolor 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]

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20 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]

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21 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

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22 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

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23 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

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24 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 modified-release 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

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25 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.

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26

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

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27 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

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28 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)

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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

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29

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 film-coated)

80 mg or less 10

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.

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30

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

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31 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

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32 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

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33 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]

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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]

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35

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

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36

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

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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 Diltiazem

hydrochloride (g) Avicel ® PH 101 (g) Eudragit ® NM 30 D aqueous dispersion (g) 1 100 100 10.5 2 100 100 22.2 3 100 100 35.3 4 100 100 50 5 100 100 66.6 6 100 100 85.7 7 100 100 107.7 8 100 100 107.9 9 100 100 130.1 10 100 100 152.3 11 100 50 7.9 12 100 50 16.7 13 100 50 26.5 14 100 50 37.5 15 100 50 50 16 100 50 64.3 17 100 25 6.6 18 100 25 13.9 19 100 25 22.1 20 100 25 31.25 21 100 25 41.7

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38 Table 8. The composition of powder mixtures with caffeine for granulates preparation

Name of sample Caffeine (g) Avicel® PH 101 (g) Eudragit

® NM 30 D aqueous dispersion (g) 22 100 100 10.5 23 100 100 22.2 24 100 100 35.3 25 100 100 50 26 100 100 66.6 27 100 100 85.7 28 100 100 107.9 29 100 50 7.9 30 100 50 16.7 31 100 50 26.5 32 100 50 37.5 33 100 50 50 34 100 50 64.3 35 100 50 81 36 100 25 6.6 37 100 25 13.9 38 100 25 22.1 39 100 25 31.25 40 100 25 41.7 41 100 25 53.6 42 100 25 55.6 43 100 25 67.5 44 100 25 81.4 45 100 25 95.3

Granulates were prepared in shear mixer ROTOLAB (see Figure 13). The high-shear 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.

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39 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

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40 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.

KAUNAS UNIVERSITY OF MEDICINE FACULTY OF PHARMACY DEPARTMENT OF DRUGS TECHNOLOGY AND SOCIAL PHARMACY