Eudgarit RL Odts

8/12/2019 Eudgarit RL Odts

1/13

R E S E A R C H A R T I C L E

Sustained-release diclofenac potassium orally disintegrating tabletincorporating eudragit ERL/ERS: possibility of specific

diclofenac-polymer interaction

Amjad M. Qandil Shereen M. Assaf

Enas A. Al Ani Alaa Eldeen Yassin

Aiman A. Obaidat

Received: 18 February 2013 / Accepted: 14 March 2013 / Published online: 22 March 2013

The Korean Society of Pharmaceutical Sciences and Technology 2013

Abstract Sustained-release diclofenac potassium orally

disintegrating tablet (ODT) formulations have been pre-pared and investigated. The ODTs were prepared by

incorporating diclofenac potassium (DP), as a model for

negatively ionizable drugs, in microcapsules that were

prepared by the solvent evaporation method from a mixture

of DP and different ratios of Eudragit RS and Eudragit RL,

which are positively ionized synthetic polymers. The ODTs

were prepared by direct compression of mixtures contain-

ing microcapsule formula M4, crospovidone as a super-

disintegrant and water soluble excipients (mannitol or

lactose and sorbitol). Diclofenac potassium ODT F2,

showed acceptable hardness (4.08 KP) slight friability

(2.13 %) and disintegration time of 22.41 s with a sus-

tained drug release profile. Microcapsule characterization

(DSC and FT-IR) and dissolution behavior suggests the

presence of specific interaction between the carboxylate

group of diclofenac and the quaternary ammonium group

in the polymers

Keywords Orally disintegrating tablet Sustained-release Eudragit RS Eudragit RL Diclofenac

Introduction

In 1998, theCenter of Drug Evaluation andResearch (CDER)

Nomenclature Standards Committee defined an orally dis-

integrating tablet (ODT) as a solid dosage form containing

medicinal substances which disintegrates rapidly, usually

within a matter of seconds, when placed upon the tongue

(Food and Drug Administration2008). The European Phar-

macopoeia defined orodispersible tablets as uncoated tab-

lets intended to be placed in the mouth where they disperse

rapidly before being swallowed (Council of Europe 2002).It

is worth mentioning that to date, the United States Pharma-

copoeia does not have a published definitionfor ODTs. There

are several advantages for ODTs; they are easily administered

and can be taken directly anywhere and at any time because

no water is required. They are particularly of great benefit to

people who cannot or have difficulty taking conventional

solid dosage forms, including children, elderly, patients with

swallowing difficulties and mentally impaired and disabled

patients (Ghosh and Pfister2005). They also provide rapid

onset of action and improve bioavailability via buccal or

sublingual absorption (Clarke et al.2003).

Preparing ODTs with sustained-release properties is still

a challenge. Because ODTs disintegrate or dissolve in the

oral cavity, one way to attain sustained-release from ODTs

is to formulate the drug into a microparticulate system.

Microcapsules or microspheres are microparticulate

A. M. Qandil (&)

Department of Medicinal Chemistry and Pharmacognosy,

Faculty of Pharmacy, Jordan University of Science and

Technology, Irbid 22110, Jordan

e-mail: [email protected]; [email protected]

A. M. Qandil A. E. Yassin

Pharmaceutical Sciences Department, College of Pharmacy,King Saud bin Abdulaziz University for Health Sciences,

Riyadh 11426, Saudi Arabia

S. M. Assaf E. A. Al Ani A. A. ObaidatDepartment of Pharmaceutical Technology, Faculty of

Pharmacy, Jordan University of Science and Technology,

Irbid 22110, Jordan

A. A. Obaidat

Department of Basic Medical Sciences, College of Medicine,

King Saud bin Abdulaziz University for Health Sciences,

Riyadh 11426, Saudi Arabia

1 3

Journal of Pharmaceutical Investigation (2013) 43:171183

DOI 10.1007/s40005-013-0065-4


2/13

systems, which are usually less than 1000 lm in diameter

(Lin and Alexandridis 2000). Microcapsules have many

pharmaceutical applications; they are used for taste

masking (Xu et al. 2008), drug stability improvement

(Singh et al. 2007), enteric-coated preparations (Bodmeier

and Dong 2006), targeted drug delivery (Chourasia and

Jain 2003) and sustained-release formulations (Lu et al.

2007). In microcapsules, the drug is generally dissolved in(Blanco-Pr0eto et al.2004), dispersed in (Lu et al.2007) or

coated with the polymer (Ichikawa et al. 2001).

There are many methods that can be used for the prepa-

ration of microcapsules. The most common are coacervation

phase separation (Lu et al.2007), spray drying (Oliveira and

Rattes2004), supercritical fluid (Reverchon et al. 2008) and

solvent evaporation (Li et al. 2008). Among the aforemen-

tioned methods, solvent evaporation is the most widely used

because it is simple, needs no special instrumentation, can be

performed under ambient temperatures and require only

constant stirring. Themain disadvantage of this methodis the

residual solvent (Li et al.2008). In the solvent evaporationmethod, the drug is either dissolved or suspended in an

organic volatile solvent containing dissolved polymer(s).

This solution/dispersion is then added to a stirring aqueous or

oily solution containing a dispersing agent. The organic

solvent is then evaporated by applying temperature under

atmospheric or reduced pressure.

On the other hand, the most common methods to prepare

ODTs are freeze drying (Corveleyn and Remon 1998),

molding (Dobetti 2001) and direct compression (Shimizu

et al.2003). Direct compression is the most convenient and

easiest way to manufacture ODTs because of its low

manufacturing cost and limited processing steps. The main

disadvantage of directly compressed ODTs is their pro-

longed disintegration time compared to other ODTs, which

is highly dependent and directly proportional to tablet size

(Shu et al. 2002). Direct compression depends on the

incorporation of suitable superdisintegrants (Aly et al.

2005), sugar based excipients (Sugimoto et al. 2005),

effervescent agents (Kristjansson 2008) or combination of

the aforementioned agents (Shu et al. 2002).

Although, in theory, any drug can be formulated as an

orally disintegrating tablet, suitable drug candidates for

ODT formulations include antipyretic analgesics, hypnot-

ics (sedatives), antispasmodics (Kenji et al. 2000) and an-

tiemetics (Assaf et al.2013).

Diclofenac is a non-steroidal anti-inflammatory drug

(NSAID) with an anti-inflammatory, analgesic and anti-

pyretic action. It is frequently prescribed for rheumatic

musculoskeletal complaints for the relief of minor aches

and pains in an oral daily dose of 100-200 mg given in

divided doses. Diclofenac is rapidly absorbed and exten-

sively bound to proteins with a half life of 46 h (Burke

et al.2006). The sodium and potassium salts of diclofenac

are the most common in systemic formulations, while

diethylamine diclofenac is used in topical formulations.

Diclofenac potassium (DP) is potassium [2-[(2,6-dichlo-

rophenyl) amino] phenyl] acetate with the chemical

structure shown in Fig. 1. It has higher and faster solubility

than diclofenac sodium; hence, it has a faster onset of

action (Chuasuwan et al. 2009).

Eudragit RS (ERS) and Eudragit RL (ERL) are trimeth-ylammonioethyl polymethacrylate cationic copolymers,

Fig.2. ERL has 10 % functional quaternary ammonium

groups while ERS has only 5 %. For this reason, ERL is

considered more water permeable than ERS. Both polymers

are water insoluble and are used to prepare pH-independent

sustained release formulations. (Andrews and Jones2006).

In this work, DP microcapsules were prepared by the

solvent evaporation method using different ratios of Eu-

dragit RL (ERL) and Eudragit RS (ERS). Diclofenac

potassium, here, serves as a model for other NSAIDs that

contain negatively ionizable groups. The selected formula

with acceptable sustained-release action was used in thepreparation of sustained-release diclofenac potassium

ODTs. The tablets were prepared by direct compression

method using crospovidone as a superdisintegrant. As an

ODT, these tablets can be administered to patients who

cannot swallow ordinary tables or capsule. In addition, the

formulation will offer sustained release of DP and finally, it

is designed to release DP at higher pH values which can

spare the stomach the irritant effect of free diclofenac.

Fig. 1 The chemical structure

of diclofenac potassium

Fig. 2 The general chemical structure of Eudragit RL (ERL) and

Eudragit RS (ERS) polymers

172 A. M. Qandil et al.

1 3


3/13

Materials and methods

Materials

Diclofenac potassium was kindly donated by the Jordanian

Pharmaceutical Manufacturing Company (JPM), Naor,

Jordan. Low-substituted hydroxypropyl cellulose, manni-

tol, lactose monohydrate and crospovidone were kindlydonated by The United Pharmaceuticals, Sahab, Jordan.

Sorbitol was obtained from Janssen Chemica (Geel, Bel-

gium). Potassium dihydrogen orthophosphate, trisodium

phosphate extra pure and potassium bromide IR spectros-

copy grade were obtained from Scharlau Chemie S.A.

(Barcelona, Spain). Sodium lauryl sulphate LR was

obtained from Analytical Rasayan Laboratory (Mumbai,

India) and magnesium stearate was obtained from Fizmerk

India Chemicals (Hapur, India). Eudragit RL and Eudragit

RS were kindly donated by Target Chemicals EST (Am-

man, Jordan). Other fine chemicals and solvents were

obtained from local vendors. All chemicals were used assupplied without further purification. Distilled water used

in this work.

Preparation of diclofenac potassium microcapsules

M1M5

Microcapsules M1M5 containing 1:3weight ratio of drug to

polymer were prepared using the emulsion solvent evapo-

ration method (Li et al.2008). Eudragit RL (ERL), Eudragit

RS (ERS) or their mixtures (1.5 g), Table 1, were dissolved

in acetone (40 mL) using a magnetic stirrer. Diclofenac

potassium (DP) (0.5 g) was dissolved in methanol (4 mL)

and this solution was then added to the polymer solutions and

mixed. The mixture was poured onto an already stirring

liquid paraffin (300 mL) that contains magnesium stearate

(0.2 g) using a propeller mixer (RQ-124, Mumbai, India).

The resulting emulsion was stirred at 1000 rpm for 2 h at

room temperature. Then, the formed microcapsules were

collected by filtration, washed with 6 parts of 50 mL

n-hexane and then dried at room temperature for 24 h.

Physical characterization of diclofenac potassium

microcapsules

Particle size analysis of microcapsules M1M5, sieve

analysis

DP microcapsules were passed through consecutive sieves

with the following mesh sizes: 250, 212, 180, 125, 75 and

38 lm. Microcapsule fractions were then collected and

weighed. The particle size distribution of microcapsules

was determined and the mean particle size was calculated

according to Eq.1.

mean particle size

P mean fraction particle sizefraction weight P

fraction weight

1

Particle size analysis of microcapsules M1M5, laser

diffraction analysis

Laser diffraction particle size analyzer (Microtrac S3500,

USA) was used to analyze the particle size distribution of

DP microcapsules. Measurements were performed in

triplicate.

Yield, drug loading and encapsulation efficiency

of microcapsules M1M5

The yield for microcapsules M1M5, regardless of particle

size range, was calculated by dividing the weight of mi-

crocapsules by the combined weight of DP, ERS and/or

ERL used, according to Eq.2.

%yield weight of microcapsules

weight of drugweight of polymer(s)

100

2

Drug content (encapsulated drug) was determined in

triplicate for particles in the size range of 75125 lm in all

of the microcapsule formulations. Microcapsules (10.0 mg)

were dissolved in 50 mL methanol and briefly sonicated

for 1 min. Methanol was then filtered and the concentration

of DP was determined using UV spectrophotometry at

k = 275 nm. Drug loading and encapsulation efficiency

were calculated using Eqs. 36.

Theoretical drug loading

weight of initial drug

weight of initial drug and polymer

3

Actual drug loading weight of encapsulated drug

weight of initial drug and polymer

4

%Drug loading weight of encapsulated drug

weight of microcapsules

100

5

Table 1 Microcapsules formu-

lations consisting of 1:3 weight

ratio of DP to polymer(s) with

different ERS and ERL contents

Microcapsules

formulations

Weight ratios

ERS ERL DP

M1 3 0 1

M2 2.7 0.3 1

M3 2.4 0.6 1

M4 1.8 1.2 1

M5 0 3 1

Sustained-release diclofenac potassium orally 173

1 3


4/13

% Encapsulation efficiency Actual drug loading

Theoretical drug loading

100

6

Scanning electron microscopy (SEM) of microcapsules M1,

M4 and M5

A scanning electron microscope (Philips Quanta 200,

Netherlands) was used to examine the shape and the sur-

face (topology) of particles in the size range of 75125 lm

from microcapsule formulations M1, M4, M5. Prior to

examination, microcapsules were mounted on an aluminum

stub, using double adhesive carbon films. They were

sputter coated with gold under vacuum to render them

electrically conductive.

Differential scanning calorimetric (DSC) analysis

The DSC analyses were performed using a differentialscanning calorimeter (Mettler-Toledo, Schwerzenbach-

Switzerland). Samples, 5.0 0.2 mg, of DP, ERS, ERL,

microcapsule formulations (M1M5) and DP-polymer

physical mixture (DP:ERL:ERS = 1:1.2:1.8 weight ratio)

were heated under nitrogen (80 mL/min) in sealed alumi-

num pans from 0 to 300 C at a scan rate of 10 C/min.

Thermogravimetric analysis (TGA)

TGA analyses were performed using a thermal gravimetric

analyzer (Shimadzu, TGA-50, Japan). Samples, 710 mg, of

DP, ERS, ERL, microcapsule formulations (M1M5) anddrug-polymer physical mixture (DP:ERL:ERS = 1:1.2:1.8

weight ratio) were heated under nitrogen (20 mL/min) in

aluminum pans from 20 to 500 Catascanrateof15 C/min.

X-ray powder diffraction analysis

X-Ray powder diffraction analyses were performed using

an X-ray powder diffractometer (Philips, PW 1729, Neth-

erlands) with cobalt radiation, at a voltage of 35 kV and a

current of 40 MA. The X-ray diffraction patterns were

obtained for DP, ERS, ERL, microcapsule formulation M4

and drug-polymer physical mixture (DP:ERL:ERS= 1:1.2:1.8 weight ratio).

Fourier transform infrared analysis (FT-IR)

The FT-IR spectra were obtained using an FT-IR spec-

trometer (JASCO, UK). The spectra were obtained for DP,

ERS, ERL, microcapsule formulations (M1, M4 and M5)

and drug-polymer physical mixture (DP:ERL:ERS=

1:1.2:1.8 weight ratio). Samples were prepared as

potassium bromide discs (1 % w/w). Each sample was

scanned over a frequency range of 4000400 and

0.04 cm-1 resolution.

Preparation of DP ODTs

Microcapsule formula M4 was used to prepare the sus-

tained-release DP ODTs, F1 and F2, according to thequantities shown in Table 2. For each formula, a batch of

50 tablets was prepared. The raw materials were sieved

(125 lm mesh size) prior to mixing. The drug, the filler

(mannitol, lactose monohydrate or sorbitol) and low-

substituted hydroxypropyl cellulose (L-HPC), if included,

were thoroughly blended for 5 min in a 250 mL glass

bottle. Then, crospovidone and silicone dioxide were

mixed by kneading to form a homogenous mixture, and

then added to microcapsule M4 and blended together for

another 3 min. Prior to compression, magnesium stearate

was mixed with the formulation blend. The final blends

were directly compressed using a hydraulic press with acompression force of 160 Kg to form tablets with diameter

of 12 mm.

Characterization of diclofenac potassium oral

disintegrating tablets

Hardness

Tablet hardness was evaluated by measuring the hardness

of six tablets using a Hardness Tester (Copley,

Switzerland).

Friability

Tablet friability was evaluated using friabilator (Erweka,

Germany). Accurately weighed 20 tablets were tumbled at

25 rpm for 4 min. The tablets were then de-dusted,

weighted and the percent weight loss was calculated.

Table 2 Composition of the DP ODTs, F1 and F2

Component (mg) F1 F2

Crospovidone 82.5 67.5

L-HPC 27.5

Silicon dioxide 5.5 4.5

Mannitol 51

Mg stearate 2.75 2.25

DP microcapsules (M4) 400 200

Lactose monohydrate 161

Sorbitol 20

Tablet weight 550 450


1 3


5/13

Disintegration time

The disintegration time for 6 tablets was determined using

a modified USP dissolution apparatus II (paddle method),

based on a previously reported procedure (Sunada and Bi

2002). Each tablet was placed in a basket with a mesh size

of 3-4 mm, previously inserted in 900 mL artificial saliva

and maintained at 37 0.1 C and 100 rpm. Disintegra-tion time was measured at the point when the tablet was

completely disintegrated and passed through the basket.

The artificial saliva was prepared by mixing 40 mM

sodium chloride, 1.5 mM calcium chloride and 12 mM

potassium dihydrogen phosphate then adjusting the pH to

6.2 using 1 M sodium hydroxide solution.

Dissolution studies

Dissolution of diclofenac from microcapsules (M1M5)

at pH 1.2 and 6.8

Dissolution studies were performed in a USP 23 dissolution

apparatus II, paddle method (Vankel VK700, USA). All the

studies were performed in triplicates under sink condition,

at 37 0.1 C and 100 rpm. Dissolution studies were

carried out separately at pH 1.2 using diluted HCl for 2 h

and at pH 6.8 using phosphate buffer for 9 h. Microcap-

sules (equivalent to 100 mg of DP) were added to 900 mL

of the dissolution media (pH 1.2 or 6.8) containing 0.02 %

sodium lauryl sulfate to improve the wettability of the

microcapsules (USP). Samples (5 mL) were withdrawn at

appropriate time intervals and replaced with equal volume

of fresh dissolution media. Drug content was determined

using a UVVIS Spectrophotometer (Cintra 5, GBC Sci-

entific Equipment, Australia) at k = 270 nm for pH 1.2

and k = 275 nm for pH 6.8.

Consecutive dissolution profile of diclofenac

from microcapsule M4 at pH 1.2, 5.8 and 6.8

The dissolution studies were performed in three consecu-

tive phases. Microcapsules M4 (equivalent of 100 mg DP)

were added to 750 mL of dissolution media pH 1.2 and

paddling was maintained for 2 h for phase 1. Then,

200 mL of 0.2 M trisodium phosphate solution were added

to the dissolution media to change the pH to 5.8 and

paddling was maintained for another 2 h for phase 2.

Finally, 50 mL of 0.2 M trisodium phosphate solution were

added to the media to change the pH to 6.8 and paddling

was maintained for another 3 h for phase 3. Sodium lauryl

sulfate (0.02 %) was always present in the dissolution

media. During each phase, samples (5 mL) were with-

drawn at appropriate time intervals and were replaced with

equal volume of fresh dissolution media. Drug content was

determined using UVVIS spectrophotometry at

k = 270 nm for pH = 1.2 and at k = 275 nm for pH 5.8

and 6.8.

Consecutive dissolution of diclofenac from DP-ODT F2,

at pH 1.2, 5.8 and 6.8

Dissolution studies were performed in a USP 23 dissolutionapparatus II, paddle method (Vankel Dissolution Apparatus

VK700, USA). All the studies were performed in triplicates

under sink conditions, at 37 0.1 C and 100 rpm. From

formulation F2, two tablets (equivalent of 100 mg DP)

were added to 750 mL dissolution media, pH 1.2, and

paddling was maintained for 2 h for phase 1. Then,

200 mL of 0.2 M trisodium phosphate solution were added

to the dissolution media to change the pH to 5.8 and

paddling was maintained for another 2 h for phase 2.

Finally, 50 mL of 0.2 M trisodium phosphate solution were

added to the media to change the pH to 6.8 and paddling

was maintained for another 3 h for phase 3. During eachphase, 5 mL samples were withdrawn at appropriate time

intervals and were replaced with fresh dissolution media of

the same pH. Drug content was determined using UVVIS

spectrophotometry at k = 270 nm for pH 1.2 and

k = 275 nm for pH 5.8 and 6.8.

Results and discussion

Diclofenac potassium (DP) microcapsules were prepared

using Eudragit polymers (ERL and/or ERS) in a drug to

polymer weight ratio of 1:3. The selection of this ratio was

based on a previous drug dissolution pilot study where a

lower polymer weight ratio (1:2) resulted in high burst

release of the drug during the first hour.

Characterization of diclofenac microcapsules

Particle size analysis: sieve analysis and laser diffraction

analysis

Microcapsule size distribution as determined by sieving is

summarized in Table3. The mean particle size and size

distribution for all of the formulations were similar, which

could be attributed to the fact that all microcapsule for-

mulations contained the same drug to polymer weight ratio

(1:3).

It can be seen that around 75 % of all particles in the

five formulas were in size range of 75-125lm. Hence,

most of the characterization was done on the particles with

this size range rather than the whole populations of parti-

cles in the microcapsules. In addition, size determination

by laser diffraction was also peformed on formula M4. As


1 3


6/13

seen in Fig. 3, an almost normal distribution of particle size

was obsereved with an average particle size of 85.17 lm

with minimum and maximum sizes of 37lm and 148 lm,

respectively.

Yield, drug loading and encapsulation efficiency

The yield was calculated for the whole microcapsule

population in each formula while drug loading andencapsulation efficiency was determined for microcapsules

in the size range 75125 lm. All formulations showed high

yields (C92.8 %) with 24.7325.53 % loading and almost

100 % encapsulation efficiency as shown in Table 4. This

indicates that the microcapsule preparation is not only

efficient but also reproducible.

Scanning electron microscopy (SEM)

Scanning electron micrographs of microcapsule formula-

tions M1, M4 and M5 were shown in Fig. 4 using two

magnification powers. All microcapsules were nearly

spherical with what seems to be small particles on their

surface, which wasassumed to be diclofenac andis discussed

further in the DSC and microcapsule dissolution sections.

Differential scanning calorimetry (DSC)

DSC thermograms of DP, ERL, ERS, microcapsule formula

M4 and their physical mixture (DP:ERL:ERS = 1:1.2:1.8

weight ratio) are presented in Fig. 5. DPs thermogram

shows one sharp exothermic peak at 320 C due to its

decomposition with no apparent endothermic melting. It has

been previouslyreported that above 300 C, DP decomposes

in the range of 290 350 C with a possible decarboxyl-

ation of the diclofenac anion (Fini et al. 2001). Both poly-

mers (ERL and ERS) show endothermic peaks at about

60 C due to glass transition (Tg) and melting endothermic

peaks at 199 C for ERL and 186 C for ERS. The physical

mixture shows a Tg peak that is close to that of the polymersand a broader melting peak at 188 C. DP Microcapsule M4

had a similar thermogram with glass transition (Tg) endo-

thermic peaks at 67.3 C, which occurs at temperatures

higher than that of the melting point of the pure polymers. In

addition, M4 thermogram shows a melting endothermic peak

at 170.6, which occurs at temperatures lower than that of the

pure polymers, and a new endothermic peak at 256.4 C.

Actually the latter peak can be due to a new organic dic-

lofenac salt that might be formed with the quaternary

ammonium groups in the polymer as opposed to the

decomposition temperature that was observed for the inor-

ganic diclofenac potassium salt (Fini et al. 2010). These

results indicate a possible interaction between DP and

polymers in the microcapsules but not in the physical mix-

ture. In addition, the absence of the characteristic peaks of

free DP from the DSC thermogram of the microcapsules

might also indicate that what was seen on the surface of the

microcapsules by SEM were not particles of free DP but

rather due irregularity caused by diclofenac that is conju-

gated to the quaternary ammonium groups on the surface of

the polymer.

Table 3 Microcapsule size

ditribution with their mean

particle size as determined by

sieve analysis

Microcapsule

formulations

% Fraction of Mean particle

size (lm)3875 lm 75125 lm 125180 lm 180212 lm

M1 4.04 72.31 17.52 0.00 107.92

M2 5.05 75.82 12.98 0.00 104.92

M3 6.98 75.75 12.69 0.12 103.92

M4 5.02 74.28 16.05 0.00 106.54

M5 0.00 77.20 13.60 3.02 110.70

Fig. 3 Microcapsule size distribution as determined by laser

diffraction

Table 4 Microcapsule yield, drug loading and encapsulation effi-

ciency in different microcapsule formulations

Microcapsule % Yield % Drug loading

(average SD)a

Encapsulation

efficiency

(average SD)a

M1 97.7 25.53 0.40 97.94 1.54

M2 98.85 25.11 0.44 99.58 1.75

M3 92.81 24.74 0.44 101.09 1.81

M4 93.97 25.04 0.17 99.86 0.67M5 92.81 25.35 0.97 98.71 3.71

a For microcapsule size = 75125 lm


1 3


7/13

Fig. 4 Scanning electron micrographs of microcapsules M1, M4 and M5 formulations observed under two magnification powers (9500 and

92000)

Fig. 5 DSC thermograms of a DP, ERL, ERS, M4 microcapsules and physical mixture (Ph Mix) and b ERL, ERS, M4 microcapsules and

physical mixture (Ph Mix) at different intensity


1 3


8/13

Thermogravimteric analysis (TGA)

TGA thermograms of DP, ERL, ERS, microcapsules and

their physical mixture (DP:ERL:ERS = 1:1.2:1.8 weight

ratio) containing 1:1.8:1.2 are presented in Fig. 6. DPsthermogram shows 13.6 % weight loss, as a function of

temperature, at 309 C as a result of drug decomposition.

The polymers thermograms show complete decomposition

at about 433 and 439 C for ERL and ERS, respectively.

The microcapsules have a different TGA pattern from that

of the physical mixture, which further confirms the pres-

ence of a drug-polymer interaction in microcapsules for-

mulations. The thermograms of the microcapsules show

two decomposition peaks at about 280 and 385 C, which

are attributed to the decomposition of DP and polymer,

respectively. The decomposition temperatures of both drug

and polymers in microcapsule formulation are less thanthose of the pure components. This can be attributed to a

drug and polymer interaction that causes the drug to be

present as a molecular dispersion, which leads to an

increase in the drug surface area, which accelerates the

effect of temperature on the drug and then on the polymer.

The physical mixture thermogram does not show a clear

DP decomposition peak, which might be due to the over-

lapping of the decomposition peaks of the drug and poly-

mer. Complete decomposition of the physical mixture is

observed at about 385 C, which is similar to that of the

microcapsule formulations. This observation can be a result

of heat-induced drug-polymer interaction.

X-ray powder diffraction analysis

The X-ray diffraction patterns of DP, ERL, ERS, micro-

capsule formulation (M4) and the physical mixture

(DP:ERL:ERS= 1:1.2:1.8 weight ratio) are presented in

Fig.7. DPs diffraction pattern shows sharp peaks reflecting

its crystalline nature while the diffraction patterns of both

ERL and ERS are indicative of their amorphous nature. The

physical mixture diffractogram shows sharp peaks, similar

to those of DP but with lesser intensity. Generally speaking,

the diffraction pattern of formula M4 presents an amor-

phous appearance, which agrees with its TGA analysis that

indicated a molecularly dispersed drug in the polymer. Thevery limited number of sharp peaks in the diffractogram of

M4 might be due to diclofenac molecules that are conju-

gated to the surface of the microcapsules.

Fourier transform infrared (FT-IR) analysis

The FT-IR spectra of DP, ERL, ERS, microcapsule for-

mulation M4 and the physical mixture (DP:ER-

L:ERS = 1:1.2:1.8 weight ratio) are presented in Fig. 8.

Fig. 6 Thermograms of diclofenac potassium (DP), polymers (ERL and ERS), microcapsules M4 and physical mixture (Ph Mix) a TGA and

b TGA derivative


1 3


9/13

DPs spectrum shows sharp bands at 1577 cm-1 due to the

carboxylates carbonyl group, 1502 cm-1 due to the aro-

matic ring, 1274 and 765 cm-1 due to CCl group. ERS

and ERL had similar spectra, since they have similar

skeleton but different quaternary ammonium group con-

tent, with strong characteristic bands at 1733 cm-1 due to

the carbonyl groups, 1452 cm-1 due to CH3 group and

1148 cm-1 due to CO stretching of the ester group.

Microcapsule formulations showed identical spectra to

each other. There are two carbonyl group bands at 1733

and at 1577 cm-1, which are similar to that of the polymer

and the drug, respectively, but with apparently lesser

intensity. The polymers band at 1640 cm-1 disappeared

and that at 1387 cm-1 is present but with a decreased

intensity. Generally, the microcapsules spectrum shows

more similarity to those of the polymers rather than that ofthe drug but with differences in the intensity and sharpness

of some bands. On the other hand, the spectrum of the

physical mixture is a combination of that the drug and the

polymer spectra. This indicates that in the microcapsules,

most of the diclofenac molecules are shielded by the

polymer, while in the physical mixture, the drug molecules

are exposed and not dispersed within the polymer. FT-IR

results, in combination with the DSC, TGA and X-ray,

strongly suggest that there is some sort of interaction

between diclofenac and ERL and/or ERS and that the drug

was dispersed within the polymers in microcapsules but not

the physical mix.

Dissolution of diclofenac from microcapsules (M1M5)

at pH 1.2 and pH 6.8

As mentioned earlier, UVVIS spectrophotometry wasused to determine the amount of diclofenac in solution. In

this regard, it must be noted that there was no interference

between diclofenac and any of the components of the mi-

crocapsules or the ODT formulations. However, there was

interference between diclofenac and sodium lauryl sulfate

that was used to improve wettability of the microcapsules

during the dissolution studies. In this case, the UVVIS

spectrophotometer was allowed to autozero with a solution

of identical composition of the dissolution media including

the surfactant. Many factors can affect the formation and

preparation of microcapsules prepared by solvent evapo-

ration method. These are the stirring speed, temperatureand polymer to drug ratio. Increasing the stirring speed

leads to a decrease in particle size and an increase in drug

content (Mateovic et al. 2002). On the other hand,

increasing the processing temperature leads to an increase

in microcapsule size and size distribution with the micro-

capsules becoming more spherical with a smooth surface

(Matovic-Rojnik et al. 2005). Moreover, increasing the

polymer to drug ratio leads to a decrease in microcapsule

size and yield (Klcarslan and Baykara 2003). Dissolution

of diclofenac from microcapsule M1M5 was studied at pH

1.2 and 6.8. As seen in Fig. 9, drug dissolution at pH 1.2

from all the microcapsule formulations exhibited similar

profiles with dissolution of less than 6.2 %. Such low drug

release at this pH can be beneficial since it might indicate

that the stomach will be spared from the direct irritant

action of free diclofenac. It is worth mentioning that there

was no detectable diclofenac dissolution at pH 1.2 from

pure DP (Athamneh et al.2013) which is most likely due to

the low solubility of DP at acidic pH (Shah et al. 2012;

Chuasuwan et al. 2009). Actually, it is interesting to see

that there was release of diclofenac form the microcapsules

but not from pure DP which might suggest that diclofenac

in the microcapsules is not present the form of a potassium

salt hinting to the possibility of a complex/salt formation

between the diclofenac carboxylate anion and the quater-

nary group in the polymer. Figure10shows DPs release

from the microcapsule formulations at pH 6.8. At this pH,

drug dissolution increases as the content of ERL in mi-

crocapsules decreases. Formula M5, which contains ERL

alone, shows the lowest drug release (52 % after 9 h)

whereas formula M1, which contained ERS alone, shows

the highest drug release (90 % after 9 h).

Fig. 7 X-ray diffraction pattern of DP, ERL, ERS, M4 microcapsules

and physical mixture (Ph Mix)


1 3


10/13

This variability in drug release is very important because

its strongly suggests that there is a specific interaction

between the carboxylate group of diclofenacs conjugatebase

and the quaternary ammonium in the polymers. The higher

retardation of drug release in the presence of ERL might be

due to its higher quaternary ammonium groups content

compared ERS. The higher the number of positively charged

quaternary ammonium groups in the polymer, the more theavailable sites for interaction with the negatively charged

carboxylate group in diclofenac. This salt-bridge adds

another layer of release retardation in addition to the retar-

dation that is provided by encapsulation of the drug inside the

polymer. Another important observation was the absence of

any burst release form the microcapsules which,like the DSC

results, indicates that what was seen on the surface of the

microcapsules by SEM was not uncomplexed DP.

Depending on the dissolution studies, it was decided that

microcapsules M4 showed drug dissolution with acceptable

release retardation; therefore, it was selected for further

investigations. The consecutive drug dissolution from M4microcapsules, based on USP method A for sustained-

release preparations, at pH values 1.2, 5.8 and 6.8, as three

consecutive phases was studied and the result is presented

in Fig. 11.

Fig. 8 FT-IR spectra of DP,

ERL, ERS, M4 microcapsules

and physical mixture (Ph Mix)

Fig. 9 Dissolution of diclofenac from microcapsule formulations at

pH 1.2 and at 37 C (n = 3)


1 3


11/13

It can be seen that there is an increase in drug release at

pH 5.8, compared to that at pH 1.2, with a lag time of about

15 min. This lag time is most likely due to the time neededfor microenvironment of microcapsules to change its pH.

Characterization of DP sustained-release ODTs, F1

and F2

Microcapsules M4 were used in the preparation of two DP

sustained-release ODT formulations (F1 and F2). F1 con-

tained 400 mg microcapsules (equivalent of 100 mg DP) in

addition to mannitol. F2 contained 200 mg microcapsules

(equivalent of 50 mg DP) in addition to sorbitol and lac-tose. F1 and F2 were formulated based on preliminary data

that showed that mannitol increases tablet friability

whereas sorbitol increases tablet hardness (Mizumoto et al.

2005). The porosity (e), friability (F), hardness (H) and

disintegration time (DT) of the investigated ODTs (F1 and

F2) are presented in Table 5.

Although the disintegration of F1 ODT is considered

acceptable (less than 1 min), the tablets showed no hardness,

which means that they have no resistance to mechanical

stress and have very high friability. The presence of high

content of microcapsules can lead to such high friability; the

spherical nature of microcapsules makes the contact pointbetween the tablets blend very low. On the other hand, F2

ODT shows good disintegration time and the tablets show

acceptable hardness and slight friability. This formula con-

tains only 50 % of the microcapsules content of F1 (equiv-

alent of 50 mg DP) in addition to lactose and sorbitol, which

improves the tablet hardness and friability.

Consecutive dissolution of diclofenac from F2

sustained-release ODT

Further dissolution study was performed on F2. Consecu-

tively dissolution of diclofenac at three different pH valuesis shown in Fig.12. The cumulative percent of drug

released at pH 1.2 after 2 h was 4.6 %. Although it is is less

than that of microcapsules M4, it is acceptable for such

kind of formulations as mentioned earlier. At pH 5.8,

Diclofenacs release from the ODT is greater than that for

the microcapsules themselves as 39 % of the drug was

released. The release at pH 6.8 was similar to that of the

microcapsules as 50 % of the drug was released after 3 h.

The most interesting variation between in dissolution of

diclofenac from microcapsules M4 versus F1 ODT is the

increased dissolution at pH 5.8, which can be due to the

presence of lactose, sorbitol and crospovidone thatenhanced the solubility of the drug.

A comparison of the dissolution profile of diclofenac

from microcapsules and from the ODT formula was carried

out by calculating the similarity factor (F2). AlthoughF2 is

not commonly used for such purpose it will give an indi-

cation to whether the release behavior has been changed

due to incorporation of excipients and/or application of

compression. Similarity factor (F2) can be calculated

according to Eq.7.

Fig. 10 Dissolution of diclofenac from DP and microcapsule

formulations at pH 6.8 and at 37 C (n =3)

Fig. 11 Consecutive dissolution of diclofenac from microcapsules

M4 at pH 1.2, 5.8 and 6.8 and at 37 C (n = 3)

Table 5 The porosity (e), friability (F), hardness (H) and disinte-

gration time (DT) of F1 and F2 ODTs

Formula e % F % H (KP) DT (s)

F1 21.44 0.64 25.79 0.00 0.00 43.65 5.53

F2 12.21 1.09 2.13 4.08 0.64 22.41 3.96


1 3


12/13

F2 50log 1 1=n Xnt1

Rt Tt 2

" #0:5100

8

Documents

Eudgarit RL Odts