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Spray-dried microparticulate systems containingacetaminophen
A. BILLON, B. BATAILLE*, M. DELALONDE and M. JACOB
Universite Montpellier 1, U.F.R. Sciences Pharmaceutiques et Biologiques,Laboratoire de Pharmacie Gale nique, Pharmacotechnie et Biopharmacie,E.A. 3008 `Ge nie des Proce de s et Sciences des Aliments’, 15, Avenue CharlesFlahault, F-34060 Montpellier Cedex 2, France
(Received 28 December 2000; revised 20 April 2001; accepted 5 May 2001)
The present work investigates the preparation and the release of acetaminophenfrom spray-dried microparticles. Two cellulose derivatives were tested assustaining agents: microcrystalline cellulose (MCC) and sodium carboxy-methylcellulose (NaCMC). In-vitro dissolution studies were carried out indissolution media of di� erent pH. With MCC, the adsorption of acetamino-phen on the surface or in the pores of the polymer does not allow a signi®cantsustained release of the drug, which completely dissolves in 1 h. Conversely, theuse of NaCMC retards the release of acetaminophen over a period of 6±8 h. Thedrug release depends on the plasticizer used and on the pH of the dissolutionmedium, and the mechanism consists essentially in the di� usion of the drugthrough the swollen polymeric matrix. The pH dependence observed can becorrelated with a lower hydrophylicity of the polymer in acidic medium, whichretards gel formation.
Keywords: Controlled release, matrix system, spray-drying, acetaminophen,cellulosic derivatives, microparticle.
Introduction
Controlling the release of drugs is of great interest to increase their therapeutice � ect by improving patient compliance or reducing side e � ects (Alderman 1984).
Among the various drug delivery devices used to sustain drug release, hydrophilic
matrix systems are generally preferred because of their ability to release drugs at a
constant rate. The matrix is often composed of a drug mixed with a gelling agent
(hydrophilic polymer). Cellulose derivatives are often chosen to develop such
systems because of their low toxicity and low cost (Salsa et al. 1997).In a previous study, the production of microparticles of acetaminophen and
cellulose derivatives by a spray-drying process was optimized (Billon et al. 2000).
The purpose was to sustain drug release for several hours. Two polymers of
di� erent solubility were studied as sustaining agents: microcrystalline cellulose
(MCC) and sodium carboxymethylcellulose (NaCMC) associated with di� erent
additives: polyvinylpyrrolidone (PVP) as binder with MCC, oxalic acid (OA) andtartaric acid (TA) as plasticizers with NaCMC.
j. microencapsulation, 2002, vol. 19, no. 2, 165±172
* To whom correspondence should be addressed: e-mail: [email protected]
Journal of Microencapsulation ISSN 0265±2048 print/ISSN 1464±5246 online # 2002 Taylor & Francis Ltdhttp://www.tandf.co.uk/journals
DOI: 10.1080/02652040110065459
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The aim of the present study is to evaluate the release of acetaminophen fromthe spray-dried microparticles in media of di� erent pH. Mathematical models,
especially linearization methods (Weibull and Higuchi’s laws) were used tounderstand the drug release mechanism (Bentejac et al. 1992). In this study,three di� erent formulations are compared.
Materials and methods
Materials
Acetaminophen (Rhodapap pulve rise ®n1, Rhoà ne-Poulenc, batch n° 9717826,Eur. Ph. 3rd edn) is used as a model drug. The polymers are microcrystallinecellulose (MCC: Vivapur1 PH101, Rettenmaier & SoÈ hne, Eur. Ph. 3rd edn) and
sodiumcarboxymethylcellulose (NaCMC: Blanose1 cellulose gum 7LF, Hercules,Eur. Ph. 3rd edn). Additives used in this study are polyvinylpyrrolidone (PVP:Kollidon1 30, BASF, Eur. Ph. 3rd edn) and carboxylic acids including oxalic acid(OA, Prolabo) and tartaric acid (TA, Aldrich Chemie, Eur. Ph. 3rd edn). Colloidal
silicon dioxide (SiO2: Aerosil1 200, Degussa) was added to all formulations.
Preparation of spray-dried microparticles
Acetaminophen and polymers in a mass ratio 1/1 were dissolved (NaCMC) orsuspended (MCC) in distilled water. The amount of additive added is a function ofthe mass of polymer. With NaCMC, the quantity of tartaric acid or oxalic acidrepresents 30% of the mass of polymer and the amount of SiO2 is 8% of the total
mass. With MCC, the ratio PVP/MCC used is 3%w/w and the amount of SiO2
represents 18.8% of the total amount (Billon et al. 2000).These feeds were spray-dried using a Niro Minor Mobile (Niro Atomizer,
Denmark) through a rotating wheel. The operating parameters were set as follows:
dry air rate 85 m3/h; atomizing air pressure 8 bars; inlet temperature 140°C withNaCMC and 160°C with MCC; feed rate 20 ml/min (NaCMC) and 30 ml/min(MCC) (Billon et al. 2000).
Scanning Electron microscopy
The spray-dried products were coated under an argon atmosphere with gold/palladium and examined with an electron microscope (Hitachi S 4000, Japan).
Dissolution studies
Drug dissolution pro®les from the spray-dried microparticles were obtained bythe paddle rotating dissolution apparatus (Eur. Ph. 3rd edn). Spray-dried products(375 mg) placed in hard-shell capsules were immersed in 900 ml dissolution media(pH 1, distilled water of pH 5.5 and phosphate bu� er pH 6.8) maintained at
37°C 0.5°C, with the rotating paddle set at 50 rpm. Sinkers with a helix shapewere used to maintain the capsules at the bottom of the beaker. Samples wereautomatically collected (Gaudy et al. 1989) at regular intervals using a peristalticpump over a period of 8 h and assayed spectrophotometrically at 244 nm (Perkin
Elmer ¶15) before being replaced in the medium.
166 A. Billon et al.
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Data analysis
In order to make comparisons between the di � erent formulations and tofacilitate the understanding of the drug release mechanisms, each dissolutionpro®le was ®tted to the Weibull’s equation (Langenbucher 1976):
Q ˆ 1 e …T=td † …1†
where Q represents the percentage of drug released; T, the time; td, the time for63.2% released; and , the form parameter. This mathematical function can beapplied to most dissolution pro®les and the parameters td and allow thecomparison of di� erent formulations. Moreover, the drug release mechanismcan be partly determined from the form parameter.
Formulations for which the form parameter was less than one were thenstudied using Higuchi’s model (Higuchi 1963):
Q ˆ Kp
t …2†
where Q represents the percentage of drug released; K, a constant; and t, the time.This model characterizes a drug release controlled by di� usion through a poly-meric matrix (Salsa et al. 1997). The regression parameters were calculated to
determine the ®tting of the pro®le to Higuchi’s model.
Results and discussion
Dissolution studies were carried out on six samples of each formulation in threedissolution media. The means of the results were computed and dissolutionparameters t20%, t50% and t100% are shown in table 1. The dissolution valuesobtained in this study are reproducible for the three formulations (standarderror <5).
In¯uence of formulations in drug delivery 167
Table 1. Means and standard error of dissolution parameters of acetaminophen releasedfrom di� erent microparticles (n = 6).
pH 1 Distilled water pH 6.8(pH 5.5)
M SD M SD M SD
MCC/PVPt20% 6 min 4 7 min 1.6 8 min 3t50% 8 min 4.2 11 min 3.57 12 min 5t100% 45 min 0.23 60 min 2.67 60 min 2.86
NaCMC/tartaric acidt20% 35 min 0.93 55 min 2.47 70 min 1.32t50% 155 min 0.95 200 min 2.38 275 min 1.55t100% >8 h 1.31 >8 h 3.5 >8 h 1.8
NaCMC/oxalic acidt20% 35 min 1.85 65 min 1.67 45 min 1.49t50% 150 min 2.52 200 min 3.07 100 min 2.61t100% >8 h 4.15 >8 h 5 370 min 2.85
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Release rates of acetaminophen
The results obtained indicate two di� erent release behaviours depending on thesolubility of the polymer used.
Microcrystalline cellulose microparticles. With MCC, which is not water-soluble,the total amount of acetaminophen is released in less than 1 h in all media. Thedelay in drug dissolution is not di� erent compared to the pure acetaminophen(t50% ˆ13 min and 12 min for spray-dried pure drug and microparticles, respect-ively).
MCC behaves as an inert matrix, but the adsorption of the drug on the surfaceor in the pores of MCC is not su� cient to permit the sustaining of acetaminophenrelease. SEM observations (®gure 1) show a signi®cant amount of drug and otherexcipients which appear as totally free small particles, not retained by the cellulose.
Sodium carboxymethylcellulose microparticles. When using NaCMC as polymer,the complete dissolution of the drug required 6±8 h, depending on the plasticizerand on the pH of the dissolution medium (®gures 2(a) and (b)).
This sustaining is partly due to an aggregation of the particles, which occursinto the gelatinous capsules by contact with the dissolution medium and persistsafter the dissolution of the capsules. The amount of spray-dried microparticlesforms a compact mass and behaves as an unique entity (a monolith). Thisphenomenon is due to the hydrophilic properties of NaCMC, which permit therapid formation of a gelatinous protective layer at the system surface.
The particles prepared also show a pH-dependent behaviour. This can beexplained by the higher hydrophily of the polymer in neutral or alkaline media(Boraie et al. 1990). In such conditions, the gel barrier appears more quickly,which delays the release of the drug.
The sustaining of the drug release reinforces the hypothesis of a drugencapsulation, which could be supposed ®rstly from the SEM photographs (®gure3) showing pseudospherical particles with a smooth surface and, secondly, by the
taste masking observed.At the end of the dissolution study, i.e. after 8 h, nearly 80% of the drug is
dissolved. Moreover, dissolution curves on ®gure 3 show that the drug delivery is
not completely ®nished. This indicates that the total amount of acetaminophen can
168 A. Billon et al.
10 µm
Figure 1. SEM photographs of Acetaminophen/MCC/PVP/colloidal silica.
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be released by the hydrophilic matrix. The drug is not partly retained by thepolymer. In this case, the spray-drying of solutions containing acetaminophen,NaCMC and plasticizers induces the formation of hydrophilic controlled releasesystems.
Mechanism of drug release
To understand the mechanism of drug release from the NaCMC microparti-
cles, the dissolution curves were linearized using Weibull’s method (equation 1).
In¯uence of formulations in drug delivery 169
0
10
20
30
40
50
60
70
80
90
100
0 100 200 300 400 500
pH 1
E.D.
pH 6,8
Dru
g re
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%)
pH 1
pH 5.5
pH 6.8
Time (minute)
0
10
20
30
40
50
60
70
80
90
1 00
0 1 00 2 00 30 0 4 00 500
pH 1E.D .pH 6 ,8
Dru
g re
leas
ed (
%)
PH 1
PH 5.5
PH 6.8
Time (minute)
Figure 2. Acetaminophen dissolution pro®les from NaCMC microparticles with (a) OAand (b) TA as plasticizers.
(a)
(b)
10 µm
Figure 3. SEM photographs of acetaminophen/NaCMC/TA/colloidal silica.Jour
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This mathematical study permits to obtain two parameters td (time parameter
corresponding to 63.2% of drug released) and (shape parameter), which facilitate
the comparison of the di � erent formulations and give information on the release
mechanism (Gibassier et al. 1982, Brossard and Wouessidjewe 1990). The valuesobtained for these parameters are indicated in table 2. This study was carried out
on the formulations containing NaCMC which are especially suitable for con-
trolled release.
The results obtained for td con®rm the pH-dependence of the systems
produced, the slower release rates being obtained in neutral or alkaline media
for the reasons mentioned above. The di� erence in drug dissolution appears from
the beginning of the study, as indicated by t20%.Concerning the parameter, with oxalic acid as plasticizer, its value varies
depending on the pH of the dissolution media, indicating di � erent release
mechanisms. In acidic medium, < 1, which corresponds to a dissolution curve
having an exponential pro®le. In this case, the release mechanism consists
essentially in a di� usion of the drug throughout the gel barrier formed by the
swollen polymer.
In the pH 5.5 medium, ˆ 1, the pro®le of the curve is parabolic. The releaseseems to occur in two steps: during the ®rst 2 h, acetaminophen is released by a
di� usion mechanism. The drug is then released at a constant rate linked to a
di� usion mechanism associated with the erosion of the system. In the phosphate
bu� er, > 1, the di � usion is in this condition, quickly accompanied by a
disintegration of the system, inducing the dispersion of the microparticles in the
dissolution medium. This explains the increase of the release rate observed in the
second part of the curve.Concerning the formulation containing tartaric acid as plasticizer, the shape
parameter is almost constant in all dissolution media, showing a similar mechan-
ism of release by di � usion across the gel layer. This di� usion mechanism is
con®rmed by applying Higuchi’s model (equation 2) to the results (Brossard and
Wouessidjewe 1990). The graphs obtained, relating the amount of drug released to
the square root of time, are linear, as indicated by the regression equations and the
correlation coe� cients indicated in table 3. Moreover, the slope of the graphsincreases with the acidity of the medium, a result which correlates with the pH
dependence already observed.
This formulation associating NaCMC and TA presents a special interest in the
development of sustained release forms. The drug release occurs over a period of
170 A. Billon et al.
Table 2. Weibull’s dissolution parameters for NaCMC microparticlescalculated by linearization of the mean dissolution curve (n = 6).
pH 1 Distilled water pH 6,8
NaCMC/tartaric acidtd 227 min 298 min 407 min 0.828 0.879 0.865
NaCMC/oxalic acidtd 228 min 277 min 130 min 0.818 1.04 1.273
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more than 8 h, which meets the requirements of prolonged release. Moreover, the
same mechanism governs the release in all dissolution media, which facilitates theprediction of the pharmaceutical form behaviour.
Conclusion
Through these in-vitro dissolution studies, one has shown that the use ofmicrocrystalline cellulose is not convenient in these conditions of work tosigni®cantly modify the drug release rate. Conversely, the e� ciency of sodiumcarboxymethylcellulose was demonstrated, the best formulation consisting in the
association of NaCMC with tartaric acid. These microparticles produced by thespray-drying process behave as hydrophilic matrices that allow a prolonged drugrelease over a period of 8 h. This sustaining permits a long administration intervalto maintain the therapeutic e � ects, and so meets the requirements for thedevelopment of controlled release systems.
Following this work, studies are performed to develop a directly administrablepharmaceutical form from the NaCMC/TA/Acetaminophen spray-dried micro-particles.
References
Alderman, D. A., 1984. A review of cellulose ethers in hydrophilic matrices for oralcontrolled-release dosage forms. International Journal of Pharmaceutical Technology& Product Manufacture, 5, 1±9.
BentE jac, R., and Leverge, E. R., 1992, Les essais de dissolution des formes solides pourvoie orale. Mise au point biopharmaceutique et relations avec la biodisponibilite .Rapport d’une commission SFSTP. S.T.P. Pharma Pratiques, 2, 500±506.
Billon, A., Bataille, B., Cassanas, G., and Jacob, M., 2000, Develoment of spray-driedacetaminophen microparticles using expetrimental designs, International Journal ofPharmaceutics, 203, 159±168.
Billon, A., Petit, M., Doko, B., Bataille, B., and Jacob, M., 1999, E� ects of cellulosederivatives and additives in the spray-drying preparation of acetaminophen deliverysystems. Drug Developments in Industrial Pharmacy, 25, 1149±1156.
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In¯uence of formulations in drug delivery 171
Table 3. Regression equations using Higuchi’s model.
pH1 Y ˆ 4:36 4:04 R ˆ 0:9982Distilled water Y ˆ 4:03
pt 7:78 R ˆ 0:9988
pH 6,8 Y ˆ 3:69p
t 10:97 R ˆ 0:9995
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Langenbucher, F., 1976, Parametric representation of dissolution rate curves by theRRSBW distribution. Pharmaceutical Industry, 38, 472±477.
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172 In¯uences of formulations in drug delivery
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