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17th International Drying Symposium (IDS 2010) Magdeburg,
Germany, 3-6 October 2010
PHARMACEUTICAL SOLID DISPERSIONS YIELD DURING SPRAY
CONGEALING
R.M. Martins, L.A.P. Freitas
Faculdade de Ciências Farmacêuticas de Ribeirão Preto
Universidade de São Paulo Via do Café s/n CEP 14040-903, Ribeirão
Preto, SP, Brazil
Tel.: +55 16 3602 4225 and Fax: 55 16 3602 4872 Email:
[email protected]
Abstract: The purpose of the present study was to employ the
spray congealing technique to obtain microparticles of
carbamazepine solid dispersion using Gelucire 50/13® as carrier and
to investigate the influence of spraying process parameters using a
Box Behnken design on process yields. The independent variables
selected were atomization pressure, cooled airflow and molten
dispersion feed rate. The yields ranged from of 54% to 80%. The
yield was strongly affected by their squared terms and as well as
their interactions terms. The data obtained showed that this
process is suitable to produce microparticles of CBZ solid
dispersions with good yield. Keywords: microparticles,
carbamazepine, Gelucire 50/13®, spray dryer, Box Behnken design
INTRODUCTION
The interest for the improvement of the dissolution properties
of active pharmaceuticals ingredients (APIs) is growing because the
percentage of poor water soluble drugs has increased in recent
years (Leuner and Dressman, 2000). Poorly soluble drugs represent a
problem due to their low availability and dissolution rate (Fini et
al., 2005). Therefore, besides permeability, the solubility and
dissolution behavior of a drug are fundamental parameters for its
oral bioavailability (Cavallari et al., 2007). Together with
micronization, other methods have been proposed to increase the
APIs dissolution rates, such as manufacturing of soluble salt or
complexes, use of surfactants and the preparation of solid
dispersion (Fini et al., 2002).
Preparation of solid dispersion is a useful method to disperse
drugs in the molecular state in a carrier matrix (Takeuchi et al,
2004). Numerous solid dispersion systems (SDS) have been proposed
in the pharmaceutical literature to improve the dissolution
properties of poorly water-soluble drugs (Dhirendra et al, 2009).
However SDS presents some drawbacks related to the method of
preparation, reproducibility, physicochemical properties; scale up
of manufacturing processes and the physical and chemical stability
of drug and vehicle (Serajuddin, 1999).
The spray congealing technique is an interesting alternative to
overcome these drawbacks, because it produces microparticles with
nearly spherical shape, sizes in the micrometric range, and the
drug is evenly distributed within the entire volume of the particle
(Ilic et al., 2009). Besides, in the last two decades, spray
congealing has attracted increasing attention because it does not
require the use of aqueous or organic solvents and hence, is
environmentally friendly and less time and energy consuming
compared to other methods like spray drying, for example (Passerini
et al., 2009). In spray congealing and spray drying the basic
principles are very similar and the same equipment can be used with
some modifications. In general, the feed tubes of peristaltic pump
and the nozzle must be heated to avoid unwanted solidification, and
air flowing through the process chamber should be cooled (Ilic et
al., 2009). Therefore, spray congealing represents a very
attractive method for the preparation microspheres of solid
dispersion with the objective of increasing the dissolution rate of
poor water soluble drugs. Spray congealing was successfully
employed for the preparation of microspheres loaded with drugs such
as carbamazepine (Passerini et al, 2002), indomethacin (Fini et
al., 2002), praziquantel (Passerini et al., 2006), diclofenac
(Cavallari et al., 2005) and glimepiride (Ilic et al., 2009).
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The aim of the present study was to investigate the effects of
spray congealing conditions on the process yield during
carbamazepine SDS microparticles preparation. The carbamazepine
(CBZ) was used as a model of poor water soluble drug and the
polyoxilglyceride Gelucire 50/13® as the hydrophilic carrier. The
experiments followed a Box Behnken design, resulting in total of 15
experiments.
MATERIAL AND METHODS
The CBZ was supplied by Cristalia Farmoquímica Ltd. (São Paulo,
Brazil) and the Gelucire 50/13® was kindly donated by
Gatefossé-France (Saint-Priest, France).
Microspheres Preparation
The microspheres were manufactured using a mini spray drier
model LM MSD 0.5 (Labmaq do Brasil Ltda, Ribeirão Preto, Brazil)
with capacity of drying up to 0.5 liter per hour. The cylindrical
drying chamber is made of borosilicate glass and has diameter of
130 mm and 510mm in height. Figure 1 shows a picture of this
apparatus. This apparatus was modified to be used as a spray
congealing system and was operated in concurrent flow, A 3/4 HP
chiller was connected to the exit of the air blower and the air was
chilled to 18±1ºC. The atomization was carried out with a
double-fluid pneumatic nozzle with 1.2 mm orifice. This spray
nozzle was jacketed in its whole extension, allowing the flow of a
heating fluid pumped from a thermostatic oil bath at 120ºC. The
molten solid dispersion was fed using a peristaltic pump adapted
with an especially designed heated head, with temperature
controlled at 80oC by an On/Off controller. The silicon tubing was
heated by a flexible heating wire along the distance from
peristaltic pump to spray nozzle. The liquid feed was prepared by
melting the Gelucire 50/13® in a beaker immersed in a thermostatic
oil bath at 70ºC and slowly adding the CBZ, until the proportion of
10% CBZ in Gelucire (w/w). The weight of molten carrier plus CBZ
used in each experiment was always 100g. The other experimental
factors were varied according to the Box-Behnken design, as shown
in the next item. After the atomization the microspheres were
collected and dried in a desiccator under vacuum at room
temperature for at least 48 hours and then weighed.
Design of Experiments
The experiments were carried out following a 3-level, 3-factor
Box-Behnken design with a total of 15 experimental runs (Box et al,
1978). The factors studied were atomizing pressure (PA), cooling
airflow rate (WCA), and molten dispersion feed rate (WMD). The
levels of the
factors studied are presented in Table 1, which shows the coded
and non-coded values of the factors. The factors were coded to
allow the ANOVA analysis following the coding rule given by Eq.
(1)
( )( )LowHigh
LowHighValueXi
−
+−=
21
21
(1)
Analysis of variance on experimental data was performed by
surface response methodology using the module Visual General Linear
Model (VGLM) from the software Statistica ’99 (Statsoft Inc, USA).
A multiple linear equation as given by Eq. (2) was applied for the
response function.
++++= 3322110% XAXAXAAY
++++ 326315214 XXAXXAXXA
239
228
217 XAXAXA +++ (2)
The experimental design may be applied to determine the range of
factor levels to maximize the yield, based on the corresponding
response surface.
Table 1. Factors and their levels
Levels Factors -1 0 +1 X1, PA (bar) 5.0 6.0 7.0 X2 WCA (m3/min)
0.9 1.0 1.1 X3, WMD (ml/min) 5.0 6.0 7.0
The factors studied were considered significant when ANOVA
result in a probability low 5% (p
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Fig.1. Lab scale spray dryer model MSD 0.5 (source:
http://www.labmaqdobrasil.com.br)
RESULTS AND DISCUSSION
The yields were determined to each experiment and are shown in
Table 2. The values ranged from 54% (exp. 1 and 4) to 80% (exp. 8).
These results were satisfactory for a lab scale spray apparatus,
since very low (
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by spray congealing with atomization pressures from 5 to 6 bar
and reported yields between 78.70 to 95.10%. The different ranges
of yields found by Maschke et al (2007) and this work may be
related to carrier properties, like melting point and viscosity,
and spray congealing operational conditions.
Table 3. Analysis of variance on yield
Factor SS DF MS p
PA 22.78 1 22.78 0.10
WCA 24.50 1 24.50 0.09
WMD 9.03 1 9.03 0.26
PA x WCA 182.25 1 182.25 0.0023
PA x WMD 390.06 1 390.06 0.0004
WCAx WMD 6.25 1 6.25 0.3415
PA 2 40.51 1 40.51 0.0440
WCA 2 364.63 1 364.63 0.0004
WMD 2 40.51 1 40.51 0.0441
Error 28.31 5 5.66
Besides the effect on droplets size, spray high pressure tend to
form a jet cone with lower opening angle and then avoiding losses
to the chamber wall. In this work, the loss of material to the
chamber wall occurs mainly due to Gelucire 50/13® low melting
point, forming a stick and tacky mass (Araújo et al, 2010) during
the residence time inside the chamber. This phenomenon was observed
by Araújo et al, 2010 during the preparation of curcumin/Gelucire
44/14® microparticles, which showed a high adhesion onto the walls
of the chamber during spray drying which resulted in low
yields.
Fig. 2. Surface response of yield as function of atomization
pressure (PA) and cooling airflow
rate (WCA)
Fig. 3. Surface response of yield as function of atomization
pressure (PA) and molten dispersion
feed rate (WMD)
The authors were able to overcome this problem by the addition
of colloidal silicon dioxide (Aerosil®) in the formulation (Freitas
et al, 2010). The polyoxylglycerides Gelucire® are a group of
lipid-based excipients, characterized by two numbers, the first
corresponding to the melting point of the material and the second
to the hydrophilic-lipophilic balance (HLB) that reflects the
proportions of water or lipid soluble matter in each material
(Cavallari et al., 2005).
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Fig. 4. Surface response of yield as function of molten
dispersion feed rate (WMD) and cooling
air flow rate (WCA)
However, the low melting point of the excipient and the use of a
lower atomizing pressure (5 bar) led to a strong loss of material
to the walls of the chamber, around 50%. As discussed before, this
high stickiness is due to larger droplets size and smaller contact
surface area between molten mixture and cooling air, causing a low
heat transfer rate due to smaller transfer area. The amount of
energy that needs to be removed from molten droplets is equal to
the latent heat of solidification, plus sensible heat to bring
droplet temperature to melting point. As contact time between
droplet and cooling air is limited by the residence time inside the
chamber, only partial solidification of droplet and as a
consequence, sticking to the walls occurs. In the case of larger
droplets, the heat transfer rate is expected to be lower and
cooling residence time should be prolonged by increasing chamber
size. Another option to solve this problem could be the use of
lower air inlet temperature, increasing air-droplet temperature
difference and thus allowing complete solidification of solid
dispersion.
A polynomial equation was fitted to experimental data (Eq. 3),
considering only the factors with effects significant at 5%. Eq. 3
was fitted with a squared correlation coefficient (R2) of
0.9736.
+⎟⎟⎠
⎞⎜⎜⎝
⎛ −⎟⎠
⎞⎜⎝
⎛ −−=
1.01
168.674% CAA
WPY
−⎟⎠
⎞⎜⎝
⎛ −−⎟⎠
⎞⎜⎝
⎛ −⎟⎠
⎞⎜⎝
⎛ −+2
16
3.31
61
69.9 AMDA
PWP
(3)
0 25 50 75 1
Experimental ( % )00
0
25
50
75
100
Pred
icte
d ( %
)
+5%
-5%
Fig. 5. Experimental versus predicted (response surface
methodology) values for yield
The comparison of the experimental values of yield with the
values predicts by Eq. 3 is shown in Figure 5. Most part of the
data could be predicted within ±5%, except for one data point.
CONCLUSION
The yield were affected by the quadratic terms of atomizing
pressure (PA), cooling airflow rate (WCA), liquid feed rate (WMD),
as well as the interaction terms between PA and WCA and PA with
WMD. The best condition was using high PA (7 bar), high WMD (7
mL/min) and intermediate values of WCA (1 m3/min) with 80% of yield
(exp.8). The data obtained showed that this process is suitable to
produce CBZ solid dispersion microparticles with great yield.
NOMENCLATURE
Ai polynomial coefficients; APIs active pharmaceuticals
ingredients; CBZ carbamazepine; DF degree of freedom in ANOVA; HLB
hydrophilic-lipofilic balance; MS mean squares in ANOVA; PA coded
atomizing pressure (bar); SDS solid dispersion systems; SS sum of
squares in ANOVA; X1 coded atomizing pressure (PA); X2 coded
cooling airflow rate (WCA);
22
13.3
1.019.9
⎠⎝⎛ −−
⎠⎞
⎜⎝⎛ − MDCA WW 6 ⎟⎞⎜⎟−
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X3 coded molten dispersion feed rate (WMD); Y1 yield (dependent
variable); WCA cooling airflow rate (m3/min); WMD molten dispersion
feed rate (ml/min).
ACKNOWLEDGEMENTS
Financial support from FAPESP (08/07115-0 and 08/02848-9) and
CNPq (PQ-2) are gratefully acknowledged.
REFERENCES
Araújo, R. R., Teixeira, C. C. C., Freitas, L. A. P. (2010). The
preparation of ternary solid dispersions of an herbal drug via
spray drying of liquid feed. Drying Technology, 28, 412-421.
Borini, G.B.; Freitas, L.A.P. (2006). Study on the Spray
Congealing of a Pharmaceutical Wax. Proceedings of 15th
International Drying Symposium, Ed. A.S. Mujumdar and I. Farkas,
Budapest, Hungary, pp. 1169-1173.
Box, M.; Hunter, W.G.; Hunter, J.S. (1978). Statistics for
experimenters. John Wiley & Sons, N.Y.
Cavallari, C.; Luppi, B.; Di Pietra, A.M.; Rodriguez, L.; Fini,
A. (2007). Enhanced release of indomethacin from PVP/stearic acid
microcapsules prepared coupling co-freeze-drying and ultrasound
assisted spray-congealing process. Pharmaceutical Research, 24 (3),
521-529.
Cavallari, C.; Rodriguez, L.; Albertini, B.; Passerini, N.;
Rosetti, F.; Fini, A. (2005). Thermal and fractal analysis of
diclofenac/gelucire 50/13 microparticles obtained by
ultrasound-assisted atomization. Journal of pharmaceutical
sciences, 94 (5), 1124-1134.
Dhirendra, K.; Lewis, S.; Udupa, N.; Atin, K. (2009). Solid
dispersions: A review. Pack. J. Pharm. Sci., 22 (2), 234-246.
Fini, A.; Moyano, J.R.; Perz-Martinez, J.I.; Rabasco, A.M.
(2005). Diclofenac salts, II. Solid dispersions in PEG 6000and
Gelucire 50/13. European Journal of Pharmaceutics and
Biopharmaceutics, 60, 99-11.
Fini, A.; Rodriguez, L.; Cavallari, C.; Albertini, B.;
Passerini, N. (2002). Ultrasound-compacted and spray congealed
indomethacin/polyethylenoglycol systems. International Journal
Pharmaceutics, 247, 11-22.
Freitas, L. A. P., Andrade, T. C., Teixeira, C. C. C., Tacon, L.
A., Tsukada, M. (2010). Innovative applications of spray drying.
Chapter No 1 of Advances in Chemical Engineering/ ed. Maria Jose
San Jose, Transworld Res. Network, Kerala, India, pp. 1-12.
Leuner, C.; Dressman, J. (2000). Improving drug solubility for
oral delivery using solid dispersions. European Journal
Pharmaceutics and Biopharmaceutics, 50, 47-60.
Maschke, A., Becker, C., Eyrich, D., Kiermaier, J., Blunk, T.,
Göpferich, A. (2007). Development of a spray congealing process for
the preparation of insulin-loaded lipid microparticles and
characterization thereof. European Journal Pharmaceutics and
Biopharmaceutics, 65, 175-187.
Ilic, I.; Dreu, R.; Burjak, M.; Homar, M.; Kerc, J.; Srcic. S.
(2009). Microparticle size control and glimepiride
microencapsulation using spray congealing technology. International
Journal Pharmaceutics, 381, 176-183.
Passerini, N.; Albertini, B.; Perissuti, B.; Rodriguez, L.
(2006). Evaluation of melt granulation and ultrasonic spray
congealing as techniques to enhance the dissolution of
praziquantel. International Journal of Pharmaceutics, 318,
92-102.
Passerini, N.; Perissutti, B.; Moneghini, M.; Voinovich, D.;
Albertini, B.; Cavallari, C.; Rodriguez, L. (2002).
Characterization of carmazepine-gelucire 50/13 microparticles
prepared by a spray-congealing process using ultrasounds. Journal
of Pharmaceutical Sciences, 91, 699-707.
Serajuddin, A.T.M. (1999). Solid Dispersion of poorly
water-soluble: early promises, subsequent problems, and recents
breakthroughs. Journal of Pharmaceutical sciences, 88(10),
1058-1066.
Takeuchi, H., Nagira, S., Yamamoto, H., Kawashima, Y. (2004).
Solid dispersion particles of talbutamide prepared with fine sílica
particles by the spray-drying method. Powder Tecnology, 141,
187-195.
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