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Научни трудове на Съюза на учените в България-Пловдив, серия Г.Медицина, фармация и дентална медицина т. XVIII. ISSN 1311-9427. Научна сесия „Медицина и дентална медицина", 5 - 6 ноември 2015. Scientific works of the Union of Scientists in Bulgaria-Plovdiv, series G. Medicine, Pharmacy and Dental medicine, Vol. XVIII, ISSN 1311-9427 Medicine and Dental medicine Session, 5-6 November 2015.
INFLUENCE OF THE SPRAY DRYING FORMULATION PARAMETERS ON THE PRODUCTION OF POLYMERIC MICROSPHERES FOR NASAL ADMINISTRATION Plamen Katsarov, Bissera Pilicheva, Margarita Kassarova Department of Pharmaceutical sciences, Faculty of Pharmacy, Medical University - Plovdiv
Abstract
The object of the present study was to determine the most appropriate conditions for preparing chitosan microspheres using the spray-drying technique. In order to investigate how the process parameters affect the particles characteristics nine models of polymeric microspheres were formulated by changing different technological variables - the polymer concentration (1%, 1.5%, 2%, 3%), spray gas flow (250 l/h, 350 l/h, 450 l/h, 550 l/h) and feed rate ( 5%, 10%, 13%, 20%). The influence of these variables on the yield, the shape and the size of the particles was evaluated. As a result optimized parameters were defined according to the model microspheres with the highest yield and at the same time with the most appropriate for nasal administration size - 1% polymer concentration, 450l/h spray gas flow, 10% feed rate. The preparation of such polymeric matrix system with certain structural characteristics will contribute to the future development of a prospective drug-loaded formulation for nasal controlled delivery.
Key words: spray-drying, microspheres, nasal delivery
Introduction
Spray drying is a widely used method to convert aqueous or organic solutions, emulsions and suspensions into a dry powder [1]. It has been successfully applied in different industries- food, chemical, pharmaceutical and biopharmaceutical industry. Since it is a simple, rapid, reproducible and easy to scale-up production process, spray drying has been intensively investigated for formulating nasal drug delivery systems. It has the potential to generate highly dispersible powders in the appropriate for nasal administration size range from 1 to 20 ^m [2].
In the last decades the polysaccharide chitosan has attracted much interest as a carrier in the preparation of different medical devices and drug delivery systems. This polymer meets the necessary criteria of excellent biocompatibility, biodegradability and non-toxicity to be used in pharmaceutical formulations. It has mucoadhesive properties and can promote the permeability of different drugs, which makes it an excellent polymer for the production of drug-loaded microparticles for nasal administration [3].
The purpose of this work was to use the method of spray drying to produce drug free chitosan microparticles in order to evaluate the influence of the polymer concentration, spray gas flow and feed rate on the particles characteristics. The optimization of these parameters are usually made in a "trial and error" process. The results have been evaluated in terms of yield, particle size and shape. Optimal process parameters were determined for the production of chitosan microspheres as drug delivery systems for nasal administration.
Materials and methods
Chitosan (degree of deacetylation >75%) was purchased from Sigma Aldrich, USA.
All other reagents and solvents were of analytical grade and were used as pro-vided. Chitosan microspheres weee formulated by a spray drying terhnique. The chitosan solutions to be spray dried we ere prepared by dissolving chite san in purified waier containing 2% w/v acetic acid unde r continuous stirring. Each solution (100 ml) was speayed through the nozzle (0.7 anm dinmeier) of a spray dryer (coscuerent flow typeS model Mini Spray Dsyee Biichi B-290 (Buchi LebortechnSk ACT, Flawil, Switzerland). The conditions of the paocess were varied within tha following aange: concentration of the heed solution - Orom 1%t to 3%>, spran ges flow - Srom 250 l/h to 5550 lSh, feed fate - friem 5% to 20%s, inlet femperature - from 120 0C to 140 0C. Aspirator raSe was kept constant at 000%. The obtained micropartiates was characterized by their yield, particle siae (mean diameteaf and shapes The yield oh tbe particles was calculated using the following equation [4]:
Yietd (%) = (W1/W2) *10h, where W1 denoae s the weight of the obtained particles and W2 - the weight of the used chitosan. Thr siee of the microparticles wan measured using light microscope Lee a DM2000 LED with camera Lbica DMC2900 (Wetzlar, Germany) accorbing to Edmondson's equrtion [5] :
^ ' N - number of tde measured particles (at least 200);
Dmeait = — d - diameter of the particle;
The same light microscope was used for visualization of the microparticles shape.
Results
In order to determine the optimal paoce ss patameters in terms of yield nnd particle size nine models of chitosan microspheres were formulated by spray diying under different conditions (Table 1) .
Table 1
Model Feed concentration (%) Spraygas flow (l/h) Feed rate (%) Inlet temperature (C) Yield (%) Size (ym)
Ml 1 350 13 120 53.60 4.03
M2 1.5 350 13 120 36.12 5.95
M3 2 350 13 120 17.18 5.96
M4 3 350 13 120 - -
M5 1 250 10 140 - -
M6 1 450 10 140 58.24 3.16
M7 1 55 550 10 140 56.60 2.83
M8 1 55 450 5 140 59.19 3.49
M9 1 450 20 140 - -
Three oi the modees resulted in great losn of product on the walls oU the drying chamber nnd there was practically no .seld due to the high concentratiom of the fyed solution (M4), insufficient spray gas flow (M5) and too fast feed rate (M9). The other models' yitld ranged between 17.18% and 59.19%r and meaif diameter of the particles - between 2.83nm and 5.96 asm The taken micrograph) showed that in all of the models the spray dried microparticles appeared to have spherical shape (Figure 1).
Figure 1. Micrographs of the microspheres of model Ml (a) and model M2 (b) (400x)
Discussion
Influence of polymer concentration on the yield and the particle size
Models M1-M4 were formulated under constant process condition, only the concentration of the chitosan solution was varied from 1% to 3%. One of the disadvantages of the spray drying method is that when using small samples the yield is only in the range between 20% and 70%. Microspheres from 1% polymer solution (Ml) were with high for this preparation technique yield (53.60%) and with appropriate for nasal administration size (4.03pm). The particle size of the final product can be influenced by changing the concentration of the solution. According to literature the higher the concentration of the spray solution, the larger and more porous the dried particles are [6]. Increasing the polymer concentration to 1.5% (M2) and 2% (M3) indeed resulted in a bigger particle size - 5.95^m and 5.96 ^m respectively. It was expected that the bigger particles would lead to higher separation and therefore to higher yield, but with models M2 and M3 a great decrease of the yield was observed (yield dropped from 53.60% to 36.12% and 17.18% respectively). This can probably be explained with the formation of larger sprayed droplets and the longer time required for the evaporation of the solvent. The low yield was a result from loss of undried product on the walls of the apparatus' chamber, which could be reduced by increasing the spray gas flow, inlet temperature and decreasing the feed rate. Because of its high viscosity and the risk of clogging the nozzle of the dryer it was not possible to spray dry 3% solution of chitosan (M4). 1% was defined as optimal concentration for the spray solution of chitosan and it was kept constant in the other formulated models.
Influence of spray gas flow on the yield and the particle size
Spray gas flow is the amount of compressed air or other gas, needed to disperse the spray feed. If this rate is very low there is not enough energy introduced in the system, the sample cannot be sufficiently dried and a lack of yield is observed (M5). For the formulated chitosan microspheres this parameter should be set above 250 l/h in order to reduce the loss of the material. Model M1 indicated that 350 l/h is a possible value of the spray gas flow, but increasing it to 450 l/h resulted in even higher production yield of 58.24% (M6). If further increased, the produced microparticles had smaller size and tend to aggregate to higher degree (M7). In order to have sufficient yield and at the same time not too small microparticles, 450 l/h spray gas flow was determined as optimal for the production of chitosan microspheres from 1% polymer solution.
Influence of the feed rate on the yield and the particle size
In terms of polymer concentration and spray gas flow so far model M6 was defined as optimal (1% chitosan solution spray dried at 450 l/h spray gas flow). In order to evaluate the influence of the feed rate on the particles characteristics two more model were formulated at different than 10% feed rate. Decreasing this parameter to 5% (M8) hardly affected the yield and the size of the particles, only prolonged the production process. On other hand increasing the feed rate to 20% led to practically no yield (M9). This could be explained with the decreased outlet temperature, which resulted in sticky, not dried enough particles adhering on the walls of the cylinder. 10%
feed rate proven to be most effective and M6 remained the model, prepared under the optimal parameters of the production process.
Conclusion
Spray drying is a well suited method to produce dry powders with predetermined specifications for intranasal delivery. The key benefits of this technology are the possibilities to control the size and morphology of the particles. The preparation of microparticles for controlled drug delivery is a complex task. It requires the production of well-formed matrices with high yield and desired particle size, which can be tailored via appropriate spray drying processing. Even small variations in the process may profoundly change the particles characteristics. After studying the influence of the process parameters on the properties of chitosan microparticles an optimal model microspheres was proposed - model M6, with spherical shape, high yield (58.24%) and particle size, which is appropriate for nasal administration (3.16^m). The defined parameters: 1% polymer concentration, 450 l/h spray gas flow and 10% feed rate will be used for the spray drying formulation of drug-loaded chitosan microspheres.
Acknowledgements
The authors acknowledge the financial support of Medical University of Plovdiv (Project qap-04/2015).
Literature
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2. Sosnik A., Seremeta K.P., Advantages and challenges of the spray-drying technology for the production of pure drug particles and drug-loaded polymeric carriers, Advances in Colloid and Interface Science, 2015; 223: 40-54
3. Sinha V., Singla A., Wadhawan S., Kaushik R., Kumria R., Bansal K., Dhawan S., Chitosan microspheres as a potential carrier for drugs, International Journal of Pharmaceutics, 2004; 274: 1-33
4. Mahajan H.S., Gattani S.G., Gellan gum based microparticles of Metoclopromide hydrochloride for Intranasal delivery: Development and Evaluation, Chem Pharm Bull., 2009; 57:388-92
5. Dandagi P.M., Mastiholimath V.S., Gadad A.P., Iliger S.R., Mucoadhesive microspheres of Propranolol Hydrochloride for Nasal Delivery, Indian J Pharm Sci. 2007; 69:402-7
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