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 Table of Contents  
ORIGINAL/BRIEF
Year : 2012  |  Volume : 4  |  Issue : 5  |  Page : 50-53  

Effects of spray drying conditions on the physicochemical properties of the Tramadol-Hcl microparticles containing Eudragit® RS and RL


Department of Pharmaceutics, Anand Pharmacy College, Anand, Gujarat, India

Date of Web Publication21-Mar-2012

Correspondence Address:
A S Patel
Department of Pharmaceutics, Anand Pharmacy College, Anand, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-7406.94134

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   Abstract 

The preparation of Tramadol-HCL spray-dried microspheres can be affected by the long drug recrystallization time. Polymer type and drug-polymer ratio as well as manufacturing parameters affect the preparation. The purpose of this work was to evaluate the possibility to obtain tramadol spray-dried microspheres using the Eudragit® RS and RL; the influence of the spray-drying parameters on morphology, dimension, and physical stability of microspheres was studied. The effects of matrix composition on microparticle properties were characterized by Laser Light scattering, differential scanning calorimetry (DSC), X-ray diffraction study, FT-infrared and UV-visible spectroscopy. The spray-dried microparticles were evaluated in terms of shape (SEM), size distribution (Laser light scattering method), production yield, drug content, initial drug loding and encapsulation efficiency. The results of X-ray diffraction and thermal analysis reveals the conversion of crystalline drug to amorphous. FTIR analysis confirmed the absence of any drug polymer interaction. The results indicated that the entrapment efficiency (EE), and product yield were depended on polymeric composition and polymeric ratios of the microspheres prepared. Tramadol microspheres based on Eudragit® blend can be prepared by spray-drying and the nebulization parameters do not influence significantly on particle properties.

Keywords: Tramadol, spray-drying parameters, microspheres, Eudragit®


How to cite this article:
Patel A S, Soni T, Thakkar V, Gandhi T. Effects of spray drying conditions on the physicochemical properties of the Tramadol-Hcl microparticles containing Eudragit® RS and RL. J Pharm Bioall Sci 2012;4, Suppl S1:50-3

How to cite this URL:
Patel A S, Soni T, Thakkar V, Gandhi T. Effects of spray drying conditions on the physicochemical properties of the Tramadol-Hcl microparticles containing Eudragit® RS and RL. J Pharm Bioall Sci [serial online] 2012 [cited 2019 Sep 23];4, Suppl S1:50-3. Available from: http://www.jpbsonline.org/text.asp?2012/4/5/50/94134

The main goal of drug delivery research is to develop formulations that fulfil the therapeutic needs related to particular pathological conditions. Technological advancements have brought many new innovative drug delivery systems into commercial circulation. Biodegradable and non biodegradable biocompatible microparticulate systems have shown clear advantages by controlled drug release and drug targeting for parenteral and oral drug delivery.

The production of structured microparticles via spray drying is of interest due to the fact that the prepared particles exhibit unique properties that permit their use in various fields. Tramadol-Hcl is a nonsteroidal anti-inflammatory drugs (NSAIDs) drug widely formulated in microspheres and microcapsules for pharmaceutical controlled release systems owing to its short half- life, the irritation in the gastrointestinal mucosa, and its unpleasant taste. The drug is freely water soluble and hence judicious selection of release retarding excipients is necessary to achieve a constant in vivo input rate of the drug. The preparation of tramadol microspheres by spray-drying is possible only under certain experimental conditions, and it is affected by the polymer type and by drug-polymer ratio. The aim of the present study was to study the influence of the spray-drying technological parameters on the physicochemical properties of tramadol microspheres and on the yield of microparticles and encapsulation efficiency. Spray dryer parameters that we have changed are Inlet temperature, aspirator capacity, pump capacity and feed pump solution rate. We have concluded from our results that the inlet temperature is important parameter for both particle dimensions and recovery; it must be compatible with the material (drug and polymer) and solvent utilized. Air aspirator significantly influences the transformation of nebulized droplets in solid particles. The peristaltic pump influences the time and efficacy of the drying process as well as the particle dimensions.


   Subjects and Methods Top


Materials

Tramadol-HCL was gifted by Sun Pharmaceuticals PVT. LTD Eudragit® RS 100 (RS) and Eudragit® RL 100 (RL) were kindly provided by Evonik Pharma Polymers GmbH (Mumbai).Dichloromethane and ethanol were of analytical grade.

Microsphere preparation

Tramadol Hcl microspheres were prepared using a mini spray dryer (LU222, Labultima Pvt. Ltd, Mumbai), equipped with the high-performance cyclone. Tramadol Hcl microparticles were prepared by spraying a 2% (wt/vol) solution of drug and polymer in 100 ml solvent (50 mlCH 2 Cl 2+ 50ml Ethanol), obtained by dissolving 100 mg of Tramadol and 750?mg of Eudragit mg of Eudragit® polymers which contain 375 mg of both RS and RL, 150 mg Aerosil) All spray-drying parameters used are reported in [Table 1]. This formulation was produced three times for verifying the method reproducibility. To prove the influence of the manufacturing parameters on microsphere characteristics, air aspirator or peristaltic pump capacity or drying temperature was changed: The formulations obtained and the respective spray-drying conditions used are listed in [Table 1]. Formulations B and C were produced by spraying the feed solution previously described, setting the air aspirator capacity at 40% respectively; three different formulations (D-F) were produced decreasing the peristaltic pump capacity. The inlet temperature was reduced from 50 to 40°C for preparing the G formulation. On the basis of the results obtained from the in vitro characterization of A-G, a new spray-dried microparticle batch, H, was prepared choosing the following parameters: The heating was set at 40°C and the aspirator and pump capacity at 40% and 4%,wth feed pump rate 2.5 ml/min respectively [Table 1].{Table 1}

Microsphere characterization

After formulation, the microspheres were stored for 24 h in a desiccators at 12% relative humidity (RH) and 20±1°C. They were then characterized by DSC, XRD, % yield, drug content, encapsulation efficiency, particle size and particle size distribution by SEM analysis and morphological properties during physical stability studies.

Yield of production

Dried microspheres were accurately weighed, and considering the total amount of drug and polymers used for preparing the feed solution, the yield of production (YP) was calculated, as a percentage, using the following equation:



where MC stands for the amount of produced microspheres and (RS + RL + T) for the sum of the amounts of two types of Eudragit® and tramadol solubilized for the preparation of microparticles.

Encapsulation efficiency determination

To determine the exact amount of tramadol encapsulated into RS/RL matrix, weighed amount of microspheres were solubilized in 100 mL ethanol. The UV absorbance of the solution was measured using a Schimadzu UV-Visible spectrophotometer, model at 271 nm. These resulting values were interpolated at the calibration curve of tramadol in ethanol, elaborated earlier.



where Tr is the amount (grams) of tramadol microspheres, and Tt is the grams of tramadol theoretically the polymeric matrix.

Particle size and particle size distribution analyses

The mean diameter and size distribution of microsphere were determined by laser diffraction (Coulter LS 100Q Laser Sizer, Beckman Coulter, Miami, FL, USA). A sample of microspheres (5.0 mg) was suspended in 0.5 mL volatile silicone fluid and sonicated in ultrasound bath for 5 s before particle size analysis. Because a Gaussian-like distribution of particle size was observed, the particle size is described by the volume/surface mean diameter (d vs ) and the standard deviation (SD), whereas microparticle size distribution is expressed as SPAN Index (SI) calculated applying the following equation: SI = d 90 - d 10 /d 90 where d 10 , d 50 , and d 90 indicate the volume percentage of particles (10, 50, and 90% respectively) having a mean diameter lower than the obtained value.

Morphological analysis

Microsphere morphology was studied by scanning electron microscopy (SEM) (ISI-DS 130 Scanning Electron Microscope, Akashi Beam Technology Corporation, Tokyo, Japan).Completely dried microspheres were mounted on aluminium stubs using double-sided adhesive tape. They were then gold sputtered and analyzed with accelerating voltage of 20 kV. The resulting images were photographed.


   Differential Scanning Calorimetric Studies Top


The thermal behavior of tramadol in A and C formulations was determined using differential scanning calorimeter (DSC) (DSC Q100 V9.0, TA Instrument, New Castle, DE, USA). As a comparison, the thermal behavior of pure drug (raw material), polymers, and blank microspheres (prepared using a mixture of RS and RL 100) was studied. Samples of 5 mg were scanned in crimped sealed aluminum pans, under static air atmosphere. An empty pan was used as reference. The heating rate was 10°C/min, and the temperature interval used was -40 to 250°C.

Statistical analysis

Statistical analysis was performed using Softwar. Unpaired t-test was applied to test the significance of the effect of each spray-drying parameter on the yield of production, the drug content, and the encapsulation efficiency, and particle size of microsphere formulations. The significant level was set at P<0.05.


   Results and Discussion Top


Tramadol microspheres can be produced by spray-drying technique using Eudragit® RS 100 and RL 100 as polymers. The technological parameters employed for A preparation [Table 1] allow to obtain microspheres with good yield of production (59.4±1.5%); drug content (30.2±0.8%) and encapsulation efficiency values (81.65±0.89%).

DSC analysis

From DSC study it was shown that drug shows sharp peak around 180°C which shows melting point of drug, while peak at 180°C was disappear in prepared formulation which indicates that interaction between drug and polymer has taken place.

XRD study and SEM analysis

The X-ray diffraction spectra were recorded for Tramadol Hcl microspheres for investigating the crystallanity of the drug in the polymeric microspheres Figure. The X-ray diffractogram showed sharp peaks at diffraction angle 18.95° depicting a typical crystalline pattern. Drug loaded microspheres showed peaks, but of low intensity, indicating that some amount of drug was converted to amorphous form. SEM analysis shows that the decrease of aspirator capacity does not influence particle morphology: B and C microspheres are spherical but the smallest particles appear partially sticking to each other.

Particle size and particle size distribution

The microspheres have 8.7±2.1 μm dvs and narrow size distribution as indicated by SI value (1.42).

The reduction to 10% of the air aspirator capacity determines, in case of D formulation, a significant decrease of production yield (P=0.013) caused by the loss of dried particles inside the nebulization chamber. Drug content and encapsulation efficiency of B microspheres (P<0.05) decrease. B and C microspheres are spherical but the smallest particles appear partially sticking to each other. Compared with A, the use of 8% pump capacity (D) causes a significant increase of the yield production and the particle size distribution, as expressed by the highest SI (1.52), whereas applying 2% pump ratio (F) the DC and EE slightly decrease (P<0.05). As the temperature reduction increases the particle size, the percentage of particles mainly consisting of polymers sucked up from the aspirator decreases. Because the feed rate of polymeric solution could influence the efficacy of drying process and particle size. Three Eudragit® microparticle formulations, called D, E, and F, were produced changing the peristaltic pump capacity to 8, 4, and 2%, respectively. Compared with A, the use of 8% pump (D) causes a significant increase of the yield production and the particle size distribution, as expressed by the highest SI (1.52), whereas applying 2% pump ratio (F) the DC and EE slightly decrease (P<0.05) [Table 2].{Table 2}

The feed rate does not influence significantly the particle dimensions (P>0.05), even if the lowest pump capacity (2%) produces the smallest particles (6.87 μm): No differences are observed among D-F and A. This could be attributed to the low viscosity of feed solutions and to the high volatility of the solvent used. The reduction of heating from 50 to 40°C determines a significant increase (P=0.03) of microsphere recovery (YP of G is about 65.43%), As the temperature reduction increases the particle size, the percentage of particles mainly consisting of polymers sucked up from the aspirator decreases. The dimensions and the shape of G are similar to those of A microspheres. The H formulation was prepared changing, with respect to A at the same time heating (40°C), aspirator (40%) and pump capacities (4%). In fact the use of a temperature of 40°C allows to obtain the highest YP value, and the aspirator at 40% of its capacity shows DC and EE% significantly different from A; finally, the pump capacity of 4% was chosen for controlling the outlet temperature. The characterization shows that by these parameters it is possible to produce microspheres with similar properties in terms of yield, drug content, size, and morphology than A.

Briefly the in vitro characterization demonstrates that G shows the highest value of yield of production compared with the other formulations; all the microspheres are produced with good EE% 76-95%. All microparticles present d vs values lower than A, but in any case they range from 6.9 to 7.8 μm; no differences are revealed in size distribution profiles: SI data are between 1.42 and 1.52.


   Physical Stability Studies Top


The stability tests were carried out to evaluate the possible variations of microparticle morphology and dimension both after drying and after storage. After production, the microspheres were dried for 24 h in oven at 30°C; the microspheres were then studied by SEM As shown in [Figure 5], after the thermal treatment at 30°C, the A microspheres loose their integrity and sphericity: Mainly the small particles are inclined to merge and make aggregates


   Conclusion Top


Tramadol microspheres based on Eudragit® RL and RS blend can be prepared by spray-drying with good yields of production, high drug content, and encapsulation efficiency using appropriate spray-drying technological parameters. All formulations have good morphological and dimensional characteristics: Spherical shape, smooth surface, and narrow size distribution. Thus, RS and RL 100 used as mixture and in the drug-to-polymer ratio of 1:3 are suitable to produce microspheres containing tramadol, by spray-drying. A large choice of manufacturing parameters can be used to obtain microparticle but specific temperature of drying and way of storage are required.


   Acknowledgement Top


The authors are grateful to thank the Principal, Anand Pharmacy College, and SICART, Vallabh Vidhynagar, Anand, Gujarat, for providing the necessary facilities, also to Evonik Pharma Pvt. Ltd., Mumbai, India for specific grades of Eudragit polymer.[11]

 
   References Top

1.Botti BY and Nusrat MT.Optimization of experimental parameters for the production of LMWH-loaded polymeric microspheres.Drug Design Development and Therapy 2008;2: p 39-48.  Back to cited text no. 1
    
2.Corrigan D. Preparation and release of salbutamol from chitosan and chitosanco-spray dried compacts and multiparticulates. European journal of pharmaceutics and biopharmaceutics 2006;62:295-305.  Back to cited text no. 2
    
3.Ammar H.O., Polymeric Matrix System for Prolonged Delivery of Tramadol Hydrochloride, Part I: Physicochemical Evaluation, J Control Release Back Issue.  Back to cited text no. 3
    
4.Bodmeier R, Chen H. Preparation and characterization of microspheres containing the anti-inflammatory agents, Indomethacin, Ibuprofen and Ketoprofen. J Controlled Release 1989;10:167-175.  Back to cited text no. 4
    
5.Broadhead, J., Rouan, S.K.E., Rhodes, C.T., The spray drying of pharmaceuticals. Drug Dev Ind Pharm 1992;8:1169-1206.  Back to cited text no. 5
    
6.Bolton S. Pharmaceutical Statistics. Second ed. Marcel Decker, New York, USA, 1990;234.  Back to cited text no. 6
    
7.Esposito E., Roncarati R., Cortesi R., Cervellati F., Nastruzzi C., Production of Eudragit microparticles by spray-drying technique: Influence of experimental parameters on morphological and dimensional characteristics, Pharm Dev Technol 2000;5:267-278.  Back to cited text no. 7
    
8.Franz RM, Browne JE, Lewis AE. Experiment design, modeling and optimization strategies for product and process development. In: Libermann HA, Reiger MM, Banker GS, eds. Pharmaceutical Dosage Forms: Disperse Systems. Marcel Dekker, New York, USA, 1988;1:427-519.  Back to cited text no. 8
    
9.George M, Grass IV, Robinson JR. Sustained and controlled release delivery systems, Marcel Dekker, New York, USA, 1978:124-127.  Back to cited text no. 9
    
10.Gohel M.C., Amin A F. Formulation optimization of controlled release diclofenac sodium microspheres using factorial design. J Controlled Release 1998;51:115-122.  Back to cited text no. 10
    
11.Harish N. M., Improved Bioavailability of pefloxacin by formulationg controlled release ocular inserts. Int J Pharm Sci and Research 2009.  Back to cited text no. 11
    



 
 
    Tables

  [Table 1]JPharmBioallSci_2012_4_5_50_94134_t1.jpg, [Table 2]JPharmBioallSci_2012_4_5_50_94134_t2.jpg


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