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EFFECT OF TABLET FORMULATION VARIABLES ON TRAMADOL HCL ELEMENTARY OSMOTIC PUMP TABLET

Basani Gavaskar1 *, Subash Vijaya Kumar2 , Dilip Dodda1
  1. Department of Pharmaceutics, VCOP, Warangal, Andhra Pradesh
  2. Department of Pharmacy Practice, VCOP, Warangal, Andhra Pradesh
 
Corresponding Author: Basani Gavaskar, Department of Pharmaceutics, VCOP, Warangal, Andhra Pradesh, E-mail: gavapharma @yahoo.com, Telephone : 09949507620
 
Received: 10 August 2010 Accepted: 25 November 2010
 
Related article at Pubmed, Scholar Google
 

Abstract

Osmotic drug delivery system utilize osmotic pressure as a energy source and driving force for delivery of drugs, pH presence of food under physiological factors may affect drug release from conventional controlled release system (Matrices and reservoirs), where as drug release from osmotic system is independent of these factors to a large extent. The aim of the current study was to formulate elementary osmotic pump tablets of water soluble Tramadol HCl. Formulation were prepared based on wet granulation method, coated with cellulose acetate solution containing varying amount of Dibutylphthalate (DBP), and Polyethylene glycol 400 (PEG-400). Drug release from the osmotic drug delivery system was studied using USP Type I Paddle type apparatus. The excipients of physio-chemical property of the drug were determined by DSC (Differential scanning calorimetry). The optimized formulation was subjected to accelerated stability testing as per ICH guidelines. Optimization results indicated that to a certain extent drug release was less effected by the orifice size, concentration of coating solution and coating weight. DSC showed the excipients used in the formulation did not alter physicochemical properties of the drug. The results confirmed that the factors responsible for drug release were osmotic agents (core) and orifice size membrane.

Key words

 
Elementary osmotic pump; Differential scanning colorimetry; Osmotic agent; Orifice size; Tramadol HCl.
 

Introduction

 
In recent years, considerable attention has been focused on the development of novel drug delivery systems (NDDS). Among various NDDS available in the market, per oral controlled release (CR) systems hold the major market share because of their advantages over others [1]. Many different systems have been developed based on principles of osmotic pressure such as elementary osmotic pump, EOP,[2][3][4][5] sandwiched osmotic tablet system, SOTS [2], push–pull systems[2][4][6][7][8], controlled porosity osmotic pumps[4] [9][10][11], asymmetric membrane osmotic pumps[12][13][14], single composition osmotic tablet, SCOT [1] and osmotic systems made by swellable core technology [15]. An EOP device basically consists of an osmotically active core surrounded by a semipermeable membrane (SPM) usually of cellulose acetate and a small orifice drilled through the coating using LASER or mechanical drills[3][5]. EOPs are the most commercially important osmotic devices and more than 240 patents have been devoted [3]. Procardia XL and Adalat CR (nifedipine), Acutrium (phenylpropanolamine), Minipress XL (prazocine) and Volmax (salbutamol) are examples of EOPs available in the market. In this study, an attempt was made to design a new EOP like osmotic system for delivery of an insoluble drug with constant release rate (zero order release).
 
The rate at which the core absorbs water depends on the osmotic pressure generated by the core components and the permeability of the membrane coating. As the core absorbs water, it expands in volume, which pushes the drug solution or suspension out of the tablet through one or more delivery ports. Tramadol is a nonsteroidal anti-inflammatory drug, which is used in the treatment of osteoarthritis when NSAIDs like acetaminophen, or COX-2 inhibitors alone produce inadequate pain relief. After oral administration, tramadol is rapidly and almost completely absorbed. Long term treatment with sustained-release tramadol once daily is generally safe in patients with osteoarthritis or refractory low back pain and is well tolerated. It has the potential to provide patients increased control over the management of their pain, fewer interruptions in sleep, and improved compliance [16][17][18]
 

Material and Methods

 
Tramadol HCl was obtained as a gift sample from Hetero drugs Ltd. Hyderabad, India. Cellulose acetate and poly ethylene glycol were obtained as a gift sample from ISP Technologies, Hyderabad, India. Dibutyl phthalate, Sodium chloride, Magnesium stearate and acetone were also obtained as a gift from Indo remedies Mumbai, India. All other chemicals used in the study were of analytical grade.
 

Preparation of core tablet

 
Core tablet of EOP were prepared by wet granulation method. In the wet granulation method all the ingredients were weighed accurately as per table 2. Screened through a sieve of aperture size 250µm and blend for 5minutes, using double cone blender at 50rpm to get a uniform mix. A mixture was granulated with a granulating fluid prepared by dissolving the binding and wetting/solubilizing agent in water. The resulting wet mass passed through a sieve aperture size 710 µm and the granules where dried at 50°C for 30minutes. The granules were screened through a sieve of aperture size 350 µm and blend with magnesium stearate for 2 minutes. The granules obtained by this method were compressed at the pressure of 6tons in laboratory press (Rimek RSB-4, Mini press, Gujarat, India.)
 

Coating and Drilling:

 
Tablets were coated with Cellulose acetate (3grams) and plasticizers (PEG) were dissolved in 100 of acetone. Coating was carried out by spraying in the coating pan (REMIK Kalveka HD-410 AC Gujarat, India) equipped with a hot air blower. The stainless steel pan was set a rotating speed of 20rpm and a spraying rate of 3ml/minutes. The coated tablets were dried at 30°C for 30minutes. For coated tablets a small orifice was drilled through the one side of the each coated tablet by standard mechanical microdrill with various diameters (Ranging from 0.6-1mm)
 

Invitro Drug Release Studies

 
Invitro drug release of the formulations was carried out in a USP dissolution apparatus (Paddle type) set a rotating speed of 100rpm and a temperature of 37±0.5°C .The dissolution media used was water 0.1NHCl, 6.8phospate buffer individually. The sample5ml were withdrawn at a different time interval and replace with equivalent volume of fresh material. The dissolution sample after filtration through 0.45µm nylon membrane filter were analyzed using validated UV spectrophotometric (Shimadzu- UV 160 A Spectrophotometer, Japan) method at 271nm. The amount of drug present in the samples was calculated.
 

Stability Studies

 
Stability studies were conducted on Tramadol HCl along with Optimized EOP tablets, to assess their stability with respect to their physical appearance, drug content, and drug-release characteristics after storing them at 40°C and relative humidity (RH) 75% for 3 months [19]
 

FTIR Studies

 
IR spectra for Tramadol HCl and Optimized tablet formulation of Tramadol HCl EOP Tablets were recorded in a Fourier transform infrared spectrophotometer (FTIR 1615, Perkin Elmer, USA.) with Potassium bromide pellets.
 

DSC Studies

 
DSC scans of about 5mg; using an automatic thermal analyzer system performed accurately weighed tramadol hydrochloride and EOP of optimized tablet formulation containing the same amount of drug. (DSC 60, Shimadzu, Japan) Sealed and perforated aluminum pans were used in the experiments for all the samples. Temperature calibrations were performed using indium as standard. An empty pan sealed in the same way as the sample was used as a reference. The entire samples were run at a scanning rate of 10°C/min from 50-300°C. [20]
 

Results and Discussion

 

Influences of tablet formulation variables on drug release

 
To investigate the influences of tablet core formulation variables on drug release, tablets with different formulations were prepared, coated with the same coating solution; an orifice with a diameter of 0.7 mm was drilled into the center of the surface.
 

Influence of amount of Sodium Chloride

 
In figure 1 shows the influence on release of different contents of sodium chloride (130,170,250 mg) respectively. As shown in this figure 1 the different amount of sodium chloride can effect the drug release from the EOPT. This indicates that apart from osmotic pressure, influence amount of sodium chloride, the release rate was accelerated in EOPT.
 

Influence of amount of HPMCK15

 
Figure 2 shows the drug release profiles of different amounts of HPMCK15 (14, 24,34mg) respectively. As shown in this Figure2, the different amounts of HPMC k15 can markedly affect the drug release from the EOPT. HPMC K15 14mg compared to other amounts this shows the better drug release from the EOPT, With increasing HPMCK15, the release rate clearly slowed. This is because, as HPMCK15 increased, the swelling rate and viscosity in the core increased, so that the water entry into the core was hindered.
 

Influence of amount of MCC

 
Tablets with different amounts of MCC were prepared. It has been shown in the Figure 3. The amount of MCC had a significant effect on the drug release rate. This can be taken in an account for extra membranous water was imbibed into the intra membrane, the swelling of MCC would lead to increasing the static pressure, which results accelerate drug release from the core.
 

Optimal tablet core formulation

 
The tablet core formulation was optimized by orthogonal designs using three factors and three levels which were shown in Table 1. The three factors set as follows: A, amount of sodium chloride; B, amount of MCC; C, amount of HPMCK15. Evaluation indexes: (1) Accumulated amount of drug release of 8 h-F1, 0.99 as the standard; (2) Accumulated amount of drug release of the first 2 h-F2, 0.25 as the standard ; (3)The correlation coefficient-r for 0–8 h release profile of time–accumulated amount, 0.99 as the standard. Generally grade method has been adopted to evaluate formulation. Therefore in this study amount of drug release of 8 h and the first 2 h were determined as 1, respectively, and that of the correlation coefficient-r was determined as 5. Then the calculation formula was obtained as the Eq. 1. If the value of L is smaller, the release effect will be better. The optimal tablet core formulation was illustrated in Table 2.
 
L = [F1 – 0.90] × 1 × 100 + [F2 – 0.25] × 1 × 100 + [r – 0.99] × 5 × 100 Eq. 1
 

Influences of coating formulation on drug release

 

Influence of coating solution concentration

 
Influence of coating solution concentration depends upon cellulose acetate acetone solutions of 2%, 3%, and 4% (g/100 ml) with the same quantities of DBP and PEG-400. Then, the core tablets were coated with the above mentioned coating solution. Figure 4 shows that, the concentration of coating solution was not significant with drug release characteristics. The concentration of coating solution was above 4%, the viscosity of the coating solution was greater to do the coating process. Mean while the concentration of the coating solution is lower than 2%, it is difficult to do the coating process. Hence our results showed that 3% cellulose acetate acetone solution had better performance in coating.
 

Influence of amount of plasticizer

 
DBP was chosen as the plasticizer. CA acetone solutions with different amounts of DBP were used to coat the cores of tablets with the same lot number. Figure 5 shows that an increase in the amount of DBP led to a decrease in the drug release rate. If CA acetone solution alone is used for coating, the coating membrane will be easily ruptured over the course of drug release. Plasticizer is good for improving the nature of the coating membrane and plasticity of the coating material. Meanwhile, it can improve the membrane’s adherence to the core and mechanical character. Therefore, plasticizer is very important in order for the coating film to form [9].
 

Influence of the amount of PEG-400

 
In this study PEG-400 was used as a porogen. It is commonly used in cellulose acetate semi- permeable membranes as a porogen. Different amounts of PEG- 400 were added to 3% CA coating solution to coat the cores of tablets with the same lot number. The influence of PEG-400 on release was investigated. The results are shown in Figure 6. It was observed that PEG-400 had a marked influence on drug release. With the increase in the amount of PEG-400, the drug release rate increased. This may be explained as follows: porous channels in the surface of the coating membrane increased with the increasing amount of PEG-400. Therefore, water could be imbibed into the membrane very quickly, accelerating the release rate of the drug
 

Influence of different coating weights

 
The same core tablets were coated with different coating weights (2%, 4%, 6%, and 8%). The influence of different coating weights is shown in Figure 7. The result shows that the release rate slowed following the increase of the coating membrane thickness. So, the release rate of EOPT can be controlled by adjusting the thickness of the coating membrane.
 

Optimal coating solution formulation

 
The coating solution formulation was optimized by orthogonal designs using four factors and three levels which are shown in Table 3. Four factors: A: amount of PEG-400; B: amount of DBP; C: coating weight; D: concentration of coating solution. The same method was used the similar core formulation. The optimal coating solution formulation is shown in Table 4.
 

Influence of pH of the medium on release

 
Three types of medium were chosen to carry out the release test. The results are shown in Figure 8. Thus indicate that the rate was unaffected by pH of the medium. Hence it provided further evidence that the osmotic pump tablets aren’t affected by the medium pH.
 

Influence of release orifice size

 
Release orifices with different diameters were made in osmotic pump tablets with the same lot number. Figure 9 shows that within certain ranges, the release results were basically the same. So, in practice, the releasing orifice size could be controlled within a certain range, which is convenient for industrial production.
 

Influence of the number of release orifices

 
The release profiles of EOPT with one release orifice and two release orifices are presented in Figure 10. The results showed that the release rate didn’t increase significantly with an increasing number of release orifices. The release mechanism of the osmotic pump preparation was also demonstrated: the rate depends on the osmotic pressure across the coating membrane.
 

Stability data

 
No visible change in the appearance of the formulation Optimized tablet formulation was observed at the end of the storage period. The drug content and dissolution of Tramadol HCl was almost similar to that at time zero during the whole period of investigation. It has been shown in table 5.
 

FTIR Study

 
In figure 11 shows the IR spectra of Tramadol HCl and Optimized tablet formulation (OTF). IR spectrum of Tramadol hydrochloride shows a broad peak at 3304 cm-1 may be due to hydrogen bonding, 3048 cm-1 may be due to aromatic C-H stretching, 2926 cm-1 may be due to C-H stretching of –OCH3, 2512, 2602, 2860 cm- 1 may be due to C-H stretching of –CH2 and - CH3 groups. 1606, 1578 cm-1 may be due to C=C ring stretching. 1288, 1301 cm-1 –C-H bending of symmetric and asymmetric of – CH2 and - CH3 groups 1045 cm-1 may be due to –C-O-C group. 781 cm-1 may be due to substituted benzene ring. The IR spectrum of the best formulation obtained during the present work showed, the characteristic absorption bands at 3300, 3064, 2926, 2512, 2602, 2860, 1606, 1578, 1288 cm-1 and 1045, 781 cm-1. In addition to this, IR spectrum of the best formulation also shown the major characteristic absorption bands of the polymers micro crystalline cellulose and HPMC K 15M with negligible difference of absorption band values. From these results, it is clear that, there is no appreciable change in the positions of the characteristic bands of the drug along with the IR spectrum of the best formulation derived during the present investigation. Since there is no change in the nature and position of the bands in the formulation, it can be concluded that the drug maintains its identity without going any chemical interaction with the polymers used.
 

DSC study

 
Figure 12 shows the DSC thermographs of Tramadol HCl and optimized tablet formulation (OTF). It’s revealed that melting point of pure drug was 185?C and formulated is 183?C as there is no much difference in the melting point of the drug in the thermographs of drug and that of in the formulation. It may be concluded that, the drug is in the same pure state even in the formulation without interacting with the polymers.
 

Conclusion

 
The optimized formulation of Tramadol EOPT was obtained by orthogonal designs based on the single factor influence test. Stability studies, FTIR, and DSC indicated that drug was stable in the tablet formulation. An EOP based drug delivery system can be designed for controlled release of highly water soluble drug Tramadol HCl. It is evident from the result that, the rate of drug release can be controlled through osmotic pressure of the core the level of pore former, and membrane weight with release to be fairly independent of pH and hydro dynamic conditions of the body. Tramadol HCl from the development formulations was directly proportional to the osmotic pressure of the release media, conforming osmotic pumping to be the major mechanism of drug release.
 

Acknowledgment

 
The authors thank M.Pharmacy, students for constant encouragement and support. Authors also thank Head Department of Pharmaceutics and Staff/Colleagues of Vaagdevi College Pharmacy for their valuable suggestions and support.
 

Conflict of Interest

 
NIL
 

Source of Support

 
NONE
 

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