Development and Evaluation of Tramadol Hydrochloride Sustained Release Tablet

Mukund G Tawar 1*, Pawar M D2 and P D Chaudhari1

1Pad. Dr D. Y. Patil Institute of Pharmaceutical Science and Research, Pune-411 018

2Micro Laboratories Ltd. Bangalore, Karnataka

*Corresponding Author E-mail: mukundgtawar@yahoo.co.in

 

ABSTRACT

The objective of this study was to develop competitive sustained release tablets of Tramadol Hydrochloride which releases the drug in a sustained manner, by using different polymers and study on there effect on release pattern. The effect of HPMC K100M, HPC, ethyl cellulose, xanthan gum, sodium CMC, ckarbopol 934P, hydrogenated castor oil, with tramadol HCl in ratio (1:1) on release rate was studied. SR tablet of tramadol HCl (dose 100mg) were prepared by wet granulation, dry granulation, melt granulation and direct compression technique. In-vitro dissolution studies performed using USP apparatus type I in the phosphate buffer media (pH 6.8) upto 12 h. For 12 h release, the ratio of drug with alone carbopol 934P (1:0.8) was found to be best suited for modulating the delivery of highly water soluble drug tramadol HCl.

 

KEYWORDS: Tramadol HCl, polymers, non-fickian release, sustained release

 


INTRODUCTION:

Tramadol HCl (Tramadol Hydrochloride), a synthetic opioid of the aminocyclohexanol group, is a centrally acting analgesic with weak opioid agonist properties. Tramadol is used in the treatment of osteoarthritis when nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, or COX-2 inhibitors alone produce inadequate pain relief.1 After oral administration. The half-life of the drug is about 5.5 hours and the usual oral dosage regimen is 50 to 100 mg every 4 to 6 hours with a maximum dosage of 400 mg/day. To reduce the frequency of administration and to improve patient compliance, a sustained-release formulation of tramadol is desirable. The drug is freely soluble in water and hence judicious selection of release retarding excipients is necessary to achieve a constant in vivo input rate of the drug. The most commonly used method of modulating the drug release is to include it in a matrix system. Hydrophilic polymer matrix systems are widely used in oral controlled drug delivery because of their flexibility to obtain a desirable drug release profile, cost-effectiveness, and broad regulatory acceptance. The drug release for extended duration, particularly for highly water-soluble drugs, using a hydrophilic matrix system is restricted due to rapid diffusion of the dissolved drug through the hydrophilic gel network. For such drugs with high water solubility, hydrophobic polymers (waxes) are suitable as matrixing agents for developing sustained-release dosage forms.

 

Hydrophobic polymers provide several advantages, ranging from good stability at varying pH values and moisture levels to well-established safe applications. In the present study, various matrix systems were designed and tested for sustained delivery of tramadol. Hydrophobic matrix tablets were produced to sustain formulations of tramadol using hydrogenated castor oil and glyceryl behenate. Hydrophilic polymers are becoming very popular in formulating oral controlled-release tablets. As the dissolution medium or biological fluid penetrates the dosage form, the polymer material swells and drug molecules begin to move out of the system by diffusion at a rate determined by the nature and composition of the polymer as well as formulation technology. 1, 2, 3

 

MATERIALS AND METHODS:

Tramadol Hydrochloride, Hydroxypropyl methylcellulose (HPMC K100M, 6cps), Hydroxy propyl cellulose (HPC XHF), Ethyl cellulose, Sodium Carboxy methylcellulose (Na CMC), Hydrogenated Castor oil (HCO), Carbopol 934P, Xanthan Gum, Microcrystalline cellulose (Avicel PH101, 102), PVP K30 (polyvinyl pyrrolidone K-30), Polyethylene glycol (6000), magnesium stearate, colloidal silicon dioxide (aerosil), Titanium dioxide and Talc.

 

Preparation of Tramadol Hydrochloride sustained release tablets:

Different tablet formulations were prepared by wet granulation,dry granulation, melt granulation and direct compression.The formulations are composed of polymers in the ratio 1:1 with respect to drug. All powders were passed through 60 mesh sieve (#).

 


Table no.1: Formulation of Batch T1 to T11

Ingredients

(mg)

Formulation No.

T1

T2

T3

T4

T5

T6

T7

T8

T9

T10

T11

Drug

100

100

100

100

100

100

100

100

100

100

100

HPMC K100M

100

-

-

-

-

-

-

120

-

-

30

HPC

-

100

-

-

-

-

-

-

-

-

-

Ethyl Cellulose

-

-

100

-

-

-

-

-

-

-

-

Xanthan gum

-

-

-

100

-

-

-

-

-

-

-

Sod.CMC

-

-

-

-

100

-

-

-

120

-

-

Carbopol 934P

-

-

-

-

-

100

-

-

-

80

70

HCO

-

-

-

-

-

-

100

-

-

-

-

Avicel PH101

-

-

-

-

-

-

-

63.5

-

115.5

95.5

Avicel PH102

-

95.5

95.5

95.5

95.5

95.5

95.5

-

75.5

-

-

PVP K30

12.0

-

-

-

-

-

-

12.0

-

-

-

Aerosil

3.0

3.0

3.0

3.0

3.0

3.0

3.0

3.0

3.0

3.0

3.0

Mg. St.

1.5

1.5

1.5

1.5

1.5

1.5

1.5

1.5

1.5

1.5

1.5

Total Weight

300

300

300

300

300

300

300

300

300

300

300

 

Fig.1: Comparative Dissolution Profile of Batch T1 to T11 in pH 6.8 phosphate buffer

 

 


Table no. 2: Kinetic treatment of dissolution data for batch T1 to T11

Batch
Code

Drug release kinetics, correlation coefficients (R2)

Release exponent (n)

Zero order

Higuchi

Korsmeyer’s

T1

0.8054

0.9741

0.9948

0.35

T2

0.8383

0.9862

0.9973

0.39

T3

0.7725

0.9654

0.9525

0.34

T4

0.7884

0.9616

0.9718

0.33

T5

0.9448

0.9939

0.9957

0.53

T6

0.9595

0.9894

0.9861

0.54

T7

0.8387

0.9835

0.9638

0.46

T8

0.8894

0.9972

0.9979

0.45

T9

0.8809

0.9885

0.9649

0.42

T10

0.9381

0.9984

0.9993

0.53

T11

0.9071

0.9912

0.9777

0.47

Market Sample

0.8762

0.9917

0.9970

0.41

 

a) Wet granulation (T1, T3, and T8):  Accurately weighed quantity of drug, polymer and avicel pH 101 were passed through 40 # and mixed uniformly for 10 min. The solution of PVP k30 in water was added to the above mixture for making granules. Dried the granules for 2 hrs. at 60o c till the LOD is 2-3 % . The resulting granules were sifted through 20#. Aerosil was sifted through 20# and mixed in polyethylene bag with granules for 3 min. Sifted magnesium Stearate was added to the mixture and lubricate for 2 min. The lubricated blend was compressed using 9 mm N/C punch (10 station single punch tablet machine) in to tablets at 5-6 kg/cm2 compression pressure.  The total weight of tablet was kept at 300 mg.4

 

Fig. 2: Comparative Dissolution Profile of Batch T10 with market sample in pH 6.8 phosphate buffer

 

b) Dry granulation (T6, T10, and T11): Accurately weighed quantity of drug, polymer and avicel pH 101 were passed through 40 # and mixed uniformly for 10 min. The blend was lubricated with aerosil and magnesium Stearate for 5 min. The blend was compressed in big tablets to produce the slug and crushed to produce granules. These granules were then compressed using 9.5 mm N/C punch (10 station single punch tablet machine) in to tablets at 5-6 kg/cm2 compresion pressure.  The total weight of tablet was kept at 300 mg. 4

c) Melt granulation (T7): Accurately weighed quantity of drug and hydrogenated castor oil were mixed homogeneously; the blend was then heated (85°C-90°C) in a water bath  with continuous agitation. The molten mass was allowed to cool at room temperature. The congealed solid mass was then sieved, lubricated, and compressed.4

 

d) Direct compression (T2, T4, T5, and T9): Accurately weighed quantity of drug, polymer and avicel pH 102 were passed through 40 # and mixed uniformly for 10 min. The blend was lubricated with aerosil and mg. Stearate for 5 min. and compressed into tablets4. (Table no.1)

 

Preparation of film coating solution:

Dissolved poly ethylene glycol 6000, hydroxy propyl methylcellulose (6 cps) in a mixture of isopropyl alcohol and methylene chloride and Dispersed Talc, Titanium Dioxide in mixture of I.P.A with methylene Chloride and passed through colloidal mill and mix for 10 mins and both solutions mix for 5 mins. Finally coating solution was taken to coat the tablets.

 

Dissolution Study:

Medium(6.8 pH phosphate buffer), Volume (900 ml), Apparatus USP type I (basket), Rotation (100 rpm), Time (12 hours), Detection (UV, 271nm), Amount (6 tablets). 10 ml solution of sample from each vessel and filtered and took absorbance at 271nm on double beam UV spectrophotometer and replaced the volume with dissolution medium maintaining the temperature.5, 6, 7

 

Treatment of Dissolution Data with Different Kinetic Equations:

Further to understand the order and mechanism of drug release the data was subjected to various kinetic equations and plotted according to zero order,

Higuchi and Korsmeyer’s Peppas equation.8, 9, 10, 11, the kinetic values obtained from different plots are listed in table no.2 the dissolution data obtained from the above experiments were treated with the different release kinetic equations.

Zero order release equation:

Q = K0 t ------------------------ (1)

Higuchi’s square root of time equation:

Q = KH t1/2 --------------------- (2)

Korsmeyer and Peppas equation:

F = (Mt/M) = Km tn ------------ (2)

 

Where, Q is amount of drug release at time t, Mt is drug release at time t, M is total amount of drug in dosage form, F is fraction of drug release at time t, K0 is zero order release rate constant KH is Higuchi square root of time release rate constant, Km is constant depend on geometry of dosage form and n is diffusion exponent indicating the mechanism of drug release, where for cylinder value of n is 0.45 indicate fickian diffusion, between 0.45 and 0.89 indicate anomalous transport and 0.89 indicate case-II transport

 

RESULTS AND DISCUSSION:

The sustained release tablet of Tramadol Hydrochloride were prepared by wet granulation, dry granulation, melt granulation and direct compression method and were substituted for film coating to mask the bitter taste and for protection from light. The data of uniformity of content indicated that tablets of all batches had drug content within B.P. limits. The release of Tramadol hydrochloride from sustained release tablet of the various formulations varied according to the ratio and degree of the different polymer.  In case of tablets of T1, containing drug and HPMC in the ratio 1:1, the release profile, it was showing high initial burst of 46.97% and 100.04 % release in 8 hours. The dissolution study was shown that HPMC in 1:1 ratio cannot control the release upto 12 hours.  In case of tablets of T2, containing drug and HPC in the ratio 1:1, the release profile was showing some what slower release than T1 but 100.44% release in 8 hours. In case of tablets of T3, containing drug and EC in the ratio 1:1,  the release profile was showing very high initial burst of 63.33% and complete release in only 4 hours. Ethyl cellulose is hydrophobic polymer but it can not form strong matrix with Tramadol hydrochloride so it shown the complete release in only 4 hours. In  case of tablets of T4, containing drug and xanthan gum in the ratio 1:1,  the release profile was showing 8 hours retardation of  drug but not upto 12 hours. Xanthan gum is also the hydrophilic natural polymar. In 1:1 ratio it cannot control the release of Tramadol hydrochloride. In  case of tablets of T5, containing drug and sodium CMC  in the ratio 1:1,  the release profile was showing 8 hours retardation of  drug slower than T4 showing good retardation of drug release  but not upto 12 hours. In case of tablets of T6, containing drug and carbopol 934 P in the ratio 1:1, the release profile was showing drug release more than 12 hours, with very slower release than all formulation. The drug release upto 12 hours is only 89.82%. In case of tablets of T7, containing drug and HCO in the ratio 1:1, the release profile was showing control the release in first two hours but after that it can not be controlled the release and within 6 hours the whole drug was release. In case of tablets of T8, containing drug and HPMC in the ratio 1:1.2 prepared for controlling  the release because in 1:1 ratio it can not be controlled the release upto 12 hours, only initial burst  was decrease due to increase in  concentration of polymer, after that within 8 hours complete drug was dissolved.  HPMC is hydrophilic polymer get swelled very fast in aqueous medium with fast release of drug because Tramadol hyrochloride highly soluble in water. In  case of tablets of T9, containing drug and sodium CMC  in the ratio 1:1.2 prepared for controlling  the release, only release rate had to be decreased due to increase in concentration of polymer, but it can not controlled the release upto 12 hours. In  case of tablets of T10, containing drug and carbopol 934 P  in the ratio 1:0.8 prepared for the release upto 12 hours because in high concentration it was showing very slower release , due to decrease in concentration it was seen the increase in release of drug and shown complete drug release in 12 hours profile. In  case of tablets of T11, containing drug, carbopol 934 P and HPMC in the ratio 1:0.7:0.3 prepared to be seen in the effect of combination of polymer in release of drug but it was showing very slower release given 91.81% upto 12 hours.

 

From the above results and discussion the batch T10 was subjected to seen the in-vitro dissolution study in different media. It was seen that the release in different media was given near about the same release. For comparison, the in-vitro dissolution study in different media of market sample was seen. In  kinetic assessment the data was plotted according to zero order shows R2 (0.7725 to 0.9595) suggested the rate of drug released was followed zero order for carbopol and sodium CMC batch only. The data was fitted with higuchi with R2 (0.9616 to 0.9984) indicating the mechanism was diffusion controlled. To known the preciously whether the fickian and non-fickian release mechanism, the data was fitted to korsmeyer’s Peppas equation. It shows the n value lies in between 0.33 to 0.54, which indicates the fickian  and non-fickian release or anomalous, as if n value is less than 5 or lies in between 5 to 1 shows fickian and non-fickian release mechanism(Table 2).  According to korsmeyer’s Peppas equation for T10 n value was 0.53 indicates non-fickian release mechanism while n value was 0.41 for market sample indicates fickian release mechanism. For similarity, F2 calculation was done in 6.8 pH phosphate buffer showing the value of similarity factor (F2) i.e. 63.80.

 

Results of stability studies of batch T10 indicates that it is stable at 400C/75% ± 5% relative     humidity as there was no significant difference observed for dissolution after 2 month.

 

CONCLUSION:

From the above results and discussion it is concluded that formulation of sustained release tablet of Tramadol hydrochloride containing CARBOPOL 934P, 80mg per Tablet (1:0.8 ratio) i.e. T10 can be taken as an ideal or optimized formulation of sustained release tablets for 12 hour release as it fulfills all the requirements for sustained release tablet and our study encourages for the further clinical trials on this formulation.

 

ACKNOWLEDGEMENT:

The author would like to sincerely gratitude the Micro Labs Ltd., Hosur, Tamilnadu, for providing all requirements for this project.

 

REFERENCES:

1        Information for Health Professionals Data Sheet for Tramadol Hydrochoride

2        Thomson’s Physicians Desk Reference, 2494-2496

3        Tiwari S. B. et. al. Controlled Release Formulation of Tramadol Hydrochloride Using Hydro-philic and Hydrophobic Matrix System. AAPS Pharm. Sci. Tech, 2003, 4:3,31

4        Lachman Leon and Liberman HA. The Theory and Practice of Industrial Pharmacy, Varghese publishing House Bombay. 443-453.

5        United State Pharmacopoeia, 26: NF: 21

6        British Pharmacopoeia, 2008, Vol. No. IV: 2174.

7        FDA guidance for Industry, 1997, extended release solid oral dosage forms; Development, Evaluation and Application of IVIVC correlations.

8        Khan GM and Zhu JB. Studies on drug release kinetics from ibuprofen carbomer hydrophilic matrix tablets. Journal of Controlled Release. 1999;57: 197-203.

9        Hoyashi T and Kanbe H et. al. Formulation study and drug release mechanism of a new theophylline Sustained Release preparation. International J. Pharmaceutics. 2005; 304: 91-101.

10      Solinis MA et. al. Release of Ketoprofen enantiomeres  from HPMC K100M matrices –Diffusion studies. International J. Pharmaceutics. 2002; 239, 61-68.

11     Qiu Y and Chidambaram N et. al. Formulation and characterization of new diffusional matrices for Zero – order sustained release. Journal Controlled release. 1998; 52:149-158.

 

 

 

Received on 26.01.2009       Modified on 23.03.2009

Accepted on 12.05.2009      © RJPT All right reserved

Research J. Pharm. and Tech.2 (3): July-Sept. 2009,;Page 470-473