Effect of Cross-linking Agent on the Release of Drug from the Transdermal Matrix Patches of Tramadol Hydrochloride.


Kevin C Garala1, Romal J Garala2, Harinath N More1 and Anil J Shinde1*.


1Department of Pharmaceutics, Bharati Vidyapeeth College of Pharmacy, Kolhapur-413016, Maharashtra, India.

2Department of Pharmaceutics, Padm. Dr.DY.Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Maharashtra, India.

* Corresponding Author E-mail: ajshinde07@rediffmail.com



The present work was designed to develop suitable transdermal matrix patches of Tramadol hydrochloride, a non-steroidal anti-inflammatory drug, using hydroxy propyl methyl cellulose (HPMC) and Eudragit RS 100 with triethyl citrate as a plasticizer in group A and in group B, other than HPMC and Eudragit RS 100, cross-linking agent, succinic acid was added. A 32 full factorial design was employed for both groups. The concentration of HPMC and Eudragit RS-100 were used as independent variables, while percentage drug release was selected as dependent variable. Physical evaluation was performed such as moisture content, moisture uptake, tensile strength, flatness and folding endurance. Invitro diffusion studies were performed using cellulose acetate membrane (pore size 0.45 µ ) in a Franz’s diffusion cell.

The concentration of diffused drug was measured using UV-visible spectrophotometer (Jasco V-530) at λ max 272 nm. The experimental results shows that the patch containing HPMC in higher proportion gives increase in the release of drug and patches containing cross linking agent shows more release than those do not contains succinic acid.


 KEY WORDS     Tramadol hydrochloride (TH), Cross linking agent, Transdermal delivery.                                                      



Transdermal drug delivery system attracts many scientists   around   the   world.   There   has   been   an increased interest in  the  drug administration via  the skin for both local therapeutic effects on diseased skin (topical delivery) as well as for systemic delivery (transdermal delivery) of drugs. The skin as a route for systemic   drug   administration   has   become   very attractive   since   the   introduction   of   transdermal therapeutic systems in the form of patches. There are a number of routes by which a molecule can cross the stratum corneum, these are, intercellular, transcellular and   appendageal   but   the   intercellular   route   is considered to be the major pathway for permeation of most drugs across the stratum corneum1.


The skin as a site of drug delivery has a numbers of significant advantages over many other routes of drug administration, including the ability to avoid problems of  gastric  irritation,  pH,  and  emptying  rate  effects; avoid hepatic first pass metabolism thereby increasing the bioavailability of drug; reduce the risk of systemic side effects by minimizing plasma concentrations compared to oral therapy; provide a sustained release of drug at the site of application; rapid termination of therapy by removal of the device or formulation2; the reduction of fluctuations in plasma levels of drugs3 and avoids pain associated with injections.  The  transdermal  delivery  can  also  eliminate pulsed entry into the systemic circulation, which might often cause undesirable side effects. Transdermal therapeutic systems may produce sustained, constant and controlled levels of drug in the plasma, thereby improving patient compliance, since frequent intake of the drug is not necessary.


Transdermal therapy also has its some disadvantages, like, higher molecular weight candidates (>500 Dalton) fail to penetrate the stratum corneum without modifying the nature of stratum corneum, drugs with very low or high partition coefficient  fail  to  reach  systemic  circulation  and  high melting drugs, due to their low solubility both in water and fat4. The effective barrier properties of the skin may prevent the entry of drug molecules from the external environment. Molecules may activate allergic responses and the drug may be metabolized by mircoflora on the surface of skin or by enzymes in the skin5,6,7. An ideal penetration enhancer reversibly reduces the barrier resistance of the stratum corneum without damaging the skin. The safest and most widely used penetration enhancer is water which increased hydration and diminishes the resistance of the skin8,9.


Table No.1: Full factorial experimental design layout



Variable level in coded form































Tramadol hydrochloride is  used  in  the  treatment of osteoarthritis. It has a molecular weight 299.8, melting point is 179°C - 180°C10 and an octanol water partition coefficient 1.35 at pH 7, so it is suitable to administer through transdermal route. In this study we observed the   effect   of   different   types   of   polymers   (i.e. hydrophilic and lipophilic) on the release of drug from the prepared transdermal matrix patches along with cross linking agent.




Tramadol hydrochloride (TH) was a gift sample from Rantus Pharma Pvt Ltd. (Hyderabad, India).  Eudragit RS-100  was  obtained  from Degussa India  Pvt.  Ltd. (Mumbai, India). HPMC obtained from Colorcon Asia Pvt. Ltd. (Goa, India). 3MTM ScotchpackTM  9733 backing membrane and 3MTM ScotchpackTM  1022 release liner were obtained from 3M (USA). Cellulose acetate membrane was purchased from Sartorious Biotech GmbH (Germany). All other ingredients were used of pharmaceutical grade.



Preparation of transdermal film

The transdermal films containing HPMC and Eudragit RS 100 with 15% wt/wt of TH, 5% wt/wt of plasticizer (triethyl citrate) in Group A and 5% wt/wt of cross linking agent (succinic acid) along with Group A excipients in Group B were prepared by film casting technique  on  the  mercury.  Hydrophilic  ingredients were dissolved in water and hydrophobic ingredients were dissolve in dimethyl formamide, then mixed both solution and stir on magnetic stirrer to accomplished homogeneous mixture. The resulting solution was poured in a petri dish containing mercury. The solvent was  allowed  to  evaporate  at  40°C  for  24  hours  to obtain medicated transdermal film. A backing membrane (3MTM  ScotchpackTM  9733) and a release liner (3MTM ScotchpackTM 1022) on either side of the film were applied to complete the transdermal therapeutic system for TH. The prepared TH patches were store in dessicator until further use.


Table No.2: Values Amount of Variables in a 32 Factorial Design



Actual Values

X1 = HPMC (mg)

X2 = Eudragit RS 100 (mg)











Factorial Design

A 32 factorial design was used in this study and two factors were evaluated, each at three levels; experimental batches were performed at all nine possible combinations (Table-1). The amount of HPMC (X1) and Eudragit RS-100 (X2) were selected  as  independent  variables.  The  percentage  drug release was selected as dependent variable. The data were subjected  to  3-D  response  surface  methodology  in  PCP Disso 2.08 to determine the effect of polymers on the release of drug, dependent variable. The values of variables in a 32

Factorial Design are indicated in Table-2. A statistical model incorporating interactive and polynomial terms was used to calculate the responses.


Y = bo + b1X1 + b2X2 + b12X1X2 + b11X12 + b22X22


Where, Y  is  the  dependent variable, bo   is  the  arithmetic mean response of the 9 trials, and bi (b1, b2, b12, b11 and b22) is the estimated coefficient for the corresponding factor Xi (X1, X2, X1X2, X12  and X22), which represents the average result of changing one factor at a time from its low to high value. The interaction term (X1X2) shows how the response changes when 2  factors are simultaneously changed. The polynomial terms (X1and X22) are included to investigate the nonlinearity.


Figure No.1: Drug release profile of group A


Evaluation of Transdermal Films

The   physical   parameters   such   as   thickness,   folding

endurance,  tensile  strength,   moisture  content,   moisture uptake and drug content were determined.

I) Thickness

Patch thickness was measured using digital micrometer screw gauge (Mitutoyo, Japan) at three different places and the mean value was calculated.


II) Folding endurance

Folding endurance of patches was determined by repeatedly folding a small strip of film (2 cm x 2cm) at the same place till it broke. The number of time the film could be folded at the same place without breaking was the folding endurance value.


III) Tensile strength

The  tensile  strength  was  determined  by  using  a modified   pulley   system.   Weight   was   gradually increased so as to increase the pulling force till the patch broke. The force required to break the film was consider as a tensile strength and it was calculated as kg/cm2.


IV) Drug Content

A 5 cm2 film was cut into small pieces, put into a 100 ml buffer (pH 7.4), and shaken continuously for 24 hours. Then the whole solution was ultrasonicated for

15  minutes. After filtration, the  drug  was estimated spectrometrically at wavelength of 272 nm and determined the drug content.


Figure No.2: Drug release profile of group


V) Flatness

Three longitudinal strips were cut out from each film: one from the center, one from the left side, and one from the right side. The length of each strip was measured and the variation in length because of non- uniformity in flatness was measured by determining percent constriction, with 0% constriction equivalent to

100% flatness11, 12.


VI) Percentage of Moisture Content

The  films  were  weighed  individually and  kept in  a desiccator containing activated silica at room temperature   for   24   hours.   Individual   films   were weighed  repeatedly  until  they  showed  a  constant weight. The percentage of moisture content was calculated as the difference between initial and final weight with respect to final weight13.


VII) Percentage of Moisture Uptake

A weighed film kept in a desiccator at room temperature for

24  hours  was  taken  out  and  exposed  to  84%  relative humidity (a saturated solution of aluminum chloride) in a desiccator until a constant weight for the film was obtained. The percentage of moisture uptake was calculated as the difference between final and initial weight with respect to initial weight14.


VIII) In vitro Drug Release study

In  vitro  drug release  studies  were  performed by using a Franz diffusion cell with a receptor compartment capacity of 20 ml. The cellulose acetate membrane (pore size 0.45µ ) was mounted between the donor and receptor compartment of  the  diffusion cell.  The  prepared transdermal film  was placed on the cellulose acetate membrane and covered with aluminum foil. The receptor compartment of the diffusion cell was filled with phosphate buffer pH 7.4. The whole assembly was fixed on a hot plate magnetic stirrer, and the solution in  the  receptor compartment was constantly and continuously stirred using magnetic beads and the temperature was  maintained at  32 ±  0.5°C. The  samples were withdrawn at different time intervals and analyzed for drug content spectrophotometrically. The receptor phase was replenished with an equal volume of phosphate buffer at each sample withdrawal.



The results of the thickness and flatness of both the groups shown in Table-3. The flatness of films was found much closed to 100%. The folding endurance and tensile strength were lies in between 67 & 203 and 0.395 & 0.734 kg/cm2; the difference depended on the composition of polymer and excipients used. The low value of moisture content and moisture uptake are recommended for good stability of patch (Table-4), and moisture content and moisture uptake was found in the range of 2.63% to 4.66% and 4.12% to 7.34%. The drug content found shown in Table-5.  The drug release profiles of  drug shown in  Figure-1 and 2. The diffusion studies reveled that as the concentration of HPMC increased, the rate of drug released also increase.



The  low  standard  deviation  of  result  of  the  thicknesses indicates physical uniformity of the prepared patches. The flatness study showed that all the formulations had the near to same strip length before and after their cuts, indicating good uniformity of the polymers through out the transdermal films. It indicates all patches had a smooth and flat surface. Folding endurance test results indicated that the patches would  not  break and  would  maintain their  integrity with general skin folding when used. The folding endurance  is  higher  in  the  patches  containing  the higher proportion of the Eudragit. Tensile strength test results showed that the patch contains HPMC in higher amount   were   less   strengthens.   Moisture   content   and moisture uptake studies indicated that the increase in the concentration of hydrophilic polymer was directly proportional to the increase in moisture content and moisture uptake of the patches. The moisture content of the prepared transdermal film was low, which could help the formulations  remain  stable   and   reduce   brittleness during storage. The moisture uptake of the transdermal formulations was also  low,  which could protect the formulations from  microbial  contamination and  also reduce bulkiness of films.


Table No.3: Result of Thickness and Flatness

Trials	Thickness (mm)	Flatness (%)	Trials	Thickness (mm)	Flatness (%)
A1	0.13 ± 0.01	100.02 ± 0.02	B1	0.14 ± 0.03	96.23 ± 0.01
A2	0.16 ± 0.03	99.98 ± 0.01	B2	0.16 ± 0.08	100.45 ± 0.05
A3	0.20 ± 0.12	100.12 ± 0.03	B3	0.21 ± 0.09	99.44 ± 0.03
A4	0.16 ± 0.21	98.84 ± 0.03	B4	0.17 ± 0.18	96.97 ± 0.04
A5	0.21 ± 0.04	98.93 ± 0.02	B5	0.21 ± 0.11	100.32 ± 0.02
A6	0.24 ± 0.19	99.81 ± 0.01	B6	0.25 ± 0.06	95. 94 ± 0.01
A7	0.21 ± 0.05	100.01 ± 0.01	B7	0.20 ± 0.01	100.18 ± 0.03
A8	0.25 ± 0.18	100.06 ± 0.04	B8	0.25 ± 0.12	100.23 ± 0.02
A9	0.28 ± 0.02	97.23 ± 0.02	B9	0.29 ± 0.05	100.02 ± 0.02

Results are the mean of triplicate observations ± SD


Table No.4: Result of Folding endurance and Tensile strength

Trials	Folding Endurance	Tensile Strength (kg/cm2)	Trials	Folding Endurance	Tensile Strength (kg/cm2)
A1	76 ± 0.56	0.395 ± 0.024	B1	67 ± 0.05	0.401 ± 0.012
A2	94 ± 0.95	0.459 ± 0.031	B2	90 ± 0.34	0.458 ± 0.023
A3	112 ± 0.03	0.632 ± 0.011	B3	117 ± 1.21	0.583 ± 0.016
A4	119 ± 0.43	0.443 ± 0.083	B4	112 ± 0.34	0.482 ± 0.042
A5	137 ± 0.44	0.562 ± 0.014	B5	131 ± 0.95	0.523 ± 0.053
A6	185 ± 0.03	0.694 ± 0.094	B6	169 ± 0.24	0.654 ± 0.025
A7	173 ± 0.13	0.402 ± 0.055	B7	170 ± 0.09	0.399 ±0.032
A8	194 ± 0.65	0.621 ± 0.046	B8	182 ± 0.04	0.594 ± 0.041
A9	203 ± 1.04	0.734 ± 0.081	B9	198 ± 0.53	0.705 ± 0.073

Results are the mean of triplicate observations ± SD


Table No.5: Result of Moisture content and Moisture uptake

Trials	Moisture Content (%)	Moisture Uptake (%)	Trials	Moisture Content (%)	Moisture Uptake (%)
A1	3.15 ± 0.11	5.32 ± 0.05	B1	3.42 ± 0.02	5.83 ± 0.03
A2	2.76 ± 0.06	4.93 ± 0.02	B2	3.21 ± 0.05	5.42 ± 0.03
A3	2.63 ± 0.01	4.12 ± 0.03	B3	2.94 ± 0.12	5.01 ± 0.01
A4	3.68 ± 0.04	6.03 ± 0.08	B4	4.02 ± 0.01	6.99 ± 0.03
A5	3.53 ± 0.10	5.58 ± 0.02	B5	3.75 ± 0.04	6.43 ± 0.02
A6	3.31 ± 0.03	4.74± 0.05	B6	3.62 ± 0.02	5.92 ± 0.01
A7	4.87 ± 0.05	6.84 ± 0.02	B7	4.91 ± 0.01	7.34 ± 0.12
A8	4.56 ± 0.02	6.01 ± 0.02	B8	4.74 ± 0.04	6.64 ± 0.08
A9	4.43 ± 0.01	5.32 ± 0.03	B9	4.66 ± 0.05	6.12 ± 0.02

Results are the mean of triplicate observations ± SD


Table No.6: Result of Drug content and Drug Release

Trials	Drug Content (%)	Drug Release (%)	Trials	Drug Content (%)	Drug Release (%)
A1	99.32 ± 0.03	69.35 ± 0.21	B1	98.44 ± 0.12	72.43 ± 1.36
A2	98.29 ± 0.11	62.75 ± 0.07	B2	99.76 ± 0.08	65.58 ± 0.83
A3	100.03 ± 0.02	59.94 ± 0.32	B3	99.34 ± 0.01	62.12 ± 048
A4	97.56 ± 0.05	75.72 ± 0.82	B4	100.32 ± 0.23	78.91 ± 0.31
A5	99.03 ± 0.09	65.33 ± 1.23	B5	96.93 ± 0.03	68.25 ± 1.19
A6	99.74 ± 0.23	63.81 ± 0.91	B6	97.62 ± 0.12	64.02 ± 0.33
A7	98.32 ± 0.15	81.55 ± 0.73	B7	98.59 ± 0.05	84.25 ± 1.08
A8	99.42 ±0.05	73.28 ± 1.06	B8	99.95 ± 0.04	75.39 ± 0.23
A9	97.90 ± 0.01	61.27 ± 0.87	B9	97.04 ± 0.04	66.93 ± 0.47

Results are the mean of triplicate observations ± SD


Figure No.3: Surface response plot for drug release of group A


The  study was  designed to  formulate a  transdermal system of TH using a polymeric matrix film. This allows one to control the overall release of the drug via an  appropriate choice  of  polymers and  their  blends studied here, utilizing the several diffusion pathways created due to the blend of the polymers to generate overall desired steady and sustained drug release from the patches. The manner by which drug release in most of   the   controlled/sustained   release   drug   delivery devices including transdermal patches is governed by diffusion15.


Figure No.4: Surface response plot for drug release of group B


When this matrix patch comes into contact with an in vitro study fluid, the fluid is absorbed into the polymer matrix and this initiates polymer chain dissolution process in the matrix. Initially there was rapid release of drug from the patch as shown in Figure. This rapid drug release (burst effect) from the prepared transdermal patch, which might be due to rapid dissolution of the surface drug16,17.


The response surface plot for the drug release, of both the group,   from   the   patches   shown   in   Figure-3   and   4 respectively. It is clearly observed that the drug release was increased with increasing the concentration of HPMC and as the amount of Eudragit increased the drug release was sustained.   The   incorporation   of   succinic   acid   as   a crosslinking agent in the matrix is one of the method to modulate the release of drug from the prepared patches18. The  results of  in  vitro  drug  release  study show that  the release of drug increases in the Group B as compared to Group A and that is because of the presence of succinic acid in Group B. The incorporation of 5 % w/w succinic acid increased the drug release from the prepared patches. The increase in the release of drug on using succinic acid can be attributed to the change in the matrix properties and hence drug  diffusivity  and  thermodynamic  activity  within  the cross-linked transdermal patches. The trial B 7 shows 84.25 % release in 12 hours, which is the maximum concentration of drug release as compared to other formulations as that contain maximum amount of hydrophilic polymer and also due to presence of succinic acid. The physical evaluation of patches showed  that  the  addition of  succinic acid  is  not much  affect  the  physical  characteristic  of  the  prepared transdermal patches. The final polynomial equation of both the groups shows the effect of dependent variables on the response.


Final Equation:

For Group A: Y = 68.11 + 4.01 X1 – 6.93 X2

For Group B: Y = 70.87 + 4.40 X1 – 7.08 X2


The bo is the arithmetic mean of all nine trials. The value of bo of group B was found to be 70.87 and that is higher than that of the group A, which indicates that the addition of succinic acid enhance the release of drug from the polymer matrix. The positive X1 coefficient of the both groups indicates that as the concentration of X1 (HPMC) increases; there is increase in the release of drug. The negative X2 coefficient of group A and B indicates that as the concentration of X(Eudragit RS 100) increase, the drug release from the matrix was decrease. Thus, the molecular diffusion through polymer matrix is an effective, simple and reliable means to achieve sustained/controlled release of a variety of  active agents from the  transdermal therapeutic system.



We  are  grateful to  the  3M,  USA for  the  gift  sample of backing membrane and release liner. We are also grateful to Degussa India Pvt. Ltd for the gift sample of Eudragit. The gift sample of Tramadol Hydrochloride by Rantus Pharma, India is highly acknowledged.



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Received on 09.06.2008    Modified on 10.07.2008

Accepted on 25.08.2008   © RJPT All right reserved

Research J. Pharm. and Tech. 1(3): July-Sept. 2008; Page 187-192