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Available online at ajdhs.com 

Asian Journal of Dental and Health Sciences 
Open Access to Dental and Health Research 

Copyright  © 2022 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 
which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the 

original author and source are credited 
 

 

 

Development and Characterization of Tramadol Hydrochloride Rectal 
Suppository 

Nanci Dangi, Sunil K. Jain, Vivek Jain, Rupesh K. Jain, Pushpendra Kumar Khangar* 

Adina Institute of Pharmaceutical Sciences, Nh86 Lahadara Naka Bhopal Road Sagar, M.P., India  

Article Info: 
_______________________________________ 
Article History: 
Received 09 Sep 2022      
Reviewed 28 Oct 2022 
Accepted 11 Nov 2022 
Published 28 Nov 2022 

_______________________________________ 
Cite this article as:  

Dangi N, Jain SK, Jain V, Jain RK, Khangar PK, 
Development and Characterization of Tramadol 
Hydrochloride Rectal Suppository, Asian 
Journal of Dental and Health Sciences. 2022; 
2(3):19-22 

DOI: http://dx.doi.org/10.22270/ajdhs.v2i3.29                                       

_______________________________________

*Address for Correspondence:   

Pushpendra Kumar Khangar, Adina Institute of 
Pharmaceutical Sciences, NH86A, Lahdara, 

Sagar, MP, 470001, India 

Abstract 
___________________________________________________________________________________________________________________ 
Tramadol is a centrally acting analgesic drug. Rectal administration of tramadol is useful in the 
treatment of post-operative pain or malignant pain in cases where it cannot be administered orally. 
Rectal suppositories of tramadol hydrochloride were prepared using different bases and polymers and 
the effect of different additives on in vitro release of tramadol hydrochloride was studied. The agar-
based suppositories were non-disintegrating/non-dissolving. All the prepared suppositories were 
evaluated for various physical parameters like weight variation, drug content and hardness. In vitro 
release study was performed by USP type I apparatus. Addition of 10% w/w propylene glycol 
accelerates the release of tramadol hydrochloride significantly (P<0.05) as in A1, which may be due to 
decrease in the gel matrix of agar. In formulation A2, A3 Addition of HPMC (1%, 3% w/w) and in 
formulation A3 and A4 addition of PVP (1%, 3% w/w) retards the release significantly (P<0.05), which 
may be due to increase in the viscosity and gel strength of the polymer matrix. Hence, PVP, HPMC and 
similar polymers in higher concentration can be used to formulate sustained released suppositories. The 
sustained release suppositories can be prepared by addition of PVP, HPMC in agar-based suppositories. 

Keywords: Tramadol, Rectal suppositories, PVP, HPMC, Agar. 

Mail id: pushpendra.rai16@gmail.com 

Introduction 

Rectal drug delivery has a number of advantages such as 
reduced hepatic first pass elimination of high clearance drugs, 
avoidance of gastric irritation associated with certain drugs in 
case of nausea, vomiting and when the patient is unconscious. 
Rectal route of administration is specifically useful for infants 
and children who have difficulty in swallowing oral medicine. 
Drug administered in suppository form can produce not only 
local effect but also systemic therapeutic action1. 
Suppositories can be prepared by using lipophilic bases like 
cocoa butter or by hydrophilic bases such as PEGs1-4. These 
suppositories melt or dissolve in body fluids and release the 
drug, but are unstable at higher temperature. Agar has been 
recently used as base to produce non-disintegrating/ non-
dissolving suppositories, which are stable at higher 
temperature5,6. Tramadol is a synthetic 4-phenyl-piperidine 
analogue of codeine. It is a centrally acting analgesic with a 
low affinity for mu opioid receptors (a class of opioid 
receptors with high affinity for enkephalins and beta-
endorphin but low affinity for dynorphins). It consists of two 
enantiomers, both of which contribute to its analgesic activity 
via different mechanisms. (+)- Tramadol and its metabolite 
(+)-O-desmethyltramodol (M1), produced by liver O-
demethylation, are agonists of the mu opioid receptor. (+)-
Tramadol also inhibits serotonin reuptake whereas (-)-
tramadol inhibits norepinephrine reuptake, to enhance the 
inhibition of pain7,8. Its use is indicated for the management of 
moderate to moderately severe pain including chronic pain 
and pain associated with molar extraction in adults9. Tramadol 

is an effective and well-tolerated agent to reduce pain 
resulting from trauma, renal or biliary colic, and labor, and for 
the management of chronic pain of malignant or nonmalignant 
origin, particularly neuropathic pain. Tramadol appears to 
produce less constipation and dependence than equianalgesic 
doses of strong opioids8. However, after intravenous and oral 
administration, peak concentrations are reached rapidly, and 
this has been associated with postoperative nausea and 
vomiting10. Thus, this limits the use of tramadol as a 
postoperative analgesic, especially in day surgery. Rectal 
administration of tramadol may be an alternative in this 
situation. It could be used at the same dose range as that of the 
oral form to maintain effective pain relief11. Furthermore, it is 
useful in the treatment of post-operative pain or malignant 
pain in cases where oral administration is not possible12. In 
the present study attempts were made to formulate rectal 
suppositories of tramadol hydrochloride with bases, as the 
rectal route avoids first pass metabolism and side effects. 

Materials and methods 

Materials 

Tramadol hydrochloride was obtained as a gift sample from 
Sun Pharmaceutical Ltd. Ahmedabad. HPMC and PVP were 
purchased from Loba Chemie Pvt. Ltd., Mumbai. Propylene 
glycol, methyl paraben and propyl paraben were purchased 
from S. D. Fine Chemicals Pvt. Ltd., Mumbai, and all other 
chemicals used were of analytical grade and were used 
without any further chemical modification. 

                       Open Access                                                                                                                                                                                                       Research Article                                                                           

http://jddtonline.info/
http://dx.doi.org/10.22270/ajdhs.v2i3.29


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Preformulation studies13, 14 

Physical characteristics 

By visual examination, the drug was identified for physical 
characters like colour, texture, odour etc. 

Solubility 

Solubility of the drug was determined by taking some quantity 
of drug (about 10 mg) in the 10 ml volumetric flasks 
separately and added the 10 ml of the solvent (water, ethanol, 
methanol, 0.1N HCL, 0.1N NaOH, chloroform and 7.4 pH 
buffer) Shake vigorously and kept for some time. Note the 
solubility of the drug in various solvents (at room 
temperature). 

Melting point 

A small quantity of powder was placed into a fusion tube.  That 
tube was placed in the melting point determining apparatus 
(Chemline) containing castor oil.  The temperature of the 
castor oil was gradual increased automatically and read the 
temperature at which powder started to melt and the 
temperature when all the powder gets melted. 

FTIR spectroscopy 

The concentration of the sample in KBr should be in the range 
of 0.2% to 1 %. The pellet is a lot thicker than a liquid film, 
consequently a decrease concentration in the sample is 
required (Beer's Law). For the die set that you'll be the usage 
of, about 80 mg of the mixture is wanted. Too excessive of an 

attention causes typically difficulties to obtain clean pellets. 
FTIR spectra of the samples were recorded over a spectral 
region from 4700 to 400 cm-1 using 20 scans with 4 cm-1 
resolution. 

Determination of λ max of tramadol HCl 

Tramadol, 100 mg, was accurately weighted into a 100 ml 
volumetric flask, dissolved in phosphate buffer of pH 6.8 and 
the volume was made up with phosphate buffer of pH 6.8. 
Pipette 1 ml of this solution into a 10 ml volumetric flask with 
phosphate buffer of pH 6.8 as the volume and marks it as 
stock. Prepare an appropriate dilution to bring the 
concentration down to 2.5-17.5μg/ml. The resulting solution 
is scanned with a UV spectrophotometer (UV-1700 Shimadzu 
corporation, Japan) in the range of (200-400 nm) to determine 
the absorption maximum (λ max). Concentration vs. 
absorbance was shown on a graph. 

Preparation of tramadol hydrochloride rectal suppository 

Agar suppositories were prepared by molding method15, 
dissolving methyl and propyl paraben in hot water and then 
drug along with other additives like propylene glycol, HPMC, 
PVP was added and mixed well. Finally, agar was incorporated 
by maintaining the temperature at 75-80℃ and mixed 
thoroughly. The molten mass was poured into previously 
calibrated stainless-steel mould of 1g and allowed to set. The 
details of all formulations are tabulated in Table 1. All the 
prepared suppositories were packed in polyethylene 
laminated foil pouches. 

 

Table 1: Formulations of tramadol hydrochloride rectal suppositories 

Ingredients (%w/w) Formulation codes 

 A0 A1 A2 A3 A4 

Tramadol hydrochloride 5 5 5 5 5 

Agar 10 10 10 10 10 

Propylene glycol - 10 10 10 10 

Methyl paraben 0.03 0.03 0.03 0.03 0.03 

Propyl paraben 0.02 0.02 0.02 0.02 0.02 

HPMC - - 1 3 - 

PVP - - - - 1 

Water qs 100 100 100 100 100 

 

Evaluation 

Prepared suppositories were visually inspected. Randomly 
selected suppositories were cut longitudinally and the 
surfaces were examined with naked eye. For determination of 
weight uniformity, twenty suppositories were weighed 
individually and the average weights were determined16.   No 
suppositories should deviate from average weight by more 
than 5% except two, which may deviate by not more than 
7.5%. The drug content for agar suppositories was determined 
by soaking individual suppository in water for 30 min, broken 
with spatula, vortexed for 5 min, filtered, diluted to 50 ml with 
distilled water, and then tramadol hydrochloride was 
estimated by Shimadzu UV/visible spectrophotometer at 271 
nm. The hardness of the prepared suppositories was tested 
using Monsanto hardness tester.   Hardness test or breaking 
strength test was carried to determine the tensile strength of 
the suppositories to access whether they will be able to 
withstand the hazards of packing and transporting17. USP 
tablet disintegration apparatus was employed to measure the 

melting range of suppositories18. The time taken for the entire 
suppositories to melt/disperse was measured when immersed 
in water bath maintained at constant temperature of 37±0.50C. 
For in vitro dissolution studies an Electrolab USP XXIII 
dissolution apparatus was used19. The dissolution medium 
was 900 ml of distilled water, maintained at 37±0.50C. The 
suppository was placed in the metal basket and maintained at 
50 rpm. Ten millilitres of sample was withdrawn at different 
intervals of time (10, 20, 30, 45, 60, 90, 120, 180, 240 min) and 
absorbance was measured at 271 nm. 

Results and Discussions 

The melting point of tramadol hydrochloride (pure drug) was 
found to be 180-183°C. Tramadol hydrochloride was freely 
soluble in water, methanol and ethanol, soluble in chloroform 
and PBS 6.8. Identification of tramadol hydrochloride was 
done by FTIR spectroscopy with respect to marker compound. 
It was identified from the result of IR spectrum as per 
specification Figure 1. The calibration curve of tramadol 



Dangi et al                                                                                                                                    Asian Journal of Dental and Health Sciences. 2022; 2(3):19-22 

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hydrochloride was found to be linear in the concentration 
range of 2.5-17.5 µg/ml at 271nm Figure 2. All the 
suppositories were free from pits, fissures and cracks. The 
longitudinal section of the suppositories was plain and clear. 
The results of different evaluation parameters are shown in 
Table 2. The weight variation study for all the suppositories 
were found to be within the acceptable range of <5%, which 
indicates that calibration of mold was perfect. All the prepared 
suppositories showed uniformity in drug content and were 
within the permissible range (97% to 105%) indicating 
uniformity of drug dispersion in suppositories. The 
suppositories should have good mechanical strength for 
handling and transportation. All the suppositories were having 
good mechanical strength in the range of 1.50 to 2.00 kg/cm² 
showing optimum hardness. Dissolution study of agar-based 

suppositories indicated that the suppository does not 
disintegrate, melt or dissolve in the dissolution medium but 
remains intact. The drug diffuses out from the hydrophilic 
matrix with time. It was observed that more than 50% of the 
drug was released from A0 formulation within 60 min. 
Addition of 10% w/w propylene glycol accelerates the release 
of tramadol hydrochloride  significantly (P<0.05) as in A1, 
which may be due to decrease in the gel matrix of agar. In 
formulation A2, A3 addition of HPMC (1%, 3% w/w) and in 
formulation A3, A4 addition of PVP (1%, 3% w/w) retards the 
release significantly (P<0.05), which may be due to increase in 
the viscosity and gel strength of the polymer matrix. Hence, 
PVP, HPMC and similar polymers in higher concentration can 
be used to formulate sustained released suppositories Table 3. 

 

 

Figure 1: FT-IR spectrum of pure drug (Tramadol hydrochloride) 

 

 

Figure 2: Wavelength maxima of tramadol hydrochloride in PBS 6.8 

 

Table 2: Evaluation of suppositories for various parameters 

Formulation code Drug content* (%) Weight variation ±SD (g) Hardness* (kg/cm2) 

A0 97.55 1.008±0.04 1.50 

A1 97.00 0.997±0.04 2.00 

A2 98.10 0.998±0.03 2.00 

A3 101.30 1.001±0.01 2.00 

A4 105.00 1.002±0.02 2.00 

 

 



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Table 3: in vitro release of tramadol hydrochloride from suppositories 

Time (Min) % Drug Release 

 A0 A1 A2 A3 A4 

40 30 60 45 20 50 

80 40 72 55 30 59 

120 50 78 60 35 62 

160 60 80 65 40 65 

200 65 82 70 45 68 

240 70 85 75 55 70 

 

Conclusion 

In conclusion, tramadol hydrochloride suppositories prepared 
using bases showed a rapid and almost complete release of the 
drug from their bases. Rectal administration of tramadol in 
addition to oral and intravenous administration may be an 
alternative route for the treatment of pain. 

References 

1. Goodman DO. Pharmacokinetics: Disposition and metabolism of 
drugs. In: Munson PL, Muller RA, Breese GR. editors. Principles of 
pharmacology, 1st ed. New York: Chapman and Hall; 2001. p. 47. 

2. Sanyal P, Roy G. Preparation and evaluation of suppositories of 
paracetamol. East Pharma 2001; 49:95-7. 

3. Nair L, Bhargava HN. Comparison of in vitro dissolution and 
permeation of fluconazole from different suppository bases. Drug 
Develop Ind Pharm1999; 25:691-4. 
https://doi.org/10.1081/DDC-100102227 

4. Akala EO, Adedoyn A, Ogunbona FA. Suppository formulations of 
amodiaquine: In vitro release characteristics. Drug Develop Ind 
Pharm 1991; 17:303-7. 
https://doi.org/10.3109/03639049109043827 

5. Kamlinder KS, Deshpande SG, Baichwal MR. Studies on suppository 
bases: Design and evaluation of sodium CMC and agar bases. 
Indian Drugs 1994; 31:149-54. 

6. Jayaprakash S, Jawahar N, Dhachina MD, Ramkanth S, Mohamed 
Anzar A, Nagarajan M. Design and evaluation of timed release 
matrix suppositories of indomethacin. Pharm Rev 2006; 4:100-2. 

7. Dayer P, Collart L, Desmeules J. The pharmacology of tramadol. 
Drugs. 1994; 47(Suppl):3-7. https://doi.org/10.2165/00003495-
199400471-00003 

8. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin 
Pharmacokinet. 2004; 43:879-923. 
https://doi.org/10.2165/00003088-200443130-00004 

9. Micromedex Healthcare Series: Document 2007. Tramadol. 
Available from: http://www.thomsonhc.com/ 
hcs/librarian/ND_PR/Main/SBK/3/PFPUI/7z16hW4. 

10. Petrone D, Kamin M, Olson W. Slowing the titration rate of 
tramadol HCl reduces the incidence of discontinuation due to 
nausea and/ or vomiting: a double-blind randomized trial. J Clin 
Pharm Ther. 1999; 24:115-23. https://doi.org/10.1046/j.1365-
2710.1999.00203.x 

11. Mercadante S, Arcuri E, Fusco F, Tirelli W, Villari P, Bussolino C, 
Campa T, De Conno F, Ripamonti C. Randomized double-blind, 
double-dummy crossover clinical trial of oral tramadol versus 
rectal tramadol administration in opioid-native cancer patients 
with pain. Support Care Cancer. 2005; 13:702-7. 
https://doi.org/10.1007/s00520-004-0760-9 

12. Allen LV Jr. Compounding suppositories. Part I: theoretical 
considerations. Int J Pharm Compound. 2000; 4:289-93. 

13. Patel AN, Rai JP, Jain DK, Banweer JI. Formulation, development 
and evaluation of cefaclor extended release matrix tablet. Int J 
Pharm Pharm Sci. 2012; 4(4):355-7. 

14. Jain P, Nair S, Jain N, Jain DK, Jain S. Formulation and evaluation of 
solid dispersion of lomefloxacin hydrochloride. Int J Res Pharm Sci 
2012; 3(4):604-608. 

15. Block LH. Medicated topicals. In: Gennaro AR. editors. Remington: 
The science and practice of pharmacy. 21st ed. Vol. 2. Noida: 
Lippincott Williams and Wilkins; 2005. p. 885-6. 

16. British Pharmacopoieal Convention. British Pharmacopoeia. Vol. 2. 
London: H.M Stationery Offi ce; 1993. 

17. Coben LJ, Liberman HA. Suppositories. In: Lachman L, Liberman 
HA, Kanig JL, editors. Theory and practice of industrial pharmacy. 
3rd ed. Mumbai: Varghese Publishing House; 1989. p. 580. 

18. Senthil Kumaran K, Thiruganasambantham P, Viswanathan S, 
Shree Rammurthy M. Development and evaluation of 
Andrographolide (from Andrographis paniculata) rectal 
suppositories. Indian Drugs 2002; 39:648-51. 

19. Hammouda YE, Kasim NA, Nada AH. Formulation and in vitro 
evaluation of verapamil HCL suppositories. Int J Pharm 1993; 
89:111-117. https://doi.org/10.1016/0378-5173(93)90111-R

 

https://doi.org/10.1081/DDC-100102227
https://doi.org/10.3109/03639049109043827
https://doi.org/10.2165/00003495-199400471-00003
https://doi.org/10.2165/00003495-199400471-00003
https://doi.org/10.2165/00003088-200443130-00004
https://doi.org/10.1046/j.1365-2710.1999.00203.x
https://doi.org/10.1046/j.1365-2710.1999.00203.x
https://doi.org/10.1007/s00520-004-0760-9
https://doi.org/10.1016/0378-5173(93)90111-R

