Drugs from nitroimidazole category are generally bitter in taste. Oral formulation with bitter taste is not palatable. Geriatrics and pediatrics patients usually suffer from swallowing difficulties. Many other patients in some disease conditions avoid swallowing tablets. Satranidazole is a new nitro-imidazole derivative with bitter taste and is available in market as film coated tablet. The purpose of this research was to mask the bitter taste of Satranidazole by coating complexation with low melting point wax and Eudragit EPO. Different types of wax (glyceryl monostearate, stearic acid and cetyl alcohol) were tried for taste masking. The drug to stearic acid ratio 1 : 2 was found to be optimum on the basis of taste evaluation and
Masking the bitter taste of drugs is a challenge in development of all oral formulations and a necessity to ensure better patient compliance and product value where the process and formulation should be economic, rapid, and easy, involving least number of equipment, and processing steps and minimum number of excipients without adverse effect on drug bioavailability [
Taste masking can also be carried out using melt granulation technique [
Satranidazole (STZ) is a new nitroimidazole derivative with potent antiamoebic action. It is used in the treatment of intestinal and hepatic amoebiasis, giardiasis, trichomoniasis, and anaerobic infections. Its dose is 300 mg twice daily for 3–5 days in the treatment of amoebiasis and 600 mg as a single dose in the treatment of giardiasis and trichomoniasis. It is reported that Satranidazole exhibits significantly higher plasma concentrations than metronidazole and has a plasma elimination half-life of 1.01 hour which is significantly shorter than the corresponding metronidazole half-life of 3.62 hour [
The present study aims for the development, optimization and evaluation of Satranidazole taste masked granular formulation using different types of low melting point wax with Eudragit EPO as a functional polymer by melt granulation technique.
Satranidazole was obtained as a gift sample from Alkem Laboratories, Mumbai. Eudragit EPO was obtained from Evonik Degussa, Mumbai. Satrogyl tablets (strength: 300 mg) were purchased from local market. All the chemicals and reagents used were of analytical grade.
UV and FTIR spectrum of Satranidazole were taken to confirm the identity of drug. Compatibility study between the drug and the excipients was done using FTIR. IR spectra were recorded in Fourier Transform Infrared spectrophotometer (Shimadzu Corporation) with KBr pellets.
In preliminary study, three different trial batches of granules were prepared using glyceryl monostearate, stearic acid, and cetyl alcohol. The purpose of these trials was to select the wax suitable for taste masking of Satranidazole in low concentration since the dose of the drug is high. The required quantity of wax was weighed and melted in porcelain dish. Eudragit EPO was dissolved in molten wax and drug was added followed by mixing. At slightly lower temperature all the other ingredients were added and mixed. Finally the mixture was allowed to cool slightly and the solidified mass was passed through 12 # sieve and then through 16 #. The granules obtained were then lubricated with flavorant, sweetener and lubricant. The composition of granules is shown in Table
Composition of preliminary trial batches.
Ingredients | Batches | Role | ||
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Trial 1 | Trial 2 | Trial 3 | ||
Quantity in mg per dose | ||||
Satranidazole | 300 | 300 | 300 | Active ingredient |
Glyceryl monostearate | 600 | — | — | Low melting point wax |
Cetyl alcohol | — | — | 600 | Low melting point wax |
Stearic acid | — | 600 | — | Low melting point wax |
Eudragit EPO | 100 | 100 | 100 | Functional polymer |
Starch 1500 | 200 | 200 | 200 | Disintegrant |
Magnesium oxide | 70 | 70 | 70 | Additive for taste masking |
Mannitol | 498 | 498 | 498 | Diluent |
Xylitol | 42 | 42 | 42 | Sweetener |
Sodium carboxymethyl cellulose |
20 | 20 | 20 | Disintegrant |
Hydroxyllpropyl cellulose |
80 | 80 | 80 | Disintegrant |
Vanilla | 20 | 20 | 20 | Flavorant |
Aspartame | 65 | 65 | 65 | Sweetener |
Magnesium stearate | 5 | 5 | 5 | Lubricant |
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37.81 | 23.33 | 33.14 | — |
Different batches of granules were prepared using wax selected in above trials to optimize drug to ratio for successful taste masking of STZ. The composition of the formulated batches is as shown in Table
Composition of batches prepared using selected wax for optimization.
Ingredients | F1 | F2 | F3 | F4 |
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Ratio of drug : stearic acid | ||||
1 : 1 | 1 : 1.5 | 1 : 2 | 1 : 2.5 | |
Quantity in mg per dose | ||||
Satranidazole | 300 | 300 | 300 | 300 |
Stearic acid | 300 | 450 | 600 | 750 |
Eudragit EPO | 100 | 100 | 100 | 100 |
Starch 1500 | 200 | 200 | 200 | 200 |
Magnesium oxide | 70 | 70 | 70 | 70 |
Mannitol | 798 | 648 | 498 | 348 |
Xylitol | 42 | 42 | 42 | 42 |
Sodium CMC | 20 | 20 | 20 | 20 |
HPC | 80 | 80 | 80 | 80 |
Vanilla | 20 | 20 | 20 | 20 |
Aspartame | 65 | 65 | 65 | 65 |
Magnesium stearate | 5 | 5 | 5 | 5 |
The prepared batches were evaluated for the following parameters.
The granules were evaluated for following flow properties using following parameters [
Fixed funnel method was used to determine angle of repose and was calculated using following equation:
To measure density, the granules were filled in a 100 mL capacity measuring cylinder up to at least 3/4th the height. Bulk density is the quotient of weight to the volume of the sample. Tapped density is the quotient of weight of the sample to the volume after taping a measuring cylinder 500 times from a height of ~1.5 in.
Hausner’s ratio was calculated using the following formula:
The percentage compressibility (Carr’s index) was calculated as 100 times the ratio of the difference between tapped density and bulk density to the tapped density:
Ten grams of uncoated granules was subjected to friabilator at 25 rpm. After 4 minutes, the granules were sieved on a 200 mesh. The amount of granules passed through 200 mesh was calculated as percentage granular friability.
Particle size distribution was performed on optimized batch using nest of standard sieves (20 #, 40 #, 60 #, 100 #, and 120 #). The sieves were agitated mechanically for 10 minutes on a sieve shaker and the weight of granules retained on each smaller sieve was noted.
The surface morphology of uncoated and coated granules was examined using a scanning electron microscope (Zeiss Ultra Plus-FESEM). The samples of granules were previously sputter-coated with gold.
The assay of different batches of granules of Satranidazole with stearic acid was carried out using previously developed and validated HPLC method. Isocratic elution at a flow rate of 1.0 mL/min was employed on BDS Hypersil C18 (250 mm × 4.6 mm, 5
Threshold value of STZ was determined based on the bitter taste recognized by eight volunteers in the age group of 21–28 years. Aqueous solutions of STZ with different concentrations (10, 20, 30, and 40
Granules equivalent to 25 mg of STZ were placed in a volumetric flask with 50 mL of phosphate buffer (pH 6.8) and stirred for 5 minutes. The mixture was filtered, and the filtrate was analyzed for STZ concentration at 320 nm by UV-Visible spectrophotometer and that was compared with the threshold value [
Two procedures were used for Gustatory sensation taste: informed consent was first obtained from 8 healthy volunteers and taste evaluation study was carried out. The whole dose was added to 100 mL of water for 15 seconds. STZ was used as control. After 15 seconds, 1 mL of dispersion was held in the mouth of each volunteer for 30 seconds and then spat out [ Granules equivalent to 50 mg STZ were held in mouth of each volunteer for 30 seconds. After expectoration, bitterness level was recorded by using the numerical scale shown in Table
Numerical scale for bitterness level.
Score | Inference |
---|---|
0 | Pleasant |
1 | Tasteless |
2 | Slightly bitter |
3 | Moderately bitter |
4 | Extremely bitter |
The optimized granular formulation was subjected for stability study for one month according to ICH guidelines. Tests were conducted at room temperature (RT) and accelerated stability conditions. The samples were designated as time 0 and 1 month for RT and 0 and 1 month for accelerated studies. Samples designed for RT storage were kept at 25 ± 2°C and 60 ± 5% relative humidity (RH). The samples in the accelerated stability study were kept at 40 ± 2°C and 75 ± 5% RH in humidity chamber. Samples were tested for its appearance, flow properties, taste masking,
The UV spectrum of STZ in methanol is shown in Figure
UV spectrum of STZ in methanol.
FTIR of STZ.
FTIR of drug with Eudragit EPO.
FTIR of STZ with Stearic acid.
FTIR of optimized formulation (F3).
All the excipients were selected based on preformulation study results and extensive literature survey. Low melting point wax was used to form dense coating around the drug particle to mask the taste. Eudragit EPO was used as a functional polymer which is insoluble above pH 5 and thus prevents release of STZ in mouth. Preliminary trials were taken for the selection of wax. The ratio of the drug to wax was selected based on literature survey [
The results of bulk density, tapped density, Carr’s index, Hausner ratio, and angle of repose are summarized in Table
Results of flow evaluation.
Parameters | F1 | F2 | F3 | F4 |
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Bulk density (gm/cm3) |
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Tapped density (gm/cm3) |
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Carr’s compressibility index (%) |
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Angle of repose (°) |
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Hausner ratio |
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The taste recognition threshold of STZ was determined on the basis of Table
Taste recognition threshold determination.
Concentration |
Volunteers | |||||||
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1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | |
10 | N | N | N | N | N | N | N | N |
20 | N | N | N | N | N | N | N | N |
22 | N | N | N | N | N | N | N | N |
24 | N | N | N | N | N | N | N | N |
26 | N | N | N | N | N | N | N | N |
28 | N | N | N | Y | N | Y | N | N |
30 | Y | N | Y | N | Y | Y | Y | Y |
32 | Y | Y | Y | Y | Y | Y | Y | Y |
35 | Y | Y | Y | Y | Y | Y | Y | Y |
40 | Y | Y | Y | Y | Y | Y | Y | Y |
Under
Results of drug release from granules of batches F1 and F2 were found to be more than the threshold value, that is, 28
Results of
Batch | Taste masking score by gustatory sensation test |
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F1 | 3 | 32.01 |
F2 | 2 | 30.97 |
F3 | 1 | 23.33 |
F4 | 1 | 21.12 |
Typical HPLC chromatogram of test solution is represented in Figure
Typical chromatogram of test solution.
The results of
% cumulative release and assay in 0.1 N HCL.
Time (minutes) | F1 | F2 | F3 | F4 | Marketed formulation |
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5 |
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10 |
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15 |
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30 |
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45 |
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60 |
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Assay (%) |
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Comparison of
The Granular friability of granules of optimized batch (F3) was found to be 0.15%. The size of the granules was found in the range of 341.93
SEM image of drug particle.
SEM image of optimized granular formulation (F3).
Stability study results indicated that there was no change in physical appearance of granules and taste at room temperature as well as accelerated conditions. The results of percent dissolution, assay, and flow properties of the optimized batch F3 at RT and accelerated stability conditions are summarized in Table
Stability study results.
Parameters | At RT | At accelerated conditions | ||
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0 month | 1 month | 0 month | 1 month | |
Assay (%) | 98.94 | 98.75 | 98.87 | 98.62 |
% dissolution |
85.01 | 84.70 | 84.68 | 84.97 |
Flow property | Good | Good | Good | Good |
Taste masking of bitter drugs with higher dose is challenging. STZ is having a dose of 300 mg twice daily in amoebiasis and is available in market in the form of film coated tablet. Difficulty in swallowing tablets is a major problem especially in case of geriatrics and pediatrics as well as patients who are not able to swallow tablets. In the above technique, low melting point wax was used for dissolving Eudragit EPO instead of organic solvent which led to the formation of dense coating around the drug and also step of removal of organic solvent by carrying out drying step was not required by using wax. Granules formed by coating with Eudragit EPO showed similar release of STZ like that of marketed tablet. From the above results, it can be concluded that complete taste masking of bitter STZ is achieved by granulating drug with stearic acid and Eudragit E100 by melt granulation technique. The efficiency of stearic acid was tested for the purpose of taste masking with the possible method of melt granulation. Taste masking by the above technique is achieved by decreasing the surface area of the drug by increasing its particle size and the method was found to be very simple.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors are very much thankful to Dr. P. S. Gide, Principal of Hyderabad Sindh National Collegiate Boards (HSNCBs), Dr. L. H. Hiranandani College of Pharmacy, Ulhasnagar, for his continuous support, guidance, and encouragement.