Swarnali Dutta1, Biswajit Basu2*
1Birla Institute of Technology (BIT), Mesra, Ranchi, Jharkhand – 835215.
2Department of Pharmaceutical Technology, School of Health and Medical Sciences, Adamas University, Kolkata - 700126, West Bengal, India.
*Corresponding Author E-mail: bbasu.pharma@gmail.com
ABSTRACT:
Mouth dissolving pills, which dissolve or disintegrate quickly on the tongue or buccal cavity, have been developed in response to the growing demand for more patient-compliant dosage forms. It is utilized to improve bioavailability by reducing dose frequency in order to reduce adverse effects and make tablets with high first-pass metabolism more cost-effective. The most commonly used drug for diarrhoea is loperamide hydrochloride. It is an opioid receptor agonist that targets the mu opioid receptors in the large intestines of the myenteric plexus. It specifically works by lowering myenteric plexus activity, which lowers the motility of the circular and longitudinal smooth muscles of the intestinal wall. It is a synthetic anti-diarrheal that is used to treat the symptoms of inflammatory bowel disease-related chronic diarrhoea as well as acute, non-specific diarrhoea. Due to substantial hepatic first-pass metabolism, loperamide hydrochloride has a very limited systemic bioavailability. Therefore, the primary goal of the study was to develop Loperamide hydrochloride orally disintegrating tablets to obtain a better breakdown rate, enhance the drug's bioavailability, and provide very rapid relief from diarrhoea. The pre-compression parameters, such as bulk density, compressibility, angle of repose, etc., for orally disintegrating tablets manufactured by direct compression and using three super disintegrants, croscarmellose sodium (CCS), Microcrystalline cellulose (MCC), and sodium starch glycolate (SSG), were prepared and assessed. The manufactured batches of tablets passed tests for satisfactory results. The highest amount of medicine was released at all-time intervals in the optimised formulation, which also displayed a favourable release profile.
KEYWORDS: Loperamide hydrochloride, Orally disintegrating tablets, Opioid, Superdisintegrants, Crospovidone, Sodium starch glycolate.
1. INTRODUCTION:
The majority of the currently available drug delivery technologies are tablets and hard gelatin capsules. However, numerous patient populations, including the elderly, kids, and patients who are recalcitrant, mentally challenged, sick, or on diets with restricted fluid intake, have trouble swallowing these dose forms.1,2 Due to hand tremors and dysphasia, administering standard oral dose forms can be challenging for many elderly people.
Children frequently experience swallowing issues due to their immature neurological and muscular systems. Swallowing traditional pills can be challenging in situations like motion sickness, sudden attacks of allergy or coughing, and when water is not readily available. Fast water-dispersible tablets are a novel type of dosage form for oral administration that formulators have worked hard to develop in order to meet these medical objectives.3-5
Over the past two decades, there has been an increased desire for dose forms that are more patient-compliant. The outcome has been a 3-fold annual growth in the demand for the technology. Pharmaceutical companies are concentrating on developing novel drug delivery methods for an existing drug with increased efficacy and bioavailability and reduced dose frequency to minimise the adverse effects because the development cost of a new chemical entity is very costly.6-8
Up to 50–60% of all dosage forms are accepted by the oral mode of drug delivery. Popularity of solid dosage forms is attributed to their ease of administration, accuracy in dosage, ability to be used for self-medication, ability to reduce pain, and, most significantly, patient compliance. Among solid dose forms, tablets and capsules are most widely used. The inability to swallow these dose forms is a significant flaw in them.9,10 Candidates for this dosage form include a large variety of drugs. Techniques like tablet moulding, spray drying, lyophilization, sublimation, and the inclusion of disintegrants are used to create fast-dissolving tablets. Zydis, OraSolv, DuraSolv, Flash Dose, Wow tab (Without Water), and Flashtab are a few of the patented methods for creating fast-dissolving tablets.11-13
A drug called loperamide is used to lessen the frequency of diarrhoea and is marketed under the brand names Imodium and other names. Short bowel syndrome, inflammatory bowel disease, and gastroenteritis are among the conditions where it is frequently applied for this purpose. Blood in the stool is a contraindication, so avoid using it. It is an opioid receptor agonist that targets the mu-opioid receptors in the large intestine's myenteric plexus. Specifically, it works by reducing the activity of the myenteric plexus, which in turn reduces the motility of the circular and longitudinal smooth muscles of the intestinal wall.14-16
A fresh approach is the development of orally disintegrating tablets, which dissolve or disintegrate quickly on the patient's tongue or buccal mucosa. This meets the growing desire for a dosage form that is more patient-compliant. It is used to improve bioavailability by reducing dose frequency to reduce side effects and make it more cost-effective for tablets with high first-pass metabolism.17 The drug of choice for diarrhoea is loperamide hydrochloride. Due to substantial hepatic first-pass metabolism, loperamide hydrochloride has a very limited systemic bioavailability. Therefore, it is necessary to create quickly disintegrating tablets that dissolve in the mouth within a few seconds, minimising first-pass metabolism, boosting bioavailability, and also hastening the commencement of pharmacological action. Therefore, the primary goal of the study was to develop Loperamide hydrochloride orally disintegrating tablets to obtain a greater breakdown rate, enhance the drug's bioavailability, and fast relieve diarrhoea. The pre-compression properties, such as bulk density, compressibility, angle of repose, etc., of orally disintegrating tablets manufactured by direct compression and using super disintegrants such CCS, MCC, SSG, and crospovidone were prepared and assessed. The manufactured batches of tablets passed tests for satisfactory results in terms of hardness, weight variation, friability, drug content, disintegration time, and in-vitro dissolution profile.10,18
The objective of the study was to enhance the dissolution and absorption of the drugs, which may produce a rapid onset of action in the treatment of Diarrhoea.
2. MATERIALS AND METHODS:
Materials:
From Yarrow Chemicals in Mumbai, India, we bought loperamide and CCS. Maple Biotech India Pvt. Ltd. (Pune, India) sent SSG and MCC as a gift sample. Magnesium stearate and Sodium saccharine were purchased from Fine chemicals, and camphor was obtained from the Research Lab. All other ingredients were of analytical grade.
2.1 Preparation of standard curve of loperamide in phosphate buffer (pH 6.8):
From the working standard of different concentrations (0, 10, 20, 30, 40, 50, 60μg/ml) were analyzed using UV-Visible spectrophotometer at λmax value. A graph was plotted against concentration (μg/ml) vs. absorbance.19
2.2 Compatibility Studies: Drug–Excipient Compatibility Study:
By using Fourier Transform Infrared Spectroscopy (FTIR) and the FTIR spectra of the pure loperamide with excipients like SSG, CCS, MCC, saccharin sodium, etc., the chosen polymers were analyzed and characterized. The produced formulation's IR spectra was compared to the loperamide and polymer's IR spectrum.A dry air purge was used to operate the device, and scans were taken at a speed of 2mm/sec with a resolution of 4 cm-1 over an area of 4000-400 cm-1. The scans were examined for the presence of the drug's principal peaks, drug peaks that had moved or been covered up, and drug peaks that had formed as a result of interactions with polymers.20-22
Potassium bromide (KBr) pellets were used to record the FT-IR spectra of pharmacological samples at a resolution of 4 cm-1 for the purpose of authenticating the data and studying the primary peaks with an FT-IR spectrophotometer. The samples were validated by comparing the indicated peaks to the primary peaks of the published IR spectra. To determine if loperamide and the polymer might interact chemically, the FT-IR spectra of loperamide were examined. Compatibility is one of the criteria for choosing appropriate polymers or carriers for the pharmaceutical formulation. Therefore, a compatibility analysis was conducted in the current work utilising Infra-Red spectroscopy (IR) to determine whether there could be a chemical interaction between loperamide and the polymers.5,23
2.3 Pre formulation studies:
The rational development of a drug substance's dosage form begins with preformulation research. The goal of preformulation research is to assemble a database of knowledge about the drug substance that will be helpful in creating the formulation. Preformulation is the process of analysing the physical and chemical characteristics of pharmacological compounds both on their own and in combination with excipients.24,25
It was almost white color crystalline powder, odorless and tasteless.
Using melting point equipment, the melting points of the drugs were identified. The drug sample was tested between 100 and 2500 C, and the temperature at which the substance melted was reported.26
2.3.4 Solubility
Loperamide's solubility was assessed in a variety of solvents, including distilled water, 0.1 N HCl, phosphate buffer pH 6.4, alcohol, acetone, etc.27,28
2.4.1 Angleofrepose:
The angle of powder repose was calculated using the funnel method. The precisely weighed powder was gathered with a funnel. The funnel was raised to a height where the tip just touches the top of the powder stack. It was let for the powder to freely flow onto the surface through the funnel. The angle of repose was estimated using the following equation after measuring the powder cone's diameter.29,30
Where, h and r are the height and radius of the powder cone, respectively.
A precise amount of powder that had previously been put through sieve # 40 [USP] was weighed out and then precisely placed into a graduated cylinder. The powder bed was then created consistently and without disturbance after being poured into the graduated cylinder. The capacity was then calculated as ml directly from the cylinder's graduation marks.(31, 32) The bulk density was calculated by the following formula;
2.4.3 Tapped Density:
The tap density device was activated for 500 taps and configured to drop 300 taps per minute. Volume was first documented as (Va) and then 750 more times, at which point volume was noted as (Vb). Vb is regarded as the final tapped volume if the difference between Va and Vb is not larger than 2%.31 The following formula was used to calculate the same.
2.4.4 Carr’s Index and Hausner’sRatio:
The ability of powder to flow and be crushed is measured by Carr's index and Hausner's ratio. The bulk and tapped density can be used to calculate Carr's index and Hausner's ratio.33
Tapped density
Hausner’sratio= -----------------------
Bulk density
2.4.5 Angle of repose estimation:
The microcapsules were put through the glass funnel on a horizontal surface to measure their angle of repose (q=tan-1 h/r). This study was carried out three times. The cone base's radius (r) and the height (h) of the heap that formed were both observed and computed.33
2.5 Preparation of tablets:
2.5.1 Preliminary Trial Batch:
Before combining, all of the basic components were put through an 80 mesh screen. For 15 minutes, loperamide, excipients, and camphor, a subliming substance, were physically mixed in a glass mortar. To help the tablet's porosity, camphor was added in a concentrated form. The pleasant flavour of the formulation is impacted by the sweetener addition. To check the combined impact of two formulation variables—the quantity of SSG and CCS, 32 complete factorial design was used. The powder combination was then compacted into tablets using a flat face 3 mm diameter rotary tablet punching machine after being greased with 1% magnesium stearate. The final tablets were sublimated for 12 hours at 60 degrees Celsius in a hoover dryer.(33) The composition of the preliminary batch to optimize the amount of camphor and the factorial batch has been shown in Table 1 and 2 respectively. Statistical data is not discussed in this report.
Table 1: Optimising the amount of Camphor in the initial batch's composition
|
Ingredients (mg) |
Formulation Code |
|||
|
PB1 |
PB2 |
PB3 |
PB4 |
|
|
Loperamide |
12 |
12 |
12 |
12 |
|
Camphor |
5 |
10 |
15 |
20 |
|
SSG |
10 |
10 |
10 |
10 |
|
CCS |
10 |
10 |
10 |
10 |
|
MCC |
qs |
qs |
qs |
qs |
|
Saccharine sodium |
3 |
3 |
3 |
3 |
|
Magnesium stearate |
3 |
3 |
3 |
3 |
|
Dispersion time (Sec) |
85 |
47 |
39 |
31 |
|
% Friability |
0.33 |
0.46 |
1.1 |
1.5 |
Table 2: Composition of various batches of Loperamide tablets as per 32 factorial designs
|
Ingredients (mg) |
Tablet Formulation Code |
||||||||
|
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
|
|
Loperamide |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
|
SSG |
10 |
10 |
10 |
12 |
12 |
12 |
14 |
14 |
14 |
|
CCS |
10 |
12 |
14 |
10 |
12 |
14 |
10 |
12 |
14 |
|
Camphor |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
MCC |
qs |
qs |
qs |
qs |
qs |
qs |
qs |
qs |
qs |
|
Saccharine sodium |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
|
Magnesium stearate |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
*All the quantities expressed in mg
2.6 Evaluation of Prepared Tablets:
2.6.1 Weight Variation:
A Shimadzu digital balance was used to weigh the twenty tablets that were chosen at random from each formulation. The average values were computed.15
2.6.2 Thickness:
10 tablets from each formulation were taken randomly and their thickness was measured with a digital screw gauge micrometer. The mean SD values were calculated.34
2.6.3 Hardness and Friability:
Using a tablet hardness tester (Monsanto type), the crushing strength of all the formulations was measured. Using a USP-type Roche friabilator (Campbell Electronics, Mumbai), the friability of a sample was assessed. A plastic chamber attached to a motor rotating at a speed of 25 rpm was filled with pre-weighed tablets and run for 4 minutes. The tablets were de-dusted, reweighed and the % weight loss (friability) was measured.(34)
Initial weight - Final weight
% Friability = ------------------------------------ x 100
Initial weight
2.6.4 Wetting Time:
A Petri dish with a 10cm diameter was filled with five round tissue papers. The petri dish was filled with ten millilitres of water that had 0.5% of a water-soluble dye called eosin in it. The dye solution was used to determine if the tablet surface had been completely moistened. The tissue paper in the Petri dish was covered with a tablet and heated to 250C. The wetting time was measured as the amount of time needed for water to completely wet the tablets' upper surface. Six replicates of these measurements were performed. Using a timer, we measured the wetting time.34
2.6.5 In vitro Dispersion Time:
The dispersion time (DT) was calculated using a Petri dish with a diameter of 10cm was filled with 10 ml of phosphate buffer at pH 6.8 and 25°C. After carefully placing the tablet in the middle of the Petri dish, the time it took to completely break down into tiny particles was recorded. Six tablets were used for the measurement process in duplicate, and mean SD values were recorded.35,36
2.6.6 In Vitro Release Studies:
USP Dissolution apparatus type II (TDT-06T, Electrolab, Mumbai, India), was used to conduct in vitro release of loperamide from various formulations. The dissolution medium was 900 ml phosphate buffer (pH 6.8), and the paddle speed was kept constant at 50 rpm. Every two minutes, samples (10 ml) were taken and replaced with an equivalent volume of new medium. The medium was then filtered using Whatman filter paper and subjected to UV—Visible spectrophotometer analysis (Shimadzu, Japan). Drug concentration was expressed as a cumulative percentage of the drug dissolved.35,36
2.6.7 Assay:
Drug content in tablets was evaluated. From each formulation, ten tablets were chosen at random and ground into a fine powder. A UV-VIS spectrophotometer (Model UV/Visible 1700 double beam Spectrophotometer, Shimadzu, Japan) was used to measure the amount of drug present in weighed aliquots that were obtained in triplicate.35,36
2.6.8 Wetting time and Water absorption ratio:
In a little Petri dish with an interior diameter of 5 cm and a water content of 6 ml, a piece of tissue paper folded twice was inserted (Figure 1). After placing a tablet on the paper and timing how long it took it to completely wet, the tablet was then weighed.37,38
Water absorption ratio ‘R’ was determined using the following equation
R = [100 × (Wb – Wa)/ Wa]
Where Wa is the weight of the tablet before water absorption and Wb is the weight of the tablet after water absorption.37,39
Figure 1: Wetting time and water absorption ratio determination shown schematically
3. RESULT AND DISCUSSION:
3.1 Analytical Method:
3.1.1 Calibration curve of Loperamide using phosphate buffer (pH 6.8)
The calibration curve of loperamide was taken in phosphate buffer (pH 6.8). The absorbance values for all the solutions in PBS were table 3 respectively and their standard curve is given in figure 2 respectively. The drug was found to obey Beer Lambart's law with regression co-efficient values 0.9947 in PBS (pH 6.8).
Table 3: UV absorbance of Loperamide using PBS (pH 6.8)
|
Sl. No. |
Concentration (μg/ml) |
Absorbance |
Mean Absorbance |
||
|
|
|
I |
II |
III |
|
|
1 |
0 |
0 |
0 |
0 |
0 |
|
2 |
10 |
0.012 |
0.012 |
0.013 |
0.012 |
|
3 |
20 |
0.020 |
0.020 |
0.020 |
0.020 |
|
4 |
30 |
0.028 |
0.029 |
0.029 |
0.029 |
|
5 |
40 |
0.039 |
0.039 |
0.038 |
0.039 |
|
6 |
50 |
0.044 |
0.044 |
0.044 |
0.044 |
|
7 |
60 |
0.054 |
0.055 |
0.055 |
0.055 |
*All results are shown in mean (n=3)
Figure 2: Calibration curve of Loperamide using PBS (pH 6.8)
3.2 COMPATIBILITY STUDIES:
3.2.1 Fourier Transform Infrared (FTIR) spectral analysis
Figure 3: FTIR spectra of pure drug Loperamide drug-polymer mixture
10 mg of the pure Loperamide drug and 10mg of the drug-polymer mixture were compressed and then scanned from 4000 – 400-1 cm using FTIR 8201 PC spectrophotometer separately. FTIR spectra are shown in Figures 3. Pure Loperamide showed different characteristic peaks at 1698.77, 1621.41, 1539.91, 981.22, 822.40, 744.63 and 710.54 cm-1. It was observed that all the major peaks of Loperamide were intact when it was incorporated into the tablet’s formulation and no considerable changes in the IR peaks were observed. So FTIR spectra indicate the stable nature of Loperamide in the prepared formulations.
3.3 PreformulationStudies:
3.3.1 Meltingpoint:222°C
3.3.2 Solubility: Almost white colour crystalline Soluble in methanol or chloroform.
3.4 Determination of Micromeritics Properties:
Micromeritics properties of pure drug was calculated and expressed in table 4.
Table 4: Pre-compression parameters of Loperamide HCl pure drug
|
Material |
Angleof repose |
Bulkdensity (gm/ml) |
Tappeddensity (gm/ml) (100 tapings) |
|
Loperamide |
27°.85'' |
0.28 |
0.36 |
Pre-CompressionParametersofLoperamideTablets
Table 5: Pre-compression parameters of Loperamide tablets
|
Formulation code |
Bulk Density (g/cc) |
Tapped density (g/cc) |
The angle of repose (degree) |
Carr’ sindex (%) |
Hausner’s ratio |
|
F1 |
0.50 |
0.58 |
25.33 |
13.21 |
1.15 |
|
F2 |
0.49 |
0.56 |
25.18 |
11.47 |
1.13 |
|
F3 |
0.47 |
0.54 |
22.29 |
12.32 |
1.14 |
|
F4 |
0.44 |
0.50 |
23.61 |
11.51 |
1.13 |
|
F5 |
0.42 |
0.48 |
23.85 |
11.54 |
1.15 |
|
F6 |
0.40 |
0.43 |
24.36 |
10.12 |
1.11 |
|
F7 |
0.48 |
0.65 |
25.19 |
13.52 |
1.15 |
|
F8 |
0.49 |
0.62 |
24.52 |
12.55 |
1.14 |
|
F9 |
0.45 |
0.54 |
22.21 |
12.68 |
1.11 |
*Readingsare an average of 3 determinations
3.5 Preliminary trial result:
Nine formulations in total were developed and assessed. Four batches of the subliming material camphor, ranging in concentration from 0 to 20 mg, were prepared for the preliminary tests, which aimed to optimize the concentration. The results revealed that as camphor concentration increased, the porosity of the tablet also increased, resulting in the fastest dispersion but also making the tablet more fragile due to higher porosity. Batch PB2 (DT-47 sec, Friability 0.46%), which contained 10 mg of camphor, demonstrated the good outcome. 10 mg of camphor was therefore chosen as the optimal dose for further research. (Table 5).
3.6 Evaluation of Loperamide Mouth Dissolving Tablets:
Weight changes in all of the formulations were within 2.47%, while hardness variations were within 0.15%. The assay for medication content is successful for all formulations. In all formulations, there was greater than 95% uniformity in the medication content. According to preliminary batch data on friability, the formulation becomes more friable as camphor concentration rises. According to IP, none of the formulations exceeded the % friability restriction.
For each formulation, the wetting time was calculated. All of the formulations took more than 42 seconds to wet due to their quick water absorption properties, which involved both the capillary and swelling mechanisms of the SSG and CCS. When choosing the best formulation for an oral disintegrating tablet, dispersion time is a key consideration. It was discovered that lowering the DT as shown led to an increase in the superdisintegrant concentration. When comparing friability and dispersion time, the F7, F8, and F9 batches had a lower dispersion time than other formulas and did not exceed the friability limit. The F9 batch, which had a maximum superdisintegrant concentration, was a well-optimized batch with a dispersion time of 34.67 seconds and a friability of 0.62% (Table 6).
Table 6: Evaluations of All Batches of loperamide Tablets
|
Batch Code |
Average weight* (mg) ± SD |
Hardness * (Kg/cm2) ± SD |
Wetting time* (sec.) ± SD |
Friability* (%) |
Content uniformity* |
Dispersion time* (sec) ± SD |
Surfaces pH |
|
F1 |
148.16±1.83 |
3.37±0.06 |
65.00±2.00 |
0.6026±0.10 |
97.26 |
56.67±3.05 |
6.85 |
|
F2 |
148.70±2.47 |
3.37±0.15 |
58.33±4.04 |
0.5081±0.10 |
100.58 |
47.33±2.52 |
6.89 |
|
F3 |
148.98±2.25 |
3.03±0.06 |
67.33±5.03 |
0.4893±0.07 |
97.95 |
54.00±3.60 |
6.92 |
|
F4 |
149.05±2.25 |
3.03±0.06 |
68.00±3.00 |
0.7291±0.14 |
96.57 |
56.00±3.60 |
6.94 |
|
F5 |
149.18±2.10 |
3.47±0.06 |
61.00±4.00 |
0.5183±0.20 |
97.67 |
61.67±2.08 |
6.97 |
|
F6 |
148.48±1.92 |
3.90±0.10 |
64.67±9.29 |
0.5902±0.08 |
95.87 |
60.33±1.53 |
6.74 |
|
F7 |
149.26±2.03 |
3.10±0.10 |
44.33±5.03 |
0.7609±0.11 |
97.40 |
37.33±2.08 |
6.93 |
|
F8 |
149.66±2.38 |
3.03±0.06 |
43.00±7.21 |
0.6250±0.28 |
98.09 |
39.33±2.52 |
6.99 |
|
F9 |
148.51±2.18 |
3.30±0.10 |
42.33±4.04 |
0.6227±0.23 |
99.47 |
34.67±1.53 |
6.95 |
*Average of three determinate, ± Standard Deviation ± (SD)
Table 7: In vitro drug release of loperamide in pH 6.8 phosphate buffer
|
Time (Sec) |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
|
0 |
0.00 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
27.35 |
52.196 |
27.054 |
34.277 |
54.774 |
53.195 |
44.149 |
47.915 |
49.761 |
|
4 |
78.81 |
56.844 |
62.937 |
61.609 |
59.174 |
60.878 |
57.742 |
76.217 |
75.170 |
|
6 |
81.30 |
61.801 |
72.985 |
70.162 |
62.060 |
62.269 |
67.302 |
82.247 |
82.623 |
|
8 |
85.35 |
68.601 |
78.492 |
73.748 |
64.009 |
64.622 |
73.833 |
83.719 |
86.094 |
|
10 |
87.36 |
75.607 |
81.475 |
76.891 |
68.959 |
61.325 |
81.425 |
82.139 |
90.587 |
|
12 |
90.92 |
78.617 |
74.264 |
79.382 |
70.417 |
63.744 |
91.111 |
88.194 |
93.103 |
|
14 |
91.93 |
80.534 |
78.750 |
82.921 |
75.452 |
70.869 |
96.741 |
95.809 |
95.625 |
|
16 |
95.00 |
84.447 |
82.238 |
87.512 |
82.935 |
72.816 |
96.832 |
97.895 |
99.152 |
3.7 In Vitro Release Studies:
In the absence of taste masking, oral disintegrating tablet dissolution techniques are comparable to those used for regular tablets. Within 10 minutes, every orally disintegrating tablet formulation (table 7) released more than 80% of the drug. Formulation F9 was thought to be preferable to less CCS and SSG when taking into account wetting time, in vitro DT,%friability, and cumulative% drug released. Out of the nine formulations investigated in this study, F9 was deemed to be the best option for orally disintegrating tablets (Figure 4).
Figure 4: In vitro Dissolution of all batches in 6.8 pH phosphate buffer
Table 8: Wetting time and water absorption time of loperamide tablets
|
Sl. No |
Formulation code |
Wetting time (Sec)(±SD) |
Water absorption ratio % (±SD) |
|
1 |
F1 |
65.00±2.00 |
59.33±2.89 |
|
2 |
F2 |
58.33±4.04 |
57.22±2.46 |
|
3 |
F3 |
67.33±5.03 |
57.33±1.12 |
|
4 |
F4 |
68.00±3.00 |
54.71±1.51 |
|
5 |
F5 |
61.00±4.00 |
63.26±1.86 |
|
6 |
F6 |
64.67±9.29 |
60.41±1.93 |
|
7 |
F7 |
44.33±5.03 |
61.47±0.26 |
|
8 |
F8 |
43.00±7.21 |
63.56±0.31 |
|
9 |
F9 |
42.33±4.04 |
67.47±0.26 |
3.9 Stability Studies:
Selected tablet batches' stability was examined for three months in a stability chamber at 40° C and 75% RH (Remi Instruments, India). The physical properties of the tablet were examined at various temperatures and times to ascertain the stability of a tablet formulation.
4. DISCUSSIONS:
4.1 Preformulation Study:
Loperamide was evaluated for all of its micromeritics characteristics in the preformulation investigation. All materials have sufficient compressibility and flow qualities, according to the results.
4.2 Compatibility Study:
Utilising an IR spectrophotometer, compatibility investigations were carried out. We looked at the IR spectra of both the pure drug and the physical mixture of the drug and the super disintegrant. The typical loperamide absorption peaks were measured at the following wavelengths: 1698.77, 1621.41, 1539.91, 981.22, 822.40, 744.63, and 710.54 cm-1. The peaks found in the spectra of each formulation correspond to the peaks found in the original loperamide medication. This suggests that the medicine and the formulation's components were compatible.
4.3 Analytical Method:
UV spectroscopy was used as an appropriate analytical technique to ascertain the composition of loperamide. In a phosphate buffer with a pH of 6.8, loperamide exhibits an absorption peak at 253.5nm, and absorption was linear from 1g/ml to 10g/ml. This technique was discovered to be reliable, exact, and particular for loperamide.
4.4 Selection of Tableting Methodology:
In order to formulate mouth-dissolving tablets using the direct compression approach, the effervescent method and the super disintegrants addition method have been investigated. The super disintegration addition approach was determined to be the best way when compared to the other methods because it shows the shortest disintegration duration.
4.5 Effect of concentration camphor in the trial series:
Four batches of the 0 to 20mg concentration of camphor were prepared for the preliminary tests, which aimed to optimise the concentration of the subliming material. The results revealed that as camphor concentration increased, the porosity of the tablet also increased, which caused it to disintegrate more quickly but also made it more fragile. Batch C3 (DT-47 sec, Friability 0.46%), which contained 10mg of camphor, demonstrated the positive outcome. 10mg of camphor was therefore optimised for further research.
4.6 Characterization of loperamide mouth dissolving tablets:
For the development of mouth dissolve tablets, SSG, CCS, and MCC were utilised. The angle of repose, Hausner's ratio, and percent compressibility of the powder mixture were assessed. Physical characteristics, wetting time, in-vitro disintegration time, assay, and in-vitro drug release were all assessed for the produced tablet.
5.1 Evaluation of powder blend:
5.1.1 Angle of Repose (θ)
The θ value was found to be in the range 23.02o to 26.40o indicating the good flow property of the powder blend.
5.1.2 Hausner’s ratio and Carr’s index
Hausner’s ratio and Carr’s indexwas found to be in the range 1.12 to 1.16 and 11.36% to 14.06% respectively that indicated that all formulation has good flow properties.
5.2 Physical Parameters:
5.2.1 Weight variation:
As long as the weight variation stayed within the IP limitations of 7.5% of the weight, all of the formulations (F1 to F9) passed the weight variation test. All of the tablets had consistent weights. All the developed formulation passes the weight variation test.
5.2.2 Hardness and Friability:
The tablet's hardness ranged from 3.03 to 3.9Kg/cm2. It was discovered that the formulation's maximum friability was 0.76%. It was determined that the formulation had a minimum friability of 0.489%. Each formulation's percentage of friability was less than 1%, ensuring the mechanical stability of the tablets.
5.2.3 Drug content:
It was discovered that the minimum drug content from all formulations was 95.87% and the maximum drug content for all formulations was 100.58%. The outcomes fell inside the IP's allowed range.
5.2.4 In vitro Dispersion time:
It was discovered that the in vitro dispersion time was between 34.67 to 61.67 seconds. The formula F9 has the shortest dispersion time of all (34.67 sec).
5.2.5 Wetting Time:
Wetting Time was found to be in the range of 42.33 to 68.00 sec. From all formulations, F9 has a minimum wetting time (table 8).
5.2.6 In vitro drug release:
All the 9 formulations were subjected to in vitro dissolution studies by using pH 6.8 phosphate buffer. According to dissolution studies, formulation F9 had better dissolve than other formulations, and a total drug release of 99.15% was found at 16 minutes.
5.3 Stability Study:
Using an ideal batch F9 in accordance with ICH standards, stability investigations were carried out for 90 days under stability conditions (40°C/75 percent RH). According to Table 9, physical-chemical properties and release profile exhibited no significant changes for batch F9. Even in conditions of great stress, the formulation maintains a high degree of stability. Following three months of stability testing, as seen in Figure 3, the in vitro drug release curves for the F9 tablet are identical to those of the initial F9 batch (before stability). This demonstrates that after three months of stability testing, there has been no change in the drug release behaviour of the F9 batch (table 9).
6 CONCLUSIONS:
By creating a quick drug delivery method for loperamide with the use of super disintegrating agents and a subliming material, the objective of this experiment was accomplished. The batch that has been optimised can be sold. Techniques for administering loperamide quickly and effectively without the need for water include accurate dose, simple portability, an alternative to liquid dosage forms, and quick onset of action.
Table 9: Stability study data of F9 batch
|
Time |
Wetting time* (sec.) ± SD |
Friability (%) |
Hardness (kg/cm2) |
Dispersion time (seconds) |
Wetting time (seconds) |
% drug release |
|
15 days |
42.33±4.04 |
0.6227±0.23 |
3.30±0.10 |
34.67±1.53 |
42.33±4.04 |
99.152±1.23 |
|
30 days |
42.35±4.05 |
0.6225±0.25 |
3.22±0.21 |
34.81±1.57 |
41.03±2.21 |
99.130±0.57 |
|
1 month |
42.15±3.54 |
0.6210±0.12 |
3.24±0.15 |
33.85±1.02 |
42.52±4.01 |
99.050±0.25 |
|
3 months |
42.10±3.64 |
0.5210±0.23 |
3.33±0.17 |
34.82±0.25 |
42.81±1.25 |
99.049±0.11 |
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Received on 24.04.2023 Modified on 28.08.2023
Accepted on 18.11.2023 © RJPT All right reserved
Research J. Pharm. and Tech 2024; 17(4):1632-1640.
DOI: 10.52711/0974-360X.2024.00258