Study of effect of Muco Adhesive Polymers on Domperidone Hard Candy Lozenges
R. Sailaja1*, N. Kamakshi2, S. Sandhya2, P. Jogi Naidu2
1Asisstant Professor, Department of Pharmaceutics, Raghu College of Pharmacy,
Dakamarri (v), Bheemunipatnam, Mandal, Visakhapatnam – 531162.
2Department of Pharmaceutics, Raghu College of Pharmacy,
Dakamarri (v), Bheemunipatnam, Mandal, Visakhapatnam – 531162.
*Corresponding Author E-mail: rongalisailaja2011@gmail.com
ABSTRACT:
Objective: The main object of the work is to formulate and evaluate hard lozenges of Domperidone using different mucoadhesive polymers. Methods: The solubility of Domperidone was enhanced by co crystallization technique. The cocrystals were prepared with different coformers (PABA, Succinic acid, Salicylic acid) at different weight ratios (1:1, 1:3) by solvent evaporation method. With these conformers hard lozenges were prepared by hot congealing technique. The 6 formulations were prepared and F1 to F3 formulations were prepared with tamarind kernel powder as muco adhesive polymer and F4, F5 and F6 were prepared with sodium carboxy methyl cellulose. Microbial attack test was performed for all the formulations by streak plate method and cylinder method. All the formulation s evaluated for various parameters like weightvariation, hardness, thickness, disintegration, mouth dissolving time and dissolution. Mucoadhesive strength was measured using modified physical balance method. Results: The results for solubility enhancement ratio has shown that increase in the concentration of coformer increases the aqueous solubility of Domperidone and PABA (1:3) has shown 50 folds increase in solubility. The formulations without preservative have shown microbial growth hence in F4toF6 methyl paraben was added as preservative. All the evaluation parameters with in the acceptance limits and the formulation with PABA at 1:3 ratio has shown 93.6 % drug release within 30minutes. Conclusion: The research has concluded that the solubility of Domperidone increased more with Para amino benzoic acid with cocrystallization technique. Mucoadhesive studies has concluded that tamarind kernel powder has high muco adhesive strength and hence it can be used as mucoadhesive polymer in various formulations.
KEYWORDS: Co-crystallization, Solvent evaporation, Hot congealing, Microbial attack, Muco adhesive strength and solubility enhancement ratio.
INTRODUCTION:
Lozenges are medicated dosage forms which were made with sugar syrups. Lozenges may dissolve in mouth or pharynx and avoid first pass metabolism.
Definition:
“Lozenges are solid dosage form containing the flavoring and sweetening agents that are intended to dissolve or disintegrate slowly in the mouth or oral cavity”. They are most often used for localized effect into oral cavity and can also show systemic effect if it is well absorbed in the buccal lining and pharynx1.
Drug candidates which can be incorporated in lozenges include antiseptics, local anesthetics, antibiotics, antihistamines, antitussives, analgesics, decongestants and demulcents2.
Domperidone is a dopamine-2 receptor antagonist. It acts as an antiemetic and a prokinetic agent through its effects on the chemoreceptor trigger zone and motor function of the stomach and small intestine3.
Sajan maharajan etal prepared Domperidone lozenges with different ratios of HPMC by using heat congealing technique. Dextrose and sucrose were heated separately fused together and reheated after polymers and excepients were added and moulded. They concluded that the Domperidone lozenges prepared with HPMC at different ratios has shown better results both invitro dissolution studies and rug content4.
B. Moulika lakshmi et al prepared hard candy lozenges of Domperidone with HPMC E 15 and HPMC K100M and concluded that the lozenges with HPMC E5 showed better result in heat congealing technique. candy lozenges can be used as efficient means of formulation to enhance solubility and bioavailability of the drug as carried through oral cavity5.
The present work mainly includes the solubility enhancement of Domperidone by cocrystallization technique with different conformers. Tamarind kernel powder used as mucoadhesive polymer and its muco adhesive ability compared with sodium carboxy methyl cellulose. We have prepared Domperidone lozenges by hot congealing technique with cocrystals of Domperidone.Sucrose syrup was used and as it lead to microbial attack in the later formulations Preservative was included. All the lozenges were subjected various evaluation parameters.
MATERIALS:
Tamarind seeds obtained from the local market, Tagarapu valasa, Visakha patnam. Domperidone and all the chemicals were purchased from yarrow chemicals, Mumbai.
METHODS:
Extraction of Tamarind kernel gum Powder5,6: To extract tamarind kernel powder the outer part of seeds was peeled out. The white part of the seeds was crushed and soaked in water for 24hrs and placed in muslin cloth to release gum. The marc was removed from the gum and equal quantity of absolute ethyl alcohol was added to precipitate the gum and separated by filtration. The marc was sent for multiple extractions. The separated gum was dried in hot air oven at temperature 40ºC. Then the dried gum was powdered and stored in airtight container at room temperature.
Preformulation studies of TKP:
The Tamarind kernel powder was evaluated for bulk density, angle of repose, Hausners ratio and also for the presence of carbohydrates and results were given in the table 2 and fig1.
Standard graph of Domperidone in pH 6.8 buffer and water:7
Phosphate buffer pH 6.8 was prepared according to the IP. 50mg of pure drug was dissolved in the 50ml of pH 6.8 buffer. From this stock solution serial dilutions were done to make different concentrations like 10, 20, 30, 40, 5μg/ml the absorbance was measured by using uv visible spectroscopy at lambda max of 284nm and the results were given in the table 3 and standard graphs have shown in fig 2 and 3.
Preparation of Co-Crystals (co -crystallisation)8-10:
Solvent Evaporation Method: The accurately weighed concentration of drug and co-former were dissolved in sufficient amount of solvent on heating until complete dissolution of drug and left for slow evaporation for 24hrs and cocrystals were formed. Then the cocrystals were dried and placed in air tight bag until further use.
Measurement of Solubility Enhancement Ratio:
The prepared Domperidone co crystals were weighed which were equivalent to 10mg of the pure drug and dissolved in the 100ml of distilled water .Then the absorbance of the solution was measured by using uv Spectrophotometry at the lamda max of 284nm. The number of folds increase in the of co crystals were measured and the results were given in the table no 4.
Formulation of Hard Candy lozenges11-14:
Required quantity of sugar syrup (12gm of sucrose+required amount of water) was prepared by mixing sugar and honey. Sugar syrup was dissolved in honey and heated it to 160℃ till it dissolves completely forming as clear viscous syrup till the colour changes to golden yellow. The temperature was bought down to 90oC and drug, polymer and other ingredients were added. The solution was poured into the mould having 2.8cm diameter and 6.5mm thickness. The prepared lozenges were stored wrapped in aluminium foil and stored in desiccators to prevent moisture uptake. The final weight of each lozenge is 5gms. The composition of each formulation were given in table no1 and figure no 5.
Table 1:Formulation of Hard candy lozenges
|
Ingredients |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
Drug |
Drug+ PABA |
Drug+ succinic acid |
Drug+ PABA |
Drug + succinic acid |
Drug+ salicylic acid |
Drug+ Salicyclic acid |
|
Sucrose |
2g |
2g |
2g |
2g |
2g |
2g |
|
Honey |
5ml |
5ml |
4ml |
4ml |
4ml |
4ml |
|
Tamarind gum |
25 mg |
25 mg |
50mg |
50mg |
- |
- |
|
NaCMC |
- |
- |
- |
- |
50mg |
50mg |
|
Peppermint oil |
Qs |
Qs |
Qs |
Qs |
Qs |
Qs |
|
Amaranth |
Qs |
Qs |
Qs |
Qs |
Qs |
Qs |
|
Mannitol |
- |
- |
- |
- |
200 mg |
200mg |
|
Methyl paraben |
- |
- |
- |
- |
0.2%- 0.3% |
0.2%- 0.3% |
|
Glycerol |
3-4 drops |
3-4 drops |
3-4 drops |
3-4 drops |
3-4 drops |
3-4 Drops |
Evaluation of cocrystals:15-18
%yield: The percentage yield for the cocrystals were measured and results were given in the table 4.
Moisture Content:
By using Gravimetric method cocrystals were placed in dessicator. Final weight is subtracted from initial and the difference in moisture content was calculated and results were given in table 4.
Melting Point:
The co-crystals are introduced into a tiny amount into a small capillary tube, attaching this to the stem of a thermometer centred in a heating bath, heating the bath slowly, and observing the temperatures at which melting begins and is complete and results were given in table 4.
Evaluation Tests for Lozenges:
The lozenges were evaluated for organoleptic properties, weight variation,hardness,thickness,friability and all the results were given in table no 2.
Assay:
The assay of the lozenges were performed by dissolving the lozenges in 100ml phosphate buffer 6.8 and absorbance of the solutions were measured using uv spectroscopy at 284nm and results were given in table 7.
Microbial Attack:
Microbial check was performed which can be used to recognized or to check out the presence of any bacteria ,mold,spores in the raw materials. Microbial attack was performed by the required test they are:
Cup plate and Streak Plate Method:
Culture medium - nutrient agarmedium
Preparation Nutrient Agar Medium:
The agar medium was prepared by weighing the required amount of beef extract and peptone sodium chloride agar ,and distilled water in a beaker and boiled the medium until the formation of jelly of agar medium the agar medium was transferred into the steriled peteridishes and cooled .Then the agar medium was streaked and lozenge solutions were poured.In another petridish cups were made with sterile cavity loop and lozenge solutions were poured. In the cavities lozenge solutions were introduced with micro syringes. These petridishes were placed in an incubator for the time priod of 24hrs and obsreved for the microbial growth and results were given in the table 6.
In vitro - Disitegration:
Mouth Dissolving Time:
The time taken by the lozenges to dissolve completely was determined by USP disintegration apparatus, where lozenges were placed in each tube of the apparatus and time taken for the lozenges to dissolve completely was noted by using 900ml phosphate buffer of pH 6.8 at 370C. This test was done in triplicate. The average dissolving time for lozenges was calculated and presented with standard deviation in the table 6.
In- vitro drug dissolution studies:
Dissolution medium: phosphate buffer pH-6.8
Sample time points : 0, 5, 10, 15, 20, 25, 30 mins
Rpm (revolutions per minute):100rpm
Dissolution apparatus : USP dissolution apparatus type II
Temperature: 37℃
In vitro dissolution studies were carried out using USP dissolution test apparatus type II (paddle type) at 100 rpm and 37±0.50C PH 6.8 buffer was used as dissolution medium for in In vitro dissolution studies. A lozenge was placed in each flask of the dissolution apparatus and samples of 5ml were withdrawn at predetermined time travels for 60minits in order to maintain sink conditions an equal volume of medium was replaced. The sample was analyzed by using UV. Visible spectrophotometer at 284nm and percentage drug released was calculated and results were given in table 7. Dissolution data was fitted into various kinetic models and correlation coeffecients were given in table 8 and graphs were represented in fig 10-17.
Measurement of mucoadhesive strength by Modified physical balance method19-24:
Fresh goat mucosa was collected in the buffer immediately after slaughter. The mucosa was tied to cork and hanged on left side of physical balance. on other side of mucosa lozenge was attached, such that lozenge was in immediate contact with the surface of buffer placed in a beaker. Later in the right plan slowly weights were added and the weight at which lozenge was separated is noted and used to calculate muco adhesive strength of the polymers used.The results were given in table 9 and set up for modified physical balance method was shown in fig18.
RESULTS AND DISCUSSION:
TKP Extraction: Tamarind kernel was extracted and percentage yield was 85%.
Identification Tests:
Test for carbohydrates: Violet colour appeared after molisch test and confirms the presence of carbohydrates.
Preformulation studies of TKP:
The results for preformulation of Tamarind kernel powder were given in table 2.
Table 2: Results for Preformulatin studies of TKP
|
Bulk density |
0.57 |
|
Tapped density |
1.32 |
|
Compressiability Index |
5.82 |
|
Angle of repose |
26.5% |
|
Hausner Ratio |
1.38 |
|
Porosity |
1.45 |
Standard graph of Domperidone in pH 6.8 buffer and water:
Standard graph for Domperidone was constructed by measuring absorbance in uv spectrometry using the solvents water and pH 6.8 buffer. In both the solvents the absorbance values increases linearly with increase of concentration with correlation coeffecients 0.999 the results were given in table 3 figures 1 and 2.
Table 3: Results for standard graph of Domperidone in Water and pH 6.8 buffer
|
Concentration (µg/ml) |
Water |
pH buffer 6.8 |
|
0 |
0 |
0 |
|
10 |
0.1598 |
0.1498 |
|
20 |
0.3241 |
0.3017 |
|
30 |
0.4931 |
0.4573 |
|
40 |
0.6473 |
0.6173 |
|
50 |
0.8047 |
0.7837 |
|
60 |
0.9486 |
0.9456 |
Fig 1: Standard graph of Domperidone in water
Fig 2: Standard graph of Domperidone in pH6.8 buffer
Preparation of Co-Crystals:
Co crystals were prepared by solvent evaporation method and shown in the figures all the formulations clear white in colour and free flowing %yields were calculated and results were given in table solubility enhancement ratio was calculated for each solid dispersion and results were given in table 4
Fig 3: Co crystals f Domperidone with different conformers
Table 4: Results for solubility enhancement ratio
|
Formulation type (co-crystals) |
Pure drug |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
%yield |
- |
88 |
82 |
85 |
95 |
90 |
94 |
|
Solubility enhancement ratio |
|
39.54 |
67.86 |
48.78 |
83.86 |
85.86 |
90.23 |
|
Melting point |
190.050c |
1150c |
1500c |
1200c |
1550c |
1750c |
1780c |
|
Moisture content |
|
15% |
13% |
9% |
8% |
7% |
6% |
Preparation of Domperidone Lozenges:
Domperidone lozenges were formulated by hot congealing technique according to the formula given in table no and were shown in figure 4.
Fig 4: Domperidone lozenges
FTIR studies:
FTIR analysis confirmed co-crystal formation through characteristic peak shifts and disappearance of functional groups. Domperidone's CO-NH peak at 3072.26 cm⁻¹ disappeared and C=O shifted, indicating interactions with succinic acid and para-aminobenzoic acid. Tamarind kernel powder showed a broad -OH band at 3555.17 cm⁻¹, confirming polysaccharide presence. The disappearance of major Domperidone peaks in co-crystal spectra supports successful co-crystallization. FTIR graphs were given in Fig 5 to 9 and Characteristic peaks of Domperidone was given in table no5.
Fig 5: FTIR graph for Domperidone
Fig 6: FTIR graph for Tamarind kernel powder
Fig 7: FTIR graph for Domperidone and Succinic acid.
Fig 8: FTIR graph for Domperidone and Tamarind kernel powder.
Fig 9: FTIR graph for Domperidone,TKP and salicylic acid.
Table 5: Frequency values and functional groups of Domperidone
|
Frequency |
Functional group |
|
3073.26 cm−1 |
CO-NH |
|
1683.95cm−1 |
C=O |
|
1101.41cm−1 |
C-N |
|
1622.15cm−1 |
C=C |
|
3369.00cm−1 |
N-H |
Evaluation of Domperidone lozenges:
Domperidone lozenges were evaluated for various parameters and results were given in table and all the parameters were with in the range.
Table 6: Evaluation parameters for Domperidone loznges
|
Parameter |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
Organoleptic tests : a)Shape b)Colour c)Texture d)Taste |
Spherical Brown Smooth Sweet |
Spherical Brown Smooth Sweet |
Spherical Brown Smooth Sweet |
Spherical Brown Smooth Sweet |
Spherical Brown Smooth Sweet |
Spherical Brown Smooth Sweet |
|
WeightVariation |
9% ±0.1 |
7% ±0.15 |
5.5% ±0.25 |
6.8%±1.24 |
8.1% ±1.3 |
5.4% ±3.0 |
|
Hardness |
4.2kg/cm2 |
4.7kg/cm2 |
4.1kg/cm2 |
3.8kg/cm2 |
4.6kg/cm2 |
3.4kg/cm2 |
|
Thickness |
3.4mm |
3.8mm |
3.6mm |
3.5mm |
3.7mm |
3.8mm |
|
Friability |
pass |
pass |
pass |
pass |
pass |
pass |
|
Assay (%) |
86.54 |
63.75 |
97.45 |
79.46 |
85.47 |
79.36 |
|
Microbial attack |
Present |
Present |
Present |
Absent |
Absent |
Absent |
|
Mouth dissolving time(minutes) |
25 |
22 |
23 |
22 |
23 |
24 |
Results for in Vitro Dissolution:
The dissolution samples analysed by the UV and values were given in table and tha data fitted into various kinetic models and correlation coeffecients(r2) were given in table 8. Based on r2 values the drug release follows zero order in which drug release is independent of concentration and based higuchi graph the drug released follows diffusion mechanism and based on n values from korse meyer graph the drug release followed supercaseII transport.
Table 7: Results for Drug Release from in vitro Dissolution Studies
|
Time |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
0 |
15.6 |
15.6 |
18.6 |
15.6 |
15.6 |
18.6 |
|
5 |
27 |
24.6 |
27 |
21.6 |
24.6 |
24.6 |
|
10 |
36.4 |
30.6 |
33.6 |
30.6 |
33.6 |
30.6 |
|
15 |
39.4 |
36.4 |
48.6 |
45.6 |
51.6 |
57.6 |
|
20 |
63 |
60.6 |
66.5 |
63.6 |
69.6 |
66.6 |
|
25 |
72 |
84.6 |
81.6 |
87.6 |
84.6 |
84.6 |
|
30 |
81 |
87.6 |
84.6 |
93.6 |
90.6 |
87.6 |
Table 8 : r2 Values
|
Formulation |
R2 Zero Order |
R2 First Order |
R2Higuchi Graph |
Korse-meyer Graph n value |
|
F1 |
0.9737 |
0.9338 |
0.8644 |
0.9315 |
|
F2 |
0.9383 |
0.8585 |
0.7789 |
0.8564 |
|
F3 |
0.9747 |
0.9315 |
0.8497 |
0.8941 |
|
F4 |
0.9677 |
0.9682 |
0.8088 |
0.8717 |
|
F5 |
0.9835 |
0.8644 |
0.8639 |
0.9211 |
|
F6 |
0.9617 |
0.9234 |
0.8367 |
0.8583 |
Fig 10 : Zero order curve for F1 tot F3
Fig 11: Zero order graph for F4 to F6
Fig 12: First order graph F1 to F3
Fig 13: First order graph F4 to F6
Fig 14: Higuchi graph for F1 to F3
Fig 15: Higuchi graph for F4 to F6
Fig 16: Korsemeyer peppas graph for F1 to F3
Fig 17: Korsemeyer peppas graph for F4 to F6
Table 9: Mucoadhesive strength
|
Mucoadhesive strength |
Weight(g) |
|
Tamarind kernel powder (F4) |
20.85g |
|
Sodium CMC (F6) |
20.76g |
Fig 18: Measurement of muco Adhesive Strength by Modified Physical Balance Method
CONCLUSION:
The Domperidone co crystals were prepared by using different polymers like PABA (para-amino benzoic acid) succinic acid and salicyclic acid by solvent evaporation method. The co crystals formed showed the increase in the aqueous solubility of Domperidone. Formation of co crystals confirmed by change in melting point and FTIR studies. These co crystals were used to prepare the lozenges by heat and congealing method. The prepared lozenges were evaluated for various tests like weight variation, hardness, thickness, drug content. Mucoadhesive strength was determined by modified physical balance method. The formulation (F4) with tamarind kernel powder has shown better mucoadhesive strength than the formulation with Sodium carboxy methyl cellulose(F6). The formulationsF1 to F4 has shown microbial growth and the F5 and F6 have not shown microbial growth concluded that addition of preservative is required for Lozenge preparation. The drug release studies shown that the lozenge containing PABA, succinic acid, salicyclic acid in the ratio 1:3 have shown 87.6%,93.6 and 87.6% of drug release in 30minutes.The work has concluded that the tamarind kernel powder has better muco adhesive properties and solubility of Domperidone can be enhanced more by cocrystallisation with salicylic acid.
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Received on 05.07.2025 Revised on 18.08.2025 Accepted on 22.09.2025 Published on 18.10.2025 Available online from November 03, 2025 Res. J. Pharma. Dosage Forms and Tech.2025; 17(4):223-230. DOI: 10.52711/0975-4377.2025.00031 ©AandV Publications All Right Reserved
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