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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access   Full Text Article                                                                                                                                                             Research Article

Formulation and evaluation of bioadhesive buccal Films of Domperidone co-crystals by using Tamarind kernel powder as mucoadhesive polymer

Sailaja Rongali ¹*, Jagadeesh Panda ², Kala Jyotsna Bankuru ³, Hanumanth Badri ³, Manju Priya Bonela ³, Bhavya Gonthupalli ³

1. Assistant professor, Department of pharmaceutics, Raghu college of pharmacy, Visakhapatnam, Andhra Pradesh, India-53662 

2. Principal, Raghu college of pharmacy, Visakhapatnam, Andhra Pradesh, India -53662

3. Students, Raghu college of pharmacy, Visakhapatnam, Andhra Pradesh, India -53662

 

 

INTRODUCTION:

A multi-component crystalline system is not new but recently the term co-crystal has gained momentum in the glossary of the pharmaceutical world. The physicochemical properties of a drug like melting point, hygroscopicity, solubility, dissolution, and stability are improved for better drug bioavailability, which leads to gain better therapeutic effect of the drug with reduced adverse effects. Solubility as well as dissolution is some of the mechanical characteristics of an active pharmaceutical ingredient (API) that should be thoroughly studied in pharmaceutical drug development.¹

The buccal delivery of drugs has recently emerged as an effective and safe alternative over other conventional routes of drug administration. Buccal administration easily releases the loaded drug into the buccal cavity for either local or systemic effects. This route of administration is especially suitable in pediatric and geriatric, where patients often struggle to ingest traditional oral solid dosage forms. Moreover, the buccal route is very convenient for drugs that are inactivated in the gastric environment, drugs that irritate the gastrointestinal tract, and during nausea and vomiting episodes^.2

Bio adhesive mucosal dosage forms including adhesive tablets, gels and patches are outcomes of technological development. Among various dosage forms, the use of polymeric films for delivering medication into buccal cavity has developed great potential in recent era^.3.

Domperidone    is prescribed for prevention of chemotherapy-induced nausea and for pre-and post-surgical nausea and vomiting. It     is an antiemetic drug that blocks the action of dopamine and has strong affinities for the D2 and D3 dopamine receptors. It is well   absorbed from GIT, but its bioavailability is low due to extensive first pass metabolism. This condition makes it a suitable drug candidate for Mouth Dissolving Films⁴.

In order to provide a convenient and effective mean of administration of drug to patients suffering from vomiting and nausea, the present study was aimed at developing a rapid onset, fast acting, “patient friendly” and stable mouth dissolving film of Domperidone cocrystals using HPMC and tamarind kernel powder.

 

 

MATERIALS 

Tamarind seeds were obtained from local market, tagarapuvalasa, Visakhapatnam, Andharapradesh. Domperidone, other polymers and solvents were purchased from yarrow chemicals, Mumbai, India.

METHODS 

Flow chart of work

Step1: Extraction of tamarind kernel powder from the seeds

Step2: Evaluation of tamarind kernel powder

Step3: Standard graph construction of domperidone in various buffers

Step4: Preparation of cocrystals of domperidone

Step 5: Evaluation of cocrystals

Step6: Preparation of buccal films of domperidone cocrystals

Step7: Evaluation of buccal films and optimization

Extraction of tamarind kernel powder: Tamarind seeds were collected and dried in sunlight. The kernels are than crushed to fine powder. 20g of fine kernel powder was added to 200ml of cold distilled water to prepare slurry. The slurry obtained is than poured into 800ml of boiling distilled water and are boiled for 20min on a water-bath; a clear solution was centrifuged at 5000 rpm for 20min to separate all foreign matter. Supernatant liquid was separated.⁵

Evaluation of tamarind kernel powder:

Flow properties of the extracted tamarind kernel powder was measured and the values were given in the table2.the mucoadhesive strength of tamarind kernel powder was determined by modified physical balance method and results were given in table 3.

A modified balance method used for determining the ex vivo mucoadhesive strength. Fresh goat mucosa was obtained and used within 2hr of slaughter. The mucosal membrane separated by removing underlying fat and loose tissues. The membrane was washed with distilled water and then with pH6.8 phosphate buffer at 37⁰C. The mucosa was cut into the pieces and washed. A piece of mucosa was tied to the Teflon piece, which was kept in beaker filled with pH6.8 phosphate buffer, at 37⁰C. The Teflon pieceswas tightly fitted into a glass beaker so that it just touched the mucosa surface. The bioadhesive patch was stuck to the lower side of a pan. The weight was kept in the right-hand pan, which lowered the pan along with patch over the mucosa. The balance was kept in this position for 5min to provide contact time for bioadhesion. The weight was removed and measured^.6

Force of adhesion (N)= [bioadhesive strength]*9.81]/1000

Bond strength(N-m^-2)= Force of adhesion/Disc surface area

Preparation of Co-Crystals: 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 observed for formation of co-crystals. Trails were made with different co-formers like succinic acid, Para amino benzoic acid, tartaric acid, citric acid, and by using solvent as ethanol.From the trials it was found that co-crystals of domperidone were formed using succinic acid and Para amino benzoic acid (1:1, 1:2) as a co-former. Hence further studies were continued by synthesizing co-crystals of domperidone with succinic acid and Para amino benzoic acid in the ratios 1:1, 1:2.⁷

Construction of Standard graph of Domperidone in various solvents:

For the construction of standard graph 50mg drug was dissolved in 50ml solvent. From this stock solution various concentrations were prepared by suitable dilution with the corresponding solvent and the absorbance was measured against suitable solvents as blank at lambda max and the values were given in table 

Solubility enhancement ratio:

The cocrystals of domperidone equivalent to 10mg drug was weighed and dissolved in 100ml water. Suitable dilutions were made and absorbance was measured in uv spectrophotometer at lambda max and the vresults were given in table no5.

Preparation of Domperidone buccal films:

Mucoadhesive buccal film of domperidone was prepared by solvent casting technique using a film forming mucoadhesive polymer. The polymers HPMC K15, PEG 6000 were weighed accurately and dissolved in 5ml ethanol. In another beaker Tamarind kernel powder, Dehydrated banana powder, drug and co-former and sodium saccharin were dissolved in a sufficient quantity of solvent.  Then the drug containing solution and polymeric solution are mixed evenly to form a homogeneous casting solution. The whole solution poured in the pre-lubricated glass petri-plate at 40C and left for 12 hr. The film was removed carefully after drying and cut into 2*2 cm. The film was stored in butter paper covered with aluminium foil and stored at room temperature. Similarly 4 patches are prepared with succinic acid and paba with 1:1 and 1:2 ratio.⁸

 

 

Table 1: Formulation of domperidone buccal films:

Excepient	PDBF1	PDBF2	SDBF1	SDBF2
Drug and co former	Equivalent to 150mg drug	Equivalent to 150mg drug	Equivalent to 150mg drug	Equivalent to 150mg drug
HPMC K15	500mg	400mg	500mg	400mg
PEG 6000	200mg	200mg	200mg	200mg
Tamarind kernel powder	50mg	50mg	50mg	50mg
Dehydrated banana powder	20mg	20mg	20mg	20mg
Sodium Saccharin	20mg	20mg	20mg	20mg
Ethanol , Water	10ml q.s	10ml q.s	10ml q.s	10ml q.s

RESULTS AND DISCUSSION:

Table 2: Flow properties of Tamarind kernel powder

Bulk density	0.59
Porosity	1.29
Compressibility index	5.78
Angle of repose	27.9
Hausners ratio	1.45
Porosity	1.46

 

The flow properties of tamarind kernel powder indicates that the powder is free flowing and pluffy.

Figure1: FTIR of Pure Domperiodne                                                             Figure 2: FTIR of Pure Para amino benzoic acid                   

                 Figure 4: FTIR of pure succinic acid                   Figure 5: FTIR of cocrystals of drug and Para amino benzoic acid                                  

Figure 6: FTIR of cocrystals of Domperidone and Succinic acid

Figure 7: FTIR of Tamarind kernel powder

 

 

 

FTIR spectrum of sharp characteristic bands at 3125.18, 1694, 1486.33, 1382.68 and 1150 cm−1 due to stretching vibration bands of C=O, N-H, C-N, and two C-O respectively.  The FT-IR spectrum of Domperidone showed a strong C=O stretch band around 1683.95 cm⁻¹ and CO-NH stretching at 3072.26 cm⁻¹. FTIR spectrum of succinic acid showed a strong peak at 1201 cm−1 is a characteristic peak of dicarboxylic acid. The prepared co-crystal shows absence of CO-NH at 3072.26 cm⁻¹ and shifting of characteristic peak 1683.06 cm−1 of amide to 1693.27 cm⁻¹ in crystal form In SA crystal graph. It indicates the formation of crystal forms by carboxylic acid-amide heterosynthon. The CO-NH peak at 3072.26cm^-1of Domperidone disapper in the graph of cocrystal with para-amino benzoic acid indicates formation of bonding between drug and conformer. The broad absorption band in tamarind kernel powder at 3555.17 indicates the presence of -OH functional group. These can prove the theoretical chemical structure of tamarind seed consists of polysaccharide polymers of glucose, xylose and galactose. These structures are known to be responsible for the presence of -OH functional group in tamarind seeds. The spectrum of carboxylic acid represented by two absorption band. The first band is at the peak 1523.66 cm−1 with a C-O stretching vibration and the second band is 1679.03 cm−1 with C=O stretching vibrations. A sharp band occurs at peak of 2928.04 cm−1 because of the C-H stretching vibrations. These functional groups contain properties that can induced the process of coagulations for tamarind seeds.

Muco-adhesive strength:

Table 3: Force of adhesion and bond strength of tamarind kernel powder

Force of adhesion(N)	0.49
Bond strength(N-m-2)	0.102

 

The values of force of adhesion and bond strength indicates the tamarind kernel powder has sufficient mucoadhesive properties.

 

Figure 8: Modified physical balance method for measuring mucoadhesive strength of tamarind kernel powder

 

 

Table 4: Construction of standard graph of Domperidone:

	Absorbance values
Concentration (µg/ml)	water	pH buffer 6.8	pH buffer 7.4
10	0.1996	0.1520	0.1630
20	0.2132	0.2338	0.2386
40	0.4648	0.4668	0.4927
60	0.6868	0.6550	0.6093
80	0.8625	0.8797	0.8101
100	0.9835	0.9623	0.9814

 

 

 

 

 

      Figure 9: standard graph of domperidone in water                      Figure 10: standard graph of domperidone in pH 6.8 buffer

                            

 

 

In the standard graph the increase in concentration increases absorbance. Standard graph was constructed using UV spectrophotometry at lambda max of 284nm. The graph has linear relationship between concentration and absorbance with correlation coefficient values of 0.985 in water 0.987 in pH6.8 phosphate buffer.

Table 5: Solubility enhancement ratio 

Formulation	Solubility enhancement ratio
PDBF1	39.54
PDBF2	48.78
SDBF1	67.86
SDBF2	83.76

 

Solubility gets enhanced by co crystallization there is 48.73 fold increase in aqueous solubility with paraamino benzoic acid and 83.76fold increase with succinic acid.

Table 6: Melting Point Values

	Original	Acquired
Pure Drug	200C	1900C
Paba	187C	1650C
Paba co-former	-	1000C
Succinic acid	185C	1700C
Succinic acid co-former	-	15 oC

 

The change in melting point from the pure compounds (drug and coformers) indicate the formation of cocrystals.

 

 

Table 7: Evaluation of buccal films

Formulation	Folding endurance	Drug content	Swelling index	Surface pH
PDBF1	190.6	63%	1.1	6.67
PDBF2	181.8	72%	0.75	6.66
SDBF1	156.4	80%	2.1	6.68
SDBF2	126.3	82%	1.1	6.73

 

The folding endurance of all the four formulations ensures sufficient mechanical strength for the films and drug content values were in the range of 63-82%, sufficient swelling index and pH values wihin the range.

In vitro diffusion studies:

Figure 11: Zeroorder graph

Figure 12: First order graph

Figure 13: Higuchi graph

Figure 14: korsemeyer peppas graph

Table 8: correlation coefficient values and n values of korsemeyer peppas graph

	r2 values
Formulation	Zero order	First order	Higuchi Graph	Korsemeyer n values
PDBF1	0.9486	0.9454	0.9365	0.2315
PDBF2	0.9541	0.9364	0.9295	0.2672
SDBF1	0.9825	0.9968	0.9676	0.3497
SDBF2	0.9705	0.9915	0.9543	0.3683

 

 

Based on the r² values the drug release follows first order that is the drug release depends on the concentration. The drug release is follows diffusion mechanism and as n values of korsemeyer peppas graph indicates the drug release is case 1 fickian diffusion. Based on diffusion studies the SDBF2 has shown 86% drug release in 4hrs and has concluded as optimized formula.

 

CONCLUSION

The solubility of domperidone gets enhanced by crystallization with para amino benzoic acid and succinic acid. The prepared buccal films have sufficient strength, pH and swelling index and in-vitro diffusion studies has shown that the buccal films prepared with domperidone with succinic acid 1:2 ratio has shown better drug release and it was the optimized formula. the work has also concluded that the tamarind kernel powder has sufficient muco adhesive strength and can be used as mucoadhesive polymer in novel formulations

Acknowledgment

Authors are thankful to Dr. Jagadeesh panda, principal, Raghu college of pharmacy, Visakhapatnam, for providing support to carry out this work.

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