INTRODUCTION:

Pharmaceutical products designed for oral delivery are mainly immediate release or conventional drugs systems, which are designed for immediate release of drug for rapid absorption. These dosage forms have some limitations like:

1) Drugs with short half-life are required to be administrated frequently, which increases chances of missing dose of drug leading to poor patient compliance.

2) The attainment of steady state condition difficult due to typical plasma peak in concentration-time profile.

3) The occurrence of unavoidable fluctuations in the drug concentration may lead to under medication or overmedication as values of C_SS get below or above the therapeutic range.

4) The occurrence of fluctuating in drug levels cause precipitation of adverse effects especially of a drug with small therapeutic index.^1,2

In order to overcome the drawbacks of conventional drug delivery systems several technical development have done which could prove to be beneficial method of medication and provide a number of therapeutic benefits. Now days pharmaceutical companies are looking for development of sustained release formulations due to its inherent boons. Sustained release dosage forms are designed to release a drug at a predetermined rate by maintaining a constant drug level for a particular period of time with minimum side effects. The basic objective of sustained release drug delivery system optimizes the biopharmaceutical, pharmacokinetic and pharmacodynamics properties of a drug in such a way to have maximum use, reduced side-effects and the disease is cured as well. Domperidone is a dopamine D2 – receptor (D2R) antagonist which is used as an antiemetic. It has also been used to stimulate lactation by release of prolactin. For the symptomatic relief in migraine, it is also given along with paracetamol. Its Chemical formula is 5-chloro-1-[1-[3-(2,-3-dihydro-2- oxo-1H-benzimidazol-1-yl)-propyl]-4-piperidinyl]-1,3- dihydro-2H-benzimidazol-2-one.³Domperidone facilitates gastric emptying and decreases small bowel transit time by increasing esophageal and gastric peristalsis and by lowering esophageal sphincter pressure. The antiemetic properties of domperidone are related to its dopamine receptor blocking activity at both the chemoreceptor trigger zone and at the gastric level. It has strong affinities towards D2 and D3 dopamine receptors, which are found in the chemoreceptor trigger zone, located just outside the blood brain barrier, which - among others - regulates nausea and vomiting. (Figure 1)

Sustained release drug delivery system

It includes any drug delivery system achieves release of drug over an extended period of time, which not depend on time. Hydrophilic polymer matrix is widely used for formulating a Sustained dosage form. The role of ideal drug delivery system is to provide proper amount of drug at regular time interval and at right site of action to maintain therapeutic range of drug in blood plasma.^{4, 5}

Figure 1: A hypothetical plasma concentration-time profile from conventional multiple dosing and single doses of sustained and controlled delivery formulations.

The immediate release drug delivery system lacks some features like dose maintenance, sustained release rate and site targeting. The oral Sustained drug delivery has some potential advantage like sustain release rate and dose maintenance in plasma. The sustain release drug delivery system have some swelling polymers or waxes or both which controls the release rate. The use of reservoir system is also well known for controlling release rate. (Figure 1) shows the relation between plasma concentration verses time.

Advantages of sustained release formulations

1. Improved patient compliance and convenience.

2. Reduction in dosing frequency.

3. Chances of fluctuations in circulating drug levels.

4. More uniform effect.

5. Employ less total drug that,

a) Minimize or eliminates local side effects.

b) Minimize or eliminates systemic side effects.

c) Minimize drug accumulation with chronic dosing.

d) Obtains less potentiation or reduction in drug activity on chronic use.

6. Improved safety margin of potent drug by technically excellent designing of formulation.

7. Improve efficiency in treatment by

a) Cure or control of condition.

b) Improve or control condition.

c) Make use of specific effect. Eg.SR Aspirin for morning relief of arthritis

d) Improve bioavailability of some drugs.

8. Patient care time is reduced.

9. Night time dosing can be avoided for patient convenience

10. Enhancement of product life time in sustained release formulations. Particles of drug are coated with matrix or entire product is matrix coated which along with its main function of sustained action, avoid exposure of unstable drug to the environment and render it stable.⁴

Disadvantages of sustained release formulations

1. Sustained release does not permit immediate termination of therapy.

2. More costly process and equipment are needed in manufacturing of SRDFs.

3. Less flexibility in adjusting dosage regimen.

4. Risk of dose dumping, usually SRDFs contain drug amount that is 3-4 times more than conventional formulations. Sometimes this large quantity of drug may get rapidly released leading to toxicity.

5. Reduced drug absorption may delay onset of action.

6. Drug absorbed at specific time in GIT cannot be formulated in SRDFs.

7. Increased potential for first pass clearance.

8. For oral SRDF effective drug release is influenced and limited by GI residence time.

9. SRDF‟s are designed for normal population that is on the basis of the biological half-lives. Since disease state that alters drug dispositions as well as inter-patient variability in pharmacokinetics parameters are not accommodated.

10. Drugs which are acted upon by enzymes in intestine undergo significant enzymatic breakdown as drug remains in body for longer time.

11. In case of accidental failure of the product effective antidote may be difficult to employ.⁵

Classification of sustained release drug delivery system

Considering the mechanism of controlling the drug release the system is classified as follows⁶:-

1. Chemically controlled systems a. Biodegradable system

b. Drug polymer conjugates

2. Diffusion controlled systems

a. Matrix diffusion

b. Polymer erosion

c. Polymer swelling

d. Geometry⁷

A Useful Classification is based on drug release from the sustain release drug formulations is as follows:-

Continuous release systems

These systems release the drug continuously for prolonged period of time along the entire length of GIT with normal transit time. Different systems under this class are⁸-

1. Dissolution controlled release systems

2. Diffusion controlled release systems

3. Dissolution and diffusion controlled release systems

4. Ion exchange resin drug complex

5. Slow dissolving salts and complexes

6. pH dependent formulations

7. Osmotic pressure controlled systems

8. Hydrodynamic pressure controlled systems

Delayed transit and continuous release systems

These systems are designed to prolong release of drug with increased residence time in GIT so these dosage forms are designed to remain in the stomach. Therefore the drug presented in such systems should be stable at gastric pH. This class includes following systems⁹

1. Altered density systems

2. Mucoadhesive systems

3. Size based systems

Delayed release systems

These systems are fabricated to release the drug only at specific site in the GIT. The drugs those are⁹-

a. destroyed in stomach or by intestinal enzymes

b. known to cause gastric irritation

c. absorbed from specific site in intestine, or exert local effect at specific GI site are formulated in such systems.

The two types of delayed release systems are:-

1. intestinal release systems

2. colonic release system

Oral Controlled Drug Delivery Systems

Oral controlled release drug delivery is a drug delivery system that provides the continuous oral delivery of drugs at predictable and reproducible kinetics for a predetermined period throughout the course of GI transit and also the system that target the delivery of a drug to a specific region within the GI tract for either a local or systemic action. All the pharmaceutical products formulated for systemic delivery via the oral route of administration, irrespective of the mode of delivery (immediate, sustained or controlled release) and the design of dosage form (either solid dispersion or liquid), must be developed within the intrinsic characteristics of GI physiology. Therefore the scientific framework required for the successful development of oral drug delivery systems consists of basic understanding of (i) physicochemical, pharmacokinetic and pharmacodynamic characteristics of the drug (ii) the anatomic and physiologic characteristics of the gastrointestinal tract and (iii) physicochemical characteristics and the drug delivery mode of the dosage form to be designed. The main areas of potential challenge in the development of oral controlled drug delivery systems are:-

1) Development of a drug delivery system: To develop a viable oral controlled release drug delivery system capable of delivering a drug at a therapeutically effective rate to a desirable site for duration required for optimal treatment.

2) Modulation of gastrointestinal transit time: To modulate the GI transit time so that the drug delivery system developed can be transported to a target site or to the vicinity of an absorption site and reside there for a prolonged period of time to maximize the delivery of a drug dose.

3) Minimization of hepatic first pass elimination: If the drug to be delivered is subjected to extensive hepatic first-pass elimination, preventive measures should be devised to either bypass or minimize the extent of hepatic metabolic effect.

Sustained drug release has been attempted to be achieved with various classes of sustained drug delivery system

1. Diffusion sustained system

i) Reservoir type

ii) Matrix type

2. Dissolution sustained system

i) Reservoir type

ii) Matrix type

3. Methods using Ion-exchange.

4. Methods using osmotic pressure.

5. pH independent formulations.

6. Altered density formulations.¹⁰

Diffusion sustained system

Basically diffusion process shows the movement of drug molecules from a region of a higher concentration to one of lower concentration. The flux of the drug J (in amount / area -time), across a membrane in the direction of decreasing concentration is given by Fick’s law.

J= - D dc/dx

where; D = diffusion coefficient in area/ time

dc/dx = change of concentration 'c' with distance 'x'

In common form, when a water insoluble membrane encloses a core of drug, it must diffuse through the membrane. The drug release rate dm/ dt is given by

dm/ dt= ADKΔ C/L

where; A = Area

K = Partition coefficient of drug between the membrane and drug core

L= Diffusion path length (i.e. thickness of coat)

ΔC= Concentration difference across the membrane.¹¹

1. Reservoir type: In the system, a water insoluble polymeric material encases a core of drug. Drug will partition into the membrane and exchange with the fluid surrounding the particle or tablet. Additional drug will enter the polymer, diffuse to the periphery and exchange with the Surrounding media.

Description -The drug core surrounded by polymer membrane which controls release rate.

Advantages -Zero order delivery is possible, release rates variable with polymer type.

Disadvantages- System must be physically removed from implant sites. Difficult to deliver high molecular weight compound, generally increased cost per dosage unit, potential toxicity if system fails.¹¹

2. Matrix type : A solid drug is dispersed in an insoluble matrix and the rate of release of drug is dependent on the rate of drug diffusion and not on the rate of solid dissolution. Higuchi has derived the appropriate equation for drug release for this system:

Q = Dε/ T [2 A –εCs] Cst½

where; Q = Weight in gms of drug released per unit area of surface at time t

D = Diffusion coefficient of drug in the release medium

A = Concentration of drug in the tablet, as gm/ ml

Cs = Solubility of drug in release medium.

T= Tortuosity of the matrix.

ε = Porosity of the matrix.

Description- Homogenous dispersion of solid drug in a polymer mixture is possible.

Advantages- Easier to produce than reservoir or encapsulated devices, can deliver high molecular weight compounds.

Disadvantages - Cannot provide zero order release, removal of remaining matrix is necessary for implanted system. A third possible diffusional mechanism is the system where a partially soluble membrane encloses a drug core. Dissolution of part of membrane allows for diffusion of the constrained drug through pores in the polymer coat.

The release rate can be given by following equation.

Release rate = AD / L = [C1- C2] Where; A = Area

D = Diffusion coefficient

C1 = Drug concentration in the core

C2 = Drug concentration in the surrounding medium

L = Diffusional path length

Thus, diffusion sustained products are based on two approaches the first approach entails placement of the drug in an insoluble matrix of some sort. The eluting medium penetrates the matrix and drug diffuses out of the matrix to the surrounding pool for ultimate absorption. The second approach involves enclosing the drug particle with a polymer coat. In this case the portion of the drug which has dissolved in the polymer coat diffuses through an unstirred film of liquid into the surrounding fluid.¹²

Dissolution sustained systems

A drug with a slow dissolution rate is inherently sustained and for those drugs with high water solubility, one can decrease dissolution through appropriate salt or derivative formation. These systems are most commonly employed in the production of enteric coated dosage forms. To protect the stomach from the effects of drugs such as Aspirin, a coating that dissolves in natural or alkaline media is used. This inhibits release of drug from the device until it reaches the higher pH of the intestine. In most cases, enteric coated dosage forms are not truly sustaining in nature, but serve as a useful function in directing release of the drug to a special site. The same approach can be employed for compounds that are degraded by the harsh conditions found in the gastric region.

1. Reservoir type: Drug is coated with a given thickness coating, which is slowly dissolved in the contents of gastrointestinal tract. By alternating layers of drug with the rate controlling coats as shown in figure, a pulsed delivery can be achieved. If the outer layer is quickly releasing bolus dose of the drug, initial levels of the drug in the body can be quickly established with pulsed intervals. Although this is not a true sustained release system, the biological effects can be similar. An alternative method is to administer the drug as group of beads that have coating of different thickness. This is shown in figure. Since the beads have different coating thickness, their release occurs in a progressive manner. Those with the thinnest layers will provide the initial dose. The maintenance of drug levels at late times will be achieved from those with thicker coating. This is the principle of the spansule capsule. Cellulose nitrate phthalate was synthesized and used as an enteric coating agent for acetyl salicylic acid tablets.¹³

2. Matrix type: The common type of dissolution sustained dosage form. It can be either a drug impregnated sphere or a drug impregnated tablet, which will be subjected to slow erosion. Two types of dissolution sustained pulsed delivery systems

(a) Single bead type device with alternating drug and rate-controlling layer.

(b) Beads containing drug with differing thickness of dissolving coats.

Amongst sustained release formulations, hydrophilic matrix technology is the most widely used drug delivery system due to following advantages:

(i) Provide desired release profiles for a wide therapeutic drug category, dose and solubility.

(ii) Simple and cost effective manufacturing using existing tableting unit operation equipment.

_(iii)_{Robust formulation.}

(iv) Broad regulatory and patient acceptance.

(v) Ease of drug release modulation through level and choice of polymeric systems and function coatings.

Methods Using Ion Exchange

It is based on the fact that when anionic solution is kept in contact with ionic resins formation of drug resin complex formed. The drug from these complexes gets exchanged in gastro intestinal tract and released with excess of Na+ and Cl- present in gastro intestinal tract.

Anion Exchangers: Resin+ - Drug- + Cl- goes to Resin+- Cl-+ Drug-

Cation Exchangers: Resin-- Drug+ + Na+ goes to Resin- - Na+ + Drug+

These systems generally utilize resin compounds of water insoluble cross linked polymer. They contain salt forming functional group in repeating positions on the polymer chain. The rate of drug diffusion out of the resin is sustained by the area of diffusion, diffusional path length and rigidity of the resin which is function of the amount of cross linking agent used to prepare resins. The release rate can be further sustained by coating the drug resin complex by microencapsulation process.¹⁴

Methods Using Osmotic Pressure

A semi permeable membrane is placed around a tablet, particle or drug solution that allows transport of water into the tablet with eventual pumping of drug solution out of the tablet through a small delivery aperture in tablet coating. Two types of osmotically sustained systems are

(a) Type A contains an osmotic core with drug.

(b) Type B contains the drug in flexible bag with osmotic core surrounding.

pH– Independent Formulations

The gastrointestinal tract present some unusual features for the oral route of drug administration with relatively brief transit time through the gastrointestinal tract, which constraint the length of prolongation, further the chemical environment throughout the length of gastrointestinal tract is constraint on dosage form design. Since most drugs are either weak acids or weak bases, the release from sustained release formulations is pH dependent. However, buffers such as salts of amino acids, citric acid, phthalic acid phosphoric acid or tartaric acid can be added to the formulation, to help to maintain a constant pH thereby rendering pH independent drug release. A buffered sustained release formulation is prepared by mixing a basic or acidic drug with one or more buffering agent, granulating with appropriate pharmaceutical excipients and coating with gastrointestinal fluid permeable film forming polymer. When gastrointestinal fluid permeates through the membrane, the buffering agents adjust the fluid inside to suitable constant pH thereby rendering a constant rate of drug release e.g. propoxyphene in a buffered sustained release formulation, which significantly increase reproducibility.¹⁵

Altered Density Formulations

It is reasonable to expect that unless a delivery system remains in the vicinity of the absorption site until most, if not all of its drug content is released, it would have limited utility. To this end, several approaches have been developed to prolong the residence time of drug delivery system in the gastrointestinal tract.

High Density Approach

In this approach the density of the pellets must exceed that of normal stomach content and should therefore, it should be at least 1-4gm/cm3.

Low Density Approach

Globular shells which have an apparent density lower than that of gastric fluid can be used as a carrier of drug for sustained release purpose.¹⁶

LITERATURE REVIEW FOR DOMPERIDONE:

Bhavna Patel et al (2009) has explained A RP-HPLC method has developed for simultaneous estimation of lansoprazole and Domperidone in combined capsule dosage form. Lansoprazole is a proton pump inhibitor and used in the treatment of duodenal and gastric ulcers and gastro esophageal reflux disease (GERD), a condition in which the acid in the stomach washes back up into the esophagus. Sometimes lansoprazole is used in combination with antibiotics to treat ulcers associated with infection caused by the H. pylori bacteria, gastro-oesophageal reflux disease (GERD), peptic ulcer and Zollinger- Ellison syndrome. Domperidone is indicated for treating symptoms associated with upper gastrointestinal motility disorders caused by chronic and sub-acute gastritis. It is a gastrointestinal emptying (delayed) adjunct, a peristaltic stimulant and exhibit antiemetic properties.¹⁷

Daniel Flanders et al (2009) has explained Domperidone is a peripheral dopamine antagonist classically used to treat gastro-esophageal reflux and upper gastro-intestinal motility disorders. It is also used to prevent side effects associated with the treatment of Parkinson‟s disease. It has been used in Canada since the mid-1980s, both in children and adults. Domperidone also increases prolactin levels in the blood and has been used with success to increase milk supply in women with insufficient milk production. It does this by blocking the D2 and D3 dopamine receptors in the pituitary gland. As a result, prolactin, the secretion of which is blocked by dopamine, now is liberated from the anterior pituitary and stimulates the milk producing cells of the breast. ¹⁸

Daniel E. McDonald et al (2012) has explained Domperidone, a peripherally acting dopaminergic antagonist with few side effects, has been used in number of small clinical trials to treat OH of various etiologies. We reviewed nine studies of Domperidone in the treatment of OH. Although limited by small sample sizes and poor design, these studies generally showed successful treatment of OH by Domperidone. Further controlled studies of Domperidone for anti-depressant induced OH in relevant patient samples are warrented.¹⁹

NEED FOR STUDY:

Sustained release dosage forms are designed to complement the pharmaceutical activity of the medicament in order to achieve better selectivity and longer duration of action. Sustained release preparations are helpful to reduce the dosage frequency and side effects of drugs and improve patient’s convenience.²⁰ In this project, an attempt is made for Sustained release matrix tablets of Domperidone which is used in the treatment of vomiting, peptic ulcer and Gastro esophageal reflux disorder (GRED). This formulation will be evaluated for tablet characteristic, drug content in-vitro dissolution studies. Domperidone is a synthetic Benzimidazole compound that is used as a prokinetic agent for treatment of Upper Gastrointestinal motility disorders and as an anti-emetic. It is also used in treatment of Parkinson‟s disease, with a focus on Diabetic gastropathy. Domperidone blocks the action of dopamine. It has strong affinities for the D₂and D₃ dopamine receptors, which are found in the chemoreceptor trigger zone, located just outside the blood brain barrier, which, among others, regulates nausea and vomiting (area postrema on the floor of the fourth ventricle and rhomboid fossa). Domperidone, by acting as an anti-dopaminergic, results in increased prolactin secretion, and thus promotes lactation.it has bioavailability high, protein binding 91-93, half-life of 7 hrs.²¹ The Oral Dose of Domperidone is 30 mg; Dosage is 1-2 times per day. Matrix tablets composed of drug and polymer as release retarding material offer the simplest approach in designing a sustained release system. The present study aims to develop sustained release matrix tablets using natural and synthetic polymers along with drug in varying proportions by wet granulation method.²²

MATERIAL AND METHOD:

Material

Domperidone and HPMC 5CPS were purchased from Morepen Lab Ltd, Parwanoo,Himachal Pradesh,India while MCC Plain of AR grade was obtained from Juku Orchem Private limited Chennai, Tamilnadu, India. PVP K30 of LR grade was purchased from ISP Technologies, Inc Texas City, Texas,USA. Aerosil AR grade was purchased from Cabot Sanmar, Chennai, Tamilnadu, India. While Magnesium Stearate of AR grade was purchased from Loba Chemie, Mumbai,India. Other chemicals and reagents (analytical grade or higher) were obtained from local distributors and used as received without further purification.

Instruments used

The equipments or instruments used during the work are summarized in Table 1 as follows.

Table-1.

S.No	Instruments/Equipment’s	Company
1.	Electronic balance	Sartorius, Edgewood, NY
2.	Hardness tester	Scientific Engineering Corp, Delhi
3.	Friability test apparatus	Scientific Engineering Corp, Delhi
4.	Tablet Compression Machine	Rimek RSB, Minipress, Banglore
5.	Vernier	Ayesh.
6.	Tablet dissolution tester (USPXX III)	Shimadzu, Japan
7.	UV Spectrophotometer	Shimadzu, Japan
8.	FTIR Spectrophotometer	Buck Scientific Inc.
9.	pH meter	Hanna Instrument, Italy
10.	Humidity chamber	Thermo Lab.
11.	Filter Paper (41)	Whatman
12.	Hot air oven	Narang Scientific and Electronic
13.	Sonicator	Leela Electronics, Mumbai
14.	Disintegration Appratus	Shimadzu, Japan

Method

Preparation of sustained release matrix tablets of Domperidone with HPMC K100M and Acrypol 974p / HPMC-5CPS material (Formulation of matrix tablets of domperidone)

Domperidone, HPMC-5CPS/ (HPMC K100M and Acrypol), MCC plain were weighted and shifted through #40 mesh mixed in planetary mixer for 10 minutes with PVP K-30 dissolved into Isopropyl alcohol by means of mechanical stirring. (iv) Add step one materials and binder solution for granulation, until dried.Then the Granules were loaded on FBD (fluidized bed dryer) at 50 °C for 15 minute, semi dry granules pass through #24 mesh, again dry it oven till LOD (2-3%)._{Weighed the Aerosil and magnesium stearate and passed through
#40 mesh,}lubricated for 5 minute by mixing and checked the blend parameters. Finally compressed tablets using punch size 7 mm with 16 station compressed machine and finally check in process parameters. (Formulation table-2).

Preparation of calibration curves

(a) Preparation of standard curve of Domperidone using 0.1 N HCl (Table 3, Graph 1)

8.5 ml of concentration HCl was taken and diluted with distilled water to 1000 ml. Calibration curve in 0.1 N HCl:-First stock solutions were prepared by dissolving 100 mg Domperidone in 100 ml of 0.1 N HCl (1 mg/ml). From this the second solution was prepared by diluting 5 ml to 50 ml to 50 ml of mixed 0.1N HCl (100 µg/ml). From second stock solution 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30 µg/ml dilution were prepared. The absorbance of each sample was measured at 290 nm. Standard curve of concentration versus absorbance was plotted as shown in table no. 3 with graph no. 1.

Table no.3

S.NO.	Concentration (ug/ml)	Absorbance
1.	0	0
2.	2	0.09
3.	4	0.178
4.	6	0.255
5.	8	0.345
6.	10	0.412
7.	12	0.475
8.	14	0.568
9.	16	0.655
10.	18	0.775
11.	20	0.825
12.	22	0.908
13.	24	1.05
14.	26	1.16
15.	28	1.19
16.	30	1.248

Graph no. 1

(b)Preparation of standard curve of Domperidone using Phosphate buffer pH 6.8 (Table 2, Graph 2)

11.45 gm of potassium di hydrogen phosphate and 28.80 gm of disodium hydrogen phosphate were taken and made upto 1000 ml with distilled water.

Calibration curve in phosphate buffer pH 6.8:- First stock solutions were prepared by dissolving 100 mg Domperidone in 100 ml of phosphate buffer pH 6.8 (1 mg/ml) , from this the second solution was prepared by diluting 5 ml to 50 ml to 50 ml of mixed (100 µg/ml) phosphate buffer pH 6.8,from the second stock solution 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 ,28 and 30 µg/ml dilution were prepared. The absorbance of each sample was measured at 290 nm. Standard curve of concentration versus absorbance was plotted as shown in table no. 4 with graph no. 2.

Table no.4

S.NO.	Concentration (ug/ml)	Absorbance
1.	0	0
2.	2	0.09
3.	4	0.178
4.	6	0.255
5.	8	0.345
6.	10	0.412
7.	12	0.475
8.	14	0.568
9.	16	0.655
10.	18	0.775
11.	20	0.825
12.	22	0.908
13.	24	1.05
14.	26	1.16
15.	28	1.19
16.	30	1.248

Graph no. 2

Drug-excepients compatibility studies by I.R^{23, 24}

Compatibility studies were performed using IR spectrophotometer. The IR spectrum of pure drug and physical mixture of drug and polymer were studied making a KBr disc. The characteristic absorption peaks of Domperidone were obtained at different wave numbers in different samples. The peaks obtained in the spectra of each formulation correlates with the peaks of drug spectrum. This indicates that the drug is compatible with the formulation components. The spectra for all formulations are shown below.^24,25The spectral details for all types of formulations are shown in Table 4 and table 5 with respect to graphs 3 and graph 4.

Table no.5: FT-IR Interpretation of Domperidone

S.No.	Group	Peaks cm^-1	Nature
1.	O-H (Alcohol)	_3122.0	Strong
2.	C-H (Alkane)	2937.5	Strong
3.	C=O (Carbonyl)	1693.8	Strong
4.	C=C (Aromatic)	1542.5	Weak
5.	C-O (Ether)	1289.7	Strong
6.	C-Cl (Alkyl Halide)	664.1	Strong

Graph no. 3: FT-IR Interpretation of Domperidone

Table no.6: FT-IR Interpretation of blend of Domperidone

S.No.	Group	Peaks cm^-1	Nature
1.	O-H (Alcohol)	3421.1	Strong
2.	C-H (Alkane)	2922.9	Strong
3.	C=O (Carbonyl)	1717.8	Strong
4.	C=C (Aromatic)	1508.0	Weak
5.	N-H (Amid)	1636.4	-----
6.	C-Cl (Alkyl Halide)	731.8	Strong

Graph no. 4: FT-IR Interpretation blend of Domperidone

RESULT AND DISCUSSION:

Evaluation of pre-compression parameter^{26,
27, 28}

1) Angle of repose (θ): -

The values obtained for angle of repose for all (F 1 -F 7) formulations are tabulated in Table 7. The values were found to be in the range from 23.65±0.7 – 44.95±0.4 .This indicates good flow property of the granules in F₄, F₅andF₆.

2) Compressibility index: -

The values obtained for compressibility index for all (F 1-F 7) formulations are tabulated in Table 7. Compressibility index value ranges between 9.34±0.5 – 49.56±0.4 indicating that the granules have the good flow property for compression in F₄, F₅andF₆.

3) Hausner’s ratio:-

The values obtained for Hausner’s ratio for all (F 1 -F 7) formulations are in Table 7. Hausner’s ratio value ranges between 1.175 - 2.664 indicate that the granules have the required flow property for compression.

4) Drug uniformity: -

The percentage of drug uniformity was found to be between 91.94±040 - 99.75±0.34 of Domperidone, which was within acceptable limits. Table 7 showed the results of drug content uniformity in each batch.

Table no. 8

Formulations	Diameter± SD (mm)*	Thickness±SD (mm)*	Weight variation # ± SD (mg)	Hardness± SD (kg /cm²)*	Friability± SD (%)	Drug content* ± SD (%)
F₁	7.03±0.2	3.25±0.2	125±2	6.50±0.2	0.49±0.04	98.6±2.6
F₂	7.04±0.2	3.25±0.2	126±2	5.00±0.2	0.45±0.03	99.2±2.4
F₃	7.04±0.3	3.26±0.3	129±2	3.00±0.2	1.12±0.03	98.5±2.1
F₄	7.02±0.2	3.27±0.2	127±2	7.50±0.2	0.51±0.03	98.3±2.8
F₅	7.04±0.2	3.25±0.2	126±2	8.00±0.2	0.47±0.05	88.7±2.6
F₆	7.03±0.2	3.25±0.2	125±2	9.00±0.2	0.41±0.04	99.2±2.1
F₇	7.04±0.4	3.26±0.2	125±2	2.50±0.2	1.22±0.05	87.4±2.2

Table no 9. : Swelling Index Behavior Study of selected Formulations*

Time (hr)	F1	F2	F3	F4	F5	F6	F7
1	12.5	15.45	17.56	27.2	39.2	48.32	14.3
2	18.3	22.34	24.34	42.6	61.34	72.21	20.09
3	21.78	27.14	30.4	55.2	77.34	93.32	28.34
4	23.34	31.98	36.87	53.2	75.03	87.23	35.67
5	27.34	36.45	36.45	49.2	65.03	83.32	33.21
6	29.56	38.67	48.14	45.01	59	79.24	29.4
7	25.23	33.4	45.87	33.01	54.02	68.21	27.23
8	19.9	28.3	41.76	25.03	48.23	62.1	26.34
9	16.45	25.9	38.56	19.14	42.21	54.21	24.8
10	13.6	19.34	32.4	15.09	33.8	47.28	23.8
11	10.34	14.34	26.5	14.06	24.27	41.09	20.35
12	8.45	11.1	22.8	12.08	19.2	37.4	19.23

CONCLUSION:

In present investigation an attempt has been made to design and develop some Domperidone matrix tablets using, Hydroxy propyl methyl cellulose K100M, 5CPS and Acrypol as release retarding polymers. Domperidone facilitates gastric emptying and decreases small bowel transit time by increasing esophageal and gastric peristalsis and by lowering esophageal sphincter pressure and has been selected to prepare sustained release dosage forms.

1. Domperidone sustained release matrix tablet were prepared using Hydroxy Propyl Methyl Cellulose K100M, 5CPS and Acrypol their combination as base polymer by wet granulation method.

2. FT-IR spectral analysis showed that characteristic peak of Domperidone pure drug was retained in the spectra of all the formulations indicating the intactness of the drug in all the formulations.

3. The prepared tablets were evaluated for number of parameters like thickness, diameter, weight variation, swelling index and in vitro release studies.

4. All the prepared tablets were of smooth surface and elegant texture.

5. The tablets prepared were checked visually for its appearance and surface texture.

6. The weights of the tablets were in the range of 125 ± 2 mg. The thickness of the tablet was in the range of 3.25 ± 0.2 to 3.27 ± 0.2 mm. As the time increases, the swelling index was increased; later on it decreases gradually due to dissolution of outermost –gelled layer of tablet into dissolution medium. Comparison between Hydroxy Propyl Methyl Cellulose K100M and 5CPS, It has been observed that swelling index isomer in Hydroxy Propyl Methyl Cellulose. Drug content uniformity study showed uniform dispersion of the drug throughout the formulation in the range of 96.33 ±0.41 to 99.75 ± 0.34.

7. The maximum drug release was found to be 99.2±2.1% over a period of 10 hours in HPMC K100M and Acrypol 974p based tablets (F₆). Similarly maximum drug release was found to be ^{98.3±2.8over
a period of 10 hours in HPMC-5CPS based tablets (F}₄^{) and maximum
drug release} was found to be 92.42% over a period of 10 hours in marketed formulation vomistop 30mg SR. This indicates that the minimum quantity of HPMC-5CPS and maximum quantity of HPMC K100M required to prepare the sustain release matrix tablets of Domperidone.

8. The formulations were also subjected to model fitting analysis to know the order and mechanism of drug release from the formulations by treating the data according to zero – order, first – order, Higuchi and peppas equations. The data clearly shows that, the release kinetics revealed that the formulations containing HPMC K100M and Acrypol 974p follows first – order drug release with non-fickian diffusion, formulation containing HPMC-5CPS follows first – order drug release with non-fickian diffusion and the marketed sample Vomistop 30 mg SR follows first – order drug release with non-fickian diffusion.

9. Stability studies reveled that there were no significant changes in physical properties and drug contain of formulation F₆and F₄thus formulation were stable.

10. It can be concluded that Hydroxy Propyl Methyl Cellulose K100M and Acrypol 974p combination and individual Hydroxy Propyl Methyl Cellulose - 5CPS respectively can be used as an effective matrix former to sustain the release of Domperidone for an extended period of 10 hrs.

CONFLICT OF INTEREST:

There is no conflict of interest and plagirism report is attached for this.

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Received on 11.06.2018 Modified on 16.08.2018

Research J. Pharm. and Tech 2018; 11(12): 5599-5610.

DOI: 10.5958/0974-360X.2018.01018.1

Formulations	Angle of repose (θ)	Carr’s Index (%)	Hausner’s ratio	*Drug uniformity(%)**
_F1	42.53±0.5	46.37±0.5	2.664	91.94±040
_F2	44.95±0.4	49.56±0.4	2.478	89.31±0.32
_F3	24.63±0.7	10.44±0.5	1.196	96.33±0.41
_F4	26.51±0.8	12.17±0.5	1.204	99.75±0.22
_F5	25.45±0.6	10.74±0.4	1.175	98.94±0.21
_F6	23.65±0.7	09.34±0.5	1.204	99.75±0.34
_F7	27.88±0.4	11.24±0.6	1.182	99.75±0.18

S.No.	Drug+Excipient	Parameter	Initial Value of Parameter	Conditions		Comments
				RT40°C±2°C/7 5%±5%RH
				15 days	30 days
1	Domperidone	Any colour change	No colour change	No colour change	No colour change	Compatible
2	Domperidone +HPMC K100M	Any colour change	No colour change	No colour change	No colour change	Compatible
3	Domperidone + MCC	Any colour change	No colour change	No colour change	No colour change	Compatible
4	Domperidone + Aerosil	Any colour change	No colour change	No colour change	No colour change	Compatible
5	Domperidone + Magnesium chloride	Any colour change	No colour change	No colour change	No colour change	Compatible

Ingredients (mg/tablet)	F1	F2	F3	F4	F5	F6	F7
Domperidone	30	30	30	30	30	30	30
HPMC-5CPS	18	12	10	11	--	--	--
HPMC K100M	--	--	--	--	15	10	10
Acrypol-974P	--	--	--	--	5	4.50	3.50
MCC Plain	66.50	72.00	73.50	73.50	74.50	70.00	70.00
PVP K-30	8	8	8	8	8	8	8
Aerosil	0.50	0.50	0.50	0.50	0.50	0.50	0.50
Magnesium Stearate	2	2.50	3	2	2	2	2
IPA	q.s.	q.s.	q.s.	q.s.	q.s.	q.s.	q.s.
Total weight	125	125	125	125	125	125	125