Enhancement of Solubility and effect of Granulation methods on drug release in sustained release matrix tablets of a poorly soluble drug

 

A.V.S. Ksheera Bhavani*, A. Lakshmi Usha², E. Radha Rani², A. Vyasa Murty³

¹Department of Pharmaceutics, Sri Venkateswara College of Pharmacy, Etcherla, Srikakulam, A.P., India.

²Department of Pharmaceutics, Maharajah’s College of Pharmacy, Vizianagaram, A.P., India.

³Department of Pharmaceutical Sciences, Univesity of Tasmania, Hobart, Australia.

 

ABSTRACT:

Domperidone, a BCS Class II drug chosen as a model drug which is highly permeable and poorly soluble, mainly used in the treatment of Emesis. It has a strong affinity for D₂ receptors, chemically related to Haloperidol, but pharmacologically related to metaclopramide. Sustained release tablet of Domperidone are preferred because of prolonged drug release in order to reduce the frequency of dosing. In the present study, it was decided to design controlled release formulation of Domperidone with pH dependent release profile so as to minimize/prevent initial drug release in the stomach in order to reduce the possible gastro-irritant and ulcerogenic effects of the drug The study was carried out using release retarding polymers like HPMC (hydrophilic matrix polymer), Eudragit (polyacrylate polymers) and natural polymers like guar gum and xanthan gum were used. An ideal matrix formulation prepared using different polymer and diluent concentrations. The formulation were prepared using various compression techniques like wet granulation technique and direct compression techniques in order to release their contents in a sustained manner over a certain period of time. As Domperidone is class II drug having low solubility and more permeability and, the solubility of Domperidone was initially enhanced by preparing solid dispersions using solvent evaporation method by using drug and polymer (β-cyclodextrin) in three different ratios i.e. 1:0.75, 1:1, 1:1.5 and the solid dispersion mixture containing drug and polymer in the ratio 1:1.5 showed 97% drug release in one hour was optimized as the best mixture. In the present work drug and polymer mixture in the ratio 1:1.5 was further formulated into tablets by incorporating natural and synthetic gums by using different granulating techniques like direct compression and wet granulation in three different concentrations. Formulation (F3) containing drug and Xanthan gum in the ratio 1:1 prepared by wet granulation technique could sustain the drug release over a period of 12h and hence considering all the post compression parameters it was optimised as the better formulation. FTIR, DSC, X-Ray Diffraction, SEM studies were performed for optimised solid dispersion mixture and also the optimised formulation.

 

 

 

 

INTRODUCTION:

Among all the routes that have been explored for the systemic delivery of drugs, Oral drug delivery has been known for decades as the most widely utilized route of administration. Nowadays most of the pharmaceutical scientists are involved in developing an ideal drug delivery system. This ideal system should have an advantage of single dose for long duration of the treatment and it should deliver the drug directly at specific site. The goal in designing sustained delivery systems is to reduce the frequency of the dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required or providing uniform drug delivery.¹

 

During the past two decades, there has been a profound increase in the development of sustained release drug delivery system due to various factors like expiration of various international patents, prohibitive cost of developing new drug entities, discovery of new polymeric materials that are suitable for retarding the release of the drug, improvement in therapeutic efficiency and safety². Of all sustained release dosage forms, matrix tablets are considered to be the commercially feasible dosage forms that involve the least processing variables, utilize the conventional facilities and accommodate large doses of drug. Matrix devices had gained steady popularity in pharmaceutical research due to their chemical inertness, drug embedding ability and drug release character³.

 

Vomiting is regulated centrally by the vomiting centre and the chemoreceptor trigger zone (CTZ), which are present in the medulla. The CTZ is sensitive to chemical srimuli and is the main site of action of many emetic and antiemetic drugs. Dopamine (acting through D2 receptors) is an inhibitory transmitter in the GIT normally acts to delay gastric emptying when food is present in stomach. It also appears to cause gastric dilation and LES relaxation attending nausea and vomiting⁴. Domperidone blocks D2 receptors and has an opposite effect-hastening gastric emptying and enhancing LES tone by augmenting Ach release, clinically this action is exerted through 5HT receptors. The central anti dopamergic action on CTZ responsible for antiemetic property⁵.

 

The main aim of the present work is to formulate and evaluate sustained release matrix tablets of Domperidone by using natural polymers like Xanthan gum and Guar gum using various compression techniques like wet granulation technique and direct compression techniques.

 

MATERIALS AND METHODS:

MATERIALS:

Domperidone, Xanthan gum, Guar gum, Eudragit RS 100, and Hydroxyl propyl ß cyclodextriene were obtained from Yarrow chem products, Mumbai. Lactose was purchased from and Talc from Otto Chemika Biochemika reagents.

 

METHOD:

Domperidone a BCS class II drug is a poorly soluble in water. Therefore, solubility of Domperidone was enhancing by preparing solid dispersions using solvent evaporation technique. Solvent evaporated mixtures were by using drug and carrier in different ratios such as 1:0.75, 1:1 1:1.5. Solid dispersions were characterised by FTIR spectroscopy, DSC studies, X-ray diffraction, and dissolution studies. Dissolution studies were performed for the solvent evaporated mixtures using USP dissolution type II apparatus (paddle method) with 50 rpm 6.8pH phosphate buffer as dissolution mediums at 37±0.5^oC. Based on physicochemical characterization, solvent evaporated mixture containing drug and carrier in the ratio of 1:1.5 (equivalent to 30mg of drug) was selected to formulate into sustain release tablets.

 

Table 1: Formulation table for Solid Dispersions

 

Sustained release matrix tablets of Domperidone were prepared by using direct compression technique and wet granulation techniques.

 

DIRECT COMPRESSION TECHNIQUE:

All the ingredients were weighed separately dried for 30 mins at 50^°C and cooled to room temperature. They were then passed through #40 sieve separately to attain fine powder. The sieved powders were weighed and added geometrically (except glidant and lubricant), mixed properly and then finally lubricant and talc added just before compression. This mixture was directly compressed using rotary tablet punching machine equipped with 8mm flat faced circular punches at a constant compression force⁶.

 

WET GRANULATION TECHNIQUE:

In this technique all the ingredients except lubricants and anti- adherent were mixed properly and then the mixture is formed into dough using 2% starch paste as a binding agent. Then the dough is then passed through the sieve #22 to form the granules.

 

Table 2: Formulation table for Preparation of tablets:

 

The so formed granules were dried at 50°C and then cooled at room temperature. Lubricant and glidant were added. Then the mixture was compressed using rotary tablet punching machine equipped with 8mm flat faced circular punches at a constant compression force.⁷

 

Evaluation Parameters:

Pre Compression Parameters:

Prior to the compression of tablets, the blend of drug and excipients of all the batches were evaluated for various micromeritic properties like Angle of repose, bulk density, tapped density, Carr’s Compressibility index and Hausner’s ratio⁸.

 

Post Compression Parameters:

Thickness:

Thickness of the sustained release tablets were tested using calibrated Vernier-calipers. The tablet thickness was controlled within a ±5% variation.

 

Hardness test or crushing strength:

Hardness is the force required to break a tablet across the diameter. It is measured in kilograms and a crushing strength of usually 4kg is considered to be the minimum satisfactory for tablets. The hardness was tested using Monsanto hardness tester.

 

Friability test:

This is an in process quality control test performed to ensure the ability of tablets to withstand shocks during processing, handling, transportation, and shipment. It is usually measured by using Roche Friabilator⁹.

 

                        Weight_initial – Weight_final

% friability =_{–––––––––––––––––––––––––––––––––}× 100

                                 Weight_initial

 

Uniformity of weight or Weight variation test:

This test is performed to check the weight of the tablet frequently (every half an hour) so that in case of any corrections will be made during the compression of tablets. Any variation in the weight of the tablet may lead to over dose or under dose of medication. Therefore every tablet in each batch should have a uniform weight¹⁰.

 

                         individual weight-average weight

% deviation= ––––––––––––––––––––––––––––– ×100

                                       average weight

 

Estimation of drug content:

Drug content was determined accurately by weighing 5 tablets and crushing them in motor with the help of a pestle. Content uniformity was calculated using the following formula.

 

% purity =10 C (Au/As)

 

Where, C= Concentration, Au and As= absorbance obtained from the standard preparation and assay preparation respectively.

 

In–vitro drug release studies:

The dissolution behaviour of Domperidone was recorded using a dissolution apparatus (Disso 2000 LAB INDIA, Mumbai). USP dissolution apparatus with rotating paddle assembly (type II) was used at 50 rpm, in 900 ml of deionised water (phosphate buffer pH 6.8). The mean of the three determinations was used to calculate the drug release from the tablets. The samples were withdrawn at predetermined time intervals, and equal amount of fresh buffer was replaced. The obtained samples were filtered and assayed spectrophotometrically at 285nm¹¹.

 

FT-IR Study:

The FT-IR spectra of pure drug, polymers and optimised formulation were scanned over a frequency range 4000-400 cm-1 by placing sample on diamond ATR and analyzing for the presence of characteristic peaks¹².

 

Thermal Analysis:

DSC was performed using DSC calorimeter to study the thermal behaviour of pure drug, polymers and mixture of optimised formulation. The required amounts of samples were heated in sealed aluminium pans under nitrogen flow (30ml/min) at a scanning rate 5°C per min from 40°C to 250°C. The heat flow as a function of temperature and enthalpy change was measured for the drug, polymers and mixture of optimised formulation¹³.

 

X-ray diffraction analysis:

X-ray diffraction is an important tool to investigate the crystal structure as well as the average structural spacing between the layers or rows of atoms in an unknown material. Formulations were subjected to X-ray diffraction analysis, using Cu target slit 10 mm to investigate the physical state of Domperidone, HP-β-CD and Domperidone solvent evaporated mixtures.[14]

 

Scanning Electron Microscopy:

Scanning electron microscope (SEM) allows viewing and surface analysis of solid dispersions as well as spatial pattern formation for the scanned object. This is very important for the qualitative assessment of their properties such as particle size, their shape, morphology, porosity, presence of crystalline forms, as well as tested powders texture monitoring¹⁵.

 

Characterization of pure drug Domperidone:

Identification of Domperidone by UV- visible spectrophotometer:

Standard plot of Domperidone was constructed by taking series of concentration in pH 6.8 phosphate buffer and pH 1.2 N HCl buffer. The absorption spectra were recorded in the wavelength region of 200-400 nm in the UV visible spectrophotometer. The absorption maximum of Domperidone was found to be 285 nm.

 

Melting point:

Melting point of Domperidone was determined using melting point apparatus and DSC. The temperature at which the drug starts to melts is recorded and compared to its standard value. Melting point of Domperidone was found to be 245.98°C by DSC and 242-246°C by melting method, which complies with the standard values in the official monograph as per USP- NF. The above determined results show the drug is pure and free from impurities¹⁶.

 

Solubility:

Solubility determination of Domperidone was carried out in water and organic solvents. As it is class II drug, Domperidone shows poor solubility. It was found that Domperidone is practically insoluble in water, but soluble in organic solvents like ethanol, dimethylsulfoxide. The above estimation done was beneficial for further studies¹⁷.

 

Compatibility studies of solid dispersions:

Visual inspection:

Visual inspections were conducted to check the compatibility between drug and excipients in its physical mixture when stored in glass container at room temperature for a certain period of time. The main objective of this inspection was to observe any colour change in the physical mixture. Throughout the examination, there was no change in the colour of the physical mixture throughout the examination period, indicating that drug and excipients are quite compatible each other.

 

FTIR (Fourier transformer infrared spectroscopy):

The physical mixture of drug and excipients was characterized by FTIR spectrum by yris Diamond TG/ DTA. The FTIR of the pure drug and solid dispersion did not show any peak indicating the absence of any chemical reaction between Domperidone and β-cyclodextrin

 

DSC (Differential scanning Calorimetry):

DSC thermogram of Domperidone showed a sharp peak at due to the melting point of the drug and indicating its crystalline nature. This shows that the drug considered for the research is in pure form. The measured melting endotherm of the β- cyclodextrin is 91.27°C.

 

XRD (X-ray diffraction):

The X-ray diffractograms of Domperidone showed characteristics sharp intensity diffraction peaks at 27.353°C

 

Determination of drug content and percent yield in solid dispersions:

All the solid dispersions prepared by solvent evaporation method were in the form of free flowing powders. The values of % drug content and % yield values were determined.

 

IN- VITRO DISSOLUTION STUDIES OF SD’S:

The in vitro dissolution studies were performed for the solid dispersions. The drug release from solid dispersions was 74.57, 89.51 and 96.53% respectively in 1 hr.

 

Table 3: In vitro dissolution profile for solid dispersions.

 

From the above data Solid dispersion SD3 was optimised as the best formulation and was used further for compression into tablets.

 

PRECOMPRESSION PARAMETERS:

Precompression studies are conducted in order to determine the flow-ability, compressibility studies of the powder blend and granules.

 

Different tablet batch formulations F1-F6 were prepared by wet granulation and F7–F12 by direct compression methods. Solid dispersion mixture (75mg) and other all excipients were passed individually through #40 sieve and mixed well for 10 min in a mortar and pestle to form a powder blend. This blend was compressed into tablets by wet granulation and direct compression techniques using single punch rotary tablet punching machine using 8mm flat punches.

 

Table 4: Post compression parameters of various formulations prepared by Wet granulation and Direct Compression Techniques

 

In-vitro drug release studies:

Prepared tablets were evaluated by conventional In-vitro dissolution testing USP type II apparatus at 50 rpm. Initially the dissolution studies were out in 900 ml of 0.2 N HCl for 2 hours. After the completion of the 2 hours the remaining time period i.e., 10 hours the dissolution studies were performed in 6.8 pH phosphate buffer. Both the media was maintained at the temperature 37±5°C. The volume in order to maintain the sink condition; 5 ml of the dissolution media was withdrawn at the predetermined intervals and fresh preheated dissolution media was replaced.

 

Table 5: In vitro dissolution profile of Domperidone Sustained release tablets by wet granulation and Direct Compression Techniques.

 

 

Fig 1: FTIR spectrum of Optimised Formulation

 

 

Fig 2: DSC thermo gram of Optimized formulation

 

 

Fig 3: XRD of Optimised formulation

 

 

Fig 4: SEM image of Solid Dispersion mixture

 

 

Fig 5: SEM image of optimized drug mixture

 

DISCUSSION:

As Domperidone is BCS Class II drug, having less solubility and more permeability. Therefore, the solubility of Domperidone was enhanced by preparing solid dispersions using solvent evaporation technique. β-cyclodextrin inclusion complexes were prepared in three different ratios like 1:0.75, 1:1, 1:1.5. In the present work drug:polymer in the ration 1:1.5which showed 97% of drug release in 1 hour was optimised as the best mixture and further formulated into tablets by incorporating natural gums in three different ratios using wet granulation and direct compression techniques.

 

The active pharmaceutical ingredient Domperidone was evaluated for its physical characteristics and drug polymer compatibility studies. The precompression powder blends of different batches were evaluated for various parameters like angle of repose, bulk density, tapped density, compressibility index Hausner’s ratio. The results obtained were found to be satisfactory and within the specified limits.

 

The matrix tablets were prepared by wet granulation (F1-F6) and direct compression (F7-F12) containing different ratios of drug and polymer were subjected to various evaluation tests such as thickness, uniformity of weight, drug content, hardness and friability. The results have complied with the official pharmacopeial limits. It has been observed in this investigation that the formulation (F3) containing drug and Xanthan gum in the ratio 1:1 prepared by wet granulation technique could sustain the drug release over a period of 12h and hence considering all the post compression parameters it was optimised as the better formulation.

 

CONCLUSION:

Domperidone a BCS class II drug having low solubility and highly permeability was chosen as a model drug. It is mainly used in the treatment of Emesis. It has a strong affinity for D₂ receptors, chemically related to Haloperide, but pharmacologically related to Metaclopramide. Sustained release tablet of Domperidone is preferred because of its prolonged drug release manner, and therefore frequency of the dosing can be reduced.

 

In the present study, it was decided to design controlled release formulation of Domperidone with pH dependent release profile so as to minimize/ prevent initial drug release in the stomach that will reduce the possible gastro-irritant and ulcerogenic effects of the drug. At the same time, there was no compromise on the biopharmaceutical profile of the drug as Domperidone is reported to be well absorbed through\out the GI tract by increasing the half-life eventually producing the sustained action. The study was carried out using release retarding polymers like Xanthan gum, Guar gum and different granulation techniques. This gives advantage in reducing the frequency of the dosage to increase effectiveness of the drug by localizing at the site of action.

 

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Received on 16.12.2019           Modified on 21.02.2020

Accepted on 11.04.2020         © RJPT All right reserved