The major goal of Modified-release drug delivery system was supplied a therapeutic amount of drug to a goal site of actiom, so that the desired drug concentration can be achieved swiftly and then maintained. Target drug delivery implies careful and effective localization of drug into the target at therapeutic concentrations with limited entrée to non target sites. The Modified-release for Drug Delivery Systems have recently gained importance for delivering a variety of drugs. Modified-release formulation technology offer an effective means to optimize the bioavailability and resulting blood concentration-time profiles of drug that otherwise suffer from such limitation. Within the context of this chapter, the term “modified release formulations” refers to both delayed system designed specifically to modify the release of water-soluble drug. Also included are the enteric coated dosage forms for which absorption occurs primarily in the GIT & colonic pleace.1,2
1.1 Classification of Modified release drug delivery systems:-
1.1.1 Delayed release:- Delayed release system is one that uses repetitive intermittent drug dosage from one or more immediate release units combined into a single dosage form. e.g, repeat-action tablets/capsules, enteric coated tablets, & colonic site specific time release. Since the transit time of dosage forms in the small intestine is less variable i.e. about 3±1 hr.30 the time-release function (or timer function) should work more proficiently in the small intestine as compared the stomach. In the colonic drug delivery system will be delivered to the goal side, and the drug release will begin at a determined time point after GIT emptying. On the other hand, in the stomach, the drug release should be suppressed by a pH sensing function (acid resistance) in the dosage type, which would reduce variant in gastric residence time. The tablets doesn’t discharge the drug in the stomach due to the acid struggle of the outer enteric coating layer Enteric coated time-release press coated tablets, are composed of three components, a drug containing core tablet, the press coated sellable hydrophobic polymer film shellac, guar gum and zein mixture, time release and site specific drug delivery system function) and an enteric coating layer.5 1.1.2 Sustained release:- In a sustained release system slow drug release over an extended period of time takes place. If the system can achieve spatial or temporal or both control of drug release in the body or if the system is able to successfully control the release of drug to target tissue or cells. the system is therefore referred to as a modified release delivery systems. Colon targeted drug delivery is an example of modified drug delivery system.2
1.1.3 Site-specific targeting or receptor targeting or particular site:- Diseases intended to be treated when colon drug targeting is adopted are ulcerative colitis, Crohn’s disease (chronic inflammation of the digestive tract, especially of the lower small intestine and colon, which may develop thick scars)/irritable bowel disease, carcinomas/colorectal cancer, amebiasis and other colonic infections. Furthermore colon targeted drug delivery could be used to achieve chronotherapy for diseases and symptoms in the early morning, such as nocturnal asthma, angina and arthritis. Anti-inflammatory, antibacterial, antiamebic, protein drugs, are a few out of other drugs that can be targeted for site specific delivery to the colon. Sustained release dosage forms for colonic targeting may be classified as single unit or multiple unit dosage forms. Single unit dosage forms are formulated as enteric coated tablets with extended release polymers, coated with pH dependent polymers. When the coating dissolves in the upper intestine, the core tablet releases the drug in a sustained manners in the colon. The multiple unit dosage forms consist of a number of single unit dosage forms, in the form of tablet, granules or microspheres, enclosed within a capsule or tablet. When the tablet or capsule disperses to release its contents, each of the particulates behaves as single unit dosage form.6,7
1.2 Advantages of Modified release drug delivery systems:-
Reproducible rate and prolong delivery of drug.
Administration of drug is less frequent. So, drug accumulation on chronic dosing is minimized.
Patient compliance is better.
Side effects (local and systemic) are reduced because effective plasma concentration is maintained.
Targeting can eliminate damage to non-target organs.
The colon targeted drug delivery can also be used for chronotherapy for effective treatment of diseases like asthma, angina and arthritis.
1.3 Disadvantages of Modified release delivery systems :-
Cost factor is high.
Unpredictable and often poor in-vitro/in-vivo correlation exists.
There is reduced potential for first pass clearance.
Generally, systemic availability is poor.
For oral dosage form, there is an addition disadvantage that the release period is influenced and limited by gastrointestinal transit time.
The pH level in the small intestine and caesium are similar which reduces site specificity of formulation.
Enzymatic degradation may be excessively slow which can cause interruption in polymer degradation and thus alters the release profile of drugs.
Tablet dissolution process Fig. 1.1
1.4 Challenges to Modified release delivery systems :-
a. Cost of formulation (preparation and processing) is a major challenge.
b. Fate of Modified release delivery systems , if not biodegradable.
c. Biocompatibility of formulation. 8,9
Modified drug delivery systems have acquired a centre stage in the area of pharmaceutical R&D business. Such systems offer temporal and/or spatial control over the release of drug and grant a new lease on life to a drug molecule in terms of patentability. Oral modified drug delivery systems. Such systems release the drug with constant or variable release rates.1 These dosage forms offer many advantages, such as nearly constant drug level at the site of action, prevention of peak-valley fluctuations, reduction in dose of drug, reduced dosage frequency, avoidance of side effects, and improved patient compliance.10,11
The oral Modified-release system shows a typical pattern of drug release (Fig:1.2) in which the drug concentration is maintained in the therapeutic window for a prolonged period of time (sustained release), thereby ensuring sustained therapeutic action. The colon targeted drug delivery is beneficial for the localized treatment of several colonic diseases mainly inflammatory bowel diseases (IBD), irritable bowel syndrome and colonic cancer. The pH dependent systems are designed to release the drug at particular pH of gastrointestinal tract (GIT), was very well established. The timed Thus, specific approach as compared to the other approaches. These polymers shield the drug from the environments of stomach and small intestine and are able to deliver the drug to the colon. the release commences as soon as the dosage form is administered as in the case of conventional dosage forms.12
Fig.1.2:Plasma Drug Concentration Profile of Conventional Tablet.
1.5 Colonic drug delivery system:
Over the past two decades, the pharmaceutical market has been demonstrated increasing preferably for modified and targeted drug delivery system. Such systems have been focused on constant, variable; sustain drug release and/or targeting the therapeutic agent to a specific site/tissue/organ. However, recently there are certain conditions for which such release pattern is not suitable. Such conditions that lead to the requirements of a time programmed therapeutic system, which are capable of releasing drug after predetermined time delay and maintain constant drug levels throughout the day.13,14
Matching of drug release to the body’s circadian rhythms have been fundamental strategies involves for selecting a new drug delivery system which increase the efficacy and safety of drugs by proportioning their peak plasma concentrations during the 24 hours in synchrony with biological rhythm. The recent literature reports on a variety of chronotherapeutic drug delivery systems, which have been recognized as potentially beneficial to the chronotherapy of widespread chronic diseases that display time-dependent symptoms such as ulcers, asthma and cardiovascular disease. Such chronotherapeutic drug delivery system controls drug release according to circadian rhythms and the timing of symptoms.15,16,17
While newer and more powerful drugs continue to be developed, increasing attention is being given to the methods by which these active substances are administered. A new development, polymeric Modified drug delivery, has evolved from the need for prolonged and better control of the drug administered. The Modified release devices, which are already available commercially, can maintain the drug in the desired therapeutic range with just a single dose, localize delivery of the drug in to a particular body compartment, which lowers the systemic drug level, reduces the need for follow-up care, preserves medications that are rapidly destroyed by the body and increases patient comfort or compliance. The basic approach that drug concentration effect relationships are significantly invariant as a function of time in man has lead to the development of constant rate drug delivery systems.
Nevertheless, there are a number of clinical situations where such an approach may not be sufficient. These include delivery of insulin for patient with diabetes mellitus, antiarrhythmics for patients with heart rhythm disorder, gastric acid inhibitors for ulcer control, nitrates for patients with angina pectoris, as well as selective ?-blockade, birth control, general hormone replacement, immunization, and cancer chemotherapy. Recent studies in the field of chronopharmacology indicate that the onset of certain diseases exhibit strong circadian temporal dependency. Thus, drug delivery patterns can be further optimized by pulsed or self- regulated delivery, adjusted to the staging of biological rhythms.18,19 With the advancement of the technologies in the pharmaceutical field, drug delivery systems have drawn an increasing interest over the last few decades. Nowadays, the emphasis of pharmaceutical galenic research is turned towards the development of more efficacious drug delivery systems with already existing molecule rather going for new drug discovery because of the inherent hurdles posed in drug discovery and development process.
Traditionally, drug delivery has meant for getting a simple chemical absorbed predictably from the gut or from the site of injection. A second-generation drug delivery goal has been the perfection of continuous, constant rate delivery of bioactive agents. However, living organisms are not ”zero-order” in their requirement or response to drugs. They are predictable resonating dynamic systems, which require different amounts of drug at predictably different times within the circadian cycle which will maximize desired and minimize undesired drug effects.20 Till early nineties efforts have been made to design the drug delivery system which will release the drug at fairly constant rate. In fact these systems turned to be one of the most successful systems in delivering the drug molecule. But still for many of the drugs, use of such systems is not suitable because of a number of reasons. This is particularly true in cases where the drug is subjected to large metabolic degradation. Due to ‘first pass effect’ there will be reduction in the bioavailability of the drug because gradual release can result in greater degradation. Secondly drugs with short half-life need to be administered repeatedly which results in patient non-compliance. Further, in case of chronic treatment, where the drug is given in sustained release dosage form, continuous exposure of the drug to body may lead to adverse effect. For example, diabetes mellitus requires chronic treatment with sustained release formulations of drugs like sulfonylurea which will damage the pancreas earlier than the corresponding immediate release dosage form. Lastly, drugs which exhibit tolerance should not be delivered at a constant rate, since the drug effect decreases with time at constant drug level. In addition drug toxicity increases with time when drug levels are held constant. In such cases it is preferable to opt for dosage form which will provide desired concentration of drug at particular time point only. Nowadays, concept of chronopharmaceutics has emerged, wherein; research is devoted to the design and evaluation of drug delivery systems that release a therapeutic agent at a rhythm that ideally matches. Colon drug delivery systems (CDDS) are gaining importance as these systems deliver the drug at specific time as per the path physiological need of the disease, resulting in improved patient therapeutic efficacy and compliance. Colonic drug delivery may be achieved by either oral or rectal administration. Rectal administrations of drugs for colon targeting always face high variability in the distribution of drug, when they are administered in the form of dosage forms like enemas and suppositories, which are not always effective. Therefore, the oral route is the most preferred. Conventional oral formulations dissolve in the stomach or intestine and are absorbed from these regions. The major obstacle with the delivery of drugs by oral route to the colon is the absorption and degradation of the drug in the upper part of the gastrointestinal tract (GIT) which must be overcome for successful colonic drug delivery system.1
Fig.1.3 (Gastrointestinal tract)
Table 1.1 pH values of different parts of the gastrointestinal tract
Region of the gastrointestinal tract pH
Transverse colon 6.6
Descending colon 7.0
1.6 Functions of colon:-
It creates suitable environment for the growth of colonic microorganisms.
Fecal contents storage reservoir.
Eviction of the contents of the colon and
To secrete K+ and HCO3-
1.7 Absorption of Drug from Colon:-
Studies in rat have revealed that paracellular absorption is constant through the small intestine, but transcellular absorption appears to be limited to the small intestine, with negligible colonic absorption by this route. The epithelial cell junctions are very tight which may leads to poor paracellular absorption of many drugs in the colon. The drug stay in contact with mucosa in colon for a longer period than in small intestine which compensates the much lower surface areas of colon for absorption The colonic contents become more viscous with absorption of water as content travels through the colon. This cause a reduction in dissolution, and sluggish diffusion of dissolved drug through the mucosa.2
1.8 Factors Affecting Drug Absorption from Colon:-
The colon specific drug delivery primarily affected by two physiological factors, these are pH level and the transit time. The other factors which need to be considered are as follows:
Physical characteristic of drug ( pka, degree of ionization).
Colonic residence time as detected by gastrointestinal tract motility.
Degradation by bacterial enzymes and byproducts.
Selective and non selective bindings to the mucus.
Local physiological actions of drug.
Use of chemical absorption enhancers.
Diseases wherein CDDS are promising include asthma, peptic ulcer, cardiovascular diseases, arthritis, attention deficit syndrome in children and hypercholesterolemia. CDDS can be classified into time Modified systems wherein the drug release is Modified primarily by the delivery system; stimuli induced PDDS in which release is Modified by the stimuli, like the pH or enzymes present in the intestinal tract or enzymes present in the drug delivery system and externally regulated system where release is programmed by external stimuli like magnetism, ultrasound, electrical effect and irradiation. Diseases where a constant drug levels are not preferred but needs a pulse of therapeutic concentration in a periodic manner acts as a push for the development of “colonic Drug Delivery Systems.” In these systems, there is rapid and transient release of a certain amount of drug molecules within a short time-period immediately after a predetermined off release period. Various techniques are available for the colonic delivery like pH dependent systems, time dependent systems, micro-flora activated systems etc. which can be designed as per the physiology of disease and properties of the drug molecule. The focus of the present review is primarily on the colonic drug delivery methodologies and the upcoming technologies, which are being exploited on an industrial scale.21,22
Fig.1.4: Drug Release Profile of Colonic Drug Delivery Systems.
In recent years considerable attention has been focused on the development of colonic drug delivery system. Delivery system with colonic release pattern has gained most popular form of modified release delivery systems because conventional systems with a continuous release are not ideal. Oral modified drug delivery systems are generally used due to convenient dosage form ; it also releases drug in constant or variable rates. In these system drug release generally occurs within therapeutic window for prolong period of time. Hence these systems show sustained release of drug from dosage form. 23
1.9 Advantages of colonic drug delivery system :-
Extended daytime or night-time activity
Reduced side effects
Reduced dosage frequency
Reduction in dose size
Improved patient compliance
Lower daily cost to patient due to fewer dosage units are required by the patient in therapy.
Drug adapts to suit circadian rhythms of body functions or diseases.
Drug targeting to specific site like colon.
Protection of mucosa from irritating drugs.
Drug loss is prevented by extensive first pass metabolism. 24
1.10 Need of colon targeted drug delivery system:-
There are certain conditions for which constant a release pattern is not suitable. These conditions demand release of drug after a lag time. In other words, it is required that the drug should not be released at all during the initial phase of dosage form administration. Such a release pattern is known as colonic release. The conditions that demand such release include:
Much body functions that follow circadian rhythm, i.e., their activity waxes and wanes with time. A number of hormones like rennin, aldosterone, and cortisol show daily.
fluctuations in their blood levels. Circadian effects are also observed in case of pH and acid secretion in stomach, gastric emptying and gastro-intestinal blood transfusion.
Diseases like bronchial asthma, myocardial infarction, angina pectoris, rheumatic disease, ulcer and hypertension display time dependence. A sharp increase in asthmatic attacks during early morning hours. Such a condition demands considerations of diurnal progress of the disease rather than maintaining constant plasma drug level. A drug delivery system administered at bedtime but releasing drug well after the time of administration (during morning hours), would be ideal in this case. Same is true for preventing heart attacks in the middle of the night and the morning stiffness typical of people suffering from arthritis.
Drugs that produce biological tolerance demand for a system that will prevent their continuous presence at the diphase as this tends to reduce their therapeutic effect.
The lag time is essential for the drugs that undergo degradation in gastric acidic medium (e.g., peptide drugs) irritate the gastric mucosa or induce nausea and vomiting. These conditions can be satisfactorily handled by enteric coating and in this sense; enteric coating can be considered as a colonic drug delivery system.
Targeting a drug to distal organs of gastro-intestinal tract (GIT) like the colon requires that the drug release is prevented in the upper two-third portion of the GIT.
All of these conditions demand for a time-programmed therapeutic scheme releasing the right amount of drug at the right time. This requirement is fulfilled by Colonic Drug Delivery Systems. A colonic drug delivery system is characterized by a lag time that is an interval of no drug release followed by rapid drug release.25,26
1.11 Diseases requiring colonic drug delivery:-
Through understanding of the disease physiology is required before designing the colonic drug delivery system. Diseases where rhythmic circadian organization of the body plays an important role, pharmacokinetics and/or pharmacodynamics of the drugs is not constant within 24 hrs. Table1.2 enumerates various diseases showing such a chronological behaviour. Asthma is one such disease where colonic drug delivery system can be useful. Circadian changes are seen in normal lung function, which reaches a low in the early morning hours. In case of cardiovascular diseases, several functions (e.g. BP, heart rate, stroke volume, cardiac output, blood flow) of the cardiovascular system are subject to circadian rhythms. For instance, capillary resistance and vascular reactivity are higher in the morning and decrease later in the day. Platelet aggregability is increased and fibrinolytic activity is decreased in the morning, leading to a state of relative hypercoagulability of the blood.
Circadian variations of glucose and insulin in diabetes have been extensively studied and their clinical importance in case of insulin substitution in type 1 diabetes has been well exploited. Furthermore diverse directions of circadian changes in lipid fractions in patients ansd normal subjects may contribute to alteration in the rhythmicity of other metabolisms and in the blood coagulation system, thus leading to various complications. A circadian rhythm occurs during hepatic cholesterol synthesis. In case of arthritis there is a circadian rhythm in the plasma concentration of C – reactive protein and interleukin-6 of patients with rheumatoid arthritis.
Table 1.2 Diseases requiring Colonic Drug Delivery 27
Disease Chronological behaviour Drugs used
Peptic ulcer/Cron,s diseases Acid secretion is high in the afternoon and at night H2 blockers
Asthma Precipitation of attacks during night or at early morning hour 2 agonist,
Cardiovascular diseases BP is at its lowest during the sleep cycle andrises steeply during the early morning awakening period Nitroglycerin,Calcium channel blocker, ACE inhibitors etc.
Arthritis Pain in the morning and more in night NSAIDs, Glucocorticoids
Diabetes mellitus Increase blood sugar level after meal Sulfonylurea,
Attention deficit syndrome Increase in DOPA level in afternoon Methylphenidate
Hypercholesterolemia Cholesterol synthesis is generally higher during night than during day time HMG CoA reductase inhibitors
Roy P. et al. 200937 reported statistical optimization of ranitidine HCl floating colonic delivery system for chronotherapy of nocturnal acid breakthrough. Using a programmed delivery of ranitidine hydrochloride from a floating tablet with time-lagged coating. In this study, investigation of the functionality of the outer polymer coating to predict lag time and drug release was statistically analyzed using the response surface methodology (RSM).
Schellekens RC. 200834 developed and evaluated colonic drug delivery to ileo-colonic segments by structured incorporation of disintegrants in pH-responsive polymer coatings.
Janjira I. et al. 200835 demonstrated colonic release of biomolecules from polydimethylsiloxane (PDMS) chips with hydrolytically degradable seals. The PDMS chip with arrays of wells was constructed by replica molding. Poly (lactic acid-co-glycolic acid) (PLGA) polymer films of varying composition and thickness were used as seals to the wells. The composition, molecular weight and thickness of the PLGA films were all parameters used to control the degradation rate of the seals and therefore the release profiles. Degradation of the films followed the PLGA composition order of 50:50 PLGAN75:25 PLGAN85:15 PLGA at all time-points beyond week.
Lin HL. et al. 200836 described and release characterized in vitro-in vivo correlation of colonic pattern for a colonic drug delivery system activated by rupture via osmotic pressure and swelling. The influence of core and coating formulations on the release profiles to establish in vitro/in vivo correlations of colonic pattern for a colonic drug delivery system activated by membrane rupture based on three core tablet formulations (A-core: HPMC 50+4000 cps, B-core: E10M, and C-core: K100M) coated with various thicknesses of a semipermeable ethyl cellulose membrane plasticized with HPMC 606(Pharmacoat 606) at different ratios with/without adding various amounts of water to dissolve it in the coating solution.
Rajendra Kotadiya., (2008)43 studied the various properties of guar gum for usage as better polysaccharide for colonic drug delivery. It includes general properties and chemistry of guar gum. The author also reviewed the various application of guar gum as a carrier for colon drug delivery systems.
Ashutosh Mohapatra et al., (2008)47 prepared, orally disintegrating tablets using direct compression and wet granulation method. First, the tablets of metformin were prepared using starch RX1500 and microcrystalline cellulose by direct compression. The tablets showed erosion behavior rather than disintegration. The optimized batches prepared by direct compression and wet granulation showed 85% drug release at 4 and 8 min, respectively.
Mastiholimath VS. et al. 200730 investigated time and pH dependent colon specific, colonic delivery of theophylline for nocturnal asthma based on chronopharmaceutical consideration. The basic design consists of an insoluble hard gelatin capsule body, filled with eudragit microcapsules of theophylline and sealed with a hydrogel plug. The entire device was enteric coated, so that the variability in gastric emptying time can be overcome and a colon-specific release can be achieved.
Moriyama K. et al. 200731 reported colonic peptide release from multi-layered hydrogel formulations consisting of poly(ethylene glycol)-grafted and ungrafted dextrans. Multi-layered hydrogel formulations consisting of poly (ethylene glycol)-grafted dextran (PEG-g-Dex) and ungrafted Dex were investigated as a model of colonic drug release. The formulations exhibited surface-controlled degradation by dextranase, and insulin release was observed in a colonic manner because of the multi-layered structure: PEG-g-Dex hydrogel layers containing insulin and insulin-free Dex hydrogel layers.
Ghimire M. et al. 200732 investigated in-vitro/in-vivo correlation of colonic drug release from press-coated tablet formulations: a pharmacoscintigraphic study in the beagle dog. A press-coated tablet (PCT) intended for time delayed drug release,consisting of a rapidly disintegrating theophylline core tablet, press-coated with barrier granules containing glyceryl behenate (GB) and low-substituted hydroxypropylcellulose (L-HPC).
Ross AC.et al. 200733 prepared and evaluated chronopharmaceutical drug delivery from a colonic capsule device based on programmable erosion. The drug formulation is sealed inside the insoluble capsule body by an erodible tablet (ET). The release time was determined by ET erosion rate and increases as the content of an insoluble excipient (dibasic calcium phosphate) and of gel-forming excipient (hydroxypropylmethylcellulose; HPMC) increased. The time-delayed release of a model drug (propranolol HCI) was investigated by dissolution testing (USP XXIII paddle method). Both composition and weight of ET influenced the time of drug release.
Brahma N Singh., (2007)40 reviewed on modified release solid formulations for colonic delivery and discussed about the various benefits of solid formulations intended for targeted drug release into the colon. The author discussed that the colon targeted drug delivery systems can be utilized for chemotherapy of diseases which are affected by circadian rhythms (e.g., asthma, hypertension and arthritis). He summarized the recent patent literatures concerning various modified release formulation technologies that are claimed to provide colonic delivery of drugs.
Sameer S. et al. 200628 reported low density multiparticulate system for colonic release of Meloxicam. A multiparticulate floating-colonic drug delivery system was developed using porous calcium silicate (Florite RE®) and sodium alginate, for time and site specific drug release of Meloxicam. Meloxicam was adsorbed on the Florite RE® (FLR) by fast evaporation of solvent from drug solution containing dispersed FLR. Drug adsorbed FLR powder was used to prepare calcium alginate beads by ionotropic gelation method, using 32 factorial designs.
Mohammad A. et al. 200629 developed evaluated pH-independent colonic drug delivery system based on hard gelatin capsules and coated with aqueous dispersion Aquacoat-ECD. The drug release was induced by rupturing of the top-coating, resulting by expanding of swellable layer upon water penetration through the top-coating. Valentine C Ibekwe et al., (2004) reviewed the advantagesand different approaches of colonic drug delivery via oral route. In their review they quoted that colon can be site of drug targeting to synchronize the circadian rhythm of asthma, arthritis etc10.
M. K. Chourasia et al., (2003)45 proposed that colon targeting is naturally of value for the topical treatment of diseases of colon such as chron’s disease, ulcerative colitis, colerectal cancer and amoebiasis. Microbially degradable polymers especially azo cross linked polymers have been investigated for use in targeting of drugs to colon. Certain plant polysaccharides such as amylose, inulin, pectin and guar gum remains unaffected in the presence of gastrointestinal enzymes and pave the way for the formulation of colon targeted drug delivery systems.
Ishino R. et al. 199238 prepared and evaluated absorption of diltiazem in beagle dog from colonic release tablet. In this using diltiazem hydrochloride was used as the model drug, and a polyvinyl chloride-hydrogenated castor oil-polyethyleneglycol mixture as the outer shell of the tablet. In vitro drug release from the prepared tablet exhibited a typical colonic pattern with a 7 h lag phase (non-drug release period).
Ashford M and Fell JT., (1994)42 reviewed the approaches taken to achieve a universal system for delivery. The design of such a system requires the identification and exploitation of a unique feature of the colonic environment. The use of transit times, pH and bacterial enzymes are critically assessed. In addition, the system must provide protection for the drug during transit to the colon. Upper gastrointestinal physiology and the transit of pharmaceuticals through these regions are reviewed with reference to their relevance in achieving site specificity.
Amnon Sintov et al., (1995)46 prepared a series of crosslinked products of chondroitin sulfate with 1, 12- diaminodecane. The water solubility of the modified polymers were low. The swelling of films made of the cross-linked polymers were measured in water and they found that an exponential- like dependency between the degree of swelling and extent of cross-linking. They prepared indomethacin tablets using two types of crosslinked polymers of chondroitin sulfate. Based on the physiochemical properties, water uptake and drug release characteristics, an optimal product with a potential to serve as a colon-specific drug carrier was suggested.
Kinget. R et al., (1998)41 aimed at providing insight into the design considerations and evaluation of colon drug delivery. They surveyed the anatomy and physiology of the lower GI tract and biopharmaceutical aspects in relation to the drug absorption in the colon by various approaches.
Reddy SM et al., (1999)44 reviewed on novel oral colon specific drug delivery systems for pharmacotherapy of peptide and non-peptide drug which was found to be obvious advantage over parentral administration. Sustained release colonic drugs are used in the treatment of nocturnal asthma, angina, and arthritis. Peptides, proteins, oligonucleotides and vaccines are the potential candidates for colon specific drug delivery. Sulfasalazine, ipsalazide and olsalazine are used for the treatment of inflammatory bowel disease. Recent developments in pharmaceutical industries including coating drugs with pH sensitive and bacterial degradable polymers, embedded in bacterial degradable matrices and designing into new prodrugs, have provided renewed hope to effectively target drug to colon. Polysaccharide and azopolymer coating have been used for colon specific targeting, which provides for the refinements in pharmacotherapy of colon specific drug delivery.
Kowanko I.C et al. (1981)39studied the circadian variations in the signs and symptoms of rheumatoid arthritis and in the therapeutic effectiveness of flurbiprofen at different times of the day. Results concluded taking long acting NSAIDs like flurbiprofen, at bedtime optimizes their therapeutic effect and minimizes or averts their side effects8.
PLAN OF WORK
Aims and objectives:
The aim of present work is to prepare colon specific delivery system of Orindazole using different ratio of shellac, zein and guar gum.
Orindazole is a drug that cures some protozoan infections, Crohn’s disease and inflammatory bowel syndrome. From literature it revealed that shellac, zein and guar gum released drug from dosage form at the pH of 6.9, 11.5, 7-9 respectively.
The main problem associated with colon targeted drug delivery system is degradation of drug in the acidic environment of stomach to circumvent the present problem different combinations of shellac, zein and guar gum were employed in the formulation of colon targeted tablet.
Plan of work:
To achieve the current objective work was planned as follow:
Selection of drug and polymers
Characterization of drug by U.V spectroscopy.
Drug-excipients compatibility study
Melting point determination
Solubility of drug
4) Selection of method for formulation of colon release tablets of Orindazole.
5) Characterization of granules.
Paricle size analysis
Angle of repose
7) Formulation and evaluation colonic release tablets.
DRUG ; POLYMER
Drug and polymer profile:
1. Drug (Ornidazole):
Ornidazole is a drug that cures some protozoan infections. It has been investigated for use in Crohn’s disease after bowel resection.
Structure of Ornidazole (C7H10CLN3O3)
Mol. Mass 219.62
Mechanism of Action of Ornidazole
Ornidazole is a nitro imidazole which has broad spectrum cidal activity against Protozoa and some anaerobic bacteria. Its selective toxicity to anaerobic microbes involves, 1. Drug enters the cell by diffusion, 2. Nitro group of drug is reduced by redox proteins present only in anaerobic organisms to reactive nitro radical which excerts cytotoxic action by damaging DNA and other critical biomolecules, 3. DNA helix destabilization &strand breakage has been observed.
Bioavailability oral bioavailability 50%
Half life : half life is 12-24 hours
Inhalation : 5-15 minutes
Duration of action : 8 to 12 hours
Metabolism : It is subject to first pass metabolism in the liver
Exretion : Readily 5 days excreated in the urine 63% as metabolite and unchanged drug Some excreate in faeces 22% .
Storage Requirements for Ornidazole
Store at cool dry place. Protect from heat and light. Keep out of the reach of children
Side Effects of Ornidazole
Abdominal pain, Vertigo, Nausea, Vomiting, Fatigue and Dry mouth
Shellac is the purified product of lac, a natural resinous oligomer (MW ? 1000 D) secreted by the parasitic insect Kerria lacca on various host trees in India,Thailand, and Myanmar.
Structure of shellac
Solubility – shellac is soluble in alkaline solutions such as ammonia, sodium boret, sodiam carbonete, and sodium hydroxide,and also in various organic solvents.
Color- red light yellow.
Molecular weight- 1000 D.
Melting point- 95. C.
Storage- Cool dry place.
Zein is a class of prolamine protein found in maize (corn). It is usually manufactured as a powder from corn gluten meal. Zein is the plant protein pure zein is clear and Odorless,
Tasteless, Hard,Water-insoluble Solubility in ethanol and it has a variety of industrial and food uses. Zein has been used in the manufacture of a wide variety of commercial products including coatings for paper cups, soda bottle cap linings, clothing fabric, buttons, adhesives, coatings and binders.
2.3 Guar gum:-
Guar gum, also called guaran, is a galacto mannan. It is primarily the ground endosperm of guar beans. The guar seeds are dehusked , milled and screened to obtain the guar gum. The guar bean is principally grownin India, Pakistan, US, China, Australia and Africa. India produces 2.5 – 3.5 million tons of guar annually, making it the largest producer with about 80% of world production The gum may be washed with ethanol or isopropanol to control the microbiological load (washed guar gum).
Description: White to yellowish-white, nearly odorless, free-flowing powder.
Synonyms: Gum cyamopsis, guar flour.
Structure of Guar gum
Chemical name: modified polyethylene terephthalate.
English name: hot melt adhesive powder.
Molecular formula: (CH3-CH2-CH2-CH2-O-C…C-O-CH2-CH2-CH2CH3)n
Melting point: 110-120°c
Appearance: it can be used in printing, wool and other fields.
molecular weight: (50,000-8,000,000)
Solubility: Insoluble in ethanol
Loss on drying : Not more than 15.0% (105o, 5 h)
5. Material, method and equipments:
Zein, Shellac & Guar gum.
UV Spectrophotometer, Electronic balance, pH-meter, Magnetic stirrer, Hot-oven, Dissolution apparatus, Tablet machine (hand operating) & Hardness tester.
For preparation Orindazole granules :- Wet granulation method.
For preparation of tablets :- Direct compression method.
Tablet coating :- coating pan.
5.1 Raw Materials procurement :
Table: 5.1 Details of material used
Material Name Source
Drug Ornidazole Glenmark, Pithampur
Carrier Material Microcrystalline cellulose Qualikems, Vadodara
Coating Material Shellac, Zein, Guar gum & PVA Fisher Scientific, Mumbai
Lubricant PEG 400 Ranbaxy, Dewas
Flow activator Megnisium oxide Central drug house, Mumbai
Disintigrants Sodium stach glycolate Qualikems, Vadodara
Antiadherant Megnisium stearats, Talk Himedia, Mumbai
Liquid used Ethenol Fisher Scientific, Mumbai
Table: 5.2 Details of instrument used
Tablet Punch Machine National Scientifico
Dissolution Apparatus Rolex, Teknik
Disintigration Apparatus Teknik
UV Spectrophotometer Sistonic
Monsanto hardness tester Hicon, NASCD
Verniar calipers scale Teknik
Oven Dhruv ovan
Ornidazole was obtained as a gift sample from Micro Lab. Limited, Chennai, India, from Rohm Pharma, India. Guar gum, shellac,zein, Micro crystalline cellulose (MCC), Poly vinyl alcohal (PVA), Aerosil, purchased from Lobachemie, Mumbai India. All the other chemicals and solvents used were of laboratory reagent grade.
5.3 Preformulation studies:
Characterization of drug and analytical studies
The drug was characterized for Physical appearance, Solubility, UV spectral analysis, IR Spectral analysis.
5.3.1 Melting Point:
Melting point of the drug was determined by taking a small amount of drug in a capillary tube closed at one end and it was place in melting point apparatus and the temperature at which the drug melts was note. Average of triplicate readings was take.
5.3.2 FTIR spectroscopy: FTIR studies was performed to determine the chemical interaction between the drug and Excipients used in the formulation. The presence of drug peaks in the formulation and absence of extra peaks indicates there is no chemical interaction. The IR spectra were recorded using Fourier Transform Infra-Red spectrophotometer with diffuse reflectance principle. Sample preparation involved mixing the sample (2 mg) with potassium bromide (KBr), triturating in glass mortar and finally placing in the sample holder. The spectrum was scanned over a frequency range 4000– 400 cm-1.
5.3.3 Determination of ?max : The standard stock solutions of Ornidazole was separately prepared by dissolving 100 mg of Ornidazole in 100 ml of three different dissolution media. A stock solution of Ornidazole was further diluted with respective media to get a standard solution of concentration 100 ?g/ml.28
5.3.4 Preparation of calibration curve: The standard solution of Ornidazole (12 ?g/ml) in three different dissolution media namely 0.1 N HCl, phosphate buffer pH 6.8, and phosphate buffer 7.4 were prepared and scanned in the entire UV range to determine the ?max of both the drugs. The ?max of Ornidazole was found to be 275 nm in 0.1 N HCl and 310 nm in both the phosphate buffers. A series of standard solution were prepared in different dissolution media in the concentration range of 1–40 ?g/ml using a working standard solution. The absorbance of those standard solutions was taken at ?max in respective media, and calibration curves were plotted at these wavelengths.29
5.3.5 Partition coefficient:
Mixture of 50 ml water and 50 ml benzene was taken in a separating funnel . 100 mg of drug was added to mixture. Mixture was shaken, and set aside for help an hour. Both phases were separated. Concentration of drug is each layer was determine drug uv spectrophotometer.
5.4 Preparation of core tablets: A tablet is a pharmaceutical dosage form. Tablets may be defined as the solid unit dosage form of medicament or medicaments with or without suitable diluents and prepared either by molding or by compression.
Ingredients except glidants and lubricants were thoroughly mixed and passed through sieve no. 60. Granulation was done with 5% starch paste. The wet mass was passed through sieve no. 12 and dried at 50 C for 1 hr. the dried granules were lubricated with magnesium stearate and talk then compressed in to tablet using single station punch machine.30
Table: 5.3 Composition formula for Ornidazole enteric coated for colon.
(single tablet) (total weight = 200 mg)
Quantity (mg) present per Core tablet
S. No. Ingredients FM1
1 Ornidazole 200
2 PVA 25
3 Microcrystalline cellulose 30
4 Starch 10
5 Talc 10
6 Magnesium Sterate 15
7 Solvent q.c.
Total weight tablet 300 mg
5.5 Preparation of granules: Wet Granulation In wet granulation, a liquid binder or an adhesive is first added to the powder mixture. The wetted mass is then passed through a screen of the desired mesh size, and resulting granules are dried. The dried granules can be passed through a second screen of a smaller mesh to reduce the size of the granules even further. Overwetting usually results in granules that are too hard for proper tableting, while underwetting usually results in the preparation of tablets that are too soft and tend to crumble.
5.6 Evaluation of granules:
5.6.1 Angle of repose: Angle of repose is defined as the maximum angle bpossible between the surface of a pile of the powder and horizontal plane. The frictional force in a loose powder or granules can be measured by angle of repose.31
tan ? = h/r
where ? is the angle of repose, h is the height of the pile, r is the radius of the base of pile.
Table: 5.4 Relationship between Angle of repose and flow properties
S. No. Angle of repose Flow
1 <25 Excellent
2 25-30 Good
3 30-40 Passable
4 >40 very poor
Method: A funnel was filled to the brim and the test sample was allowed to flow smoothly through the orifice under gravity. A graph sheet was kept below. A aired was drawn across conical pile formed on graph paper. Height and radius of pile was measured.32
5.6.2 Carrs index: is called the Compressibility The flow ability of powder can beevaluat by compar the bulk debsity and tapped density of powder and the rate at which it pack down. Compressibility index is calculate by the table.33,12
Compressibility index (%) = DT-DBDT×100Where,DT = Tapped density, DB = Bulk density
Table: 5.5 Compressibility index is calculate.
% Carr’s index Flow type
18-21 Fare passable
33-38 very poor
;40 extremely poor
5.6.3 Hausner’s ratio: It is the ratio of tapped density to bulk density. It is given by-
Hausner’s ratio = DT/DB
Where DT = Tapped density, DB = Bulk density
5.6.4 Bulk density: It is the ratio of total mass of powder to the bulk volume of powder. The bulk density of powder depends primarily on particle size distribution, particle shape and the tendency of particle to adhere to one another. It is expressed in gm/cc and is given by- DB = MVDM = Mass of powder,Vo= Bulk volume of powder
Method: It was measured by pouring the weighted powder in to a measuring cylinder and the initial volume was noted. This initial volume is called bulk volume. From this, the bulk density was calculated according to the formula mentioned above.12,5
5.6.5 Tapped density: It is the ratio of total mass of powder to the tapped volume of powder. It is expressed in gm/cc and is given by-
DT = MV0Method: This volume was measured by tapping the powder for 500 times. Then the tapping was done for 750 times and then tapped volume was noted (the difference between these two volume should be less then 2%). If it is more then 2% ,tapping was continued for 1250 times and tapped volume was noted.
5.7 Evaluation of core tablet:
5.7.1 Weight variation test: Twenty tablets of the formulation were weighed using a electronic balance and the test was performed according to the official method.
5.7.2 Hardness: The hardness of five tablets was determined using the Monsanto type hardness tester and the average values were calculated.
5.7.3 Thickness and diameter: The thickness and diameter of the tables was determined by using Vernier calipers. Five tablets were used, and average values were calculated.
5.7.4 Friability: It is the phenomenon whereby tablet surfaces are damaged and/or show evidence of lamination or breakage when subjected to mechanical shock or irritation. The friability of tablet was determined by using Roache Friabilator. It is expressed in percentage(%). Ten tablets were initially weighted (Winitial) and transferred into friabilator. Weighted tablet sample is placed in the chamber and the friabilator was operated at 25 rpm for 4 min. or run up to 100 revolutions and drop the tablet from a hight of 15 cm with each revolution. The tablets were weighted again (Wfinal). The percentage friability was then calculated by- % friability of the tablet less than 1% is considered acceptable
Friability (%) = Winitial – Wfinal / Wfinal x 100
.5.7.5 Content uniformity: The enteric coated tablets of Ornidazole were tested for their drug content. Ten tablets were finely powdered; quantities of the powder equivalent to 20mg of Ornidazole were accurately weighed and transferred to a 100ml of volumetric flask. The flask was filled with phosphate buffer pH 8.0 and mixed thoroughly. Volume was made up to mark with phosphate buffer pH 8.0 and filtered. The absorbance of the resulting solution was measured at the 240nm using a UV/Vis double beam spectrophotometer. The linearity equation obtained from calibration curve as described previously was used for the estimation of Ornidazole in the tablet formulations.
5.7.6 Disintegration time: Disintegration testing of core tablets was carried out in the six tablet basket rack USP disintegration apparatus. One tablet was introduced into each tube of the basket rack assembly of the disintegration apparatus without disc. The assembly was positioned in the beaker containing disintegration media maintained at 37±2°C.
5.7.7 In vitro dissolution studies: The in vitro dissolution study of uncoated tablets of Ornidazole was performed using USP dissolution testing apparatus II (paddle type). The dissolution test was performed using 900ml of 7.4 pH phosphate buffer, at 37±0.5°C and 100 rpm. A sample (10ml) of the solution was withdrawn from the dissolution apparatus at regular interval for 60 minutes, and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45?m membrane filter and absorbance of these solutions was measured at suitable ?max UV/Vis double beam spectrophotometer. Cumulative percentage of drug release was calculated using the equation obtained from a standard curve.
5.8 Tablet coating:
The coating were coated using coating pan machine by using the coating polymers. Pan Coating is among the oldest industrial processes for forming small coated particles or coated tablets. Active cores ~2mm and larger are cascaded through a spray region within a rotating perforated pan. Drying air is directed through or over the cascading bed of material as atomized coat solution or suspension spray is directed at the rapidly passing product. Spray rate, atomized spray pattern, spray gun distance from the bed, pan speed, temperature, and airflow are adjusted for optimal coating efficiency. This technology is most commonly used for coating of tablets or other similarly size materials the table 8.
Table:5.6 Tablet coating Polymers ratio (mg)
Formulation Polymers ratio (mg)
Shellac Guar gum Zein
FM1 200 : 0 : 0
FM2 0 : 200 : 0
FM3 0 : 0 : 200
FM4 100 : 100 : 0
FM5 100 : 0 : 100
FM6 0 : 100 : 100
FM7 66.66 : 66.66 : 66.66
5.9 Preparation of enteric coated Ornidazole tablets42,43:
The outer coating layer was applied on the matrix tablets using dip coating method. An organic polymer solution consisting of 5% w/v in acetone was used for the coating. Castor oil was incorporated in the coating solution as a plasticizer (20% w/w based on the polymer). An Opacifier, titanium dioxide (0.05% w/w) and an Antiadherant, talc (5% w/w) to prevent adhering of tablets during the coating process were also added to the coating solution. The enteric coated Ornidazole tablets (OM1 to OM5) with 5% solution were coded as FM1 to FM7.
5.10 Evaluation of colonic tablets of Ornidazole:-
5.10.1 Physical characterization of tablet:-
All the batches of tablet formulations were characterized for official evaluation parameters like Weight variation, Hardness, Friability, Tablet thickness and reported for further optimization and evaluation.
5.10.2 Drug content uniformity:-44
Ten tablets from each formulation were powdered and a quantity equivalent to 100 mg of drug content was dissolved in 100 ml of phosphate buffer pH 6.8. 10ml of filtrate was suitably diluted and analyzed for drug content by spectrophotometry at 319nm.
5.10.3 In vitro drug release study from tablets:-46,47
In vitro drug release studies were carried out using USP apparatus (Paddle type, Lab India Tablet Dissolution apparatus, Mumbai, India) at 100 rpm, 37 ± 0.5oC and 900 ml dissolution medium by buffer change technique. Tablet bearing Ornidazole were suspended in simulated gastric fluid pH 1.2 (900 ml), for 2hr. The dissolution media was then replaced with mixture of simulated gastric fluid and simulated intestinal fluid pH 4.5 (900 ml) for next 2hrs, then for next 2 hrs simulated intestinal fluid pH 6.8 (900ml) and the release study was carried out further in simulated intestinal fluid (900ml) pH 7.4. Samples were withdrawn periodically and compensated with an equal amount of fresh dissolution media. The samples were analyzed for drug content by measuring absorbance at corresponding ?max of the dissolution medium, using UV- spectrophotometer (UV-18OO, Shimadzu, Japan). The percentage cumulative release for Ornidazole was calculated over the sampling times using Beer Lambert’s curve generated in the respective medium. Studies were performed in triplicate and the mean cumulative percentage of drug calculated (± SD) and plotted against time.
5.10.4 Uniformity of thickness:- The crown thickness of individual tablet may be measured with a vernier calliper which permit accurate measurements and provide information on the variation of tablets. Other technique employed in production involves placing 5 or 10 tablets in a holding tray, where there total crown thickness may be measured with a sliding calliper scale. Thickness should not deviate by ±5% from the standard thickness. It depends mainly upon die filling, physical property of material being compressed force and compression force.42
5.10.5 Hardness:-Tablet requires a certain amount of strength, or hardness and resistance to friability, to withstand mechanical shock of handling in manufacture, packaging and shipping. The hardness of tablet was determined using Monsanto hardness tester. The tablet was placed between both the punches of hardness tester and force was applied. The force at which the tablet was about to crush was noted. It was expressed in kg/cm2. Three tablets are randomly pick from each formulation and the mean and standard deviation values are calculat.41
5.10.6 Friability test:- It is the phenomenon whereby tablet surfaces are damaged and/or show evidence of lamination or breakage when subjected to mechanical shock or irritation. The friability of tablet was determined by using Roaches Friabilator. It is expressed in percentage (%). Ten tablets were initially weighted (Winitial) and transferred into friabilator. Weighted tablet sample is placed in the chamber and the friabilator was operated at 25 rpm for 4 min. or run up to 100 revolutions and drop the tablet from a height of 15 cm with each revolution. The tablets were weighted again (Wfinal). The percentage friability was then calculated by- % friability of the tablet less than 1% is considered acceptable
Friability (%) = Winitial – Wfinal / Wfinal x 100
5.10.7 Weight variation:- The tablet were selected randomly from each formulation and weight individually to check for weight variation. According to the official test, 20 tablets are generally weight individually and collectively. Average weight per tablet was calculated from the collective weight. Then the weight of individual tablet was compared with the average weight to determine weight variation. The U.S. pharmacopoeia allows a little variation in the weight of the tablet. 49
Table 5.7 The percentage deviation in the weight variation is shown.
Average weight of a tablet % deviation
130mg or less 10
Mere then 130mg & less then 324mg 7.5
324mg or more 5
5.10.8 Disintegration time In vitro:- The process of breakdown of tablet into smaller particles is called disintegration. The in-vitro disintegration time of a tablet was determined using disintegration apparatus as per IP specification.
Method:- For a drug to be absorbed from a solid dosage form after oral administration, it must first be in solution, and the first important step towards this condition is usually the break-up of the tablet; a process known as disintegration. One tablet in each of the six tubes of the basket was placed and the apparatus subjected to run. The assembly be raised and lowered between 50 cycles per minute. The time in minute taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus is measure and record. Disintegration was measure in 900 ml purified water according to IP method without using disc at room temp.(25oC ± 2oC ).29,30,31
5.10.10 Dissolution studies:- Dissolution studies were carried out using tablet USP II dissolution test apparatus. Two objectives in the development of in vitro dissolution test showed that,
1. Release of the drug from tablet is as close as possible up to 100% and
2. Rates of drug release is uniform from batch and is the same as the release rate from those proven to be bioavilable and clinically effective.12,14
Table: 5.8 Dissolution studies In-vitro
S.N. Parameter Specification
1 Dissolution medium 900 ml 0.1 N HCl
2 Temperature 37oC ± 5oC
3 Rotation Speed 50 rpm
4 Volume Withdrown 5 ml
5 ?max 277 nm
6 Tablet Taken 1 tablet
5.10.11 In vitro drug release studies In vitro studies were carried out using a USP type II dissolution apparatus. The tablet was placed in 900ml of 0.1N HCl at paddle speed of 100 rpm maintained at 37°C ± 0.5°C for 2 hrs. 10 ml of Sample was taken and analyzed using UV spectrophotometer at 263 nm. Then the dissolution medium was replaced with pH 6.8 phosphate buffer (900 ml) and tested for drug release for 1 hr at same temperature and same rotation speed.14
6. Results and discussion:
6.1 Raw materials:- The following drug, polymers, Excipients and were gift from respected manufacturing Companies.
6.1.1 Drug :- The drug Ornidazole was gift sample from Aristo pharmaceutical Pvt.Ltd.
6.1.2 Excipients :- Procurement of Excipients are given in table.
6.2 Preformulation Studies:-
Ornidazole is select as the in vitro model drug for this study, since it is a slightly water-soluble substance and, thus, an ideal candidate for test the potential of sustained – release tablet compacts. In addition, it can be easily assayed and quantities in solution using spectrophotometer principles and procedures. From the standard calibration curve of Ornidazole in ethanol it is observe that the Ornidazole obeys Beer-lambert’s law in concentration range of 5-50 µg/ml.
6.2.1 Identification of drug:-
Table: 6.1 Organoleptic properties of Ornidazole
S. No. Parameter Drug
1 Colour Darkened urine
2 Odour Odorless
3 Taste Tasteless complex
4 Appearance White powder
6.2.2 Melting Point:- The melting point was found to be in the range of 77-78oC which is in good agreement with the reported values.
6.2.3 Solubility:- Solubility study of Ornidazole was carried out using saturation method it is freely soluble in ethanol and soluble in water.
6.2.4 Partition Coefficient:-
Partition coefficient of Ornidazole was carried out in distilled Water ethenol and phosphate buffer result are 0.412 and 0.522 which shows drug are hydrophilic in nature.
Table: 6.2 Solubility study of Ornidazole
Ornidazole Partition coefficients value
Water/Ethanol Ethanol/phosphate buffer
6.2.5 Determination Of Ornidazole ?max :-
Fig.6.1 The ?max of Ornidazole in 0.1 N HCl 275 nm
Fig.6.2. The ?max Ornidazole in phosphate buffers. 310 nm
6.3 Preparation of calibration curve:-
Table: 6.3 Phosphate buffer of pH- 7.4
Concentration (µg/ml) Absorbance
Table: 6.4 Phosphate buffer of pH 6.8
Concentration (µg/ml) Absorbance
Table: 6.5 pH HCL of pH 1.2
Concentration (µg/ml) Absorbance
6.4 FTIR Spectroscopy:-
FTIR was performed on Ornidazole, PVA and solid dispersion of Ornidazole with all carriers. The IR spectra of solid dispersion (Figure 2) showed all the principal IR absorption peak of Ornidazole at 3174.00 cm-1, 1536.37 cm-1, 1361.80 cm-1, 1268.25 cm-1, 1150.59 cm-1, 828cm-1. FTIR of formulations of drug and polymers used in studies shows that all the peaks of drug and polymer as it is and drug is present in free form. This indicates that there is no Chemical interaction in between Ornidazole and the polymers employed in formulations.
Table: 6.6 FTIR Peak Interpretation of Ornidazole
S. No. Assignment Reported Peak (cm-1) Observed Peak (cm-1)
1. O-H stretching mode asymmetric 3174.1 3174.00
2. NO2 stretching mode 1536.9 1536.37
3. NO2 stretching mode symmetric 1361, 1269.5 1361.80, 1268.25
4. C-O stretching mode 1149 1150.59
5. C-N, N2 stretching mode 828 828.46
Fig.6.3 FTIR of Ornidazole.
6.5 Micromeritic properties of Ornidazole granules-
6.5.1 Bulk Density, Tapped Density and Angle of repose:
The formulation show in table, which shows free flowing nature of form granules of all.
Table: 6.7 bulk and tapped density showed of the granules.
Granules code Bulk Density Tapped Density Angle of Repose
Mean Mean Mean
1 0.5 0.55 21.35
2 0.51 0.71 20.15
3 0.47 0.52 22.10
6.5.2 Hausner’s ratio:-
Hausner’s ratio is an indirect index of ease of powder flow. upon considering the micromerities properties of all formulation, formulation 3 of granules had best flow properties of my products.
6.5.3 Carr’s index:-
Carr’s index from 5.76-9.13%. formulation 3 of granules had lowest Carr’s index indicating excellent compressibility.
Table: 6.8 showed the value of Carr’s ; Hausner’s ratio.
Granules code Hausner’s ratio Carr’s index
1 1.03 7.08
2 1.05 8.52
3 1.08 5.24
6.5.4 Formulation and In vitro Characterization of Ornidazole Colon specific Enteric coated tablets:-
The Ornidazole tablet formulations were prepared successfully by wet granulation method, using the combination of shellac, Guar gum and zein in different proportions (FM1 to FM5) as rate retarding and forming polymers (The composition of the Ornidazole tablet formulations were shown in Table 1). The enteric tablets were further enteric coated with Eudragit® S100 (5% found to be optimized ,coated tablets were coded as FM1 to FM5).
All the tablet formulations under study were assessed and characterized for weight variation, hardness and friability, disintegration time, drug content uniformity. data were found to be satisfactory as revealed in Table 18.
Table: 6.9 Evaluation parameters of Ornidazole core tablets.
Test parameters FM1 FM2 FM3 FM4 FM5
Hardness(kg/cm2 ) 5.1 4.9 5.1 4.8 5.6
Diameter (in mm) 9.514 9.162 9.475 9.612 9.557
Thickness (in mm) 5.421 5.216 5.426 5.456 5.422
% Friability 0.457 0.512 0.465 0.575 0.412
Weight variation test Passes Passes Passes Passes Passes
Drug content*(mg) 95.59 94.79 95.21 95.51 95.04
Table: 6.10 Evaluation parameters of Ornidazole coated tablets.
Test parameters FM1 FM2 FM3 FM4 FM5
Hardness* (kg/cm2 ) 5.3 5.4 5.3 5.4 5.4
Diameter (in mm) 9.56 9.567 9.571 9.569 9.567
Thickness (in mm) 5.44 5.416 5.420 5.416 5.418
% Friability 0.57 0.532 0.565 0.565 0.423
Weight variation test Passs Passes Passes Passes Passes
Drug content*(mg) 95.62 94.85 95.25 95.53 95.01
Table: 6.11 In vitro drug release Studies of the formulation.
Time (hrs) Formulation % Release
F1 F2 F3 F4 F5 F6 F7
1 15.2 21.4 18.2 20.2 15.2 18.3 18.1
2 28.7 39.3 36.9 38.3 39.6 38.2 39.4
3 49.3 48.2 52.8 56.7 65.5 54.7 59.3
4 58.4 69.7 63.7 79.8 77.3 67.3 68.7
5 72.2 78.8 72.2 88.9 82.8 74.2 82.5
6 90.1 86.7 84.6 92.3 88.2 82.5 96.4
6.5.4 In vitro drug release Studies:-
In vitro drug release study was done by buffer change method to mimic the GI environment and the drug release study was continued for 6 hours for all formulations in order to check the variability of the drug release pattern. The drug release kinetics and mechanism of drug release was studied by fitting the in vitro dissolution data into different kinetic models like zero order, first order, Higuchi’s model and Korsemeyer – peppas model. The tablet formulations were subjected to in vitro drug release rate studies in 0.1 HCL (pH 1.2) for 2 hrs and in mixture of the capability of the formulation to withstand the physiological environment of the stomach and small intestine. The Ornidazole enteric coated tablets optimized formulation FM7 shows desired drug release 96.4±0.26% after 12 hrs as it is composed of equal amount of shellac, zein and guar gum (66:66:66), but it releases around 32.37±0.33% of drug in 2 hrs. So it was further enteric coated with coating material 5% coded as FM1. It prevents the drug release in upper part of GIT and shows 28% of drug release after 6 hrs as compared than other formulations.
The aim of this work was to prepare and evaluation colon targeted tablets of Ornidazole using different proportions of shellac, zein and guar gum.
Ornidazole is used for the treatment of several local diseases of colon such as Crohn’s disease etc. Formulation containing combination of shellac, zein and guar gum released least amount of drug in the acidic environment of stomach and released most of the drug in colon. It is evident from above discussion that targeted delivery to colon will result in lesser side effects and maximum utilization of drug.
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