In recent years, there has been rapid growth in the number of Fast Dissolving / Disintegrating Tablet (FDT) product on the market. Fast Dissolving Tablets are solid tablets and designed to dissolve/disintegrate in the patient’s mouth within a few second or minutes, without the need to drink or chew. However, the fear of taking solid tablets and the risk of choking for certain patient populations still exist despite their short disintegration/dissolution times.
However, some patients, particularly pediatric and geriatric patients have difficulty swallowing or chewing solid dosage forms many pediatric and geriatric patients are unwilling to take these solid preparations due to fear of choking. 1 Fast Dissolving Tablets (FDT) disintegrates and/or dissolves rapidly in the mouth without the need for water. Some tablets are designed to dissolve in saliva remarkably fast within a few seconds. Others contain agents to enhance the rate of tablet disintegration in the oral cavity and are more appropriately termed Fast Dissolving Tablets (FDT) as they may take up to a minute to complete disintegration.
A major claim of the some Fast Dissolving Tablets (FDT) increased bioavailability compared to traditional tablets. Because of dispersion in saliva while still in the oral cavity, there can be pre-gastric absorption from some formulation in those cases where the drug dissolves quickly. Buccal, pharyngeal and gastric regions are all areas of absorption of the many formulations. However, other formulations show nearly identical plasma concentration profiles. Any pre-gastric absorption avoids first pass metabolism and can be a great advantage in drugs that undergo a great deal of hepatic metabolism.
However, if the amount of swallowed drug varies, there is the potential for inconsistent bioavailability. While the claimed increase in 2 bioavailability is disputable, it is clear that the major advantage of these formulations is convenience. 2 In addition, they allow for effective life-cycle management. Fast dissolving drug delivery system offers a giant leap forward in drug administration by providing a new and easy way of taking medication. FAST DISSOLVING DOSAGE FORMS3 Fast dissolving drug delivery systems have rapidly gained acceptance as an important new way of administering drugs.
A fast dissolving drug delivery system, in most cases is a tablet that dissolves or disintegrates in the cavity without the need for water or chewing. Most fast dissolving delivery system tablet must include substances to mask the taste of the active ingredient. This masked active ingredient is then swallowed by the patient’s saliva along with the soluble and insoluble excipients. This fast dissolving action is primarily due to the surface area of the tablet, which wets quickly when exposed to the moist oral environment. These additional, superior benefits allow patients to take their medication anytime and anyplace under all circumstances.
These tablets are either very porous or inherently soft molded matrices or tablets compacted at very low compression forces in order to maximize tablet porosity and minimize oral dissolution/disintegration time. The delivery system is simply placed on a patient’s tongue or any oral mucosal tissue. Instantly wet by saliva, the tablet rapidly hydrates onto the site of 3 application. It then rapidly disintegrates and dissolves to release the medication for oromucosal absorption or with formula modifications will maintain the quick dissolving aspect but allow for gastrointestinal absorption to be achieved when swallowed.
CHARACTERSTICS OF FAST DISSOLVING TABLETS (FDT) 2, 4 1. Taste of the medicament As most drugs are unpalatable fast dissolving delivery systems usually contain the medicament in a taste masked form. Delivery systems dissolve or disintegrate in patient’s mouth, thus releasing the active ingredients which come in contact with the taste buds and hence, taste masking of the drugs becomes critical to patient compliance. Many oral suspensions, syrups and chewable tablets simply contain flavours, sugars and other sweeteners to overwhelm or complement the bitter taste of the drug. 2. Hygroscopicity
Several fast dissolving dosage forms are hygroscopic and cannot maintain physical integrity under normal conditions of temperature and humidity. Hence they need protection from humidity which calls for specialized product packaging. 3. Friability In order to allow Fast Dissolving Tablets to dissolve in the mouth they are made of either very porous or soft moulded matrices or compressed in tablets with very low compression force, which makes the tablets friable and/or brittle which are difficult to handle often requiring specialized peel-off blister packing. 4 4. Drug and dosage form stability. 5.
Mechanical strength of final product. 6. Smooth mouth feel. 7. Rate of dissolution of drug formulation in saliva. 8. Swallowability. 9. Rate of absorption from the saliva solution. 10. Overall bioavailability. 11. To allow maximal patient acceptability. 12. Most of the Fast Dissolving Tablet technologies use sugar based excipients. 13. Sugars are pleasant tasting and are a good addition to other taste masking methods. 14. They are also highly water soluble and dissolve quickly in saliva. 15. Amount of sugars in Fast Dissolving Tablets (FDT) is much smaller than in more traditional liquid dosage forms. 6. These tablets can be used in children with poor oral hygiene or history of dental carriers. 17. Low-moisture, easy packing, handling and application. ADVANTAGES4 1. Ease of administration for patients who are mentally ill, disabled and uncooperative. 2. Requires no water intake. 3. No risk of choking. 4. Quick disintegration and dissolution of the dosage form. 5. Overcomes unacceptable taste of the drugs by taste masking. 5 6. Can be designed to leave minimal or no residue in the mouth after administration and also to provide a pleasant mouth feel. 7. Allow high drug loading. 8. Enhanced stability. . Improved patient compliance. 10. Life cycle management. 11. Ideal for both pediatric and geriatric patients. 12. Optimum versatility with low manufacturing cost. RELEASE MECHANISM3 The typical disintegration time, which is defined as the time at which the tablets begins a break when brought into contact with water is only 30-60 seconds. The dissolving time, which is defined as the time at which not less than 90% of the tested tablet is dissolved in aqueous media, is around 60 seconds. PHARMACOKINETICS5 In this consideration study has done on absorption, distribution, metabolism and excretion.
After absorption, drug attains therapeutic level and therefore elicits pharmacological effect, so both rate and extend of absorption is important. In conventional dosage form there is delay in disintegration and therefore dissolution while FDT is rapidly disintegrates in oral cavity and dissolution is fast. Due to disintegration of FDT in mouth absorption in started from mouth, pharynx and esophagus. Some factors like age, Gastrointestinal pH, blood flow through 6 gastrointestinal are taken into consideration because elderly be considered as separate unique Medicare population.
Drug disintegration depends on many factors like tissue permeability, perfusion rate binding of drug to tissue, disease state, drug interaction etc. In geriatric patients decrease in lean body mass and total body water result in decreased volume of distribution of water soluble drugs and increased volume of distribution (Vd) of lipid soluble drugs. Duration and intensity of action depends upon rate of drug removal from the body or site of action i. e. bio-transformation. Decrease in liver volume, regional blood flow to liver reduces the bio-transformation of drug through oxidation, reduction and hydrolysis.
Excretion by renal clearance is slowed, thus half life of renally excreted drugs increased. GENERAL PROPERTIES 1. Excellent mouth feel: Disintegrants has a small particle size narrow particle size distribution that imparts a smooth mouth feel to quick dissolve. Large particles tend to result in a gritty mouth feel that many consumers find objectionable. Therefore, smaller particles which are not felt in the mouth are preferred. These benefits are especially important in Fast Dissolving Tablets (FDT). 2. Taste masking6 Aspartame is used as an intense sweetening agent in pharmaceutical preparations including tablets.
It enhances flavor systems and can be used to mask 7 some unpleasant bitter taste characteristics the approximate sweetening power is 180- 200 times that of sucrose. Unlike some other intense sweeteners, aspartame is metabolized in the body and consequently has some nutritive value. 1g provides approximately 4 kcal. However, in practice the small quantity of aspartame consumed provides a minimal nutritive effect and in fast dissolving formulations are more suitable for diabetic patients also. Table. 1 Approaches have been taken to mask the unpleasant taste of drugs Sensory approaches Using flavoring and sweetening agents nhibiting bitterness Numbing of taste buds Complexation & adsorption Complexation with ion-exchange resins Formation of inclusion complexes with ?-Cyclodextrin derivatives Adsorption of drugs onto clays or other adsorbents Wax embedding of drugs Chemical approaches Formation of prodrugs Formation of different salts Barrier approaches Using viscosity modifiers Using Emulsions Using Liposomes Using Microspheres 3. Fast disintegration1 When introduced into water, disintegrant which is used in fast dissolving tablets (FDT), quickly wicks water into its capillaries and swells which results in rapid tablet disintegration.
The disintegrant particles are granular and highly porous. 8 This porous particle morphology allows for better wicking of liquid into the particle and tablet. This sugar disintegrant polymer does not form gels which could retard drug release or result in a gummy texture. 4. Tablet hardness1 To archive rapid disintegration, fast dissolve tablets (FDT) are often porous and/or have low hardness and high friability. As a result, there can be a high level of tablet breakage unless special packaging systems are used.
Therefore, the challenge is to develop formulations with rapid disintegration and robust physical properties. Due to its unique particle morphology the super disintegrant is a highly compressible material and increases tablet hardness and reduces friability. Fast dissolving delivery system comprises low moisture that is convenient for doing, suitable for labeling and easy packing, handling and application. At the same time the rapid hydration rate facilitates an almost immediate softening of the Fast Dissolving Tablet (FDT) upon application in the oral cavity. The friability nd strength of the tablet may be selected / modified to facilitate automatic rewinding, die punching and packaging during manufacturing. DIRECT COMPRESSION TECHNOLOGY7, 8 Direct compression consists of compressing tablets directly from powdered material without modifying the physical nature of the material itself. In the past years the number of medicinal substances that could be tableted without prior granulation was quite small. Today the use of special pharmaceutical excipients imparts to certain tablet formulations the required qualities for tablet production by direct compression.
The pharmaceutical industry favors manufacture of tablet dosage form by using direct 9 compression technique due to drastic reduction in process time and manpower requirement compared to wet granulation/dry granulation method. It is an obvious way to reduce production time and hence cost and to minimize the number of operations involved in the pretreatment of powder mixture before tableting. Tablet production by direct compression involves only two operations in sequence, powder mixing and tableting. As heat and water are not involved, this is one of the major advantages of direct compression.
Also the drug dissolution might be faster from a tablet prepared by direct compression, owing to fast tablet disintegration into primary drug particles. This project was carried out with an objective of switching over to direct compression. Required quantities of polymers were taken and other ingredients were added directly into the mortar and further added accurate amount of drug and mix well. This homogeneous mixture containing pure drug, polymers and other excipients were punched by single tablet punching machine having machine having hardness of about 2. 0 to 2. 5 kg/cm2 then packed in a well closed air tight container.
An advantage of this technology is tablet can easily dissolve in the medium, less friable, better hardness and low manufacturing cost. FORUMULATION TECHNIQUES Conventional Technologies4 1. Tablet moulding: By using water-soluble ingredients, moulded tablets are prepared, so that tablets dissolve rapidly & completely. Powder moist with the help of hydro alcoholic 10 solvent and then moulded into tablets under pressure less than conventional dosage form. Removal of solvent is done by air-drying. Moulded tablets posses porous structure, which facilitate easy dissolution.
Passing a powder blend through very fine screen increases dissolution rate. To increase mechanical strength sucrose, acacia or polyvinyl pyrollidone are added. Molded tablets shows poor taste masking characteristics. To overcome this drug containing spray congealing forms discrete particles. PEG, lecithin and active ingredients are congealing into lactose based tablet triturate form. 2. Spray drying By this technique dissolution rate increases as highly porous and fine particles are formed. The formulations are prepared by using hydrolyzed & nonhydrolyzed gelatin as supporting agent.
Mannitol as bulking agent, sodium strarch glycolate as disintegrating agent & acidic (citric acid) and or alkali material (NaHCo3) as dissolution and disintegration enhancer. Generally, compressed tablet disintegrated within 20 second. 3. Sublimation Low porosity prolonged dissolution, even tablets containing highly watersoluble ingredients. Inert solid ingredients that volatilize readily (urea, ammonium carbonate, ammonium bicarbonate, hexa methelene tetramine, benzene, camphor) were mixed with other ingredients and then mixture compressed into tablets. Volatile materials removed by applying sublimation which tends to porous structure. 1 4. Addition of disintegrants Addition of integrants in Fast Dissolving Tablets (FDT), leads to quick disintegration of tablets and hence improves dissolution. Microcrystalline cellulose, cross linked carboxy methylcellulose sodium, cross linked polyvinyl pyrrolidone and partially substituted hydroxypropyl cellulose, though water insoluble, absorb water and swell due to capillary action and are considered as effective disintegrants in the preparation of Fast Dissolving Tablets (FDT). Patented Technologies4,9 1. ZYDIS Technology The most advance version of Fast Dissolving Tablet (FDT) technology is Zydis technology.
The technology involves incorporation of the drug in water soluble matrix which is then transferred to the perform blister with peel able foil, as the zydis uits are not strong enough to withstand being pushed through the lidding foil of a conventional blister. Then freeze-drying is done to remove water by sublimation. Polymers generally used to form the matrix in Zydis are gelatin, dextrans or alginates. Mannitol or sorbitol may be added to impart crystallinity and hardness. Water used as medium ensures porous formation. To prevent microbial contamination preservatives may added.
Suspending & pH adjusting excipients may add. Collapse protectant such as glycine prevents the shrinkage of units. Some drawbacks of Zydis technology, like loading of water-soluble is only up to 400mg/tab. While water-soluble drug up to 60mg/tablet. Freeze drying is relative 12 expensive and time consuming. Moisture stability in long storage may create problems therefore the packs from PVC/PCDE to aluminum foil wraps over units. 2. Wove tab technology Generally low and high mold ability saccharides used. Tablets produced by this technology will have sufficient hardness and characteristic until contact with saliva.
The active ingredients may constitute up to 50% w/w of the tablets weight. 3. Flashtab Prographarm laboratories have patented the Flashtab technology. This technology involves the preparation of rapidly disintegrating tablet which consists of an active ingredient in the form of microcrystals. Drug micro granules may be prepared by using the conventional techniques like coacervation, microencapsulation, extrusion-spheronization or simple pan coating method. The micro crystals or micro granules of the active ingredient are added to the granulated mixture of excipients prepared wet or dry granulation and compressed into tablets.
All the processing utilized the conventional tableting technology and the tablets produced are reported to have good mechanical strength and disintegration time less than one minute. 4. OraSolv technology In this technology mainly excipients are used effervescence and taste masking agent and required conventional manufacturing process and equipment. OraSolv dosage form have been developed up to 100mg of load and capable of formulate multiple active ingredients in same dosage form. 13 5. DuraSolv DuraSolv is another Fast Dissolving Technology patented by CIMA labs.
The tablets made by this technology consist of a drug, fillers and a lubricant. DuraSolv tablets are prepared by using conventional tableting equipment and have good rigidity (friability less that 2%). They can be packed into conventional packaging systems like blisters, pouches or bottles. DuraSolv is an appropriate technology for products requiring low amounts of active ingredients. FUNDAMENTAL DESIGNING OF FAST DISSOLVING TABLETS (FDT) 5 For rapid dissolution of dosage, water must rapidly penetrate into the tablet matrix to cause quick disintegration & instantaneous dissolution of tablet.
Several techniques are used to achieve these fundamentals to formulate FDT; like tablet molding, freeze-drying, spray drying, sublimation and addition of disintegrating agents. The oral Fast Dissolving Tablet (FDT) are known as mouth dissolving, rapid disintegrating tablets, however the concept and function of all these forms are similar. To formulate FDT several technologies are in existence some of them reach to pharma industry. 14 Mixing of drug in aqueous solution of carrier matrix materials Filling of suspension (dosing by weight) into pockets of preformed blisters Blister stress passes through freezing tunnel
Freeze drying of the frozen units, leading to porous Zydis units Sealing of blister packs Packaging of Blister and final product release 15 REVIEW 0F FAST DISSOLVING DOSAGE FORM Hedenstrom, H. Alm, et al. 10 Intragastric pH after oral administration of single doses of Ranitidine HCl effervescent tablets, omeprazole capsules and famotidine fast-dissolving tablets to fasting healthy volunteers. The therapeutic effect of drugs inhibiting acid production on acid-related discomforts is related to both the onset and duration of action of the drug. This randomized, single-dose, 4-way crossover study included 15 healthy fasting subjects.
Effervescent Ranitidine HCl tablets 150 and 300 mg, fast-dissolving famotidine tablets 20 mg and capsules of omeprazole 20 mg were administered. Measurements of intragastric pH were performed every 4 s for 10 min prior to drug administration and during the following 4 h. The effervescent Ranitidine HCl tablets (150 or 300 mg) produced similar changes in intragastric pH: Following an immediate increase to about pH 5, intragastric pH decreased slightly over the next 10-20 min. Thereafter pH increased steadily, reaching pH 4 after 20-40 min and pH 6 after about 70 min.
After famotidine, pH 4 was reached after 80 min, significantly slower than ranitidine. After omeprazole, pH 3 was never reached. Ranitidine 150 and 300 mg showed significantly larger integrated pH responses over the 4hr observation period, compared to famotidine (P = 0. 0288 and 0. 0074) or omeprazole (P < 0. 001). After single-dose administration to healthy fasting volunteers, ranitidine effervescent tablets showed a significantly more rapid onset of action and a significantly larger integrated pH response compared to either famotidine 20 mg fast-dissolving tablets or omeprazole 20 mg capsules.
Makino et al. 11 described a method of producing a fast dissolving tablet using water as a pore forming material. A mixture containing active ingredient and 16 carbohydrates (glucose, manitol, xylitol etc) were moistened with water (1- 3 %w/w) and compressed into tablets. The water was then removed yielding highly porous tablet that exhibited excellent wetting properties. Popa G et al. 12 studied the pharmaceutical market shows lately an increasing interest in orally disintegrating tablets, due to their good acceptability among certain age categories (ex.
Elderly, children), and other patients with difficulties in swallowing classic solid dosage forms. Some of the methods of preparing such tablets have gained industrial applicability: molding, lyophilization, direct compression with highly soluble excipients, super disintegrants and / or effervescent systems. Some of the patients had a good impact on the pharmaceutical market and more improvements are expected in future years, with new drugs to be formulated as fast dissolving dosage formulations. Bi and Watanbe et al. 3 used microcrystalline cellulose (MCC) and low substituted hydroxypropyl cellulose (HPC) to manufacture rapidly disintegrating tablets. The ratios of MCC to HPC varied from 8:2 to 9:1. Ito and Sugihan investigated applying agar powder as a disintegrants because the powder absorbs water and swells considerably without forming a gel at physiological temperatures40 Fast disintegration of tablets can also be achieved by incorporating effervescent disintegrating agents, which generates carbon dioxide. This phenomenon also resulted in partial taste masking of unacceptable taste of the drug.
The major drawback of effervescent excipients is their hygroscopicity (i. e. , the ability to absorb atmospheric moisture). Hence, their manufacture requires control of humidity conditions and protection of the final product. This is reflected by the overall cost of the product. 17 Koizumi et al. 14 applied sublimation technology to manufacture tablets that rapidly dissolve in saliva34. Mannitol is used as a matrix former, and camphor was used as a sublimating agent. The tablets dissolved in 10-20 s and displayed satisfactory handling properties. Makino et al. eported a method using water as poreforming material35with a mixture of drug and a carbohydrate (e. g. , erythritol, glucose, maltitol, sucrose, xylitol). The water was then removed, yielding highly porous tablets with satisfactory mechanical strength and a high dissolution rate. Cousin et al. 15 using carboxymethyl cellulose as disintegrating agent and one swelling agent consisting of modified starch or microcrystalline cellulose formulated rapidly disintegrable multi particular tablets. The tablets disintegrate in the mouth in less than 60 seconds.
Corveleyn and Remon 16investigated the influence of various formulation and process parameters on the characteristics of rapidly disintegrating tablets in lyophilized form using hydrochlorthiazide as a model drug. They have concluded that maltodxtrins are useful in the formulation of fast dissolving tablets made by freezedrying. J. Michaelson 17 describe the use of intimate mixture of alginic acid and a water-soluble metal carbonic acid to prepare tablets. When tablet was placed in water, an acid base reaction takes place forming a metal alginic acid salt and carbonic acid.
The salt caused the tablet to swell and the carbonic acid produced carbon dioxide within the swelling tablet whereby rapid disintegration of tablet was effected. Jaccard and Leyder et al. 18 described the process in which water is sublimated from the product after freezing. Lyophilization is a pharmaceutical 18 technology which allows drying of heat sensitive drugs and biologicals at low temperature under conditions that allow removal of water by sublimation21. Lyophilization results in preparations, which are highly porous, with a very high specific surface area, which dissolve rapidly and show improved absorption and bioavailability.
They used lyophilization to create an oral pharmaceutical preparation that not only dissolve rapidly but also improved the bioavailability of several drugs such as spironolactone and trolendomycin22. Shu . T. et al. 19 carried out studies of rapidly disintegrating tablets in the oral cavity using co-ground mixtures of mannitol with crosspovidone. The tablets manufactured from a physical mixture of 30% (w/w) co-ground mixture of Dmannitol and crosspovidone (mixed ratio 9:10) with 65. 5% (w/w) of non-ground mannitol, 4% (w/w) of crosspovidone, and 0. % (w/w) of magnesium stearate had good properties for rapidly disintegrating tablets in the oral cavity. Therefore, it was presumed that crosspovidone acted as a grinding assistant for D- mannitol in the cogrinding process, enhancing the hardness of tablets by increasing the contact area among powder particles. Schermeier. S. et al. 20 formulated and developed fast dispersible ibuprofen tablets, a direct compression method was used to prepare these two types of tablet containing coated ibuprofen as a high dosed model drug.
The selected tablet formulation, containing 26% galactomannan and 5% crospovidone, disintegrates before the galactomannan starts to swell. These tablets disperse in water within 40 seconds and show a crushing strength of 95 N. to develop an orodispersible tablet; a rotatable central composite design was predicted the effects of the quantitative factors mannitol and crospovidone as well as compression force on the characteristics of the 19 tablets. Special emphasis was paid to the development of a wetting test, replacing the normal disintegration method.
An optimum tablet formulation, containing 34% mannitol and 13% crospovidone, provides a short wetting time of 17 sec and a sufficient crushing strength of 40 N. In conclusion, fast dispersible tablets with acceptable hardness and desirable taste could be prepared within the optimum region Shimizu. T. et al. 21 reported that the prepared lansoprazole fast disintegrating tablets (LFDT) were a patient-friendly formulation that rapidly disintegrated as a basic excipients. Microcrystalline cellulose, low substituted hydroxypropyl cellulose (L-HPC), and crosspovidone were used as binders and disintegrants.
The 47. 4% content of the enteric coated micro granules was selected to give sufficient tensile strength and rapid disintegration time in the mouth (NMT 30sec), and dissolution behavior in the acid stage and buffer stage were similar to current lansoprazole capsules. Abdelbary. G. et al. 22 prepared rapidly disintegrating tablet (RDT) and reported the problem of certain RDT as low physical resistance and highly friability. This work describes a new approach to prepare RDT with sufficient mechanical integrity, involving the use of a hydrophilic waxy binder (Superpolysate, PEG-6- stearate).
So it will not only act as a binder but also increases the physical resistance of tablet and will also helps in the disintegration of the tablets as it melts in the mouth and solubulises rapidly leaving no residues. A. Shirwaikar. et al. 23 reported that co-processed excipients of mannitol and microcrystalline cellulose are superior to physical mixtures of mannitol and microcrystalline cellulose used in fast dissolving tablets. Co-processed excipients were prepared by incorporating one of the excipients into the particle structure of 20 other excipients using a process such as co-drying.
Co-drying of mannitol and microcrystalline cellulose leads to the formation of excipients granulates with superior properties compared to physical mixtures of components or with individual components. These attributes improve the binding of the tablet, increase the water uptake and thereby decrease the disintegration time of tablets. Swamy, et. al. 24 reported that a combination of super disintegrants i. e sodium starch glycollate- crosscarmellose sodium or sodium starch glycollate- crospovidone were used along with directly compressible mannitol to enhance mouth feel.
Based on in vitro drug release dispersion time, two formulations were tested for in vitro drug release pattern (in pH 6. 8 phosphate buffer) short term stability and drug excipients interaction. Among the two formulations, the formulation prepared by direct compression method using 2%w/w sodium starch glycollate & 1. 5% crosscarmellose sodium was found to be better formulation based on in vitro drug release characteristics compared to conventional commercial tablet formulation. Allen et al. 25 used a spray drying technique to prepare fast dissolving tablets. The tablets made from this technology are claimed to disintegrate within 20 seconds.
Tagarro. I. et al. 26 carried out pharmacokinetic assessment of a fast release or dispersible tramadol tablet compared to a conventional tramadol capsule. This new formulation, once placed into the mouth, disintegrates rapidly in contact with the saliva. Therefore, when he saliva is swallowed, the drug reaches the gastrointestinal tract. This orally dispersible formulation, being bioequivalent to the standard capsules so far used, has the practical advantage that it can be taken without liquids. This facilitates an early treatment of emergent pain, irrespective of the place or situation where it may arise. 21 Mattsson. S. t al. 27 formulate high tensile strength rapidly disintegrating tablets and evaluated the effect of some binder properties by using different combinations of binder, compound, and a superdisintegrant with a swelling mechanism to ascertain which binder properties were important in obtaining rapidly disintegrating tablets, which also had high tensile strength. Duchene et al. 28 Rapidly dissolving capsules prepared in accordance with the present invention typically contain water-insoluble or sparingly soluble drugs in an amount of about 6 to about 600 mg of the capsule. The capsules typically contain the solubilizing agent ? , ? r ? ,-cyclodextrin or derivative thereof in an amount of from about 0. 1 to 5% of the capsule and the solubilization augmenting hydroxy-carboxylic or polycarboxylic acid in an amount of from about 0. 1 to about 5% of the capsule. The formula generally contains additives to give body to the granules, e. g. , calcium hydrogen phosphate, and Avicel™ in amounts from about 25 to about 30% and about 5 to about 10% of the capsule, respectively. Binding agents and/or wetting agents such as PEG 4000, Tween™80, sodium lauryl sulfate and PVP to granulate the powder mix are typically added to the formula in an amount of from about 0. to about 5% of the capsule. The formula typically contains disintegrants and swelling agents such as Primojel™, maize starch, and Aerosil™ in an amount of from about 1 to about 10%. The formula can contain other ingredients, such as a sweetener. In any event, the weight ratio of cyclodextrin to acid in rapidly dissolving capsule formulations will be as broadly described hereinabove, but preferably will be from about 1:5 to 5:1, and more preferably from about 3:1 to about 1:1. Bradley JU, Lawrence et al. 29 An attempt was made for preparation of fast dissolving tablets of a model bronchodilator, salbutamol sulphate with an aim of 22 educing the lag time and providing faster onset of action to relieve immediately acute asthmatic attack. This would be advantageous as conventional solid oral dosage forms are often associated with a longer lag time and thus slower onset of action, while oral liquids prove to have faster onset of action but require careful handling. Aerosol systems are specific but fail to deliver the actual dose of drug with only ten percent of administered dose deposited on the bronchi while rest of the drug is deposited in oropharynx and is swallowed.
Also, metered dose system are less potable while dry powder inhalers cause clogging of device and require skillful operation. A fast dissolving tablet form would thus be advantageous, as salbutamol sulphate is watersoluble and its preparation into a fast dissolving form would render it to dissolve rapidly and thereby result in rapid absorption without any lag time. Habib, W. , Khankari et al. 30 To overcome these drawbacks, mouth dissolving tablets (MDT) or orally disintegrating tablets (ODT), has emerged as alternative oral dosage forms. These are novel types of tablets that disintegrate/dissolve/ disperse in saliva within few seconds’.
According to European Pharmacopoeia, the ODT should disperse/disintegrate in less than three minutes. The basic approach used in development of MDT is the use of superdisintegrants like Cross linked carboxymelhylcellulose (Croscarmeliose), Sodium starch glycolate (Primogel, Explotab), Polyvinylpyrrolidone (Polyplasdone) etc. which provide instantaneous disintegration of tablet after putting on tongue, thereby releasing the drug in saliva. The bioavailability of some drugs may be increased due to absorption of drugs in oral cavity and also due to pregastric absorption of saliva containing dispersed drugs that pass down into the stomach.
Moreover, the amount of drug that is subject to first pass metabolism is reduced as compared to standard tablets. 23 Makino, T. , Yamada, M. et al. 31 Disintegrant addition technique is one popular techniques for formulating Fast-dissolving tablets . The basic principle involved in formulating Fast-dissolving tablets by disintegrant addition technique is addition of superdisintegrants in optimum concentration so as to achieve rapid disintegration along with the good mouth feel. Microcrystalline cellulose and low substituted hydroxypropylcellulose were used as disintegrating agents in the range of 8:2 – 9. to prepare fast dissolving tablet. Agar powder is used as disintegrant for the development of rapidly disintegration tablets by enhancing the porosity of agar by water treatment. Rapidly disintegrating tablets of bitter drugs oxybutynin & pirenzepine were prepared by using the taste masked granules and mixture of excipients consisting of crystalline cellulose (Avicel PH 02) and low-substituted hydroxypropy cellulose HPC, LH-11). Ishikawa et al. prepared rapidly disintegrating tablets using microcrystalline cellulose (Avicel PH-M series) that was spherical and had a very small particle size 7-32 ? , instead of conventional microcrystalline cellulose (PH 102). Tablets prepared using microcrystalline cellulose; PH-M06 and LHPC in the ratio of 9:1 were very rapidly disintegrating) in saliva. They concluded that Avicel PH-M06 was superior to Avicel PH 102 in terms of the feeling of roughness in the mouth. Fast dissolving tablets of Efavirenz (anti HIV agent) were formulated by using combination of microcrystalline cellulose and sodium starch glycolate as super disintegrant.
Gillis et al, 32 prepared a fast-dissolving tablet of Galanthamine hydrobromide which comprises of spray dried mixture of lactose monohydrate and microcrystalline cellulose (75:25) as a diluent, a cross linked polymeric disintegrant such as cross povidone and with a direct compression process of preparing such fast-dissolving tablets. Fast-dissolving tablets having analgesic activity was formulated using a 24 combination of superdisintegrants. Rapid oral disintegration tablets were developed by direct compression using co-ground mixture of D-mannitol and crospovidone.
CIMA labs patented Orasolv technology by employing the evolution of carbon dioxide or the effervescence as disintegration mechanism in the formulation of fastdissolving tablets. The OraSolv technology is an oral dosage form, which combines taste-masked drug ingredients with a quick dissolving effervescent excipient system. Taste masking is achieved through a process of microencapsulation, which coats or entraps the active compound in an immediate release matrix. The effervescent excipient system aids in rapid disintegration of the tablet, permitting swallowing of pharmaceutical ingredients before they come in contact with the taste bud.
The OraSolv tablet dissolves quickly without chewing or without water and allows for effective taste masking of a wide variety of active drug ingredients, both prescription and non-prescription. Flashtab technology™ is a patented technology of Prographarm, which employ combination of taste-masked multiparticulate active drug substances, a disintegrating agent, a swelling agent and other excipients to form a multiparticulate tablet that disintegrates rapidly. Rapidly disintegrating multiparticulate tablet was prepared by using taste-masked microcrystals of drugs, crosslinked disintegrating agent and soluble diluent with binding properties. 5 REVIEW OF RANITIDINE HCl Hedenstrom, H. Alm, et al. 10 Intragastric pH after oral administration of single doses of Ranitidine HCl effervescent tablets, omeprazole capsules and famotidine fast-dissolving tablets to fasting healthy volunteers. The therapeutic effect of drugs inhibiting acid production on acid-related discomforts is related to both the onset and duration of action of the drug. This randomized, single-dose, 4-way crossover study included 15 healthy fasting subjects. Effervescent Ranitidine HCl tablets 150 and 300 mg, fast-dissolving famotidine tablets 20 mg and capsules of omeprazole 20 mg were administered.
Measurements of intragastric pH were performed every 4 s for 10 min prior to drug administration and during the following 4 h. The effervescent Ranitidine HCl tablets (150 or 300 mg) produced similar changes in intragastric pH: Following an immediate increase to about pH 5, intragastric pH decreased slightly over the next 10-20 min. Thereafter pH increased steadily, reaching pH 4 after 20-40 min and pH 6 after about 70 min. After famotidine, pH 4 was reached after 80 min, significantly slower than ranitidine. After omeprazole, pH 3 was never reached.
Ranitidine 150 and 300 mg showed significantly larger integrated pH responses over the 4hr observation period, compared to famotidine (P = 0. 0288 and 0. 0074) or omeprazole (P < 0. 001). After single-dose administration to healthy fasting volunteers, ranitidine effervescent tablets showed a significantly more rapid onset of action and a significantly larger integrated pH response compared to either famotidine 20 mg fast-dissolving tablets or omeprazole 20 mg capsules. Deshpande AA, Rhodes et al. 47 The purpose of this research was to develop and optimize a controlled-release multiunit floating system of a highly water oluble 26 drug, ranitidine HCl, using Compritol, Gelucire 50/13, and Gelucire 43/01 as lipid carriers. Ranitidine HCl–lipid granules were prepared by the melt granulation technique and evaluated for in vitro floating and drug release. Ethyl cellulose, methylcellulose, and hydroxypropyl methylcellulose were evaluated as release rate modifiers. A 32 full factorial design was used for optimization by taking the amounts of Gelucire 43/01 (X1) and ethyl cellulose (X2) as independent variables, and the percentage drug released in 1(Q1), 5(Q5), and 10 (Q10) hours as dependent variables.
The results revealed that the moderate amount of Gelucire 43/01 and ethyl cellulose provides desired release of ranitidine hydrochloride from a floating system. Batch F4 was considered optimum since it contained less Gelucire and was more similar to the theoretically predicted dissolution profile (f2 = 62. 43). The temperature sensitivity studies for the prepared formulations at 40°C/75% relative humidity for 3 months showed no significant change in in vitro drug release pattern.
These studies indicate that the hydrophobic lipid Gelucire 43/01 can be considered an effective carrier for design of a multiunit floating drug delivery system for highly water soluble drugs such as ranitidine HCl. Watson RG, Johnston BT et al. 49 An effervescent formulation of ranitidine may be absorbed faster and achieve a faster onset of action than conventional tablet form. The aim of this study was to compare the effects of effervescent formulations of ranitidine with equivalent dose standard tablets, in terms of intragastric pH and plasma pharmacokinetics in the initial 6 h following dosing.
Fifteen fasting healthy males, aged 18-31 (mean 29) years, were each randomly given, at weekly intervals, 150 mg standard and effervescent ranitidine and 300 mg standard and effervescent ranitidine. Ambulatory gastric pH was performed and plasma drug levels measured at regular intervals. Plasma ranitidine levels increased more rapidly with both 27 effervescent formulations compared with standard tablets as indicated by mean area under curve (AUC) at 1 h (P < 0. 001). However, the pH profiles produced by all four treatments were similar with a steep rise in pH at 0-60 min to give a sustained level of pH 7 for the following 5 h. The effervescent formulations produced a transient rise in pH immediately following dosing, and for 300 mg this rise was significantly different at 10-20 min compared with the standard tablet (median pH 4. 75 vs. 2. 3, P < 0. 05). V. S. Mastiholimath, P. M. Dandagi et al. 50 The real issue in the development of oral controlled release dosage forms is not just to prolong the delivery of drugs but also to prolong the presence of dosage forms in the stomach in order to improve the bioavailability of drugs with a ‘narrow absorption window’.
In the present study, an anti-ulcer drug, ranitidine hydrochloride, is delivered through a gastroretentive ethyl cellulose-based microparticulate system capable of floating on simulated gastric fluid for>12 h. Preparation of microparticles is done by solvent evaporation technique with modification by using an ethanol co-solvent system. The formulated microspheres were free flowing with good packability and encapsulation efficiencies were up to 96%. Scanning electron microscopy confirmed porous, spherical particles in the size range 300–750 ? m. Microspheres showed excellent buoyancy and a biphasic controlled release pattern with 12 h.
In vivo bioavailability studies performed on rabbits and Tmax, Cmax, AUC were calculated and confirmed significant improvement in bioavailability. The data obtained thus suggests that a microparticulate floating delivery system can be successfully designed to give controlled drug delivery, improved oral bioavailability and many other desirable characteristics. 28 Shah NH et al. 51 The present research is based on the hypothesis that leaky enteric-coated pellets formulations are able to provide sustained input for drugs that have an absorption window, such as ranitidine hydrochloride, without jeopardizing their bioavailability.
Leaky enteric-coated pellets formulations are defined as entericcoated pellets that allow some of the drug to be released from the formulation in gastric fluid. Different approaches to making leaky enteric-coated pellets were investigated using extrusion–spheronization followed by spray coating. Leaky enteric coats were formulated using a commonly used enteric polymer, Eudragit® L 30 D-55, combined with soluble compounds including lactose, PEG 8000 and surfactants (Span 60 (hydrophobic) or Tween 80 (hydrophilic)).
The rate of drug release from the formulations in simulated gastric fluid can be tailored by varying the additive’s amount or type. All leaky enteric-coated formulations studied completely released the drugs within 30 min after changing dissolution medium to phosphate buffer, pH 6. Predictions of plasma concentration–time profiles of the model drug ranitidine hydrochloride from leaky enteric-coated pellets in fasted conditions and from immediate-release formulations were performed using computer simulations.
Simulation results are consistent with a hypothesis that leaky enteric-coated pellets formulations provide sustained input for drugs shown to have an absorption window without decreasing bioavailability. The sustained input results from the combined effects of the formulation and GI transit effects on pellets. AA, Rhodes CT, et al. 52 The purpose of this research was to develop and optimize a controlled-release multiunit floating system of a highly water soluble drug, ranitidine HCl, using Compritol, Gelucire 50/13, and Gelucire 43/01 as lipid carriers.
Ranitidine HCl–lipid granules were prepared by the melt granulation technique and evaluated for in vitro floating and drug release. Ethyl cellulose, methylcellulose, and 29 hydroxypropyl methylcellulose were evaluated as release rate modifiers. A 32 full factorial design was used for optimization by taking the amounts of Gelucire 43/01 (X1) and ethyl cellulose (X2) as independent variables, and the percentage drug released in 1(Q1), 5(Q5), and 10 (Q10) hours as dependent variables. The results revealed that the moderate amount of Gelucire 43/01 and ethyl cellulose provides desired release of ranitidine hydrochloride from a floating system.
Batch F4 was considered optimum since it contained less Gelucire and was more similar to the theoretically predicted dissolution profile (f2 = 62. 43). The temperature sensitivity studies for the prepared formulations at 40°C/75% relative humidity for 3 months showed no significant change in in vitro drug release pattern. These studies indicate that the hydrophobic lipid Gelucire 43/01 can be considered an effective carrier for design of a multiunit floating drug delivery system for highly water soluble drugs such as ranitidine HCl. Lederer, P. C. et al. 3 The present invention provides an osmotic device containing controlled release ranitidine in the core in combination with a prokinetic agent in a rapid release external coat. A wide range of prokinetic agents can be used in this device. Particular embodiments of the invention provide osmotic devices having predetermined release profiles. One embodiment of the osmotic device includes an external coat that has been spray coated rather compression coated onto the device. The device with spray-coated external core is smaller and easier to swallow than the similar device having a compression-coated external coat.
The device is useful for the treatment of gastric acid related disorders. The device can be tailored for once or twice daily administration. The amounts of ranitidine and prokinetic agent can be varied. One embodiment provides two different charges of 30 ranitidine (one rapid release and the other controlled release) and a rapid release charge of prokinetic agent. Somade S, Singh K et al. 54 The purpose of this research was to prepare a gastroretentive drug delivery system of ranitidine hydrochloride. Guar gum, xanthan gum, and hydroxypropyl methylcellulose were evaluated for gel-forming properties.
Sodium bicarbonate was incorporated as a gas-generating agent. The effects of citric acid and stearic acid on drug release profile and floating properties were investigated. The addition of stearic acid reduces the drug dissolution due to its hydrophobic nature. A 32 full factorial design was applied to systemically optimize the drug release profile. The amounts of citric acid anhydrous (X1) and stearic acid (X2) were selected as independent variables. The times required for 50% (t50) and 80% drug dissolution (t80), and the similarity factor f2 were selected as dependent variables.
The results of the full factorial design indicated that a low amount of citric acid and a high amount of stearic acid favors sustained release of ranitidine hydrochloride from a gastroretentive formulation. A theoretical dissolution profile was generated using pharmacokinetic parameters of ranitidine hydrochloride. The similarity factor f2 was applied between the factorial design batches and the theoretical dissolution profile. No significant difference was observed between the desired release profile and batches F2, F3, F6, and F9.
Batch F9 showed the highest f2 (f2=75) among all the batches, and this similarity is also reflected in t50 ( 214 minutes) and t80 ( 537 minutes) values. These studies indicate that the proper balance between a release rate enhancer and a release rate retardant can produce a drug dissolution profile similar to a theoretical dissolution profile. 31 AIM OF THE WORK Ranitidine HCl is a H2-receptor antagonist. Ranitidine HCL is used orally for the treatment of active duodenal or gastric ulcer, gastroesophageal reflux disease, endoscopically diagnosed erosive esophagitis and as maintenance therapy for duodenal ulcer.
It may be used to treat severe irritation of the esophagus (erosive esophagitis) and to maintain healing of erosive esophagitis. It may be used for shortterm treatment of stomach or small intestinal ulcers. It may be used to treat conditions that cause our body to make too much stomach acid (eg, Zollinger-Ellison syndrome). Oral Ranitidine HCl also is used for the management of pathological GI hypersecretory conditions. Ranitidine HCl is used in hospitalized individuals with pathological GI hypersecretory conditions or intractable ulcers, or when oral therapy is not feasible. The plasma half –life following a single oral dose is 2. -4 hrs. The success of therapy depends on selection of appropriate delivery system as much as it depends on the drug itself. It works by blocking the action of histamine in the stomach. This reduces the amount of acid the stomach makes. Reducing stomach acid helps to reduce heartburn, heal irritation of the esophagus, and heal ulcers of the stomach or intestines. Ranitidine HCl is available as tablets. The dose of 150-300mg is required and it can be seen that this dosage form has several draw backs as inconvenient dosing, risk of chocking, bitter taste, difficulty to swallow for both pediatric and geriatric patients. 2 Hence a unique attempt has made to design and evaluate the Fast Dissolving Tablets (FDT) of Ranitidine HCl using various polymers and super disintegrants with the following objectives. 1. Convenient dosage 2. No water needed 3. No risk of chocking 4. Masked bitter taste 5. Fast disintegration 6. Quick dissolving 7. Rapid release 8. Improved patient compliance 9. Optimum versatility with low manufacturing costs 10. Efficient life cycle management 11. Bioavailability of drug is significantly greater than those observed from conventional tablet dosage from like oral tablets, gels and ointment. 12.
Reduces the first pass metabolism. 33 PLAN OF WORK The present work was carried out to formulate and evaluate rantidine fast dissolving tablets (FDT), using different polymers and super disintegrants in various proportion. This work is carried out as outlined below, 1. Masking bitter taste of drug. 2. Preparation of fast dissolving tablets by direct compression method. 3. Evaluation of fast dissolving tablets (FDT) for the following physiochemical parameters. ? Hardness ? Thickness & diameter ? Friability test ? Wetting time ? Water absorption ratio ? Weight variation test ? Drug content uniformity 4.
In vitro studies ? In vitro dispersion time ? In vitro dissolution time ? Comparative drug release studies with marketed sample 34 MATERIALS AND INSTRUMENTS USED MATERIALS 1. Drug: ? Ranitidine Hydrochloride (Drugs India, Hyderabad ) 2. Polymers: ? Crosspovidone NF (Microlabs,Hosur), ? ? -Cyclodextrin (Microlabs,Hosur) 3. Other materials ? Mannitol DC(Microlabs,Hosur) ? Talc(SD fine chemicals,Boisar) ? Aspartame(Microlabs,Hosur) ? Mango flavour(Microlabs,Hosur) ? Magnesium stearate(Microlabs,Hosur) ? Sodium hydroxide IP(SD fine chemicals,Boisar) ? Potassium dihydrogen phosphate IP(SD fine chemicals,Boisar) ?
Hydrochloric acid(SD fine chemicals,Boisar) ? Ehanol IP (SD fine chemicals,Boisar) ? Distilled water 35 INSTRUMENTS 1. Agilent Ultra Violet – Visible Spectrometer 2. Digital Balance 3. Single Punch Tablet punching machine 4. Dissolution apparatus USPXXI paddle (LAB INDIA DISCO 2000) Other instruments 1. Monsanto tablet hardness tester 2. Screw gauge (Thickness tester) 3. Roche friabilator 36 DRUG PROFILE 34 Drug : Ranitidine hydrochloride Chemical structure Chemical name: N[2-[[[5-[(dimethylamino)methyl]-2-furanyl] methyl] thio] ethyl] – N’-methyl-2-nitro-1,1 -ethenediamine, HCl.
Empirical formula : C13H22N4O3S•HCl Molecular weight : 350. 87 Melting point : 140°C Physical state : white to pale yellow ,granular substance Solubility : Ranitidine HCl is freely soluble in water, methanol and ethanol (95%) very slightly soluble in chloroform, dichloromethane. Category : Histamine H2-receptor antagonist Mechanism of action Histamine is a natural chemical substance that stimulates the stomach cells to produce acid. Rantidine HCl belongs to the class of medications, called H2-blockers, 37 that blocks the action of histamine on stomach cells, thus reducing stomach acid production.
Pharmacokinetics Absorption: Ranitidine HCl is 50% absorbed after oral administration, compared to an intravenous (IV) injection with mean peak levels of 440 to 545 ng/mL occurring 2 to 3 hours after a 150-mg dose. Absorption is not significantly impaired by the administration of food or antacids. Propantheline slightly delays and increases peak blood levels of Rantidine HCl, probably by delaying gastric emptying and transit time. In one study, simultaneous administration of high-potency antacid (150 mmol) in fasting subjects has been reported to decrease the absorption of Ranitidine HCl.
Distribution: The volume of distribution is about 1. 4 L/kg. Serum protein binding averages 15%. Metabolism: In humans, the N-oxide is the principal metabolite in the urine; however, this amounts to 1000000 5. Structural Formula 6. Functional category: Tablet disintegrant 7. Applications 40 ? Stabilizers for beer, vinegar, fruit and wine, prolonging the storage life. Disintegrants and fillers in pharmaceutical tablets and capsules. ? Detoxicants in detoxifiers or toxin absorbents. ? Stabilizers for moisture sensitive active ingredients(e. G. Vitamins, enzymes). 8. Description:
Crosspovidone is the crosspolymer of Polyvinylpyrrolidone, which also called as polyvinylpolypyrrolidone or PVPP. It complies to USP/BP standand. 9. Typical Properties Table. 2 Acidity/alkalinity pH=5. 0-8. 0(1%w/v aqueous slurry) Density 1. 22g/cm2 Moisture content Maximum moisture sorption is approximately 60% Particle size distribution Less than 400 ? m for polyplasdone xl less than polyplasdone xl-10. approximately 50% greater than 50 ? m and maximum of 3% greater than 250 ? m in size for kollidon CL minimum of 90% of particles are below 15 ? m for kollidon CL-M
Solubility Practically insoluble in water and most common organic solvents 10. Stability and storage conditions Since crospovidone is hygroscopic, it should be stored in airtight containers in a cool dry place. 11. Safety 41 Crospovidone is used in oral pharmaceutical formulations and is generally regarded as a nontoxic and nonirritant material. Short-term animal toxicity studies have shown no adverse effects associated with crospovidone however owing to the lack available data acceptability daily in take in human has been specified by the WHO. ? – CYCLODEXTRINS36 1. Non proprietary name ? BP : betadex USPNF : betadext 2. Synonym ?-cycloamylose; dextrinsloamylose; ? -dextrin; cavamax W7 Pharma; cycloheptaamylose kleptose; 3. Chemical name and CAS Registry number: ? -cyclodextrin [7585-39-9] 4. Empirical formula and molecular formula: ? -cyclodextrin C56H98O35 = 1135 5. Structural formula 42 Note the structure of beta cyclodextrin is shown R’,R” = H for natural ? -,? -and ? -cyclodextrin R’,R” = CH3 for methyl cyclo dextrin R’,R” = CHOHCH3 for 2-hydroxy ethyl cyclodextrin R’,R” = CH2CHOHCH3 for 2- hydroxyl propyl cyclodextrin 6. Functional category Solubilizing agent, stabilizing agent. . Applications ?- cyclodextrin is the most commonly used cyclo dextrin although it is least soluble. It is least expensive cyclodextrin; it is commercially available from a number of sources and it is able to form inclusion complexes with a number of complexes with a number of molecules of pharmaceutical interest. However, ? -cyclodextrin is nephrotoxic and should not be used in parental formulation. In parental formulation, cyclodextrin have been used to produce stable and soluble preparation of drug that would other wise have been formulated using a aqueous solvent.
In eye drop formulation, cyclodextrin forms water soluble complexes with lipophilic drugs such as corticosteroids. They have been shown to increase the water solubility of the drug to enhance drug absorption into the eye, to improve aqueous stability and to reduce local irritation. Cyclodextrin have been used in the formulation of solutions suppositories and cosmetics. 43 8. Description Cyclodextrin occurs as white, practically odorless, fine crystalline powder, having slightly sweet taste. Some cyclodextrin derivatives occur as amorphous powder. 9. Typical properties Table-3 Compressibility 21. 0-44. 0% for ,? -cyclodextrin
Density (bulk) 0. 523g/cm3 Density ( tapped) 0. 754g/cm3 Melting point 255-265°c Moisture content 13. 0-15. 0%w/w Particle size distribution 7. 0-45. 0? m 10. Physical characteristics Table-4 Characteristics ? -Cyclodextrin Cavity diameter (A) 6. 0-6. 5 Height of tour(A) 7. 9 Diameter of periphery(A) 15. 4 Approximate volume of cavity(A) 262 Approximate cavity volume (A) – Per mol cyclo dextrin(ml) 157 Per g cyclodextrine(ml) 0. 14 44 10. Solubility ? –cyclodextrin is soluble 1 in 200 parts of propylene glycol, 1 in 50 parts of water at 20°c, 1in 20 at 50°c, practically insoluble in acetone, ethanol and methylene chloride. 1. Surface tension: ? -cyclodextrin : 71 dynes/cm 12. Stability and storage conditions ?-cyclodextrin and other cyclodextrins are stable in the solid state if protected from high humidity. Cyclodextrin should be stored in tightly sealed containers in a cool, dry place. 13. Incompatibility The activity of some antibacterial preservative in aqueous solution can be reduced in the presence of hydroxypropyl ? -cyclodextrin. 14. Safety Cyclodextrins are starch derivatives and are mainly used in oral and parental formulations. They are also used in topical and ophthalmic formulations.
Cyclodextrin is also used in cosmetics and food products and is generally regarded as essentially nontoxic and non irritant material; however when administered parenteraly, ? -cyclodextrin is not metabolized but accumulates in the kidney as insoluble cholesterol complexes resulting in sever nephrotoxicity. Other cyclodextrins such as 2-hydroxypropyl ? -cyclodextrins, have been the subject of extensive toxicological studies. They are not associated with nephrotoxicity and are reported to be safe for use in parental formulation. 45 CONSTRUCTION OF STANDARD CURVE OF RANITIDINE HYDROCHLORIDE
Method of preparation of Sorenson’s buffer pH 6. 2 37, 38, 39 1. Preparation of primary solution (potassium phosphate solution) 9. 078g of monobasic potassium phosphate was weighed and dissolved in small quantity of distilled water and the volume was made up to liter with distilled water. 2. Preparation of secondary solution (sodium phosphate solution) 11. 876gm of dibasic sodium phosphate was weighed and dissolved in small quantity of distilled water. The above solution primary and secondary were mixed in the ratio of 2:8 to get Sorenson’s phosphate buffer and the pH was checked and adjusted to 6. 2. 3.
Preparation of 0. 2M sodium hydroxide solution 8gm of sodium hydroxide was dissolved in distilled water and made up to 1000ml with distilled water. 2. Procedure 40 100mg ranitidine HCl was accurately was weighed and dissolved in a small portion of NaOH in a volumetric flask and then the volume was made up to 100ml Sorenson’s phosphate buffer(pH 6. 2). This is the primary stock solution. From the primary stock solution, 1ml was accurately pipetted out and transferred into a 100ml 46 volumetric flask. Then the volume was made up to 100ml with Sorenson’s buffer . From the stock solution, aliquots equivalent to 10 ? , 20 ? g, 30 ? g, 40 ? g, 50 ? g, 60 ? g, 70 ? g, 80 ? g, 90 ? g, 100 ? g (1ml, 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml, 10ml) were pipetted out into a series of 10ml volumetric flasks and the final volume was made up to 10ml with Sorenson’s buffer. The absorbances of above solutions were measured against Sorenson’s buffer as blank at 285 nm. Then a calibration curve was plotted taking concentration on x-axis and absorbance on y-axis. Table . 5 Standard curve for Ranitidine HCl using Sorenson’s buffer pH 6. 2 Concentration (? g/ml) Absorbance 10 0. 012 20 0. 038 30 0. 045 40 0. 047 50 0. 059 60 0. 071 70 0. 077 0 0. 082 90 0. 120 100 0. 120 47 PREPARATION OF RANITIDINE HCl FAST DISSOLVING TABLETS Fast dissolving tablets were prepared using the following carriers: a) Crospovidone b) ? -cyclodextrin The fast dissolving tablets (FDT) with the above polymer in different proportions of 5%,10% Direct compression method 8,12,40 Accurate amount of polymer was taken in a dry and clean mortar in different proportions separately (5% 10%) as shown in the table. To this weighed amount of Ranitidine Hydrochloride (150mg) was added along with mannitol (DC), aspartame and flavour. Finally, add magnesium stearate and talc and mix well.
The dry blend was compressed into tablets in a single punch tablets at 30 PCI. The tablets were evaluated for hardness, thickness &diameter, friability, wetting time, water absorption ratio, weight variation test and drug content uniformity. Table. 6 Composition of Fast Dissolving Tablets of Ranitidine HCl Batch code Drug in mg Cros povidine in mg ?- cyclodextrin in mg Mannitol in mg Talc In mg Aspartame in mg Flavour in mg Mg. stearate in mg CP-5 150 25 – 275 5 15 20 10 CP-10 150 50 – 250 5 15 20 10 BD-5 150 – 25 275 5 15 20 10 BD-10 150 – 50 250 5 15 20 10 48 EVALUTION OF PHYSICO CHEMICAL PROPERTIES 1. HARDNESS TEST 7,41
Tablet requires a certain amount of strength or hardness ad resistance to friability to withstand mechanical shocks of handling in manufacture and packaging and shipping. The device used for measuring the hardness of the tablets is Monsanto hardness tester. Method Three tablets were taken from each batch and tested for hardness using Monsanto hardness tester. Table. 7 s/no Batch code Average hardness of tablets in kg/cm2 Standard deviation(±) 1 CP-5 2. 8 ± 0. 28 2 CP-10 2. 5 ± 0. 50 3 BD-5 2. 9 ± 0. 11 4 BD-10 2. 7 ± 0. 25 2. THICKNESS AND DIAMETER 41 Thickness and diameter of the tablet was carried out using a screw guage. 49
Table-8 s/no Batch code Thickness Diameter Average thickness in (mm) Standard deviation (±) Average diameter in (mm) Standard deviation (±) 1 CP-5 0. 33 0. 01 3. 15 ± 0. 05 2 CP-10 0. 32 0. 01 3. 20 ± 0. 20 3 BD-5 0. 40 0. 01 3. 10 ± 0. 05 4 BD-10 0. 35 0. 02 3. 10 ± 0. 05 3. FRIABILITY TEST 7,41 20 tablets were given in the combined effects of abrasion and shock by utilizing a plastic chamber that revolves at 25 rpm, dropping the tablets a distance of 6 inches with each revolution. Method 20 tablets were weighed and placed in the friabilator operated for 100 revolutions, dusted and weighed. Table-9 s/no Batch code Initial weight of 0 tablets (gm) Final weight 20 tablets in (gm) Weight variation (gm) Friability loss % Result 1 CP-5 4. 94 4. 85 0. 09 1 Pass 2 CP-10 4. 82 4. 79 0. 03 0. 62 Pass 3 BD-5 5. 10 5. 00 0. 10 1 Pass 4 BD-10 4. 90 4. 87 0. 03 0. 6 Pass 50 4. WETTING TIME 18 A piece of tissue paper folded twice was placed in a small Petri dish (ID=6. 5cm) containing 6ml of stimulated saliva pH, a tablet was put on the paper, and time for complete wetting was measured. Three trials for each batch were performed and standard deviation was also determined. Table-10 s/no Batch code Average wetting time in seconds Standard deviation (±) 1 CP-5 250 ± 3. 4 CP-10 180 ± 2. 0 3 BD-5 300 ± 3. 8 4 BD-10 240 ± 3. 6 5. WATER ABSORPTION RATIO 42 A piece of tissue paper was placed in small Petri dish containing 6ml of water. A tablet was put on the paper and the time required for complete wetting was measured. The wetted tablet was then weighed. Water absorption ratio was determined using following equation, Where ? Wa is weighed of tablet after water absorption ? Wb is weighed of tablet before water absorption. Wa-Wb R=10 ? Wb 51 Table-11 S/NO Batch code Average water absorption ratio in mg(before wetting) Average water absorption ratio in mg(after wetting) Mean Standard deviation Mean
Standard deviation 1 CP-5 490 ± 3 510 ± 5 2 CP-10 480 ± 2 490 ± 3 3 BD-5 490 ± 4 500 ± 6 4 BD-10 490 ± 5 500 ± 7 6. WEIGHT VARIATION TEST43 Twenty tablets were selected at random, individually weighed and the average was calculated. The uniformity of weight was determined according to IP specification. As per IP not more than two of individual weight should deviate from average weight by more than 7. 5% and none deviate more than twice that percentage (15%). 52 Table. 12 Batch code CP-5 Tablet no Weight of individual tablet(mg) Average(mg) %deviation No. of tablets showing % deviation more than allowed 1 500 495 1 Nil 2 500 1 3 500 1 500 1 5 500 1 6 500 1 7 500 1 8 500 1 9 500 1 10 500 1 11 500 1 12 490 1. 02 13 490 1. 02 14 490 1. 02 15 490 1. 02 16 490 1. 02 17 490 1. 02 18 490 1. 02 19 490 1. 02 20 490 1. 02 53 Table. 13 Batch code CP-10 Tablet no Weight of individual tablet(mg) Average(mg) %deviation No. of tablets showing % deviation more than allowed 1 500 497 0. 6 Nil 2 490 1. 4 3 500 0. 6 4 500 0. 6 5 500 0. 6 6 500 0. 6 7 500 0. 6 8 500 0. 6 9 500 0. 6 10 500 0. 6 11 480 3. 5 12 480 3. 5 13 500 0. 6 14 510 2. 5 15 490 1. 4 16 490 1. 4 17 490 1. 4 18 510 2. 5 19 510 2. 5 20 490 1. 4 54 Table. 14 Batch code BD-5 Tablet no Weight of individual tablet (mg)
Average (mg) %deviation No. of tablets showing % deviation more than allowed 1 500 472. 5 5. 5 Nil 2 500 5. 5 3 500 5. 5 4 500 5. 5 5 490 3. 5 6 490 3. 5 7 490 3. 5 8 490 5. 5 9 500 5. 5 10 500 5. 5 11 500 5. 5 12 500 5. 5 13 500 5. 5 14 500 5. 5 15 500 5. 5 16 510 7. 3 17 500 5. 5 18 500 5. 5 19 480 1. 5 20 490 3. 5 55 Table. 15 Batch code BD-10 Tablet no Weight of individual tablet(mg) Average(mg) %deviation No. of tablets showing % deviation more than allowed 1 500 468. 5 6. 3 Nil 2 500 6. 3 3 490 4. 3 4 490 4. 3 5 490 4. 3 6 490 4. 3 7 500 6. 3 8 500 6. 3 9 500 6. 3 10 480 2. 3 11 510 8. 1 12 480 2. 3 13 480 2. 3 14 490 4. 3 5 500 6. 3 16 500 6. 3 17 510 8. 1 18 480 2. 3 19 490 4. 3 20 490 4. 3 56 7. DRUG CONTENT UNIFORMITY 43 Ten tablets were weighed and taken in the mortar and crushed to powder. A quantity of powder weighing equivalent to 150mg of Ranitidine HCl hydrochloride was taken in 100ml volumetric flask and 0. 1N NaOH was added. It was then heated at 60? c for 30 minutes. Then 10ml of the solution was transferred to a 100ml standard flask and made up to 100ml with 0. 1N NaOH. From this, 1ml of this solution was transferred to a 10ml standard flask and made up to 10ml with 0. 1NaOH. Then the solution was filtered using membrane filter 0. 5? m and then the solution’s absorbance was measured at 285nm. Then the amount of the drug was calculated using standard graph. Table. 16 Data for drug content uniformity s/no Batch code Drug content in mg % of drug content No/of tablets out side 90%-110% limit 1 CP-5 150 100. 0 Nil 2 CP10 170 110. 0 3 BD-5 170 110. 0 4 BD-10 160 106. 6 57 INVITRO DRUG RELEASE STUDIES 1. IN VITRO DISPERSION TIME 44,45 In vitro dispersion time was measured by dropping a tablet in a measuring cylinder containing 6ml of pH 6. 2 (stimulated saliva fluid). The time for the tablet to completely disintegrate into fine particles was noted.
Three tablets from each formulation were randomly selected and in vitro dispersion time was performed. Table. 17 Data for in vitro dispersion time S. No Batch code In vitro dispersion time Mean & SD % Drug release 1 CP-5 49 ± 0. 17 92. 09 2 CP10 46 ± 0. 15 95. 86 3 BD-5 58 ± 0. 20 88. 27 4 BD-10 62 ± 0. 21 84. 54 58 2. IN VITRO DISSOLUTION STUDY45,46 Dissolution apparatus II USP XXI model was used for carried out in- vitro drug release studies on the prepared batches of tablets. 650ml of Sorenson’s buffer solution (pH 6. 2) was used. The tablet kept in the bowel and the paddle was rotated at 50rpm.
The temperature of the dissolution fluid was maintained at 37 ? c ± 0. 5 ? C. Analysis of samples 1ml of the sample was drawn at periodic intervals 1st, 2 nd, 4th, 6th, 8th, 10th minutes and it was made up to 10ml with Sorenson’s buffer solution. 1ml of fresh dissolution medium was replaced after each time. The samples were analyzed spectrophotometrically at 285nm for the drug content against the respective buffer blank. The mean percentage of Ranitidine hydrochloride released at various time intervals was calculated and plotted against time. Table. 18 In vitro drug release for data for batch CP-5 Time (min) Absorbance concentration ? g/ml) Cumulative amount of drug release (mg ) % cumulative amount of drug release 1 0. 016 12. 51 81. 37 54. 25 2 0. 018 14. 24 92. 69 61. 79 4 0. 020 15. 96 104. 02 69. 34 6 0. 023 18. 54 120. 96 80. 64 8 0. 025 20. 26 132. 34 88. 22 10 0. 026 21. 12 138. 13 92. 09 59 Table. 19 In vitro drug release for data for batch CP-10 Time (min) Absorbance concentration (? g/ml) Cumulative amount of drug release (mg ) % cumulative amount of drug release 1 0. 015 11. 65 75. 78 50. 52 2 0. 020 15. 96 103. 87 69. 24 4 0. 023 18. 54 120. 81 80. 54 6 0. 025 20. 26 132. 19 88. 12 8 0. 026 21. 12 137. 98 91. 99 10 0. 027 21. 98 143. 79 95. 86
Table. 20 In vitro drug release for data for batch BD-5 Time (min) Absorbance concentration (? g/ml) Cumulative amount of drug release (mg ) % cumulative amount of drug release 1 0. 012 9. 07 58. 99 39. 33 2 0. 014 10. 79 70. 27 46. 85 4 0. 018 14. 24 92. 76 61. 84 6 0. 020 15. 96 104. 09 69. 39 8 0. 023 18. 54 121. 04 80. 69 10 0. 025 20. 26 132. 41 88. 27 60 Table. 21 In vitro drug release for data for batch BD-10 Time (min) Absorbance concentration (? g/ml) Cumulative amount of drug release (mg ) % cumulative amount of drug release 1 0. 011 8. 21 53. 40 35. 60 2 0. 012 9. 07 59. 08 39. 38 4 0. 016 12. 51 81. 55 54. 36 6 0. 23 18. 54 120. 83 80. 55 8 0. 024 19. 40 126. 61 84. 41 10 0. 024 19. 40 126. 81 84. 54 61 COMPARATIVE DRUG RELEASE STUDIES OF THE PREPARED FAST DISSOLVING TABLETS WITH COMMERCIALLY AVAILABLE RANITIDINE HCL TABLETS To compare drug release studies of the prepared fast dissolving tablets with commercially available Zinetac tablets was selected as a choice and carried out dissolution studies. Here 1ml sample is withdrawn periodically and proceeded for the previous mentioned standard analysis the results of the in vitro drug release studies was given in the following tables Table No. 22 In vitro drug release data for marketed sample
Time(min) Absorbance concentration (? g/ml) Cumulative amount of drug release (mg ) % cumulative amount of drug release 1 0. 011 8. 21 53. 40 35. 60 2 0. 013 9. 93 64. 67 43. 11 4 0. 014 10. 79 70. 36 46. 91 6 0. 016 12. 51 81. 66 54. 44 8 0. 022 17. 68 115. 35 76. 90 10 0. 023 18. 54 121. 13 80. 75 62 RESULTS AND DISSCUSSION: The aim of the present work is to prepare Fast Dissolving Tablets (FDT) of Ranitidine HCl. The Fast Dissolving Tablets (FDT) was prepared by using various polymers like crospovidone and ? -cyclodextrin. For the preparation of FDT tablets, accurate amount of polymer was taken in lean mortar in different proportions separately (5%, 10%). To this, weighed amount of Ranitidine HCl (150mg) was added along with mannitol (DC), aspartame, flavour. Finally, talc and magnesium stearate was added and mixed well. The dry blend was compressed in to tablets in a single punch tablet machine. The tablets were evaluated for hardness, thickness and diameter, friability, wetting time, water absorption ratio, weight variation test, drug content uniformity and dissolution studies. a) Hardness: The prepared tablets in all formulations possess good mechanical strength with sufficient hardness.
Hardness of tablets was found to increase with increase polymer concentration (Ref table-7) .b) Thickness and diameter: The thickness and diameter of tablets was found to be in the range of 0. 3mm to 0. 35mm and 3. 1mm to 3. 2mm respectively (Ref table-8) 63 c) Friability: The friability loss of tablet was found to be 0. 6 to 1% examined by Roche friabilator all the batches of tablets passed the test and are with in the limits. It indicated that the tablets were mechanically stable. (Ref table-9) d) Wetting time: Wetting time corresponds to the time taken foe the tablet to disintegrate when kept motionless on the tissue paper in a Petri dish.
The values of wetting time were shown in the Ref. Table – 10, Fig. No. 2. The range of wetting time is 180 – 300 sec. The wetting time with saliva preparation was found to be very fast and has the capacity to absorb buffer in the order of CP-10 < BD-10 < CP-5 < BD-5. e) Water absorption ratio: Water absorption ratio is an important criteria for understanding the capacity of tablets to swell in presence of little amount of (6ml) simulated saliva pH-6. 2 buffer. It was in the range 450 – 510mg (Ref table-11). f) Weight variation test: All the batches of tablets were found to pass the weight variation test.
The percentage of deviation of individual tablet weights from the average tablet weight was found to be with in the I. P limits ± 7. 5% (Ref. Table- 12,13,14,15. ) 64 g) Drug content uniformity: The drug content uniformity was examined as per I. P specification. All the batches of tablets were found to comply with uniformity of drug content test. None of the individual drug content was out side the limits 90% to 110% (Ref. Table-16). INVITRO DISPERSION TIME In vitro dispersion was absorbed in the range of 46-62 seconds for all the formulations.
Formulation containing crospovidone have lower dispersion time 46- 49sec while formulations with cyclodextrin have dispersion time of 58-62 seconds. Results indicate that rapid disintegration was seen in CP-5 and CP-10 (49 & 46sec. respectively). Delayed disintegration was observed in BD-5, BD-10 (58 & 62 sec. respectively) (Ref. Table No. 17, Fig. 3) IN VITRO DISSOLUTION STUDY Dissolution apparatus II USP XXI model was used to carry out in vitro drug release studies on the prepared batches of tablets. 650 ml of Sorenson’s buffer solution (pH 6. 2) was used. The tablet was kept in bowel and the paddle was rotated at 50 rpm.
The temperature was maintained at 37°C ± 0. 5°C. Analysis of samples 1ml of sample was drawn at periodic intervals 1st, 2nd, 4th, 6th, 8th, 10th minutes and it was made up to 10ml with Sorenson’s buffer. 1ml of fresh dissolution medium was replaced after each time the sample was drawn. The samples were analyzed at 65 285nm spectrophotometrically. The mean percentage of Ranitidine HCl released at various time intervals was calculated and plotted against time. Batches CP-5 & CP-10 Formulations CP-5 & CP-10 releases 138. 13mg, 92. 09% and 143. 79mg, 95. 86% of drug respectively. This is due to the presence of super disintegrant, rospovidone (Ref. Table-18, 19, Fig No. 4, 5) Batches BD-5 & BD-10 Formulations BD-5 & BD-10 releases the drug 132. 41mg, 88. 27% and 126. 81mg, 84. 54% respectively at the end of 10 minutes (Ref. Table-20, 21, Fig. No. 5, 6) From the results obtained, it was observed that drug-CP complexes disintegrate quickly, soluble in water and make drug available for absorption. 66 CONCLUSION In the present work, efforts have been made to prepare and evaluate Fast Dissolving Tablets of Ranitidine HCl using various polymers associated with increased in the overall cumulative drug release.
Release profile of CP-10 having Crospovidone 10%, prepared by using mannitol (DC), talc, aspartame, flavor was found to have maximum release of 143. 79mg, 95. 86% of drug at the end of 10 minutes. The super disintegrants were also found to be compatible with the other excipients of the formulation as well as with drug, which is evident from the drug content values. Comparative drug release study revealed that the formulated Fast Dissolving Tablets (FDT) have more rapid drug release effect than the marketed (Ref. Table-22, Fig. 9).