Challenges in development of orally disintegrating and dispersible tablets
IntroductionCONTENTS Advantages over conventional tablet dosage forms Challenges in formulation and development Materials required Mechanism of drug release Formulation techniques Conventional methods Patented technologies Marketed products Evaluation tests Future developments Conclusion References
INTRODUCTION Definitions of ODTs: According to US FDA: “A solid dosage form containing medicinal substance, which disintegrates rapidly usually within a matter of seconds, when placed upon the tongue”. According to European pharmacopoeia: “A tablet that is to be placed in the mouth where it disperses rapidly before swallowing”.
Terminologies for ODTs also known asRapidly dissolving tablets are Melt in Mouth tablets Mouth dissolving tablets (MDT) Fast disintegrating tablets (FDT) Orally disintegrating tablets Rapid disintegrating tablets (RDT) Oro dispersible tablets (ODT) Quick dissolving tablets.
Advantages over the conventional dosage form No risk of choking. Requires no water intake. Overcomes unacceptable taste of the Drugs. Quick disintegration and dissolution of the dosage form. Facilitates faster onset of therapeutic action. Improved bioavailability can be achieved. Avoids First Pass Metabolism due to pregastric absorption. Ideal dosage form for Peadiatric and geriatric patients. Ease of administration for patients who are mentally ill, disabled and un co-operative.
Challenges in the product design, formulation andmanufacture of ODTs.PalatabilityMechanical strengthAmount of drugSize of tabletHygroscopicityAqueous solubilityShort half-lifeCost of the tablet
PALATABILITY As most of the drugs are unpalatable, orally disintegrating drug deliverysystems usually contain the medicament in a taste masked form. Delivery systems disintegrate or dissolve in patient’s oral cavity, thusreleasing the active ingredients which come in contact with the taste buds;hence taste masking of drugs become critical to patient compliance.
General taste masking technologies in oral solid dosage forms:1. Taste masking with hydrophilic vehicleHydrophilic vehicles- carbohydrates, proteins, gelatin, ZeoliteIon Exchange resins- Indion 204, 214, 224, 234CyclodextrinsFlavors, sweeteners, amino acids.2. Taste masking with lipophilic vehicleEx: fats, fatty acids.3. Miscellaneous masking agentsEx: Effervescent agents, Rheological modifications, salt preparations, solid dispersions etc.
Detection threshold of sensors compared to Human receptors Pharmaceutical taste assessment requires human test panel that increases time and money to the development process. During the last decade, amultisensor system and a device for the liquid analysis that can be collected under the term “Electronic tongue” was developed. Taste Taste basic Human tongue Electronic substance tongue Sweetness Sucrose 1x10-2 2x10-6 Bitterness Caffeine 0.7x10-3 1x10-6 Sourness HCl 9x10-4 5x10-6
The active moiety in pharmaceutical product cannot be therapeuticallybeneficial unless it has preference and acceptance by the patient. Thus,pleasant taste is important for the therapeutic success of the drug formulation. Human tongue with taste Sample Electronic receptors. tongue
Objectives of electronic tongue: Identification between bitter, sweet and sour substances by using electronic tongue. Separating the different substances eliciting the same taste (sour, bitter, sweet). Identify drug preparations containing active substance and placebo substance. Quantification of the effect of taste masking of bitter substances by sweet ones.
MECHANICAL STRENGTH In order to allow ODTs to disintegrate in the oral cavity, they are made ofeither very porous and soft-molded matrices or compressed into tablets withvery low compression force, which makes the tablets friable and/or brittle,difficult to handle, and often requiring specialized peel-off blister packing thatmay add to the cost.
AMOUNT OF DRUG Application of technologies used for ODTs is limited by the amount of drug that can be incorporated into each unit dose. In case of Lyophilized dosage forms, drug dose must be less than 400mg – insoluble drugs less than 60mg -- soluble drugs This parameter is particularly challenging when formulating a fast- dissolving oral films.
SIZE OF TABLET The degree of ease when taking a tablet depends on its size. It has been reported that the easiest size of tablet to swallow is 7-8 mm. While the easiest size to handle was one larger than 8 mm. Therefore, the tablet size that is both easy to take and easy to handle is difficult to achieve
HYGROSCOPICITY Several orally disintegrating 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.
AQUEOUS SOLUBILITY Water soluble drugs pose various formulation challenges because they form eutectic mixtures, which result in freezing point depression and the formation of a glassy solid that may collapse upon drying because loss of supporting structure during the sublimation process. This collapse can be prevented by using various matrix-forming excipients like Mannitol which induces crystallinity and hence impart rigidity to the
SHORT HALF-LIFE ODTs being immediately releasing dosage forms and the absorption of maximum amount of dose takes place in the pre-gastric region, these have sort half life. This character may render drug unsuitable for delivery as prolonged release or sustained release dosage form.
COST OF THE TABLET As ODTs are easily fragile, these products require special unit-dose packaging which may add to the cost of the dosage form.
THE IDEAL CHARACTERISTICS OF DRUG For disintegration and dissolution in oral cavity i.e., the pre-gastric absorption from an ODT include,1. No bitter taste2. Dose lower than 20mg3. Small to moderate molecular weight4. Good solubility in water and saliva5. Partially nonionized at the oral cavity’s pH.6. Ability to diffuse and partition into the epithelium of upper GIT.7. Ability to permeate oral mucosal tissue.
EXCIPIENTS FILLER SUPERDISINTEGRANTSEg: More potent drugs like codeine are required in very low amount which Eg: Cross povidone, require diluent such as lactose to Crosscarmellose sodium, makeup volume of drug. Sodium starch glycolate, calcium carboxy methyl cellulose, Various fillers used are Lactose, Alginates, Directly compressed spray Micro crystalline cellulose, dried mannitol, Amberlite IRP 88, Sorbitol, Guargums, Calcium carbonate, Modified corn starch, Pregelatinised starch, Pregelatinized starch Magnesium trisilicate, Chitin chitosan Al(OH)3 etc. Smecta
FORMULATION TECHNIQUES COVENTIONAL TECHNIQUES Tablet moulding Direct compression Spray drying Sublimation Freeze drying (or) Lyophilization Mass extrusion Cotton candy process
Tablet Molding Molded tablets are prepared by using water soluble ingredients so that the tablets dissolve completely and rapidly. The powder blend is moistened with a hydro-alcoholic solvent and is molded into tablets under pressure lower than that used in Conventional tablet compression. The solvent is then removed by air-drying.Eg: Benadryl, Fastmelt(diphenhydramine citrate, pseudoephidrine HCl) – Allergy, sinus
DIRECT COMPRESSION Easiest way to manufacture tablets is direct compression. Low manufacturing cost, conventional equipments and limited number of processing steps led this technique to be a preferable one. However disintegration and dissolution of directly compressed tablets depend on single or combined effect of disintegrant, water soluble excipients and effervescing agents.
SPRAY DRYINGcan produce highly porous and fine powders that dissolve Spray drying rapidly. The formulations are incorporated by hydrolyzed and non hydrolyzed gelatins as supporting agents, Mannitol as Bulking agent, sodium starch glycolate or crosscarmellose sodium as disintegrating and an acidic material (e.g. citric acid) and / or alkali material (e.g. I sodium bicarbonate) to enhance disintegration and dissolution. Tablet compressed from the spray dried powder disintegrated within 20 seconds when immersed in an aqueous medium
SUBLIMATION To generate porous matrix in ODTs, volatile ingredients are incorporated in the formulation which is subjected to sublimation (by vacuum drying) leaving behind the porous matrix.
FREEZE DRYING OR LYOPHILIZATION It is a process in which water is sublimed from the product after freezing. Lyophilization is a pharmaceutical technology which allows drying of HEAT SENSITIVE DRUG and biological at low temperature under conditions that allow removal of water by sublimation. Lyophilization results in preparations, which are highly porous, with a very high specific surface area, which dissolves rapidly and show improved absorption and bioavailability.
MASS EXTRUSION This technology involves softening the active blend using the solvent mixture of water soluble polyethylene glycol, using methanol and expulsion of softened mass through the extruder or syringe to get a cylinder of the product into even segments using heated blade to form tablets. The dried cylinder can also be used to coat granules of bitter tasting drugs and thereby masking their bitter taste.
COTTON CANDY PROCESS Cotton candy process is also known as “candy floss” process and forms the basis of the technologies such as Flash Dose (Fuisz technology). An ODT matrix is formed from saccharides or polysaccharides processed into amorphous floss by a simultaneous action of flash melting and centrifugal force. The matrix is cured or partially recrystallised to provide a compound with good flow properties and compressibility. The candy floss can then be milled and blended with active ingredients and Excipients and subsequently compressed into ODT. Limitation: The high processing temperature limits the use of this technology to Thermo stable compounds only
ZYDIS TECHNOLOGY A Zydis tablet is produced by lyophilizing or freeze-drying the drug in a matrix usually consisting of gelatin. The product is very lightweight and fragile, and must be dispensed in a special blister pack. Patients should be advised not to push the tablets through the foil film, but instead peel the film back to release the tablet. The Zydis product is made to dissolve on the tongue in 2 to 3 seconds.
ORASOLV TECHNOLOGY In this system active medicament is taste masked. It also contains effervescent disintegrating agent. Tablets are made by direct compression technique at low compression force in order to minimize oral dissolution time.Eg: Remeron ( mirtazapine) - Depression
DURASOLV TECHNOLOGY The tablets made by this technology consist of a drug, fillers and a lubricant. Tablets are prepared by using conventional tableting equipment and have good rigidity. These can be packed into conventional packaging system like blisters.Eg: Fazaclo (clozapine) - antipsychotic
WOWTAB TECHNOLOGY Yamanauchi pharmaceutical company patented this technology. ‘Wow’ means ‘without water’. The active ingredients may constitute up to 50% w/w of the tablet. In this technique, saccharides of both low and high mouldability are used to prepare the granules. Mouldability is the capacity of a compound to be compressed.Eg: Fast melt (diphenhydramine citrate, pseudoephidrine HCl) – allergy
FLASH DOSE TECHNOLOGY This technology is patented by Fuisz. A sugar based matrix, called ‘Floss’ is used, which is made up of a combination of excipients (crystalline sugars) alone or in combination with drugs.Eg: Nurofen meltlet, a new form of Ibuprofen, as a mouth-dissolving tablet is the first commercial product prepared by this technology and launched by Biovail Corporation.
FLASH TAB TECHNOLOGY Prographarm labs have a patent over this technology. In this technology, microgranules of the taste-masked active drug are used. Micro granules may be prepared by using conventional techniques like coacervation, micro encapsulation, and extrusion-spheronisation. All these processes utilize conventional tabletting technology. These taste-masked micro crystals of active drug, disintegrating agent, a swelling agent and other excipients like soluble diluents etc are compressed to form a multiparticulate tablet that disintegrates rapidly.Eg: Excedrin Quick Tabs (acetaminophen, caffeine) – head ache
PREFORMULATION STUDIES Compatability studies = FTIR / DSC Angle of repose Ө = tan -1 (h/r) Determination of Bulk density = W / Vo Tapped density = W / Vf Hauser’s Ratio= Tapped density/Bulk density compressibility index : CI = 100 (Vo – Vf )/ Vo Moisture content
Some of the Marketed ODTs in India Name of product Active IngredientFeldene Melt Piroxicam(10-20 mg)Zyprexa Zydis Olanzapine (5, 10, 15 or 20 mg)Nimulid -MD NimesulideClaritin Reditab Micronized LoratadinePepcid RPD Famotidine (20-40 mg)
EVALUATION TESTS WEIGHT VARATION TEST I.P. procedure for uniformity of weight was followed, twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was determined from the collective weight. The weight variation test would be a satisfactory method of determining the drug content uniformity
The pharmacopoeial limit of friability test for a tablet is not more thanFRIABILITY TEST friability apparatus, carried out at 25 rpm for 4 min 1% using Tablet (100 rotations). This test is again not applicable for lyophilized and flash dose tablets, but is always recommended for tablets prepared by direct compression and moulding techniques to ensure that they have enough mechanical strength to withstand the abrasion during shipping and shelf life. Percentage friability = 100(initial weight-final weight)/initial weight
WETTING TIME AND WATER ABSORPTION RATIO Wetting time and water absorption ratio reported the use of a piece of double folded tissue paper placed in a Petri dish containing 6 ml of water. One tablet was placed on this paper and the time for complete wetting of tablet was noted as wetting time. The wetted tablet was then weighed and the water absorption ratio, R, was determined according to equation. R = 100 (Wa−W b) /Wb Wb and Wa are the weights of tablet before and after water absorption
HARDNESS TEST The tablet tensile strength is the force required to break a tablet by compressing it in the radial direction and is measured using a tablet hardness tester. Monsanto hardness tester Phyzer type hardness tester
MOISTURE UPTAKE TEST The test can be carried out by keeping ten tablets along with calcium chloride in a desiccator maintained at 37 °C for 24 hrs to ensure complete drying of the tablets. The tablets are then weighed and exposed to 75% RH, at room temperature for 2 weeks. The required humidity can be achieved by keeping saturated sodium chloride solution in the dessicator for 24 hrs. The tablets are reweighed and the percentage increase in weight is recorded. If the moisture uptake tendency of a product is high, it requires special dehumidified area for manufacturing and packing.
MEASUREMENT OF TABLET POROSITY The mercury penetration porosimeter can be used to measure the tablet porosity which is a relative assessment of the degree of water penetration in the formulation, responsible for its fast disintegration.
IN-VITRO DISPERSION TIME The test is performed by placing two tablets in 100 ml water and stirring it gently, till the tablets get completely disintegrated. The formulation is considered to form a smooth dispersion if the complete dispersion passes through a sieve screen with a nominal mesh aperture of 710 μm without leaving any residue on the mesh.
IN-VITRO DISINTEGRATION TESTThis test are carried out by using any one of the following method Tablet disintegration apparatus Modified dissolution apparatus (as per J.Pharm) Disintegration Test on Shaking Water Bath Disintegration Test with Rotary Shaft Method Disintegration Test using Texture Analyzer Disintegration Test using Electro Force
DISINTEGRATION APPARATUS Apparatus with wire basket in a beaker.
DISINTEGRATION USING TEXTURE ANALYZER The in vitro disintegration behavior of fast dissolving systems manufactured by the main commercialized technologies was studied using the texture analyzer (TA) instrument.
IN-VITRO DISSOLUTION STUDY The dissolution method for oral disintegrating tablets is the same as that of conventional tablets. USP 2 paddle apparatus is most suitable and common choice for dissolution test of oral disintegrating tablets, where the paddle speed is 50 rpm is used. The USP 1 (basket) apparatus may have certain application for such tablets but is used less, frequently due to specific physical properties of tablets. Specifically tablet fragments or disintegrating tablet masses become trapped on the inside top of the basket spindle where little or no effective stirring occurs, yielding irreproducible results in dissolution profiles.
FUTURE DEVELOPMENTS ODTs can offer several biopharmaceutical advantages over conventional solid dosage forms such as, Improved efficacy Require small amount of the drug to be effective Offer better drug bioavailability ODTs may be suitable for oral delivery of drugs such as proteins and peptide based therapeutics that has limited bioavailability when administered by conventional tablets. Because drugs delivered in ODTs may be absorbed in the pre gastric sites of highly permeable buccal and mucosal tissues of the oral cavity, they may be suitable for delivering relatively low-molecular weight and highly permeable drugs.
CONCLUSION Orally disintegrating tablets (FDTs) have better patient acceptance and compliance and may offer improved biopharmaceutical properties, improved efficacy, and better safety compared with conventional oral dosage forms. Prescription FDT products initially were developed to overcome the difficulty in swallowing conventional tablets with water among pediatric, geriatric, and psychiatric patients with dysphagia. Future possibilities for improvements in FDTs and drug delivery are bright, but the technology is still relatively new.
1. International journal of research in Ayurveda and Pharmacy.REFERENCES 2. Journal of Chemical and Pharmaceutical Research, 2009, 1(1): 336-341. 3. The Indian Pharmacist, Volume 3, Issue 19, p.72-75 (2004). 4. United States Pharmacopoeia 24/NF 19. The Official Compendia of Standards. Asian ed. Rockville, MD: United States Pharmacopoeial Convention Inc; 2000:1913-1914. 5. Bentham science Publishers- Recent patents on Drug delivery and Formulations, Volume 4, Number 3, November 2010. 6. Aulton’s Pharmaceutics- The design and manufacture of medicines, Edited by Michael E.Aulton- 3rd Edition, 2008. 7. FDA, Guidance for Industry: Orally Disintegrating Tablets Draft Guidance, (Rockville, MD, April 2007). 8. Review article- Recent Patents and Trends in Orally Disintegrating Tablets by Farhan A. AlHusban, Amr M. El-Shaer, Rhys J. Jones and Afzal R. Mohammed