A REVIEW ON FAST DISSOLVING TABLET TECHNOLOGY

Freeze drying or Lyophilization
A process in which water is sublimated from the product after freezing. Lyophilization is a pharmaceutical technology which allows drying of heat sensitive drugs and biological at low temperature under conditions that allow removal of water by sublimation. The ideal drug characteristics for this process are relative water insolubility with fine particle size and good aqueous stability in suspensions. Primary problems associated with water-soluble drugs are formation of eutectic mixture, because of freezing point depression and formation of glassy solid on freezing, which might collapse on sublimation. The addition of mannitol or crystal forming materials induces crystallinity and imparts rigidity to amorphous material Lyophilization results in preparations, which are highly porous, with a very high specific surface area, which dissolve rapidly and show improved absorption and bioavailability. Jaccard and Leyder used lyophilization to create an oral pharmaceutical preparation that not only dissolves rapidly but also improved the bioavailability of several drugs such as spironolactone and trolendomycin. Corveleyn and Remon studied various formulation and process parameters by using hydrochlorothiazide as a model drug on the basis of which US Patent 6,010,719 was granted. Tablets prepared by lyophilization, are fragile and possess low mechanical strength, which make them difficult to handle and they also exhibit poor stability on storage under stressed conditions. Glassy amorphous porous structure of excipients as well as the drug substance produced with freeze drying results in enhanced dissolution
Freeze drying process normally consists of three steps:
• Material is frozen to bring it below the eutectic point.
• Primary drying to reduce the moisture around 4% w/w of dry product.
• Secondary drying to reduce the bound moisture up to required final volume.

Entire freeze drying process is carried out at non elevated temperature; therefore, nullifying adverse thermal effects that may affect drug stability during processing. R.P. Scherer patented Zydis technology utilizing lyophilization or freeze drying process in development of mouth dissolving tablets on the basis of patents issued to Gregory.

Excipients Used in the Manufacture of FDT Using Freeze Drying Technique

Molding
Tablet produced by moulding are solid dispersion. Moulded tablets disintegrate more rapidly and offer improved taste because the dispersion matrix is in general made from water soluble sugars. The active ingredients in most cases are absorbed through the mucosal lining of the mouth.  The manufacturing process of molding tablets involves moistening the powder blend with a hydro alcoholic solvent followed by pressing into mold plates to form a wetted mass (compressing molding). The solvent is then removed by air drying. Thus the process is similar to what is used in the manufacture of tablet triturates. Such tablets are less compact than compressed tablets and possess a porous structure that hastens dissolution.
Molded forms are also prepared using a heat-molding process that involves setting the molten mass that contains a dispersed drug. The heat-molding process uses an agar solution as a binder and a blister packaging well as a mold to manufacture a tablet. The process involves preparing a suspension that contains a drug, agar, and sugar (e.g., mannitol or lactose), pouring the suspension into the blister packaging well, solidifying the agar solution at room temperature to form a jelly, and drying at -30oC under vacuum.
Another process used is called no-vacuum lyophilization, which involves the evaporation of a solvent from a drug solution or suspension at standard pressure. Pebley et al., evaporated a frozen mixture containing a gum (e.g., acacia, carageenan, guar, tragacanth, or xanthan), a carbohydrate (e.g., dextrose, lactose, maltose, mannitol, or maltodextrin), and a solvent in a tablet shaped mould. Moulded tablets typically do not possess great mechanical strength. Erosion and breakage of the moulded tablet often occur during handling and opening of blister packs.

Direct compression
Direct compression is one of the popular techniques for preparation of these dosage forms. The advantages of this method include easy implementation, use of conventional equipments along with commonly available excipients, limited number of processing steps and cost effectiveness.
Disintegration and solubilization of directly compressed tablets depend on single or combined action of disintegrants, water-soluble excipients and effervescent agents. The basic principle involved in development of these dosage forms using this technique is addition of superdisintegrants in optimum concentrations so as to achieve rapid disintegration along with pleasant mouth feel. It is considered as the best method to prepare orally disintegrating dosage forms since the prepared tablets offer higher disintegration due to absence of binder and low moisture contents. This approach is also considered as disintegrant addition technology.
Bi et al and Watanabe et al developed fast-dissolving tablets using microcrystalline cellulose and low substituted Hydroxypropyl cellulose as disintegrating agents in the range of 8:2-9:1. Shu et al also prepared rapid oral disintegrating tablets by direct compression using co-ground mixture of D-Mannitol and Crosspovidone.

Ideal Requirements, Advantages and Limitations of Direct Compression

Spray drying
Spray drying is a process by which highly porous, fine powders can be produced. Spray-dryers are invariably used in the pharmaceutical industry to produce highly porous powders. Allen et al. have reported applying this process to the production of fast dissolving tablet. The formulations that were produced contained hydrolyzed and unhydrolyzed gelatin as a support agent for the matrix, Mannitol as a bulking agent, and sodium starch glycolate or crosscarmellose as a disintegrant. Disintegration and dissolution was further enhanced by adding an acid (e.g., citric acid) or an alkali (e.g., sodium bicarbonate). The formulation was spray dried to yield a porous powder. Tablets manufactured from this powder disintegrated in less than 20 s in an aqueous medium.
A typical procedure involved in the manufacturing of ODT using this technique is mentioned here. The active drug is dissolved or dispersed in an aqueous solution of a carrier/polymer. The mixture is dosed by weight and poured in the wells of preformed Blister Packs. The trays holding the blister packs are passed through liquid Nitrogen freezing tunnel to freeze the drug solution or dispersion. Then the frozen blister packs are placed in refrigerated cabinets to continue the freeze drying. After Freeze drying aluminum foil backing is applied on a blister sealing machine. Finally the blisters are packed and shipped. The main drawbacks of lyophilization technique are that it is time consuming and expensive. Fragility makes conventional packaging unsuitable for these products and poor stability under stressed conditions.

Sublimation
The key to rapid disintegration for mouth dissolving tablets is the presence of a porous structure in the tablet matrix. Conventional compressed tablets that contain highly water-soluble ingredients often fall to dissolve rapidly because of low porosity of the matrix. Hence to generate porous matrix, volatile ingredients are used that are later subjected to a process of sublimation. In studies conducted by Heinemann and Rothe, Knitsch and Roser and Blair, inert solid ingredients that displayed high volatility (e.g., ammonium bicarbonate, ammonium carbonate, benzoic acid, camphor, Hexamethonium tetramine, naphthalene, Phthalic anhydride, urea, and urethane were compressed along with other excipients into a table. The volatile material was then removed by sublimation, leaving behind a porous matrix.
Solvents such as cyclohexane and benzene were also suggested for the generation of porosity in the matrix. Koizumi et al. applied sublimation technology to manufacture tablets that rapidly dissolve in saliva. 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. reported a method using water as pore-forming material. 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. Gohel M. et al prepared mouth dissolving tablets of Nimesulide using vacuum drying technique and found that it would be an effective alternative approach compared to the use of more expensive adjuvants in the formulation of these dosage forms.

Mass-Extrusion (Melt-Extrusion)
Preparation of ODTs of NSAID and paracetamol by melt extrusion method was patented by Sherry et al. (2008). The method involved dry blending of sugar alcohol and drugs with other excipients that may be present in the granular component. This powder mixture was heated at a temperature of 100 to 165°C in an extruder in order to completely melt the sugar alcohol. This resultant mass consisting of fully or partially molten sugar alcohol (xylitol, sorbitol, mannitol, etc.) and non-molten (NSAID (ibuprofen, naproxen, diclofenac) or paracetamol) and other optional excipients was poured on cooled stainless steel trays or a cooled moving belt (10°C) and allowed to cool The molten mixture typically solidified within 60 sec. The solid mass thus formed was milled by passing through a cone mill fitted. with a screen with a round hole of 1 mm diameter. The resulting granules were blended with extra-granular components namely, colloidal silicon dioxide, magnesium stearate, stearic acid, lactose, dicalcium phosphate and microcrystalline cellulose in a blender. The blended material was fed to a rotary tableting machine and compressed into tablets under compaction force ranging from 4 kN to 14 kN. This technology involves softening the active blend using the solvent mixture of water-soluble polyethylene glycol and methanol and subsequent 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 for bitter drugs and thereby achieve taste masking.

Melt Extrusion Temperature Conditions of Sugar Alcohols

Cotton candy process
This process is so named as it utilizes an inimitable spinning mechanism to produce floss like crystalline structure, which mimics cotton candy. This technique involves formation of matrix of polysaccharides or saccharides by simultaneous action of flash melting and spinning. The matrix formed is partially recrystallized to have better flow properties and compressibility. This matrix is milled and blended with active ingredients as well as excipients and subsequently compressed to ODTs. This process can accommodate high doses of drug and offers improved mechanical strength. However, high process temperature limits the use of this process.