Slide 1: FORMULATION OF TABLETS & ITS RECENT ADVANCES . Presented by : B.Chandra sekhar, M.pharm 1st year, Pharmaceutical technology, Yalamarty Pharmacy college , Visakhapatnam. Introduction: Introduction TABLETS Definition : Tablets may be defined as the solid unit dosage form of the medicament comprising of one or more active ingredients along with suitable pharmaceutical excipients. Formulation of tablets: Formulation of tablets The formulation of tablets determines its tensile strength, disintegration and dissolution characteristics and content uniformity. In the formulation ( i.e., composition) of the tablets, the following points must be taken into consideration. 1.Physical and chemical properties of the active ingredient and the excipients. 2.Bioavailability problems of the drug. 3.Site of action of the drug. Slide 4: Formulation of tablets Active ingredient(s) or Drug(s) Based on solubility Insoluble drugs Soluble drugs Excipients or Additives Based on function Diluents or Fillers Binding agents or Binders Adsorbing agents Or Adsorbents Disintegrating agents Or Disintegrants Dissolution Modifying agents Anti- Frictional agents Wetting agents Organoleptic agents Co-processed Excipients 1. Active Pharmaceutical Ingredients (API): 1. Active Pharmaceutical Ingredients (API) Active Pharmaceutical Ingredients (API) (or) Drugs (meant for oral administration) are classified into two types based on their solubility: a). Insoluble drugs. b). Soluble drugs. a). Insoluble drugs : The therapeutic action of insoluble drugs ( seen locally in GI tract, Eg: Antacids and adsorbents) depends on the surface properties of the drug particles i.e., fine particle size and larger surface area. The bioavailability of these drugs in GIT along with its optimal surface is affected by : ( I ) Formulation (composition ) of the tablet. (II) Granulation method (dry granulation or wet granulation). (III) Method of tab letting ( compression or compaction). Slide 6: b). Soluble drugs : The therapeutic action of soluble drug is seen systemically. The disintegration and dissolution time of such tablets depends upon the excipients used in the formulation. Solubility of the drug should be considered at or above the absorption site (i.e., upper GIT or the intestinal tract). The physical and chemical properties of the drugs must be studied extensively before finalising the tablet formula so as to obtain better tab- letting characteristics. Active pharmaceutical ingredient (API), therapeutic agent Should not produce any toxic effect when it comes in contact with other additives, Should be of accurate quantity as label claim, Should be detected by various methods of analysis. Example: paracetamol, aspirin, diclofenac, metformin,telmisartan, nimesulide , nifedipine etc. Slide 7: Diluents Based on Chemical nature Solubility Organic diluents Inorganic diluents Water soluble diluents Water Insoluble diluents Dextrose, Lactose, Mannitol, MCC, Sorbitol, Starch, Sucrose. Eg: Calcium phosphate (dibasic), Calcium phosphate (tribasic), Calcium sulphate dihydrate, Calcium carbonate. Dextrose, Lactose, Mannitol, Sorbitol, Sucrose. Calcium phosphate (dibasic), Calcium phosphate (tribasic), Calcium sulphate dihydrate, Calcium carbonate, MCC, Starch. Eg: Eg: Eg: Diluents :: Diluents : Act as fillers used to make required bulk of the tablet. Diluents are used to increase the bulk content of the dosage form, this is done in a situation where the active constituent to be incorporated in the formulation is of less quantity. For ex: if the active ingredient is just 5 mg, is such a case a tablet of just 5 mg is very difficult to manufacture and handle too, thus the bulk content is increased by addition of inactive excipient. Must provide better tablet properties such as improved cohesion, to permit the use of direct compression manufacturing or to promote flow. A diluent should have following properties: Non toxic. Commercially available in acceptable grade. Low in cost. Physiologically inert. Physically & chemically stable by themselves & in combination with the drugs. Free from all microbial contamination. Should not alter the bioavailability of the drug . Colour compatible. Slide 9: Commonly used tablet diluents : • Lactose-anhydrous and spray dried lactose • Directly compressed starch- Sta Rx 1500 • Hydrolyzed starch-Emdex and Celutab • Microcrystalline cellulose-Avicel (PH 101 and PH 102) • Dibasic calcium phosphate dehydrate • Calcium sulphate dihydrate • Mannitol • Sorbitol • Sucrose- Sugartab, DiPac, Nutab • Dextrose compressed starch-Sta Rx 1500 • Hydrolyzed starch- Emdex and Celutab • Microcrystalline cellulose- Avicel (PH 101 and PH 102) • Dibasic calcium phosphate dehydrate • Calcium sulphate dihydrate • Mannitol • Sorbitol • Sucrose- Sugartab, DiPac, Nutab • Dextrose Slide 10: Most of the excipients are dehydrates,i.e. contain certain amount of bound water, this bound water is important during granulation process, it reduces the hygroscopic nature of the formulation. Making the formulation stable. For the active ingredients which are sensitive to water anhydrous excipients like anhydrous lactose or anhydrous dibasic calcium phosphate are used . Spray dried lactose, direct compressible starch and MCC (avicel) are the diluents that can be used when the formulation is prepared by direct compression. Mannitol is one of the costliest diluents but it is still used due to the refreshing sensation given by it when it is used in the chewable tablets. Sucrose or sugar based diluents are used for direct compression formulations. Sucrose based diluents include: Sugartab (90-93% sucrose + 7 to 10%invert sugar), Dipac (97% sucrose + 3% modified dextrin) and Nutab( 95%sucrose+4% invert sugar with small amount of corm starch and magnesium stearate) Slide 11: Binding agents Based on method of incorporation Dry binders Wet binders Sugars Polymeric binders Natural polymeric binders Synthetic polymeric binders Based on origin Cellulose, Methyl cellulose, Polyvinyl pyrrolidone Gelatine, Starch, Sucrose, Polyvinyl pyrrolidone. Sucrose Eg: Eg: Eg: Eg: Eg: Gelatine, Starch, Sucrose, Gums. Ethyl cellulose, Methyl cellulose, Polyethylene glycol 6000, Poly vinyl alcohols, PVP, Sodium CMC Slide 12: Binders: These are the dry powders or liquid which are added during wet granulation to promote granules or to promote cohesive compact during direct compression. It provides mechanical strength to the tablet. Binders can be in powder form and liquid form example of binders are Powder binders : cellulose, methyl cellulose, polyvinyl pyrrolidine, PEG Solution binders : gelatine, PVP, HPMC, PEG, sucrose, starch Binders can be added in the following ways to the formulation Added as powder before wet agglomerisation so that the binder is evenly distributed. As solution form it is used as agglomerisation liquid in the wet granulation. It is called as liquid binder Slide 13: As a dry powder, which is mixed with other ingredients before compaction (slugging or tabletting). It is called as dry binder. Natural binders like acacia and tragacanth are used in solution form in the concentration of 10-25%, alone (or) in combination for wet granulation and they can be added as powder for the direct compression process. Gelatine is used along with acacia (or) alone this form a better binding agent than the above two natural polymers. Polymers like MC, HPMC are used as dry powders in case of direct compaction, they act as good binding agents, in the solution form they act as good adhesives. Ethyl cellulose and HPMC can be used in alcoholic solutions, they act as anhydrous adhesives. Disintegrants : : Disintegrants : Disintegrant are added to the formulation as it breaks the dosage form into smaller particles when it comes in contact with the liquid, these smaller fragments have greater surface area which will increase the dissolution of the drug. Various mechanism of disintegrations are proposed: By breaking into fragments: When the tablet comes in contact with the liquid, the liquid penetrates into the pores of the tablets and breaks it into fragments. To improve the water uptake into the pores certain hydrophilic polymers are added to the formulation. Slide 15: By swelling: when the tablet comes in contact with the water it swells and ruptures the tablet into small particles. Examples of disintegrants are: starch, starch derivatives, clay, cellulose, alginates, PVP, cross linked Na CMC. Starch is used for in the concentration range of 5 to 20% of the tablet weight. Modified starch are also used which like Primogel, Explotab. These are used in the low concentration like 1 to 8%, Pregelatinised starch is also employed in the formulation with 5% concentration. Clay like Veegum HV and Betonite are used in 10% level, Polymers like cross linked PVP, CMC are also used as disintegrants. Slide 16: Dissolution modifiers Hydrophilic dissolution modifiers Hydrophobic dissolution modifiers pH dependent dissolution modifiers Surface active dissolution modifiers Acrylic acid, CMC, Methyl cellulose, PEG. Carnauba wax, Paraffin, White wax. Shellac , Zein, Polymethacrylate, Cellulose acetate pthallate Pluronics Eg: Eg: Eg: Eg: These are some of the commonly used Controlled- Release excipients. Slide 17: Anti - frictional agents Lubricating agents (or) Lubricants Glidants Anti-adherents Soluble Lubricants Insoluble Lubricants Based on solubility Sodium benzoate, Sodium chloride, Magnesium lauryl sulphate, PEG 4000(Carbowax 4000), PEG 6000(Carbowax 6000)etc. Calcium (or) Magnesium stearates, Mineral oil, Talc, Stearic acid. Cab-O-sil, Corn starch. Cab-O-sil, Syloid, SLS, Metallic Stearates, Talc, Corn starch. Eg: Eg: Eg: Eg: Lubricants: : Lubricants: Lubricants are used to reduce the friction between the tablet and die cavity when the tablet die cavity is getting ejected from the die. Lack of lubricant can lead to problems like capping, scratch on the sides of the tablet, fragmentation of the tablet, shape out etc… Thus to avoid this lubricants are to be used. For a lubricant the time of addition, concentration in which it is to be added and the combination are the important parameters. Concentration: as most of the lubricants are hydrophobic in nature thus the an increased concentration of lubricant would lead to problems like poor wettability, and dissolution and disintegration problem. For this reason they are added in the concentration less than 1% Slide 19: Time of mixing: It is important as overmixing may lead to reduction in tablet dissolution and disintegration. Combination: If the lubricant is mixed with the disintegrant it will lead to formation of an film of lubricant on the tablet surface which will reduce the disintegration. Examples of lubricants are: stearic acid, stearic acid salt, stearic acid derivatives, talc, PEG, surfactants, waxes ,etc. Calcium stearate and magnesium stearate (0.25–0.50%w/w) are the most commonly used lubricants followed by talc. Slide 20: Higher molecular weight poly ethylene glycol and certain polymeric surfactants are used as water soluble lubricants. Lubrication can be achieved by two ways: Fluid lubrication: it is achieved by the addition of liquid paraffin which forms an liquid film over the surface, but this is rarely followed. Boundary lubrication: in this powder is mixed to the formulation which forms a film on the surface which reduces the friction. Lubricants can be of two types: Insoluble lubricants: these are added to the formulation at the end before the compression of the tablet. Examples include: magnesium stearate, stearic acid, glyceryl palmito stearate, etc. Soluble lubricants: these are added to overcome the defects caused by the insoluble lubricants. Examples include: PEG, poly oxy ethylene stearate, lauryl sulphate salt, etc. Glidant: : Glidant: Glidants are used to improve the flow property of the formulation, it reduces the friction between the particles and between the hopper and particles and die cavity and particles. Actually glidant, lubricant and antiadherent have a close relation to each other. They have some functions in common. Most of the glidants used are hydrophobic thus they are to be carefully added i.e. concentration regulated. Examples of glidants are talc, colloidal silicone dioxide, corn starch. Glidants should be of small size so that they can retain with in the small pores of the granules that have a greater surface area. Miscellaneous: :
Miscellaneous : Apart from the above mentioned principal ingredients the following excipients also improve the dosage form
. They are : Adsorbents: Adsorbents are used when there is an need to add a liquid or semisolid ingredient in the formulation, adsorbents are capable of sorbing the liquid component on to the dry powder. Thus oil or liquid component can be incorporated into the powder. Examples of adsorbents include: magnesium oxide, kaolin/ bentonite .,etc.
Slide 23: Wetting agents Hydrophilic colloids Surfactants Alginates, Bentonite, Cellulose derivatives, Tragacanth etc. SLS, Polysorbates, Sorbitan esters etc . Eg : Eg : Slide 24: Organoleptic agents Colouring agents Flavouring agents Sweetening agents Based on origin Natural colouring agents Artificial colouring agents Carotene, Chlorophyll, Cochineal, Tio2 etc. Caramel Dyes Lakes Pigments Water soluble flavouring agents Volatile oil flavouring agents Mannitol, Dextrose, Saccharine, Sucrose etc. Fennel oil, Rose oil etc. Natural Sweetening agents Artificial Sweetening agents Sorbitol, Mannitol, Sucrose etc. Aspartame, Cyclamate, Saccharin etc. Eg: Eg: Eg: Eg: Eg: Eg: Flavorants: : Flavorants: These are incorporated into the formulation to improve the flavour or give a pleasant taste to the formulation. Flavouring agents are mostly restricted to the formulations in which are intended to be released in the mouth or chewable tablets. They are usually added in along with the granules. Slide 26: Flavours are commonly used to improve the taste of chewable tablets as well as mouth dissolved tablets. Flavours are incorporated either as solids(spraydried flavours) or oils or aqueous (water soluble) flavours. Solids that is dry flavours are easier to handle and generally more stable than oils. Oil is usually added at the lubrication step because of its sensitivity to moisture and their tendency to volatilize when heated during drying. It may also be adsorbed onto an excipient and added during the lubrication process. The maximum amount of oil that can be added to granulation without affecting tableting characteristics is 0.5 to 0.75 %(w/w). Aqueous flavors are less used because of its instability on aging. Colorants: : Colorants: Usually the colorants are added in the form of insoluble powder or in the form as liquid in the granulation liquid. Examples of colorants are: FD&C and D &C dyes and lakes. Colourants neither contribute to therapeutic activity nor do they improve product bioavailability or stability but are incorporated into tablets for purposes like to facilitate identification of similar looking products with in a product line to avoid mix ups, to facilitate identification of products of similar appearance that exist in the lines of different manufacturers, to overcome colour change on aging, disguising of off-colour drugs, for brand image in the market, to enhance the aesthetic appearance of the product to have better patient acceptance. Most widely used colourants are dyes and lakes which are FD & C and D & C approved. Slide 28: Dyes are generally applied as solution especially in the granulating agent. Lakes are usually employed as dry powders for colouring. In general, direct compression tablets are coloured with lakes because no granulation step is used. Natural colourants can be used and generally they do not require the FDA certification before use in drug products. One of the important advantage in using lakes is reduced risk of interaction between the drug and other ingredients as well as colour development is rapid which reduces processing time . While employing wet granulation , care should be taken to prevent colour migration during drying . In any coloured tablet, the formulation should be checked for resistance to colour changes on exposure to light. Reflectance Spectrophotometry, Tristimulus Colourimetric Measurements and Microreflectance Photometer used to measure the colour uniformity and gloss on a tablet surface. Slide 29: Lakes are dyes absorbed on hydrous oxide and employed as dry powder colouring. Examples: FD & C yellow 6-sunset yellow FD & C yellow 5- Tartrazine FD & C green 3- Fast Green FD & C blue 1- Brilliant Blue FD & C blue 2 - Indigo carmine D & C red 3- Erythrosine. D & C red 22 – Eosin Y FD&C Green No. 3 – Fast Green FCF, E143 (turquoise shade) Sweetening agents & Preservatives :: Sweetening agents & Preservatives : NATURAL SWEETENERS – Mannitol, Lactose, Sucrose, Dextrose, etc. ARTIFICIAL SWEETENERS- Saccharin, Cyclamate, Aspartame, etc. Saccharin is 500 times sweeter than sucrose. Its major disadvantages are that it has a bitter aftertaste and is carcinogenic. Even cyclamate is carcinogenic Aspartame is about 180 times sweeter than sucrose. The primary disadvantage of aspartame is its lack of stability in the presence of moisture. When Aspartame is used with hygroscopic components, it will be necessary to determine its stability under conditions in which the product can adsorb atmospheric moisture. Aspartame is available in market under the brand Nutrasweeto manufactured and marketed by NutraSweet Company. Preservatives: Preservatives may be a part of tablet formulation in order to prevent the growth of microorganisms in tablet formulation. Parabens like methyl, propyl, benzyl, butyl p- hydroxy benzoate are used as preservatives. Recent Trends in Tablet formulation:: Recent Trends in Tablet formulation: EXCIPIENTS A. DIRECT COMPRESSIBLE VEHICLES : Recently there has been growing impetus to develop the so-called direct compression formulations, and the range of excipients, especially diluents, designed for the specific role has expanded dramatically. It is possible to distinguish two types of Direct compressible formulations: (A) those where the major proportion is an active ingredient, and (B) those where the active ingredient is a minor component (i.e., < 10% of the compression weight. Direct compression materials in addition to possessing good flow and compressibility, they must be: Inert Tasteless Rework able, Able to disintegrate Inexpensive. Slide 32: These excipients include : Fillers : spray dried lactose, Micro crystalline cellulose (MCC); Disintegrating agents: direct compression starch, sodium carboxyl methyl cellulose ; Lubricants: magnesium stearate talc; Glidants: fumed silicon dioxide. Slide 33: B. Superdisintegrants : As day’s pass, demand for faster disintegrating formulation is increased. So, pharmacist needs to formulate disintegrants i.e. Superdisintegrants which are effective at low concentration and have greater disintegrating efficiency and they are more effective intragranularly. But, they have one drawback i.e., they are hygroscopic. Therefore, they not used with moisture sensitive drugs. And this superdisintegrants act by swelling and due to swelling pressure exerted in the outer direction or radial direction, it causes tablet to burst or the accelerated absorption of water leading to an enormous increase in the volume of granules to promote disintegration. Slide 34: SUPERDISINTEGRA--NTS EXAMPLE S OF MECHANISM OF ACTION SPECIAL COMMENT Crosscarmellose ,Ac-Di- Sol, Nymce ZSX, Primellose, Solutab, Vivasol Cross linked cellulose -Swells 4-8 folds in < 10 seconds. -Swelling and wicking both. -Swells in two dimensions. -Direct compression or granulation. -Starch free Crosspovidone, Crosspovidone M, Kollidon Cross linked PVP -Swells very little and returns to original size after compression but act by capillary action -Water insoluble and spongy in nature so get porous tablet Sodium starch glycolate Explotab, Primogel Crosslinked starch -Swells 7-12 folds in <30 seconds -Swells in three dimensions and high level serve as sustain release matrix Alginic acid NF Satialgine Crosslinked alginic acid -Rapid swelling in aqueous medium or wicking action -Promote disintegration in both dry or wet granulation C. Multi – Use excipients :: C. Multi – Use excipients : By reducing the number of ingredients in a formulation, one will generally reduce the number of problems that can arise in the manufacturing process. Hence, many formulators adhere to the motto “ Keep it Simple”. Because of the nature of the modern pharmaceutical systems, Formulators have made more complete investigations of the materials they use. This interest had identified several materials that may have more than one use in tableted systems. The type of effect that an excipient will produce is often dependent on the concentration in which it is used. Some multi-use excipients for tablet formulation:: Some multi-use excipients for tablet formulation: Ethyl cellulose 1-3% 1-3% Wet or dry binder. Controlled release coating. Magnesium aluminium silicate 2-10% 2-10% Binder. Disintegrant. Micro crystalline cellulose (MCC) 0-8% 0.2-0.5% 5-20% 5-20% 5-95% Improve adhesion of film coat to core. Glidant. Anti-adherent. Disintegrant. Binder/Filler. Starch 3-15% 5-25% 5-20% Intra granular binder/ disintegrant. Wet binder. Disintegrant. D. Co-processed Excipients :: D. Co-processed Excipients : These Excipients are a pleblend of two or more excipients that are commonly used in conjunction with each other. Advantages : Reduction in the number of raw materials and processing time required for a given formulation . Potential for improving batch to batch consistency. In addition ,investigators also found that tablets prepared from sillified MCC (co-processed MCC and colloidal silicon dioxide) exhibited: Improved tablet strength, Improved retention of compressibility after granulation and Superior flow properties compared to tablets made from these MCC and colloidal silicon dioxide added as individual components. Several Co-processed excipients :: Several Co-processed excipients : Excipient Components Manufacturer Advantose FS Fructose ,pre -gelatinised starch DMV Avicel CE-15 MCC,Guar gum FMC Cellactose MCC, alpha-lactose monohydrate Meggle GmbH Ludipress Alpha lactose monohydrate, povidone, cross povidone BASF LustreClear MCC, Carrageenan FMC Microcelac MCC alpha lactose monohydrate Meggle GmbH Pharmatose DCL Anhydrous lactose,Lactitol DMV ProSolv SMCC MCC, Colloidal Silicon dioxide Penwest REFERRENCES:: REFERRENCES: 1.Modern pharmaceutics- fourth edition ,revised and expanded. edited by Gilbert S. Banker and Christopher T. Rhodes. Page no- 287 to 306. 2.Pharmaceutical technology-II – pharma plus publications. 3. www.authorstream.com 4. www.scribd.com 5. www.pharmainfo.net Slide 40: Thank you