Universitas Sriwijaya Genap 2013/204 Solid dosage form (tablet) - Excipients Pertemuan ke -3 Decision factors in design Medical aspect Economical aspect Competitors aspect Tablet formulation process 1. Preformulation 2. Lab scale formulation 3. Stability testing 4. Trial product (scale up) formulation 5. Trial product production 6. Validation 7. Master formula Components of dosage form Active compounds Excipients Ideal characteristic of active compounds in tablet dosage form Purity Stability Compatibility Particle characteristics Flowability Optimum moisture content Absence of static charge on surface Compressibility/compactibility Organoleptic characteristics Excipients International Pharmaceutical Excipents Council (IPEC) = substansi selain obat atau prodrug yang telah dievaluasi keamanannya dan dimaksudkan untuk sistempenghantaran obat. Handbook of Pharmaceutical Excipients = zat tambahan yang digunakan untuk merubah zat aktif menjadi bentuk sediaan farmasi yang sesuai untuk digunakan pada pasien. Purpose of excipents 1. Helps manufacturing processes 2. Protects, supports and enhances stability and bioavailability 3. Identification of products 4. Increase safety and efficacy of products in shipments and usage. Criteria of excipients 1. Physiologically neutral 2. Stabile (chemical and physical) 3. Legal (under the law from officials) 4. Does not reduce the bioavailability of drugs 5. Free from pathogen microbes 6. Available in market, with relatively easy purchase and shipments. 7. Economically reachable Categories of excipients 1. Binders (pengikat) 2. Disintegrants (penghancur) 3. Fillers/diluents (pengisi) 4. Lubricants (pelicin) 5. Glidants 6. Antiadherents 7. Wetting agents (pembasah) 8. Dissolution retardants 9. Dissolution enhancers 10. Adsorbents 11. Buffers 12. Antioxidants 13. Chelating agents 14. Preservatives (pengawet) 15. Colours 16. Flavours 17. Sweeteners Fillers/diluents Function: 1. So tablets can be formed (compressed) Tablet = > 2 mm and > 50 mg; some active compounds dose is small Fillers 5 80% final weight 2. Enhance compressibility and fluidity of powder Better cohesion and flow Fillers/diluents Criteria for good filler: 1. No reaction towards active compound or other excipients 2. No physiologic or pharmacologic effect 3. Possess consistent physicochemical characteristics 4. Does not promote microbiological growth 5. Does not affect dissolution or bioavailability 6. No color 7. No odour Categories of fillers 1. Organic material (carbohydrates and modified carbohydrate) Ex: lactose, sucrose, manitol, microcrystalline celulose (MCC) 2. Inorganic material Ex: CaPO4 3. Co processed fillers/diluents Ex: filler binder for direct compression (Fast Flo lactose, Cal-Tab) Or 1. Soluble in water (lactose, mannitol) 2. Insoluble in water (CaPO4, starch, MCC) Lactose Lactose monohydrate not good for direct compression low compressibility Poor flowability Soluble in water Increase in hardness during shelf life disintegrant Incompatible with materials containing amine groups / base change of colour (yellow brownish) Anhydrous lactose has good compressibility but poor flowability Ex: Pharmatose, Respitose Spray Dried Lactose (SLD) Can be used for direct compression Good flowability Compressibility increase when dried until 3% of moisture content In high humidity colour can change to a darker shade Interact with amine and furaldehyde More expensive than normal lactose Ex: Spray Process 315 Sucrose Non compressible needs high pressure Good binding ability in liq. Form Hygroscopic Cheap Taste masking sweet Cariogenic Mannitol An optic isomer of sorbitol Poor flowability needs lubricants The most expensive sugar form of filler Non cariogenic Non hygroscopic Low calorie Used in tablet that dissolve in the mouth Ex: Pearlitol, Mannogem, Parteck Sorbitol Usually combined with manitol to reduce cost, sorbitol is cheaper Good compressibility Hygroscopic RH >65% Low calorie Non cariogenic Ex: Sorbifin, Neosorb Both mannitol and sorbitol has low absorbtion decrease small intestinal transit time less drugs absorbed Cellulose Amorph and -crystalline form Poor compressibility Poor flowability Poor binding effect Insoluble in water Cheap Ex: Elcema G-25o Microcrystalline cellulose (MCC) Very good compressibility used in direct compression Good flowability Possess deformation plastis characteristic sensitive towards lubricant Can increase disintegration process Insoluble in water Relatively expensive Ex: Avicel (2 grades; 101 powder and 102 granule), Emcocel Calcium Phosphates Anhydrate and hydrate form Dibasic and tribasic Higher bulk density compared to organic filler Used in vitamin and mineral formulation Granul form is spherical good flowability direct compression Hygroscopic in RH >70% Abrasive can cause exhaustion to tools Ex: Di-Tab, Tri-Tab Filler Binder Filler-Binder Description Single modification Avicel Modified MCC SDL Sprayed lactose Di-Tab Modified dicalcium phosphate dihydrate Co-processed Fast-Flo Lactose Sprayed result of -crystalline lactose monohydrate and amorph lactose Microcellac 75% lactose and 25% MCC Ludipress 93% -lactose monohydrate, 3,5% PVP and 3,5%crospovidone Sugartab 90-95% sucrose and 7-10% inverse sugar Cal-Tab 93% Calcium sulfate, 7% gom Calcium 90 90% Calcium carbonate, 10% starch Nu-Tab 95-9&% sucrose, 3-4% inverse sugar, 0,5% Mg stearate Di-Pac 97% Sucrose and 3% modified dextrin Emdex 93-99% dextrose, 1-7& maltose Binders Function: Add adhesion force to powder during granulation/direct compression Add cohesion force that already exists in filler so the powder can become a mass solid dosage form Addition method 1. Dry (extra granular) 2. Wet (intragranular)more effective Categories of binders 1. Natural binders Ex: tragacanth, gelatin, starch, alginate acid 2. Sugar Ex: Sucrose, glucose 3. Synthetic/semisynthetic polymers Ex: ethyl cellulose, hydroxypropylmethylcellulose (HPMC), polivinyl pyrolidone (PVP), polyethylene glycol (PEG), poly vinyl alcohol (PVA) Types of binder Binder name Concentration in formula (%) Solvent CMC-Na 10-50 Water HPC 1-5 Water HPMC 1-5 Water EC 2-7 Alcohol PVP 2-7 Water Gelatin 2-5 Water Natural Gom 1-3 Water Tragacanth 1-5 Water Acasia gom 1-3 Water Sucrose 10-25 Water Na-alginate 5-10 Water PEG 5-10 Water Amount of binder used according to filler Binder solution (ml) Fillers (3000 g) Sucrose Lactose Dextrose Mannitol Gelatin 10% 200 290 500 560 Glucose 50% 300 325 500 585 MC 2% 290 400 835 570 Water 300 400 660 750 Acasia 10% 220 400 685 675 Mucillago amylum 10% 285 460 660 810 Alcohol 50% 460 700 1000 1000 PVP in water 10% 260 340 470 525 PVP in alcohol 10% 780 650 825 900 Sorbitol in water 10% 280 440 750 655 Disintegrants Function: Helps tablet to disintegrate into smaller particles Addition method 1. Intragranular 2. Extragranular 3. Combination of intra and extra Superdisintegrant lower amount with the same effect Method of action of disintegrants 1. Capillary action 2. Swelling 3. Heat of wetting 4. Repulsion forces 5. Deformation 6. Release of gases 7. Enzymatic reaction Examples of enzyme Amilase starch Protease Gelatin Cellulase cellulose and its derivates Invertase sucrose Examples of disintegrants Starch Pregelatinized starch Modified starch Cellulose modification (ex: CMC Na, MCC) Alginate Ion exchange resin (ex: AmbreliteIPR-88) Superdisintegrants: Crosscarmellose, Ac-Di-Sol, Kollidon, Satialgine Starch One of the earliest excipient used Potato and corn Disintegrant actioncappilary, swelling, break down of hydrogen bonds When compressed has the ability to from hidrophillic bridge Amount of starch is a crucial factor less = less formation of hydrophillic channel, more = poor compressibility Pregelatinized starch Modified form of starch through hydrolisis and milling Better compressibility than normal starch Mechanism of disintegration through swelling Modified starch Modified with methylation carboxyl through cross linking Faster disintegration Ex: Primojelmodified through substitued carboxymethyl Too much cause film/gel forming because of gelling retards disintegration and dissolution CMC-Na Very hydrophilic If modified through cross linking crosslinked cellulose Ex: Crosscarmellose sodium hardly soluble, swelling ability very high MCC Insoluble in water Through wicking process water break down hydrogen bonds Can form static charges problem while granulation drying to be optimized Alginate Coloid hydrophilic Has good absorption capacity Acid or salt form Good for manufacturing acid multivatimin Disintegrant concentration Disintegrant Concentration (%) Starch 5-20 Starch 1500 5-15 Avicel 5-10 Alginic acid 5-10 Explotab (Na starch glycolate) 2-8 Guar gum 2-8 MC 5-10 CMC 5-10 HPMC 5-10 Amberlite IPR 88 0,5-5 Policlar AT (crosslinked PVP) 0,5-5 Superdisintegrants Superdisintegrants Modification Mechanism of Action Crosscarmellose Crosslinked cellulose Swelling < 10 s Ac-Di-Sol Cross linked cellulose Swelling and wicking CrossPovidone Cross linked PVP Capillary and a little bit swelling Explotab Cross linked starch Swelling < 30 s Satialgine Cross linked alginic acid Fast swelling and wicking Calcium silicate Cappilary Factors that affect disintegration Fillers Binders Lubricants Surfactants Effect of surfactant towards disintegration SLS depends on drugs Polysorbate 20 good Polysorbate 40-60 bad Polysorbate 80 Good PEG bad Lubricating agents Composed of 3 different types: 1. Lubricants 2. Glidants 3. Anti adherent Lubricants Function: To lessen friction between tablet and die walls during compression and ejection Added while mixing Two types: 1. Water soluble (ex: boric acid, sodium benzoate, sodium acetat) 2. Water insoluble (ex: stearate [Mg, Ca, Na], talc, liq. Paraffin) Lubricants Lubricants Concentration (%) Water insoluble Stearate (Magnesium, Calcium, Sodium) 0,25-1 Talc 1-2 Sterotex 0,25-1 Waxes 1-5 Stearowet 1-5 Glyceryl behapate 1-5 Liq paraffin <5 Water soluble Boric acid 1 Sodium benzoate, oleate, acetate 5 SLS 1-5 Magnesium lauryl sulphate 1-5 Glidants Function: To increase fluidity/flowability of powder that will be compressed Ex: Stearat Talk Starch Glidants Glidants Concentration (%) Stearate <1 Stearic acid 1-5 Talc 1-5 Starch 1-10 Sodium benzoate 2-5 Sodium chloride 5-20 SLS 1-3 MLS 1-3 PEG 4000 2-5 PEG 6000 2-5 Antiadherents Function: To prevent sticking of tablet surfaces on punches (upper and lower) Ex: Talk Mg stearate Corn starch Antiadherents Antiadherents Concentration (%) Talc 1-5 Mg stearate <1 Corn starch 3-10 Colloidal silica 0,25-3 DL-Leucine 3-10 SLS <1 Colours/Pigments Function: 1. To enhance better aesthetic appearance and brand image 2. Hide deformation of colours Two types: 1. Water soluble migration 2. Water insoluble better appearance result Colouring agent Colouring agent Name Red 3 Erythrosine Red 40 Allura red AC Yellow 5 Tartrazine Yellow 6 Sunset Yellow Blue 1 Brilliant Blue Blue 2 Indigotine Green 3 Fast Green Flavours and Sweeteners Usually used in chewable, buccal, sublingual, effervescent tablets Sweeteners: 1. Synthetic (ex: saccharine, siclamate, aspartame) 2. Natural (ex: mannitol, lactose, sucrose, dextrose) Flavours and Sweeteners Function: 1. To hide unsatisfactory taste especially for tablets that are intended to dissolve in mouth 2. Increase patient acceptability Method of addition: 1. Liquid form 2. Spray dried Wetting agents To increase water absorption into tablet increase disintegration and dissolution Non ionic surfactant such as SLS are used Usually added towards hydrophobic mixture Dissolution retardants Used for controlled release to slow the release of active compound Ex: stearic acid fat stearic acid esther Dissolution enhancers To increase dissolution so active compound will be released quicker Ex: Fructose Povidone Surfactant Adsorbent To adsorb an amount of liquid Ex: CaPO4 anhydrous Starch Mg CO3 MgO2 SiO2 MgSiO4 Buffer To maintain pH balance stability of drugs Ex: NaCO3 CaCO3 Antioxidant To prevent oxidation of active compound Ex: Ascorbic acid -tocopherol Natriummetabisulfit BHT BHA Chelating agents To prevent autooxidation formed complex with heavy metals prevent catalytic reaction Ex: EDTA Citric acid Tartaric acid Preservatives To prevent microbial growth Ex: Paraben (methyl, propyl, benzyl, butyl)