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1. Introducción: comprimidos (CPs)                                        Comprimidos / Tablets                           ...
2.1. Tablets: formulation                                                        Manufacturing MethodsLittle amount of dru...
Powdered cellulose                                                                                   Starch (rice, wheat, ...
2.1.1.3. Disintegrants / disintegrating agents: 1 al 5%.                                                   Disintegrant Me...
Glidants (optimum of concentration of about 0.25-0.5%)    Magnesium Stearate (< 1%)                                       ...
2.1.2.1. Celullose and derivatives               2.1.2. Direct compression excipients                                     ...
b) Compressible Sugar                                                                                  e) Sorbitol        ...
General Formula for WG and DC Tablet                                                           2.2. Tablets: Manufacturing...
2.2.2. Dry granulation                                              Ventajas / Problemas de la granulación por vía secaDry...
2.2.4. Tableting / Compression                                                2.2.4.1. Tablet presses: single-ended compre...
Punches and dies / punzones y matrices                                     2.2.4.2. Tablet presses multistation / Rotary p...
Máquinas de comprimir: sumario                                                                                            ...
2.3. Ensayos Comprimidos                                                                                        Uniformida...
Content Uniformity: assay (HPLC, spectrophotometry …)                                                         Content Unif...
Referencias                                                                                                             • ...
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Tema05 comprimidos

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Formulation and preparation of tablets

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  1. 1. 1. Introducción: comprimidos (CPs) Comprimidos / Tablets Preparaciones sólidas, cada una dosis única de uno o más p.a.(s). Se obtienen aglomerando por compresión un volumen constante de partículas y están destinados a la administración por vía oral. Algunos comprimidos se ingieren enteros, otros masticados, otros se disuelven o dispersan en agua antes de su administración y otros deben permanecer en la boca para liberar allí el principio activo. Las partículas están constituidas por uno o más p.a.(s), a los que se ha añadido o no excipientes tales como diluyentes, aglutinantes, disgregantes, deslizantes, lubricantes, sustancias capaces de modificar el comportamiento del preparado en el tracto digestivo, colorantes y aromatizantes. Son generalmente cilindros compactos cuyos extremos son planos o convexos y cuyos bordes pueden ser biselados. Pueden llevar hendiduras para su división, un símbolo u otras marcas. Pueden estar recubiertos. Se distinguen varios tipos de comprimidos para uso oral: - comprimidos no recubiertos - comprimidos recubiertos - comprimidos efervescentes - comprimidos solubles - comprimidos dispersables - comprimidos gastrorresistentes - comprimidos de liberación modificada - comprimidos bucodispersables ENSAYOS Uniformidad de contenido, Uniformidad de masa, Disolución Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. IracheComprimidos no recubiertosEste tipo incluye los comprimidos de una sola capa, resultantes de una compresión 2. Tabletsúnica de partículas, y comprimidos de varias capas, dispuestas paralela oconcéntricamente, obtenidos por compresiones sucesivas ejercidas sobre diferentes Advantages of Tabletsconjuntos de partículas. Accurate dosageENSAYOS: Disgregación. Easy to administer and patient acceptance (compliance)Comprimidos recubiertos Can control release of active - Delayed releaseLos comprimidos de este tipo tienen su superficie recubierta con una o varias capas - Extended releasede mezclas de sustancias diversas, como resinas naturales o sintéticas, gomas, Stabilitygelatina, sustancias de carga inactivas e insolubles, azúcares, plastificantes, polioles, Economical to manufactureceras, colorantes, y, en algún caso, aromatizantes y p.a.(s). Las sustancias empleadasse aplican en forma de disolución o en suspensión, en condiciones que favorezcan laevaporación del vehículo. Cuando el recubrimiento es una capa polimérica muy fina, Disadvantages of Tabletslos comprimidos se denominan «con cubierta pelicular». Mistaken as candyENSAYOS: Disgregación. Formulation sometimes limited: large dose drugs usually lack theComprimidos de liberación modificada properties to be formed into tabletsCps recubiertos o no recubiertos, que se preparan con excipientes especiales, o por Cannot be administered to patients if vomiting or unconsciousprocedimientos particulares o por ambos medios, con el fin de modificar la velocidad, Some patients have difficulty swallowing tabletsel lugar o el momento de liberación del p.a.(s). Problems in attaining acceptable content uniformity (accuracy andComprimidos gastrorresistentes precision of unit dose content) for low dose drugsCPs de liberación retardada destinados a resistir la acción del jugo gástrico y a liberar Compromised bioavailability (poor drug solubility; malformulation)su p.a.(s) en el fluido intestinal. Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache
  2. 2. 2.1. Tablets: formulation Manufacturing MethodsLittle amount of drugs / active substances can be directly Granulation (Wet, Dry): A complex process of first forming granules from the mix and then tableting the granules compressed (without any other ingredient): boric acid Direct Compression: Simply mix and compress Active (Drug) Choice of Method Depends on Several Factors - Compaction and flow properties (compactibility, fluidity, lubricant) 1. Size of dose - Salt form, polymorphs Low doses (< 25 mg): Most of the tablet will be excipients - Melting point, purity of active, particle size Content uniformity Affects segregation of powders (blend uniformity) Lower dose drugs generally can be compressed by DC Affects dissolution High Doses (> 250 mg): Most of the tablet will be drug Excipients and the method of manufacture are Compactibility and fluidity selected to provide these characteristics 2. Compactibility and/or fluidity of drug: usually bad properties - Can compensate for any lack of compactibility and/or lack of flowability by the Selection criteria: use of special direct compression fillers - Stability and compactibility with other excipients and drug - Can provide lubricity by addition of die wall lubricant - Technological key points - Can help fluidity by adding a glidant Uniformity between batches - Can assure rapid disintegration by adding disintegrant Physical properties, prize 3. Other considerations: Excipients Classification - Drug solubility (granulation, formula considerations) Classical excipients (when granulation is used) - Drug stability (granulation) Excipients for direct compressionFarmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidosUniversidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache 2.1.1. Classical ExcipientsWhen DC is not practical, i.e. large-dose, poorly compactible and/or poorly 2.1.1.1. Fillers, Diluents / Diluyentes (their use is dependent on the drug dose)flowing drugs Filler Functions : Granulate Increase the bulk volume: final product has the proper volume for patient handling Granulation is a size enlargement process: Improves Flowability - drugs used at low doses: < 50 mg and diameter of tablet higher than 5 mm Addition of a BINDER: Improves Compactibility - to minimise incompatibilities: the contact can be reduced by dilution - Selection criteria: compressibility, compactibility, flowThe Traditional Granulation Method is Wet Granulation Filler Requirements: Involves wetting the powders with binder solution ("glue") and then a drying inert, non-hygroscopic, soluble, cheap, compactable, tastefulstep. Lactose monohydrate Wet Massing Techniques - Natural disaccharide, obtained from milk: one glucose and one galactose moiety Fluid Bed Granulation - Used as filler or filler-binder in the manufacture of pharmaceutical tablets and Not practical for drugs sensitive to water or heat. capsules Lactose may undergo a Maillard-type condensation reaction with Alternative: dry granulation compounds containing a primary amine group to form brownish coloured products; this is accelerated in alkaline environments. Lactose is listed as incompatible with amino acids, aminophylline and amphetamines. Lactochem milled Granulac 200, Granulac 230, Sorbolac 400, Granulac® 140 Prismalac 40, Capsulac 60, Sachelac 80, Spherolac 100Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidosUniversidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache
  3. 3. Powdered cellulose Starch (rice, wheat, corn, potato)Derived from a natural polymer, hence it has a variable chain length and variable Natural starches contain 10-20% amylose and 80-90% amylopectin. Starchesmolecular weight. It is slightly soluble in sodium hydroxide solution. It is used as an obtained from different sources may not have identical properties. As an example,adsorbent, glidant, suspending agent, disintegrant and tablet/capsule diluent. corn starch contains about 27% amylose, potato starch about 22% and tapioca starch Arbocel®: Filler and binder for wet and dry granulation about 17%; these differences provide for different physical properties. It is insoluble in Emcocel 50M / Vivapur 101: aprox. 50 mm, Bulk density of 0.27 g/mL cold water and in alcohol. Starch has no listed incompatibilitiesGranulation Dibasic calcium phosphate (CaHPO4) anhydrous or contains two molecules water.Practically insoluble in water, insoluble in alcohol and soluble in 3 N HCl. Sucrose / SaccharoseIt should not be used to formulate tetracycline antibiotics and has been reported Sucrose may be contaminated with traces of heavy metals that can lead to anto be incompatible with indomethacin, aspirin, aspartame, ampicillin, cephalexin incompatibility with active ingredients as ascorbic acid. It also may contain sulfite fromand erythromycin the refining process.Good flow properties, but requires a lubricant when used for tableting. Others: mannitol, sorbitol, glucose, calcium carbonateThe surface of the particles is alkaline and should not be used with drugs that aresensitive to alkaline pH. Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache Starch (Starch 1500) (1-4%)2.1.1.2. Binders / Agregantes o aglutinantes (2-10%) As a dry binder, it compresses well, predominately deforming plastically. It can be Binder Functions: used with other excipients, such as MCC, lactose, and dicalcium phosphate, to - To ensure mechanical strength of tablets and granules produce tablets with excellent hardness and low friability at usual compaction forces. - To “glue” (promote adhesion) the particles together into granules helping to hold A slurry of Starch 1500 in cold water provides effective binding properties at higher the overall tablet together: Improves Compactibility solids and lower viscosity than traditional starch pastes, which must be heated and - To provide the ¨cohesiveness¨ to a formulation enhancing its compressibility prepared at lower concentrations. and flow properties (maintain the integrity of the tablet) - to improve the mechanical strength of a tablet Polyvinylpyrrolidone (PVP): Plasdone (2-5%, alcohol, water) - to improve the flowability of the powder or granules or both Povidone is a high performance adhesive polymer primarily used as a versatile wet Drawback: significant effect on bioavailability and therapeutic efficacy, granulation tablet binder. Ii is also used in the formulation of oral liquids and because it affects hardness and friability of tablet suspensions, parenterals and topical products Binders: Saccharose / Sucrose (2-20%, water) - Wet/Solution Binders: Gelatin, Cellulose derivatives, PVP, Starch, Sucrose, PEG Microcristal 120 - Dry Binders: Cellulose, Methyl cellulose, Polyvinylpyrrolidone, PEG Gelatine (1-4%, water) Hydrophillic cellulose derivatives Acacia gum (2-5%, water, alcohol) Hydroxypropylcellulose: Vivapharm®: Low viscosity (1-4%, water, alcohol…) Tragacanth gum (1-3%, water) Carboxymethylcellulose (1-4%, water) PEG 4000 y 6000 Ethylcellulose (0.5-2%, alcohol) Palmitate stearate glycerol / PEG Methylcellulose (1-4%, water) Others: glucose, sorbitol, excipients for direct compression (Elcema, Avicel, Emcompress…) Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache
  4. 4. 2.1.1.3. Disintegrants / disintegrating agents: 1 al 5%. Disintegrant Mechanisms Disintegrant Functions: To ensure that when tablets are in contact with water, All are hygroscopic and draw liquid into the matrix ("liquid uptake" or "wicking action")they are rapidly breaking into smaller fragments, facilitating their dissolution. They As they sorb liquid, they may:function primarily by drawing water into the tablet while simultaneously swelling. Swell extensively (Sodium Starch Glycolate) - important for immediate release products where rapid release is required Recover shape with little swelling (Crospovidone; Starch) - more effective if added 50% intragranularly, and 50% extra-granularly (i.e., Swell radially and straighten out [fibrous material] (Croscarmellose) in the final dry mixture) Together, these phenomena create a disintegrating force within the matrix - some tablet fillers (e.g., starch and MCC) aid in disintegration - Selection criteria: Active / drug disolution, bioavailability Starch and starch derivatives (5-15%) Starch 1500: 2-10% provides super disintegrant actions, reducing costs It has been shown to exhibit a lower propensity for moisture, thus providing excellent stabilization of moisture-sensitive active (eg, aspirin, hydrochlorthiazide). Cellulose derivatives Avicel RC591®: mixture of MCC and carboxymethycellulose sodium Polysaccharides Alginic acid, sodium alginate, tragacanth gum Guar gum (Vidogum GH®) Methylated caseine: Esma Spreng® Colloidal silicon dioxide: Aerosil®, Cab-O-Sil® Magnesium Aluminum Silicate: Veegum F® Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. IracheSuperdisintegrants (0.5-2.0%, Can be used up to 5.0%) 2.1.1.4. Lubricants 0.5 a 2%.They draw large amounts of water while simultaneously swelling To prevent the compacted powder from sticking to the equipment during theFor powder filled hard gelatin capsules, 4-8% is usually used. tabletting. It aids ejection of the tablet from the dies, and may improve powder flow.Crospovidone and Starch are not recommended for capsules. Lubricant Roles Sodium starch glycolate: Primojel®, Explotab® (1-6%) True Lubricant Role: reducing friction between sliding surfaces, at the tablet-die High concentrations may cause gelling and loss of disintegration. wall interface during tablet formation and ejection. Also applies to capsule plugs. Croscarmellose sodium / carboxymethylcellulose: VivaSol®, Ac-Di-Sol (0.5-5%) Antiadhesion Role: Preventing sticking to surfaces. To reduce adhesion between High swelling capacity, effective at low concentrations the powder and the punch faces and thus prevent tablet sticking to the punches. DC: 1-3%, wet granulation: 2-4% Glidant Role / deslizante: Improving flow by modifying the interaction between Soy polysaccharides: Emcosoy® - High-fiber, starch-free disintegrant. particles Crospovidone / Cross-linked PVP: Polyplasdone ® XL (2-4%) Concept of a "Lubricant System" Insoluble in water but it disperses and swells in water Frequently two substances are used in a formulation to maximize lubricant Greatest rate of swelling compared to other disintegrants. effect in all three areas: combining magnesium stearate with a colloidal silica L-HPC Low-substituted hydroxypropyl cellulose (1-5%) Lubricant Issues Insoluble in water. Rapidly swells in water. The most effective true lubricants are hydrophobic and if too much is used, they can interfere with disintegration and dissolution Lubricant generally interfere with bonding and can soften tablets Alkaline metal stearates are incompatible with some drugs, e.g. aspirin and AA Laminar lubricants (Mg stearate, Ca stearate) are "mixing sensitive” Under the rigors of mixing they delaminate: effect equivalent to adding too much lubricant Lubricants are always added last after all other components have been thoroughly mixed (mixing time of 2-5 min) Water soluble lubricants are not as effective: for water soluble tablets Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache
  5. 5. Glidants (optimum of concentration of about 0.25-0.5%) Magnesium Stearate (< 1%) Usually added to enhance the flowability of direct compression mixtures.Blending times should be limited. Overblending can Higher concentrations needed to correct serious adhesion (sticking) to punch facescause compaction problems. Talc (1-5%) Stearic Acid (1-5%) Starch: Starch 1500 (5-10%)Not as effective as magnesium stearate, but used in Good strategy to lower the levels of traditional lubricants (Mg St)combination with Mg St, to get a synergistic lubricant Colloidal silicon dioxide: Aerosil / Aerosil® 200 VV or compacted CSD, Labosil®effect on punch faces and die walls. Advantages Aerosil® 200 VV over non-compacted colloidal silicon dioxide includeDoesnt have the overblending problems seen with MgSt reduced dusting and better handling during weighing and dosing Vegetable based Fatty Acids (90% palmitic/stearic - Powders/Granules: 0.2-1%. As anti-caking agent, adsorbent moisture 15-50%acid) (3-5%) Laminar Structure of - Tablets: glidant 0.2-1%, improves hardness and tablet disintegrationGood tablet hardness, good for chewable tablets. Less Magnesium Stearatesensitive to overblending than metal stearates. Lessreactive, can be used with acidic substances. Sodium Benzoate, PEG 20.000, Levilita, glycine,sodium lauryl sulphate PRUV® (Sodium Stearyl Fumarate) - less reactivehydrophilic lubricant AerosilExtremely effective lubricant at low concentrations.ExpensiveDoesnt have the over blending problems seen with MgSt. Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache 2.1.1.5. Miscellaneous Lubricants (Magnesium Stearate) Sorbent: limited fluid sorbing in dry state Prevent the formulation and formed tablet from sticking to machinery Colors: Self apparent Blending times critical Flavors and Sweeteners Weaker tablet compacts Spray-dried and other flavors Slower drug dissolution Natural sweeteners Lubricant True Antiadherent Glidant Typical Artificial sweeteners Level Lubricant Activity Activity Mask bad taste of drugs/excipients Activity Mask bad odor Metallic stearates 0.5 - 1% Excellent Good Poor Protective Agents e.g. Mg St, Ca St Other Stearic Acid 1-5% Good Good 0 Colloidal Silica <1% 0 Good Excellent Corn starch 5-10% Poor Excellent Excellent Cires 3-5% Excelent Poor 0 Talc 1-5% Poor Excellent Good Glidants (Silica / Talc) Improves flowability of powders/granulation Allows formulation to flow easily through tableting machine Flowability measured using angle of repose or Flowdex Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache
  6. 6. 2.1.2.1. Celullose and derivatives 2.1.2. Direct compression excipients a) Microcrystaline cellulose, MCC Binder properties: tablet compactibility: low friability Characteristics Inherent lubricant properties: tablets self disintegrate and require little lubricant- Generally, direct compression Filler-Binders are common fillers that have Most compactible material available for pharmaceutical usebeen physically modified. Avicel PH-101, PH-102, PH-103, PH-105, PH-112, PH-200- Fillers posseses both diluent and binders properties; sometimes, also Emcocel®: contains a little amount of calcium phosphateglidants ProSolv SMCC™: combination of MCC and colloidal silicon dioxide. Permits- In general, these excipients are used in a large amount (50-80%) to reduce binder usage by more than half, cutting tablet size consequently. Hence, it- Main aspect: Improving Flowability (add glidants) is ideally suited to high-dose or multiple actives direct-compression formulations in Today, tableting equipment compressing 8,000 to 10,000 tablets per minute. which it has advantages in both flow and compactibility over conventional MCC. It is critical to have an excellent flowing granulation/powder blend. Many Others: Vivacel®, VivaPur® sugar-based excipients, such as maltose, mannitol, and sorbitol are not b) Powdered celluloses compressible in their natural state and need to be modified for use in direct Elcema®: α-cellulose compression tableting Elcema P050: 1 - 50 µm; Elcema P100: 1 - 100 µm; Elcema F150: 1 - 150 µm; Elcema G250 granulate: 90 - 250 µm; Elcema G400: 130 - 260 µm Classification: 4 groups Solka-Floc® and JustFiber® Rapid disintegration - Cellulose derivatives Reduce capping to improve the efficiency manufacturing process and uniformity - Starch derivatives tablets - Sugars Ability to absorb moisture - Mineral products Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache 2.1.2.3. Sugars2.1.2.2. Starch and starch derivatives a. LactoseStarch is formed by amylose, glucose and amilopectine. Lactochem®: α-monohydrate lactose. Available in sieved and milled forms (this - Binder last one for wet granulation). Sieved Lactochem® products have very good - Self-lubricant: permits to reduce the amount of traditionnal lubricants flowability and can be used for filling of capsules and sachets, wet granulation - Super disintegrant: 2-10% of Starch 1500 provides disintegrant action as tabletting and diluents for direct compression effective as super disintegrants, greatly reducing costs and improving stability Lactopress®: 2 different forms, good flowability and excellent compactibility and film coating quality. Lactopress® spray-dried: α-monohydrate lactose particles that are glued by - Flow aid: excellent flow properties, demanded by todays high-speed tableting amorphous lactose (up to 15%). Superior compactibility with a spherical shape (high equipment; ensuring that manufacturers can produce tablets with consistent flow). It permits to decrease the amount of lubricants required (0.2% vs 0.5-1%). uniform weight and drug content. In formulations containing starch, it is Lactopress® anhydrous characterised by superior dissolution and binding necessary to include excipients able to increase the compactability (the properties. Adequate choice for moisture-sensitive actives or formulations for DC. hardness of the resulting tablet): 5-10% Silartex® or Compressil® Microcelac 100 is a spray-dried compound containing 75 % α-lactose (magnesium silicate) monohydrate and 25 % MCC. Both filling properties of lactose and binding capacity of MCC. Low cost. Angle of repose: 34° Starch 1500 Ludipress®: lactose (93.4%), Kollidon® 30 (3.2% PVP, binder) and Kollidon®promotes formulation flexibility by complementing and enhancing the functionality of CL (3.4% cross-linked PVP, flow aid). It is also suitable as a filler for hard capsulesother excipients. Starlac: Lactose / Starch (85:15) Ludipress Sta-Rx® 1500 Others: Zeparox®, DCL-30®, Pharmatose®, Paygel® 90 Tablettose®, Lactose Fast Flow®, Flowlac 100, Cellactose 80 Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache
  7. 7. b) Compressible Sugar e) Sorbitol Used in chewable tablets It is the most common bulking agent for sugar-free products. Its compressibility minigranulation of sugar crystals "glued" together with amorphous dextrins enables the production of hard and smooth tablets by direct compression techniques. Compressible Sugar (95-98% sucrose) Neosorb®: for tablets produced either following wet granulation or by DC.It may contain starch, maltodextrin or invert sugar and a suitable lubricant. White, Neosorb60 (10%max>315 µm), Neosorb60W (105-420 µm)granular, free-flowing powder and sweet taste. Very soluble in water, non hygroscopic, Neosorb crystal 20/60 (0.2-1 mm)non-reactive with other tablet ingredients. Slightly soluble in alcohol. f) Mannitol Di-Pac®: excellent flowability, high compressibility, low hygroscopicity, sweet and Pearlitol®: low hygroscopicity and excellent chemical stability. For differentnon-reactive. It contains 97% sucrose and 3% maltodextrines. processes: wet or dry granulation, direct compression. It allows sugar-free SugarTAB®s excellent carrier for materials with compresion problems formulations (including chewing gums), because it is the least soluble and least Compressuc®: Saccharose + Maltodextrines hygroscopic crystalline polyol Others: NU-TAB® 4001, Sucre CD1®: Tabfine S100 I g) Maltose Advantose™ 100: disaccharide, with flow and tableting properties that are greatlyc) Glucose / Dextrose improved by the process of spray drying. Advantose™ particles are spherical with Emdex® (Dextrates) - The first highly compatible soluble excipient. High good flow properties. When compared to MCC, it can tolerate greater compressionflowability and compressibility. Water solubility, sweet, rapid dissolution and freshly forces without capping upon ejection from the tableting die. It also exhibits lowersensations in mouth. hygroscopicity and lower reactivity. It can be also used as sugar substitute for great-Glucose (90-92%), maltose (3-5%) and little amounts of polysaccharides. tasting sugar-free and low-calorie products. Tabfine D97 HS®: glucose (97%) and starch (3%) as binder. h) Maltitol Maltisorb® is well suited to the formulation of powder forms (sachets, dry syrups,d) Fructose / Levulose capsules) and tablet forms, whether chewable, suckable, coated or effervescent. Tabfine F94 M®: fructose (96%) and maltose (4%). Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache2.1.2.4. Mineral productsa. Dibasic calcium phosphate dihydrate: CaHPO4·2H2O Binder properties: tablet compactibility Emcompress® (Dibasic calcium phosphate dihydrate) - The first directlycompressible excipient. Diluyent and binder properties. High density Emcompress anhidrous®: similar to Emcompress but especially designed fordrugs sensible to moisture Flow Lactose A-TAB® (anhidrous), Calstar®, Di-TAB® Avicelb. Tribasic calcium phosphate: Ca3(PO4)2 ; Ca5(OH)(PO4)3 Tri-CAL® WG Tri-TAB®c. Calcium Sulphate: Ca(SO4) ; CaSO4·2H2O Compactrol: calcium sulfate with a particle size ideally suited for use in CD. It is Microcelacan efficient and relatively inexpensive tablet and capsule filler.Non-hygroscopic: offers excellent long-term stabilityHigh bulk density and free-flowing characteristics: adequate for high-speedcompaction and filling. CAL-TAB® Tabletosed. Hydrated magnesium silicateThey increase the compactability, the hardness of the resulting tablets Star-Lac Silartex® Compressil® Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache
  8. 8. General Formula for WG and DC Tablet 2.2. Tablets: Manufacturing Methods Methods of Tablet Preparation Direct Compression Wet Direct Wet Granulation Ganulation compression Dry Granulation Drug 300 mg 1 part 2.2.1. Wet Granulation Improve compressibility, flowability, and content uniformity of powder blend Size drug, weigh and blend with excipients Filler Lactose powder 2-3 parts Add liquid binder to prepare damp mass Filler - Binder 182.5 mg Adhesion of powdered particles to form granules for tableting (granulation) Disintegrant CMC Starch aids in holding tablet together after compression Binding agents: aqueous or organic 15 mg (3%) 10-20% Cautions: overwetting/underwettingSuperdisintegrant 2-5% Screen damp mass Glidant Colloidal silica Dry and size: spread evenly on shallow trays temperature and humidity controlled ovens 0.5-1% drying in fluid- bed apparatus Lubricant Mg Stearate Mg Stearate Second screening: smaller mesh screen 2.5 mg (0.5%) (0.5-1%) Lubricate formulation Compress into tabletsFarmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidosUniversidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache Ventajas / Problemas de la granulación por vía húmeda - Permite el manejo mecánico sin perder la calidad de la mezcla - Mejora características flujo polvos: aumento tamaño y esfericidad partículas - Mejora la cohesión durante y después de la compactación - Reduce el polvo fino y por lo tanto la contaminación cruzada - Permite la incorporación de líquidos a polvos - Hace superficies hidrofóbicas más hidrofílicas - Permite el control de la forma y distribución de tamaño de partículas - Permite recubrimiento gránulos p.a.: mejorar estabilidad o modificar cesión Problemas: - Tamaño de partícula y solubilidad del principio activo (Disolución) - Distribución no uniforme agentes aglutinantes o desintegrantes (Disolución-Dureza) - Segregación de p.a. inducida por amasado y secado (Uniformidad de contenido) - Exposición del p.a. a altas temperaturas y humedad (Estabilidad) - Sobrelubricación (Disolución)Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidosUniversidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache
  9. 9. 2.2.2. Dry granulation Ventajas / Problemas de la granulación por vía secaDry Granulation Method (Slugging) VentajasSteps: Size drug, weigh and blend with excipients Permite manipulación mecánica sin pérdida de los atributos de la Compact large masses of powders : no moisture/binding agent added mezcla Crush and size pieces into smaller granules Mejora el flujo de los polvos por aumento del tamaño de partícula Lubricate Mejora la cohesión durante la compactación Compress into tablets Permite la granulación sin adición de líquidos o uso de calor ProblemasActive or diluent must have cohesive propertiesDrugs that degrade in moisture or heat: ASA Tamaño de partícula y solubilidad de los p.a. (Disolución) Sobrecompactación de los tabletones iniciales (Disolución) Posible sobrelubricación debido al empleo de agentes lubricantes pre y post compresión inicial (Disolución) Erosión y segregación de partículas (Uniformidad de Contenido) Gran nivel de reprocesamiento (Disolución, Dureza-Friabilidad) No es útil para comprimidos con principios activos en dosis bajas Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache 2.2.3. Direct compression Ventajas / Problemas de la compresión directaDirect Compression: Must be a free-flowing and compressible mixture Ventajas Menores costos en instalaciones, tiempo, equipos, energía y espacioSteps: Size drug Elimina problemas en el proceso de granulación debido a la humedad y Weigh appropriate amounts of active and excipients temperatura (vía húmeda) y presión (vía seca) Blend with excipients Facilita la desintegración del CP en las partículas originales del fármaco Compress into tablets Disminuye la disparidad de tamaño de partícula en la formulación Proporciona mayor estabilidad física (disolución) y químicaDirect Compression Problems with high-dose drugs: compressibility Precauciones Problems with low-dose drugs: content uniformity Es crítico el origen de las materias primas: exigencias de control de calidad May require glidant to improve flowability Dificultad en alcanzar dureza en comprimidos con alto contenido de fármaco Segregation in hopper possible Distribución no homogénea de p.a. en bajas dosis debido a mal mezclado Blending of lubricant critical: weaker tablets, slower drug release (puede ser necesario el uso de mezclas ordenadas) Aumento de tamaño de partícula para aumentar la fluidez del fármaco en dosisStrategies altas (disminuye la velocidad de disolución) (necesidad de deslizantes) Decrease the size of drug particles: micronisators Sobrelubricación por exceso mezclado (disminución velocidad disolución) Firstly, mix the fine drug with filler-binder product. Necesidad de precompresión para comprimidos con alto contenido de fármaco Then, add the rest of ingredients and Limitaciones para preparar comprimidos coloreados Magnesium stearate at the end (mix 3 minutes and compress). Estrategias asegurar uniformidad de contenido Optimizar el empleo de diluyentes para minimizar porosidad formulación Never mix all the ingredients of the formula (drug and Mezclas ordenadas / Adición de líquidos / Dilución por trituración excipients) in only one step Aumentar fluidez Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache
  10. 10. 2.2.4. Tableting / Compression 2.2.4.1. Tablet presses: single-ended compressionTableting is a COMPACTION (Máquinas alternativas / excéntricas) Compression: Reduction in bulk volume by eliminating voids and Las máquinas de comprimir excéntricas solo necesitan 2 punzones y una matriz o pieza metálica perforadabringing particles into closer contact Los punzones ejercen una fuerza axial sobre el granulado o el polvo. Consolidation: Increased mechanical strength due to interparticulate Compresión axial del granulado/polvo dentro de la cámara de compresión deinteractions la matriz. Su forma y la de superficies de contacto de los punzonesThe Role of the Compressive Force... determinan el aspecto del comprimido. Is primarily to bring the adjacent particulate surfaces together so that Etapas esenciales del ciclo de la máquina de comprimir (prensa):forces active active at surfaces may form lasting linkages. - alimentación material granulado o pulverulento con tolva (hopper) dentro Interparticle forces are weak and only significant if the particles are cámara de compresión de la matriz - compresión entre los dos punzonestouching one another or very close (van der Waals, H-bonding) - expulsión ‘eyección’ de la masa compactada fuera de la matriz. The mechanical strength (e.g. hardness) is a function of the nature ofthe attractive forces and the area over which they act.Compactibility is... The ease with which mechanically strong tablets can be made. Tablet mechanical strength may be measured by... – Hardness (Breaking strength) – Friability (Resistance to abrasion and chipping) Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. IracheSingle-punch machine:Main components Powder hopper Powder feed system– Feed shoe or feed frame Punches and dies Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache
  11. 11. Punches and dies / punzones y matrices 2.2.4.2. Tablet presses multistation / Rotary punch Double-Ended Compression or Rotary (Multi station press) tablet machine 55 stations 495,000 tabs/hour .Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidosUniversidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache http://en.wikipedia.org/wiki/File:Tablet_press_animation.gif Punzón Matriz / CC Platina móvil circularFarmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidosUniversidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache
  12. 12. Máquinas de comprimir: sumario Excéntricas Rotatorias • Punzón (juego de punzones) se mueve • 16-32 punzones que se mueven en 2 en 1 dirección. Una o más cámaras de direcciones: ambos realizan la compresión e insertada en una pieza compresión. La tolva permanece fija, pero llamada platina. La matriz no se mueve, las matrices se mueven dentro de una pero la tolva sí lo hace. platina móvil circular de acero. El trabajo de los punzones está controlado por los • Punzón superior realiza compresión, rodillos de una rueda de oruga metálica. punzón inferior expulsa CP. Punzón • La dureza de los comprimidos se regula superior controla dureza, punzón inferior ajustando la separación entre los dos controla peso. rodillos con un tornillo. Punzón inferior • Tolva de alimentación única expulsa el comprimido, punzón inferior • Baja productividad (200 CP/min) controla peso. • Fuentes de variación relacionada con el • Tolva de alimentación doble granulado. Además, la tolva, al • Alta productividad (hasta un millón/hora) desplazarse, genera mucho polvo y no • Fuentes de variación relacionada con siempre elimina el aire interpuesto, con granulado y largo de punzones el riesgo CPs defectuosos. • Se utiliza para trabajos investigación y producciones de pequeña escala. Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. IracheTablet Ejection and Ejection Force (EF)Die wall lubricants reduce friction byinterposing a film of low shear strength betweenthe tablet mass and the confining die wall…The structure formed must be strong enoughto withstand the stresses of decompression,as well as those induced by ejection.Possible cause of capping/laminationElastic recovery + poor bonding Capping Alu/Alu blister Lamination http://www.neo-packaging.com/ingles/productos/verproceso.htm Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache
  13. 13. 2.3. Ensayos Comprimidos Uniformidad de contenido. Salvo indicación en contra o excepción justificada, CPs cuyo contenido p.a sea < 2 mg, o < 2% de masa total, satisfacen ensayo A. Uniformidad de masa Disolución. Se realizará un ensayo adecuado para demostrar liberación adecuada de p.a.(s). Si se prescribe ensayo de disolución puede no ser necesario disgregación. Disgregación. CPs no recubiertos: Utilizar agua R. Añadir un disco a cada tubo. Hacer funcionar el aparato durante 15 min y examinar el estado de las muestras. Si los comprimidos no satisfacen el ensayo debido a su adherencia a los discos, repetir el ensayo sobre otros 6, omitiendo los discos. Los CPs satisfacen el ensayo si los seis se han disgregado. No se exige que los comprimidos masticables satisfagan este ensayo. CPs recubiertos: Utilizar agua R. Colocar un disco en cada uno de los tubos. Hacer funcionar el aparato durante 60 min y examinar el estado de las muestras. Si alguno de los comprimidos no se ha disgregado, repetir el ensayo con otros 6, sustituyendo el agua R por ácido clorhídrico 0,1 M. Los comprimidos satisfacen el ensayo si los seis se han disgregado en medio ácido. Los comprimidos con cubierta pelicular satisfacen el ensayo de disgregación antes descrito, excepto que el aparato se mantiene en funcionamiento durante 30 min. No se exige que los comprimidos masticables satisfagan este ensayo.Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidosUniversidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache 2.3.2. In vitro tests of finished tablets 2.3.1. Intermediate product Content Uniformity: assay (HPLC, spectrophotometry …) Weight Uniformity Tablet density and/ or diameter Hardness Friability Disintegration Dissolution Tap density tester Measuring Hardness (Breaking Force)Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidosUniversidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache
  14. 14. Content Uniformity: assay (HPLC, spectrophotometry …) Content Uniformity: assay (HPLC, spectrophotometry …) Weight Uniformity Weight Uniformity Basket-rack device Tablet density and/ or diameter Tablet density and/ or diameter Fluids: water, SGF, SIF, buffers Hardness Hardness Record time required for disintegration Friability: The % weight loss due to chipping, abrasion and erosion Friability Disintegration Disintegration Dissolution Dissolution Factors affecting disintegration - Presence of disintegrants - Manufacturing method: granulation vs DC - Pressure used for compression - Tablet hardness FriabilatorFarmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidosUniversidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache Content Uniformity: assay (HPLC, spectrophotometry …) Weight Uniformity Tablet density and/ or diameter Hardness Friability Disintegration Dissolution Tablet dissolution Other official methods: - Apparatus I (basket) and II (paddle) Flow through cell Round bottom flasks containing dissolution media, 37ºC Dosage form placed in the basket or in the flask Media mix by paddle or basket Cell types. Samples withdrawn at specific times intervals and analised 1) Tablet cell 12mm (HPLC, spect.) 2) Tablet cell 22.6mm 3) Cell for powders and granulates Passing the dissolution test 4) Cell for implants All six tablets dissolved to a value that is some % of the 5) Cell for suppositories and soft gelatin dose (i.e. “at least 70% within 45 min”) capsules Similar procedures for capsules 6) Temperature-Measuring Head Slightly different for sustained and enteric coated tabletsFarmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidosUniversidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache
  15. 15. Referencias • Excipientes – Basf Pharma: http://www.basf-pharma.com/ – Beghin-Say: http://www.beghin-say.fr/pharmafr/ – Borculo Domo Ingredients: http://www.borculodomo.com/milk/lactosaesp/ – Brenntag NV: http://www.brenntag.be/ – Colorcon: http://www.colorcon.com/ – Chem Exper: http://www.chemexper.com/index.shtml?main=http://www.chemexper.com/s earch/cas/557-04-0.html – Degussa Pharma: http://www.degussa4pharma.com/psform.asp http://www.aerosil.com – DMV International: http://www.dmv-international.com/default.asp – FMC Biopolymer: http://www.fmcbiopolymer.com/ – Friesland Foods Domo: http://www.domo.nl/ – International Specialty Products (ISP): http://www.ispcorp.com/ Paletas – JRS Pharma: http://www.jrspharma.com/ Cestillo – Merck Farma y Química, SA: Celdas de flujo http://www.merck.de/servlet/PB/menu/1378040/index.html – Meggle Pharma: http://www.meggle-pharma.de/es/ – PFormulate: http://www.pformulate.com/ – Roquette Pharma: http://www.roquette-pharma.com/ Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. IracheReferencias Referencias• Máquinas – J. Bonals SA: http://www.jbonals.es/ Textos Generales – Manufacturers Directory » Pharmaceutical Equipment & Pharmaceutical Machinery » Tablet Making Machines: http://catalogs.indiamart.com/products/tablet-making- • Faulí y Trillo, C. (1993). Tratado de Farmacia Galénica, Luzán 5, S.A. de machines.html Ediciones, Madrid. – Riddhi Pharma Machinery: http://www.indiamart.com/riddhipharma/ • Le Hir, A. (1995). Farmacia Galénica, 6 ed., Ed. Masson, Barcelona.• Aparatos para ensayos : – Electrolab: http://www.scientificdealers.com/electrolab/ • Vila Jato, J. L. (1997). Tecnología Farmacéutica. Formas Farmacéuticas. Vol. – Erweka: http://www.erweka.com/EN/index.php II, Ed. Síntesis, Madrid. – PharmaAlliance: http://www.pharma-alliance.net/index.php – Quantachrome Instruments: http://www.quantachrome.com/index.htm • Aiache, J. M., Aiache, S. y Renoux, R. (1996). Introducción al estudio del – Sotax: http://www.sotax.com/index3.html medicamento, 2 ed., Ed. Masson, Barcelona.• Artículos • Aulton, M.E. (1988). Pharmaceutics. The science of dosage form design. – Swaminathan V, Kildsig DO. Effect of Magnesium Stearate on the Content Uniformity of Active Ingredient in Pharmaceutical Powder Mixtures. AAPS PharmSciTech. 2002; Churchill Livingstone, New York 3(3): article 19. • L.L. Augsburger, S. W. Hoag, Pharmaceutical Dosage Forms: Tablets. 3rd ed. – Lee J. Intrinsic adhesion force of lubricants to steel surface. J Pharm Sci. 2004; 93(9):2310-2318. Informa Healthcare.New York. 2008 – Michoel A, Rombaut P, Verhoye A., Comparative evaluation of co-processed lactose and microcrystalline cellulose with their physical mixtures in the formulation of folic acid tablets. Pharm Dev Technol. 2002;7(1):79-87. – Chowhan ZT, Chi LH. Drug-excipient interactions resulting from powder mixing. IV: Role of lubricants and their effect on in vitro dissolution. J Pharm Sci. 1986;75(6):542-5455 – Real Farmacopea Española (2005) Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Farmacia y Tecnología Farmacéutica Formas Sólidas Oral: comprimidos Universidad de Navarra Juan M. Irache Universidad de Navarra Juan M. Irache
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