Tema05 comprimidos

Comprimidos / Tablets

Farmacia y Tecnología FarmacéuticaUniversidad de Navarra

Formas Sólidas Oral: comprimidosJuan M. Irache

1. Introducción: comprimidos (CPs)Preparaciones sólidas, cada una dosis única de uno o más p.a.(s). Se obtienenaglomerando por compresión un volumen constante de partículas y estándestinados 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 partículasestán constituidas por uno o más p.a.(s), a los que se ha añadido o no excipientestales como diluyentes, aglutinantes, disgregantes, deslizantes, lubricantes, sustanciascapaces 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

ENSAYOSUniformidad de contenido, Uniformidad de masa, Disolución



Comprimidos no recubiertosEste tipo incluye los comprimidos de una sola capa, resultantes de una compresiónúnica de partículas, y comprimidos de varias capas, dispuestas paralela o concéntricamente, obtenidos por compresiones sucesivas ejercidas sobre diferentesconjuntos de partículas. ENSAYOS: Disgregación.Comprimidos recubiertosLos comprimidos de este tipo tienen su superficie recubierta con una o varias capasde mezclas de sustancias diversas, como resinas naturales o sintéticas, gomas, gelatina, sustancias de carga inactivas e insolubles, azúcares, plastificantes, polioles, ceras, 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 la evaporación del vehículo. Cuando el recubrimiento es una capa polimérica muy fina, los comprimidos se denominan «con cubierta pelicular». ENSAYOS: Disgregación. Comprimidos de liberación modificadaCps recubiertos o no recubiertos, que se preparan con excipientes especiales, o porprocedimientos particulares o por ambos medios, con el fin de modificar la velocidad, el lugar o el momento de liberación del p.a.(s). Comprimidos gastrorresistentesCPs de liberación retardada destinados a resistir la acción del jugo gástrico y a liberarsu p.a.(s) en el fluido intestinal.



2. Tablets

Advantages of Tablets��Accurate dosage��Easy to administer and patient acceptance (compliance)��Can control release of active

- Delayed release - Extended release

��Stability��Economical to manufacture

Disadvantages of Tablets��Mistaken as candy��Formulation sometimes limited: large dose drugs usually lack theproperties to be formed into tablets��Cannot be administered to patients if vomiting or unconscious��Some patients have difficulty swallowing tablets��Problems in attaining acceptable content uniformity (accuracy and precision of unit dose content) for low dose drugs��Compromised bioavailability (poor drug solubility; malformulation)



2.1. Tablets: formulationLittle amount of drugs / active substances can be directly

compressed (without any other ingredient): boric acid��Active (Drug)

- Compaction and flow properties (compactibility, fluidity, lubricant)- Salt form, polymorphs- Melting point, purity of active, particle size

Affects segregation of powders (blend uniformity)Affects dissolution

Excipients and the method of manufacture areselected to provide these characteristics

��Selection criteria:- Stability and compactibility with other excipients and drug- Technological key points

Uniformity between batchesPhysical properties, prize

��Excipients ClassificationClassical excipients (when granulation is used)Excipients for direct compression



��Manufacturing MethodsGranulation (Wet, Dry): A complex process of first forming granules from the mix and then tableting the granulesDirect Compression: Simply mix and compress

��Choice of Method Depends on Several Factors1. Size of dose

Low doses (< 25 mg): Most of the tablet will be excipients� Content uniformity� Lower dose drugs generally can be compressed by DC

High Doses (> 250 mg): Most of the tablet will be drug� Compactibility and fluidity

2. Compactibility and/or fluidity of drug: usually bad properties- Can compensate for any lack of compactibility and/or lack of flowability by the

use of special direct compression fillers- Can provide lubricity by addition of die wall lubricant- Can help fluidity by adding a glidant- Can assure rapid disintegration by adding disintegrant

3. Other considerations:- Drug solubility (granulation, formula considerations)- Drug stability (granulation)



When DC is not practical, i.e. large-dose, poorly compactible and/or poorly flowing drugs��Granulate

� Granulation is a size enlargement process: Improves Flowability� Addition of a BINDER: Improves Compactibility

The Traditional Granulation Method is Wet Granulation��Involves wetting the powders with binder solution ("glue") and then a drying step.

� Wet Massing Techniques� Fluid Bed Granulation

��Not practical for drugs sensitive to water or heat.� Alternative: dry granulation



2.1.1. Classical Excipients2.1.1.1. Fillers, Diluents / Diluyentes (their use is dependent on the drug dose)��Filler Functions :

Increase the bulk volume: final product has the proper volume for patient handling- drugs used at low doses: < 50 mg and diameter of tablet higher than 5 mm- to minimise incompatibilities: the contact can be reduced by dilution - Selection criteria: compressibility, compactibility, flow

��Filler Requirements:inert, non-hygroscopic, soluble, cheap, compactable, tasteful

��Lactose monohydrate- Natural disaccharide, obtained from milk: one glucose and one galactose moiety- Used as filler or filler-binder in the manufacture of pharmaceutical tablets and capsules Lactose may undergo a Maillard-type condensation reaction with 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 milledGranulac 200, Granulac 230, Sorbolac 400, Granulac® 140Prismalac 40, Capsulac 60, Sachelac 80, Spherolac 100



��Powdered celluloseDerived from a natural polymer, hence it has a variable chain length and variable molecular weight. It is slightly soluble in sodium hydroxide solution. It is used as an adsorbent, glidant, suspending agent, disintegrant and tablet/capsule diluent.

Arbocel®: Filler and binder for wet and dry granulationEmcocel 50M / Vivapur 101: aprox. 50 mm, Bulk density of 0.27 g/mL

Granulation

��Dibasic calcium phosphate (CaHPO4)anhydrous or contains two molecules water.

Practically insoluble in water, insoluble in alcohol and soluble in 3 N HCl. It should not be used to formulate tetracycline antibiotics and has been reportedto be incompatible with indomethacin, aspirin, aspartame, ampicillin, cephalexinand erythromycinGood flow properties, but requires a lubricant when used for tableting. The surface of the particles is alkaline and should not be used with drugs that are sensitive to alkaline pH.



��Starch (rice, wheat, corn, potato)Natural starches contain 10-20% amylose and 80-90% amylopectin. Starches obtained from different sources may not have identical properties. As an example, corn starch contains about 27% amylose, potato starch about 22% and tapioca starch about 17%; these differences provide for different physical properties. It is insoluble in cold water and in alcohol. Starch has no listed incompatibilities

��Sucrose / SaccharoseSucrose may be contaminated with traces of heavy metals that can lead to an incompatibility with active ingredients as ascorbic acid. It also may contain sulfite from the refining process.��Others: mannitol, sorbitol, glucose, calcium carbonate



2.1.1.2. Binders / Agregantes o aglutinantes (2-10%)��Binder Functions:

- To ensure mechanical strength of tablets and granules - To “glue” (promote adhesion) the particles together into granules helping to hold

the overall tablet together: Improves Compactibility- To provide the ¨cohesiveness¨ to a formulation enhancing its compressibility and flow properties (maintain the integrity of the tablet)

- to improve the mechanical strength of a tablet- to improve the flowability of the powder or granules or bothDrawback: significant effect on bioavailability and therapeutic efficacy,

because it affects hardness and friability of tablet

��Binders:- Wet/Solution Binders: Gelatin, Cellulose derivatives, PVP, Starch, Sucrose, PEG- Dry Binders: Cellulose, Methyl cellulose, Polyvinylpyrrolidone, PEG

��Hydrophillic cellulose derivativesHydroxypropylcellulose: Vivapharm®: Low viscosity (1-4%, water, alcohol…) Carboxymethylcellulose (1-4%, water)Ethylcellulose (0.5-2%, alcohol)Methylcellulose (1-4%, water)



��Starch (Starch 1500) (1-4%)As a dry binder, it compresses well, predominately deforming plastically. It can be used with other excipients, such as MCC, lactose, and dicalcium phosphate, to produce tablets with excellent hardness and low friability at usual compaction forces. A slurry of Starch 1500 in cold water provides effective binding properties at higher solids and lower viscosity than traditional starch pastes, which must be heated and prepared at lower concentrations.

��Polyvinylpyrrolidone (PVP): Plasdone (2-5%, alcohol, water)Povidone is a high performance adhesive polymer primarily used as a versatile wet granulation tablet binder. Ii is also used in the formulation of oral liquids and suspensions, parenterals and topical products

��Saccharose / Sucrose (2-20%, water) Microcristal 120��Gelatine (1-4%, water)��Acacia gum (2-5%, water, alcohol)��Tragacanth gum (1-3%, water)��PEG 4000 y 6000��Palmitate stearate glycerol / PEG��Others: glucose, sorbitol, excipients for direct compression (Elcema, Avicel, Emcompress…)



2.1.1.3. Disintegrants / disintegrating agents: 1 al 5%.��Disintegrant Functions: To ensure that when tablets are in contact with water, they are rapidly breaking into smaller fragments, facilitating their dissolution. They function primarily by drawing water into the tablet while simultaneously swelling.

- important for immediate release products where rapid release is required- more effective if added 50% intragranularly, and 50% extra-granularly (i.e., in the final dry mixture)

- 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 derivativesAvicel RC591: mixture of MCC and carboxymethycellulose sodium

��PolysaccharidesAlginic acid, sodium alginate, tragacanth gumGuar gum (Vidogum GH)

��Methylated caseine: Esma Spreng��Colloidal silicon dioxide: Aerosil, Cab-O-Sil��Magnesium Aluminum Silicate: Veegum F



��Disintegrant MechanismsAll are hygroscopic and draw liquid into the matrix ("liquid uptake" or "wicking action")��As they sorb liquid, they may:

Swell extensively (Sodium Starch Glycolate)Recover shape with little swelling (Crospovidone; Starch)Swell radially and straighten out [fibrous material] (Croscarmellose)

��Together, these phenomena create a disintegrating force within the matrix



Superdisintegrants (0.5-2.0%, Can be used up to 5.0%)They draw large amounts of water while simultaneously swellingFor powder filled hard gelatin capsules, 4-8% is usually used. Crospovidone and Starch are not recommended for capsules.��Sodium starch glycolate: Primojel®, Explotab® (1-6%)

High concentrations may cause gelling and loss of disintegration.��Croscarmellose sodium / carboxymethylcellulose: VivaSol®, Ac-Di-Sol (0.5-5%)

High swelling capacity, effective at low concentrations DC: 1-3%, wet granulation: 2-4%

��Soy polysaccharides: Emcosoy® - High-fiber, starch-free disintegrant.��Crospovidone / Cross-linked PVP: Polyplasdone XL (2-4%)

Insoluble in water but it disperses and swells in waterGreatest rate of swelling compared to other disintegrants.

��L-HPC Low-substituted hydroxypropyl cellulose (1-5%)Insoluble in water. Rapidly swells in water.



2.1.1.4. Lubricants 0.5 a 2%.To prevent the compacted powder from sticking to the equipment during the

tabletting. It aids ejection of the tablet from the dies, and may improve powder flow. ��Lubricant RolesTrue Lubricant Role: reducing friction between sliding surfaces, at the tablet-die wall interface during tablet formation and ejection. Also applies to capsule plugs.Antiadhesion Role: Preventing sticking to surfaces. To reduce adhesion between the powder and the punch faces and thus prevent tablet sticking to the punches.Glidant Role / deslizante: Improving flow by modifying the interaction between particles��Concept of a "Lubricant System"

Frequently two substances are used in a formulation to maximize lubricant effect in all three areas: combining magnesium stearate with a colloidal silica

��Lubricant Issues��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



��Magnesium Stearate (< 1%) Blending times should be limited. Overblending can cause compaction problems. ��Stearic Acid (1-5%)Not as effective as magnesium stearate, but used in combination with Mg St, to get a synergistic lubricant effect on punch faces and die walls.Doesn't have the overblending problems seen with MgSt��Vegetable based Fatty Acids (90% palmitic/stearicacid) (3-5%)Good tablet hardness, good for chewable tablets. Less sensitive to overblending than metal stearates. Less reactive, can be used with acidic substances.

��Sodium Benzoate, PEG 20.000, Levilita, glycine, sodium lauryl sulphate��PRUV® (Sodium Stearyl Fumarate) - less reactive hydrophilic lubricantExtremely effective lubricant at low concentrations. ExpensiveDoesn't have the over blending problems seen with MgSt.

Laminar Structure ofMagnesium Stearate



��Glidants (optimum of concentration of about 0.25-0.5%)� Usually added to enhance the flowability of direct compression mixtures.� Higher concentrations needed to correct serious adhesion (sticking) to punch faces��Talc (1-5%)��Starch: Starch 1500 (5-10%)

Good strategy to lower the levels of traditional lubricants (Mg St)��Colloidal silicon dioxide: Aerosil / Aerosil 200 VV or compacted CSD, LabosilAdvantages Aerosil® 200 VV over non-compacted colloidal silicon dioxide include reduced dusting and better handling during weighing and dosing

- Powders/Granules: 0.2-1%. As anti-caking agent, adsorbent moisture 15-50%- Tablets: glidant 0.2-1%, improves hardness and tablet disintegration

Aerosil



Lubricant Typical Level

True Lubricant Activity

Antiadherent Activity

Glidant Activity

Metallic stearates e.g. Mg St, Ca St

0.5 - 1% Excellent Good Poor

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

Lubricants (Magnesium Stearate)Prevent the formulation and formed tablet from sticking to machineryBlending times criticalWeaker tablet compactsSlower drug dissolution

Glidants (Silica / Talc)Improves flowability of powders/granulationAllows formulation to flow easily through tableting machineFlowability measured using angle of repose or Flowdex



2.1.1.5. Miscellaneous��Sorbent: limited fluid sorbing in dry state��Colors: Self apparent��Flavors and Sweeteners

Spray-dried and other flavorsNatural sweetenersArtificial sweeteners

Mask bad taste of drugs/excipientsMask bad odor��Protective Agents��Other



2.1.2. Direct compression excipients��Characteristics- Generally, direct compression Filler-Binders are common fillers that have been physically modified.- Fillers posseses both diluent and binders properties; sometimes, also glidants- In general, these excipients are used in a large amount (50-80%)- Main aspect: Improving Flowability (add glidants)Today, tableting equipment compressing 8,000 to 10,000 tablets per minute.

It is critical to have an excellent flowing granulation/powder blend. Many sugar-based excipients, such as maltose, mannitol, and sorbitol are not

compressible in their natural state and need to be modified for use in direct compression tableting

��Classification: 4 groups- Cellulose derivatives- Starch derivatives- Sugars- Mineral products



2.1.2.1. Celullose and derivativesa) Microcrystaline cellulose, MCC

Binder properties: tablet compactibility: low friabilityInherent lubricant properties: tablets self disintegrate and require little lubricantMost compactible material available for pharmaceutical use

��Avicel PH-101, PH-102, PH-103, PH-105, PH-112, PH-200��Emcocel®: contains a little amount of calcium phosphate��ProSolv SMCC™: combination of MCC and colloidal silicon dioxide. Permits to reduce binder usage by more than half, cutting tablet size consequently. Hence, it is ideally suited to high-dose or multiple actives direct-compression formulations in which it has advantages in both flow and compactibility over conventional MCC.��Others: Vivacel, VivaPur®

b) Powdered celluloses��Elcema: α-cellulose

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

� Solka-Floc® and JustFiber®Rapid disintegration Reduce capping to improve the efficiency manufacturing process and uniformity tablets Ability to absorb moisture



2.1.2.2. Starch and starch derivativesStarch is formed by amylose, glucose and amilopectine.

- Binder- Self-lubricant: permits to reduce the amount of traditionnal lubricants- Super disintegrant: 2-10% of Starch 1500 provides disintegrant action as effective as super disintegrants, greatly reducing costs and improving stability and film coating quality.

- Flow aid: excellent flow properties, demanded by today's high-speed tabletingequipment; ensuring that manufacturers can produce tablets with consistent uniform weight and drug content. In formulations containing starch, it is necessary to include excipients able to increase the compactability (the hardness of the resulting tablet): 5-10% Silartex® or Compressil®(magnesium silicate)

��Starch 1500promotes formulation flexibility by complementing and enhancing the functionality of other excipients.��Sta-Rx® 1500��Paygel® 90



2.1.2.3. Sugarsa. Lactose�Lactochem®: α-monohydrate lactose. Available in sieved and milled forms (this last one for wet granulation). Sieved Lactochem® products have very good flowability and can be used for filling of capsules and sachets, wet granulation tabletting and diluents for direct compression��Lactopress®: 2 different forms, good flowability and excellent compactibility

Lactopress® spray-dried: α-monohydrate lactose particles that are 'glued' by amorphous lactose (up to 15%). Superior compactibility with a spherical shape (high flow). It permits to decrease the amount of lubricants required (0.2% vs 0.5-1%).

Lactopress® anhydrous characterised by superior dissolution and binding properties. Adequate choice for moisture-sensitive actives or formulations for DC. ��Microcelac 100 is a spray-dried compound containing 75 % αααα-lactose monohydrate and 25 % MCC. Both filling properties of lactose and binding capacity of MCC. Low cost. Angle of repose: 34°��Ludipress®: lactose (93.4%), Kollidon® 30 (3.2% PVP, binder) and Kollidon®CL (3.4% cross-linked PVP, flow aid). It is also suitable as a filler for hard capsules��Starlac: Lactose / Starch (85:15)��Others: Zeparox®, DCL-30®, Pharmatose®, Tablettose®, Lactose Fast Flow®, Flowlac 100, Cellactose 80

Ludipress



b) Compressible Sugar� Used in chewable tablets� minigranulation of sugar crystals "glued" together with amorphous dextrins

��Compressible Sugar (95-98% sucrose)It may contain starch, maltodextrin or invert sugar and a suitable lubricant. White, granular, free-flowing powder and sweet taste. Very soluble in water, non hygroscopic, non-reactive with other tablet ingredients. Slightly soluble in alcohol.��Di-Pac®: excellent flowability, high compressibility, low hygroscopicity, sweet and non-reactive. It contains 97% sucrose and 3% maltodextrines. ��SugarTAB®'s excellent carrier for materials with compresion problems��Compressuc®: Saccharose + Maltodextrines��Others: NU-TAB® 4001, Sucre CD1®: Tabfine S100 I

c) Glucose / Dextrose��Emdex® (Dextrates) - The first highly compatible soluble excipient. High flowability and compressibility. Water solubility, sweet, rapid dissolution and freshly sensations in mouth.Glucose (90-92%), maltose (3-5%) and little amounts of polysaccharides.��Tabfine D97 HS®: glucose (97%) and starch (3%) as binder.

d) Fructose / Levulose��Tabfine F94 M®: fructose (96%) and maltose (4%).



e) SorbitolIt is the most common bulking agent for sugar-free products. Its compressibility enables the production of hard and smooth tablets by direct compression techniques.��Neosorb®: for tablets produced either following wet granulation or by DC.

Neosorb60 (10%max>315 µm), Neosorb60W (105-420 µm) Neosorb crystal 20/60 (0.2-1 mm)

f) Mannitol�� Pearlitol®: low hygroscopicity and excellent chemical stability. For different processes: wet or dry granulation, direct compression. It allows sugar-free formulations (including chewing gums), because it is the least soluble and least hygroscopic crystalline polyolg) Maltose�� Advantose™ 100: disaccharide, with flow and tableting properties that are greatly improved by the process of spray drying. Advantose™ particles are spherical with good flow properties. When compared to MCC, it can tolerate greater compression forces without capping upon ejection from the tableting die. It also exhibits lower hygroscopicity and lower reactivity. It can be also used as sugar substitute for great-tasting sugar-free and low-calorie products. h) Maltitol��Maltisorb® is well suited to the formulation of powder forms (sachets, dry syrups, capsules) and tablet forms, whether chewable, suckable, coated or effervescent.



2.1.2.4. Mineral productsa. Dibasic calcium phosphate dihydrate: CaHPO4·2H2O

Binder properties: tablet compactibility ��Emcompress® (Dibasic calcium phosphate dihydrate) - The first directly compressible excipient. Diluyent and binder properties. High density��Emcompress anhidrous®: similar to Emcompress but especially designed fordrugs sensible to moisture��A-TAB® (anhidrous), Calstar®, Di-TAB®b. 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 an efficient and relatively inexpensive tablet and capsule filler. Non-hygroscopic: offers excellent long-term stabilityHigh bulk density and free-flowing characteristics: adequate for high-speed compaction and filling.��CAL-TAB®d. Hydrated magnesium silicateThey increase the compactability, the hardness of the resulting tablets��Silartex®��Compressil®



AvicelFlow Lactose

Star-Lac

Tabletose

Microcelac



Wet Ganulation

Direct compression

Drug

300 mg

1 part

Filler Filler - Binder

Lactose powder 182.5 mg

2-3 parts

Disintegrant

Superdisintegrant

CMC 15 mg (3%)

Starch 10-20% 2-5%

Glidant Colloidal silica 0.5-1%

Lubricant Mg Stearate 2.5 mg (0.5%)

Mg Stearate (0.5-1%)

General Formula for WG and DC Tablet



2.2. Tablets: Manufacturing MethodsMethods of Tablet Preparation

Direct CompressionWet GranulationDry Granulation

2.2.1. Wet GranulationImprove compressibility, flowability, and content uniformity of powder blend

Size drug, weigh and blend with excipientsAdd liquid binder to prepare damp massAdhesion of powdered particles to form granules for tableting (granulation)

aids in holding tablet together after compressionBinding agents: aqueous or organicCautions: overwetting/underwetting

Screen damp massDry and size: spread evenly on shallow trays

temperature and humidity controlled ovens drying in fluid- bed apparatus

Second screening: smaller mesh screenLubricate formulationCompress into tablets





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 cesiónProblemas:- 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)



2.2.2. Dry granulation

Dry Granulation Method (Slugging)Steps:

Size drug, weigh and blend with excipientsCompact large masses of powders : no moisture/binding agent addedCrush and size pieces into smaller granulesLubricate Compress into tablets

Active or diluent must have cohesive propertiesDrugs that degrade in moisture or heat: ASA



Ventajas / Problemas de la granulación por vía seca

VentajasPermite manipulación mecánica sin pérdida de los atributos de la mezclaMejora el flujo de los polvos por aumento del tamaño de partículaMejora la cohesión durante la compactaciónPermite la granulación sin adición de líquidos o uso de calor

ProblemasTamaño 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



2.2.3. Direct compressionDirect Compression: Must be a free-flowing and compressible mixtureSteps: Size drug

Weigh appropriate amounts of active and excipientsBlend with excipientsCompress into tablets

Direct CompressionProblems with high-dose drugs: compressibilityProblems with low-dose drugs: content uniformityMay require glidant to improve flowabilitySegregation in hopper possibleBlending of lubricant critical: weaker tablets, slower drug release

StrategiesDecrease the size of drug particles: micronisatorsFirstly, mix the fine drug with filler-binder product. Then, add the rest of ingredients andMagnesium stearate at the end (mix 3 minutes and compress).

Never mix all the ingredients of the formula (drug andexcipients) in only one step



VentajasMenores costos en instalaciones, tiempo, equipos, energía y espacioElimina problemas en el proceso de granulación debido a la humedad y temperatura (vía húmeda) y presión (vía seca)Facilita la desintegración del CP en las partículas originales del fármacoDisminuye la disparidad de tamaño de partícula en la formulaciónProporciona mayor estabilidad física (disolución) y química

PrecaucionesEs crítico el origen de las materias primas: exigencias de control de calidadDificultad en alcanzar dureza en comprimidos con alto contenido de fármacoDistribución no homogénea de p.a. en bajas dosis debido a mal mezclado (puede ser necesario el uso de mezclas ordenadas)Aumento de tamaño de partícula para aumentar la fluidez del fármaco en dosis altas (disminuye la velocidad de disolución) (necesidad de deslizantes)Sobrelubricación por exceso mezclado (disminución velocidad disolución)Necesidad de precompresión para comprimidos con alto contenido de fármacoLimitaciones para preparar comprimidos coloreados

Estrategias asegurar uniformidad de contenidoOptimizar el empleo de diluyentes para minimizar porosidad formulaciónMezclas ordenadas / Adición de líquidos / Dilución por trituraciónAumentar fluidez

Ventajas / Problemas de la compresión directa



2.2.4. Tableting / CompressionTableting is a COMPACTION��Compression: Reduction in bulk volume by eliminating voids and bringing particles into closer contact��Consolidation: Increased mechanical strength due to interparticulateinteractionsThe Role of the Compressive Force...��Is primarily to bring the adjacent particulate surfaces together so that forces active active at surfaces may form lasting linkages.� Interparticle forces are weak and only significant if the particles are touching one another or very close (van der Waals, H-bonding)� The mechanical strength (e.g. hardness) is a function of the nature of the 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)



2.2.4.1. Tablet presses: single-ended compression (Máquinas alternativas / excéntricas)



Las máquinas de comprimir excéntricas solo necesitan 2 punzones y una matriz o pieza metálica perforada

Los punzones ejercen una fuerza axial sobre el granulado o el polvo. Compresión axial del granulado/polvo dentro de la cámara de compresión de la matriz. Su forma y la de superficies de contacto de los punzones determinan el aspecto del comprimido.

��Etapas esenciales del ciclo de la máquina de comprimir (prensa):- alimentación material granulado o pulverulento con tolva (hopper) dentro cámara de compresión de la matriz- compresión entre los dos punzones- expulsión ‘eyección’ de la masa compactada fuera de la matriz.

Single-punch machine:Main components

Powder hopperPowder feed system

– Feed shoe or feed framePunches and dies





.

PunchesPunches andand diesdies / punzones y matrices/ punzones y matrices



2.2.4.2. Tablet presses multistation / Rotary punch Double-Ended Compression or Rotary (Multi station press) tablet machine55 stations495,000 tabs/hour



Punzón

Matriz / CC Platina móvil

circular



http://en.wikipedia.org/wiki/File:Tablet_press_animation.gif





Excéntricas Rotatorias • Punzón (juego de punzones) se mueve

en 1 dirección. Una o más cámaras de compresión e insertada en una pieza llamada platina. La matriz no se mueve, pero la tolva sí lo hace.

• Punzón superior realiza compresión,

punzón inferior expulsa CP. Punzón superior controla dureza, punzón inferior controla peso.

• Tolva de alimentación única • Baja productividad (200 CP/min) • Fuentes de variación relacionada con el

granulado. Además, la tolva, al desplazarse, genera mucho polvo y no siempre elimina el aire interpuesto, con el riesgo CPs defectuosos.

• Se utiliza para trabajos investigación y producciones de pequeña escala.

• 16-32 punzones que se mueven en 2 direcciones: ambos realizan la compresión. La tolva permanece fija, pero las matrices se mueven dentro de una platina móvil circular de acero. El trabajo de los punzones está controlado por los rodillos de una rueda de oruga metálica.

• La dureza de los comprimidos se regula ajustando la separación entre los dos rodillos con un tornillo. Punzón inferior expulsa el comprimido, punzón inferior controla peso.

• Tolva de alimentación doble • Alta productividad (hasta un millón/hora) • Fuentes de variación relacionada con

granulado y largo de punzones

Máquinas de comprimir: sumario



Tablet Ejection and Ejection Force (EF)Die wall lubricants reduce friction by interposing a film of low shear strength between the tablet mass and the confining die wall…The structure formed must be strong enough to withstand the stresses of decompression,as well as those induced by ejection.

Possible cause of capping/laminationElastic recovery + poor bonding

Capping

Lamination



Alu/Alu blister

http://www.neo-packaging.com/ingles/productos/verproceso.htmFarmacia y Tecnología FarmacéuticaUniversidad de Navarra




2.3. Ensayos ComprimidosUniformidad 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 masaDisolución. Se realizará un ensayo adecuado para demostrar liberación adecuadade 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 otros6, 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. Hacerfuncionar el aparato durante 60 min y examinar el estado de las muestras. Si algunode 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 seisse han disgregado en medio ácido. Los comprimidos con cubierta pelicular satisfacenel 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.



2.3.1. Intermediate product

Tap density tester



2.3.2. In vitro tests of finished tablets��Content Uniformity: assay (HPLC, spectrophotometry …)��Weight Uniformity��Tablet density and/ or diameter��Hardness��Friability��Disintegration��Dissolution

Measuring Hardness(Breaking Force)



��Content Uniformity: assay (HPLC, spectrophotometry …)��Weight Uniformity��Tablet density and/ or diameter��Hardness��Friability: The % weight loss due to chipping, abrasion and erosion ��Disintegration��Dissolution

Friabilator



��Content Uniformity: assay (HPLC, spectrophotometry …)��Weight Uniformity��Tablet density and/ or diameter��Hardness��Friability��Disintegration��Dissolution

Basket-rack deviceFluids: water, SGF, SIF, buffersRecord time required for disintegration

Factors affecting disintegration- Presence of disintegrants- Manufacturing method: granulation vs DC- Pressure used for compression- Tablet hardness



��Content Uniformity: assay (HPLC, spectrophotometry …)��Weight Uniformity��Tablet density and/ or diameter��Hardness��Friability��Disintegration��Dissolution

Tablet dissolution- Apparatus I (basket) and II (paddle)

Round bottom flasks containing dissolution media, 37ºCDosage form placed in the basket or in the flaskMedia mix by paddle or basketSamples withdrawn at specific times intervals and analised

(HPLC, spect.)Passing the dissolution test

All six tablets dissolved to a value that is some % of the dose (i.e. “at least 70% within 45 min”)Similar procedures for capsulesSlightly different for sustained and enteric coated tablets



Cell types.1) Tablet cell 12mm2) Tablet cell 22.6mm 3) Cell for powders and granulates4) Cell for implants5) Cell for suppositories and soft gelatincapsules 6) Temperature-Measuring Head

Other official methods:Flow through cell



PaletasCestilloCeldas de flujo



• 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/search/cas/557-04-0.html

– Degussa Pharma: http://www.degussa4pharma.com/psform.asphttp://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/– JRS Pharma: http://www.jrspharma.com/– Merck Farma y Química, SA:

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/



Referencias

• Máquinas– J. Bonals SA: http://www.jbonals.es/– Manufacturers Directory » Pharmaceutical Equipment & Pharmaceutical Machinery »

Tablet Making Machines: http://catalogs.indiamart.com/products/tablet-making-machines.html

– Riddhi Pharma Machinery: http://www.indiamart.com/riddhipharma/• Aparatos para ensayos :

– Electrolab: http://www.scientificdealers.com/electrolab/ – Erweka: http://www.erweka.com/EN/index.php– PharmaAlliance: http://www.pharma-alliance.net/index.php– Quantachrome Instruments: http://www.quantachrome.com/index.htm– Sotax: http://www.sotax.com/index3.html

• Artículos– Swaminathan V, Kildsig DO. Effect of Magnesium Stearate on the Content Uniformity

of Active Ingredient in Pharmaceutical Powder Mixtures. AAPS PharmSciTech. 2002; 3(3): article 19.

– Lee J. Intrinsic adhesion force of lubricants to steel surface. J Pharm Sci. 2004; 93(9):2310-2318.

– Michoel A, Rombaut P, Verhoye A., Comparative evaluation of co-processed lactoseand microcrystalline cellulose with their physical mixtures in the formulation of folicacid 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)



ReferenciasReferenciasTextos Generales• Faulí y Trillo, C. (1993). Tratado de Farmacia Galénica, Luzán 5, S.A. de

Ediciones, Madrid.• Le Hir, A. (1995). Farmacia Galénica, 6 ed., Ed. Masson, Barcelona.• Vila Jato, J. L. (1997). Tecnología Farmacéutica. Formas Farmacéuticas. Vol.

II, Ed. Síntesis, Madrid.• Aiache, J. M., Aiache, S. y Renoux, R. (1996). Introducción al estudio del

medicamento, 2 ed., Ed. Masson, Barcelona.• Aulton, M.E. (1988). Pharmaceutics. The science of dosage form design.

Churchill Livingstone, New York• L.L. Augsburger, S. W. Hoag, Pharmaceutical Dosage Forms: Tablets. 3rd ed.

Informa Healthcare.New York. 2008



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