Solid Dosage Forms - Traditional Tabletting, Film Coating, Capsules - King's College London - PDF

Faculty of Life Science & Medicine Dr Hao-Ying Li Formulation & Analysis of Drugs (FAD) MPharm2 Institute of Pharmaceutical Science [email protected] Slides adapted with permission from Dr. Powder Technology To Quality Contro...

Faculty of Life Science & Medicine Dr Hao-Ying Li Formulation & Analysis of Drugs (FAD) MPharm2 Institute of Pharmaceutical Science [email protected] Slides adapted with permission from Dr. Powder Technology To Quality Control Bahijja Raimi-Abraham  Content Overview Role of Pharmaceutics from Lab to the Patient  Particle Size & Methods  Particle Solid State  Powder Milling  Powder Granulation  Powder mixing and flow  Excipients  Traditional Tablet Manufacturing Methods  Tablet Film Coating  Capsules  New formulation and Manufacturing Methods Formulation & Analysis of Drugs (FAD) Tableting Solid Dosage Forms: Traditional Tablet Manufacturing Methods Learning Outcomes: After completing this section, you should be able to:  Discuss the differences between direct compression and other tabletting methods. Explain the advantages and disadvantages of the different methods.  Describe the process of tablet compaction in detail.  Discuss how powder properties can affect tablet compaction.  Discuss common problems that occur during tabletting and how these may be solved. What Is a Tablet? (Summary: Definition Eur. Ph. )  Tablets are solid preparations each containing a single dose of one or more active substances and usually obtained by compressing uniform volumes of particles.  The tablets consist of one or more active substances with or without excipients.  Tablets may have lines or break-marks and may bear a symbol or other markings.  Tablets may also be coated. What Is a Tablet? -Route of administration: Oral Oral administration: o Where a substances is taken through the mouth Per os (P.O). o Medications taken orally are intended to have a systemic effect (reaching the bloodstream). What Is a Tablet? - Route of administration: Oral (GI) o Oral administration is part of enteral administration - Food or drug administration via the human gastrointestinal tract. o Oral administration is the most common route of drug delivery - Convenient, cost effective, and ease of administration = high level of patient acceptability o Obstacles that could affect patient acceptability - Age/disease related dysphagia - Emergency/critical care  What Is a Tablet? - Route of administration: Oral (oral cavity) Drug delivery to the oral cavity  Buccal/sublingual  Local/systemic diseases Advantages Disadvantages Accessibility & removal Saliva can wash drug Avoidance of first pass away effect Small surface area Fast systemic delivery Taste masking required (nitroglycerin/angina) Low permeability of the Patient acceptability oral mucosa Why Tablets for Oral Drug Delivery? Chemical and physical stability Accurate drug dosing Convenient handling Low cost of manufacturing, packaging, shipping  How to Make Compressed Tablets Compressed tablets are the most widely used solid dosage form. They must satisfy a number of physical requirements in terms of hardness, disintegration ability, friability and uniformity. To provide these tablet characteristics in accordance with the chosen ingredients, manufacturers can use different processing technologies: Granulation (wet/dry) Direct compression (powder mix)  How Are Solid Dosage Forms Manufactured? Quality Target Product Profile (QTPP) Physicochemical characterization of API & excipients  Proposed (CMAs, CQAs) dosage form Powder processing: Milling &  Delivery  Particle size characterisation system  Particle Dosage form specific  Strength shape,  Milling manufacture morphology  Mixing Quality Control  Purity  Solid state  Powders Characterisation  Stability  Flowability  Chemical  Granules (CQAs) stability  Pellets  Uniform  Capsules content  Tablets  Uniform weight  Specialised systems  Dosage form specific QC parameters  Stability 12 Tablet Manufacturing Use liquids (binders) for Mechanical force granulation No liquid Wet-G Dry-G Direct Compression Tablet Lubricant Compression Lubricant  Wet Granulation RECAP  Prevents segregation Granulation increases particle size  Improves mixing properties  Improves flow properties  Avoids dustiness  Improves compressibility  Improves appearance  Densifies material  Dry Granulation RECAP Granulation without adding liquids, this is called dry granulation. This operation is achieved using slugging/roller press, which can have different configurations and equipment design. The process is used if the ingredients to be granulated are sensitive to moisture or heat. Direct Compression Excipients API Lubricant Blending Compression Processing Steps API, Excipients Blend Granulation Binder Sieve Sieve Blend Lubricant  Processing of Tablet Manufacturing Direct Compression Advantages: Disadvantages:  Simplified validation  Tablet defects (e.g. sticking,  Highly efficient process capping, lamination) are  Cost effective production usually associated with direct  Reduced strain on API, compression. making it highly suitable for  Excipient choice restricted sensitive APIs Appropriate compressibility  Faster dissolution Good flowability  Lower microbial Stable homogeneity (no contamination demixing) Sticking Capping Lamination How to Make Compressed Tablets Operations involved in tablet manufacturing Types of Tablet Presses Single punch tablet press Multi-station tablet press - Stamping press - Rotary press - Lab scale - Industrial scale Modern Tablet Presses How do they work? Examples of Tablets: Oral Drug Delivery Conventional Tablets Conventional Tablets Effervescent (immediate) (modified release) tablets Chewable Sublingual/Buccal Lozenges tablets tablets Drug-Release Types of Tablets ► Immediate drug release ► Modified drug release  Extended release ○ Diffusion controlled ○ Dissolution controlled ○ Erosion controlled ○ Osmosis controlled  Delayed release Type of Tablets: Immediate Release Formulated to release the API immediately after oral administration. No deliberate effort is made to modify the drug release rate. Immediate-release products Paracetamol 500mg generally result in relatively rapid Fast release drug absorption and onset of Fever accompanying pharmacodynamic effects.  Type of Tablets: Effervescent Tablets Tablets which are designed to dissolve on contact with liquid such as water. Products of compression of component ingredients in the form of powders into a dense mass. They are packaged in blister pack, or with a hermetically sealed package with incorporated desiccant in the cap. Effervescent tablets are becoming increasingly popular in a variety of sectors including supplements and pharmaceutical use due to the ease in which they can be consumed. Often taste better than regular tablets  Type of Tablets: Effervescent Tablets Great alternative for those who may have trouble swallowing either due to illness or age. Older individuals may have difficulty swallowing but need to take medication or supplements on a regular basis and in this respect, effervescent tablets can be a lot easier than having to swallow a tablet. Type of Tablets: Immediate Release VS Extended Release Oscillating drug concentration Extended drug release Toxic Immediate drug release Ineffective  Improved patient compliance  Reduced side effects  Enhanced therapeutic effect  Type of Tablets: Modified Release Extended-release (ER) drug products A dosage form that allows at least a twofold reduction in dosage frequency as compared to that drug presented as an immediate- release (conventional) dosage form. Other terms, such as ER/XR (extended-release), SR (sustained-release ), XL (prolonged release), and CR (controlled-release ), are also used to indicate an extended-release drug product.  Types of Tablets: Extended Release Tablets Diffusion controlled H2O (membrane): Release by diffusion through pores in a water-insoluble membrane H2O Diffusion controlled (matrix): Release by diffusion through pores in a water-insoluble polymer matrix H2O Erosion controlled: Release by erosion of matrix H2O Osmosis controlled: Release by osmotic pressure Dosage forms tend to use one or more of these processes combined!  Extended Release Tablets H2O Diffusion controlled (matrix): Release by diffusion through pores in a water-insoluble swellable polymer matrix  Extended Release Tablets: Concerta XL (Methylphenidate) Osmosis controlled: Release by osmotic pressure H2O  A sophisticated 3-phase delivery system that allows 12 hour symptom control to cover the full active day. The immediate release component provides effective relief from symptoms in the first one to two hours after taking. The extended release components gradually release the remaining MPH, providing attention-deficit/hyperactivity disorder (ADHD) symptom control for school/work and home. Type of Tablets: Modified Release Delayed-release drug products A dosage form that releases a discrete portion or portions of drug at a time other than promptly after administration. Enteric coating : An initial portion may be Methacrylic acid - ethyl acrylate copolymer (1:1) released promptly after administration. Stable in stomach but dissolved in intestine to Enteric-coated dosage forms protect gastric mucosa are common delayed-release Fever/Pain treatment product. Extended Release Tablets: Paraxyl CR (Paroxetine) Antidepressant: Each enteric, film-coated, bilayer, controlled-release tablet contains paroxetine hydrochloride equivalent to paroxetine as follows: 12.5 mg /25 mg. Two layers: (1) A degradable barrier layer (pale yellow 12.5 mg/pink 25 mg); (2) Active material in a hydrophilic matrix (White) Film Coating of Tablets Solid Dosage Forms: Film Coating of Tablets Learning outcomes: After completing this section, you should be able to:  Take any commercial coated tablet product off the shelf, look at the inactive ingredients, and describe what role each component plays in the tablet formulation, including the coating.  Identify, based on the coating excipients, whether the coating will be dissolved immediately in the GI tract or whether the coating will modify drug release.  Explain the mechanisms behind how functional coatings achieve their intended effects.  Describe the process of coating solid dosage forms, including new methods.  Discuss common problems that occur during coating of solid dosage forms and how these may be solved. What Are Coated Tablets? Tablets covered with one or more layers of a mixture of various substances. E.g. Sugars, plasticizers, waxes, coloring material and/or flavoring material. Tablets can either be ‘sugar coated’, ‘film coated’, ‘enteric coated’ or coated to modify how the drug is released into the body (modified release). Each of these coatings are there for different reasons and it is important to understand these reasons.  Why Coat Tablets? Therapeutic Technological  Avoids irritation of  Reduces influence of moisture esophagus and stomach  Avoids dust formation  Avoids bad taste  Reduces influence of  Avoids inactivation of atmosphere drug in the stomach  Improves drug stability  Improves drug  Prolongs shelve life effectiveness  Prolongs & improves Marketing/Patient dosing interval  Avoid bad taste  Improve patient  Improve appearance and compliance acceptability  Improve product identity Types of Coating Sugar coating Film coating (on the basis of a solvent system) ○ Conventional film coating ○ Functional film coating Controlled release coating Other coating methods ○ Compression coating ○ Electrostatic coating ○ Dip coating ○ Vacuum film coating  Types of Coating: Sugar Coating A sugar coating is basically is a thick, hard coating of sugar surrounding the tablet. It is a traditional method used to hide the flavour of particularly unpleasant tasting drugs e.g. ibuprofen and quinine, both of which are very bitter. An advantage of a sugar coating is that it can prevent light or moisture from entering the tablet, which causes the drug to break down too quickly. Types of Coating: Sugar Coating Description of tablets: Smooth, rounded and polished to a high gloss Process: Multistage Process involving 6 separate operations 1. Seal tablet core 2. Subcoating 3. Smoothing 4. Colouring 5. Polishing 6. Printing Types of Coating: Sugar Coating 1. Sealing of tablet core Prevents contact of tablet core with water Strengthens tablet core Sealants are typically polymers Applied as alcohol solutions 2. Subcoating Addition layers of coating to obtain desired shape Accomplished by Application of gum/sucrose solution followed by powder dusting Application of a suspension of dry powder in the gum/sucrose solution followed by drying Types of Coating: Sugar Coating 3. Smoothing Application of dilute syrup to improve surface appearance 4. Coloring Using either water-soluble dyes or water-insoluble pigments 5. Polishing Application of a wax surface to improve appearance 6. Printing To aid in identification Sugar Coating: Disadvantages Process is tedious and time- consuming Requires the expertise of highly skilled technician Tablet size and weight are almost doubled Batch-to-batch variability Cariogenic ○ Causing tooth decay  Types of Coating: Film Coating Film coating: Deposition of a thin polymer film surrounding the tablet core  Process: Single stage process, which involves spraying a coating solution containing the following:  Polymer  Solvent  Plasticizer  Colourant (Image 1-4) The solution is sprayed onto a rotating tablet bed followed by drying which facilitates the removal of the solvent leaving behind the deposition of thin film of coating materials around each tablet. When to Apply Film Coating? The following questions should be addressed: Is it necessary to mask objectionable taste, colour or odour? Is it necessary to control drug release? What tablet properties (size, shape, colour) constrain the developmental design? Note: The shape, size and especially COLOUR are essential to patient identification and thus tablet marketing strategies. Film Coating Process 1. Coating liquid (solution or suspension) contains a polymer in a suitable medium together with other ingredients, such as pigments and plasticizers. 2.The coating liquid is sprayed onto a rotating tablet bed (see below) or a fluidized bed (see next slide). 3.Drying (removal of the solvent) so as to leave a thin film around tablet core.  Film Coating Process: Drum Coating The coating liquid is sprayed onto a rotating tablet bed  Film Coating in a Fluidized Bed Wurster film coating = Polymeric solution is sprayed from the bottom into a fluidized bed of tablets. Coating and drying are combined in one process. Film Coating in a Fluidized Bed Wurster film coating = Polymeric solution is sprayed from the bottom into a fluidized bed of tablets. Coating and drying are combined in one process. Main Components in a Tablet Film Film formers (immediate release and functional film coating) Solvents Plasticizers Colourants & opaquants-extenders Immediate Release Film Formers Immediate release coatings do not affect tablet disintegration, drug dissolution or drug bioavailability Reasons for use:  See slide on Why Coat Tablets? Example of material:  Hydroxypropyl methyl cellulose (HPMC) Functional Coatings: Enteric Film Formers An enteric coating is a polymer barrier that prevents its dissolution or disintegration in the gastric environment Reasons for use:  To prevent degradation of acid sensitive API  To prevent irritation of stomach by certain drugs like sodium salicylate  Delivery of API into intestine  To provide a delayed release component for repeat action tablets Example of material: Eudragits, Polyvinyl acetate phthalate (PVAP) Functional Coatings: Sustained Release Film Formers Sustained release coatings resist dissolution or disruption at all pH values; drug release is diffusion-controlled Reasons for use:  To control the release rate of a drug over a specific period of time  To reduce the dosing frequency of the drug  To increase patient compliance Example of material:  Ethylcellulose (EC) Ideal Film Former Properties  Chemically inert, non-toxic  Capacity to form a smooth, elegant film  Soluble in the solvent of choice  Compatibility with other film  Solubility requirement for excipients intended use (e.g. controlled release, immediate release, etc.)  High resistance to cracking  Low enough viscosity for easy  No bridging or filling of tablet spraying embossments  High stability against heat, light,  Compatible with printing moisture, air and tablet procedures components  No colour, taste or odour Film Additives: Plasticizers  Important class of low molecular weight non- volatile compounds that are widely used in polymer industries as additives  Improve flexibility and handling of films Example of material: Polyethylene glycol 400 (low m.w. liquid state) Organic esters: diethyl phthalate, dibutyl sebacate Oil/glycerides: fractionated coconut oil Film Additives: Colourants Permitted colorants in a film coat formulation are water-insoluble colours (pigments). Advantages over water-soluble colors: Chemically stable towards light Better opacity and covering power Enhance impermeability of a given film to water vapor  Iron oxide pigments  Titanium dioxide  Aluminium lakes  Film Additives: Colourants There are a number of reasons to colour tablets, including: Identification.  To help pharmacists and patients on multi-dosage regimes.  A patient will often refer to the colour and shape of dosage form rather than the generic nomenclature and dosage level of the tablet. Film Additives: Colourants Quality perception.  Colour can be added to increase the aesthetic value of the product, thereby increasing the perception of quality Counterfeit prevention.  The development of unique colours for a particular active drug and the application of coloured printing can help to reduce the risk of counterfeiting. Film vs Sugar Coating FEATURES FILM COATING SUGAR COATING Tablet: Appearance Retain core contours, not Rounded with a high as shiny degree of polish Weight increase 2-3% 30-50% Logo or ‘break lines’ Possible Not possible Process Operator training Usually automated, less Considerable skills skills required required Adaptability to GMP Easy Difficulties may arise Process stages Usually single stage Multistage process Functional coatings Easily adaptable for Not usually possible controlled release apart from enteric coating Types of Coating Sugar coating Film coating (on the basis of a solvent system) Conventional film coating Functional film coating Controlled release coating Other coating methods ○ Compression coating ○ Electrostatic coating ○ Dip coating ○ Vacuum film coating Compression Coating Compression coating uses compression to form a coat of material around a pre-formed core. Used mainly to separate chemically incompatible materials. A dry process Electrostatic Coating  Phoqus Ltd.’s electrostatic coating process is based on photocopying technology.  It can be used to create tablet coatings with highly distinctive patterns important to brand identification.  The technology may also be used to load very low dose drugs onto tablets. Vacuum Film Coating In vacuum film coating a sealed container containing tablets is heated by a water bath and placed under vacuum. The coating solution is sprayed into the container and evaporated solvent is removed using a vacuum pump.  Very low energy requirements  High coating efficiency  Organic solvents may be used with minimal environmental impact or safety concerns Coating Problems and Remedies Picking = Tablets stick together Solution: Decreasing the spray rate, increasing the inlet air temperature Pitting = Occurs when temperature of the tablet core exceeds the Chipped tablets melting point of the material= pinholing Chipping = The film becomes chipped and dented, usually at the edges of the tablet Solution: Decreasing the speed of drum rotation, increasing the hardness of the film Coating Problems and Remedies Roughness or orange peel The film is rough with a surface appearance similar to that of a orange Uneven spreading of coating before drying ‘Orange peel’ Mottling An uneven distribution of color within the film coating Cracking is a result of: Post-compaction stress relaxation in tablet Stress incurred during drying Formulation & Analysis of Drugs (FAD) Hard Capsules  What are hard capsules?  What do they contain?  How are they made?  What are their advantages and limitations? Solid Dosage Forms: Hard Capsules Learning outcomes: After completing this section, you should be able to:  Take any commercial hard capsule product off of the shelf, look at the inactive ingredients (including the shell), and describe what role each component plays in the formulation.  Discuss the differences between tablets and capsules as solid dosage forms. Explain the advantages and disadvantages of the formulations.  Describe the process of hard capsule manufacture in detail.  Discuss how fill properties can affect hard capsule manufacture. Capsules Solid dosage forms consisting of a shell and a fill, designed to enclose and administer medications Advantages  Precise dosing.  Masking taste and odour.  Customizable formulations.  Ease of swallowing.  Require fewer excipients Disadvantages  Limited capacity for high-dose drugs.  Moisture-sensitive formulations.  Specialized manufacturing equipment may be required. Oral delivery of the neat active in pre-clinical animal studies Chemical structure Coni-Snap Gelatine Capsules Advantages A tapered rim on the body engages easily with the cap allowing for problem-free closure A dual snap-ring locking system provides full circumference leak-free containment Air vents allow air to escape during filling on high-speed capsule filling machines Rounded hemispherical ends are stronger and more resistant to deformation at high speeds How Are Hard Capsule Shells Made?  30-40 % in demineralized water  60-70 0C  Colourants and pigments  Degas under vacuum How Are Hard Capsule Shells Made?  Required viscosity of solution achieved  Pins completely submerged in the solution How Are Hard Capsule Shells Made?  Drying in furnace  Control temperature and humidity for moisture removal Advantages of Hard Capsules Advantages of Hard Capsules Ultra-Long-lasting Pill Can Release Medication Needed for Weeks Soft Capsules or Softgels  What are soft capsules?  What do they contain?  How are they made?  What are their advantages and limitations?  What Are Soft Capsules? Soft capsules are formed, filled and sealed in one single operation. The result is a one-piece hermetically sealed gelatin capsule with an extremely long shelf life. Softgels are the most preferred and advanced oral dosage form available. Consumers prefer soft capsules to other solid dosage forms.  Benefits of Soft Capsules  Excellent dosage precision and uniformity  Enhanced stability and long shelf life: minimal degrading of the active ingredients, minimal influence of light and oxygen  Bio - Organic certification for several ingredients  Unique shapes, sizes and forms  Easy to swallow Organic certification is  Neutral flavour and taste a certification process for producers of organic food and  Wide range of ingredients other organic agricultural products. Rotary Die Method of Manufacturing Soft Capsules Seam Developed by R.P. Scherer in the 1930’s Rotary Die Method of Manufacturing Soft Capsules Seam Globex Seamless Method of Manufacturing Soft Capsules Oil + drug Heated gelatin + plasticizer+ dye Drug encapsulation in gelatin droplets Seamless capsules Cooled oil for gelatin solidification  Content Overview Role of Pharmaceutics from Lab to the Patient Day Date Title Thu 26-SEPT (Powder Technology) Particle Size Methods (Powder Technology) Summary Particle Size Methods Fri 27-SEPT (Powder Technology) Pharmaceutical Solid State (Powder Technology) Pharmaceutical Solid State (Powder Technology) Powder Processing: Milling, mixing & flow Thu 03-OCT (Powder Technology) Powder Processing: Granulation (Solid Dosage Forms) Excipients (Solid Dosage Forms) Traditional Tablet Manufacturing Methods Fri 04-OCT (Solid Dosage Forms) Tablet Film Coating (Solid Dosage Forms) Capsules Thu 10-OCT (Solid Dosage Forms) New Formulation and Manufacturing Methods (Solid Dosage Forms) Summary of Solid Dosage Forms (Quality control of solid dosage forms) Quality Control & Product Quality Issues Fri 11-OCT (Quality control of solid dosage forms) Quality Control & Product Quality Issues Thu 24-OCT Q/A Supportive Tutorial