Solid Dosage Forms PDF

Tablets/Caplets  Tablets are the most widely used oral dosage forms o Two types – compressed, molded  Tablets are solid dosage forms that consist of one or more active ingredients together with various excipients.  One may start with the drug in a very fine powder form, and then proceed to compre...

Tablets/Caplets  Tablets are the most widely used oral dosage forms o Two types – compressed, molded  Tablets are solid dosage forms that consist of one or more active ingredients together with various excipients.  One may start with the drug in a very fine powder form, and then proceed to compress/mold it into a single dosage unit. Tablets/Caplets  Advantages o Convenient and compliance o Large scale manufacturing at minimal cost/dose (compared to capsules) o Exact dose (1 table = 1 dose)  Disadvantages o Unit dose (inflexible dosage form) -Dose adjustment errors when splitting o Dose >20% of total tablet weight, difficult to compress/swallow o Swallowing difficulties -Can dose adjust by -Perception splitting/crushing -Accessibility (e.g., visually impaired) o Different shapes, sizes -Trademarking -Identification o Good stability -Coatings Tablet Size and Shape               discoid oval - Premarin square - Capoten pentagonal - Decadron heptaonal - Ascendin oblong – Isoptin SR triangular - Tofranil hexagonal - Inderal octagonal – Levsin/SL kidney - Thalidone mottled – Bellergal-S holes – Valilum layered - Robaxisal embossed - Tranxene Embossing, color, shape, etc adds to appearance and I.D. Typical Tablets  Compressed tablet (CT) – e.g. aspirin  Sugar coated tablet (SCT) – e.g. Dimetapp  Film coated tablet (FCT) – (Aquacoat, LustreClear are film coatings), e.g. K-Tab  Enteric coated tablet (ECT) – e.g. Dulcolax, Arthrotec (Searle) Special Tablets  Buccal Tablets o Tablets that are intended to be placed between the cheek and gums (buccal cavity). They are formulated to dissolve slowly.  Sublingual Tablets o Tablets that are placed under the tongue to quickly dissolve and release the drug. The drug enters the blood stream via the capillary bed beneath the tongue. e.g., Nitroglycerin, Lorazepam  Chewable Tablets o These tablets are supposed to be chewed before swallowing; usually contain sugars or flavoring agents (e.g., sorbitol, mannitol) e.g. multivitamins, antacids, antibiotics  Lozenges/Troches/Lollipops o Intended to be dissolved slowly in oral cavity for localized effects o flavors and sweeteners are added to make palatable o prepared by fusion or candy molding process Lozenges  Lozenges commonly used for local action in mouth/ throat; e.g. antiseptics, antibiotics, demulcents, or astringents Troches (trOH-keys) (polyethylene glycols)  Prepared and dispensed in plastic calibrated molds that contain an accurate and precise dosage unit.  Historically used as mouth and throat pain relievers but recently being used for natural hormone replacement therapy (systemic), anesthetics (Cepacol), antifungal (Mycelex), and other combinations of medicines In practice the term Lozenges and Troches are used interchangeably. https://www.youtube.com/watch?v=ugxfuLUqBW4 https://www.youtube.com/watch?v=nMDwhYm9OBE  Multiple Compressed Tablets o Tablets made by more than one compression o Can be used for extended release o Two Types: -Layered tablet compression of an additional granulation on a previous compressed granulation, i.e., 2-3 layer tablet -Tablet in tablet compress second granulation on first preformed tablet  Buffered Tablets o tablets are prepared with buffers to minimize drug irritation to upper GI tract. e.g. Tribuffered Aspirin  Effervescent Tablets o To be placed in water to release carbon dioxide for flavor or assist with disintegration and dissolution, e.g. Alka-seltzer  Instant Disintegrating/Dissolving Tablets o Designed to disintegrate without the need for chewing or a liquid, e.g. Zofran ODT; pediatric and geriatric uses (patients with difficulty swallowing)  Tablet Triturates “molded tablets” o Tablets made for oral administration by a pharmacist Ingredients in a typical tablet formulation Others- Buffers, Flavors, Colorants Advil manufacturing process: http://www.youtube.com/watch?feature=player_detailpage&v=d4ELztGCAI8 Overview of Tablet Production: WET GRANULATION DRY GRANULATION DIRECT COMPRESSION 1. Milling and mixing of drugs and excipients 1. Milling and mixing of drugs and excipients 1. Milling and mixing of drugs and excipients 2. Preparation of binder solution 2. Compression into slugs or roll compaction 2. Compression of tablet 3. Wet massing by addition of binder solution or granulating solvent 3. Milling and screening of slugs and compacted powder 4. Screening of wet mass 4. Mixing with lubricants and disintegrants 5. Drying of the wet granules 5. Compression of tablet 6. Screening of dry granules 7. Blending with lubricant and disintegrants to produce “running powder” 8. Compression of tablet https://youtu.be/zbvKS7yryhg Comminution & Milling (particle size reduction) Objectives • increase the available surface area – to improve bioavailability • regulate flow properties of a powder (uneven flow causes segregation of API) • regulate the uniformity of powder mixes (non-uniformity causes unacceptable tablet weight uniformity) • Ensures compressibility and retention of tablet Common tableting problems: Capping (splitting) Blending & Mixing Objectives     to produce uniform dosage forms to blend together active drug and diluents or other excipients to admix granulating fluids in powders Blending of dried granules and lubricants Manual - Small scale  Mortar and pestle – crushing/grinding of materials into a fine paste or powder  Spatulation - combining materials by continuously heaping them together and smoothing the mass out on a smooth surface with a spatula Granulation  Prepare agglomerates of smaller particles  Granules are free flowing o used for filling tablet or capsule machines  Prepared by wet and dry methods o passed through screens of desired size High Shear Granulator Screw Granulator High Shear Granulator Fluid-Bed Granulator Granulation Granulation - https://youtu.be/ZnQrZo0zbjE Extrusion - http://www.youtube.com/watch?feature=p layer_detailpage&v=FspZayc7Pyg Spheronization - https://youtu.be/w1pxsuO9i9o Note that granules can also be used in gelatin capsules Disintegration Agents  Disintegrants are hydrophilic agents added to formulations to promote the breakup of the tablet into smaller fragments, thereby increasing the available surface area and promoting release of the drug substance. o Capillary Action o Swelling o Gas Producing (effervescent) Gas producing Hard Gelatin Capsules - HGCs • A two-piece hard gelatin capsule was patented by James Murdoc, London, England 1865 • Capsules are usually made largely from gelatin  they contain 12-16% water when “dry”  if too much water is removed, they may become brittle and break easily  if stored under high humidity conditions the gelatin may absorb too much water and become too soft to use  also contain  colorants – identification  opacifying agents – protect from light, e.g., titanium dioxide • Soluble in water, gastric fluid, intestinal fluid • Immediate Release  generally dissolve in the stomach within 10-20 minutes Capsule filling process - https://youtu.be/HoKjepJ4osU Advantages • • • • • • convenient easily compounded exact doses (compared to other powder dose forms) can be sealed oily (non-polar) liquids can be filled commercial capsule dosage forms can be made readily identifiable by different color combinations, printed letters or numbers on caps Disadvantages • cannot be filled with polar liquids – water or glycerin, propylene glycol • cannot be filled with very hygroscopic or deliquescent (melting) substances, or efflorescent substances • not useful for volatile compounds • since contents are usually released in the stomach, drugs that are irritating to the stomach may cause nausea (vs. enteric coated tablet) • capsules will soften or become sticky if stored in un-sealed containers under humid, tropical conditions • Unit dose Various sizes and colors of HGCs HCG manufacturing process http://www.rjengineering.com/process.htm  Preparation o o o o Gelatin solution is moulded onto metallic pins Pin bars are removed and dried Capsule halves are stripped from the pins Cap and base are cut to proper length and joined Approximate Capacity of Gelatin Capsules Capsule Size and Volume (mL) 000 00 0 1 2 3 4 5 Examples of Drug Capacity (mg) 1.40 0.95 0.70 0.50 0.37 0.30 0.25 0.15 Aspirin 1040 650 520 325 260 195 160 100 Quinine Sulfate 650 390 325 225 195 130 100 65 Sodium Bicarbonate 1430 975 715 510 390 325 260 130 Common HGC Excipients  Diluents o Bulking agents o e.g. lactose monohydrate, microcrystalline cellulose, mannitol, magnesium carbonate  Lubricants o lubricants keep the formulation ingredients sticking to the machine parts and to improve formulation flow in the machine o e.g. magnesium stearate – usually <1%, stearic acid, talc  Disintegrating agents o disintegrants improve release of the drug from granules  Surfactants o to improve the wettability of a formulation, bioavailability o e.g. sodium lauryl sulfate Soft Elastic Gelatin Capsules – SECs  Appearance o Soft, elongated or globular gelatin shells containing sufficient plasticizer (glycerin or sorbital) to retain flexibility o produced in a variety of shapes, sizes, colors  Uses o most often for single liquid or mixture of liquid drugs  Manufacture and Production o Require specialized equipment, not compounded extemporaneously  Examples o o o o Nifedipine – Procardia Chloral Hydrate – Noctec Digoxin – Lanoxicaps Dutasteride - Avodart Manufacture of SEC: https://youtu.be/uUrKRphf6GI  Advantages o improved bioavailability – increased drug absorption o Masks tastes of liquid formulations o enhanced drug stability – protection against oxidation, photodegradation, and hydrolysis in lipophilic systems o superior patient compliance/consumer preference (ease of swallowing, appealing appearance, absence of objectionable taste, and convenience) and pharmaceutical elegance o excellent dose uniformity o better tamper evidence – tampering leads to puncturing and visible leakage o safer handling of highly potent or cytotoxic drug compounds  Disadvantages o specialized manufacturing equipment requirements o Heat/moisture sensitive o Unit dose Components of a SEC  Capsule Shell – similar to HGC o o o o o o o gelatin plasticizer – glycerin, sorbitol, propylene glycol water preservatives, colorants opacifying agents – titanium dioxide flavoring agents e.g. ethyl vanillin and essential oils  Capsule Filling Material o single liquid, blends of miscible liquids. solutions of solid(s) in liquid(s) suspensions, semisolids SEC drug encapsulation process: http://www.youtube.com/watch?feature=player_detailpage&v=pu9b vGlCxVc Coatings  Reasons for Coating • To improve stability • • • • • o to protect hygroscopic “water proofing” or unstable active ingredients o Light, air o Separate incompatible ingredients into the core and the coat To mask unpleasant tastes To provide a more readily identified product Improve compliance – easier to swallow? To control the site of drug release (e.g. enteric coating) To control the rate of drug release o sustained or controlled delivery (e.g. osmotic pump)  Types of Coatings • Sugar Coating • Film Coating Sugar Coating  Widely used process of a relatively thick high-quality coating consisting mainly of sucrose o aqueous-based!  Many thin coats are applied to build up coating thickness to 0.5 mm or more.  The coating may weigh as much as the original compressed tablet. o a major disadvantage Immediate Release Film Coating  A solution of a film forming material is applied to the tablets and dried rapidly  The films are very thin, much like paint films except that they are usually water soluble or will disintegrate in the presence of aqueous solutions.  Film coatings can be applied very rapidly  More versatile than sugar coating o Functional film coating, e.g. enteric coatings Enteric Coating – Functional film coating Enteric coatings prevent disintegration/dissolution in the acidic environment of the stomach but allow the tablet to release its contents in the less acidic juices in the intestines. Reasons for Enteric Coating: 1. to protect drugs that are degraded by gastric juices (acid labile) 2. to prevent irritation of the stomach, e.g., iron compounds 3. to provide higher concentration of drug in the intestinal tract for local effect, e.g. intestinal antiseptics, intestinal enzymes 4. to prevent nausea or vomiting, 5. to delay the release of the medication Advantages of Film Coating  No significant increase in tablet weight o reduced shipping volume and storage space  Resistant to chipping and cracking  Embossed monograms or logos on compressed tablet are visible Disadvantages of Film Coating  Use of organic solvents o Toxicity, flammability, enviropollution Film Coating Materials  Film Formers o Water insoluble and soluble polymers requiring organic solvents o Latex or pseudolatex dispersions (Aquacoat) may be used o Must not affect bioavailability  Solvents o Organic solvents/mixtures : methylene chloride, acetone; Expensive and not environmentally friendly o Water – Latex type; Safer but long time for water base to evaporate  Plasticizer – to improve flexibility of coating, reduces cracking o Water insoluble or soluble (e.g. Triacetin, propylene glycol, glycerin)  Opacifiers/colorants – improve appearance, identification o Titanium Dioxide  De-tackifiers – to reduce stickiness of the film o Talc A typical aqueous film coating  Film forming polymer (7-18%) o Ex: cellulose ether polymers (HPMC, hydroxypropyl cellulose, methylcellulose)  Plasticizer (0.5-2.0%) o Ex: Glycerin, propylene glycol, PEG, diethyl phthalate, dibutyl subacetate  Colorant and opacifier (2.5-8%) o Ex: FD&C or D&C lakes and iron oxide pigments  Vehicle o Water to make 100% Methods of Coating • Pan Coating  Motor driven rotating coating pans that have attached exhaust and hot air fixtures are used. For final polishing of sugar-coated tablets, a canvas line pan is used. http://www.youtube.com/watch?feature=player_detailpage &v=oqCsbManpYs Methods of Coating • Air Suspension Coaters - great for granules http://www.youtube.com/ watch?feature=player_det ailpage&v=snLEMu1NAd M