Drug Manufacture: Solid Dosage Forms

• Drug manufacture: Solid Dosage Forms
• Topics include powders and granules, granulation, drying, tablets and compaction, coating of tablets and multiparticulates, hard gelatine capsules, soft gelatine capsules, and rectal and vaginal drug delivery

Powders and Granules

• Powders are the simplest dosage forms and the basis for tablets, capsules, etc.
• Many drugs or ingredients exist as powders before processing
• Powders were originally for administering hard vegetable drugs like roots, barks, and woods
• Powders were also convenient for dispensing insoluble chemicals like calomel, bismuth salts, and chalk
• Divided powders are convenient way for administering bitter or nauseous drugs

Advantages vs Disadvantages of Powders and Granules

• Advantages: Chemical stability (2-3 years) and ability to dispense large doses
• The dissolution rate is faster compared to tablets or capsules
• Disadvantages: Large volume, taste masking problems, and not appropriate for potent drugs with low doses
• Not suitable for drugs inactivated in or cause damage to the stomach

Preparations of Powders and Granules

• Bulk powders:
• Divided powders: individual doses that are separated and wrapped
• Hygroscopic, volatile e.g. effervescent powders in plastic laminates for moisture protection
• Bulk granules: contain similar medicaments to powders, with low toxicity, and high-dose drugs
• Divided granules: one dose is individually wrapped with protective packaging
• Dusting powders:

Powder Characterization

• Particle size
• Flow properties
• Quantity of material to be treated

Obtaining Powders as Dosage Forms

• Powders contain one or more drug powders, with excipients
• Mixing all components and the operation's validation are very important
• The aim of mixing is to obtain a homogeneous association of several solid products
• Each fraction or dose sampled must contain all the components in the same proportion
• A good mixture requires consideration of the raw material, the finished mixture, equipment, and operating conditions

Factors Influencing Mixing

• Particle size is the most important factor; mixing powders should have similar characteristics to avoid segregation
• All powders should have the same particle size, achieved through milling and sieving before mixing
• The density of each component affects the mixture's stability
• Amount (proportion) of each component is another factor, and good homogeneity is harder to obtain if one component is small
• Small quantities of constituents should be mixed first, with progressive additions following
• Small drug amounts can be dissolved in a volatile solvent, mixed in, then evaporated

Powdered and Granulated Products as Usage

• Granules consist of aggregated powder particles (2-4mm in diameter) resistant to handling
• Powdered and granulated products can be dispensed as:
  • Bulk powders or granules for internal use
  • Divided powders or granules (single-dose preparations)
  • Dusting powders for external use
  • Insufflations for ear, nose, or throat administration
• Powder for reconstitution into injections
• Dry powder inhalers

Advantages vs Disadvantages of Powdered and Granulation Products

• Advantages: Chemically stable with a shelf-life of 2-3 years, convenient for large dose drugs (powder in water), and faster dissolution than tablets/capsules for soluble drugs
• Disadvantages: Less convenient to carry, difficulty masking unpleasant tastes, not suitable for potent drugs with low doses, and not suitable drugs inactivated in or cause damage to the stomach

Preparations of Powdered and Granulation Products

• Bulk powders: relatively non-toxic medicines with a large dose
• Divided powders: individual doses wrapped separately
• Modern packaging uses foils and plastic laminates for hygroscopic, volatile, or deliquescent ingredients
• Powders and granules should be stored in a dry place to prevent deterioration
• Bulk granules: granulating prevents segregation of constituents of powders and contain similar medicaments
• Divided granules: one dose is individually wrapped (e.g., effervescent granules)
• Dusting powders: contain therapeutic, prophylactic, or lubricant ingredients and are for external use with sterile powders and lubricants on superficial skin
• Dispensed in glass or metal with perforated lid, powder must flow well
• The Powder Active Ingredient must be diluted with materials having good flow properties e.g. purified talc or maize starch
• Insufflations: medicated powders blown into regions such as the ear, nose, and throat using an insufflator
• Dry-powder inhalers: systems for pulmonary drug delivery for asthma and obstructive pulmonary diseases, requiring appropriate devices
• Oral antibiotic syrups: antibiotics instable as a solution or suspension, resulting in the dry ingredients of liquid preparation in powder or granules with water added to reconstitute the solution or suspension
• Powders for injection: medicaments instable in solution and made immediately prior to use as sterile powders in ampoules with sufficient diluent (e.g. sterile water) and used immediately

Mixing

• Mixing aims to create a homogeneous association of products.
• Each sampled fraction must have the same component proportion.
• A good mix requires considering the raw material, equipment, and operating conditions

Importance of Mixing

• Very few pharmaceutical products contain only one component
• Several ingredients ensure the dosage form's required functions, like manufacturing and patient handling
• Required in the manufacturing process
• Purpose is even distribution of active components
• Is involved in the production of pharmaceutical preparations

Objectives of Mixing

• Treating components in an unmixed or partially mixed state so that each unit (particle, molecule) lies in contact with a unit of each of the other components
• Approaching a perfect mix depends on the manufactured product along with the objective of the mixing operation

Types of Mixing

• Positive mixtures: Gases or miscible liquids that spontaneously and irreversibly mix by diffusion, requiring no energy
• Negative mixtures: Components tend to separate if energy is not input continuously to keep components dispersed, making them more difficult to form and maintain
• Neutral mixtures: Static behavior where components do not spontaneously mix or segregate once mixed (e.g., powder, pastes, ointments), and demixing requires energy input

Mixing Process

• Situations to consider are equal quantities of powdered components of the same size, shape and density
• Significant differences in quantities
• Same and different colors
• Scale of mixing occurs in large bulk that is subsequently subdivided into individual doses

Factors Influencing the Mixing of Powders

• The particle size is important for preventing segregation, requires mixing powders with very close characteristics
• All powders should have the same particle size achieved by milling and sieving before mixing
• The density of each component affects the stability of the mixture
• Amount (proportion) of each component affects homogeneity (more difficult if significantly small)
• Start with small quantities of constituents and continue progressive additions
• Introduce small drug amounts into the mixture as a solution in a volatile solvent, then evaporate it

Evaluation of the Degree of Mixing

• Generation of mixing index compares the content standard deviation of samples taken from a mix under investigation
• Two basic requirements: Ensure a sufficient representative # of samples (minimum of 10), and use suitable analytical technique
• Low content variation can be achieved if the proportion of active component is high

Granulation

• Granulation is a process in which primary powder particles are made to adhere to form larger multiparticle entities (0.2-0.4mm in diameter)
• Granules can be intermediate products (tablets, capsules or liquid preparations)
• Granules can be a dosage form
• Provides a uniform distribution of each ingredient through the mix

Advantages of Granulation

• Prevents segregation of powder mix constituents because granules would have same densities
• Improves mix flow properties through effect of size, shape or surface of cohesivity of particles
• Improves the compaction characteristics of the mix through the distribution of adhesive within granules and binder-rich outer layer
• Reduces the hazard with generation of toxic dust
• Reduces the effect moisture adsorption on flowability
• Reduces the volume occupied by the product

Methods of Granulation

• Needed Excipients are diluents, disintegrating agents, and adhesives in dry powder mix
• Dry granulation: Aggregates primary powder particles at high pressure or by squeezing the powder between two rollers, and produce/break the intermediate product through material milling
• Wet granulation: A granulating fluid is used in the process; a volatile solvent like water or organic solvents for water sensitive drugs
• The wet mass is forced through a sieve to make wet granules, which are dried and screened, resulting in final granules

Granulation Mechanisms

• Strong bonds between particles must be formed between particles.
  • 1.adhesion and cohesion forces in thin immobile films can decrease interparticulate distance
  • 2.interfacial forces in mobile liquid films involves liquid distributed as films around and between the particles
  • 3.solid bridges through partial melting, hardening binders, and crystallisation of dissolved substances
  • 4.attractive forces between particles through electrostatic and van Der Waals forces
  • 5.mechanical interlocking

Mechanisms of Granulation Formation

• Dry methods: adhesion of particles by high pressure
• Wet granulation: liquid distributes through the powder to adhere particles through liquid films and agitation
• Nucleation: particle-particle contact and adhesion for nuclei formation for granule growth
• Transition: nuclei grow from particle addition or by combining two or more nuclei
• Ball growth: growth produces spherical granules that will increase with time

Wet Granulation Equipment

• Shear granulators ((planetary granulation): dry powder blending, transfer to another equipment for granulation
• High speed mixer/granulators: involves same equipment
• Fluidized-bed granulators: powders are fluidized in a stream of air where granulation fluid is sprayed onto the bed of powders
• Spray driers: create granular from a solution or suspension where granular are free owing hollow spheres and good compaction
• Spheronizers/pelletizers create spherical pellets and controlled drug release
• Extrusion/spheronization: make uniformly sized round particles and incorporate controlled drug release
• Rotorgranulation

Dry Granulation Equipment

• Does not use liquid to avoid heat combination, which degrades the product
• 2 pieces of equipment are needed
  • Compressing machine
  • Mill for breaking up intermediate products into granules
• Slugging: compaction of dry powders using a conventional tablet machine or a large heavy-duty rotary press (slugging), using a hammer mill
• Roller compaction: powder is squeezed between two counter-rotating rollers for compressed sheet formation that is weak and need treatment to break it into flakes

Drying

• Drying reduces water and organic solvent in pharmaceutical materials to acceptable levels
• This unit process includes resources for facilities, equipment, human labor, and time
• The drying rate impacts material properties, functionality, and quality
• Three processes occur simultaneously: energy transfer, phase transformation, and vapor transfer

Type of Drying

• Drying depends on heat sensitivity, physical characteristics, the nature of the liquid to be removed, the scale of operation, available source of heat
• Dryers in the pharmaceutical industry use miniaturized production equipment that facilitates manufacturing batches
• Pharmaceutical dryers are classified with employ based on the heat transfer method: convection, conduction, or radiation

Convective Drying of Wet Solids

• Fluidized-bed dryer: provides contact between the warm drying air and wet particles within a perforated vessel that enables fluid passage from below
• The fluid may be liquid or gas, but air will be assumed

Radiation Drying of Wet Solids

• Radiant heat transmission: if it falls on a body capable of absorbing it, it appears as heat
• Microwave radiation: Use of of wavelenght range between 10mm and 1m for heating and drying The generation and action of microwaves include a magnetron to a waveguide to and window into a dry chamber
• A microwave dryer for granules
• There are both advantages and disadvantages to microwaves

Freeze Drying

• Drying where the liquid is frozen
• The pressure above the frozen state is reduced
• The water is removed by sublimation

Tablets and Compaction

• Tablets are solid preparations with a single dose of one or more active ingredient(s), compressed with uniform volume
• Contain ingredients beside the drug(s)
• Tablets are intended for oral administration with systemic use
• Tablets can swallowed whole, after chewed, dissolved/dispersed in water, or kept in the mouth
• Variety of tablets
• Different types of excipients

Tablets vs Other Dosage Forms

• The oral route offers convenient and safe drug administration
• Dosage has high chemical and physical stability to the drug
• Tablets can be mass produced with quality-controlled production procedures
• Main disadvantage of tablets = bioavailability of drugs poorly soluble in water
• Some drugs irritate the gastrointestinal mucosa

Required Tablet Qualities

• Tablets should include the correct dose of drug
• The appearance should be elegant with a consistent weight, size, and appearance
• Drug release should be controlled and reproducible
• Tablets should be biocompatible and stable (chemically, physically, and microbiologically)
• Tablets should be a product acceptable by patients

Tablet Manufacturing

• Stages in tablets formation
• Tablets are made by forcing particles close together by compression inside a die with punches, where compression forces operate
• The process of tableting may be divided into three stages (compaction cycles)
  • Die filling: powder flows gravitationally from a hopper
  • Tablet formation: upper punch descends and enters the die to compress the powder
  • Tablet ejection: lower punch rises to push the tablet out of the die and tablet is removed from the die

Tablet Presses

• 2 types of press: Single-punch and rotary
• Single-punch press: Uses a die with one pair of punches, the powder is held in a hopper connected to a hopper shoe located at the die table.
  • The hopper moves over to feed powder into the die
  • Output: About 200 tablets per minute for small batch
• Rotary press: Uses many dies and set of punches to output tablets over 10,000 tablets per minute.
  • The dies are mounted in a circle in the die table with punches that rotate together with the material
  • Punches operate vertical movement during powder compression

Tablet Tooling

• Tablets can be circular, oval and oblong
• Be flat or convex, with or without bevelled edges
• Bear break marks, symbols or markings
• Tooling controls shape, size and appearance of tablets
• Punches and dies are precision tools that must be handled and stored carefully
• Manufacturing problems may be related to the quality of the compression tooling

Tableting Technical Problems

• High weight and dose variation occur
• Low mechanical strength
• Capping and lamination
• Adhesion or sticking of powder to punch tips
• High friction during tablet ejection
• Homogeneity and segregation tendency
• Flowability
• Compression properties and compactibility
• Friction and adhesion properties

Tablet Production with Granulation

• Wet granulation: two mechanisms involve adjacent particles, and dissolution can occur
• Natural or synthetic polymers are usually added as aqueous solutions or dispersions
• A granulation process using nonaqueous liquids can be used if the active ingredient is unstable in the presence of water (e.g. povidone dissolved in isopropanol)
• Wet granulation is a process made a long procedure made better by high-speed mixer granulators

Production by Direct Compaction

• Reduces production time and costs by minimizing previous operations
• Only 2 operations: powder mixing and tableting
• Involves direct compactable excipients, specially designed fillers and dry binders, which are usually expensive
• Drug dissolution dissolves faster with dsintegration into primary drug particles
• Direct compression disadvantages: Acceptable flowability, acceptable bulk density, and is affected with technological and powder property issues

Tablet Categories

• Uncoated and coated tablets
• Effervescent and soluble tablets
• Dispersible and Orodispersible tablets
• Gastroresistant and modified release tablets
• Tablets to suck

List of Excipients

• API
• Fillers, binders, and disintegrants
• Lubricants, antiadherents
• Flow, weting and colorant agents
• Antioxydants and conservative agents

Tablet Preparation

• Tablet preparation involves formulation and excipient selection
• There is product variation and some may contain fillers, binders, disintegrating agents, glidants, lubricants, and coating agents, flavor, and colorant
• A Filler is required to incrase the bulk volume and size of tablets

Disintegrants

• Disrupt tablets in liquid, and promotes drug dissolution
• Liquid wets the solid that then breaks into small fragments
• Includes agents that facilitate disintegration with liquid and that ruptures the tablets
• CO₂ can be produced in effervescent tablets through carbonate or bicarbonate salts

Binders or Adhesives

• Ensure granules and tablets are formed with the required mechanical strength
• Binders may be dry powder mixed with other ingredients before wet granulation or compaction
• Binder concentration needs to be at low concentrations

Glidant

• Improves blend flowability
• Usually a concentrate or slurry
• Lubricant: Tablet formulation is compressed to have a tight die wall
• Must be hydrophobic to prevent disintegration

Types of Tablets

• Disintegrant tablets: Swallowed to release content in short period of time for formulation and drug release
• Chewable tablets: Disintegrate in mouth but drugs are not dissolved
• When dropped into a glass of water, Effervescent tablets have liberated CO₂ that facilitates disintegration and drug dissolution
• CO₂ is produced by carbonate, bicarbonate, and citric/tartic
• Are rapid action e.g. analgesic

Special Types of Tablets

• Compressed lozenges: Dissolved slowly in the mouth and does not have disintegrants
• Sublingual tablets and buccal tablets: Drug release in mouth with systemic uptake and no liver first pass metabolism
• Prolonged-release tablets: Swallowed tablets that have slow/extended/austained/prologned release
  • Increase the time period with therapeutic drug maintenance conc

Types of Tablets Related to Release Mechanisms

• Diffusion-controlled release
• Dissolution-controlled release
• Erosion-controlled release
• Osmosis-controlled release

Aspects of Powder Compression

• Mechanisms of particle compression
• Behavior and and evaluation
• Inspection of tablets
• Pore and Specific area structure of tablets
• Evaluation of die and wall compression during compression

Tablet Testing

• Uniformity of content of active ingredients
• Disintegration and Dissolution
• Mechanical strength
• Attrition and Fracture resistance