Pharmceutics - Jenny section

• particle or aggregate size reduction

• important for preparing drug and excipient materials for dosage forms

• can impact effectiveness, dissolution, stability

• method and conduct of comminution - involves particle size, shape, and particle distrubution

• includes cutting, chopping, crushing, grinding, reduction particles to micron in size, trituration

• based and size and nature of material

• very little of the applied energy - results in a particle size reduction - 2%

• losses occur in elastic and plastic deformation with no fracture due to heat, sound vibration and friction

comminuation

• requires chopping, cutting

comminuation for fibrous material

• cutting, crushing, grinding

• based on melting point, brittleness, hardness, moisture content

• may be brittle to plastic - moldable

• influences ease of comminuated

comminuation for chemical material

• occurs via - cracking initiation - weak point of material grows as stress is applied, releasing energy, propagation forming new materials when stress is applied

particle size reduction occurs

• crack propagation - small cracks in the material grow due to applied stress

• more plastic material can deform without crack propagation

• rapid in brittle material

• more plastic (moldable material) can deform without crack propagation

Toughness

• Moh scale (1-10) - shows the hardness

• diamond - above 7 and talc below 3

• the harder the surface the more force needs to be applied for comminution

• softer materials may need a temperature reduction below glass transition temperature to make them brittle and allow crack propagation

Surface hardness

• gummy or resinous material can adhere to the machines, making it difficult to for comminution to occur and can block the sizing mesh e.g. sieve

Stickness

• generation of heat during comminution can soften waxy materials which can impact particle size reduction

• thus cooling is required

softening temperature

• for dry grinding moisture must be less than 5%

• for wet grinding moisture must be more than 50%

moisture content

• cutting - blade

• compression - apply pressure

• impact - striking a stationery particle or moving particle striking a stationery surface

• attrition - a particle is between two surfaces the surfaces apply pressure and can move to break the particle - shearing forces - pushes one end of the particle in one direction and the other end of the particle in the opposite direction

mechanisms of particle size reduction

• milling - breaks the material into fine powders

• bi modal distribution - different particle size undergo different size reduction

• after milling it becomes a unimodal peak

• then the particles reach a minimum size based on equipment type and how the particles accumulate

Change in the particle size distrubution by millling

• used to grind, cut or process material

• different mills have different mechanisms of size reduction

• many have screen which allow small particles to leave the mill and large particle to remain which narrow the distribution of particle size - like sieving

• types of mills: 1. coarse crushers - very coarse grinding, 2. intermediate grinders - particle 50-1000 microns, fine grinding mills - less than 50 microns

Mills

• intermediate size, cutting action

• used for fibrous materials

• knives attached to rotor and fixed blades on body of mill produce cutting action

• screen at bottom allows for small particles to move through the screen and reduces excessive fine particles

• 100-100000 microns

Cuter mills

• intermediate grinding size, impact action - striking action

• hammers attaching with swivel joints to a central rotor, rotor rotates inside the mill and hammers swing out to contact the material for milling

• screen allows for small particles to move

• 10-1000 microns

Hammer mill

• intermediate grinder size, compressing

• two cyclindrical rolls with adjustable gap between them

• one roller uses friction

• one roller uses a motor

• other moves by fricition

• material is compressed

• 1000-10000 microns material

Roller mill

• fine to intermediate size, attrition action

• materials undergo this with two rotating grinding plates

• for friable, med-hard materials

• 1-100 microns

Attrition Mill

• combination of attrition and impact

• horizontal rolling cylinder, containing ceramic or metal balls of different sizes

• fully enclosed to reduce dust, can grind wide range of materials

• not for sticky or soft materials

• needs correct operating speed

• cascading action

Ball mill

• fine grinding, impact, attrition

• circular or oval chamber

• uses high pressure air

• turbulent flow and forces the particles of material to collide to reduce particle size

• primary impact reduces particle size alot

Fluid energy mill/microniser/ jet mill

• reduced by a mortar and pestle

• firm grip

• grinding action

• attrition to reduce particle size

• for gummy (camphor) - may be ground by process of pulverisation by intervention - triturating with a volatile solvent (alcohol) solvent evaporate to produce a fine powder

• glass mortar - strong smell or coloured

Titration

• very important in dosage form preparations

• imporant when it has more than one component

• correct amount for the correct dosage unit

• equal portions

Mixing

• cant be achieved

• not necessary

• may have negative effect

• exactly equal portion

Perfect mixing

• probability of finding a particular type of particle is the same anywhere in the mix

• relatively equal proportion of particles

• different samples may have a different proportion of particles

• larger sample - closer proportion to overall mix

Random mixing

• size of the sample which is examined to determine the success of mixing

• for the end purpose of mixture

• e.g. if each dosage form need 100mg, 100mg samples must be taken from the bulk powder

• if higher amounts are required, 5g can be taken, thus lower standard mix is acceptable

• number of particles in scale of scrutiny depends on the weight of the sample, particle size and density, proportion of active ingredient

• active ingredient proportion decreases - variation in fixed sample increases, making dose consistency more difficult

• reducing particle size creates more particles- reduces variation and causes clustering

• high active ingredient proportion - acceptable variation may occur before complete random mix is achieved

Scale of scrutiny

• minimising variation in sample content is controlled by particle size and mixing process

• percentage coefficent of variation indicates the % of variation of content from expected value

• standard dev of actual is compared to standard dev of random mix - generated Mixing index if it is 1 - random

co-efficient of variation

• closely packed together

• particles separated into looser arrangement

• then particles move away from each other as the bed dilates and moves through spaces

• microscopic mixing

• slow process

diffusive mixing

• movement of large numbers of particles from one area of powder to another with mixing blade

• rapid mixing

• macroscopic level

• more time for random mix

convective mixing

• layers of powder relative to each other

• tilting powder bed - powder slides over each other

• intermediate mixing

• semi microscopic mixing

shear mixing

• spherical shapes segregate easily than non spherical - as they lock and reduce segregation

• non spherical are more prone to dusting out due to higher surface area to weight

• optimal mixing time is required

• increasing the degree of mixing - how uniform mixing is and increasing time can lead to segregation

segregation

• small particles fall through spaces between large particles

• issue if bed is subject to vibration or if small particles are heavier

• can occur if the particles dilate during mixing

Percolation segregation

• difference in kinetic energy of moving particles of different size and or density

• in mixing motion. larger or more dense particles segregate

• in a clump, larger particles are at the bottom while smaller particles are at the top

Trajectory segregation

• during mixing or transfer - small particles can be suspended in air currents, settling out on the surface of the powder bed or area of low air flow

Elutriation

• mill all components to similar, narrow particle size

• choose excipients of similar density to active ingredient

• minmise vibration after mixing

• minimum handling/transport after mixing

ways to minimise segregation

• alternative mixing type

• exploits forces between particles - vanderwall and electrostatic

• small active particles adhere to larger water soluble carrier particles

• needs longer mixing time

• ordered unit behaves as one and cant separate achieving a uniform mix - lowering coefficient of variation

• forces between small-small molecules must be less than forces between small-big molecules - which can be done using vibration

• useful for low concentration of potent drug

• many powdered mixes use random and ordered mixing

ordered mixing

• varying particle size of carrier

• narrow particle size distribution ideal

Ordered unit segregation

• inadequate amount of carrier particle present

• fine material remains unbound - can segregate

Saturation segregation

• displacement of the bound particles by another component

• e.g. addition of lubricant

displacement segregation

• mortar and pestle

• pestle held as a pencil and powders added by method of doubling to improve efficiency of mixing

• light trituration and circular motion with scarping of the sides

• using shearing forces and diffusive mechanisms

small scale mixing

• rotating drum around a horizontal axis

• speed is important

• uses baffles - curved or flat plates - asymmetric and improve mixing

• shear and diffusive mixing

• free flowing powders

• segregation may occur

• can achieve ordered mixing if slow

Tumbling mixers

• screw paddle, wave shaped mixer

• spirals or ribbon paddles mounted on rotor shaft

• convective - shovel mixing moving material from top to bottom and shear mechanisms

• avoid segregation

• poorly flowing materials

• nauta mixer - moves around in a circle in a cone shape - diffusive

• rapid achievement of random mix

agitator mixer

• rotating mixing blade - rotating inside edge of mixing bowl

• convective - shovel mixing moving material from top to bottom

• good for poor flowing material

planetary mixer

• multi-purpose

• central mixing blade forces powder to walls of vessel, causing it to rise and fall into the center

• a big bowl

• high shear, convective and diffusive mechanisms

• ordered mixing for fine clustered particles

high speed mixer granulators

• granulator and dryer

• powder mixer

• air is from the bottom of the mixing vessel, lifiting the particles into a turbulent air flow to mix

• diffusive mechanism

• free flowing powders

Fluidised bed - blender

• removal of all, or most of, the liquid from a material (solid) by the application of heat.

• achieved by the transfer of the liquid from the surface of the material into an unsaturated vapour phase

• done to increase drug stability, to minimise the growth of micro-organisms, to achieve free-flowing properties of the solid particles

• final stage of drug manufacture before packaging, but may be a step in formulation process

• effects flow properties and Solubility

• small amount of moisture is needed

• Over-drying and overheating can cause degradation or burn the material.

Drying

• kg of moisture associated with one kg of “moisture free” or dry

Moisture content

• is the moisture content of the air (kg) of water per unit mass (kg) of bone-dry air.

• not altered by change of temp

Absolute humidity

• the humidity at which the air is completely saturated with water and therefore cannot absorb any more moisture from drying material at a given temperature.

• Saturated humidity=100% relative humidity

Saturated humidity:

• point where a solid material has reached a perfect "balance" with the surrounding air—it is neither absorbing moisture nor losing it.

• may change if the environmental conditions are altered

• Depends on the relative humidity of the environment.

• No point drying to an EMC that is less than the product will have at the RH at which it will be stored

Equilibrium moisture content:

• the temperature of a thermometer which has been immersed in water then lifted up in the air.

• lower due to cooling of the water

Wet bulb temp

• the temperature of a thermometer that stays in the air.

Dry bulb temp

• Latent heat of vaporisation (heat which generates steam without temperature change) must be provided

• The liberated vapour must be removed, eg by a moving air stream.

• Unbound (free) water – surface water

• Bound water – water contained in cells or in capillaries or internal pores of solid, or an integral part of crystal structure eg hydrate - Does not develop full

drying proccess

• AK(Ps-Pa)

• A - surface area

• K - mass transfer content - change in state

• Ps: vapour pressure at the surface of solid

• Pa; vapour pressure of air stream

• Ps - pa - net ability to evaporate

Rate of Drying

• maximum amount of water vapour that air can hold, but it is determined by temperature,

• reduced by silica and phosphorous pentoxide

relative humidity

• Large surface area to promote heat transfer

• Efficient transfer of water vapour through boundary layers

• Efficient vapour removal (sufficient movement of low RH air)

• Efficient heat transfer per unit area

rate of drying principles

• Substance is dried on trays on shelves. Hot air is passed over the shelves and vented to the outside

• spread powder in thin layers - increase surface area

• Temperature increases evaporation

Hot air oven

• Slow

• Temp variation in trays

• Product may “cake”

• Not suitable for removal of organic solvents

• not for dusty solids.

Hot oven disadvantages

• Cheap

• simple

Hot oven advantages

• less heat is required to vaporise water lower 25-35oC)

• Ps-Pa is increased

• Oven with shelves and strengthened cabinet so that vacuum can be drawn

• advantages - Increased rate of drying, Low temperature drying , No risk of oxidation

• disadvantages drying time still relatively long and Fine particles may be sucked out

Vacuum oven

• Tumbling Vacuum Dryer – rotating drum + vacuum

• Increased A, K, (Ps–Pa)

• Advantages: More efficient Drying time short

• Disadvantages - Produces fine powders

Tumbling vaccum dryer

• vessel with a perforated base through which warm air is passed.

• velocity of air is sufficient, the particles separate and move freely - fully fluidised.

• A – high, K – high, (Ps-Pa) increased.

• rapid drying

• constant rate period of drying

• Continuous process possible with conveyor belt - reduced handling and labour costs

Fluidised Bed Dryer

• Minimum heating time for heat-labile materials (20-40mins drying)

• Economical, high output

• Drying mostly at constant rate, falling rate short,

• minimises chance of overheating.

• Precise and uniform temperature control

• Produces a free-flowing product

advantages of fluidised bed dryer

• May break down product forming fine particles.

• Fine particles must be collected and returned to avoid loss of fines

• Static electricity may be generated

• Intra-granular solute migration possible

disadvantages of fluidised bed drying

• solutes move towards the surface of the bed and deposit there when the fluid evaporates. Intergranular migration occurs in convective drying .

• Lack of uniformity

• Mottling of compressed tablet

Intergranular migration:

• solutes move towards the periphery of each granule.

• fluidised bed drying and tumbling drying.

• Loss of active ingredient when enriched outer layer is abraded.

• Mottling of coloured compressed tablets

• Migration of soluble binders

Intragranular migration

• Minimise amount of granulating fluid & ensure it is well distributed.

• Prepare small granules

• Avoid tray drying

• Mixing granules before compression if use tray drying

Minimisation of solute migration

• contains a molecule with solvent around it

• feed liquid is solution or suspension which is sprayed to increase surface area

• feed liquid passes through an atomizer that creates an aerosol of small droplets of liquid.

• it is sprayed into a drying chamber with heated gas evaporating the solvent

• high surface to mass ratio droplets produced will rapid evaporate of the solvent forming spherical particles

• very fast

• used to create dry powder from dilute suspensions or solutions

• uniform, spherical particles produced

• Large surface area for heat and mass transfer is achieved

• the dried material moves out of the spherical feed solution through a small hole

• suspension feed are solid

Spray drying

• uniform apperance

• spherical with good flow

• retain properties of original solution

• very rapid drying

• free flowing

• formed particles are soluble and dispersible when water is added

• AK (pS-Pa) are all high

advantages of spray dried products

• bulky

• expensive

• low thermal efficency - not hot enough at outlet

• sterile filtration of large volume of air

• low yield

disadvantages of spray dried products

• Preparation of the feed liquid: solution, suspension or emulsion. Not too viscous

• Set up the drying conditions: inlet & outlet air temp, feed rate c

• Atomize the solution/suspension/emulsion via atomizer into the drying chamber

• uniform sized small droplets with high surface-tomass ratio

• rapid evaporation of the solvent to form solid particles

• collect samples

spray drying procedure

• controls the formation of the droplet, therefore its type is important.

• Rotary atomizer: effective for both solution and suspension; gives uniform spray and is not easily blocked – 50micron particle size

• Two-fluid nozzle - delivers feed liquid and atomising air/gas simultaneously. High capacity – 2micron particle size from co-current (top) delivery.

atomiser

• Microencapsulation - Vitamins A, D in gelatin; masking taste

• Useful for drying heat-sensitive materials

• Widely used in the food processing industry, instant coffee, milk powder

• Micronisation: uniform reduction of particle size, increasing solubility of a product.

• Change solid structure from crystalline form to amorphous form:

spray drying applications

• process that involves the sublimation of ice to water vapour at low pressure and temperature

• Used to remove water from materials that are heat or moisture sensitive or prone to oxidation

• dried powder product with prolonged stability and ready reconstitution

Freeze drying

• Freeze to very low temperature at normal atmospheric pressure

• Apply vacuum (<<4.58mmHg), apply heat, but do not increase temperature above collapse temperature, glass transition temperature’ or eutetic temp

• Unbound water (ice) removed by sublimation

• Reduce pressure further (vacuum) and slowly increase temperature to 30-50C – vacuum drying (vaporisation) of bound water

steps for freeze drying

• measured by Differential Scanning Calorimetry (DSC) - temp above which softening of the material occurs and the materialexhibits viscous flow and eventual matrix solubilization or collapse.

• goes from hard to viscous

• characterises mobility change of frozen state.

glass transition temperature

• determined by freeze-drying microscopy (FDM), indicates the onset of visible collapse or full collapse at the drying front.

collapse temperature

• achieved by immersion method using liquid N2 or combination of dry ice, ie solid CO2 + acetone or alcohol.

• PEG or glycerol prevent harmful freezing effects

• small degree of supercooling, small ice crystal size, minimal solute concentration change

• fast rate of drying, small ph shift

fast cooling

• conventional shelf freezing or refreezing in a freezer

• large degree of supercooling, large ice crystal size, small solute concentration change

• slow rate of drying, large ph shift

slow cooling

• liquid cools below its freezing point without freezing.

• nucleation and crystallisation occur, latent heat is released raising the product temperature back to normal freezing

supercooling

• unbound water” of the product removed by sublimation

• temperature is controlled by eutectic temp or collapse & glass transition temp

• Latent heat of sublimation

• used to continuously remove the vapour.

• vapour cooled in a condenser

primary drying

• Removes bound water eg water of hydration, ion-dipole, hydrogen bonded;

• water associated with amorphous glassy masses

• Temp is raised gradually - +20 to +300C for bio-products and +50 0C for many drugs

• vacuum level increased (pressure decreased) to boil off remaining water

secondary drying

• sample chamber for vacuum drying

• a vacuum source (pump)

• a heat source for latent heat

• vapour removal system

• Ps > Pa – high vacuum achieves this

freeze dryer components

• excipients added to to avoid of too much material

• manitol

bulking agents

• buffers and salts

• potential dehydrating agents

pH and osmotic adjustments

• prevents liquid molecules from being broken or crushed while being frozen

• stabilises shifts in ph and harmful salt concentrations

• modify glass temperature and collapse temperature

• stabilising agent, increases glass transitional temperature, absorbs moisture, slows down secondary drying and minimise over drying

cyroprotectants

• glass temperature occurs before collapse temperature

glass transitional temperature vs collapse temperature

• Product is light and porous (no case hardening) same volume as original sample.

• Porous product is easily reconstituted.

• Minimises degradation by heat, oxidation and micro-organisms.

• Stability of product can be achieved and maintained

freeze drying advantages

• Product is very hygroscopic – packaging implications.

• Process is slow.

• expensive

freeze drying disadvantages

• Spray drying is more economical

• Freeze-drying is very expensive.

• Spray drying gives better control of particle size and shape in final product

• readily reconstituted

• freezing drying very slow, spray drying is fast

• freeze drying - biological drugs with low aqueous and thermal stability

spray vs freezing drying

• 2 phases

2 immiscible solutions

• two phases

mixture of two solids

• two components

• as carbon dioxide is determined by the others

calcium carbonate to calcium oxide and carbon dioxide

• 4.58

• 0.0098 degrees

triple point of water

• move from right to left

• larger over smaller

• add the fraction together

Lever rule

• anything above the curve is one phase full miscible

• anything within is two phases

Water and phenol

• horizontal line drawn on a phase diagram across a two-phase region

Tie line

• thymol- salol

• thymol - camphor

• phenol -menthol

• menthol - thymol

• can increase the solubility

• uses condensed phase rule

eutectic mixture

• used for topical anaesthetics

application of a eutectic mixture

• liquify at room temperature

• add talc, magnesium oxide, starch talc to delay eutectic formation

issues with eutectic mixtures

• improve solubility and rate of dissolution

• good for poorly soluble drug

• improve wettability

• helps in the crystallisation of a metastable drug

• good for very fine powdered drugs

advantages of eutectic mixture