Formulations SAQ

What is the cause of "hardness" in water and why can hard water be a problem in some pharmaceutical formulations?

· Hard water: potable water may be hard if it contains significant quantities of calcium and magnesium salts

· Why hard water can be a problem:

· calcium present affects gelling power of alginate

· Colour of some pharmaceutical mixtures varies due to variation in water pH if hard water is present

· Precipitates may form when hard water is used

Give a brief description of one pharmaceutical process which can be used for removing dissolved ionic contaminants from water in a pharmaceutical water purification system.

· Potable water passed through columns of anionic and cationic ion-exchange resins to remove ionisable compounds (mainly inorganic salts)

o Ions we want to remove attach to the resin and replaces in water by H+ or OH-

· Single resin columns or mixed bed resins

· Cationic exchange resin (+): cations in the water are replaced by hydrogen ions from the resin. Regenerated using Hydrochloric acid.

· Anionic exchange resin (-): anions in the water are replaced by hydroxyl ions from the resin. Regenerated using Sodium hydroxide.

What are endotoxins, and why is there a strict limit on endotoxin levels allowed in Water for Injection?

· Endotoxin: part of the outer membrane of the cell wall of Gram-negative bacteria and are released upon cell lysis

· Can be pyrogenic: cause febrile reaction, low blood pressure, increased heart rate and low urine output if they get into bloodstream.

What are "pyrogens"? Why should formulations for injection be pyrogen-free?

· Pyrogen: of bacterial origin and consists of lipids associated with a polysaccharide or protein or both (e.g., Endotoxins)

· Can cause febrile reactions if they enter bloodstream (low blood pressure, increased heart rate and low urine output if they get into bloodstream.

Give a concise description of the processes of electrodeionization for water purification. What are the main differences between electrodeionization and simple standard deionization processes?

· EDI system uses a combination of mixed resin, selectively permeable membranes and an electric charge

· Ion exchange resins bound by semi permeable membrane (known as concentrating department)

· Anode and cathode on either side of concentrating compartment

· Cations and anions are pulled out through the semi-permeable membrane out of the water and drips out of concentrating compartment (collected as concentrate)

· Differences: Used electricity to remove ions from water - has higher purity rates - automatic regeneration of resin bed

What is Water for Injection in Bulk Ph. Eur. and how does it differ from Purified Water in Bulk Ph. Eur.?

· Purifies water in bulk: clear, colourless, and tasteless liquid prepared from suitable potable water either by distillation, ion-exchange, or other suitable methods (can't be used in parental preparations as it does not have strict specifications for bacterial endotoxins like WFI)

· Water for Injection: intended for use as a vehicle In parental preparations - obtained from purified water by distillation or reverse osmosis coupled with other methods like EDI or ultrafiltration

· WFI strict has specifications unlike purified water in bulk: WFI Microbial Limit: less than 10 CFU/ml , WFI Endotoxin limit: less than 0.25 IU/ml

Give a concise description of distillation as a process used in the production of pharmacopeial grade purified water. What advantage does a multiple effect still offer in comparison to a simple single stage distillation process?

· Water is separated as vapour from non-volatile (high-boiling point) impurities and is subsequently condensed.

o Water is boiled until it changes to vapour, vapour is collected and condensed (condensate is purified water)

o Anything with higher boiling point is left behind in the still.

· Type one: Single Still Effect - water heated to boiling and vapour condensed on a cooled coil.

· Type Two: Thermocompression Still - vapour condenses it releases energy - this energy emitted is captured and used to reheat the water being distilled.

· Type Three: multiple-effect still - between 3 to 7 stages of "effects" of distillation.

· Advantage of multiple effect still: energy inefficiency is combatted because condensation energy is used to heat subsequent stages and lowering pressures at each stage)

Why is potable water unsuitable for certain pharmaceutical purposes?

· Potable water may be hard (large quantities of calcium or magnesium)

· Why hard potable water can be a problem:

· calcium present affects gelling power of alginate

· Colour of some pharmaceutical mixtures varies due to variation in water pH if hard water is present

· Precipitates may form when hard water is used

What are impurities found in water?

· Particulate matter : includes suspended solids of various types

· Fully dissolved impurities : organic e.g. Carbohydrates, inorganic e.g. salts

o Carbon adsorption removes chlorine (damages cellulose RO membranes)

· Colloidal matter : particles from 0.005-0.2ûm which do not sediment

o Removed via Ultrafiltration

· Microorganisms: Microfungi, bacteria, viruses, algae

o Removed via UV and Ozone

What are the requirements for purified water?

· Water for preparation of medicinal products other than those than are required to be both sterile and apyrogenic (unless otherwise justified and authorised)

· Must be apyrogenic (free from pyrogens)

What is dialysis and what is its purpose?

· Dialysis: procedure to remove waste products and excess fluid from the blood when the kidney stops working properly

· 2 types: Haemodialysis and peritoneal dialysis

· Haemodialysis: blood circulated outside the body and cleaned inside a machine before returning to the patient - dialysate holds blood, and the other part of the machine holds dialysing solution (separated by semi-permeable membrane). Waste from blood pass through microscopic holes in membrane and into the dialysate and washed away so clean blood is returned to the patient.

· Peritoneal dialysis: collects waste from blood by washing the empty space in the abdomen (peritoneal cavity)

Explain the different methods of purifying water. (Deionisation)

o Potable water passed through columns of anionic and cationic ion-exchange resins to remove ionisable compounds (mainly inorganic salts)

§ Ions we want to remove attach to the resin and replaces in water by H+ or OH-

o Single resin columns or mixed bed resins

o Cationic exchange resin (+): cations in the water are replaced by hydrogen ions from the resin. Regenerated using Hydrochloric acid.

o Anionic exchange resin (-): anions in the water are replaced by hydroxyl ions from the resin. Regenerated using Sodium hydroxide.

Explain the different methods of purifying water (Distillation)

o Water is separated as vapour from non-volatile (high-boiling point) impurities and is subsequently condensed.

o Water is boiled until it changes to vapour, vapour is collected and condensed (condensate is purified water)

o Anything with higher boiling point is left behind in the still.

o Type one: Single Still Effect - water heated to boiling and vapour condensed on a cooled coil.

o Type Two: Thermocompression Still - vapour condenses it releases energy - this energy emitted is captured and used to reheat the water being distilled.

o Type Three: multiple-effect still - between 3 to 7 stages of "effects" of distillation.

o Advantage of multiple effect still: energy inefficiency is combatted because condensation energy is used to heat subsequent stages and lowering pressures at each stage)

Explain the different methods of purifying water (Reverse Osmosis)

o The raw water is fed into a modulator or permeator containing a semi-permeable membrane (e.g. Cellulose)

o High pressure applied to the raw water, exceeds osmotic pressure, and thus reverses the direction of normal osmotic flow.

o Water molecules are forced through membrane and impurities are left behind.

What is meant by reverse osmosis?

· The raw water is fed into a modulator or permeator containing a semi-permeable membrane (e.g. Cellulose)

· High pressure applied to the raw water, exceeds osmotic pressure, and thus reverses the direction of normal osmotic flow.

· Water molecules are forced through membrane and impurities are left behind.

What are the requirements for water for injection?

· Microbial contamination limit: less than 10 IU/ml

· Endotoxin limit: less than 0.25 IU/ml

Types of surfactants

· Anionic surfactant e.g. Potassium laurate, Sodium lauryl sulphate

· Cationic surfactant e.g. Quaternary ammonium halides

· Àmpholytic/Zwitterionic surfactants e.g. Sulphobetaines

· Non-ionic surfactants e.g. Polysorbates, Cetomacrogol, Sorbitan esters

Provide an explanation of why it is important to (1) include a suspending agent and (2) reduce the particle size of the active pharmaceutical ingredient in a simple oral suspension formulation

· 1) suspending agent helps active ingredient to stay suspending in formulation and prevents caking at the bottom of the container (easily resuspended by moderate agitation or shaking)

· 2) Reduce particle size: reduces rate and likelihood of sedimentation (helps maintain dispersion)

Briefly describe three (3) strategies for improving the solubility of a poorly water soluble drug to be incorporated into an oral solution preparation.

· Co-solvency: use of a cosolvent like ethanol or glycerol - reduces the interfacial tension between aqueous solution and hydrophobic solute.

· pH Control: For ionic compounds containing basic anions solubility increases as pH of solution decreases.

· Solubilization with micelles: includes hydrophobic molecules in the hydrophobic micellar core - hydrophilic heads of micelles can then dissolve)

· Complexation (e.g. Cyclodextrins): uses chelating agent to convert inorganic ions to a complex which has higher solubility in the organic extraction solvent.

· Chemical modification (e.g. Salt formation): formation of salt can shift the pH of the solution to a more basic or acidic value (can increase solubility of a drug.

Describe two possible functions of a surfactant in a suspension formulation.

· Aids dispersion of solid particles in the liquid (important if powder is not readily wetted by liquid vehicle)

· Reduces interfacial tension between solid particles and liquid vehicle (advancing contact angle is reduced and wetting of the solid particles promoted - deflocculated)

· Flocculating agent

What is the difference between a flocculated and deflocculated suspension and what is the advantage of using a flocculated suspension formulation approach?

· Flocculated particles are weakly bonded, settle rapidly and do not form a cake (easily resuspended)

· Deflocculated particles settle slowly and eventually form a sediment cake which is difficult to resuspend.

When preparing an oral suspension formulation in an emergency situation from solid dosage forms such as tablets, why is it advised to prepare a suspension rather than a solution, even when the drug is very water soluble?

· If tablet is available rather than pure drug powder (API)

o Grind required number of tablets to fine powder and form slurry by adding small volume of water.

o Antimicrobial preservatives, suspending agents and flavouring agents are added to make final product.

o Other agents may be added (e.g. pH buffers to provide pH stability or activity of antimicrobial agent)

o If drug is water soluble it may seem appropriate to filter out tablet excipients - this is not appropriate (also filters out significant amounts of drug if extraction of drug from tablet is incomplete)

What is the difference between a diffusible and diffusible solid? In terms of an oral suspension formulation, how would your formulation design/composition be influenced by whether you have a diffusible or in-diffusible solid?

· Diffusible solid: does not dissolve in the vehicle but may be mixed with the vehicle so that, upon shaking, the powder is evenly diffused throughout the liquid for sufficient time to ensure unform distribution in each dose

· Indiffusible solid: does not remain evenly distributed in the vehicle long enough to ensure uniformity of the measured dose - the vehicle must therefore be increased in (use a suspending agent)

Some oral suspension formulations demonstrate "pseudoplastic flow". Explain what is meant by the term "pseudoplastic flow" and why this can be a useful characteristic of oral suspension formulations

· Simple fluids (e.g. Water) exhibit Newtonian flow (constant viscosity with zero shear rate at zero shear stress - shear rate and sheer stress are directly proportional)

· Most pharmaceutical fluids are non-Newtonian: viscosity varies with stress applied (e.g. Suspensions, emulsions, gels)

· Pseudoplastic flow: viscosity decreases as shear stress increases (viscosity calculated with slope of tangent)

Some oral suspension formulations demonstrate "thixotropy". Explain what is meant by the term "thixotropy" and why this can be a useful characteristic of oral suspension formulations.

· Decrease in the apparent viscosity as a function of time upon shearing, followed by a gradual recovery when shear is removed (decrease in viscosity over time at a constant shear rate)

· Effect is time dependent (if viscosity reduces and immediately returns after the material is "shear thinning" or pseudoplastic.

· Area enclosed between up and down curve (hysteresis loop) gives indication of the extend of thixotropy

o Gel like when unsheared - energy applied (shear stress), bonds break and viscosity falls (gel-sol formation). Stress removed then bonds reform (takes several minutes to days) - time to reform related to length of time material is subjected to shear stress

Name a polysaccharide and a cellulose derivative, both of which could be used as a suspending agent in an oral suspension and as a gelling agent in a tropical product.

· Polysaccharide: Tragacanth

· Cellulose derivative: Methylcellulose

List six types of excipients that would typically be in an aqueous-based oral paediatric suspension formulation.

· Colouring agent