Pharmaceutical Formulation and Excipients

Created on Thu, 09/07/2017 - 20:06
Last updated on Wed, 09/13/2017 - 18:35

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This chapter answers parts from Section A(ii) of the 2017 CICM Primary Syllabus, which invites the exam candidate to "describe the pharmaceutics and formulation of drugs",  which includes drug excipients. No written paper exam question has ever interrogated this topic. As such, it can be safely omitted from exam preparation in the interest of preserving time and sanity. For the candidate well endowed with one and not the other, this chaper offers an unstructured exploration of the topic on a fairly superficial level.

In summary, pharmaceutical excipients are everything in the medication which is not the active ingredient. They tend to make up the bulk of the weight of a medication. These substances are supposed to be inert, and their main role is to render the active ingredient more "useable" in a pragmatic sense. They protect the drug from degradation, they improve the palatability of tablets or the spreadability of ointments, they maintain stability of dissolved drugs in solution and they prevent bacterial contamination by antagonising microbial growth. They can also interact with the active ingredient, they can be noxious or toxic in their own right and there is a potential for completely unpredictable allegic reactions in suceptible or unlucky individuals.

Probably the best single article on this topic is the extensive review by Kalasz et al (2006). A good discussion of excipient safety issues can be found in the 2003 article by Pifferi and Ristani. Specific pharmacologically non-intert excipients are named and shamed in Golightly et al (1988) - Part I and Part II. Even greater detail can be found in the Handook of Drug Excipients by Rowe et al (my 5th edition was published in 2006 and is therefore more a historical document than reference manual). This was my main resource for difficult-to-find properties of some of the substances discussed below. 

What is an "excipient"

The term comes from the Latin verb excipiere, meaning "to take out". Following this term into pharmacology, the term "excipent" therefore refers to everything which is taken out of the medication, leaving behind the active ingredient. A proper definition is lacking, but we can concoct one for potential exam uses:

"A relatively inert substance which functions to ensure the dosage, stability and bioavailability of the active agent"

Another definition might be to describe the excipient as "everything in the medication which is not the active ingredient". That's probably no less accurate and much easier to remember.

Interactions between the active ingredient and excipients

Obviously nothing is completely inert, unless you have decided that argon is going to be your drug delivery vehicle. The excipient has molecules which have some sort of chemical activity and these will make some attempt to interact with the drug molecules and with your patient. To be sure, the excipients are selected carefully in order to not do that, but still it could happen, particularly if the drug is improperly stored.

This can lead to:

  • Degradation of the active ingredient
  • Decreased bioavailability
  • Creation of toxic byproducts

The most common excipient-agent reaction is hydrolysis, where ambient humidity enters the (usually, solid) preparation and degrades the active ingredient. Oxidation may occur, particularly in the presence of water (catalysed by metal ions in the drug or in the foil packaging). The presence of metallic ions in the medication may result in some sort of weird redox reaction which directly degrades the active ingredient. Photolysis, isomerisation and polymerisation are less common but still worth mentioning. Ionised excipients may react with soluble ionised agents, forming insoluble salts (for example, neomycin and sodium alginate). These all sound bad, but basic principles of chemistry tend protect the drug consumer: generally, kinetics of chemical reactions occuring in solid drug formulations are very low, which prevents tablets from gradually degrading themselves as they sit on the shelf.

Classification of excipients

A table is the best way to present a group of substances with classes, examples and the purposes they serve. This table is a summary of the excellent article by Kalasz and Antal (2006), and is far from exhaustive.

Classification of Pharmacological Excipients
Class Example Action

Lubricants

Various stearates
Polyethylene glycol
Corn starch
Vegetable oil
Glyrceryl behenate

These substances are used in tablets to prevent the tablet from sticking to the tablet press at the time of manufacture. They are a matter of manufacturing convenience. They act to create a hydrocarbon layer around the particles. As a side effect, they may cause decreased disintegration and dissolution, which affects bioavailability

Antioxidants

Phenolic compounds
Ascorbic acid
Butylated hydroxyanisole (BHA)
Fumaric acid
Maleic acid
Alpha-tocopherol

These prevent the chemical degradation of the active ingredient by oxidation; they do this by consuming oxygen faster than the active ingredient.

Some can be quite toxic on their own, for instance BHA has a mouse LD50 of ~2mg/kg. Fortunately the usual dose for even topical preparations never exceeds a range of 50-100ppm.

Binders

Sodium alginate
Bentonite
Maltodextrin
Methylcellulose
Gelatin

Ensures that the tablet stays together during storage, basically the glue that promotes the aggregation of all the independent ground-up particles which make up a tablet. 

Buffers

Citric acid
Hydrochloric acid
Sodium bicarbonate
Tartaric acid

The pH of the medication needs to be carefully considered because in a number of situations the stability or bioavailability of the drug relies significantly on the pH of the solution. Ergo, these buffers are added until the pH is optimal.

Carriers

Water
Ethyl alcohol
Glycine
Vegetable oils
Lanolin
Hydrocarbon gas
Calcium phosphate
Calcium carbonate
Maltodextrin
Sorbitol
Light kaolin

These substances act as the bulking agentm, diluent or solvent for the active ingredient. These make up the majority of the medication by weight and volume. Depending on what it is and where it is going the carrier could be:

  • solid, eg. calcium phosphate for tablets
  • aqueous (for IV infusions)
  • oil-based (for IM injections)
  • made of buttery vegetable oils or lanolin for creams and ointments
  • consisting of a volatile hydrocarbon propellant for those drugs which are expected to blast out of the nozzle of an aerosol canister.
Chelators

Edetic acid
Various edetates
Cyclodextrins
 

Celating agents are included so that metallic ions might be safely deactivated before they cause problems. Cyclodextrins go one step further by concealing a molecule within their cavity and thereby preventing any undesirable interactions.

Coatings

Ethyl cellulose
Cetyl alcohol
Saccharose
Gelatin
Glucose

Coating substances can be further subclassified as film-producers, softeners and adhesion inhibitors. The main objective is primarily to make swallowing easier and to improve the predictability of dissolution;  and secondarily to create a second exterior seal agaisnt the penetration of moisture, heat and light.

Colouring

Beta caroteine
Indigo carmine
Sunset yellow
Titanium dioxide

To quote Kalasz et al (2006), artificial colouring  "offers psychological significance through appearance without particular therapeutic advantage".

Flavours

Aspartame
Saccharin

If your medication is hideously foul-tasting, compliance will be poor. 

Disintegrants

Starches
Microcrystalline cellulose
Croscarmellose sodium

These serve to break up the tablet when it is in an appropriate environment; ideally into small granules with a high surface area, so that absorption can be maximal. Typically these are hydrophilic compounds

Emulsifiers

Sodium lauryl sulfate
Triethanolamine
Sorbitan esters
Lecithin

These substances are surface-active compounds which act to reduce the surface tension at the interface between oily and aqueous phases of the solution, thereby forming a mixture of tiny dropls (eg. propofol uses lecithin).

Preservatives

Benzoic acid
Benzalconium chloride
Ethyl hydroxybenzoate
Sodium metabisulfate
Sodium benzoate

The thing these substances "preserve" from is actually bacterial contamination. They inhibit the growth of microorganisms. 

Pharmacological effects of excipients

Frequently these supposedly inert substances have real pharmacological effects which can range from minor to not so minor. An excellent article by Golighly at al (1988) explores this in great detail. In short, this can happen when:

  • Drug companies use something which is clearly toxic, eg. diethylene glycol, which has resulted in mass poisoning epidemics (Schep et al, 2009) whenever it has been used in pharmaceutical preparations.
  • The excipient is relatively safe but is inadvertantly given in a relatively high dose to a susceptible population. eg. low birth weight neonates or people with impaired clearance mechanisms
  • The patient has an idiosyncratic or allergic reaction to the excipient
  • The drug is accidentally given using a route of administration which it is not meant for (eg. when you idiotically crush a tablet up and inject the contents)

Examples of adverse effects associated with specific classes include the following examples:

  • Fluorinated hydrocarbon propellants, which cause arrhythmias similar to the toxicity of inhaling solvent fumes
  • Preservatives such as chlorbutol, which can cause hypotension, and sodium benzoate which displaces bilirubin from albumin and which can cause kernicterus in the jaundiced neonate
  • Colouring agents, such as tartrazine which can cause urticaria anaphylaxis and exacerbations of asthma in the group of aspirin-sensitive asthmatics
  • Emulsifying agents, such as α-tocopherol which can cause renal and hepatic failure in infants
  • Perfumes, which can cause contact dermatitis 
  • Paraffin wax, which can burst into flames when the ointment is used prior to diathermy (this was reported from experiences of ophthalmic surgeons)
  • Solvents such as ethanol, which can cause - wait for it - intoxication

 

References

Kalasz, Huba, and Istvan Antal. "Drug excipients.Current medicinal chemistry 13.21 (2006): 2535-2563.

Nema, Sandeep, R. J. Washkuhn, and R. J. Brendel. "Excipients and their use in injectable products." PDA Journal of Pharmaceutical Science and Technology 51.4 (1997): 166-171.

Pifferi, Giorgio, and Patrizia Restani. "The safety of pharmaceutical excipients." Il Farmaco 58.8 (2003): 541-550.

Crowley, Patrick, and Luigi G. Martini. "Drug-excipient interactions." Pharm Technol 4 (2001): 7-12.

Golightly, Larry K., Susan S. Snmiinskc, and L. Bennett A'Iiclzacl. "Pharmaceutical Excipients Adverse Effects Associated with Inactive Ingredients in." Medical Toxicology 3 (1988): 128-165.

Schep, Leo J., et al. "Diethylene glycol poisoning." Clinical toxicology 47.6 (2009): 525-535.