Drug stability

• Measure of the capability of a drug or drug formulation to resist decomposition/degradation

• Extent to which a drug retains the same properties and characteristics it possessed at its time of manufacture

• must comply to above specifications throughout its period of storage and use

drug stability

• chemical structure

• physical state

• formulation and dosage form

• formulation excipients

• environmental conditions

• time between use and manufacture

rate/degree of compostion is due to

• drug loss

• decrease therapeutic efficiency 

drug composition results in

• appearance and taste

• toxicity profile

• impurity profile

Presence of drug degradants may lead to

• antioxidant degradation

• preservative degradation 

• flavouring degradation 

excipient stability may include

• Include a wide variety of chemical processes

• Essentially consists of THERMALLY INDUCED reaction processes

• The most common chemical decomposition processes in drugs and drug formulations include:

• hydrolysis

• oxidation

• racemisation

• epimerization

chemical decomposition 

• due to hydrolytic nucleophilic substitutions of water

• most common

• prevalent in aqueous solutions - injections, IV, ear drops and suspensions

• pH dependent proccess

• aqueous solutions buffered to prevent hydrolysis

• temperature dependent

• dependent on the drug container system due to the influence of environmental humidity

• effects carboxylic acid derivatives and aliphatic halides

• ester - most unstable

• rate of hydrolysis increases with r/x groups and decreases with lipophilicity 

hydrolysis

• reaction with oxgyen (auto-oxidation)

• reversible electron loss

• 2nd most common decomposition 

• prevalent in solution-based formulations but also common in certain solid-based formulations

• results in the formation of HIGHLY COLOURED and occasionally malodorous degradation products

• result in the generation of toxic drug degradants

• Influenced by temperature and significantly reduced by drug refrigeration

oxidation 

• INITIATION – Begins with formation of a reactive ‘drugbased free radical’ (D.). Process is typically initiated by HEAT, light or trace metal ions (heat)

• PROPAGATION - then reacts with molecules of O2 (from air or dissolved in solution) to generate highly reactive peroxides. Unstable peroxide products rapidly decompose to generate a range of oxidised compounds e.g. aldehydes, ketones, quinones.

• TERMINATION - Various radicals react with each other and also ‘neutral’ molecules (e.g. drug, antioxidant) to generate ‘non-reactive’ oxidised/unoxidised products

free radical reactions

• affects several drugs due to a large number of susceptible groups 

• phenols -  typically highly unstable and will degrade to form quinones and coupled products

• anilines - oxidised to N-oxides and coupled products

• alphiatic amine - most notably 3o amines to initially generate N-oxides then potentially to a range of products

• thioethers - fairly unstable to sulfoxides, then sulfones

auto-oxdiation (functional groups)

• chemical structure 

• temp

• light

• presence and amount of atmospheric oxygen and metal ions

• formulation type

• pH

• packaging 

auto-oxdiation depends on

• Predominant in drug aqueous solutions and primarily influenced by high temperature and pH level >6

• Prevented and reversed by REDUCTANT antioxidants

• Most susceptible drugs include CATECHOLAMINES

oxidation - reversible loss of electrons

• can be inhibited, reduced or reversed by certain chemical additive agents. 

• Additives can be added to a range of drug formulations but are especially useful for aqueous parenteral

• chelating agents - used to ‘trap’ metal ions that initiate and/or catalyse drug oxidation. Function by ion binding via complexation Commonly used examples include disodium edetate (EDTA) and citric acid:

preventative agents of oxidation

• basically serve to reverse drug oxidation processes and non-preventative.

• function as ‘sacrificial’ or preferentially oxidised agents (oxygen scavengers).

• Effective against drug autoxidation and reversible e- loss processes. Must be more susceptible to oxidation than the drug.

• Used mostly for aqueous drug formulations. Commonly used examples include Vitamin C and various sulphurous acid salts:

preventive agents of oxidation -  reducing agents

• used to prevent autoxidation by interfering with propagation reactions and act as ‘chain terminators’

• reacts with free radicals auto-oxidants

• NON functional against drug oxidation by reversible e- loss.

• Comprise a variety of ‘water-soluble/polar’ thiols and ‘lipid-soluble/fatty’ phenolic additive agents with commonly used examples including:

• lipid soluble - creams

• aqueous solutions - water soluble

PRIMARY ANTIOXIDANTS

• needs to be R or S form

• near stereocentre a C double bond O 

• hydrogen in stereocentre 

• Generally influenced by pH and light conditions

• Depending on above can be very rapid or slow process

• Typically involves complex multi-step reaction pathway

• Often occurs concurrently with hydrolysis 

racemisation

• same as racemisation

• mutiple stereocentres - one changes form

• Results in a drug mixture with variable amounts of drug stereoisomers

• Epimerisation leads to the formation of EPIMERS

• Influenced by similar conditions and occurs in similar drug systems e.g. chiral C with H next to C=O group

epimerisation

Catechol

double phenol

1. catechol 

2. Primary alcohols

3. 3rd amines

4. thioether 

highest oxidation capability t

• uses oxygen 

auto-oxidation 

• reversible oxygen loss - highly susceptible to oxidation

• reducing agent - vita c

catecholamine

1. b-lactams (4 carbon or below)

2. esters forms (lactones, thioester)

3. carbamate

4. carboxylic acid derviates

5. alphatic halides

highest hydrolysis

• not suitable for aqueous injection

high hydrolysis